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The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Nursing is a competitive field. In 2022, nursing schools rejected more than 78,000 qualified applications, and the students whose applications were accepted faced demanding schedules and rigorous academics and clinical rotations. Is this a recipe for depression?

In 2024, 38% of nursing students experienced depression — a 9.3% increase over 2019, according to research from higher education research group Degreechoices. Catherine A. Stubin, PhD, RN, assistant professor of nursing at Rutgers University–Camden in New Jersey, calls it “a mental health crisis in nursing.”

“Nursing is a very rigorous, difficult, psychologically and physically demanding profession,” she said. “If students don’t have the tools and resources to adequately deal with these stressors in nursing school, it’s going to carry over to their professional practice.”

A growing recognition of the toll that nursing programs may have on students’ mental health has led schools to launch initiatives to better support the next generation of nurses.

 

Diagnosing the Problem

Higher than average rates of depression among nursing students are not new. Nursing students often work long shifts with limited breaks. The academic rigors and clinical demands of caring for patients with acute and chronic conditions while instructors evaluate and watch for mistakes can cause high levels of stress, Stubin told this news organization. “Eventually, something has to give, and it’s usually their mental health.”

Clinical practicums often start when nursing students are still freshmen, and asking 18-year-old students to provide patient care in often-chaotic clinical environments is “overwhelming,” according to Stubin. The COVID-19 pandemic further exacerbated the issue.

During lockdown, more than half the nursing students reported moderate to severe symptoms of anxiety and depression, which was attributed to the transition to online learning, fear of infection, burnout, and the psychological distress of lockdown.

“The pandemic exacerbated existing mental health problems in undergraduate nursing students,” said Stubin. “In the wake of it ... a lot of [registered nurses] have mental health issues and are leaving the profession.”

 

Helping Nurses Heal

A significant shift in the willingness to talk about mental health and seek treatment could help. In 2011, just one third of students participated in the treatment for a mental health disorder. The latest data show that 61% of students experiencing symptoms of depression or anxiety take medication or seek therapy or counseling.

Incoming health sciences students at Ohio State University (OSU), Columbus, are screened for depression, anxiety, and suicidal ideation and directed to campus health services as needed. Bernadette Mazurek Melnyk, PhD, APRN-CNP, OSU’s chief wellness officer and former dean in the College of Nursing, believes it’s an essential step in supporting students, adding, “If you don’t screen, you don’t know the students are suffering, and we’re able to get help to the students who need it quickly.”

 

Prioritizing Solutions

Counseling services available through campus health centers are just one part of a multipronged approach that nursing schools have taken to improve the health and well-being of students. Nursing programs have also introduced initiatives to lower stress, prevent burnout, and relieve emotional trauma.

“In nursing education, we have to lay the groundwork for the self-care, wellness, and resilience practices that can, hopefully, be carried over into their professional practices,” Stubin said.

At Rutgers University–Camden, the wellness center provides counseling services, and the Student Nursing Association offers a pet therapy program. Stubin also incorporates self-care, resilience-building strategies, and wellness programming into the curriculum.

During the pandemic, the University of Colorado College of Nursing, Aurora, created a class called Stress Impact and Care for COVID-19 to provide content, exercises, and support groups for nursing students. The class was so popular that it was adapted and integrated into the curriculum.

The University of Vermont, Burlington, introduced the Benson-Henry Institute Stress Management and Resiliency Training program in 2021. The 8-week program was designed to teach nursing students coping strategies to reduce stress.

Offering stress management programs to first-year nursing students has been linked to improved problem-solving skills and fewer emotional and social behavioral symptoms. However, for programs to be effective, Melnyk believes that they need to be integrated into the curriculum, not offered as electives.

“We know mindfulness works, we know cognitive behavior skills-building works, and these types of evidence-based programs with such efficacy behind them should not be optional,” she said. “Students are overwhelmed just with their coursework, so if these programs exist for extra credit, students won’t take them.”

 

Creating a Culture of Wellness

Teaching nursing students how to manage stress and providing the resources to combat depression and anxiety is just the first step in building a healthy, resilient nursing workforce.

Prioritizing wellness in nursing isn’t just essential for addressing the nationwide nursing shortage. Burnout in the medical field costs the United States healthcare system $4.6 billion per year, and preventable medical errors are the third leading cause of death in the United States.

“There is a nice movement across the United States to reduce these mental health issues because they’re so costly,” Melnyk said.

There are also national efforts to address the issue. The National Academy of Medicine introduced the Action Collaborative on Clinician Well-Being and Resilience, which has grown to include more than 200 organizations committed to reversing burnout and improving mental health in the clinical workforce. The American Nurses Foundation created The Nurse Well-Being: Building Peer and Leadership Support Program to provide resources and peer support to help nurses manage stress.

Health systems and hospitals also need to prioritize clinical well-being to reduce stress and burnout — and these efforts must be ongoing.

“These resources have to be extended into the working world ... and not just once a year for Nurses Week in May, but on a regular continued basis,” said Stubin. “Healthcare corporations and hospitals have to continue these resources and this help; it has to be a priority.”

Until the culture changes, Stubin fears that nursing students will continue facing barriers to completing their programs and maintaining nursing careers. Currently, 43% of college students considered leaving their program for mental health reasons, and 21.7% of nurses reported suicidal ideation.

“There’s a nursing shortage, and the acuity of patient care is increasing, so the stressors in the clinical area aren’t going to decrease,” Stubin said. “We as nursing faculty must teach our students how to manage these stressors to build a resilient, mentally and physically healthy workforce.”

A version of this article first appeared on Medscape.com.

Nursing is a competitive field. In 2022, nursing schools rejected more than 78,000 qualified applications, and the students whose applications were accepted faced demanding schedules and rigorous academics and clinical rotations. Is this a recipe for depression?

In 2024, 38% of nursing students experienced depression — a 9.3% increase over 2019, according to research from higher education research group Degreechoices. Catherine A. Stubin, PhD, RN, assistant professor of nursing at Rutgers University–Camden in New Jersey, calls it “a mental health crisis in nursing.”

“Nursing is a very rigorous, difficult, psychologically and physically demanding profession,” she said. “If students don’t have the tools and resources to adequately deal with these stressors in nursing school, it’s going to carry over to their professional practice.”

A growing recognition of the toll that nursing programs may have on students’ mental health has led schools to launch initiatives to better support the next generation of nurses.

 

Diagnosing the Problem

Higher than average rates of depression among nursing students are not new. Nursing students often work long shifts with limited breaks. The academic rigors and clinical demands of caring for patients with acute and chronic conditions while instructors evaluate and watch for mistakes can cause high levels of stress, Stubin told this news organization. “Eventually, something has to give, and it’s usually their mental health.”

Clinical practicums often start when nursing students are still freshmen, and asking 18-year-old students to provide patient care in often-chaotic clinical environments is “overwhelming,” according to Stubin. The COVID-19 pandemic further exacerbated the issue.

During lockdown, more than half the nursing students reported moderate to severe symptoms of anxiety and depression, which was attributed to the transition to online learning, fear of infection, burnout, and the psychological distress of lockdown.

“The pandemic exacerbated existing mental health problems in undergraduate nursing students,” said Stubin. “In the wake of it ... a lot of [registered nurses] have mental health issues and are leaving the profession.”

 

Helping Nurses Heal

A significant shift in the willingness to talk about mental health and seek treatment could help. In 2011, just one third of students participated in the treatment for a mental health disorder. The latest data show that 61% of students experiencing symptoms of depression or anxiety take medication or seek therapy or counseling.

Incoming health sciences students at Ohio State University (OSU), Columbus, are screened for depression, anxiety, and suicidal ideation and directed to campus health services as needed. Bernadette Mazurek Melnyk, PhD, APRN-CNP, OSU’s chief wellness officer and former dean in the College of Nursing, believes it’s an essential step in supporting students, adding, “If you don’t screen, you don’t know the students are suffering, and we’re able to get help to the students who need it quickly.”

 

Prioritizing Solutions

Counseling services available through campus health centers are just one part of a multipronged approach that nursing schools have taken to improve the health and well-being of students. Nursing programs have also introduced initiatives to lower stress, prevent burnout, and relieve emotional trauma.

“In nursing education, we have to lay the groundwork for the self-care, wellness, and resilience practices that can, hopefully, be carried over into their professional practices,” Stubin said.

At Rutgers University–Camden, the wellness center provides counseling services, and the Student Nursing Association offers a pet therapy program. Stubin also incorporates self-care, resilience-building strategies, and wellness programming into the curriculum.

During the pandemic, the University of Colorado College of Nursing, Aurora, created a class called Stress Impact and Care for COVID-19 to provide content, exercises, and support groups for nursing students. The class was so popular that it was adapted and integrated into the curriculum.

The University of Vermont, Burlington, introduced the Benson-Henry Institute Stress Management and Resiliency Training program in 2021. The 8-week program was designed to teach nursing students coping strategies to reduce stress.

Offering stress management programs to first-year nursing students has been linked to improved problem-solving skills and fewer emotional and social behavioral symptoms. However, for programs to be effective, Melnyk believes that they need to be integrated into the curriculum, not offered as electives.

“We know mindfulness works, we know cognitive behavior skills-building works, and these types of evidence-based programs with such efficacy behind them should not be optional,” she said. “Students are overwhelmed just with their coursework, so if these programs exist for extra credit, students won’t take them.”

 

Creating a Culture of Wellness

Teaching nursing students how to manage stress and providing the resources to combat depression and anxiety is just the first step in building a healthy, resilient nursing workforce.

Prioritizing wellness in nursing isn’t just essential for addressing the nationwide nursing shortage. Burnout in the medical field costs the United States healthcare system $4.6 billion per year, and preventable medical errors are the third leading cause of death in the United States.

“There is a nice movement across the United States to reduce these mental health issues because they’re so costly,” Melnyk said.

There are also national efforts to address the issue. The National Academy of Medicine introduced the Action Collaborative on Clinician Well-Being and Resilience, which has grown to include more than 200 organizations committed to reversing burnout and improving mental health in the clinical workforce. The American Nurses Foundation created The Nurse Well-Being: Building Peer and Leadership Support Program to provide resources and peer support to help nurses manage stress.

Health systems and hospitals also need to prioritize clinical well-being to reduce stress and burnout — and these efforts must be ongoing.

“These resources have to be extended into the working world ... and not just once a year for Nurses Week in May, but on a regular continued basis,” said Stubin. “Healthcare corporations and hospitals have to continue these resources and this help; it has to be a priority.”

Until the culture changes, Stubin fears that nursing students will continue facing barriers to completing their programs and maintaining nursing careers. Currently, 43% of college students considered leaving their program for mental health reasons, and 21.7% of nurses reported suicidal ideation.

“There’s a nursing shortage, and the acuity of patient care is increasing, so the stressors in the clinical area aren’t going to decrease,” Stubin said. “We as nursing faculty must teach our students how to manage these stressors to build a resilient, mentally and physically healthy workforce.”

A version of this article first appeared on Medscape.com.

Nursing is a competitive field. In 2022, nursing schools rejected more than 78,000 qualified applications, and the students whose applications were accepted faced demanding schedules and rigorous academics and clinical rotations. Is this a recipe for depression?

In 2024, 38% of nursing students experienced depression — a 9.3% increase over 2019, according to research from higher education research group Degreechoices. Catherine A. Stubin, PhD, RN, assistant professor of nursing at Rutgers University–Camden in New Jersey, calls it “a mental health crisis in nursing.”

“Nursing is a very rigorous, difficult, psychologically and physically demanding profession,” she said. “If students don’t have the tools and resources to adequately deal with these stressors in nursing school, it’s going to carry over to their professional practice.”

A growing recognition of the toll that nursing programs may have on students’ mental health has led schools to launch initiatives to better support the next generation of nurses.

 

Diagnosing the Problem

Higher than average rates of depression among nursing students are not new. Nursing students often work long shifts with limited breaks. The academic rigors and clinical demands of caring for patients with acute and chronic conditions while instructors evaluate and watch for mistakes can cause high levels of stress, Stubin told this news organization. “Eventually, something has to give, and it’s usually their mental health.”

Clinical practicums often start when nursing students are still freshmen, and asking 18-year-old students to provide patient care in often-chaotic clinical environments is “overwhelming,” according to Stubin. The COVID-19 pandemic further exacerbated the issue.

During lockdown, more than half the nursing students reported moderate to severe symptoms of anxiety and depression, which was attributed to the transition to online learning, fear of infection, burnout, and the psychological distress of lockdown.

“The pandemic exacerbated existing mental health problems in undergraduate nursing students,” said Stubin. “In the wake of it ... a lot of [registered nurses] have mental health issues and are leaving the profession.”

 

Helping Nurses Heal

A significant shift in the willingness to talk about mental health and seek treatment could help. In 2011, just one third of students participated in the treatment for a mental health disorder. The latest data show that 61% of students experiencing symptoms of depression or anxiety take medication or seek therapy or counseling.

Incoming health sciences students at Ohio State University (OSU), Columbus, are screened for depression, anxiety, and suicidal ideation and directed to campus health services as needed. Bernadette Mazurek Melnyk, PhD, APRN-CNP, OSU’s chief wellness officer and former dean in the College of Nursing, believes it’s an essential step in supporting students, adding, “If you don’t screen, you don’t know the students are suffering, and we’re able to get help to the students who need it quickly.”

 

Prioritizing Solutions

Counseling services available through campus health centers are just one part of a multipronged approach that nursing schools have taken to improve the health and well-being of students. Nursing programs have also introduced initiatives to lower stress, prevent burnout, and relieve emotional trauma.

“In nursing education, we have to lay the groundwork for the self-care, wellness, and resilience practices that can, hopefully, be carried over into their professional practices,” Stubin said.

At Rutgers University–Camden, the wellness center provides counseling services, and the Student Nursing Association offers a pet therapy program. Stubin also incorporates self-care, resilience-building strategies, and wellness programming into the curriculum.

During the pandemic, the University of Colorado College of Nursing, Aurora, created a class called Stress Impact and Care for COVID-19 to provide content, exercises, and support groups for nursing students. The class was so popular that it was adapted and integrated into the curriculum.

The University of Vermont, Burlington, introduced the Benson-Henry Institute Stress Management and Resiliency Training program in 2021. The 8-week program was designed to teach nursing students coping strategies to reduce stress.

Offering stress management programs to first-year nursing students has been linked to improved problem-solving skills and fewer emotional and social behavioral symptoms. However, for programs to be effective, Melnyk believes that they need to be integrated into the curriculum, not offered as electives.

“We know mindfulness works, we know cognitive behavior skills-building works, and these types of evidence-based programs with such efficacy behind them should not be optional,” she said. “Students are overwhelmed just with their coursework, so if these programs exist for extra credit, students won’t take them.”

 

Creating a Culture of Wellness

Teaching nursing students how to manage stress and providing the resources to combat depression and anxiety is just the first step in building a healthy, resilient nursing workforce.

Prioritizing wellness in nursing isn’t just essential for addressing the nationwide nursing shortage. Burnout in the medical field costs the United States healthcare system $4.6 billion per year, and preventable medical errors are the third leading cause of death in the United States.

“There is a nice movement across the United States to reduce these mental health issues because they’re so costly,” Melnyk said.

There are also national efforts to address the issue. The National Academy of Medicine introduced the Action Collaborative on Clinician Well-Being and Resilience, which has grown to include more than 200 organizations committed to reversing burnout and improving mental health in the clinical workforce. The American Nurses Foundation created The Nurse Well-Being: Building Peer and Leadership Support Program to provide resources and peer support to help nurses manage stress.

Health systems and hospitals also need to prioritize clinical well-being to reduce stress and burnout — and these efforts must be ongoing.

“These resources have to be extended into the working world ... and not just once a year for Nurses Week in May, but on a regular continued basis,” said Stubin. “Healthcare corporations and hospitals have to continue these resources and this help; it has to be a priority.”

Until the culture changes, Stubin fears that nursing students will continue facing barriers to completing their programs and maintaining nursing careers. Currently, 43% of college students considered leaving their program for mental health reasons, and 21.7% of nurses reported suicidal ideation.

“There’s a nursing shortage, and the acuity of patient care is increasing, so the stressors in the clinical area aren’t going to decrease,” Stubin said. “We as nursing faculty must teach our students how to manage these stressors to build a resilient, mentally and physically healthy workforce.”

A version of this article first appeared on Medscape.com.

Sarah Cigna, MD, sees patients every week with vulvovaginal pain and vulvar dermatoses. She’s an ob.gyn. with a focus on sexual health — often the first physician seen by patients with vulvar pain or itch — and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.

She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.

“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.

“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”

Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.

Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.

Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.

In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.

 

Approaching the History and Exam

A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.

“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.

Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.

A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”

The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”

Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.

Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.

Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.

 

Causes of Vulvar Itch: Infectious and Noninfectious

With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”

Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”

Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.

“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”

Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.

 

Common Autoimmune Vulvar Dermatoses: LS and LP

Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.

And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”

Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.

Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.

A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.

With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.

The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.

Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.

With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”

 

Vulvar Crohn’s

“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.

Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.

A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”

 

Neuropathic Itch, Pelvic Floor Muscle Spasm

Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.

“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.

Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.

Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.

 

Pelvic Floor Muscle Spasm

Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”

Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.

“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”

 

A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore

Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.

“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.

In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.

“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.

Cigna and Murphy have no relevant financial disclosures.

 

A version of this article appeared on Medscape.com.

Sarah Cigna, MD, sees patients every week with vulvovaginal pain and vulvar dermatoses. She’s an ob.gyn. with a focus on sexual health — often the first physician seen by patients with vulvar pain or itch — and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.

She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.

“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.

“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”

Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.

Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.

Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.

In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.

 

Approaching the History and Exam

A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.

“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.

Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.

A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”

The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”

Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.

Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.

Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.

 

Causes of Vulvar Itch: Infectious and Noninfectious

With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”

Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”

Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.

“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”

Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.

 

Common Autoimmune Vulvar Dermatoses: LS and LP

Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.

And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”

Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.

Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.

A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.

With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.

The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.

Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.

With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”

 

Vulvar Crohn’s

“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.

Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.

A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”

 

Neuropathic Itch, Pelvic Floor Muscle Spasm

Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.

“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.

Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.

Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.

 

Pelvic Floor Muscle Spasm

Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”

Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.

“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”

 

A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore

Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.

“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.

In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.

“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.

Cigna and Murphy have no relevant financial disclosures.

 

A version of this article appeared on Medscape.com.

Sarah Cigna, MD, sees patients every week with vulvovaginal pain and vulvar dermatoses. She’s an ob.gyn. with a focus on sexual health — often the first physician seen by patients with vulvar pain or itch — and she believes collaboration with dermatologists is essential, especially for complex cases in what she calls a neglected, data-poor area of medicine.

She also recommends that dermatologists have a good understanding of the vestibule, “one of the most important structures in vulvar medicine,” and that they become equipped to recognize generalized and localized causes of vulvar pain and/or itch.

“The problem is, we don’t talk about [vulvovaginal pain and itch] ... it’s taboo and we’re not taught about it in medical school,” Cigna, assistant professor of obstetrics and gynecology at The George Washington University (GWU), Washington, DC, said in a grand rounds lecture held recently at the GWU School of Medicine and Health Sciences Department of Dermatology.

“There are dermatologists who don’t have much training in vulvar dermatology, and a lot of gyns don’t get as much training” as they should, she said in an interview after the lecture. “So who’s looking at people’s vulvar skin and figuring out what’s going on and giving them effective treatments and evidence-based education?”

Cigna and dermatologist Emily Murphy, MD, will be co-directors of a joint ob.gyn-dermatology Vulvar Dermatology Clinic at GWU that will be launched in 2025, with monthly clinics for particularly challenging cases where the etiology is unclear or treatment is ineffective. “We want to collaborate in a more systematic way and put our heads together and think creatively about what will improve patient care,” Cigna said in the interview.

Dermatologists have valuable expertise in the immunology and genetic factors involved in skin disorders, Cigna said. Moreover, Murphy, assistant professor of dermatology and director of the Vulvar Health Program at GWU, said in an interview, dermatologists “are comfortable in going to off-label systemic medications that ob.gyns may not use that often” and bring to the table expertise in various types of procedures.

Murphy recently trained with Melissa Mauskar, MD, associate of dermatology and obstetrics and gynecology at the University of Texas Southwestern, Dallas, and founder and director of the Gynecologic Dermatology Clinic there. “It’s so important for dermatologists to be involved. It just takes some extra training that residents aren’t getting right now,” said Murphy, a member of the newly formed Vulvar Dermatoses Research Consortium.

In her grand rounds lecture, Cigna offered pearls to dermatologists for approaching a history and exam and covered highlights of the diagnosis and treatment of various problems, from vulvar Candida infections and lichen simplex chronicus to vulvar lichen sclerosus (LS), vulvar lichen planus (LP), vulvar Crohn’s disease, pudendal neuralgia, and pelvic floor muscle spasm, as well as the role of mast cell proliferation in vulvar issues.

 

Approaching the History and Exam

A comprehensive history covers the start, duration, and location of pain and/or itching as well as a detailed timeline (such as timing of potential causes, including injuries or births) and symptoms (such as burning, cutting, aching, and stinging). The question of whether pain “is on the outside, at the entrance, or deeper inside” is “crucial, especially for those in dermatology,” Cigna emphasized.

“And if you’re seeing a patient for a vulvar condition, please ask them about sex. Ask, is this affecting your sexual or intimate life with your partner because this can also give you a clue about what’s going on and how you can help them,” she told the audience of dermatologists.

Queries about trauma history (physical and emotional/verbal), competitive sports (such as daily cycling, equestrian, and heavy weight lifting), endometriosis/gynecologic surgery, connective tissue disorders (such as Ehler-Danlos syndrome), and irritable bowel syndrome are all potentially important to consider. It is important to ask about anxiety, depression, and obsessive-compulsive disorder, which do not cause — but are highly associated with — vulvar dermatoses, she said.

A surprisingly large number of people with vulvovaginal issues are being diagnosed with Ehler-Danlos syndrome, so “I’m always asking, are you hypermobile because this might be affecting the musculoskeletal system, which might be affecting the pelvis,” Cigna said. “Anything that affects the pelvis can affect the vulva as well.”

The pelvic examination should be “offered” rather than assumed to be part of the exam, as part of a trauma-informed approach that is crucial for earning trust, she advised. “Just saying, ‘we’re going to talk, and then I can offer you an exam if you like’…patients like it. It helps them feel safer and more open.”

Many diagnoses are differentiated by eliciting pain on the anterior vs the posterior half of the vulvar vestibule — the part of the vulva that lies between the labia minora and is composed of nonkeratinized tissue with embryonic origins in the endoderm. “If you touch on the keratinized skin (of the vulva) and they don’t have pain, but on the vestibule they do have pain, and there is no pain inside the vagina, this suggests there is a vestibular problem,” said Cigna.

Pain/tenderness isolated to the posterior half of the vestibule suggests a muscular cause, and pain in both the posterior and anterior parts of the vestibule suggests a cause that is more systemic or diffuse, which could be a result of a hormonal issue such as one related to oral contraceptives or decreased testosterone, or a nerve-related process.

Cigna uses gentle swipes of a Q-tip moistened with water or gel to examine the vulva rather than a poke or touch, with the exception being the posterior vestibule, which overlies muscle insertion sites. “Make sure to get a baseline in remote areas such as the inner thigh, and always distinguish between ‘scratchy/sensitive’ sensations and pain,” she said, noting the value of having the patient hold a mirror on her inner thigh.

 

Causes of Vulvar Itch: Infectious and Noninfectious

With vulvar candidiasis, a common infectious cause of vulvar itch, “you have to ask if they’re also itching on the inside because if you treat them with a topical and you don’t treat the vaginal yeast infection that may be co-occurring, they’ll keep reseeding their vulvar skin,” Cigna said, “and it will never be fully treated.”

Candida albicans is the most common cause of vulvar or vulvovaginal candidiasis, and resistance to antifungals has been rising. Non-albicans Candida “tends to have even higher resistance rates,” she said. Ordering a sensitivity panel along with the culture is helpful, but “comprehensive vaginal biome” panels are generally not useful. “It’s hard to correlate the information clinically,” she said, “and there’s not always a lot of information about susceptibilities, which is what I really like to know.”

Cigna’s treatments for vaginal infections include miconazole, terconazole, and fluconazole (and occasionally, itraconazole or voriconazole — a “decision we don’t take lightly”). Vulvar treatments include nystatin ointment, clotrimazole cream, and miconazole cream. Often, optimal treatment involves addressing “both inside and out,” she said, noting the importance of also killing yeast in undergarment fabric.

“In my experience, Diflucan [oral fluconazole] doesn’t treat persistent vulvar cutaneous skin yeast well, so while I might try Diflucan, I typically use something topical as well,” she said. “And with vaginal yeast, we do use boric acid from time to time, especially for non-albicans species because it tends to be a little more effective.”

Noninfectious causes of vulvar itch include allergic, neuropathic, and muscular causes, as well as autoimmune dermatoses and mast cell activation syndrome. Well known in dermatology are acute contact dermatitis and lichen simplex chronicus — both characterized by induration, thickening, and a “puffy” erythematous appearance, and worsening of pruritus at night. What may be less appreciated is the long list of implicated allergens , including Always menstrual pads made of a plastic-containing “dry weave” material, Cigna said. There are at least several cotton-only, low-preservative feminine products available on the market, she noted.

 

Common Autoimmune Vulvar Dermatoses: LS and LP

Vulvar LS has traditionally been thought to affect mainly prepubertal and postmenopausal women, but the autoimmune condition is now known to affect more reproductive-age people with vulvas than previously appreciated, Cigna said.

And notably, in an observational web-based study of premenopausal women (aged 18-50 years) with biopsy-confirmed vulvar LS, the leading symptom was not itch but dyspareunia and tearing with intercourse. This means “we’re missing people,” said Cigna, an author of the study. “We think the reason we’re not seeing itch as commonly in this population is that itch is likely mediated by the low estrogen state of pre- and postmenopausal people.”

Vulvar LS also occurs in pregnancy, with symptoms that are either stable or decrease during pregnancy and increase in the postpartum period, as demonstrated in a recently published online survey.

Patients with vulvar LS can present with hypopigmentation, lichenification, and scarring and architectural changes, the latter of which can involve clitoral phimosis, labial resorption, and narrowing of the introitus. (The vaginal mucosa is unaffected.) The presentation can be subtle, especially in premenopausal women, and differentiation between LS, vitiligo, and yeast is sometimes necessary.

A timely biopsy-driven definitive diagnosis is important because vulvar LS increases the risk for cancer if it’s not adequately treated and because long-term steroid use can affect the accuracy of pathology reports. “We really care about keeping this disease in remission as much as possible,” Cigna said. Experts in the field recommend long-term maintenance therapy with a mid-ultra-potent steroid one to three times/week or an alternative. “I’ve just started using ruxolitinib cream, a Janus kinase (JAK) inhibitor, and tacrolimus, a calcineurin inhibitor,” she said.

With vulvar LP, based on current evidence, the risk for malignant transformation is low, but “it crosses into the vagina and can cause vaginal adhesions, so if you’re diagnosing someone with lichen planus, you need to make sure you’re talking with them about dilators, and if you’re not comfortable, send them to [gyn],” she said.

The use of vulvoscopy is important for one’s ability to see the fine Wickham’s striae that often characterize vulvar LP, she noted. Medical treatments for vulvar LP include topical calcineurin inhibitors, high-potency steroids, and JAK inhibitors.

Surgical treatment of vulvar granuloma fissuratum caused by vulvar LS is possible (when the patient is in complete remission, to prevent koebnerization), with daily post-op application of clobetasol and retraction of tissues, noted Cigna, the author of a study on vulvar lysis of adhesions.

With both LS and LP, Cigna said, “don’t forget (consideration of) hormones” as an adjunctive treatment, especially in postmenopausal women. “Patients in a low hormone state will have more flares.”

 

Vulvar Crohn’s

“We all have to know how to look for this,” Cigna said. “Unilateral or asymmetric swelling is classic, but don’t rule out the diagnosis if you see symmetric swelling.” Patients also typically have linear “knife-like” fissures or ulcerations, the vulva “is very indurated,” and “swelling is so intense, the patients are miserable,” she said.

Vulvar Crohn’s disease may precede intestinal disease in 20%-30% of patients, so referral to a gastroenterologist — and ideally subsequent collaboration — is important, as vulvar manifestations are treated with systemic medications typical for Crohn’s.

A biopsy is required for diagnosis, and the pathologist should be advised to look for lichenified squamous mucosa with the Touton giant cell reaction. “Vulvar Crohn’s is a rare enough disorder that if you don’t have an experienced or informed pathologist looking at your specimen, they may miss it because they won’t be looking for it,” Cigna added in the interview. “You should be really clear about what you’re looking for.”

 

Neuropathic Itch, Pelvic Floor Muscle Spasm

Patients with pudendal neuralgia — caused by an injured, entrapped, or irritated pudendal nerve (originating from S2-S4) — typically present with chronic vulvar and pelvic pain that is often unprovoked and worsens with sitting. Itching upon touch is often another symptom, and some patients describe a foreign body sensation. The cause is often trauma (such as an accident or childbirth-related) as opposed to myofascial irritation, Cigna explained in her lecture.

“Your exam will be largely normal, with no skin findings, so patients will get sent away if you don’t know to look for pudendal neuralgia by pressing on the pudendal nerve or doing (or referring for) a diagnostic nerve block,” Cigna added in the interview.

Persistent genital arousal disorder (PGAD) is “more global” in that it can also originate not only from the pudendal nerve but also from nerve roots higher in the spine or even from the brain. “People feel a sense of arousal, but some describe it as an itch,” Cigna said in her lecture, referring to a 2021 consensus document on PGAD/genito-pelvic dysesthesia by the International Society for the Study of Women’s Sexual Health as a valuable resource for understanding and managing the condition.

Diagnosis and treatment usually start with a pudendal nerve block with a combination of steroid and anesthetic. If this does not relieve arousal/itching, the next step may be an MRI to look higher in the spine.

 

Pelvic Floor Muscle Spasm

Vulvar pain, skin itching, and irritation can be symptoms of pelvic floor muscle spasm. “Oftentimes people come to me and say, ‘I have a dermatologic problem,’” Cigna said. “The skin may look red and erythematous, but it’s probably more likely a muscle problem when you’re not finding anything, and no amount of steroid will help the itch go away when the problem lies underneath.”

Co-occurring symptoms can include vaginal dryness, clitoral pain, urethral discomfort, bladder pain/irritation, increased urgency, constipation, and anal fissures. The first-line treatment approach is pelvic floor therapy.

“Pelvic floor therapy is not just for incontinence. It’s also for pain and discomfort from muscles,” she said, noting that most patients with vulvar disorders are referred for pelvic floor therapy. “Almost all of them end up having pelvic floor dysfunction because the pelvic floor muscles spasm whenever there’s pain or inflammation.”

 

A Cautionary Word on Vulvodynia, and a Mast Cell Paradigm to Explore

Vulvodynia is defined as persistent pain of at least 3 months’ duration with no clear cause. “These are the patients with no skin findings,” Cigna said. But in most cases, she said, careful investigation identifies causes that are musculoskeletal, hormonal, or nerve-related.

“It’s a term that’s thrown around a lot — it’s kind of a catchall. Yet it should be a small minority of patients who truly have a diagnosis of vulvodynia,” she said.

In the early stages of investigation is the idea that mast cell proliferation and mast cell activation may play a role in some cases of vulvar and vestibular pain and itching. “We see that some patients with vulvodynia and vestibulodynia have mast cells that are increased in number in the epithelium and beneath the epithelium, and nerve staining shows an increased number of nerve endings traveling into the epithelium,” Cigna said.

“We do diagnose some people clinically” based on urticaria and other symptoms suggestive of mast cell proliferation/activation (such as flushing, abdominal cramping, diarrhea, hypotensive syncope or near syncope, and tachycardia), and “then we send them to the allergist for testing,” Cigna said.

Cigna and Murphy have no relevant financial disclosures.

 

A version of this article appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.

 

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

 

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

 

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.

 

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

 

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

 

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

Overtreatment of men with prostate cancer and limited life expectancy (LE) has persisted in the era of active surveillance and worsened in some instances, according to a new study.

“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.

The study was published online on November 11 in JAMA Internal Medicine.

‘Concerning’ Real-World Data

For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.

Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.

About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.

Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.

Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.

Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.

“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.

 

Is This Happening in the General US Population?

Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.

“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.

“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.

 

Is Overtreatment All Bad?

Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.

In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.

“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.

Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.

Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.

The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.

 

Tough to Talk About?

Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.

Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.

Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.

He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.

“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.

This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

Physician assistants (PAs) are educated as generalists — with the ability to switch medical specialties during their careers. Andrzej Kozikowski, PhD, senior director of research at the National Commission on Certification of Physician Assistants (NCCPA), said that having that kind of career flexibility is often a motivating factor for students who pursue the PA path.

“If you look at the research literature on physicians, you can see that choosing a specialty can be quite stressful,” he told this news organization. “It’s a lifelong decision. You have to commit to a residency, maybe fellowship training, and if you don’t like it and want to switch your specialty, you have to go back and do it again. It’s a decision that weighs heavily on your [physicians] shoulders.”

The PA profession, however, offers lateral movement. Rachel Porter, PhD, interim director of preclinical education at PA program, Duke University, Durham, North Carolina, said that the didactic portion of a PA’s medical education is very broad to support that kind of flexibility. And most PA students, depending on their program, have the opportunity to go through several clinical rotations to see which specialty might be the best fit.

“That initial medical education is meant to provide a good foundation across all systems, across all age groups, subpopulations, and settings — hospital, ambulatory, or outpatient,” she explained. “Once they are exposed to clinical experiences later, we find that students discover their niche and where they want to be once they start their career.”

 

Making a Lateral Move

According to the 2022 Statistical Profile of Board-Certified PAs by Specialty, based on a survey conducted by the NCCPA, approximately half of board-certified PAs have switched to a different specialty at least once during their career. Nearly 31% have done so at least twice.

Eric Van Hecke, DMSc, MPAS, PA-C, CAQ-EM, assistant professor and PA program director at Concordia University, St. Paul in St. Paul, Minnesota, works in emergency medicine, thanks to his clinical rotations during PA school, which helped him determine that a surgical specialty was not for him.

“I did some surgical rotations, and I found I hated being in the operating room,” he said. “I didn’t like the way PAs were utilized there. But then, toward the end of my PA program, I had the opportunity to do an emergency department rotation and found it was a much better fit.”

Other PAs, however, may not be as lucky to find the right practice straight out of school. Some may be limited by job availability in a specific geographic area, while others may feel more comfortable starting in a hospital setting. Lyndsey Milcarek, PA-C, MPH, a PA in Buffalo, New York, said she started in a primary care role after school but moved to geriatric home health after a year. Then, 3 years later, she switched specialties again to join an emergency department. She said her decisions to move were largely driven by organizational issues.

“In one case, I saw the organization was headed for a buyout and I wanted to get ahead of it,” she said. “In another, the workload was a lot, and you couldn’t go home at the end of your shift if there were still patients to see. It was a recipe for burnout.”

Amanda Michaud, DMSc, PA-C, in Jacksonville, Florida, said she initially enjoyed the “fast-paced environment” of emergency medicine after graduating from PA school. But when her family was looking at a move out of state, she started to consider a specialty change and ultimately ended up joining an allergy practice.

“I wanted to have a more nine-to-five kind of job. I wanted my weekends. I had missed a lot of holidays with my family,” she said. “But I also was interested in becoming more of an expert in a particular field. In the ER, you become an expert in saving lives and stabilizing patients. But I wanted an opportunity to truly learn the medicine and science behind one area.”

 

Understand Your Why — and Do the Work

The reasons a PA might choose to make a specialty switch aren’t unlike the reasons a corporate attorney might want to practice family law or a nurse practitioner might want to switch from the ICU to the pediatric ward. People might consider it a change of scenery. Some may be looking to relocate, support a better work-life balance, reduce their stress, expand their skills and knowledge, find a more palatable work environment, or make more money. But those who have made lateral moves said it isn’t as easy as it may look.

“It will take time, not just to learn the new specialty but to understand how your new practice does things,” said Michaud. “You need to expect a huge learning curve ahead when you make a change.”

Milcarek added that PAs who are considering a switch should think long and hard about the kind of environment they want to work in and, as they look at other departments or practices, spend time talking to and shadowing PAs to understand what working there will look like. Just because a particular specialty has a reputation for being low stress (or high paying) doesn’t mean that’s what you’ll find once you come on board. So much depends on your employer — and the people you work with.

“There are a lot of opportunities for PA jobs, but employers aren’t always transparent about workflows and management,” Milcarek said. “You want to have good intel upfront before you make a decision.”

Kozikowski agreed. “It takes a while to adapt to a new environment and to understand how things are done,” he explained. “Research suggests that having a good network, mentors, and good onboarding programs are really important. It’s not just finding continuing medical education, you also need to have the right support system in place.”

Despite the challenges involved with a specialty switch, Milcarek said her moves have made her a stronger overall clinician.

“I have a unique perspective because I’ve worked in so many different areas,” she said. “I’ve learned a lot in each and can apply those things in my new roles. I feel fortunate that I’ve been able to make these switches and continue to learn and grow and become a better PA.”

A version of this article first appeared on Medscape.com.

Physician assistants (PAs) are educated as generalists — with the ability to switch medical specialties during their careers. Andrzej Kozikowski, PhD, senior director of research at the National Commission on Certification of Physician Assistants (NCCPA), said that having that kind of career flexibility is often a motivating factor for students who pursue the PA path.

“If you look at the research literature on physicians, you can see that choosing a specialty can be quite stressful,” he told this news organization. “It’s a lifelong decision. You have to commit to a residency, maybe fellowship training, and if you don’t like it and want to switch your specialty, you have to go back and do it again. It’s a decision that weighs heavily on your [physicians] shoulders.”

The PA profession, however, offers lateral movement. Rachel Porter, PhD, interim director of preclinical education at PA program, Duke University, Durham, North Carolina, said that the didactic portion of a PA’s medical education is very broad to support that kind of flexibility. And most PA students, depending on their program, have the opportunity to go through several clinical rotations to see which specialty might be the best fit.

“That initial medical education is meant to provide a good foundation across all systems, across all age groups, subpopulations, and settings — hospital, ambulatory, or outpatient,” she explained. “Once they are exposed to clinical experiences later, we find that students discover their niche and where they want to be once they start their career.”

 

Making a Lateral Move

According to the 2022 Statistical Profile of Board-Certified PAs by Specialty, based on a survey conducted by the NCCPA, approximately half of board-certified PAs have switched to a different specialty at least once during their career. Nearly 31% have done so at least twice.

Eric Van Hecke, DMSc, MPAS, PA-C, CAQ-EM, assistant professor and PA program director at Concordia University, St. Paul in St. Paul, Minnesota, works in emergency medicine, thanks to his clinical rotations during PA school, which helped him determine that a surgical specialty was not for him.

“I did some surgical rotations, and I found I hated being in the operating room,” he said. “I didn’t like the way PAs were utilized there. But then, toward the end of my PA program, I had the opportunity to do an emergency department rotation and found it was a much better fit.”

Other PAs, however, may not be as lucky to find the right practice straight out of school. Some may be limited by job availability in a specific geographic area, while others may feel more comfortable starting in a hospital setting. Lyndsey Milcarek, PA-C, MPH, a PA in Buffalo, New York, said she started in a primary care role after school but moved to geriatric home health after a year. Then, 3 years later, she switched specialties again to join an emergency department. She said her decisions to move were largely driven by organizational issues.

“In one case, I saw the organization was headed for a buyout and I wanted to get ahead of it,” she said. “In another, the workload was a lot, and you couldn’t go home at the end of your shift if there were still patients to see. It was a recipe for burnout.”

Amanda Michaud, DMSc, PA-C, in Jacksonville, Florida, said she initially enjoyed the “fast-paced environment” of emergency medicine after graduating from PA school. But when her family was looking at a move out of state, she started to consider a specialty change and ultimately ended up joining an allergy practice.

“I wanted to have a more nine-to-five kind of job. I wanted my weekends. I had missed a lot of holidays with my family,” she said. “But I also was interested in becoming more of an expert in a particular field. In the ER, you become an expert in saving lives and stabilizing patients. But I wanted an opportunity to truly learn the medicine and science behind one area.”

 

Understand Your Why — and Do the Work

The reasons a PA might choose to make a specialty switch aren’t unlike the reasons a corporate attorney might want to practice family law or a nurse practitioner might want to switch from the ICU to the pediatric ward. People might consider it a change of scenery. Some may be looking to relocate, support a better work-life balance, reduce their stress, expand their skills and knowledge, find a more palatable work environment, or make more money. But those who have made lateral moves said it isn’t as easy as it may look.

“It will take time, not just to learn the new specialty but to understand how your new practice does things,” said Michaud. “You need to expect a huge learning curve ahead when you make a change.”

Milcarek added that PAs who are considering a switch should think long and hard about the kind of environment they want to work in and, as they look at other departments or practices, spend time talking to and shadowing PAs to understand what working there will look like. Just because a particular specialty has a reputation for being low stress (or high paying) doesn’t mean that’s what you’ll find once you come on board. So much depends on your employer — and the people you work with.

“There are a lot of opportunities for PA jobs, but employers aren’t always transparent about workflows and management,” Milcarek said. “You want to have good intel upfront before you make a decision.”

Kozikowski agreed. “It takes a while to adapt to a new environment and to understand how things are done,” he explained. “Research suggests that having a good network, mentors, and good onboarding programs are really important. It’s not just finding continuing medical education, you also need to have the right support system in place.”

Despite the challenges involved with a specialty switch, Milcarek said her moves have made her a stronger overall clinician.

“I have a unique perspective because I’ve worked in so many different areas,” she said. “I’ve learned a lot in each and can apply those things in my new roles. I feel fortunate that I’ve been able to make these switches and continue to learn and grow and become a better PA.”

A version of this article first appeared on Medscape.com.

Physician assistants (PAs) are educated as generalists — with the ability to switch medical specialties during their careers. Andrzej Kozikowski, PhD, senior director of research at the National Commission on Certification of Physician Assistants (NCCPA), said that having that kind of career flexibility is often a motivating factor for students who pursue the PA path.

“If you look at the research literature on physicians, you can see that choosing a specialty can be quite stressful,” he told this news organization. “It’s a lifelong decision. You have to commit to a residency, maybe fellowship training, and if you don’t like it and want to switch your specialty, you have to go back and do it again. It’s a decision that weighs heavily on your [physicians] shoulders.”

The PA profession, however, offers lateral movement. Rachel Porter, PhD, interim director of preclinical education at PA program, Duke University, Durham, North Carolina, said that the didactic portion of a PA’s medical education is very broad to support that kind of flexibility. And most PA students, depending on their program, have the opportunity to go through several clinical rotations to see which specialty might be the best fit.

“That initial medical education is meant to provide a good foundation across all systems, across all age groups, subpopulations, and settings — hospital, ambulatory, or outpatient,” she explained. “Once they are exposed to clinical experiences later, we find that students discover their niche and where they want to be once they start their career.”

 

Making a Lateral Move

According to the 2022 Statistical Profile of Board-Certified PAs by Specialty, based on a survey conducted by the NCCPA, approximately half of board-certified PAs have switched to a different specialty at least once during their career. Nearly 31% have done so at least twice.

Eric Van Hecke, DMSc, MPAS, PA-C, CAQ-EM, assistant professor and PA program director at Concordia University, St. Paul in St. Paul, Minnesota, works in emergency medicine, thanks to his clinical rotations during PA school, which helped him determine that a surgical specialty was not for him.

“I did some surgical rotations, and I found I hated being in the operating room,” he said. “I didn’t like the way PAs were utilized there. But then, toward the end of my PA program, I had the opportunity to do an emergency department rotation and found it was a much better fit.”

Other PAs, however, may not be as lucky to find the right practice straight out of school. Some may be limited by job availability in a specific geographic area, while others may feel more comfortable starting in a hospital setting. Lyndsey Milcarek, PA-C, MPH, a PA in Buffalo, New York, said she started in a primary care role after school but moved to geriatric home health after a year. Then, 3 years later, she switched specialties again to join an emergency department. She said her decisions to move were largely driven by organizational issues.

“In one case, I saw the organization was headed for a buyout and I wanted to get ahead of it,” she said. “In another, the workload was a lot, and you couldn’t go home at the end of your shift if there were still patients to see. It was a recipe for burnout.”

Amanda Michaud, DMSc, PA-C, in Jacksonville, Florida, said she initially enjoyed the “fast-paced environment” of emergency medicine after graduating from PA school. But when her family was looking at a move out of state, she started to consider a specialty change and ultimately ended up joining an allergy practice.

“I wanted to have a more nine-to-five kind of job. I wanted my weekends. I had missed a lot of holidays with my family,” she said. “But I also was interested in becoming more of an expert in a particular field. In the ER, you become an expert in saving lives and stabilizing patients. But I wanted an opportunity to truly learn the medicine and science behind one area.”

 

Understand Your Why — and Do the Work

The reasons a PA might choose to make a specialty switch aren’t unlike the reasons a corporate attorney might want to practice family law or a nurse practitioner might want to switch from the ICU to the pediatric ward. People might consider it a change of scenery. Some may be looking to relocate, support a better work-life balance, reduce their stress, expand their skills and knowledge, find a more palatable work environment, or make more money. But those who have made lateral moves said it isn’t as easy as it may look.

“It will take time, not just to learn the new specialty but to understand how your new practice does things,” said Michaud. “You need to expect a huge learning curve ahead when you make a change.”

Milcarek added that PAs who are considering a switch should think long and hard about the kind of environment they want to work in and, as they look at other departments or practices, spend time talking to and shadowing PAs to understand what working there will look like. Just because a particular specialty has a reputation for being low stress (or high paying) doesn’t mean that’s what you’ll find once you come on board. So much depends on your employer — and the people you work with.

“There are a lot of opportunities for PA jobs, but employers aren’t always transparent about workflows and management,” Milcarek said. “You want to have good intel upfront before you make a decision.”

Kozikowski agreed. “It takes a while to adapt to a new environment and to understand how things are done,” he explained. “Research suggests that having a good network, mentors, and good onboarding programs are really important. It’s not just finding continuing medical education, you also need to have the right support system in place.”

Despite the challenges involved with a specialty switch, Milcarek said her moves have made her a stronger overall clinician.

“I have a unique perspective because I’ve worked in so many different areas,” she said. “I’ve learned a lot in each and can apply those things in my new roles. I feel fortunate that I’ve been able to make these switches and continue to learn and grow and become a better PA.”

A version of this article first appeared on Medscape.com.

In our previous case-based review, I teased the opportunity to use biomarkers to increase the accuracy and expediency of the diagnosis of Alzheimer’s disease (AD). These tests are no longer confined to the research setting but are now available to specialists and primary care clinicians alike. Given that most cognitive disorders are first identified in primary care, however, I believe that their greatest impact will be in our clinical space.

The pathologic processes associated with AD can be detected approximately 2 decades before the advent of clinical symptoms, and the symptomatic period of cognitive impairment is estimated to occupy just the final third of the disease course of AD. Using imaging studies, primarily PET, as well as cerebrospinal fluid (CSF) and even blood biomarkers for beta amyloid and tau, the pathologic drivers of AD, clinicians can identify patients with AD pathology before any symptoms are present. Importantly for our present-day interventions, the application of biomarkers can also help to diagnose AD earlier.

Amyloid PET identifies one of the earliest markers of potential AD, but a barrier common to advanced diagnostic imaging has been cost. Medicare has now approved coverage for amyloid PET in cases of suspected cognitive impairment. In a large study of more than 16,000 older adults in the United States, PET scans were positive in 55.3% of cases with mild cognitive impairment (MCI). The PET positivity rate among adults with other dementia was 70.1%. The application of PET resulted in a change in care in more than 60% of patients with MCI and dementia. One quarter of participants had their diagnosis changed from AD to another form of dementia, and 10% were changed from a diagnosis of other dementia to AD.

Liquid biomarkers can involve either CSF or blood samples. To date, CSF testing has yielded more consistent results and has defined protocols for assessment. Still, collection of CSF is more challenging than collection of blood, and patients and their families may object to lumbar puncture. CSF assessment therefore remains generally in the province of specialists and research centers.

Primary care clinicians have been waiting for a reliable blood-based biomarker for AD, and that wait may be about to end. A study published in July 2024 included 1213 adults being evaluated for cognitive symptoms in Sweden. They completed a test measuring the ratio of phosphorylated tau 217 vs nonphosphorylated tau 217, with or without a test for serum amyloid ratios as well. These tests were compared with clinicians’ clinical diagnoses as well as CSF results, which were considered the gold standard.

Using only clinical tools, primary care clinicians’ and specialists’ diagnostic accuracy for MCI and dementia were just 61% and 73%, respectively. These values were substantially weaker vs the performance of either the serum tau or amyloid ratios (both 90% accurate). The authors concluded that serum testing has the potential to improve clinical care of patients with cognitive impairment.

Where does that leave us today? Commercially available blood biomarkers are available now which use different tests and cutoff values. These may be helpful but will probably be difficult to compare and interpret for primary care clinicians. In addition, insurance is less likely to cover these tests. Amyloid PET scans are a very reasonable option to augment clinician judgment of suspected cognitive impairment, but not all geographic areas will have ready access to this imaging study.

Still, it is an exciting time to have more objective tools at our disposal to identify MCI and AD. These tools can only be optimized by clinicians who recognize symptoms and perform the baseline testing necessary to determine pretest probability of MCI or dementia.

Charles P. Vega, Health Sciences Clinical Professor, Family Medicine, University of California, Irvine, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, adviser, consultant, or trustee for McNeil Pharmaceuticals.

A version of this article first appeared on Medscape.com.

In our previous case-based review, I teased the opportunity to use biomarkers to increase the accuracy and expediency of the diagnosis of Alzheimer’s disease (AD). These tests are no longer confined to the research setting but are now available to specialists and primary care clinicians alike. Given that most cognitive disorders are first identified in primary care, however, I believe that their greatest impact will be in our clinical space.

The pathologic processes associated with AD can be detected approximately 2 decades before the advent of clinical symptoms, and the symptomatic period of cognitive impairment is estimated to occupy just the final third of the disease course of AD. Using imaging studies, primarily PET, as well as cerebrospinal fluid (CSF) and even blood biomarkers for beta amyloid and tau, the pathologic drivers of AD, clinicians can identify patients with AD pathology before any symptoms are present. Importantly for our present-day interventions, the application of biomarkers can also help to diagnose AD earlier.

Amyloid PET identifies one of the earliest markers of potential AD, but a barrier common to advanced diagnostic imaging has been cost. Medicare has now approved coverage for amyloid PET in cases of suspected cognitive impairment. In a large study of more than 16,000 older adults in the United States, PET scans were positive in 55.3% of cases with mild cognitive impairment (MCI). The PET positivity rate among adults with other dementia was 70.1%. The application of PET resulted in a change in care in more than 60% of patients with MCI and dementia. One quarter of participants had their diagnosis changed from AD to another form of dementia, and 10% were changed from a diagnosis of other dementia to AD.

Liquid biomarkers can involve either CSF or blood samples. To date, CSF testing has yielded more consistent results and has defined protocols for assessment. Still, collection of CSF is more challenging than collection of blood, and patients and their families may object to lumbar puncture. CSF assessment therefore remains generally in the province of specialists and research centers.

Primary care clinicians have been waiting for a reliable blood-based biomarker for AD, and that wait may be about to end. A study published in July 2024 included 1213 adults being evaluated for cognitive symptoms in Sweden. They completed a test measuring the ratio of phosphorylated tau 217 vs nonphosphorylated tau 217, with or without a test for serum amyloid ratios as well. These tests were compared with clinicians’ clinical diagnoses as well as CSF results, which were considered the gold standard.

Using only clinical tools, primary care clinicians’ and specialists’ diagnostic accuracy for MCI and dementia were just 61% and 73%, respectively. These values were substantially weaker vs the performance of either the serum tau or amyloid ratios (both 90% accurate). The authors concluded that serum testing has the potential to improve clinical care of patients with cognitive impairment.

Where does that leave us today? Commercially available blood biomarkers are available now which use different tests and cutoff values. These may be helpful but will probably be difficult to compare and interpret for primary care clinicians. In addition, insurance is less likely to cover these tests. Amyloid PET scans are a very reasonable option to augment clinician judgment of suspected cognitive impairment, but not all geographic areas will have ready access to this imaging study.

Still, it is an exciting time to have more objective tools at our disposal to identify MCI and AD. These tools can only be optimized by clinicians who recognize symptoms and perform the baseline testing necessary to determine pretest probability of MCI or dementia.

Charles P. Vega, Health Sciences Clinical Professor, Family Medicine, University of California, Irvine, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, adviser, consultant, or trustee for McNeil Pharmaceuticals.

A version of this article first appeared on Medscape.com.

In our previous case-based review, I teased the opportunity to use biomarkers to increase the accuracy and expediency of the diagnosis of Alzheimer’s disease (AD). These tests are no longer confined to the research setting but are now available to specialists and primary care clinicians alike. Given that most cognitive disorders are first identified in primary care, however, I believe that their greatest impact will be in our clinical space.

The pathologic processes associated with AD can be detected approximately 2 decades before the advent of clinical symptoms, and the symptomatic period of cognitive impairment is estimated to occupy just the final third of the disease course of AD. Using imaging studies, primarily PET, as well as cerebrospinal fluid (CSF) and even blood biomarkers for beta amyloid and tau, the pathologic drivers of AD, clinicians can identify patients with AD pathology before any symptoms are present. Importantly for our present-day interventions, the application of biomarkers can also help to diagnose AD earlier.

Amyloid PET identifies one of the earliest markers of potential AD, but a barrier common to advanced diagnostic imaging has been cost. Medicare has now approved coverage for amyloid PET in cases of suspected cognitive impairment. In a large study of more than 16,000 older adults in the United States, PET scans were positive in 55.3% of cases with mild cognitive impairment (MCI). The PET positivity rate among adults with other dementia was 70.1%. The application of PET resulted in a change in care in more than 60% of patients with MCI and dementia. One quarter of participants had their diagnosis changed from AD to another form of dementia, and 10% were changed from a diagnosis of other dementia to AD.

Liquid biomarkers can involve either CSF or blood samples. To date, CSF testing has yielded more consistent results and has defined protocols for assessment. Still, collection of CSF is more challenging than collection of blood, and patients and their families may object to lumbar puncture. CSF assessment therefore remains generally in the province of specialists and research centers.

Primary care clinicians have been waiting for a reliable blood-based biomarker for AD, and that wait may be about to end. A study published in July 2024 included 1213 adults being evaluated for cognitive symptoms in Sweden. They completed a test measuring the ratio of phosphorylated tau 217 vs nonphosphorylated tau 217, with or without a test for serum amyloid ratios as well. These tests were compared with clinicians’ clinical diagnoses as well as CSF results, which were considered the gold standard.

Using only clinical tools, primary care clinicians’ and specialists’ diagnostic accuracy for MCI and dementia were just 61% and 73%, respectively. These values were substantially weaker vs the performance of either the serum tau or amyloid ratios (both 90% accurate). The authors concluded that serum testing has the potential to improve clinical care of patients with cognitive impairment.

Where does that leave us today? Commercially available blood biomarkers are available now which use different tests and cutoff values. These may be helpful but will probably be difficult to compare and interpret for primary care clinicians. In addition, insurance is less likely to cover these tests. Amyloid PET scans are a very reasonable option to augment clinician judgment of suspected cognitive impairment, but not all geographic areas will have ready access to this imaging study.

Still, it is an exciting time to have more objective tools at our disposal to identify MCI and AD. These tools can only be optimized by clinicians who recognize symptoms and perform the baseline testing necessary to determine pretest probability of MCI or dementia.

Charles P. Vega, Health Sciences Clinical Professor, Family Medicine, University of California, Irvine, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, adviser, consultant, or trustee for McNeil Pharmaceuticals.

A version of this article first appeared on Medscape.com.

If the name of leukemia specialist Jorge Cortes, MD, appears any more often in PubMed, they’ll need to name a wing after him. 

Over 30 years, Cortes has led or coauthored hundreds of studies, including many trials of landmark drugs to treat chronic myeloid leukemia (CML). His work has helped transform CML into an often-survivable disease instead of one that took the lives of most patients within 5 years.

“It’s been remarkable to see the evolution in CML and to be part of that transition as a fellow, as faculty, and as leader of some of the trials,” said Cortes, who directs the Georgia Cancer Center at Augusta University. “I’m the luckiest person in the world.”

In an interview, Cortes talked about his youth in Mexico, his research path, and his close connections to cancer medicine in Latin America.

Q: You grew up in Mexico City. What was your family like?

A: “My father grew up very poor in a small town in Michoacán in the southwest part of Mexico. In Mexico City, he had a tiny grocery store in an old-fashioned market, and we were lower middle class.

One of the things I learned was to work hard. There’s nobody I know who worked as hard as my father. He opened his store every day of the year, [Mexican] Independence Day or New Year’s or Christmas. He worked hard so we could have a better life than he did.

We learned English from a very young age. My elementary school was called Westminster School because he wanted a school where we would learn English.

As for my mother, she stayed with us [at home] and made sure we did our homework and were taken care of. I learned about being honest and dedicating to what you were doing.”

Q: You trained at the Salvador Zubirán National Institute of Health Sciences and Nutrition in Mexico City. Then what happened? 

A: “Through encouragement by my dermatologist older brother and a mentor at the institution where I was training as a hematologist, I decided to come to the United States.

My initial focus was going to be on coagulation and thrombosis. I came to Houston (Texas) for a fellowship at the University of Texas Health Science Center.

Then I started doing my rotation for the malignant part of the fellowship at MD Anderson Cancer Center [Houston]. One of my first rotations was with Susan M. O’Brien, [MD,] who became my greatest mentor throughout my career. I really enjoyed my rotation. I thought she was great clinically, and she was doing research and teaching. That’s what I wanted for my career.”

Q: What drew you to leukemia specifically?

A: “Dr O’Brien worked in leukemia during my initial rotation, and I really loved it. It was hard work, but it was very inspiring to see the clinical research and the things you could for patients. She had a lot of joy doing that. 

I told my program director I’d change and transfer to MD Anderson, and I ended up staying at MD Anderson for 23 years.”

Q: What was leukemia research like in those days?

A: “We didn’t have the understanding of the biology and the new drugs that we have now. When I started in Mexico, we didn’t even have hydroxyurea. What we were doing was much more basic. But still, the field sounded like a great field to be involved with because they were doing so many trials and had an outstanding database. 

Because of the influence of Dr [Moshe] Talpaz, [MD,] I started getting very involved with CML. In my initial years as a young faculty, I started working with him on interferon. Then imatinib appeared. I saw even from the phase 1 study how impressive the outcomes were in patients who had no response to anything and were in bad shape.”

Q: What CML medications have you worked on?

A: “I’ve been involved with all of them. Imatinib early on, then I led trials with dasatinib and nilotinib. Then, I led the registration trials of bosutinib and ponatinib. More recently, I was part of the development of asciminib.”

Q: What were some of the biggest challenges in CML research?

A: “We had an opportunity to do a lot of analysis about TKIs [tyrosine kinase inhibitors] when these were new drugs. It was a very steep curve of learning, how to monitor and manage side effects.

Then patients were starting to have resistance to two to three TKIs. Ponatinib came along, and it was an incredibly effective drug. But after it was approved, we started to recognize the occurrence of heart attacks and strokes.

That was unexpected and not something that was known for any TKI. It was a big challenge. The drug was taken off the market for some time, and trials were put on hold by the FDA [US Food and Drug Administration].

We scrambled to understand the mechanism of action. For a year or two, it was a stressful time. But eventually we moved past it, and we learned a lot.”

Q: What sort of work have you done in Latin America?

A: “I’ve always been very close to Latin America. I have many good friends and colleagues there, and I’ve always been interested in working with them. 

We’ve done research and studies and created an organization called Latin American Leukemia Net to develop more trials in Latin America. The most rewarding thing has been the educational programs for patients that we’ve done, helping them understand the disease, the treatments, and the goals of treatment. 

We’ve conducted a number of programs, and they have been effective, well-attended, and well received. I still work with my colleagues to develop local guidelines and do collaborative research.”

Q: What convinced you to leave MD Anderson for Georgia?

A: “I never thought I’d leave MD Anderson. I had my well-oiled machine of clinical trials, my clinic, and my fellowship program. But the one thing that I wanted to see if I could try next was to develop an institution.

That was the goal here, to take the Georgia Cancer Center to NCI [National Cancer Institute] designation. So, I thought, ‘That’s a nice challenge.’ It may be a good opportunity to try a different aspect of what it means to be an oncologist.

There are days that you think, ‘What am I doing here?’ when you have to deal with budgets and personnel and all these things. But it’s part of the process. It’s still good to know that we have a goal, and that we’re going to make it. 

Also, I still see my patients, and I enjoy that I still do some research and mentoring.”

Q: What’s the current state of CML treatment?

A: “Many patients have a pretty much normal life expectancy while [on therapy]. Still, one of the goals of many patients is to stop therapy. But that’s a reality only for a small percentage of patients. How can we make that happen for more patients?”

Q: By stopping therapy, do you mean curing the cancer?

A: “Yes, pretty much. You have a good response, you stop the therapy, and it doesn’t come back.

There are also patients who really don’t do well. We hear about CML being with a disease with such a good outcome, but we have patients for whom nothing works. Is it a matter of [needing] another TKI, or do we need to look at something else?”

Q: What do you see on the horizon?

A: “We are developing new approaches like combination therapies. We’re scratching the surface on that. We need to understand which combinations work, and where and when.

And we can make more efficient uses of the drugs we have now in terms of which ones to use when, the doses, the safety profiles. I think we can do better.”

Cortes disclosed consulting for Amphivena, Astellas, Bio-Path, BioLineRx, Bristol Myers Squibb, Daiichi Sankyo, Jazz, Novartis, Pfizer, and Takeda and research funding from Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Immunogen, Jazz, Merus, Novartis, Pfizer, Sun Pharma, Takeda, Tolero and Trovagene.
 

A version of this article appeared on Medscape.com.

If the name of leukemia specialist Jorge Cortes, MD, appears any more often in PubMed, they’ll need to name a wing after him. 

Over 30 years, Cortes has led or coauthored hundreds of studies, including many trials of landmark drugs to treat chronic myeloid leukemia (CML). His work has helped transform CML into an often-survivable disease instead of one that took the lives of most patients within 5 years.

“It’s been remarkable to see the evolution in CML and to be part of that transition as a fellow, as faculty, and as leader of some of the trials,” said Cortes, who directs the Georgia Cancer Center at Augusta University. “I’m the luckiest person in the world.”

In an interview, Cortes talked about his youth in Mexico, his research path, and his close connections to cancer medicine in Latin America.

Q: You grew up in Mexico City. What was your family like?

A: “My father grew up very poor in a small town in Michoacán in the southwest part of Mexico. In Mexico City, he had a tiny grocery store in an old-fashioned market, and we were lower middle class.

One of the things I learned was to work hard. There’s nobody I know who worked as hard as my father. He opened his store every day of the year, [Mexican] Independence Day or New Year’s or Christmas. He worked hard so we could have a better life than he did.

We learned English from a very young age. My elementary school was called Westminster School because he wanted a school where we would learn English.

As for my mother, she stayed with us [at home] and made sure we did our homework and were taken care of. I learned about being honest and dedicating to what you were doing.”

Q: You trained at the Salvador Zubirán National Institute of Health Sciences and Nutrition in Mexico City. Then what happened? 

A: “Through encouragement by my dermatologist older brother and a mentor at the institution where I was training as a hematologist, I decided to come to the United States.

My initial focus was going to be on coagulation and thrombosis. I came to Houston (Texas) for a fellowship at the University of Texas Health Science Center.

Then I started doing my rotation for the malignant part of the fellowship at MD Anderson Cancer Center [Houston]. One of my first rotations was with Susan M. O’Brien, [MD,] who became my greatest mentor throughout my career. I really enjoyed my rotation. I thought she was great clinically, and she was doing research and teaching. That’s what I wanted for my career.”

Q: What drew you to leukemia specifically?

A: “Dr O’Brien worked in leukemia during my initial rotation, and I really loved it. It was hard work, but it was very inspiring to see the clinical research and the things you could for patients. She had a lot of joy doing that. 

I told my program director I’d change and transfer to MD Anderson, and I ended up staying at MD Anderson for 23 years.”

Q: What was leukemia research like in those days?

A: “We didn’t have the understanding of the biology and the new drugs that we have now. When I started in Mexico, we didn’t even have hydroxyurea. What we were doing was much more basic. But still, the field sounded like a great field to be involved with because they were doing so many trials and had an outstanding database. 

Because of the influence of Dr [Moshe] Talpaz, [MD,] I started getting very involved with CML. In my initial years as a young faculty, I started working with him on interferon. Then imatinib appeared. I saw even from the phase 1 study how impressive the outcomes were in patients who had no response to anything and were in bad shape.”

Q: What CML medications have you worked on?

A: “I’ve been involved with all of them. Imatinib early on, then I led trials with dasatinib and nilotinib. Then, I led the registration trials of bosutinib and ponatinib. More recently, I was part of the development of asciminib.”

Q: What were some of the biggest challenges in CML research?

A: “We had an opportunity to do a lot of analysis about TKIs [tyrosine kinase inhibitors] when these were new drugs. It was a very steep curve of learning, how to monitor and manage side effects.

Then patients were starting to have resistance to two to three TKIs. Ponatinib came along, and it was an incredibly effective drug. But after it was approved, we started to recognize the occurrence of heart attacks and strokes.

That was unexpected and not something that was known for any TKI. It was a big challenge. The drug was taken off the market for some time, and trials were put on hold by the FDA [US Food and Drug Administration].

We scrambled to understand the mechanism of action. For a year or two, it was a stressful time. But eventually we moved past it, and we learned a lot.”

Q: What sort of work have you done in Latin America?

A: “I’ve always been very close to Latin America. I have many good friends and colleagues there, and I’ve always been interested in working with them. 

We’ve done research and studies and created an organization called Latin American Leukemia Net to develop more trials in Latin America. The most rewarding thing has been the educational programs for patients that we’ve done, helping them understand the disease, the treatments, and the goals of treatment. 

We’ve conducted a number of programs, and they have been effective, well-attended, and well received. I still work with my colleagues to develop local guidelines and do collaborative research.”

Q: What convinced you to leave MD Anderson for Georgia?

A: “I never thought I’d leave MD Anderson. I had my well-oiled machine of clinical trials, my clinic, and my fellowship program. But the one thing that I wanted to see if I could try next was to develop an institution.

That was the goal here, to take the Georgia Cancer Center to NCI [National Cancer Institute] designation. So, I thought, ‘That’s a nice challenge.’ It may be a good opportunity to try a different aspect of what it means to be an oncologist.

There are days that you think, ‘What am I doing here?’ when you have to deal with budgets and personnel and all these things. But it’s part of the process. It’s still good to know that we have a goal, and that we’re going to make it. 

Also, I still see my patients, and I enjoy that I still do some research and mentoring.”

Q: What’s the current state of CML treatment?

A: “Many patients have a pretty much normal life expectancy while [on therapy]. Still, one of the goals of many patients is to stop therapy. But that’s a reality only for a small percentage of patients. How can we make that happen for more patients?”

Q: By stopping therapy, do you mean curing the cancer?

A: “Yes, pretty much. You have a good response, you stop the therapy, and it doesn’t come back.

There are also patients who really don’t do well. We hear about CML being with a disease with such a good outcome, but we have patients for whom nothing works. Is it a matter of [needing] another TKI, or do we need to look at something else?”

Q: What do you see on the horizon?

A: “We are developing new approaches like combination therapies. We’re scratching the surface on that. We need to understand which combinations work, and where and when.

And we can make more efficient uses of the drugs we have now in terms of which ones to use when, the doses, the safety profiles. I think we can do better.”

Cortes disclosed consulting for Amphivena, Astellas, Bio-Path, BioLineRx, Bristol Myers Squibb, Daiichi Sankyo, Jazz, Novartis, Pfizer, and Takeda and research funding from Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Immunogen, Jazz, Merus, Novartis, Pfizer, Sun Pharma, Takeda, Tolero and Trovagene.
 

A version of this article appeared on Medscape.com.

If the name of leukemia specialist Jorge Cortes, MD, appears any more often in PubMed, they’ll need to name a wing after him. 

Over 30 years, Cortes has led or coauthored hundreds of studies, including many trials of landmark drugs to treat chronic myeloid leukemia (CML). His work has helped transform CML into an often-survivable disease instead of one that took the lives of most patients within 5 years.

“It’s been remarkable to see the evolution in CML and to be part of that transition as a fellow, as faculty, and as leader of some of the trials,” said Cortes, who directs the Georgia Cancer Center at Augusta University. “I’m the luckiest person in the world.”

In an interview, Cortes talked about his youth in Mexico, his research path, and his close connections to cancer medicine in Latin America.

Q: You grew up in Mexico City. What was your family like?

A: “My father grew up very poor in a small town in Michoacán in the southwest part of Mexico. In Mexico City, he had a tiny grocery store in an old-fashioned market, and we were lower middle class.

One of the things I learned was to work hard. There’s nobody I know who worked as hard as my father. He opened his store every day of the year, [Mexican] Independence Day or New Year’s or Christmas. He worked hard so we could have a better life than he did.

We learned English from a very young age. My elementary school was called Westminster School because he wanted a school where we would learn English.

As for my mother, she stayed with us [at home] and made sure we did our homework and were taken care of. I learned about being honest and dedicating to what you were doing.”

Q: You trained at the Salvador Zubirán National Institute of Health Sciences and Nutrition in Mexico City. Then what happened? 

A: “Through encouragement by my dermatologist older brother and a mentor at the institution where I was training as a hematologist, I decided to come to the United States.

My initial focus was going to be on coagulation and thrombosis. I came to Houston (Texas) for a fellowship at the University of Texas Health Science Center.

Then I started doing my rotation for the malignant part of the fellowship at MD Anderson Cancer Center [Houston]. One of my first rotations was with Susan M. O’Brien, [MD,] who became my greatest mentor throughout my career. I really enjoyed my rotation. I thought she was great clinically, and she was doing research and teaching. That’s what I wanted for my career.”

Q: What drew you to leukemia specifically?

A: “Dr O’Brien worked in leukemia during my initial rotation, and I really loved it. It was hard work, but it was very inspiring to see the clinical research and the things you could for patients. She had a lot of joy doing that. 

I told my program director I’d change and transfer to MD Anderson, and I ended up staying at MD Anderson for 23 years.”

Q: What was leukemia research like in those days?

A: “We didn’t have the understanding of the biology and the new drugs that we have now. When I started in Mexico, we didn’t even have hydroxyurea. What we were doing was much more basic. But still, the field sounded like a great field to be involved with because they were doing so many trials and had an outstanding database. 

Because of the influence of Dr [Moshe] Talpaz, [MD,] I started getting very involved with CML. In my initial years as a young faculty, I started working with him on interferon. Then imatinib appeared. I saw even from the phase 1 study how impressive the outcomes were in patients who had no response to anything and were in bad shape.”

Q: What CML medications have you worked on?

A: “I’ve been involved with all of them. Imatinib early on, then I led trials with dasatinib and nilotinib. Then, I led the registration trials of bosutinib and ponatinib. More recently, I was part of the development of asciminib.”

Q: What were some of the biggest challenges in CML research?

A: “We had an opportunity to do a lot of analysis about TKIs [tyrosine kinase inhibitors] when these were new drugs. It was a very steep curve of learning, how to monitor and manage side effects.

Then patients were starting to have resistance to two to three TKIs. Ponatinib came along, and it was an incredibly effective drug. But after it was approved, we started to recognize the occurrence of heart attacks and strokes.

That was unexpected and not something that was known for any TKI. It was a big challenge. The drug was taken off the market for some time, and trials were put on hold by the FDA [US Food and Drug Administration].

We scrambled to understand the mechanism of action. For a year or two, it was a stressful time. But eventually we moved past it, and we learned a lot.”

Q: What sort of work have you done in Latin America?

A: “I’ve always been very close to Latin America. I have many good friends and colleagues there, and I’ve always been interested in working with them. 

We’ve done research and studies and created an organization called Latin American Leukemia Net to develop more trials in Latin America. The most rewarding thing has been the educational programs for patients that we’ve done, helping them understand the disease, the treatments, and the goals of treatment. 

We’ve conducted a number of programs, and they have been effective, well-attended, and well received. I still work with my colleagues to develop local guidelines and do collaborative research.”

Q: What convinced you to leave MD Anderson for Georgia?

A: “I never thought I’d leave MD Anderson. I had my well-oiled machine of clinical trials, my clinic, and my fellowship program. But the one thing that I wanted to see if I could try next was to develop an institution.

That was the goal here, to take the Georgia Cancer Center to NCI [National Cancer Institute] designation. So, I thought, ‘That’s a nice challenge.’ It may be a good opportunity to try a different aspect of what it means to be an oncologist.

There are days that you think, ‘What am I doing here?’ when you have to deal with budgets and personnel and all these things. But it’s part of the process. It’s still good to know that we have a goal, and that we’re going to make it. 

Also, I still see my patients, and I enjoy that I still do some research and mentoring.”

Q: What’s the current state of CML treatment?

A: “Many patients have a pretty much normal life expectancy while [on therapy]. Still, one of the goals of many patients is to stop therapy. But that’s a reality only for a small percentage of patients. How can we make that happen for more patients?”

Q: By stopping therapy, do you mean curing the cancer?

A: “Yes, pretty much. You have a good response, you stop the therapy, and it doesn’t come back.

There are also patients who really don’t do well. We hear about CML being with a disease with such a good outcome, but we have patients for whom nothing works. Is it a matter of [needing] another TKI, or do we need to look at something else?”

Q: What do you see on the horizon?

A: “We are developing new approaches like combination therapies. We’re scratching the surface on that. We need to understand which combinations work, and where and when.

And we can make more efficient uses of the drugs we have now in terms of which ones to use when, the doses, the safety profiles. I think we can do better.”

Cortes disclosed consulting for Amphivena, Astellas, Bio-Path, BioLineRx, Bristol Myers Squibb, Daiichi Sankyo, Jazz, Novartis, Pfizer, and Takeda and research funding from Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Immunogen, Jazz, Merus, Novartis, Pfizer, Sun Pharma, Takeda, Tolero and Trovagene.
 

A version of this article appeared on Medscape.com.

I’ve tried to retire from medicine. Really. Proofs of my sincerity include a true retirement from performing procedures and the closing of two office practices. I even attended the wonderful retirement party my daughters threw for me. 

I had great plans for my newfound leisure time. I purchased about a thousand colored pencils to map my family ancestry. I wore out many magic erasers in my cleaning efforts. I cajoled my husband, Tony, to help me build not one, but three, gardens in our yard. Upon realizing I had no more weeds or closets to conquer, I began a Dante-like descent into a dark abyss. I felt my sadness was justified. After all, I had immensely enjoyed my early medical life. 

 

From Private Practice to Being Employed

I had a joint cardiology practice with the great Jim Whiteside, MD, in South Central Kentucky for 24 years. Our schedule was always bursting at the seams in the heart of tobacco country. We opened the first cath lab in our hospital, inspired the purchase of a new nuclear scanner, and expanded the stress echo lab. After a 6-year odyssey, we successfully championed primary PCI without surgery on site (along with Ephraim McDowell Regional Medical Center in Danville, Kentucky). As our services expanded, we remodeled to accommodate three cardiologists and two nurse practitioners. Simultaneously, we lobbied our city council and mayor to pass smoke-free legislation, a lightning rod topic in a culture still loyal to a burning weed whose worth had paled in comparison to the cost of its carnage. We were “running wide open” and believed that we were doing important work. 

But then our forward-thinking, appreciative CEO and friend died suddenly, and the open communication and innovation seemingly vanished. Those events inspired my first “retirement.” After this, I became employed for the first time and was blessed once again with a wonderful partner and colleagues. But despite those blessings, the global practice of medicine had begun to change. Physicians were now seen by some as widgets; their worth measured in productivity. A few years in, I needed part-time work to care for my aging parents. My employer needed more, thus inspiring my second “retirement”. 

 

My Second ‘Retirement’

My parents died within 4 months of each other in 2020. Suddenly, I was untethered from both my professional persona and role as caregiver. It was then that my sadness accelerated toward what seemed like the second circle of Hell, with many more to come. 

To many, my sadness made no sense. Our accountant reassured us that we no longer “needed” to work, and I was (and still am) happily married to my high school sweetheart. Our beautiful daughters were healthy and thriving. Although I mouthed appreciation for my blessings in prayer, I could not prevent myself from sinking further. 

My always supportive husband was worried. Tony had skipped happily into his retirement from teaching. He had hoped I would do that same. “You cannot sit on that couch and mope for the rest of your life,” he said, exasperated. 

I thought about doing just that, until one day I answered a phone call to hear, “Doctor, have you ever been to Montana?” Before I could cut her off, the woman charged into the description of a job opening for a locums cardiologist. I immediately sat up. “No office work?” I questioned. 

“No, this is strictly hospital call, rounds, and reading studies.” I didn’t know such jobs existed.

“What is the salary, and what do you cover?” I asked trying to conceal the fact that Tony would have gladly paid her to get me off the couch. 

 

Finding What Suits Me

If I’m honest, since my training days, hospital work is all I have ever wanted. I’ve always felt trapped by the imaginary timer that is part of every office visit. I found running a code less challenging than having to stand and end an office visit that might leave a patient wanting more. 

On hospital days, there are no scheduled time slots. I can triage patients according to their needs. My deadlines are self-imposed: To have a morning coffee with Tony. To deliver the best care possible. To educate as much as time will allow. To beat the midnight clock, after which billing is a little more difficult. 

I will soon begin my seventh year as an inpatient, acute-care cardiologist. Although I was flattered to be considered for full-time work, I couldn’t do that to Tony (who declined to move from Kentucky). We struck a deal that we’d travel to the same facility, where I work seven to nine jobs a year. 

I am now a less anxious “retiree.” My mood is bolstered by the knowledge that within days to weeks I’ll be back to doing what I love: Seeing patients. Making a difference. Enjoying professional comradery and appreciation.

Tony golfs while I work and he jokes that he is a “real go-getter,” explaining that “I take her to work in the morning and then at night, I go get her!” 

For those considering this line of work, it’s not for the faint of heart. My workday can stretch to over 16 hours. But I work in the best of hospital settings. On morning rounds, we present every single patient on the service. Our ER is staffed 100% of the time with at least four board-certified emergency medicine trained physicians. Everyone I work with shares a patient-first philosophy. 

Because of this, I have quite easily ascended from Dante’s inferno. I am happy again in my professional life. 

I know I’ll eventually have to retire for real, and I hope it will be at a time of my choosing and not enforced by the failings of modern medicine. I believe that these past few years will help ease that transition. And when that time comes, I’ll able to look back and know that I was blessed with a long and mostly satisfying career. 

Until then, my magic erasers, colored pencils and gardening will have to wait.

Dr. Walton-Shirley is a clinical cardiologist from Nashville, Tennessee. She reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

I’ve tried to retire from medicine. Really. Proofs of my sincerity include a true retirement from performing procedures and the closing of two office practices. I even attended the wonderful retirement party my daughters threw for me. 

I had great plans for my newfound leisure time. I purchased about a thousand colored pencils to map my family ancestry. I wore out many magic erasers in my cleaning efforts. I cajoled my husband, Tony, to help me build not one, but three, gardens in our yard. Upon realizing I had no more weeds or closets to conquer, I began a Dante-like descent into a dark abyss. I felt my sadness was justified. After all, I had immensely enjoyed my early medical life. 

 

From Private Practice to Being Employed

I had a joint cardiology practice with the great Jim Whiteside, MD, in South Central Kentucky for 24 years. Our schedule was always bursting at the seams in the heart of tobacco country. We opened the first cath lab in our hospital, inspired the purchase of a new nuclear scanner, and expanded the stress echo lab. After a 6-year odyssey, we successfully championed primary PCI without surgery on site (along with Ephraim McDowell Regional Medical Center in Danville, Kentucky). As our services expanded, we remodeled to accommodate three cardiologists and two nurse practitioners. Simultaneously, we lobbied our city council and mayor to pass smoke-free legislation, a lightning rod topic in a culture still loyal to a burning weed whose worth had paled in comparison to the cost of its carnage. We were “running wide open” and believed that we were doing important work. 

But then our forward-thinking, appreciative CEO and friend died suddenly, and the open communication and innovation seemingly vanished. Those events inspired my first “retirement.” After this, I became employed for the first time and was blessed once again with a wonderful partner and colleagues. But despite those blessings, the global practice of medicine had begun to change. Physicians were now seen by some as widgets; their worth measured in productivity. A few years in, I needed part-time work to care for my aging parents. My employer needed more, thus inspiring my second “retirement”. 

 

My Second ‘Retirement’

My parents died within 4 months of each other in 2020. Suddenly, I was untethered from both my professional persona and role as caregiver. It was then that my sadness accelerated toward what seemed like the second circle of Hell, with many more to come. 

To many, my sadness made no sense. Our accountant reassured us that we no longer “needed” to work, and I was (and still am) happily married to my high school sweetheart. Our beautiful daughters were healthy and thriving. Although I mouthed appreciation for my blessings in prayer, I could not prevent myself from sinking further. 

My always supportive husband was worried. Tony had skipped happily into his retirement from teaching. He had hoped I would do that same. “You cannot sit on that couch and mope for the rest of your life,” he said, exasperated. 

I thought about doing just that, until one day I answered a phone call to hear, “Doctor, have you ever been to Montana?” Before I could cut her off, the woman charged into the description of a job opening for a locums cardiologist. I immediately sat up. “No office work?” I questioned. 

“No, this is strictly hospital call, rounds, and reading studies.” I didn’t know such jobs existed.

“What is the salary, and what do you cover?” I asked trying to conceal the fact that Tony would have gladly paid her to get me off the couch. 

 

Finding What Suits Me

If I’m honest, since my training days, hospital work is all I have ever wanted. I’ve always felt trapped by the imaginary timer that is part of every office visit. I found running a code less challenging than having to stand and end an office visit that might leave a patient wanting more. 

On hospital days, there are no scheduled time slots. I can triage patients according to their needs. My deadlines are self-imposed: To have a morning coffee with Tony. To deliver the best care possible. To educate as much as time will allow. To beat the midnight clock, after which billing is a little more difficult. 

I will soon begin my seventh year as an inpatient, acute-care cardiologist. Although I was flattered to be considered for full-time work, I couldn’t do that to Tony (who declined to move from Kentucky). We struck a deal that we’d travel to the same facility, where I work seven to nine jobs a year. 

I am now a less anxious “retiree.” My mood is bolstered by the knowledge that within days to weeks I’ll be back to doing what I love: Seeing patients. Making a difference. Enjoying professional comradery and appreciation.

Tony golfs while I work and he jokes that he is a “real go-getter,” explaining that “I take her to work in the morning and then at night, I go get her!” 

For those considering this line of work, it’s not for the faint of heart. My workday can stretch to over 16 hours. But I work in the best of hospital settings. On morning rounds, we present every single patient on the service. Our ER is staffed 100% of the time with at least four board-certified emergency medicine trained physicians. Everyone I work with shares a patient-first philosophy. 

Because of this, I have quite easily ascended from Dante’s inferno. I am happy again in my professional life. 

I know I’ll eventually have to retire for real, and I hope it will be at a time of my choosing and not enforced by the failings of modern medicine. I believe that these past few years will help ease that transition. And when that time comes, I’ll able to look back and know that I was blessed with a long and mostly satisfying career. 

Until then, my magic erasers, colored pencils and gardening will have to wait.

Dr. Walton-Shirley is a clinical cardiologist from Nashville, Tennessee. She reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

I’ve tried to retire from medicine. Really. Proofs of my sincerity include a true retirement from performing procedures and the closing of two office practices. I even attended the wonderful retirement party my daughters threw for me. 

I had great plans for my newfound leisure time. I purchased about a thousand colored pencils to map my family ancestry. I wore out many magic erasers in my cleaning efforts. I cajoled my husband, Tony, to help me build not one, but three, gardens in our yard. Upon realizing I had no more weeds or closets to conquer, I began a Dante-like descent into a dark abyss. I felt my sadness was justified. After all, I had immensely enjoyed my early medical life. 

 

From Private Practice to Being Employed

I had a joint cardiology practice with the great Jim Whiteside, MD, in South Central Kentucky for 24 years. Our schedule was always bursting at the seams in the heart of tobacco country. We opened the first cath lab in our hospital, inspired the purchase of a new nuclear scanner, and expanded the stress echo lab. After a 6-year odyssey, we successfully championed primary PCI without surgery on site (along with Ephraim McDowell Regional Medical Center in Danville, Kentucky). As our services expanded, we remodeled to accommodate three cardiologists and two nurse practitioners. Simultaneously, we lobbied our city council and mayor to pass smoke-free legislation, a lightning rod topic in a culture still loyal to a burning weed whose worth had paled in comparison to the cost of its carnage. We were “running wide open” and believed that we were doing important work. 

But then our forward-thinking, appreciative CEO and friend died suddenly, and the open communication and innovation seemingly vanished. Those events inspired my first “retirement.” After this, I became employed for the first time and was blessed once again with a wonderful partner and colleagues. But despite those blessings, the global practice of medicine had begun to change. Physicians were now seen by some as widgets; their worth measured in productivity. A few years in, I needed part-time work to care for my aging parents. My employer needed more, thus inspiring my second “retirement”. 

 

My Second ‘Retirement’

My parents died within 4 months of each other in 2020. Suddenly, I was untethered from both my professional persona and role as caregiver. It was then that my sadness accelerated toward what seemed like the second circle of Hell, with many more to come. 

To many, my sadness made no sense. Our accountant reassured us that we no longer “needed” to work, and I was (and still am) happily married to my high school sweetheart. Our beautiful daughters were healthy and thriving. Although I mouthed appreciation for my blessings in prayer, I could not prevent myself from sinking further. 

My always supportive husband was worried. Tony had skipped happily into his retirement from teaching. He had hoped I would do that same. “You cannot sit on that couch and mope for the rest of your life,” he said, exasperated. 

I thought about doing just that, until one day I answered a phone call to hear, “Doctor, have you ever been to Montana?” Before I could cut her off, the woman charged into the description of a job opening for a locums cardiologist. I immediately sat up. “No office work?” I questioned. 

“No, this is strictly hospital call, rounds, and reading studies.” I didn’t know such jobs existed.

“What is the salary, and what do you cover?” I asked trying to conceal the fact that Tony would have gladly paid her to get me off the couch. 

 

Finding What Suits Me

If I’m honest, since my training days, hospital work is all I have ever wanted. I’ve always felt trapped by the imaginary timer that is part of every office visit. I found running a code less challenging than having to stand and end an office visit that might leave a patient wanting more. 

On hospital days, there are no scheduled time slots. I can triage patients according to their needs. My deadlines are self-imposed: To have a morning coffee with Tony. To deliver the best care possible. To educate as much as time will allow. To beat the midnight clock, after which billing is a little more difficult. 

I will soon begin my seventh year as an inpatient, acute-care cardiologist. Although I was flattered to be considered for full-time work, I couldn’t do that to Tony (who declined to move from Kentucky). We struck a deal that we’d travel to the same facility, where I work seven to nine jobs a year. 

I am now a less anxious “retiree.” My mood is bolstered by the knowledge that within days to weeks I’ll be back to doing what I love: Seeing patients. Making a difference. Enjoying professional comradery and appreciation.

Tony golfs while I work and he jokes that he is a “real go-getter,” explaining that “I take her to work in the morning and then at night, I go get her!” 

For those considering this line of work, it’s not for the faint of heart. My workday can stretch to over 16 hours. But I work in the best of hospital settings. On morning rounds, we present every single patient on the service. Our ER is staffed 100% of the time with at least four board-certified emergency medicine trained physicians. Everyone I work with shares a patient-first philosophy. 

Because of this, I have quite easily ascended from Dante’s inferno. I am happy again in my professional life. 

I know I’ll eventually have to retire for real, and I hope it will be at a time of my choosing and not enforced by the failings of modern medicine. I believe that these past few years will help ease that transition. And when that time comes, I’ll able to look back and know that I was blessed with a long and mostly satisfying career. 

Until then, my magic erasers, colored pencils and gardening will have to wait.

Dr. Walton-Shirley is a clinical cardiologist from Nashville, Tennessee. She reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.