Even before HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems), hospital leaders and clinicians were striving to provide not only high quality care, but a place patients choose to meet their future healthcare needs. Just this week, US News and World Report published an article entitled "The Patient Wish List." Although not a list generated from a scientific study, the author, Peter Pronovost, MD, PhD, who is the director of the Armstrong Institute for Patient Safety and Quality and senior vice president for patient safety and quality at Johns Hopkins Medicine, worked with Jan Hill, patient relations director at Johns Hopkins, to develop a list intended to be a "conversation starter."

So, how does this apply to hospitalists? Many of the items on the list are an easy fix and don't cost a thing. Here are a few areas hospitalist can impact:

1. I want to sleep. For example: are there standing overnight test orders that could be provided during the day?
2. Reduce noise outside my room, particularly at night. How can hospitalists contribute to reducing hallway and nursing station noise?
3. Knock before entering. It's a sign of respect to knock before entering the patient's room. Sitting down while talking to the patient and introducing yourself are also key.
4. Keep me (and my family) updated. Are you always updating the patient and family about the plan of care and if things change?
5. I want to be a part of my care. Do you always use language patients (and families) can easily understand? How do you ensure patients (and families) understand the plan of care?
6. Be professional, always. No matter where you are in the hospital, patients and families are watching you closely. Ask yourself, "How I perceive you is often how I perceive the hospital and care that I am receiving."

What else can you do to improve the patient's experience in your hospital? TH

Even before HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems), hospital leaders and clinicians were striving to provide not only high quality care, but a place patients choose to meet their future healthcare needs. Just this week, US News and World Report published an article entitled "The Patient Wish List." Although not a list generated from a scientific study, the author, Peter Pronovost, MD, PhD, who is the director of the Armstrong Institute for Patient Safety and Quality and senior vice president for patient safety and quality at Johns Hopkins Medicine, worked with Jan Hill, patient relations director at Johns Hopkins, to develop a list intended to be a "conversation starter."

So, how does this apply to hospitalists? Many of the items on the list are an easy fix and don't cost a thing. Here are a few areas hospitalist can impact:

1. I want to sleep. For example: are there standing overnight test orders that could be provided during the day?
2. Reduce noise outside my room, particularly at night. How can hospitalists contribute to reducing hallway and nursing station noise?
3. Knock before entering. It's a sign of respect to knock before entering the patient's room. Sitting down while talking to the patient and introducing yourself are also key.
4. Keep me (and my family) updated. Are you always updating the patient and family about the plan of care and if things change?
5. I want to be a part of my care. Do you always use language patients (and families) can easily understand? How do you ensure patients (and families) understand the plan of care?
6. Be professional, always. No matter where you are in the hospital, patients and families are watching you closely. Ask yourself, "How I perceive you is often how I perceive the hospital and care that I am receiving."

What else can you do to improve the patient's experience in your hospital? TH

Even before HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems), hospital leaders and clinicians were striving to provide not only high quality care, but a place patients choose to meet their future healthcare needs. Just this week, US News and World Report published an article entitled "The Patient Wish List." Although not a list generated from a scientific study, the author, Peter Pronovost, MD, PhD, who is the director of the Armstrong Institute for Patient Safety and Quality and senior vice president for patient safety and quality at Johns Hopkins Medicine, worked with Jan Hill, patient relations director at Johns Hopkins, to develop a list intended to be a "conversation starter."

So, how does this apply to hospitalists? Many of the items on the list are an easy fix and don't cost a thing. Here are a few areas hospitalist can impact:

1. I want to sleep. For example: are there standing overnight test orders that could be provided during the day?
2. Reduce noise outside my room, particularly at night. How can hospitalists contribute to reducing hallway and nursing station noise?
3. Knock before entering. It's a sign of respect to knock before entering the patient's room. Sitting down while talking to the patient and introducing yourself are also key.
4. Keep me (and my family) updated. Are you always updating the patient and family about the plan of care and if things change?
5. I want to be a part of my care. Do you always use language patients (and families) can easily understand? How do you ensure patients (and families) understand the plan of care?
6. Be professional, always. No matter where you are in the hospital, patients and families are watching you closely. Ask yourself, "How I perceive you is often how I perceive the hospital and care that I am receiving."

What else can you do to improve the patient's experience in your hospital? TH

CHICAGO – Last-minute colectomy isn’t the way to go for Clostridium difficile–induced toxic megacolon; outcomes are better with a timely loop ileostomy and colonic lavage.

University of Pittsburgh surgery professor Dr. Brian Zuckerbraun, a pioneer of the technique, explained the procedure and its benefits in an interview at the annual Clinical Congress of the American College of Surgeons.

[email protected]

CHICAGO – Last-minute colectomy isn’t the way to go for Clostridium difficile–induced toxic megacolon; outcomes are better with a timely loop ileostomy and colonic lavage.

University of Pittsburgh surgery professor Dr. Brian Zuckerbraun, a pioneer of the technique, explained the procedure and its benefits in an interview at the annual Clinical Congress of the American College of Surgeons.

[email protected]

CHICAGO – Last-minute colectomy isn’t the way to go for Clostridium difficile–induced toxic megacolon; outcomes are better with a timely loop ileostomy and colonic lavage.

University of Pittsburgh surgery professor Dr. Brian Zuckerbraun, a pioneer of the technique, explained the procedure and its benefits in an interview at the annual Clinical Congress of the American College of Surgeons.

[email protected]

Over the last couple of years, I’ve written quite a lot about the trend toward consolidation. That trend shows no sign of abating; more and more soloists and small groups are selling or merging their practices with hospitals, multispecialty groups, or other large entities.

I have seen evidence, though, that many sellers are not receiving a fair price for the equity that they have worked so hard to build over several decades. If you are contemplating selling or merging, it is important that you not simply take the buyer’s word for how much your practice is worth. You need an impartial appraisal.

Of course, a medical practice is trickier to value than an ordinary business, and usually requires the services of an experienced professional appraiser. Entire books have been written about the process, so I can’t hope to cover it completely in 750 words; but three basic yardsticks are essential for a practice appraisal:

• Tangible assets. Equipment, cash, accounts receivable and other property owned by the practice.

• Liabilities. Accounts payable, outstanding loans, and anything else owed to others.

• Intangible assets. Sometimes called “good will” – the reputation of the physicians, the location and name recognition of the practice, the loyalty and volume of patients, and other, well, intangibles.

Armed with those numbers, an appraiser can then determine the equity, or book value, of the practice.

Valuing tangible assets is comparatively straightforward, but there are several ways to do it, and when reviewing a practice appraisal you should ask which of them was used. Depreciated value is the book value of equipment and supplies as determined by their purchase price, less the amount their value has decreased since purchase. Remaining useful life value estimates how long the equipment can be expected to last. Market (or replacement) value is the amount it would cost on the open market to replace all equipment and supplies.

Intangible assets are more difficult to value. Many components are analyzed, including location, interior and exterior decor, accessibility to patients, age and functional status of equipment, systems in place to promote efficiency, reasons why patients come back (if in fact they do), and the overall reputation of the practice in the community. Other important factors include the “payer mix” (what percentage pays cash, how many third-party contracts are in place and how well they pay, etc.), the extent and strength of the referral base, and the presence of clinical studies or other supplemental income streams.

It is also important to determine to what extent intangible assets are transferable. For example, unique skills with a laser, neurotoxins, or filler substances, or extraordinary personal charisma, may increase your practice’s value to you, but they are worthless to the next owner, and he or she will be unwilling to pay for them unless your services become part of the deal.

Once again, there are many ways to estimate intangible asset value, and once again you should ask which were used. Cash Flow Analysis works on the assumption that cash flow is a measure of intangible value. Capitalization of Earnings puts a value, or capitalization, on the practice’s income streams using a variety of assumptions. Guideline Comparison uses various databases to compare your practice with other, similar ones that have changed hands in the past.

Two newer techniques, which some consider a better estimate of intangible assets, are the replacement method, which estimates the costs of starting the practice over again in the current market; and the excess earnings method, which measures how far above average your practice’s earnings (and thus its overall value) are.

Asset-based valuation is the most popular, but by no means the only method available. Income-based valuation looks at the source and strength of a practice’s income stream as a creator of value, as well as whether or not its income stream under a different owner would mirror its present one. This in turn becomes the basis for an understanding of the fair market value of both tangible and intangible assets. Market valuation combines the asset-based and income-based approaches, along with an analysis of sales and mergers of comparable practices in the community, to determine the value of a practice in its local market.

Whatever methods are used, it is important that the appraisal be done by an experienced financial consultant, that all techniques used in the valuation be divulged and explained, and that documentation is supplied to support the conclusions reached. This is especially important if the appraisal will be relied upon in the sale or merger of the practice. I’ll cover some sale and merger options that you may not have thought of next month.

 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Over the last couple of years, I’ve written quite a lot about the trend toward consolidation. That trend shows no sign of abating; more and more soloists and small groups are selling or merging their practices with hospitals, multispecialty groups, or other large entities.

I have seen evidence, though, that many sellers are not receiving a fair price for the equity that they have worked so hard to build over several decades. If you are contemplating selling or merging, it is important that you not simply take the buyer’s word for how much your practice is worth. You need an impartial appraisal.

Of course, a medical practice is trickier to value than an ordinary business, and usually requires the services of an experienced professional appraiser. Entire books have been written about the process, so I can’t hope to cover it completely in 750 words; but three basic yardsticks are essential for a practice appraisal:

• Tangible assets. Equipment, cash, accounts receivable and other property owned by the practice.

• Liabilities. Accounts payable, outstanding loans, and anything else owed to others.

• Intangible assets. Sometimes called “good will” – the reputation of the physicians, the location and name recognition of the practice, the loyalty and volume of patients, and other, well, intangibles.

Armed with those numbers, an appraiser can then determine the equity, or book value, of the practice.

Valuing tangible assets is comparatively straightforward, but there are several ways to do it, and when reviewing a practice appraisal you should ask which of them was used. Depreciated value is the book value of equipment and supplies as determined by their purchase price, less the amount their value has decreased since purchase. Remaining useful life value estimates how long the equipment can be expected to last. Market (or replacement) value is the amount it would cost on the open market to replace all equipment and supplies.

Intangible assets are more difficult to value. Many components are analyzed, including location, interior and exterior decor, accessibility to patients, age and functional status of equipment, systems in place to promote efficiency, reasons why patients come back (if in fact they do), and the overall reputation of the practice in the community. Other important factors include the “payer mix” (what percentage pays cash, how many third-party contracts are in place and how well they pay, etc.), the extent and strength of the referral base, and the presence of clinical studies or other supplemental income streams.

It is also important to determine to what extent intangible assets are transferable. For example, unique skills with a laser, neurotoxins, or filler substances, or extraordinary personal charisma, may increase your practice’s value to you, but they are worthless to the next owner, and he or she will be unwilling to pay for them unless your services become part of the deal.

Once again, there are many ways to estimate intangible asset value, and once again you should ask which were used. Cash Flow Analysis works on the assumption that cash flow is a measure of intangible value. Capitalization of Earnings puts a value, or capitalization, on the practice’s income streams using a variety of assumptions. Guideline Comparison uses various databases to compare your practice with other, similar ones that have changed hands in the past.

Two newer techniques, which some consider a better estimate of intangible assets, are the replacement method, which estimates the costs of starting the practice over again in the current market; and the excess earnings method, which measures how far above average your practice’s earnings (and thus its overall value) are.

Asset-based valuation is the most popular, but by no means the only method available. Income-based valuation looks at the source and strength of a practice’s income stream as a creator of value, as well as whether or not its income stream under a different owner would mirror its present one. This in turn becomes the basis for an understanding of the fair market value of both tangible and intangible assets. Market valuation combines the asset-based and income-based approaches, along with an analysis of sales and mergers of comparable practices in the community, to determine the value of a practice in its local market.

Whatever methods are used, it is important that the appraisal be done by an experienced financial consultant, that all techniques used in the valuation be divulged and explained, and that documentation is supplied to support the conclusions reached. This is especially important if the appraisal will be relied upon in the sale or merger of the practice. I’ll cover some sale and merger options that you may not have thought of next month.

 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Over the last couple of years, I’ve written quite a lot about the trend toward consolidation. That trend shows no sign of abating; more and more soloists and small groups are selling or merging their practices with hospitals, multispecialty groups, or other large entities.

I have seen evidence, though, that many sellers are not receiving a fair price for the equity that they have worked so hard to build over several decades. If you are contemplating selling or merging, it is important that you not simply take the buyer’s word for how much your practice is worth. You need an impartial appraisal.

Of course, a medical practice is trickier to value than an ordinary business, and usually requires the services of an experienced professional appraiser. Entire books have been written about the process, so I can’t hope to cover it completely in 750 words; but three basic yardsticks are essential for a practice appraisal:

• Tangible assets. Equipment, cash, accounts receivable and other property owned by the practice.

• Liabilities. Accounts payable, outstanding loans, and anything else owed to others.

• Intangible assets. Sometimes called “good will” – the reputation of the physicians, the location and name recognition of the practice, the loyalty and volume of patients, and other, well, intangibles.

Armed with those numbers, an appraiser can then determine the equity, or book value, of the practice.

Valuing tangible assets is comparatively straightforward, but there are several ways to do it, and when reviewing a practice appraisal you should ask which of them was used. Depreciated value is the book value of equipment and supplies as determined by their purchase price, less the amount their value has decreased since purchase. Remaining useful life value estimates how long the equipment can be expected to last. Market (or replacement) value is the amount it would cost on the open market to replace all equipment and supplies.

Intangible assets are more difficult to value. Many components are analyzed, including location, interior and exterior decor, accessibility to patients, age and functional status of equipment, systems in place to promote efficiency, reasons why patients come back (if in fact they do), and the overall reputation of the practice in the community. Other important factors include the “payer mix” (what percentage pays cash, how many third-party contracts are in place and how well they pay, etc.), the extent and strength of the referral base, and the presence of clinical studies or other supplemental income streams.

It is also important to determine to what extent intangible assets are transferable. For example, unique skills with a laser, neurotoxins, or filler substances, or extraordinary personal charisma, may increase your practice’s value to you, but they are worthless to the next owner, and he or she will be unwilling to pay for them unless your services become part of the deal.

Once again, there are many ways to estimate intangible asset value, and once again you should ask which were used. Cash Flow Analysis works on the assumption that cash flow is a measure of intangible value. Capitalization of Earnings puts a value, or capitalization, on the practice’s income streams using a variety of assumptions. Guideline Comparison uses various databases to compare your practice with other, similar ones that have changed hands in the past.

Two newer techniques, which some consider a better estimate of intangible assets, are the replacement method, which estimates the costs of starting the practice over again in the current market; and the excess earnings method, which measures how far above average your practice’s earnings (and thus its overall value) are.

Asset-based valuation is the most popular, but by no means the only method available. Income-based valuation looks at the source and strength of a practice’s income stream as a creator of value, as well as whether or not its income stream under a different owner would mirror its present one. This in turn becomes the basis for an understanding of the fair market value of both tangible and intangible assets. Market valuation combines the asset-based and income-based approaches, along with an analysis of sales and mergers of comparable practices in the community, to determine the value of a practice in its local market.

Whatever methods are used, it is important that the appraisal be done by an experienced financial consultant, that all techniques used in the valuation be divulged and explained, and that documentation is supplied to support the conclusions reached. This is especially important if the appraisal will be relied upon in the sale or merger of the practice. I’ll cover some sale and merger options that you may not have thought of next month.

 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Among postmenopausal women, breast cancers diagnosed following biennial mammography intervals are no more “unfavorable” than those diagnosed following annual intervals, according to a report published online Oct. 20 in JAMA Oncology.

“When considering recommendations regarding screening intervals, the potential benefit of diagnosing cancers at an earlier stage must be weighed against the increased potential for harms associated with more frequent screening, such as false-positive recalls and biopsies, which are 1.5 to 2 times higher in annual vs. biennial screeners,” wrote Diana L. Miglioretti, Ph.D., of the University of California, Davis, and her associates in the Breast Cancer Surveillance Consortium (BCSC).

Dr. Cecil Fox/National Cancer Institute

The optimal frequency of mammographic screening remains controversial. The American Cancer Society commissioned the BCSC to analyze the most recent information on this issue as part of its effort to update the ACS guideline for breast cancer screening for women at average risk.

BCSC registries collect patient and clinical data from community radiology facilities across the country. For this analysis, Dr. Miglioretti and her colleagues focused on 15,440 women aged 40-85 years in these registries who were diagnosed as having breast cancer from 1996 to 2012. A total of 12,070 of the women underwent annual mammographic screening and 3,370 underwent biennial mammographic screening.

Among premenopausal women, those diagnosed after biennial mammograms were more likely to have tumors with unfavorable prognostic characteristics than were those diagnosed after annual mammograms (relative risk, 1.11). In contrast, among postmenopausal women, those diagnosed after biennial mammograms were not more likely to have tumors with unfavorable prognostic characteristics than were those diagnosed after annual mammograms (RR, 1.03), the investigators wrote (JAMA Oncol. 2015 Oct 20. doi: 10.1001/jamaoncology.2015.3084).

In an editorial accompanying this report, Dr. Wendy Y. Chen of Brigham and Women’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, all in Boston, wrote, “Although the authors do not endorse annual or biennial screening, they imply that biennial screening would be acceptable for postmenopausal women but inferior for premenopausal women.”

Most developed countries outside the United States – including the United Kingdom, Canada, and Australia – recommend screening every 2 or 3 years, Dr. Chen noted (JAMA Oncol. 2015 Oct 20 doi: 10.1001/jamaoncology.2015.3286).

This study and others clearly show that, with less frequent mammography, breast cancers will be larger and have a slightly more advanced stage when they are discovered, Dr. Chen wrote. But with a better understanding of tumor biology and improvements in targeted therapy, the best approach may not be simply trying to identify a smaller tumor, she added.

“Efforts should be focused on a better understanding of how screening interacts with tumor biology with a better understanding of the types of interval cancers and sojourn times and how these characteristics differ by age and/or menopausal status,” Dr. Chen wrote.

This study was supported by the American Cancer Society and the National Cancer Institute. Dr. Miglioretti reported having no relevant financial disclosures. One of the investigators reported being an unpaid advisor on General Electric Health Care’s breast medical advisory board.

Among postmenopausal women, breast cancers diagnosed following biennial mammography intervals are no more “unfavorable” than those diagnosed following annual intervals, according to a report published online Oct. 20 in JAMA Oncology.

“When considering recommendations regarding screening intervals, the potential benefit of diagnosing cancers at an earlier stage must be weighed against the increased potential for harms associated with more frequent screening, such as false-positive recalls and biopsies, which are 1.5 to 2 times higher in annual vs. biennial screeners,” wrote Diana L. Miglioretti, Ph.D., of the University of California, Davis, and her associates in the Breast Cancer Surveillance Consortium (BCSC).

Dr. Cecil Fox/National Cancer Institute

The optimal frequency of mammographic screening remains controversial. The American Cancer Society commissioned the BCSC to analyze the most recent information on this issue as part of its effort to update the ACS guideline for breast cancer screening for women at average risk.

BCSC registries collect patient and clinical data from community radiology facilities across the country. For this analysis, Dr. Miglioretti and her colleagues focused on 15,440 women aged 40-85 years in these registries who were diagnosed as having breast cancer from 1996 to 2012. A total of 12,070 of the women underwent annual mammographic screening and 3,370 underwent biennial mammographic screening.

Among premenopausal women, those diagnosed after biennial mammograms were more likely to have tumors with unfavorable prognostic characteristics than were those diagnosed after annual mammograms (relative risk, 1.11). In contrast, among postmenopausal women, those diagnosed after biennial mammograms were not more likely to have tumors with unfavorable prognostic characteristics than were those diagnosed after annual mammograms (RR, 1.03), the investigators wrote (JAMA Oncol. 2015 Oct 20. doi: 10.1001/jamaoncology.2015.3084).

In an editorial accompanying this report, Dr. Wendy Y. Chen of Brigham and Women’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, all in Boston, wrote, “Although the authors do not endorse annual or biennial screening, they imply that biennial screening would be acceptable for postmenopausal women but inferior for premenopausal women.”

Most developed countries outside the United States – including the United Kingdom, Canada, and Australia – recommend screening every 2 or 3 years, Dr. Chen noted (JAMA Oncol. 2015 Oct 20 doi: 10.1001/jamaoncology.2015.3286).

This study and others clearly show that, with less frequent mammography, breast cancers will be larger and have a slightly more advanced stage when they are discovered, Dr. Chen wrote. But with a better understanding of tumor biology and improvements in targeted therapy, the best approach may not be simply trying to identify a smaller tumor, she added.

“Efforts should be focused on a better understanding of how screening interacts with tumor biology with a better understanding of the types of interval cancers and sojourn times and how these characteristics differ by age and/or menopausal status,” Dr. Chen wrote.

This study was supported by the American Cancer Society and the National Cancer Institute. Dr. Miglioretti reported having no relevant financial disclosures. One of the investigators reported being an unpaid advisor on General Electric Health Care’s breast medical advisory board.

Among postmenopausal women, breast cancers diagnosed following biennial mammography intervals are no more “unfavorable” than those diagnosed following annual intervals, according to a report published online Oct. 20 in JAMA Oncology.

“When considering recommendations regarding screening intervals, the potential benefit of diagnosing cancers at an earlier stage must be weighed against the increased potential for harms associated with more frequent screening, such as false-positive recalls and biopsies, which are 1.5 to 2 times higher in annual vs. biennial screeners,” wrote Diana L. Miglioretti, Ph.D., of the University of California, Davis, and her associates in the Breast Cancer Surveillance Consortium (BCSC).

Dr. Cecil Fox/National Cancer Institute

The optimal frequency of mammographic screening remains controversial. The American Cancer Society commissioned the BCSC to analyze the most recent information on this issue as part of its effort to update the ACS guideline for breast cancer screening for women at average risk.

BCSC registries collect patient and clinical data from community radiology facilities across the country. For this analysis, Dr. Miglioretti and her colleagues focused on 15,440 women aged 40-85 years in these registries who were diagnosed as having breast cancer from 1996 to 2012. A total of 12,070 of the women underwent annual mammographic screening and 3,370 underwent biennial mammographic screening.

Among premenopausal women, those diagnosed after biennial mammograms were more likely to have tumors with unfavorable prognostic characteristics than were those diagnosed after annual mammograms (relative risk, 1.11). In contrast, among postmenopausal women, those diagnosed after biennial mammograms were not more likely to have tumors with unfavorable prognostic characteristics than were those diagnosed after annual mammograms (RR, 1.03), the investigators wrote (JAMA Oncol. 2015 Oct 20. doi: 10.1001/jamaoncology.2015.3084).

In an editorial accompanying this report, Dr. Wendy Y. Chen of Brigham and Women’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, all in Boston, wrote, “Although the authors do not endorse annual or biennial screening, they imply that biennial screening would be acceptable for postmenopausal women but inferior for premenopausal women.”

Most developed countries outside the United States – including the United Kingdom, Canada, and Australia – recommend screening every 2 or 3 years, Dr. Chen noted (JAMA Oncol. 2015 Oct 20 doi: 10.1001/jamaoncology.2015.3286).

This study and others clearly show that, with less frequent mammography, breast cancers will be larger and have a slightly more advanced stage when they are discovered, Dr. Chen wrote. But with a better understanding of tumor biology and improvements in targeted therapy, the best approach may not be simply trying to identify a smaller tumor, she added.

“Efforts should be focused on a better understanding of how screening interacts with tumor biology with a better understanding of the types of interval cancers and sojourn times and how these characteristics differ by age and/or menopausal status,” Dr. Chen wrote.

This study was supported by the American Cancer Society and the National Cancer Institute. Dr. Miglioretti reported having no relevant financial disclosures. One of the investigators reported being an unpaid advisor on General Electric Health Care’s breast medical advisory board.

In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury (TBI), therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone, according to a study of 387 patients with TBI. Researchers found:

• Stage 3 treatments were needed to control intracranial pressure in 54% of controls and 44% of the hypothermia group.

• Adjusted common odds ratio for the Extended Glasgow Outcome Scale (GOS-E) was 1.53, indicating a worse outcome in the hypothermia group vs controls.

• A favorable outcome occurred in 26% of the hypothermia group vs 37% in controls. 

Citation: Andrews PJ, Sinclair HL, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. [Published online ahead of print October 7, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1507581.

In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury (TBI), therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone, according to a study of 387 patients with TBI. Researchers found:

• Stage 3 treatments were needed to control intracranial pressure in 54% of controls and 44% of the hypothermia group.

• Adjusted common odds ratio for the Extended Glasgow Outcome Scale (GOS-E) was 1.53, indicating a worse outcome in the hypothermia group vs controls.

• A favorable outcome occurred in 26% of the hypothermia group vs 37% in controls. 

Citation: Andrews PJ, Sinclair HL, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. [Published online ahead of print October 7, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1507581.

In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury (TBI), therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone, according to a study of 387 patients with TBI. Researchers found:

• Stage 3 treatments were needed to control intracranial pressure in 54% of controls and 44% of the hypothermia group.

• Adjusted common odds ratio for the Extended Glasgow Outcome Scale (GOS-E) was 1.53, indicating a worse outcome in the hypothermia group vs controls.

• A favorable outcome occurred in 26% of the hypothermia group vs 37% in controls. 

Citation: Andrews PJ, Sinclair HL, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. [Published online ahead of print October 7, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1507581.

Preclinical research suggests that compounds derived from Himalayan rhubarb could potentially treat leukemias and other cancers.

These compounds, physcion and S3, effectively inhibited 6PGD, a metabolic enzyme that is upregulated in several types of cancer cells.

In addition, physcion and S3 reduced cancer cell viability in vitro and decreased tumor size in vivo—without harming normal cells or exhibiting obvious toxicity.

Jing Chen, PhD, of Emory University School of Medicine in Atlanta, Georgia, and his colleagues described this research in Nature Cell Biology.

The team set out to find 6PGD inhibitors because 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. And previous research had revealed increased 6PGD activity in several types of cancer cells.

“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” Dr Chen said. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.”

Specifically, the investigators found that knocking down 6PGD decreased proliferation in a handful of human cancer cell lines—leukemia (K562), lung cancer (H1299, H157, and H322), and head and neck cancer (212LN).

But 6PGD knockdown did not affect normal proliferating keratinocyte HaCaT cells.

When the team screened for 6PGD inhibitors, they identified physcion—an anthraquinone originally isolated from Himalayan rhubarb—and its derivative, S3.

Experiments showed that physcion decreases cell viability in a range of cancer cell lines—K562, H1299, A549 (lung), and 212LN—in a dose-dependent manner. But the compound did not significantly affect proliferating control cells—human dermal fibroblasts (HDFs) and immortalized human melanocyte PIG1 cells.

Similarly, S3 inhibited the viability of K562 and H1299 cells but not proliferating PIG1 and HDF cells.

S3 also decreased tumor growth in mouse models of leukemia, lung cancer, and head and neck cancer. However, the treatment did not affect body weight, serum chemistry, complete blood counts, or hematopoietic properties in the mice.

Finally, the investigators found that physcion and S3 inhibit 6PGD in human primary leukemia cells (B-cell acute lymphoblastic leukemia), thereby leading to decreased cell viability.

And neither compound affected the viability of mononucleocytes in peripheral blood samples or CD34+ progenitors isolated from the bone marrow samples of healthy donors.

Preclinical research suggests that compounds derived from Himalayan rhubarb could potentially treat leukemias and other cancers.

These compounds, physcion and S3, effectively inhibited 6PGD, a metabolic enzyme that is upregulated in several types of cancer cells.

In addition, physcion and S3 reduced cancer cell viability in vitro and decreased tumor size in vivo—without harming normal cells or exhibiting obvious toxicity.

Jing Chen, PhD, of Emory University School of Medicine in Atlanta, Georgia, and his colleagues described this research in Nature Cell Biology.

The team set out to find 6PGD inhibitors because 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. And previous research had revealed increased 6PGD activity in several types of cancer cells.

“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” Dr Chen said. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.”

Specifically, the investigators found that knocking down 6PGD decreased proliferation in a handful of human cancer cell lines—leukemia (K562), lung cancer (H1299, H157, and H322), and head and neck cancer (212LN).

But 6PGD knockdown did not affect normal proliferating keratinocyte HaCaT cells.

When the team screened for 6PGD inhibitors, they identified physcion—an anthraquinone originally isolated from Himalayan rhubarb—and its derivative, S3.

Experiments showed that physcion decreases cell viability in a range of cancer cell lines—K562, H1299, A549 (lung), and 212LN—in a dose-dependent manner. But the compound did not significantly affect proliferating control cells—human dermal fibroblasts (HDFs) and immortalized human melanocyte PIG1 cells.

Similarly, S3 inhibited the viability of K562 and H1299 cells but not proliferating PIG1 and HDF cells.

S3 also decreased tumor growth in mouse models of leukemia, lung cancer, and head and neck cancer. However, the treatment did not affect body weight, serum chemistry, complete blood counts, or hematopoietic properties in the mice.

Finally, the investigators found that physcion and S3 inhibit 6PGD in human primary leukemia cells (B-cell acute lymphoblastic leukemia), thereby leading to decreased cell viability.

And neither compound affected the viability of mononucleocytes in peripheral blood samples or CD34+ progenitors isolated from the bone marrow samples of healthy donors.

Preclinical research suggests that compounds derived from Himalayan rhubarb could potentially treat leukemias and other cancers.

These compounds, physcion and S3, effectively inhibited 6PGD, a metabolic enzyme that is upregulated in several types of cancer cells.

In addition, physcion and S3 reduced cancer cell viability in vitro and decreased tumor size in vivo—without harming normal cells or exhibiting obvious toxicity.

Jing Chen, PhD, of Emory University School of Medicine in Atlanta, Georgia, and his colleagues described this research in Nature Cell Biology.

The team set out to find 6PGD inhibitors because 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. And previous research had revealed increased 6PGD activity in several types of cancer cells.

“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” Dr Chen said. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.”

Specifically, the investigators found that knocking down 6PGD decreased proliferation in a handful of human cancer cell lines—leukemia (K562), lung cancer (H1299, H157, and H322), and head and neck cancer (212LN).

But 6PGD knockdown did not affect normal proliferating keratinocyte HaCaT cells.

When the team screened for 6PGD inhibitors, they identified physcion—an anthraquinone originally isolated from Himalayan rhubarb—and its derivative, S3.

Experiments showed that physcion decreases cell viability in a range of cancer cell lines—K562, H1299, A549 (lung), and 212LN—in a dose-dependent manner. But the compound did not significantly affect proliferating control cells—human dermal fibroblasts (HDFs) and immortalized human melanocyte PIG1 cells.

Similarly, S3 inhibited the viability of K562 and H1299 cells but not proliferating PIG1 and HDF cells.

S3 also decreased tumor growth in mouse models of leukemia, lung cancer, and head and neck cancer. However, the treatment did not affect body weight, serum chemistry, complete blood counts, or hematopoietic properties in the mice.

Finally, the investigators found that physcion and S3 inhibit 6PGD in human primary leukemia cells (B-cell acute lymphoblastic leukemia), thereby leading to decreased cell viability.

And neither compound affected the viability of mononucleocytes in peripheral blood samples or CD34+ progenitors isolated from the bone marrow samples of healthy donors.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.

When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.

Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.

This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.

Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.

The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.

However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).

In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.

The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).

Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.

Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).

There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.

Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).

*Information in the abstract differs from the presentation.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.

When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.

Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.

This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.

Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.

The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.

However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).

In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.

The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).

Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.

Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).

There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.

Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).

*Information in the abstract differs from the presentation.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.

When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.

Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.

This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.

Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.

The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.

However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).

In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.

The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).

Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.

Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).

There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.

Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).

*Information in the abstract differs from the presentation.

Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.

The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.

The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.

Researchers reported these discoveries in Nature Genetics.

“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”

“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”

So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.

Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.

These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.

Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.

For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.

The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.

Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.

“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.

“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”

Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.

The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.

The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.

Researchers reported these discoveries in Nature Genetics.

“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”

“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”

So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.

Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.

These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.

Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.

For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.

The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.

Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.

“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.

“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”

Whole-exome sequencing has provided new insights that may lead to better treatment of juvenile myelomonocytic leukemia (JMML), according to researchers.

The group identified new mutations that appear to drive JMML and could be targeted with drugs that are currently available, such as JAK inhibitors.

The study also suggests it is the number of mutations a patient has—and not the type of mutations—that will influence the patient’s outcome.

Researchers reported these discoveries in Nature Genetics.

“We’ve created the most comprehensive portrait yet of how this cancer evolves from first diagnosis through remission or relapse,” said study author Mignon Loh, MD, of Benioff Children’s Hospital at University of California, San Francisco (USCF). “What we found helps make sense of why patients’ outcomes have been so wildly different.”

“We have personally treated patients with JMML at UCSF with identical driver mutations, some of whom survived, while others died,” added Elliot Stieglitz, MD. “Our frustration was the main impetus that led us to carry out this study.”

So the researchers performed whole-exome sequencing on samples collected at diagnosis and relapse in 27 JMML patients who were 1 month to 3 years of age. The team then performed targeted sequencing of suspected mutation hot spots in another 71 patients.

Previously, just 5 defects in the Ras pathway had been associated with JMML. The new analysis added 10 mutations of known oncogenes and tumor suppressors to the list, including 2 additional Ras pathway genes.

These newly identified mutations occur in genes coding for proteins that function as signaling molecules, transcription factors, epigenetic regulators, and elements of the spliceosome complex.

Several of these mutations raise the possibility of targeting subpopulations of JMML cases with existing drugs.

For instance, JAK inhibitors might inhibit signaling through a hyperactive JAK-STAT pathway identified in some patients. And 5-azacytidine could be used to reduce excessive epigenetic DNA methylation seen in others.

The researchers also performed a 10-year survival study with the same participants and found that patients’ prognosis depended more on the number of mutations they had than on the specific mutations involved.

Patients with more than 1 mutation at the time of diagnosis had a significantly worse long-term prognosis. Of the 34 patients who had at least 2 mutations, only 29% survived for 10 years, compared to a 65% survival rate for patients who had 1 or fewer detectable mutations.

“We have now shown that while driver mutations in the Ras pathway likely cause the leukemia to develop in the first place, it is the presence of these additional mutations that contribute to poor outcome,” Dr Loh said, noting that therapies will likely require targeting multiple pathways at once.

“Precisely how these secondary mutations will interact with the Ras pathway is the focus of our ongoing work.”

Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).

DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.

The team found that RPL11-deficient mice

developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.

Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.

Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.

In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.

“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”

“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”

In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.

“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.

The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.

Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid

progenitors and defective erythroid maturation.

Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia

and intestinal atrophy in adult mice. And these mice died within a few weeks.

Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).

DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.

The team found that RPL11-deficient mice

developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.

Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.

Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.

In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.

“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”

“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”

In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.

“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.

The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.

Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid

progenitors and defective erythroid maturation.

Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia

and intestinal atrophy in adult mice. And these mice died within a few weeks.

Researchers say they’ve created the first animal model that recapitulates the predisposition to cancer observed in patients with Diamond-Blackfan anemia (DBA).

DBA is caused by mutations in ribosomal genes such as RPL11, so the researchers set out to determine the effects of manipulating RPL11 in mice.

The team found that RPL11-deficient mice

developed anemia, but they also had impaired p53 responses, elevated cMYC levels, and increased susceptibility to radiation-induced lymphomagenesis.

Manuel Serrano, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues described these findings in Cell Reports.

Previous observational studies suggested that around 20% of patients with DBA develop cancers, particularly lymphomas. Other research groups have developed animal models that recapitulate certain characteristics of DBA but not the predisposition to cancer.

In an attempt to change that, Dr Serrano and his colleagues focused their work on RPL11.

“Cells need the ribosomes to function properly in order to proliferate and grow,” Dr Serrano explained. “We knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumors. This mechanism is called ribosomal stress.”

“P53 is one of the main tumor suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the ‘guardian of the genome.’ This important function made us think that the protein could play a crucial role in the cancer predisposition observed in patients with DBA. If RPL11 is mutated, it loses the ability to activate p53 to prevent tumors caused by cellular damage.”

In fact, the researchers found that total or partial deletion of RPL11 impairs the normal function of p53 and increases levels of cMYC, which can promote tumor development.

“We believe that, in DBA, both factors combined contribute to induce the development of cancer,” said Lucía Morgado-Palacín, also of CNIO.

The researchers’ experiments supported this idea, as mice with heterozygous RPL11 deletion exhibited increased susceptibility to radiation-induced lymphomagenesis.

Mice with heterozygous RPL11 deletion also developed anemia that was associated with decreased erythroid

progenitors and defective erythroid maturation.

Homozygous deletion of RPL11, on the other hand, led to bone marrow aplasia

and intestinal atrophy in adult mice. And these mice died within a few weeks.

A couple made a baby boy. Into him they poured their hopes and dreams. But life is strange with its twists and turns, and things rarely go as planned.

The baby had a rough start. His brain was severely injured. The parents were told the chances of meaningful recovery were close to nothing. With heavy hearts but their son’s best interest in mind, they made the hardest decision of their lives – to provide for his comfort and nothing more. His life supports withdrawn, he was handed to them.

He did not die. Instead, he breathed. With that singular, definitive act, he proved his presence to them. They took him home, unsure what would come next. They did what anyone faced with such terrifying circumstances would have done – they fell in love with their baby. Their goals changed, but their love did not. Tinted by love, his staring spells became looks of cognizance, his reflexes became volitional motions. Think what you may, but do not judge them.

Unexpectedly, he has reached the age of 15 months. Through it all, the mother and father have been the perfect parents of a complex patient. But now he refuses to play the role of stable complex child. Instead, he is steadily worsening. It is easy for me to see this as I take ICU calls every fourth night. Not so for them. I don’t know what it feels like to build a dream and watch it crumble like sand, then to have to learn to carry on with what is left. I cannot imagine living a moment of their lives. Yet there they sit, next to him, waiting for rounds with smiling faces.

We are stuck. We wonder what’s in his best interest – to intervene with an invasive procedure that may allow him to go home or to withdraw interventions and provide him with comfort.

In my eyes, the real question is – where does he live? His parents believe that he is in the body lying on the bed. I can see why they feel this way – if he isn’t there, then what has any of this meant? Has he never been there? Did he leave sometime between defying death and creeping back toward it? These are frightening thoughts to face, indeed. And so, thoroughly entrenched, they must press on lest it be felt that they gave up on him.

I don’t know where he lives. Somewhere else? Heaven perhaps. In his parent’s memories for certain, and in my thoughts as well. In this limp body on the bed? I’m not so sure. But as he stares into his mother’s eyes, and jerks in response to her voice, I begin to doubt myself. How can I help them make this decision?

Perhaps this is the final lesson that residency will teach me.

No. I suspect I still won’t have an answer for the next parents I meet, once his story has played out. Only more questions. …

Dr. Behere was a pediatric resident at the Children’s Hospital at Dartmouth-Hitchcock, Lebanon, N.H., when he wrote this article. He is a first-year fellow in pediatric cardiology at the Nemours Cardiac Center at the Nemours/Alfred I. duPont Hospital for Children, Wilmington, Del. E-mail him at [email protected].

A couple made a baby boy. Into him they poured their hopes and dreams. But life is strange with its twists and turns, and things rarely go as planned.

The baby had a rough start. His brain was severely injured. The parents were told the chances of meaningful recovery were close to nothing. With heavy hearts but their son’s best interest in mind, they made the hardest decision of their lives – to provide for his comfort and nothing more. His life supports withdrawn, he was handed to them.

He did not die. Instead, he breathed. With that singular, definitive act, he proved his presence to them. They took him home, unsure what would come next. They did what anyone faced with such terrifying circumstances would have done – they fell in love with their baby. Their goals changed, but their love did not. Tinted by love, his staring spells became looks of cognizance, his reflexes became volitional motions. Think what you may, but do not judge them.

Unexpectedly, he has reached the age of 15 months. Through it all, the mother and father have been the perfect parents of a complex patient. But now he refuses to play the role of stable complex child. Instead, he is steadily worsening. It is easy for me to see this as I take ICU calls every fourth night. Not so for them. I don’t know what it feels like to build a dream and watch it crumble like sand, then to have to learn to carry on with what is left. I cannot imagine living a moment of their lives. Yet there they sit, next to him, waiting for rounds with smiling faces.

We are stuck. We wonder what’s in his best interest – to intervene with an invasive procedure that may allow him to go home or to withdraw interventions and provide him with comfort.

In my eyes, the real question is – where does he live? His parents believe that he is in the body lying on the bed. I can see why they feel this way – if he isn’t there, then what has any of this meant? Has he never been there? Did he leave sometime between defying death and creeping back toward it? These are frightening thoughts to face, indeed. And so, thoroughly entrenched, they must press on lest it be felt that they gave up on him.

I don’t know where he lives. Somewhere else? Heaven perhaps. In his parent’s memories for certain, and in my thoughts as well. In this limp body on the bed? I’m not so sure. But as he stares into his mother’s eyes, and jerks in response to her voice, I begin to doubt myself. How can I help them make this decision?

Perhaps this is the final lesson that residency will teach me.

No. I suspect I still won’t have an answer for the next parents I meet, once his story has played out. Only more questions. …

Dr. Behere was a pediatric resident at the Children’s Hospital at Dartmouth-Hitchcock, Lebanon, N.H., when he wrote this article. He is a first-year fellow in pediatric cardiology at the Nemours Cardiac Center at the Nemours/Alfred I. duPont Hospital for Children, Wilmington, Del. E-mail him at [email protected].

A couple made a baby boy. Into him they poured their hopes and dreams. But life is strange with its twists and turns, and things rarely go as planned.

The baby had a rough start. His brain was severely injured. The parents were told the chances of meaningful recovery were close to nothing. With heavy hearts but their son’s best interest in mind, they made the hardest decision of their lives – to provide for his comfort and nothing more. His life supports withdrawn, he was handed to them.

He did not die. Instead, he breathed. With that singular, definitive act, he proved his presence to them. They took him home, unsure what would come next. They did what anyone faced with such terrifying circumstances would have done – they fell in love with their baby. Their goals changed, but their love did not. Tinted by love, his staring spells became looks of cognizance, his reflexes became volitional motions. Think what you may, but do not judge them.

Unexpectedly, he has reached the age of 15 months. Through it all, the mother and father have been the perfect parents of a complex patient. But now he refuses to play the role of stable complex child. Instead, he is steadily worsening. It is easy for me to see this as I take ICU calls every fourth night. Not so for them. I don’t know what it feels like to build a dream and watch it crumble like sand, then to have to learn to carry on with what is left. I cannot imagine living a moment of their lives. Yet there they sit, next to him, waiting for rounds with smiling faces.

We are stuck. We wonder what’s in his best interest – to intervene with an invasive procedure that may allow him to go home or to withdraw interventions and provide him with comfort.

In my eyes, the real question is – where does he live? His parents believe that he is in the body lying on the bed. I can see why they feel this way – if he isn’t there, then what has any of this meant? Has he never been there? Did he leave sometime between defying death and creeping back toward it? These are frightening thoughts to face, indeed. And so, thoroughly entrenched, they must press on lest it be felt that they gave up on him.

I don’t know where he lives. Somewhere else? Heaven perhaps. In his parent’s memories for certain, and in my thoughts as well. In this limp body on the bed? I’m not so sure. But as he stares into his mother’s eyes, and jerks in response to her voice, I begin to doubt myself. How can I help them make this decision?

Perhaps this is the final lesson that residency will teach me.

No. I suspect I still won’t have an answer for the next parents I meet, once his story has played out. Only more questions. …

Dr. Behere was a pediatric resident at the Children’s Hospital at Dartmouth-Hitchcock, Lebanon, N.H., when he wrote this article. He is a first-year fellow in pediatric cardiology at the Nemours Cardiac Center at the Nemours/Alfred I. duPont Hospital for Children, Wilmington, Del. E-mail him at [email protected].