The statistics reveal a serious problem: This year, an estimated 63,030 Americans will be given a diagnosis of head and neck cancer (which includes laryngeal, oropharyngeal, sinonasal, nasopharyngeal, and salivary gland cancer¹); approximately 13,360 of them will die. Furthermore, thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an estimated 56,870 cases in 2017.^1,2 Major risk factors for head and neck cancer are tobacco and alcohol exposure and infection with Epstein-Barr virus and human papillomavirus (HPV).³

In this article, we review the background for each of the principal types of head and neck cancer with which you should be familiar. We also discuss how to evaluate signs and symptoms that raise suspicion of these neoplasms; outline the diagnostic strategy in the face of such suspicion; and summarize accepted therapeutic approaches. Last, we describe the important role that you, the family physician, play in providing posttreatment care for these patients, especially prevention and management of late adverse effects of radiation therapy.

General characterizationsof these cancers

Approximately one-half of patients with head and neck cancer present initially with a nonspecific, persistent neck mass that should be deemed malignant until proven otherwise, because a delay in diagnosis is associated with a worse outcome.⁴ In a series of 100 patients with head and neck cancer, for example, delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.⁵ Guidelines for management of neck masses recommend against the use of antibiotics in patients who do not have evidence of infection.⁶

Patients with a neck mass that has been present for longer than 2 weeks or that is ulcerated, fixed to underlying tissues, of firm consistency, or > 1.5 cm should have a physical examination that includes visualization of the base of tongue, pharynx, and larynx. The mass should be evaluated with fine-­needle aspiration (FNA) biopsy, which has a positive predictive value of 96% and negative predictive value of 90% for the diagnosis of a head and neck mass. (Note: Anticoagulation therapy is not an absolute contraindication to FNA, which is not associated with an increased risk of bleeding.⁶)

Laryngeal cancer

What you need to know. More than 90% of laryngeal cancers are squamous cell carcinoma (SCC). Smoking or heavy drinking (> 8 drinks/d), compared to neither behavior, is associated with an increased risk of laryngeal cancer (odds ratio, 9.4 and 2.5, respectively).⁷ The risk of cancer is directly proportional to the degree of tobacco exposure.

One-half of head and neck cancers present with a neck mass that warrants appropriate initial assessment, so as not to delay diagnosis.

Laryngeal cancer occurs in the supraglottic region in one-third of patients; in the glottic region in one-half; and in the subglottic region in a very few.⁸ Glottic cancer presents earlier than supraglottic cancer with hoarseness, whereas supraglottic cancer presents with more advanced disease, causing stridor, dysphagia, and throat pain. (Note: Guidelines recommend against prescribing acid suppressants in patients with hoarseness who do not have symptoms of reflux.⁹)

Stage 1 and Stage 2 laryngeal cancers are localized; Stages 3-4B are locally advanced or involve lymph nodes, or both; Stage 4C is metastatic disease. Overall, 60% of patients have Stage 3 or Stage 4 disease at diagnosis.¹⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Laryngoscopy should be performed before computed tomography (CT) or magnetic resonance imaging is considered in a patient with hoarseness that does not resolve after 3 months—or sooner, if there is suspicion of malignancy.

How is it treated? Most patients presenting with Stage 1 or Stage 2 cancer can be treated with local radiation or, less commonly, larynx-preserving surgery. Patients with Stage 3 or Stage 4 disease can be treated with a combination of radiation and chemotherapy, which, compared to radiation alone, confers a decreased risk of local recurrence and increased laryngectomy-free survival.¹¹ Patients whose vocal cords are destroyed or who have recurrence following radiation and chemotherapy might need total laryngectomy and formation of a tracheostomy and prosthetic for voice creation.

Five-year overall survival for Stage 1 and Stage 2 supraglottic and glottic cancers is 80%—lower, however, for later-presenting subglottic cancers.¹²

Oropharyngeal cancer

What you need to know. The lifetime risk for cancer of the oropharynx is approximately 1%.¹³ SCC is responsible for approximately 90% of these cancers. Early detection is important: The 5-year survival rate is more than twice as high for localized disease (83%) than it is for metastatic disease (39%) at detection.¹³

At any given time, 7% of the US population has HPV infection of the oropharynx. Most of these cases clear spontaneously, but persistent high-risk HPV infection led to a 225% increase in HPV-positive oropharyngeal SCC from 1988 to 2004.¹⁴ The representative case of HPV-positive oropharyngeal SCC is a middle-aged (40- to 59-year-old) white male with a history of multiple sexual partners and with little or no tobacco exposure and low alcohol consumption.

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Oral cancers present with a lesion, often ulcerative, that should be examined by palpation with a gloved finger to describe the presence, color, and number of lesions; any tenderness; tissue consistency (soft, firm, hard); and fixation to underlying structures.¹⁵ The oropharynx should be examined without protrusion of the tongue, which obscures the oropharynx and can make it harder to depress the posterior part of the tongue.

A finding of leukoplakia (white plaques) and erythroplakia (red plaques) of the oropharynx might reflect benign hyperkeratosis or premalignant lesions; the plaques do not wipe off on examination. Referral to a dentist or otorhinolaryngologist for biopsy is indicated for all erythroplakia and leukoplakia, and for ulcers that persist longer than 2 weeks.¹⁶

(Note: Evidence is insufficient to support screening asymptomatic patients for oral and oropharyngeal cancers by physical examination. There is no US Food and Drug Administration-approved screening test for oral HPV infection.¹⁷)

How is it treated? A diagnosis of moderate dysplasia or carcinoma in situ should be treated with surgical excision to clear margins followed by routine monitoring every 3 to 6 months, for life.¹⁸ Topical medication, electrocautery, laser ablation, and cryosurgery are management options for less severe dysplasia.

Sinonasal cancer

What you need to know. Worldwide, sinonasal cancer accounts for approximately 0.7% of all new cancers but demonstrates strong genetic and regional associations, particularly among the Cantonese population of southern China.¹⁹ One-half of new sinonasal malignancies are SCC; the rest are adenocarcinoma, lymphoepithelial carcinoma, and rare subtypes.²⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Presentation tends to mimic common, nonmalignant conditions, such as sinusitis, until invasion into adjacent structures. When sinonasal passages are involved, the history might include epistaxis or nasal discharge; facial or dental pain; unilateral nasal obstruction with unexplained onset later in life; and failure to respond to treatment of presumed rhinosinusitis. Physical examination should include assessment of cranial nerves, palpation of the sinuses, and anterior rhinoscopy.

Thin-cut CT of the paranasal sinuses is the first-line imaging study. Sinonasal endoscopy, with targeted biopsy of suspicious lesions, is the evaluation of choice when malignancy is suspected.

How is it treated? Surgery is the treatment of choice, with postoperative radiation for patients at higher risk of recurrence because of more extensive disase.¹² Five-year survival for advanced disease is poor (35%); only 15% of cases are diagnosed at a localized stage because presenting symptoms are nonspecific.²¹

Nasopharyngeal cancer

What you need to know. Nasopharyngeal cancer is rare in the United States and Europe, compared with China, where it is endemic (and where a variety of risk factors, including intake of salt-preserved fish, have been proposed²²). Epstein-Barr virus infection and a history of smoking increase the risk.

Patients with nasopharyngeal cancer can present with epistaxis, nasal obstruction, and auditory symptoms, such as serous otitis media. Direct extension of the tumor can lead to cranial-nerve palsy, most commonly III, V, VI, and XII.²³

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Three-quarters of patients present with a neck mass from lymph-node metastases. Patients with the risk factors for nasopharyngeal cancer noted above who present with concerning symptoms should have nasoendoscopy with biopsy.

How is it treated? Radiation is the primary treatment, which is combined with chemotherapy for more advanced disease.²³ Screening high-risk populations for antibodies to Epstein-Barr virus and performing nasopharyngeal endoscopy on patients who screen positive increases the detection rate of nasopharyngeal cancer; however, this strategy has not been shown to improve survival.⁹

Salivary gland tumors

What you need to know. Salivary gland neoplasms are a rare and heterogeneous entity, comprising 6% to 8% of head and neck cancers.²⁴ More than 70% of these tumors are located in the parotid gland; 8%, in the submandibular glands; 1%, in the sublingual glands; and the rest, in the minor salivary glands. Most salivary gland tumors are benign; the most prevalent malignant tumors are mucoepidermoid carcinoma (30%) and adenoid cystic carcinoma (10%).²⁵ Additional identified risk factors for a salivary gland tumor include irradiation, prior head and neck cancer, and environmental exposures, including hairdressing, rubber manufacturing, and exposure to nickel compounds.²⁶

What is the diagnostic strategy? The history and physical exam are essential to distinguish a salivary gland tumor from an infectious cause and sialolithiasis. Parotid tumors most commonly present as asymptomatic parotid swelling, although pain can be present in as many as 40% of malignant parotid tumors.²⁵ Facial nerve weakness is found in 25% of parotid tumors; although the differential diagnosis of facial nerve palsy is broad, suspicion of malignancy should be raised in the presence of a parotid mass, progressive unilateral symptoms, hemifacial spasm progressing to weakness, and a history of skin cancer on the face or scalp. Additional characteristics that favor a neoplastic cause are trismus and nontender lymphadenopathy.²⁵

In a series of 100 patients with head and neck cancer, a delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.

In contrast, sialolithiasis is associated with intermittent pain caused by eating and is more common in the settings of dehydration and poor dental hygiene. Sialadenitis should be suspected when the presentation is fever, increased pain and swelling, erythema, and expression of pus from the salivary gland.

Continue to: If malignancy is suspected...

If malignancy is suspected, the initial diagnostic evaluation should include ultrasonography (US); concurrent FNA biopsy should be performed if a mass is detected.²⁷ US-guided FNA has a sensitivity of 73% to 86% for salivary neoplasm.⁷ CT and ­magnetic resonance imaging are useful for further characterization of tumors and can be advantageous for surgical planning.

How is it treated? Treatment of a salivary gland tumor involves surgical resection, followed by radiotherapy for patients in whom disease is more extensive or who exhibit high-risk pathology. Primary radiotherapy can be used in patients with an unresectable tumor. Typically, chemotherapy is used only for palliative purposes in relapsing disease, when a tumor is not amenable to radiotherapy, and in metastatic disease.²⁵

Prognosis varies by histotype but is generally favorable. The survival rates for a malignant salivary gland tumor are 83% at 1 year, 69% at 3 years, and 65% at 5 years.²⁸ Distant metastases are the most common cause of death, occurring primarily in the lungs (80%), bone (15%), and liver.²⁷ Factors that indicate poor prognosis include facial nerve involvement, trismus, a tumor > 4 cm, bone involvement, nodal spread, and recurrence.²⁵

Thyroid cancer

What you need to know. Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an annual incidence of 4.5%.¹ In the United States, most thyroid cancers are differentiated thyroid cancer (DTC), which includes papillary and follicular cancers. Less-differentiated medullary thyroid cancer (MTC), typically associated with multiple endocrine neoplasia (MEN) 2A or 2B, and undifferentiated or anaplastic thyroid cancer are less common. The increasing incidence of thyroid cancer is primarily the result of an increase in nonclinically relevant DTC.

What is the diagnostic strategy? Thyroid cancer usually presents as a thyroid nodule found by the patient or incidentally on physical examination or imaging. Other presenting signs and symptoms include hoarseness, voice changes, and dysphagia.

Continue to: Thyroid US is the study of...

Thyroid US is the study of choice for initial evaluation of the size and features of a nodule; findings are used to make recommendations for further workup. If further evaluation is indicated, FNA biopsy is the test of choice.²⁹

In 2016, the American Thyroid Association released updated guidelines for evaluating thyroid nodules (TABLE).³⁰ The US Preventive Services Task Force recommends against screening for thyroid cancer by neck palpation or US in asymptomatic patients because evidence of significant mortality benefit is lacking.³¹

How is it treated? Treatment of thyroid cancer focuses on local excision of the nodule by partial or total thyroidectomy (depending on the size and type of cancer) and surgical removal of involved lymph nodes. Differentiated thyroid cancer is categorized as high-, medium-, or low-risk, depending on tumor extension, incomplete tumor resection, size of lymph nodes > 3 cm, and distant metastases. Adjuvant treatment with radioactive iodine can be considered for intermediate-risk DTC and is recommended for high-risk DTC.³²

Following surgical treatment, thyroid-stimulating hormone suppression is recommended using levothyroxine.³³ Patients at higher risk of recurrence should have longer and more intense suppression of thyroid-stimulating hormone.³⁰ Levels of serum thyroglobulin and anti-thyroglobulin antibody should be followed postoperatively; rising values can indicate recurrent disease. The calcitonin level should be followed in patients with a history of MTC. Thyroid US should be performed 6 to 12 months postoperatively, then periodically, depending on determination of recurrence risk and any change in the thyroglobulin level.³⁰

Human papillomavirus is associated with an increasing number of cases of head and neck cancer.

(Note: Glucagon-like peptide-1 [GLP-1] receptor agonists, used to treat type 2 diabetes mellitus, carry a black-box warning for their risk of MTC and are contraindicated in patients who have a personal or family history of MTC, MEN2A, or MEN2B.³⁴)

Continue to: Anaplastic thyroid cancer...

Anaplastic thyroid cancer, a rare form of thyroid cancer, carries a high mortality rate, with a median survival of 5 months from diagnosis and 1-year survival of 20%. Patients require expeditious total thyroidectomy and neck dissection, followed by external-beam radiation with or without chemotherapy. If this strategy is not feasible, tracheostomy might be necessary to maintain a patent airway.² Family physicians treating a patient who has anaplastic thyroid cancer can fulfill a crucial role by ensuring that an advance directive is established, a surrogate decision-maker is appointed, and goals of care are well defined.

Follow-up care for head and neck Ca

The risk of adverse effects after radiation therapy for head and neck cancer calls for close monitoring, appropriate treatment, and referral and counseling as needed. See “Follow-up care after treatment of head and neck cancer.” ^35-39

CORRESPONDENCE
Anne Mounsey, MD, Family Medicine Residency, The University of North Carolina at Chapel Hill, 590 Manning Dr., Chapel Hill, NC 27599; [email protected]

The statistics reveal a serious problem: This year, an estimated 63,030 Americans will be given a diagnosis of head and neck cancer (which includes laryngeal, oropharyngeal, sinonasal, nasopharyngeal, and salivary gland cancer¹); approximately 13,360 of them will die. Furthermore, thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an estimated 56,870 cases in 2017.^1,2 Major risk factors for head and neck cancer are tobacco and alcohol exposure and infection with Epstein-Barr virus and human papillomavirus (HPV).³

In this article, we review the background for each of the principal types of head and neck cancer with which you should be familiar. We also discuss how to evaluate signs and symptoms that raise suspicion of these neoplasms; outline the diagnostic strategy in the face of such suspicion; and summarize accepted therapeutic approaches. Last, we describe the important role that you, the family physician, play in providing posttreatment care for these patients, especially prevention and management of late adverse effects of radiation therapy.

General characterizationsof these cancers

Approximately one-half of patients with head and neck cancer present initially with a nonspecific, persistent neck mass that should be deemed malignant until proven otherwise, because a delay in diagnosis is associated with a worse outcome.⁴ In a series of 100 patients with head and neck cancer, for example, delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.⁵ Guidelines for management of neck masses recommend against the use of antibiotics in patients who do not have evidence of infection.⁶

Patients with a neck mass that has been present for longer than 2 weeks or that is ulcerated, fixed to underlying tissues, of firm consistency, or > 1.5 cm should have a physical examination that includes visualization of the base of tongue, pharynx, and larynx. The mass should be evaluated with fine-­needle aspiration (FNA) biopsy, which has a positive predictive value of 96% and negative predictive value of 90% for the diagnosis of a head and neck mass. (Note: Anticoagulation therapy is not an absolute contraindication to FNA, which is not associated with an increased risk of bleeding.⁶)

Laryngeal cancer

What you need to know. More than 90% of laryngeal cancers are squamous cell carcinoma (SCC). Smoking or heavy drinking (> 8 drinks/d), compared to neither behavior, is associated with an increased risk of laryngeal cancer (odds ratio, 9.4 and 2.5, respectively).⁷ The risk of cancer is directly proportional to the degree of tobacco exposure.

One-half of head and neck cancers present with a neck mass that warrants appropriate initial assessment, so as not to delay diagnosis.

Laryngeal cancer occurs in the supraglottic region in one-third of patients; in the glottic region in one-half; and in the subglottic region in a very few.⁸ Glottic cancer presents earlier than supraglottic cancer with hoarseness, whereas supraglottic cancer presents with more advanced disease, causing stridor, dysphagia, and throat pain. (Note: Guidelines recommend against prescribing acid suppressants in patients with hoarseness who do not have symptoms of reflux.⁹)

Stage 1 and Stage 2 laryngeal cancers are localized; Stages 3-4B are locally advanced or involve lymph nodes, or both; Stage 4C is metastatic disease. Overall, 60% of patients have Stage 3 or Stage 4 disease at diagnosis.¹⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Laryngoscopy should be performed before computed tomography (CT) or magnetic resonance imaging is considered in a patient with hoarseness that does not resolve after 3 months—or sooner, if there is suspicion of malignancy.

How is it treated? Most patients presenting with Stage 1 or Stage 2 cancer can be treated with local radiation or, less commonly, larynx-preserving surgery. Patients with Stage 3 or Stage 4 disease can be treated with a combination of radiation and chemotherapy, which, compared to radiation alone, confers a decreased risk of local recurrence and increased laryngectomy-free survival.¹¹ Patients whose vocal cords are destroyed or who have recurrence following radiation and chemotherapy might need total laryngectomy and formation of a tracheostomy and prosthetic for voice creation.

Five-year overall survival for Stage 1 and Stage 2 supraglottic and glottic cancers is 80%—lower, however, for later-presenting subglottic cancers.¹²

Oropharyngeal cancer

What you need to know. The lifetime risk for cancer of the oropharynx is approximately 1%.¹³ SCC is responsible for approximately 90% of these cancers. Early detection is important: The 5-year survival rate is more than twice as high for localized disease (83%) than it is for metastatic disease (39%) at detection.¹³

At any given time, 7% of the US population has HPV infection of the oropharynx. Most of these cases clear spontaneously, but persistent high-risk HPV infection led to a 225% increase in HPV-positive oropharyngeal SCC from 1988 to 2004.¹⁴ The representative case of HPV-positive oropharyngeal SCC is a middle-aged (40- to 59-year-old) white male with a history of multiple sexual partners and with little or no tobacco exposure and low alcohol consumption.

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Oral cancers present with a lesion, often ulcerative, that should be examined by palpation with a gloved finger to describe the presence, color, and number of lesions; any tenderness; tissue consistency (soft, firm, hard); and fixation to underlying structures.¹⁵ The oropharynx should be examined without protrusion of the tongue, which obscures the oropharynx and can make it harder to depress the posterior part of the tongue.

A finding of leukoplakia (white plaques) and erythroplakia (red plaques) of the oropharynx might reflect benign hyperkeratosis or premalignant lesions; the plaques do not wipe off on examination. Referral to a dentist or otorhinolaryngologist for biopsy is indicated for all erythroplakia and leukoplakia, and for ulcers that persist longer than 2 weeks.¹⁶

(Note: Evidence is insufficient to support screening asymptomatic patients for oral and oropharyngeal cancers by physical examination. There is no US Food and Drug Administration-approved screening test for oral HPV infection.¹⁷)

How is it treated? A diagnosis of moderate dysplasia or carcinoma in situ should be treated with surgical excision to clear margins followed by routine monitoring every 3 to 6 months, for life.¹⁸ Topical medication, electrocautery, laser ablation, and cryosurgery are management options for less severe dysplasia.

Sinonasal cancer

What you need to know. Worldwide, sinonasal cancer accounts for approximately 0.7% of all new cancers but demonstrates strong genetic and regional associations, particularly among the Cantonese population of southern China.¹⁹ One-half of new sinonasal malignancies are SCC; the rest are adenocarcinoma, lymphoepithelial carcinoma, and rare subtypes.²⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Presentation tends to mimic common, nonmalignant conditions, such as sinusitis, until invasion into adjacent structures. When sinonasal passages are involved, the history might include epistaxis or nasal discharge; facial or dental pain; unilateral nasal obstruction with unexplained onset later in life; and failure to respond to treatment of presumed rhinosinusitis. Physical examination should include assessment of cranial nerves, palpation of the sinuses, and anterior rhinoscopy.

Thin-cut CT of the paranasal sinuses is the first-line imaging study. Sinonasal endoscopy, with targeted biopsy of suspicious lesions, is the evaluation of choice when malignancy is suspected.

How is it treated? Surgery is the treatment of choice, with postoperative radiation for patients at higher risk of recurrence because of more extensive disase.¹² Five-year survival for advanced disease is poor (35%); only 15% of cases are diagnosed at a localized stage because presenting symptoms are nonspecific.²¹

Nasopharyngeal cancer

What you need to know. Nasopharyngeal cancer is rare in the United States and Europe, compared with China, where it is endemic (and where a variety of risk factors, including intake of salt-preserved fish, have been proposed²²). Epstein-Barr virus infection and a history of smoking increase the risk.

Patients with nasopharyngeal cancer can present with epistaxis, nasal obstruction, and auditory symptoms, such as serous otitis media. Direct extension of the tumor can lead to cranial-nerve palsy, most commonly III, V, VI, and XII.²³

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Three-quarters of patients present with a neck mass from lymph-node metastases. Patients with the risk factors for nasopharyngeal cancer noted above who present with concerning symptoms should have nasoendoscopy with biopsy.

How is it treated? Radiation is the primary treatment, which is combined with chemotherapy for more advanced disease.²³ Screening high-risk populations for antibodies to Epstein-Barr virus and performing nasopharyngeal endoscopy on patients who screen positive increases the detection rate of nasopharyngeal cancer; however, this strategy has not been shown to improve survival.⁹

Salivary gland tumors

What you need to know. Salivary gland neoplasms are a rare and heterogeneous entity, comprising 6% to 8% of head and neck cancers.²⁴ More than 70% of these tumors are located in the parotid gland; 8%, in the submandibular glands; 1%, in the sublingual glands; and the rest, in the minor salivary glands. Most salivary gland tumors are benign; the most prevalent malignant tumors are mucoepidermoid carcinoma (30%) and adenoid cystic carcinoma (10%).²⁵ Additional identified risk factors for a salivary gland tumor include irradiation, prior head and neck cancer, and environmental exposures, including hairdressing, rubber manufacturing, and exposure to nickel compounds.²⁶

What is the diagnostic strategy? The history and physical exam are essential to distinguish a salivary gland tumor from an infectious cause and sialolithiasis. Parotid tumors most commonly present as asymptomatic parotid swelling, although pain can be present in as many as 40% of malignant parotid tumors.²⁵ Facial nerve weakness is found in 25% of parotid tumors; although the differential diagnosis of facial nerve palsy is broad, suspicion of malignancy should be raised in the presence of a parotid mass, progressive unilateral symptoms, hemifacial spasm progressing to weakness, and a history of skin cancer on the face or scalp. Additional characteristics that favor a neoplastic cause are trismus and nontender lymphadenopathy.²⁵

In a series of 100 patients with head and neck cancer, a delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.

In contrast, sialolithiasis is associated with intermittent pain caused by eating and is more common in the settings of dehydration and poor dental hygiene. Sialadenitis should be suspected when the presentation is fever, increased pain and swelling, erythema, and expression of pus from the salivary gland.

Continue to: If malignancy is suspected...

If malignancy is suspected, the initial diagnostic evaluation should include ultrasonography (US); concurrent FNA biopsy should be performed if a mass is detected.²⁷ US-guided FNA has a sensitivity of 73% to 86% for salivary neoplasm.⁷ CT and ­magnetic resonance imaging are useful for further characterization of tumors and can be advantageous for surgical planning.

How is it treated? Treatment of a salivary gland tumor involves surgical resection, followed by radiotherapy for patients in whom disease is more extensive or who exhibit high-risk pathology. Primary radiotherapy can be used in patients with an unresectable tumor. Typically, chemotherapy is used only for palliative purposes in relapsing disease, when a tumor is not amenable to radiotherapy, and in metastatic disease.²⁵

Prognosis varies by histotype but is generally favorable. The survival rates for a malignant salivary gland tumor are 83% at 1 year, 69% at 3 years, and 65% at 5 years.²⁸ Distant metastases are the most common cause of death, occurring primarily in the lungs (80%), bone (15%), and liver.²⁷ Factors that indicate poor prognosis include facial nerve involvement, trismus, a tumor > 4 cm, bone involvement, nodal spread, and recurrence.²⁵

Thyroid cancer

What you need to know. Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an annual incidence of 4.5%.¹ In the United States, most thyroid cancers are differentiated thyroid cancer (DTC), which includes papillary and follicular cancers. Less-differentiated medullary thyroid cancer (MTC), typically associated with multiple endocrine neoplasia (MEN) 2A or 2B, and undifferentiated or anaplastic thyroid cancer are less common. The increasing incidence of thyroid cancer is primarily the result of an increase in nonclinically relevant DTC.

What is the diagnostic strategy? Thyroid cancer usually presents as a thyroid nodule found by the patient or incidentally on physical examination or imaging. Other presenting signs and symptoms include hoarseness, voice changes, and dysphagia.

Continue to: Thyroid US is the study of...

Thyroid US is the study of choice for initial evaluation of the size and features of a nodule; findings are used to make recommendations for further workup. If further evaluation is indicated, FNA biopsy is the test of choice.²⁹

In 2016, the American Thyroid Association released updated guidelines for evaluating thyroid nodules (TABLE).³⁰ The US Preventive Services Task Force recommends against screening for thyroid cancer by neck palpation or US in asymptomatic patients because evidence of significant mortality benefit is lacking.³¹

How is it treated? Treatment of thyroid cancer focuses on local excision of the nodule by partial or total thyroidectomy (depending on the size and type of cancer) and surgical removal of involved lymph nodes. Differentiated thyroid cancer is categorized as high-, medium-, or low-risk, depending on tumor extension, incomplete tumor resection, size of lymph nodes > 3 cm, and distant metastases. Adjuvant treatment with radioactive iodine can be considered for intermediate-risk DTC and is recommended for high-risk DTC.³²

Following surgical treatment, thyroid-stimulating hormone suppression is recommended using levothyroxine.³³ Patients at higher risk of recurrence should have longer and more intense suppression of thyroid-stimulating hormone.³⁰ Levels of serum thyroglobulin and anti-thyroglobulin antibody should be followed postoperatively; rising values can indicate recurrent disease. The calcitonin level should be followed in patients with a history of MTC. Thyroid US should be performed 6 to 12 months postoperatively, then periodically, depending on determination of recurrence risk and any change in the thyroglobulin level.³⁰

Human papillomavirus is associated with an increasing number of cases of head and neck cancer.

(Note: Glucagon-like peptide-1 [GLP-1] receptor agonists, used to treat type 2 diabetes mellitus, carry a black-box warning for their risk of MTC and are contraindicated in patients who have a personal or family history of MTC, MEN2A, or MEN2B.³⁴)

Continue to: Anaplastic thyroid cancer...

Anaplastic thyroid cancer, a rare form of thyroid cancer, carries a high mortality rate, with a median survival of 5 months from diagnosis and 1-year survival of 20%. Patients require expeditious total thyroidectomy and neck dissection, followed by external-beam radiation with or without chemotherapy. If this strategy is not feasible, tracheostomy might be necessary to maintain a patent airway.² Family physicians treating a patient who has anaplastic thyroid cancer can fulfill a crucial role by ensuring that an advance directive is established, a surrogate decision-maker is appointed, and goals of care are well defined.

Follow-up care for head and neck Ca

The risk of adverse effects after radiation therapy for head and neck cancer calls for close monitoring, appropriate treatment, and referral and counseling as needed. See “Follow-up care after treatment of head and neck cancer.” ^35-39

CORRESPONDENCE
Anne Mounsey, MD, Family Medicine Residency, The University of North Carolina at Chapel Hill, 590 Manning Dr., Chapel Hill, NC 27599; [email protected]

The statistics reveal a serious problem: This year, an estimated 63,030 Americans will be given a diagnosis of head and neck cancer (which includes laryngeal, oropharyngeal, sinonasal, nasopharyngeal, and salivary gland cancer¹); approximately 13,360 of them will die. Furthermore, thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an estimated 56,870 cases in 2017.^1,2 Major risk factors for head and neck cancer are tobacco and alcohol exposure and infection with Epstein-Barr virus and human papillomavirus (HPV).³

In this article, we review the background for each of the principal types of head and neck cancer with which you should be familiar. We also discuss how to evaluate signs and symptoms that raise suspicion of these neoplasms; outline the diagnostic strategy in the face of such suspicion; and summarize accepted therapeutic approaches. Last, we describe the important role that you, the family physician, play in providing posttreatment care for these patients, especially prevention and management of late adverse effects of radiation therapy.

General characterizationsof these cancers

Approximately one-half of patients with head and neck cancer present initially with a nonspecific, persistent neck mass that should be deemed malignant until proven otherwise, because a delay in diagnosis is associated with a worse outcome.⁴ In a series of 100 patients with head and neck cancer, for example, delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.⁵ Guidelines for management of neck masses recommend against the use of antibiotics in patients who do not have evidence of infection.⁶

Patients with a neck mass that has been present for longer than 2 weeks or that is ulcerated, fixed to underlying tissues, of firm consistency, or > 1.5 cm should have a physical examination that includes visualization of the base of tongue, pharynx, and larynx. The mass should be evaluated with fine-­needle aspiration (FNA) biopsy, which has a positive predictive value of 96% and negative predictive value of 90% for the diagnosis of a head and neck mass. (Note: Anticoagulation therapy is not an absolute contraindication to FNA, which is not associated with an increased risk of bleeding.⁶)

Laryngeal cancer

What you need to know. More than 90% of laryngeal cancers are squamous cell carcinoma (SCC). Smoking or heavy drinking (> 8 drinks/d), compared to neither behavior, is associated with an increased risk of laryngeal cancer (odds ratio, 9.4 and 2.5, respectively).⁷ The risk of cancer is directly proportional to the degree of tobacco exposure.

One-half of head and neck cancers present with a neck mass that warrants appropriate initial assessment, so as not to delay diagnosis.

Laryngeal cancer occurs in the supraglottic region in one-third of patients; in the glottic region in one-half; and in the subglottic region in a very few.⁸ Glottic cancer presents earlier than supraglottic cancer with hoarseness, whereas supraglottic cancer presents with more advanced disease, causing stridor, dysphagia, and throat pain. (Note: Guidelines recommend against prescribing acid suppressants in patients with hoarseness who do not have symptoms of reflux.⁹)

Stage 1 and Stage 2 laryngeal cancers are localized; Stages 3-4B are locally advanced or involve lymph nodes, or both; Stage 4C is metastatic disease. Overall, 60% of patients have Stage 3 or Stage 4 disease at diagnosis.¹⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Laryngoscopy should be performed before computed tomography (CT) or magnetic resonance imaging is considered in a patient with hoarseness that does not resolve after 3 months—or sooner, if there is suspicion of malignancy.

How is it treated? Most patients presenting with Stage 1 or Stage 2 cancer can be treated with local radiation or, less commonly, larynx-preserving surgery. Patients with Stage 3 or Stage 4 disease can be treated with a combination of radiation and chemotherapy, which, compared to radiation alone, confers a decreased risk of local recurrence and increased laryngectomy-free survival.¹¹ Patients whose vocal cords are destroyed or who have recurrence following radiation and chemotherapy might need total laryngectomy and formation of a tracheostomy and prosthetic for voice creation.

Five-year overall survival for Stage 1 and Stage 2 supraglottic and glottic cancers is 80%—lower, however, for later-presenting subglottic cancers.¹²

Oropharyngeal cancer

What you need to know. The lifetime risk for cancer of the oropharynx is approximately 1%.¹³ SCC is responsible for approximately 90% of these cancers. Early detection is important: The 5-year survival rate is more than twice as high for localized disease (83%) than it is for metastatic disease (39%) at detection.¹³

At any given time, 7% of the US population has HPV infection of the oropharynx. Most of these cases clear spontaneously, but persistent high-risk HPV infection led to a 225% increase in HPV-positive oropharyngeal SCC from 1988 to 2004.¹⁴ The representative case of HPV-positive oropharyngeal SCC is a middle-aged (40- to 59-year-old) white male with a history of multiple sexual partners and with little or no tobacco exposure and low alcohol consumption.

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Oral cancers present with a lesion, often ulcerative, that should be examined by palpation with a gloved finger to describe the presence, color, and number of lesions; any tenderness; tissue consistency (soft, firm, hard); and fixation to underlying structures.¹⁵ The oropharynx should be examined without protrusion of the tongue, which obscures the oropharynx and can make it harder to depress the posterior part of the tongue.

A finding of leukoplakia (white plaques) and erythroplakia (red plaques) of the oropharynx might reflect benign hyperkeratosis or premalignant lesions; the plaques do not wipe off on examination. Referral to a dentist or otorhinolaryngologist for biopsy is indicated for all erythroplakia and leukoplakia, and for ulcers that persist longer than 2 weeks.¹⁶

(Note: Evidence is insufficient to support screening asymptomatic patients for oral and oropharyngeal cancers by physical examination. There is no US Food and Drug Administration-approved screening test for oral HPV infection.¹⁷)

How is it treated? A diagnosis of moderate dysplasia or carcinoma in situ should be treated with surgical excision to clear margins followed by routine monitoring every 3 to 6 months, for life.¹⁸ Topical medication, electrocautery, laser ablation, and cryosurgery are management options for less severe dysplasia.

Sinonasal cancer

What you need to know. Worldwide, sinonasal cancer accounts for approximately 0.7% of all new cancers but demonstrates strong genetic and regional associations, particularly among the Cantonese population of southern China.¹⁹ One-half of new sinonasal malignancies are SCC; the rest are adenocarcinoma, lymphoepithelial carcinoma, and rare subtypes.²⁰

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Presentation tends to mimic common, nonmalignant conditions, such as sinusitis, until invasion into adjacent structures. When sinonasal passages are involved, the history might include epistaxis or nasal discharge; facial or dental pain; unilateral nasal obstruction with unexplained onset later in life; and failure to respond to treatment of presumed rhinosinusitis. Physical examination should include assessment of cranial nerves, palpation of the sinuses, and anterior rhinoscopy.

Thin-cut CT of the paranasal sinuses is the first-line imaging study. Sinonasal endoscopy, with targeted biopsy of suspicious lesions, is the evaluation of choice when malignancy is suspected.

How is it treated? Surgery is the treatment of choice, with postoperative radiation for patients at higher risk of recurrence because of more extensive disase.¹² Five-year survival for advanced disease is poor (35%); only 15% of cases are diagnosed at a localized stage because presenting symptoms are nonspecific.²¹

Nasopharyngeal cancer

What you need to know. Nasopharyngeal cancer is rare in the United States and Europe, compared with China, where it is endemic (and where a variety of risk factors, including intake of salt-preserved fish, have been proposed²²). Epstein-Barr virus infection and a history of smoking increase the risk.

Patients with nasopharyngeal cancer can present with epistaxis, nasal obstruction, and auditory symptoms, such as serous otitis media. Direct extension of the tumor can lead to cranial-nerve palsy, most commonly III, V, VI, and XII.²³

Continue to: What is the diagnostic strategy?

What is the diagnostic strategy? Three-quarters of patients present with a neck mass from lymph-node metastases. Patients with the risk factors for nasopharyngeal cancer noted above who present with concerning symptoms should have nasoendoscopy with biopsy.

How is it treated? Radiation is the primary treatment, which is combined with chemotherapy for more advanced disease.²³ Screening high-risk populations for antibodies to Epstein-Barr virus and performing nasopharyngeal endoscopy on patients who screen positive increases the detection rate of nasopharyngeal cancer; however, this strategy has not been shown to improve survival.⁹

Salivary gland tumors

What you need to know. Salivary gland neoplasms are a rare and heterogeneous entity, comprising 6% to 8% of head and neck cancers.²⁴ More than 70% of these tumors are located in the parotid gland; 8%, in the submandibular glands; 1%, in the sublingual glands; and the rest, in the minor salivary glands. Most salivary gland tumors are benign; the most prevalent malignant tumors are mucoepidermoid carcinoma (30%) and adenoid cystic carcinoma (10%).²⁵ Additional identified risk factors for a salivary gland tumor include irradiation, prior head and neck cancer, and environmental exposures, including hairdressing, rubber manufacturing, and exposure to nickel compounds.²⁶

What is the diagnostic strategy? The history and physical exam are essential to distinguish a salivary gland tumor from an infectious cause and sialolithiasis. Parotid tumors most commonly present as asymptomatic parotid swelling, although pain can be present in as many as 40% of malignant parotid tumors.²⁵ Facial nerve weakness is found in 25% of parotid tumors; although the differential diagnosis of facial nerve palsy is broad, suspicion of malignancy should be raised in the presence of a parotid mass, progressive unilateral symptoms, hemifacial spasm progressing to weakness, and a history of skin cancer on the face or scalp. Additional characteristics that favor a neoplastic cause are trismus and nontender lymphadenopathy.²⁵

In a series of 100 patients with head and neck cancer, a delay in diagnosis occurred in nearly 25%—most often because of time spent providing inappropriate antibiotic treatment.

In contrast, sialolithiasis is associated with intermittent pain caused by eating and is more common in the settings of dehydration and poor dental hygiene. Sialadenitis should be suspected when the presentation is fever, increased pain and swelling, erythema, and expression of pus from the salivary gland.

Continue to: If malignancy is suspected...

If malignancy is suspected, the initial diagnostic evaluation should include ultrasonography (US); concurrent FNA biopsy should be performed if a mass is detected.²⁷ US-guided FNA has a sensitivity of 73% to 86% for salivary neoplasm.⁷ CT and ­magnetic resonance imaging are useful for further characterization of tumors and can be advantageous for surgical planning.

How is it treated? Treatment of a salivary gland tumor involves surgical resection, followed by radiotherapy for patients in whom disease is more extensive or who exhibit high-risk pathology. Primary radiotherapy can be used in patients with an unresectable tumor. Typically, chemotherapy is used only for palliative purposes in relapsing disease, when a tumor is not amenable to radiotherapy, and in metastatic disease.²⁵

Prognosis varies by histotype but is generally favorable. The survival rates for a malignant salivary gland tumor are 83% at 1 year, 69% at 3 years, and 65% at 5 years.²⁸ Distant metastases are the most common cause of death, occurring primarily in the lungs (80%), bone (15%), and liver.²⁷ Factors that indicate poor prognosis include facial nerve involvement, trismus, a tumor > 4 cm, bone involvement, nodal spread, and recurrence.²⁵

Thyroid cancer

What you need to know. Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with an annual incidence of 4.5%.¹ In the United States, most thyroid cancers are differentiated thyroid cancer (DTC), which includes papillary and follicular cancers. Less-differentiated medullary thyroid cancer (MTC), typically associated with multiple endocrine neoplasia (MEN) 2A or 2B, and undifferentiated or anaplastic thyroid cancer are less common. The increasing incidence of thyroid cancer is primarily the result of an increase in nonclinically relevant DTC.

What is the diagnostic strategy? Thyroid cancer usually presents as a thyroid nodule found by the patient or incidentally on physical examination or imaging. Other presenting signs and symptoms include hoarseness, voice changes, and dysphagia.

Continue to: Thyroid US is the study of...

Thyroid US is the study of choice for initial evaluation of the size and features of a nodule; findings are used to make recommendations for further workup. If further evaluation is indicated, FNA biopsy is the test of choice.²⁹

In 2016, the American Thyroid Association released updated guidelines for evaluating thyroid nodules (TABLE).³⁰ The US Preventive Services Task Force recommends against screening for thyroid cancer by neck palpation or US in asymptomatic patients because evidence of significant mortality benefit is lacking.³¹

How is it treated? Treatment of thyroid cancer focuses on local excision of the nodule by partial or total thyroidectomy (depending on the size and type of cancer) and surgical removal of involved lymph nodes. Differentiated thyroid cancer is categorized as high-, medium-, or low-risk, depending on tumor extension, incomplete tumor resection, size of lymph nodes > 3 cm, and distant metastases. Adjuvant treatment with radioactive iodine can be considered for intermediate-risk DTC and is recommended for high-risk DTC.³²

Following surgical treatment, thyroid-stimulating hormone suppression is recommended using levothyroxine.³³ Patients at higher risk of recurrence should have longer and more intense suppression of thyroid-stimulating hormone.³⁰ Levels of serum thyroglobulin and anti-thyroglobulin antibody should be followed postoperatively; rising values can indicate recurrent disease. The calcitonin level should be followed in patients with a history of MTC. Thyroid US should be performed 6 to 12 months postoperatively, then periodically, depending on determination of recurrence risk and any change in the thyroglobulin level.³⁰

Human papillomavirus is associated with an increasing number of cases of head and neck cancer.

(Note: Glucagon-like peptide-1 [GLP-1] receptor agonists, used to treat type 2 diabetes mellitus, carry a black-box warning for their risk of MTC and are contraindicated in patients who have a personal or family history of MTC, MEN2A, or MEN2B.³⁴)

Continue to: Anaplastic thyroid cancer...

Anaplastic thyroid cancer, a rare form of thyroid cancer, carries a high mortality rate, with a median survival of 5 months from diagnosis and 1-year survival of 20%. Patients require expeditious total thyroidectomy and neck dissection, followed by external-beam radiation with or without chemotherapy. If this strategy is not feasible, tracheostomy might be necessary to maintain a patent airway.² Family physicians treating a patient who has anaplastic thyroid cancer can fulfill a crucial role by ensuring that an advance directive is established, a surrogate decision-maker is appointed, and goals of care are well defined.

Follow-up care for head and neck Ca

The risk of adverse effects after radiation therapy for head and neck cancer calls for close monitoring, appropriate treatment, and referral and counseling as needed. See “Follow-up care after treatment of head and neck cancer.” ^35-39

CORRESPONDENCE
Anne Mounsey, MD, Family Medicine Residency, The University of North Carolina at Chapel Hill, 590 Manning Dr., Chapel Hill, NC 27599; [email protected]

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

A federal court has struck down a Trump administration rule that would have allowed clinicians to refuse to provide medical care to patients for religious or moral reasons.

In a Nov. 6 decision, the U.S. District Court for the Southern District of New York vacated President Trump’s rule in its entirety, concluding that the rule had no justification and that its provisions were arbitrary and capricious. In his 147-page opinion, District Judge Paul Engelmayer wrote that the U.S. Department of Health & Human Services did not have the authority to enact such an expansive rule and that the measure conflicts with the Administrative Procedure Act, Title VII of the Civil Rights Act, and the Emergency Medical Treatment & Labor Act, among other laws.

“Had the court found only narrow parts of the rule infirm, a remedy tailoring the vacatur to only the problematic provision might well have been viable,” Judge Engelmayer wrote. “The [Administrative Procedure Act] violations that the court has found, however, are numerous, fundamental, and far reaching ... In these circumstances, a decision to leave standing isolated shards of the rule that have not been found specifically infirm would ignore the big picture: that the rulemaking exercise here was sufficiently shot through with glaring legal defects as to not justify a search for survivors [and] leaving stray nonsubstantive provisions intact would not serve a useful purpose.”

At press time, the Trump administration had not indicated whether they plan to file an appeal.

Clare Coleman, president & CEO for the National Family Planning & Reproductive Health Association, a plaintiff in the case, said the organization was heartened by the ruling and that the judge’s decision protects health care for millions of Americans.

“The court safeguarded the public’s health by striking down the Trump administration’s health care refusal rule,” Ms. Coleman said in a statement. “This unlawful rule is an outright attack on the health and wellness of millions of people across the country, and the court heard clear and compelling arguments about the harm communities face when our health care system is distorted to the point in which a patient’s health care needs are not paramount.”

The conscience rule, finalized in May 2019 by HHS, would have allowed clinicians to refuse care to patients if they deemed that care was in conflict with their religious or moral beliefs. The provisions principally – although not exclusively – addressed objections to abortion, sterilization, and assisted suicide, as well as counseling and referrals associated with these services.

Gage Skidmore/Wikimedia Commons/CC BY-SA 2.0

According to HHS, the final rule fulfills President Trump’s promise to promote and protect rights of conscience and religious liberty. “This rule ensures that health care entities and professionals won’t be bullied out of the health care field because they decline to participate in actions that violate their conscience, including the taking of human life,” Roger Severino, director of the Office for Civil Rights, said in a statement. “Protecting conscience and religious freedom not only fosters greater diversity in health care, it’s the law.”

The judge’s order invalidating the rule consolidated three legal challenges against HHS over the rule. Plaintiffs included more than 15 states, Planned Parenthood Federation of America, and the National Family Planning & Reproductive Health Association, among others. The plaintiffs argued that the rule, scheduled to take effect on Nov. 22, would have threatened the ability of clinicians to provide essential, potentially life-saving medical care and would have exacerbated health disparities.

Stephanie Taub, senior counsel at the First Liberty Institute, an organization that represents religious freedom cases, said the court’s decision leaves health care professionals across America vulnerable to being forced “to perform, facilitate, or refer for procedures that violate their conscience.”

“The Trump administration’s HHS protections would ensure that health care professionals are free to work consistent with their religious beliefs while providing the best care to their patients,” Ms. Taub said in a statement.

The court’s decision comes less than a week after another district judge temporarily blocked an order by President Trump that would make having health insurance, or the ability to pay for medical care, a requirement for immigrants seeking U.S. visas. In that case, the judge said there are serious questions about whether President Trump’s immigration rule was arbitrary and capricious and, therefore, a violation of the Administrative Procedure Act. The order is on hold while the case continues through the courts.

[email protected]

A federal court has struck down a Trump administration rule that would have allowed clinicians to refuse to provide medical care to patients for religious or moral reasons.

In a Nov. 6 decision, the U.S. District Court for the Southern District of New York vacated President Trump’s rule in its entirety, concluding that the rule had no justification and that its provisions were arbitrary and capricious. In his 147-page opinion, District Judge Paul Engelmayer wrote that the U.S. Department of Health & Human Services did not have the authority to enact such an expansive rule and that the measure conflicts with the Administrative Procedure Act, Title VII of the Civil Rights Act, and the Emergency Medical Treatment & Labor Act, among other laws.

“Had the court found only narrow parts of the rule infirm, a remedy tailoring the vacatur to only the problematic provision might well have been viable,” Judge Engelmayer wrote. “The [Administrative Procedure Act] violations that the court has found, however, are numerous, fundamental, and far reaching ... In these circumstances, a decision to leave standing isolated shards of the rule that have not been found specifically infirm would ignore the big picture: that the rulemaking exercise here was sufficiently shot through with glaring legal defects as to not justify a search for survivors [and] leaving stray nonsubstantive provisions intact would not serve a useful purpose.”

At press time, the Trump administration had not indicated whether they plan to file an appeal.

Clare Coleman, president & CEO for the National Family Planning & Reproductive Health Association, a plaintiff in the case, said the organization was heartened by the ruling and that the judge’s decision protects health care for millions of Americans.

“The court safeguarded the public’s health by striking down the Trump administration’s health care refusal rule,” Ms. Coleman said in a statement. “This unlawful rule is an outright attack on the health and wellness of millions of people across the country, and the court heard clear and compelling arguments about the harm communities face when our health care system is distorted to the point in which a patient’s health care needs are not paramount.”

The conscience rule, finalized in May 2019 by HHS, would have allowed clinicians to refuse care to patients if they deemed that care was in conflict with their religious or moral beliefs. The provisions principally – although not exclusively – addressed objections to abortion, sterilization, and assisted suicide, as well as counseling and referrals associated with these services.

Gage Skidmore/Wikimedia Commons/CC BY-SA 2.0

According to HHS, the final rule fulfills President Trump’s promise to promote and protect rights of conscience and religious liberty. “This rule ensures that health care entities and professionals won’t be bullied out of the health care field because they decline to participate in actions that violate their conscience, including the taking of human life,” Roger Severino, director of the Office for Civil Rights, said in a statement. “Protecting conscience and religious freedom not only fosters greater diversity in health care, it’s the law.”

The judge’s order invalidating the rule consolidated three legal challenges against HHS over the rule. Plaintiffs included more than 15 states, Planned Parenthood Federation of America, and the National Family Planning & Reproductive Health Association, among others. The plaintiffs argued that the rule, scheduled to take effect on Nov. 22, would have threatened the ability of clinicians to provide essential, potentially life-saving medical care and would have exacerbated health disparities.

Stephanie Taub, senior counsel at the First Liberty Institute, an organization that represents religious freedom cases, said the court’s decision leaves health care professionals across America vulnerable to being forced “to perform, facilitate, or refer for procedures that violate their conscience.”

“The Trump administration’s HHS protections would ensure that health care professionals are free to work consistent with their religious beliefs while providing the best care to their patients,” Ms. Taub said in a statement.

The court’s decision comes less than a week after another district judge temporarily blocked an order by President Trump that would make having health insurance, or the ability to pay for medical care, a requirement for immigrants seeking U.S. visas. In that case, the judge said there are serious questions about whether President Trump’s immigration rule was arbitrary and capricious and, therefore, a violation of the Administrative Procedure Act. The order is on hold while the case continues through the courts.

[email protected]

A federal court has struck down a Trump administration rule that would have allowed clinicians to refuse to provide medical care to patients for religious or moral reasons.

In a Nov. 6 decision, the U.S. District Court for the Southern District of New York vacated President Trump’s rule in its entirety, concluding that the rule had no justification and that its provisions were arbitrary and capricious. In his 147-page opinion, District Judge Paul Engelmayer wrote that the U.S. Department of Health & Human Services did not have the authority to enact such an expansive rule and that the measure conflicts with the Administrative Procedure Act, Title VII of the Civil Rights Act, and the Emergency Medical Treatment & Labor Act, among other laws.

“Had the court found only narrow parts of the rule infirm, a remedy tailoring the vacatur to only the problematic provision might well have been viable,” Judge Engelmayer wrote. “The [Administrative Procedure Act] violations that the court has found, however, are numerous, fundamental, and far reaching ... In these circumstances, a decision to leave standing isolated shards of the rule that have not been found specifically infirm would ignore the big picture: that the rulemaking exercise here was sufficiently shot through with glaring legal defects as to not justify a search for survivors [and] leaving stray nonsubstantive provisions intact would not serve a useful purpose.”

At press time, the Trump administration had not indicated whether they plan to file an appeal.

Clare Coleman, president & CEO for the National Family Planning & Reproductive Health Association, a plaintiff in the case, said the organization was heartened by the ruling and that the judge’s decision protects health care for millions of Americans.

“The court safeguarded the public’s health by striking down the Trump administration’s health care refusal rule,” Ms. Coleman said in a statement. “This unlawful rule is an outright attack on the health and wellness of millions of people across the country, and the court heard clear and compelling arguments about the harm communities face when our health care system is distorted to the point in which a patient’s health care needs are not paramount.”

The conscience rule, finalized in May 2019 by HHS, would have allowed clinicians to refuse care to patients if they deemed that care was in conflict with their religious or moral beliefs. The provisions principally – although not exclusively – addressed objections to abortion, sterilization, and assisted suicide, as well as counseling and referrals associated with these services.

Gage Skidmore/Wikimedia Commons/CC BY-SA 2.0

According to HHS, the final rule fulfills President Trump’s promise to promote and protect rights of conscience and religious liberty. “This rule ensures that health care entities and professionals won’t be bullied out of the health care field because they decline to participate in actions that violate their conscience, including the taking of human life,” Roger Severino, director of the Office for Civil Rights, said in a statement. “Protecting conscience and religious freedom not only fosters greater diversity in health care, it’s the law.”

The judge’s order invalidating the rule consolidated three legal challenges against HHS over the rule. Plaintiffs included more than 15 states, Planned Parenthood Federation of America, and the National Family Planning & Reproductive Health Association, among others. The plaintiffs argued that the rule, scheduled to take effect on Nov. 22, would have threatened the ability of clinicians to provide essential, potentially life-saving medical care and would have exacerbated health disparities.

Stephanie Taub, senior counsel at the First Liberty Institute, an organization that represents religious freedom cases, said the court’s decision leaves health care professionals across America vulnerable to being forced “to perform, facilitate, or refer for procedures that violate their conscience.”

“The Trump administration’s HHS protections would ensure that health care professionals are free to work consistent with their religious beliefs while providing the best care to their patients,” Ms. Taub said in a statement.

The court’s decision comes less than a week after another district judge temporarily blocked an order by President Trump that would make having health insurance, or the ability to pay for medical care, a requirement for immigrants seeking U.S. visas. In that case, the judge said there are serious questions about whether President Trump’s immigration rule was arbitrary and capricious and, therefore, a violation of the Administrative Procedure Act. The order is on hold while the case continues through the courts.

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A 60-year-old man presented to our dermatology clinic with a chronic, recurrent pruritic rash on his hands and neck. He noted that the rash developed into blisters, which he would pick until they scabbed over. The rash only manifested on sun-exposed areas.

The patient did not take any medications. He admitted to drinking alcohol (4 beers/d on average) and had roughly a 50-pack year history of smoking. There was no family history of similar symptoms.

On physical exam, we noted erosions and ulcerations with hemorrhagic crust on the dorsal aspect of his hands, along with milia on the knuckle pads (FIGURE 1A). Further skin examination revealed hypopigmented scars on his shoulders and lower extremities bilaterally, with hypertrichosis of the cheeks (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the clinical presentation and the patient’s history of smoking and alcohol consumption, we suspected that this was a case of porphyria cutanea tarda (PCT). Laboratory studies, including a complete blood count, basic metabolic panel, iron studies, and liver function tests, were ordered. These revealed elevated levels of serum alanine transaminase (116 IU/L; reference range, 20-60 IU/L), aspartate aminotransferase (184 IU/L; reference range, 6-34 IU/L in men), and ferritin (1594 ng/mL; reference range, 12-300 ng/mL in men), consistent with PCT. Total porphyrins were then measured and found to be elevated (128.5 mcg/dL; reference range, 0 to 1 mcg/dL), which confirmed the diagnosis. Further testing revealed that the patient was positive for both hepatitis C virus (HCV) and hepatitis B virus infection.

Susceptibility factors for porphyria cutanea tarda include chronic alcohol use, HCV and/or HIV infection, estrogen therapy, and chronic/heavy smoking.

While PCT is the most common porphyria worldwide, it is nonetheless a rare disorder that results from deficient activity (< 20% of normal) of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway.^1,2 It is typically (~75% cases) an acquired disorder of mid- to late adulthood and more commonly affects males.¹ In the remainder of cases, patients have a genetic predisposition—a mutation of the UROD or HFE gene. Patients with a genetic predisposition may present earlier.^2,3 Susceptibility factors for both forms of PCT include chronic alcohol use, HCV and/or human immunodeficiency virus (HIV) infection, estrogen therapy, and a history of chronic/heavy smoking.^1,4

Cutaneous manifestations of PCT are caused by the accumulation of porphyrins, which are photo-oxidized in the skin.¹ Findings include photosensitivity, skin fragility, blistering, scarring, hypo- or hyperpigmentation, and milia in sun-exposed areas, such as the dorsum of the hands, forearms, face, ears, neck, and feet.^1,2 Hypertrichosis can occur, particularly on the cheeks and forearms.¹ Elevated transaminases often accompany cutaneous findings, due to porphyrin accumulation in hepatocytes and the hepatotoxic effects of alcohol, HCV infection, or iron overload.⁵ Iron overload, in part due to dysregulation of hepcidin, can lead to increased serum ferritin, iron, and transferrin saturation.¹

Differential includes autoimmune and autosomal conditions

Diseases that manifest with blistering, elevated porphyrins or porphyrin precursors, and iron overload should be included in the differential diagnosis.

Bullous pemphigoid is an autoimmune subepithelial blistering disorder that occurs when antibodies attack hemidesmosomes in the epidermis. It commonly manifests in the elderly and classically presents with tense bullae, typically on the trunk, abdomen, and proximal extremities. Serologic testing and biopsy can confirm the diagnosis.⁶

Continue to: Pseudoporphyria...

Pseudoporphyria has a similar presentation to PCT but with no abnormalities in porphyrin metabolism. Risk factors include UV radiation exposure; use of medications such as nonsteroidal anti-inflammatory drugs, diuretics, and retinoids; chronic renal failure; and hemodialysis.⁷

Acute intermittent porphyria is an autosomal dominant disorder due to deficiency of porphobilinogen deaminase, a heme biosynthetic enzyme. Clinical manifestations usually arise in adulthood and include neurovisceral attacks (eg, abdominal pain, vomiting, muscle weakness). Diagnosis during an acute attack can be made by measuring urinary 5-aminolaevulinc acid and porphobilinogen.¹

Hereditary hemochromatosis is an autosomal recessive disorder most commonly due to mutations in the HFE gene. Patients typically have iron overload and abnormal liver function test results. The main cutaneous finding is skin hyperpigmentation. Patients also may develop diabetes mellitus, arthropathy, cardiac disease, and hypopituitarism, although most are diagnosed with asymptomatic disease following routine laboratory studies.⁸

Confirm the diagnosis with total porphyrin measurement

The preferred initial test to confirm the diagnosis of PCT is measurement of plasma or urine total porphyrins, which will be elevated.¹ Further testing is then performed to discern PCT from the other, less common cutaneous porphyrias.¹ If needed, biopsy can be done to exclude other diagnoses. Testing for HIV and viral hepatitis infection may be performed when clinical suspicion is high.¹ Testing for UROD and HFE mutations may also be advised.¹

Treatment choice is guided by iron levels

For patients with normal iron levels, low-dose hydroxychloroquine 100 mg or chloroquine 125 mg twice per week can be used until restoration of normal plasma or urine porphyrin levels has been achieved for several months.¹ For those with iron excess (serum ferritin > 600 ng/dL), repeat phlebotomy is the preferred treatment; a unit of blood (350-500 mL) is typically removed, as tolerated, until iron stores return to normal.¹ In severe cases of PCT, these therapies can be used in combination.¹ Clinical remission with these methods can be expected within 6 to 9 months.⁹

Continue to: In addition...

In addition, it is important to provide patient education regarding proper sun protection and risk factor modification.¹ Underlying HIV and viral hepatitis infection should be managed appropriately by the relevant specialists.

With proper treatment, clinical remission can be expected within 6 to 9 months.

Our patient was counseled on proper sun protection and encouraged to cease alcohol consumption and smoking. We subsequently referred him to Hepatology for the treatment of his liver disease. Given that the patient’s ferritin level was so high (1594 ng/­mL), serial phlebotomy was initiated twice monthly until levels reached the lower limit of normal. He was also started on direct-acting antiviral therapy with Epclusa (sofosbuvir/velpatasvir) for 12 weeks for treatment of his HCV and is currently in remission.

CORRESPONDENCE
Christopher G. Bazewicz, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; [email protected]

A 60-year-old man presented to our dermatology clinic with a chronic, recurrent pruritic rash on his hands and neck. He noted that the rash developed into blisters, which he would pick until they scabbed over. The rash only manifested on sun-exposed areas.

The patient did not take any medications. He admitted to drinking alcohol (4 beers/d on average) and had roughly a 50-pack year history of smoking. There was no family history of similar symptoms.

On physical exam, we noted erosions and ulcerations with hemorrhagic crust on the dorsal aspect of his hands, along with milia on the knuckle pads (FIGURE 1A). Further skin examination revealed hypopigmented scars on his shoulders and lower extremities bilaterally, with hypertrichosis of the cheeks (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the clinical presentation and the patient’s history of smoking and alcohol consumption, we suspected that this was a case of porphyria cutanea tarda (PCT). Laboratory studies, including a complete blood count, basic metabolic panel, iron studies, and liver function tests, were ordered. These revealed elevated levels of serum alanine transaminase (116 IU/L; reference range, 20-60 IU/L), aspartate aminotransferase (184 IU/L; reference range, 6-34 IU/L in men), and ferritin (1594 ng/mL; reference range, 12-300 ng/mL in men), consistent with PCT. Total porphyrins were then measured and found to be elevated (128.5 mcg/dL; reference range, 0 to 1 mcg/dL), which confirmed the diagnosis. Further testing revealed that the patient was positive for both hepatitis C virus (HCV) and hepatitis B virus infection.

Susceptibility factors for porphyria cutanea tarda include chronic alcohol use, HCV and/or HIV infection, estrogen therapy, and chronic/heavy smoking.

While PCT is the most common porphyria worldwide, it is nonetheless a rare disorder that results from deficient activity (< 20% of normal) of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway.^1,2 It is typically (~75% cases) an acquired disorder of mid- to late adulthood and more commonly affects males.¹ In the remainder of cases, patients have a genetic predisposition—a mutation of the UROD or HFE gene. Patients with a genetic predisposition may present earlier.^2,3 Susceptibility factors for both forms of PCT include chronic alcohol use, HCV and/or human immunodeficiency virus (HIV) infection, estrogen therapy, and a history of chronic/heavy smoking.^1,4

Cutaneous manifestations of PCT are caused by the accumulation of porphyrins, which are photo-oxidized in the skin.¹ Findings include photosensitivity, skin fragility, blistering, scarring, hypo- or hyperpigmentation, and milia in sun-exposed areas, such as the dorsum of the hands, forearms, face, ears, neck, and feet.^1,2 Hypertrichosis can occur, particularly on the cheeks and forearms.¹ Elevated transaminases often accompany cutaneous findings, due to porphyrin accumulation in hepatocytes and the hepatotoxic effects of alcohol, HCV infection, or iron overload.⁵ Iron overload, in part due to dysregulation of hepcidin, can lead to increased serum ferritin, iron, and transferrin saturation.¹

Differential includes autoimmune and autosomal conditions

Diseases that manifest with blistering, elevated porphyrins or porphyrin precursors, and iron overload should be included in the differential diagnosis.

Bullous pemphigoid is an autoimmune subepithelial blistering disorder that occurs when antibodies attack hemidesmosomes in the epidermis. It commonly manifests in the elderly and classically presents with tense bullae, typically on the trunk, abdomen, and proximal extremities. Serologic testing and biopsy can confirm the diagnosis.⁶

Continue to: Pseudoporphyria...

Pseudoporphyria has a similar presentation to PCT but with no abnormalities in porphyrin metabolism. Risk factors include UV radiation exposure; use of medications such as nonsteroidal anti-inflammatory drugs, diuretics, and retinoids; chronic renal failure; and hemodialysis.⁷

Acute intermittent porphyria is an autosomal dominant disorder due to deficiency of porphobilinogen deaminase, a heme biosynthetic enzyme. Clinical manifestations usually arise in adulthood and include neurovisceral attacks (eg, abdominal pain, vomiting, muscle weakness). Diagnosis during an acute attack can be made by measuring urinary 5-aminolaevulinc acid and porphobilinogen.¹

Hereditary hemochromatosis is an autosomal recessive disorder most commonly due to mutations in the HFE gene. Patients typically have iron overload and abnormal liver function test results. The main cutaneous finding is skin hyperpigmentation. Patients also may develop diabetes mellitus, arthropathy, cardiac disease, and hypopituitarism, although most are diagnosed with asymptomatic disease following routine laboratory studies.⁸

Confirm the diagnosis with total porphyrin measurement

The preferred initial test to confirm the diagnosis of PCT is measurement of plasma or urine total porphyrins, which will be elevated.¹ Further testing is then performed to discern PCT from the other, less common cutaneous porphyrias.¹ If needed, biopsy can be done to exclude other diagnoses. Testing for HIV and viral hepatitis infection may be performed when clinical suspicion is high.¹ Testing for UROD and HFE mutations may also be advised.¹

Treatment choice is guided by iron levels

For patients with normal iron levels, low-dose hydroxychloroquine 100 mg or chloroquine 125 mg twice per week can be used until restoration of normal plasma or urine porphyrin levels has been achieved for several months.¹ For those with iron excess (serum ferritin > 600 ng/dL), repeat phlebotomy is the preferred treatment; a unit of blood (350-500 mL) is typically removed, as tolerated, until iron stores return to normal.¹ In severe cases of PCT, these therapies can be used in combination.¹ Clinical remission with these methods can be expected within 6 to 9 months.⁹

Continue to: In addition...

In addition, it is important to provide patient education regarding proper sun protection and risk factor modification.¹ Underlying HIV and viral hepatitis infection should be managed appropriately by the relevant specialists.

With proper treatment, clinical remission can be expected within 6 to 9 months.

Our patient was counseled on proper sun protection and encouraged to cease alcohol consumption and smoking. We subsequently referred him to Hepatology for the treatment of his liver disease. Given that the patient’s ferritin level was so high (1594 ng/­mL), serial phlebotomy was initiated twice monthly until levels reached the lower limit of normal. He was also started on direct-acting antiviral therapy with Epclusa (sofosbuvir/velpatasvir) for 12 weeks for treatment of his HCV and is currently in remission.

CORRESPONDENCE
Christopher G. Bazewicz, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; [email protected]

A 60-year-old man presented to our dermatology clinic with a chronic, recurrent pruritic rash on his hands and neck. He noted that the rash developed into blisters, which he would pick until they scabbed over. The rash only manifested on sun-exposed areas.

The patient did not take any medications. He admitted to drinking alcohol (4 beers/d on average) and had roughly a 50-pack year history of smoking. There was no family history of similar symptoms.

On physical exam, we noted erosions and ulcerations with hemorrhagic crust on the dorsal aspect of his hands, along with milia on the knuckle pads (FIGURE 1A). Further skin examination revealed hypopigmented scars on his shoulders and lower extremities bilaterally, with hypertrichosis of the cheeks (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the clinical presentation and the patient’s history of smoking and alcohol consumption, we suspected that this was a case of porphyria cutanea tarda (PCT). Laboratory studies, including a complete blood count, basic metabolic panel, iron studies, and liver function tests, were ordered. These revealed elevated levels of serum alanine transaminase (116 IU/L; reference range, 20-60 IU/L), aspartate aminotransferase (184 IU/L; reference range, 6-34 IU/L in men), and ferritin (1594 ng/mL; reference range, 12-300 ng/mL in men), consistent with PCT. Total porphyrins were then measured and found to be elevated (128.5 mcg/dL; reference range, 0 to 1 mcg/dL), which confirmed the diagnosis. Further testing revealed that the patient was positive for both hepatitis C virus (HCV) and hepatitis B virus infection.

Susceptibility factors for porphyria cutanea tarda include chronic alcohol use, HCV and/or HIV infection, estrogen therapy, and chronic/heavy smoking.

While PCT is the most common porphyria worldwide, it is nonetheless a rare disorder that results from deficient activity (< 20% of normal) of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway.^1,2 It is typically (~75% cases) an acquired disorder of mid- to late adulthood and more commonly affects males.¹ In the remainder of cases, patients have a genetic predisposition—a mutation of the UROD or HFE gene. Patients with a genetic predisposition may present earlier.^2,3 Susceptibility factors for both forms of PCT include chronic alcohol use, HCV and/or human immunodeficiency virus (HIV) infection, estrogen therapy, and a history of chronic/heavy smoking.^1,4

Cutaneous manifestations of PCT are caused by the accumulation of porphyrins, which are photo-oxidized in the skin.¹ Findings include photosensitivity, skin fragility, blistering, scarring, hypo- or hyperpigmentation, and milia in sun-exposed areas, such as the dorsum of the hands, forearms, face, ears, neck, and feet.^1,2 Hypertrichosis can occur, particularly on the cheeks and forearms.¹ Elevated transaminases often accompany cutaneous findings, due to porphyrin accumulation in hepatocytes and the hepatotoxic effects of alcohol, HCV infection, or iron overload.⁵ Iron overload, in part due to dysregulation of hepcidin, can lead to increased serum ferritin, iron, and transferrin saturation.¹

Differential includes autoimmune and autosomal conditions

Diseases that manifest with blistering, elevated porphyrins or porphyrin precursors, and iron overload should be included in the differential diagnosis.

Bullous pemphigoid is an autoimmune subepithelial blistering disorder that occurs when antibodies attack hemidesmosomes in the epidermis. It commonly manifests in the elderly and classically presents with tense bullae, typically on the trunk, abdomen, and proximal extremities. Serologic testing and biopsy can confirm the diagnosis.⁶

Continue to: Pseudoporphyria...

Pseudoporphyria has a similar presentation to PCT but with no abnormalities in porphyrin metabolism. Risk factors include UV radiation exposure; use of medications such as nonsteroidal anti-inflammatory drugs, diuretics, and retinoids; chronic renal failure; and hemodialysis.⁷

Acute intermittent porphyria is an autosomal dominant disorder due to deficiency of porphobilinogen deaminase, a heme biosynthetic enzyme. Clinical manifestations usually arise in adulthood and include neurovisceral attacks (eg, abdominal pain, vomiting, muscle weakness). Diagnosis during an acute attack can be made by measuring urinary 5-aminolaevulinc acid and porphobilinogen.¹

Hereditary hemochromatosis is an autosomal recessive disorder most commonly due to mutations in the HFE gene. Patients typically have iron overload and abnormal liver function test results. The main cutaneous finding is skin hyperpigmentation. Patients also may develop diabetes mellitus, arthropathy, cardiac disease, and hypopituitarism, although most are diagnosed with asymptomatic disease following routine laboratory studies.⁸

Confirm the diagnosis with total porphyrin measurement

The preferred initial test to confirm the diagnosis of PCT is measurement of plasma or urine total porphyrins, which will be elevated.¹ Further testing is then performed to discern PCT from the other, less common cutaneous porphyrias.¹ If needed, biopsy can be done to exclude other diagnoses. Testing for HIV and viral hepatitis infection may be performed when clinical suspicion is high.¹ Testing for UROD and HFE mutations may also be advised.¹

Treatment choice is guided by iron levels

For patients with normal iron levels, low-dose hydroxychloroquine 100 mg or chloroquine 125 mg twice per week can be used until restoration of normal plasma or urine porphyrin levels has been achieved for several months.¹ For those with iron excess (serum ferritin > 600 ng/dL), repeat phlebotomy is the preferred treatment; a unit of blood (350-500 mL) is typically removed, as tolerated, until iron stores return to normal.¹ In severe cases of PCT, these therapies can be used in combination.¹ Clinical remission with these methods can be expected within 6 to 9 months.⁹

Continue to: In addition...

In addition, it is important to provide patient education regarding proper sun protection and risk factor modification.¹ Underlying HIV and viral hepatitis infection should be managed appropriately by the relevant specialists.

With proper treatment, clinical remission can be expected within 6 to 9 months.

Our patient was counseled on proper sun protection and encouraged to cease alcohol consumption and smoking. We subsequently referred him to Hepatology for the treatment of his liver disease. Given that the patient’s ferritin level was so high (1594 ng/­mL), serial phlebotomy was initiated twice monthly until levels reached the lower limit of normal. He was also started on direct-acting antiviral therapy with Epclusa (sofosbuvir/velpatasvir) for 12 weeks for treatment of his HCV and is currently in remission.

CORRESPONDENCE
Christopher G. Bazewicz, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; [email protected]

THE CASE

A 26-year-old Hispanic/African American woman presented to our clinic with a 2-month history of nausea and vomiting, along with dizziness. The nausea and vomiting persistently worsened, and she was only able to tolerate apples and berries. During this 2-month period, she lost 20 pounds and her symptoms progressed to include pruritus, ataxia, and mild hearing loss, with reoccurring episodes of falls.

THE DIAGNOSIS

On examination, she was found to be bradycardic with a heart rate of 47 beats/min, right- axis deviation, and inverted T waves in leads I, II, and augmented vector left. Her family history included the death of an aunt who was in her early 30s due to an unknown heart condition.

Echocardiogram identified mild mitral valve regurgitation with an ejection fraction of 55% to 60% (reference range: 55%-70%). Cardiology determined that her bradycardia was not the source of her symptoms. A neurologic exam identified 3+ hyperreflexia (indicating the reflex was increased), tandem gait instability, and left oculomotor dysfunction.

Brain magnetic resonance imaging (MRI) identified bilateral parietal white matter lesions where a demyelinating process could not be excluded (FIGURE 1A). The patient’s symptoms of nausea and vomiting continued, and she only tolerated peanuts and liquids. An MRI of the spine was negative.

Laboratory testing revealed that the patient was negative for human immunodeficiency virus (HIV), syphilis, Lyme disease, and lupus. Her thyroid-stimulating hormone level was 1.7 mIU/L (reference range: 0.4-4.2 mIU/L), and her vitamin B₁₂ level was 504 pg/mL (reference range: 160-950 pg/mL).

The patient’s lumbar puncture was negative for oligoclonal bands. The IgG synthesis rate/index cerebrospinal fluid (CSF) was –3.9, ruling out multiple sclerosis. Her CSF culture was negative, with a glucose level of 42 mg/dL (reference range: 70-110 mg/dL), colorless appearance, 1 white blood cell, and spinal albumin of 12.2 mg/dL (reference range: 8-42 mg/dL). The visual evoked potential was negative. The aquaporin-4 (AQP4) antibody was positive at 3.4 U/mL, and the myelin oligodendrocyte glycoprotein (MOG) antibody was positive.

Gastroenterology concluded a normal gastric accommodation and unremarkable computed tomography (CT) enterography. Moderate erosions were identified in the stomach with an erythematous gastropathy. The patient was placed on a proton pump inhibitor.

Continue to: Following the examination...

Following the examination and laboratory testing, the patient was admitted under our family medicine service for neuromyelitis optica (NMO) affecting the area postrema. NMO, also known as Devic’s disease, is an autoimmune disorder that affects the spinal cord and optic nerves. Autoantibodies against AQP4 are created in the periphery and are directed against astrocytes in the central nervous system. These antibodies bind to the foot processes of astrocytes, inducing complement-mediated cell damage and granulocyte infiltration.^1-5

Intravenous methylprednisolone was initiated at 250 mg every 6 hours for 3 days. A repeat brain MRI demonstrated nonspecific multiple scattered foci of hyperintense signal involving the subcortical supratentorial white matter without abnormal enhancement, most likely representing nonactive demyelinating plaques (FIGURES 1B and 1C).

Dx is revisited. Our patient was referred to an NMO clinic for evaluation. After further testing (including a repeat MRI based on the neurologist’s specifications, anti-aquaporin antibody testing, and MOG-antibody testing) and case discussion, it was determined that the patient had MOG-antibody disease. This disease, along with NMO, comprise a spectrum of disorders referred to as neuromyelitis optica spectrum disorder (NMOSD).

The patient was subsequently prescribed a rituximab infusion, 500 mg/50 mL, to treat the current attack. One infusion was to be completed weekly for 2 weeks with plans to repeat treatment every 6 months to prevent flares of NMO. During the first dose, the patient had a reaction to the treatment, which caused pruritus and chest tightness. She was able to complete the infusion after being treated with diphenhydramine.

Tx continued. In order to complete the second of 2 infusions of rituximab, the patient was pretreated with oral methylprednisolone the night before the infusion, along with diphenhydramine and acetaminophen on the day of treatment. Fortunately, the patient tolerated the infusion well with no adverse effects or reactions.

Continue to: DISCUSSION

DISCUSSION

Within the NMO spectrum, the MOG antibody is positive in up to 42% of AQP4-seronegative cases.⁶ MOG is a minor myelin component that is expressed exclusively in the central nervous system on the surface of myelin and oligodendrocyte processes. The role of this glycoprotein is not well understood but is hypothesized to function as a cell surface receptor or cell adhesion molecule.⁷

Among a cohort of 252 patients from the United Kingdom who tested positive for the MOG-IgG1 antibody, optic neuritis was seen in 55%, while 18% experienced transverse myelitis, and 15% had a history of area postrema syndrome. A brain MRI identified lesions in all areas of the brain including the brain stem, cerebellum, and cerebral hemispheres.⁸

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein Barr virus seropositivity, and tobacco abuse.

Differential diagnosis. Many diseases or conditions that are inflammatory, autoimmune, infectious, or neoplastic can involve the central nervous system and mimic the clinical and radiologic phenotypes of NMOSD-AQP4. They include lupus, SjÖgren’s syndrome, multiple sclerosis, sarcoidosis, acute disseminated encephalomyelitis, HIV, and vitamin B₁₂ deficiency.

Treatment. The standard treatment is intravenous methylprednisolone, 1 g/d for 3 to 5 days followed by a steroid taper. Therapeutic plasma exchange is recommended for refractory cases and in patients with spinal cord demyelination.^9-11 Rituximab is the first-line therapy for attack prevention^12-15 in NMOSD broadly and may be effective in MOG antibody disease, as well. In an open-label study of patients with NMOSD treated with rituximab, 64% were relapse free at follow-up, which ranged from 12 to 67 months.¹³ In a long-term study of patients treated with rituximab, 87% maintained a reduced relapse rate and 93% had improvement or stability over a 5-year follow-up.¹⁴

Continue to: Our patient

Our patient. After her diagnosis of NMOSD/MOG-antibody disease, our patient’s symptoms progressed to include vertigo, vestibular ataxia, pruritus, left foot drop, lower extremity numbness, and decreased hearing. After the second rituximab infusion her symptoms continued, but over time stabilized and have not worsened. She currently receives gabapentin 300 mg every 8 hours, as needed, for extremity numbness (which has been working well) along with sertraline 100 mg/d for depression.

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein-Barr virus seropositivity, and tobacco abuse.

Subsequent office visits have showed no further weight loss. Based on the current response to the rituximab, her prognosis is undetermined by Neurology as they continue to monitor for progression.

THE TAKEAWAY

Vestibular ataxia, foot drop, pruritus, vertigo, decreased hearing, numbness, and oculomotor dysfunction in the presence of nausea and vomiting should raise suspicion for NMOSD. The presence of AQP4 antibodies along with demyelinating central nervous system lesions, is highly indicative of NMO. The presence of MOG antibodies may indicate NMOSD/MOG-antibody disease. The initial treatment of NMOSD is intravenous methylprednisolone, which can be followed by treatment with rituximab to achieve remission.

CORRESPONDENCE
Daniel Murphy, MD, FAAFP, Department of Family and Community Medicine, Texas Tech University Health Science Center El Paso, 9849 Kenworthy Street, El Paso, Texas 79924; [email protected]

THE CASE

A 26-year-old Hispanic/African American woman presented to our clinic with a 2-month history of nausea and vomiting, along with dizziness. The nausea and vomiting persistently worsened, and she was only able to tolerate apples and berries. During this 2-month period, she lost 20 pounds and her symptoms progressed to include pruritus, ataxia, and mild hearing loss, with reoccurring episodes of falls.

THE DIAGNOSIS

On examination, she was found to be bradycardic with a heart rate of 47 beats/min, right- axis deviation, and inverted T waves in leads I, II, and augmented vector left. Her family history included the death of an aunt who was in her early 30s due to an unknown heart condition.

Echocardiogram identified mild mitral valve regurgitation with an ejection fraction of 55% to 60% (reference range: 55%-70%). Cardiology determined that her bradycardia was not the source of her symptoms. A neurologic exam identified 3+ hyperreflexia (indicating the reflex was increased), tandem gait instability, and left oculomotor dysfunction.

Brain magnetic resonance imaging (MRI) identified bilateral parietal white matter lesions where a demyelinating process could not be excluded (FIGURE 1A). The patient’s symptoms of nausea and vomiting continued, and she only tolerated peanuts and liquids. An MRI of the spine was negative.

Laboratory testing revealed that the patient was negative for human immunodeficiency virus (HIV), syphilis, Lyme disease, and lupus. Her thyroid-stimulating hormone level was 1.7 mIU/L (reference range: 0.4-4.2 mIU/L), and her vitamin B₁₂ level was 504 pg/mL (reference range: 160-950 pg/mL).

The patient’s lumbar puncture was negative for oligoclonal bands. The IgG synthesis rate/index cerebrospinal fluid (CSF) was –3.9, ruling out multiple sclerosis. Her CSF culture was negative, with a glucose level of 42 mg/dL (reference range: 70-110 mg/dL), colorless appearance, 1 white blood cell, and spinal albumin of 12.2 mg/dL (reference range: 8-42 mg/dL). The visual evoked potential was negative. The aquaporin-4 (AQP4) antibody was positive at 3.4 U/mL, and the myelin oligodendrocyte glycoprotein (MOG) antibody was positive.

Gastroenterology concluded a normal gastric accommodation and unremarkable computed tomography (CT) enterography. Moderate erosions were identified in the stomach with an erythematous gastropathy. The patient was placed on a proton pump inhibitor.

Continue to: Following the examination...

Following the examination and laboratory testing, the patient was admitted under our family medicine service for neuromyelitis optica (NMO) affecting the area postrema. NMO, also known as Devic’s disease, is an autoimmune disorder that affects the spinal cord and optic nerves. Autoantibodies against AQP4 are created in the periphery and are directed against astrocytes in the central nervous system. These antibodies bind to the foot processes of astrocytes, inducing complement-mediated cell damage and granulocyte infiltration.^1-5

Intravenous methylprednisolone was initiated at 250 mg every 6 hours for 3 days. A repeat brain MRI demonstrated nonspecific multiple scattered foci of hyperintense signal involving the subcortical supratentorial white matter without abnormal enhancement, most likely representing nonactive demyelinating plaques (FIGURES 1B and 1C).

Dx is revisited. Our patient was referred to an NMO clinic for evaluation. After further testing (including a repeat MRI based on the neurologist’s specifications, anti-aquaporin antibody testing, and MOG-antibody testing) and case discussion, it was determined that the patient had MOG-antibody disease. This disease, along with NMO, comprise a spectrum of disorders referred to as neuromyelitis optica spectrum disorder (NMOSD).

The patient was subsequently prescribed a rituximab infusion, 500 mg/50 mL, to treat the current attack. One infusion was to be completed weekly for 2 weeks with plans to repeat treatment every 6 months to prevent flares of NMO. During the first dose, the patient had a reaction to the treatment, which caused pruritus and chest tightness. She was able to complete the infusion after being treated with diphenhydramine.

Tx continued. In order to complete the second of 2 infusions of rituximab, the patient was pretreated with oral methylprednisolone the night before the infusion, along with diphenhydramine and acetaminophen on the day of treatment. Fortunately, the patient tolerated the infusion well with no adverse effects or reactions.

Continue to: DISCUSSION

DISCUSSION

Within the NMO spectrum, the MOG antibody is positive in up to 42% of AQP4-seronegative cases.⁶ MOG is a minor myelin component that is expressed exclusively in the central nervous system on the surface of myelin and oligodendrocyte processes. The role of this glycoprotein is not well understood but is hypothesized to function as a cell surface receptor or cell adhesion molecule.⁷

Among a cohort of 252 patients from the United Kingdom who tested positive for the MOG-IgG1 antibody, optic neuritis was seen in 55%, while 18% experienced transverse myelitis, and 15% had a history of area postrema syndrome. A brain MRI identified lesions in all areas of the brain including the brain stem, cerebellum, and cerebral hemispheres.⁸

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein Barr virus seropositivity, and tobacco abuse.

Differential diagnosis. Many diseases or conditions that are inflammatory, autoimmune, infectious, or neoplastic can involve the central nervous system and mimic the clinical and radiologic phenotypes of NMOSD-AQP4. They include lupus, SjÖgren’s syndrome, multiple sclerosis, sarcoidosis, acute disseminated encephalomyelitis, HIV, and vitamin B₁₂ deficiency.

Treatment. The standard treatment is intravenous methylprednisolone, 1 g/d for 3 to 5 days followed by a steroid taper. Therapeutic plasma exchange is recommended for refractory cases and in patients with spinal cord demyelination.^9-11 Rituximab is the first-line therapy for attack prevention^12-15 in NMOSD broadly and may be effective in MOG antibody disease, as well. In an open-label study of patients with NMOSD treated with rituximab, 64% were relapse free at follow-up, which ranged from 12 to 67 months.¹³ In a long-term study of patients treated with rituximab, 87% maintained a reduced relapse rate and 93% had improvement or stability over a 5-year follow-up.¹⁴

Continue to: Our patient

Our patient. After her diagnosis of NMOSD/MOG-antibody disease, our patient’s symptoms progressed to include vertigo, vestibular ataxia, pruritus, left foot drop, lower extremity numbness, and decreased hearing. After the second rituximab infusion her symptoms continued, but over time stabilized and have not worsened. She currently receives gabapentin 300 mg every 8 hours, as needed, for extremity numbness (which has been working well) along with sertraline 100 mg/d for depression.

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein-Barr virus seropositivity, and tobacco abuse.

Subsequent office visits have showed no further weight loss. Based on the current response to the rituximab, her prognosis is undetermined by Neurology as they continue to monitor for progression.

THE TAKEAWAY

Vestibular ataxia, foot drop, pruritus, vertigo, decreased hearing, numbness, and oculomotor dysfunction in the presence of nausea and vomiting should raise suspicion for NMOSD. The presence of AQP4 antibodies along with demyelinating central nervous system lesions, is highly indicative of NMO. The presence of MOG antibodies may indicate NMOSD/MOG-antibody disease. The initial treatment of NMOSD is intravenous methylprednisolone, which can be followed by treatment with rituximab to achieve remission.

CORRESPONDENCE
Daniel Murphy, MD, FAAFP, Department of Family and Community Medicine, Texas Tech University Health Science Center El Paso, 9849 Kenworthy Street, El Paso, Texas 79924; [email protected]

THE CASE

A 26-year-old Hispanic/African American woman presented to our clinic with a 2-month history of nausea and vomiting, along with dizziness. The nausea and vomiting persistently worsened, and she was only able to tolerate apples and berries. During this 2-month period, she lost 20 pounds and her symptoms progressed to include pruritus, ataxia, and mild hearing loss, with reoccurring episodes of falls.

THE DIAGNOSIS

On examination, she was found to be bradycardic with a heart rate of 47 beats/min, right- axis deviation, and inverted T waves in leads I, II, and augmented vector left. Her family history included the death of an aunt who was in her early 30s due to an unknown heart condition.

Echocardiogram identified mild mitral valve regurgitation with an ejection fraction of 55% to 60% (reference range: 55%-70%). Cardiology determined that her bradycardia was not the source of her symptoms. A neurologic exam identified 3+ hyperreflexia (indicating the reflex was increased), tandem gait instability, and left oculomotor dysfunction.

Brain magnetic resonance imaging (MRI) identified bilateral parietal white matter lesions where a demyelinating process could not be excluded (FIGURE 1A). The patient’s symptoms of nausea and vomiting continued, and she only tolerated peanuts and liquids. An MRI of the spine was negative.

Laboratory testing revealed that the patient was negative for human immunodeficiency virus (HIV), syphilis, Lyme disease, and lupus. Her thyroid-stimulating hormone level was 1.7 mIU/L (reference range: 0.4-4.2 mIU/L), and her vitamin B₁₂ level was 504 pg/mL (reference range: 160-950 pg/mL).

The patient’s lumbar puncture was negative for oligoclonal bands. The IgG synthesis rate/index cerebrospinal fluid (CSF) was –3.9, ruling out multiple sclerosis. Her CSF culture was negative, with a glucose level of 42 mg/dL (reference range: 70-110 mg/dL), colorless appearance, 1 white blood cell, and spinal albumin of 12.2 mg/dL (reference range: 8-42 mg/dL). The visual evoked potential was negative. The aquaporin-4 (AQP4) antibody was positive at 3.4 U/mL, and the myelin oligodendrocyte glycoprotein (MOG) antibody was positive.

Gastroenterology concluded a normal gastric accommodation and unremarkable computed tomography (CT) enterography. Moderate erosions were identified in the stomach with an erythematous gastropathy. The patient was placed on a proton pump inhibitor.

Continue to: Following the examination...

Following the examination and laboratory testing, the patient was admitted under our family medicine service for neuromyelitis optica (NMO) affecting the area postrema. NMO, also known as Devic’s disease, is an autoimmune disorder that affects the spinal cord and optic nerves. Autoantibodies against AQP4 are created in the periphery and are directed against astrocytes in the central nervous system. These antibodies bind to the foot processes of astrocytes, inducing complement-mediated cell damage and granulocyte infiltration.^1-5

Intravenous methylprednisolone was initiated at 250 mg every 6 hours for 3 days. A repeat brain MRI demonstrated nonspecific multiple scattered foci of hyperintense signal involving the subcortical supratentorial white matter without abnormal enhancement, most likely representing nonactive demyelinating plaques (FIGURES 1B and 1C).

Dx is revisited. Our patient was referred to an NMO clinic for evaluation. After further testing (including a repeat MRI based on the neurologist’s specifications, anti-aquaporin antibody testing, and MOG-antibody testing) and case discussion, it was determined that the patient had MOG-antibody disease. This disease, along with NMO, comprise a spectrum of disorders referred to as neuromyelitis optica spectrum disorder (NMOSD).

The patient was subsequently prescribed a rituximab infusion, 500 mg/50 mL, to treat the current attack. One infusion was to be completed weekly for 2 weeks with plans to repeat treatment every 6 months to prevent flares of NMO. During the first dose, the patient had a reaction to the treatment, which caused pruritus and chest tightness. She was able to complete the infusion after being treated with diphenhydramine.

Tx continued. In order to complete the second of 2 infusions of rituximab, the patient was pretreated with oral methylprednisolone the night before the infusion, along with diphenhydramine and acetaminophen on the day of treatment. Fortunately, the patient tolerated the infusion well with no adverse effects or reactions.

Continue to: DISCUSSION

DISCUSSION

Within the NMO spectrum, the MOG antibody is positive in up to 42% of AQP4-seronegative cases.⁶ MOG is a minor myelin component that is expressed exclusively in the central nervous system on the surface of myelin and oligodendrocyte processes. The role of this glycoprotein is not well understood but is hypothesized to function as a cell surface receptor or cell adhesion molecule.⁷

Among a cohort of 252 patients from the United Kingdom who tested positive for the MOG-IgG1 antibody, optic neuritis was seen in 55%, while 18% experienced transverse myelitis, and 15% had a history of area postrema syndrome. A brain MRI identified lesions in all areas of the brain including the brain stem, cerebellum, and cerebral hemispheres.⁸

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein Barr virus seropositivity, and tobacco abuse.

Differential diagnosis. Many diseases or conditions that are inflammatory, autoimmune, infectious, or neoplastic can involve the central nervous system and mimic the clinical and radiologic phenotypes of NMOSD-AQP4. They include lupus, SjÖgren’s syndrome, multiple sclerosis, sarcoidosis, acute disseminated encephalomyelitis, HIV, and vitamin B₁₂ deficiency.

Treatment. The standard treatment is intravenous methylprednisolone, 1 g/d for 3 to 5 days followed by a steroid taper. Therapeutic plasma exchange is recommended for refractory cases and in patients with spinal cord demyelination.^9-11 Rituximab is the first-line therapy for attack prevention^12-15 in NMOSD broadly and may be effective in MOG antibody disease, as well. In an open-label study of patients with NMOSD treated with rituximab, 64% were relapse free at follow-up, which ranged from 12 to 67 months.¹³ In a long-term study of patients treated with rituximab, 87% maintained a reduced relapse rate and 93% had improvement or stability over a 5-year follow-up.¹⁴

Continue to: Our patient

Our patient. After her diagnosis of NMOSD/MOG-antibody disease, our patient’s symptoms progressed to include vertigo, vestibular ataxia, pruritus, left foot drop, lower extremity numbness, and decreased hearing. After the second rituximab infusion her symptoms continued, but over time stabilized and have not worsened. She currently receives gabapentin 300 mg every 8 hours, as needed, for extremity numbness (which has been working well) along with sertraline 100 mg/d for depression.

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein-Barr virus seropositivity, and tobacco abuse.

Subsequent office visits have showed no further weight loss. Based on the current response to the rituximab, her prognosis is undetermined by Neurology as they continue to monitor for progression.

THE TAKEAWAY

Vestibular ataxia, foot drop, pruritus, vertigo, decreased hearing, numbness, and oculomotor dysfunction in the presence of nausea and vomiting should raise suspicion for NMOSD. The presence of AQP4 antibodies along with demyelinating central nervous system lesions, is highly indicative of NMO. The presence of MOG antibodies may indicate NMOSD/MOG-antibody disease. The initial treatment of NMOSD is intravenous methylprednisolone, which can be followed by treatment with rituximab to achieve remission.

CORRESPONDENCE
Daniel Murphy, MD, FAAFP, Department of Family and Community Medicine, Texas Tech University Health Science Center El Paso, 9849 Kenworthy Street, El Paso, Texas 79924; [email protected]

ILLUSTRATIVE CASE

A 54-year-old woman with a history of hypertension presents with a chief complaint of dizziness. You require an assessment of orthostatic vital signs to proceed. In your busy clinical practice, when should assessment take place to be most useful?

Orthostatic hypotension (OH) is defined as a postural reduction in systolic blood pressure (BP) of ≥ 20 mm Hg or diastolic BP of ≥ 10 mm Hg, measured within 3 minutes of rising from supine to standing. This definition is based on consensus guidelines from the American Academy of Neurology and the American Autonomic Society² and has been upheld by European guidelines.³

The prevalence of OH is approximately 6% in the general population, with estimates ranging from 10% to 55% in older adults.^{4 ­}Etiology is often multifactorial; causes may be neurogenic (mediated by autonomic failure as in Parkinson’s disease, multiple system atrophy, or diabetic neuropathy), non-­neurogenic (related to medications or hypovolemia), or idiopathic.

It’s important to identify OH because of its associated increase in morbidities, such as an increased risk of falls (hazard ratio [HR] = 1.5),⁵ coronary heart disease (HR = 1.3), stroke (HR = 1.2), and all-cause mortality (HR = 1.4).⁶ Treatments include physical maneuvers (getting up slowly, leg crossing, and muscle clenching), increased salt and water intake, compression stockings, the addition of medications (such as fludrocortisone or midodrine), and the avoidance of other medications (such as benzodiazepines and diuretics).

The guideline-recommended 3-minute delay in assessment can be impractical in a busy clinical setting. Using data from the Atherosclerosis Risk in Communities (ARIC) study, investigators correlated the timing of measurements of postural change in BP with long-term adverse outcomes.¹

STUDY SUMMARY

Early vs late OH assessment in middle-aged adults

The ARIC study is a longitudinal, prospective, cohort study of almost 16,000 adults followed since 1987. Juraschek et al¹ assessed the optimal time to identify OH and its association with the adverse clinical outcomes of fall, fracture, syncope, motor vehicle crash, and mortality. The researchers sought to discover whether BP measurements determined immediately after standing predict adverse events as well as BP measurements taken closer to 3 minutes.

Study participants were between the ages of 45 and 64 years (mean 54 years), and 26% were black and 54% were female. They lived in 4 different US communities. The researchers excluded patients with missing OH assessments or other relevant cohort or historical data, leaving a cohort of 11,429 subjects.

Continue to: As part of their...

As part of their enrollment into the ARIC study, subjects had their BP measurements taken 2 to 5 times in the lying position (90% of participants had ≥ 4 measurements) and after standing (91% participants had ≥ 4 measurements) using a programmable automatic BP cuff. All 5 standing BP measurements (taken at a mean of 28, 53, 76, 100, and 116 seconds after standing) were measured for 7385 out of 11,429 (64.6%) participants. Subjects were asked if he or she “usually gets dizzy on standing up.”

This study found that orthostatic hypotension identified within 1 minute of standing was more clinically meaningful than OH identified after 1 minute.

Researchers determined the association between OH and postural change in systolic BP or postural change in diastolic BP with history of dizziness after standing. They also determined the incidence of falls, fracture, syncope, motor vehicle crash, and mortality via a review of hospitalizations and billing for Medicaid and Medicare services. Subjects were followed for a median of 23 years.

Results

Of the entire cohort, 1138 (10%) reported dizziness on standing. Only OH identified at the first BP measurement (mean 28 secs) was associated with a history of dizziness upon standing (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.18-1.89). Also, it was associated with the highest incidence of fracture, syncope, and death (18.9, 17, and 31.4 per 1000 person-years, respectively).

After adjusting for age, sex, and multiple other cardiovascular risk factors, the risk of falls was significantly associated with OH at BP measurements 1 to 4, but was most strongly associated with BP measurement 2 (taken at a mean of 53 secs after standing) (HR = 1.29; 95% CI, 1.12-1.49), which translates to 13.2 falls per 1000 patient-years. Fracture was associated with OH at measurements 1 (HR = 1.16; 95% CI, 1.01-1.34) and 2 (HR = 1.14; 95% CI, 1.01-1.29). Motor vehicle crashes were associated only with BP measurement 2 (HR = 1.43; 95% CI, 1.04-1.96). Finally, risk of syncope and risk of death were statistically associated with the presence of OH at all 5 BP measurements.

WHAT’S NEW

Earlier OH assessments are more informative than late ones

This study found OH identified within 1 minute of standing to be more clinically meaningful than OH identified after 1 minute. Also, the findings reinforce the relationship between OH and adverse events, including injury and overall mortality. Evaluation for OH performed only at 3 minutes may miss symptomatic OH.

Continue to: CAVEATS

Could a healthy population skew the results?

The population in this study was relatively healthy, with a lower prevalence of diabetes and coronary artery disease than the general population. While there is no reason to expect detection of OH to differ in a population with more comorbidities, the possibility exists.

If OH is not identified in < 1 minute of standing, standard OH evaluation within 3 minutes after standing should be performed, as OH identified at any time point after standing is associated with adverse events and increased mortality.

This study did not address the effects of medical intervention for OH on injury or mortality. Also, whether OH is the direct cause of the adverse outcomes or a marker for other disease is unknown.

CHALLENGES TO IMPLEMENTATION

A change to protocols and guidelines

Although none were noted, any change in practice requires updating clinical protocols and guidelines, which can take time.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 54-year-old woman with a history of hypertension presents with a chief complaint of dizziness. You require an assessment of orthostatic vital signs to proceed. In your busy clinical practice, when should assessment take place to be most useful?

Orthostatic hypotension (OH) is defined as a postural reduction in systolic blood pressure (BP) of ≥ 20 mm Hg or diastolic BP of ≥ 10 mm Hg, measured within 3 minutes of rising from supine to standing. This definition is based on consensus guidelines from the American Academy of Neurology and the American Autonomic Society² and has been upheld by European guidelines.³

The prevalence of OH is approximately 6% in the general population, with estimates ranging from 10% to 55% in older adults.^{4 ­}Etiology is often multifactorial; causes may be neurogenic (mediated by autonomic failure as in Parkinson’s disease, multiple system atrophy, or diabetic neuropathy), non-­neurogenic (related to medications or hypovolemia), or idiopathic.

It’s important to identify OH because of its associated increase in morbidities, such as an increased risk of falls (hazard ratio [HR] = 1.5),⁵ coronary heart disease (HR = 1.3), stroke (HR = 1.2), and all-cause mortality (HR = 1.4).⁶ Treatments include physical maneuvers (getting up slowly, leg crossing, and muscle clenching), increased salt and water intake, compression stockings, the addition of medications (such as fludrocortisone or midodrine), and the avoidance of other medications (such as benzodiazepines and diuretics).

The guideline-recommended 3-minute delay in assessment can be impractical in a busy clinical setting. Using data from the Atherosclerosis Risk in Communities (ARIC) study, investigators correlated the timing of measurements of postural change in BP with long-term adverse outcomes.¹

STUDY SUMMARY

Early vs late OH assessment in middle-aged adults

The ARIC study is a longitudinal, prospective, cohort study of almost 16,000 adults followed since 1987. Juraschek et al¹ assessed the optimal time to identify OH and its association with the adverse clinical outcomes of fall, fracture, syncope, motor vehicle crash, and mortality. The researchers sought to discover whether BP measurements determined immediately after standing predict adverse events as well as BP measurements taken closer to 3 minutes.

Study participants were between the ages of 45 and 64 years (mean 54 years), and 26% were black and 54% were female. They lived in 4 different US communities. The researchers excluded patients with missing OH assessments or other relevant cohort or historical data, leaving a cohort of 11,429 subjects.

Continue to: As part of their...

As part of their enrollment into the ARIC study, subjects had their BP measurements taken 2 to 5 times in the lying position (90% of participants had ≥ 4 measurements) and after standing (91% participants had ≥ 4 measurements) using a programmable automatic BP cuff. All 5 standing BP measurements (taken at a mean of 28, 53, 76, 100, and 116 seconds after standing) were measured for 7385 out of 11,429 (64.6%) participants. Subjects were asked if he or she “usually gets dizzy on standing up.”

This study found that orthostatic hypotension identified within 1 minute of standing was more clinically meaningful than OH identified after 1 minute.

Researchers determined the association between OH and postural change in systolic BP or postural change in diastolic BP with history of dizziness after standing. They also determined the incidence of falls, fracture, syncope, motor vehicle crash, and mortality via a review of hospitalizations and billing for Medicaid and Medicare services. Subjects were followed for a median of 23 years.

Results

Of the entire cohort, 1138 (10%) reported dizziness on standing. Only OH identified at the first BP measurement (mean 28 secs) was associated with a history of dizziness upon standing (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.18-1.89). Also, it was associated with the highest incidence of fracture, syncope, and death (18.9, 17, and 31.4 per 1000 person-years, respectively).

After adjusting for age, sex, and multiple other cardiovascular risk factors, the risk of falls was significantly associated with OH at BP measurements 1 to 4, but was most strongly associated with BP measurement 2 (taken at a mean of 53 secs after standing) (HR = 1.29; 95% CI, 1.12-1.49), which translates to 13.2 falls per 1000 patient-years. Fracture was associated with OH at measurements 1 (HR = 1.16; 95% CI, 1.01-1.34) and 2 (HR = 1.14; 95% CI, 1.01-1.29). Motor vehicle crashes were associated only with BP measurement 2 (HR = 1.43; 95% CI, 1.04-1.96). Finally, risk of syncope and risk of death were statistically associated with the presence of OH at all 5 BP measurements.

WHAT’S NEW

Earlier OH assessments are more informative than late ones

This study found OH identified within 1 minute of standing to be more clinically meaningful than OH identified after 1 minute. Also, the findings reinforce the relationship between OH and adverse events, including injury and overall mortality. Evaluation for OH performed only at 3 minutes may miss symptomatic OH.

Continue to: CAVEATS

Could a healthy population skew the results?

The population in this study was relatively healthy, with a lower prevalence of diabetes and coronary artery disease than the general population. While there is no reason to expect detection of OH to differ in a population with more comorbidities, the possibility exists.

If OH is not identified in < 1 minute of standing, standard OH evaluation within 3 minutes after standing should be performed, as OH identified at any time point after standing is associated with adverse events and increased mortality.

This study did not address the effects of medical intervention for OH on injury or mortality. Also, whether OH is the direct cause of the adverse outcomes or a marker for other disease is unknown.

CHALLENGES TO IMPLEMENTATION

A change to protocols and guidelines

Although none were noted, any change in practice requires updating clinical protocols and guidelines, which can take time.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 54-year-old woman with a history of hypertension presents with a chief complaint of dizziness. You require an assessment of orthostatic vital signs to proceed. In your busy clinical practice, when should assessment take place to be most useful?

Orthostatic hypotension (OH) is defined as a postural reduction in systolic blood pressure (BP) of ≥ 20 mm Hg or diastolic BP of ≥ 10 mm Hg, measured within 3 minutes of rising from supine to standing. This definition is based on consensus guidelines from the American Academy of Neurology and the American Autonomic Society² and has been upheld by European guidelines.³

The prevalence of OH is approximately 6% in the general population, with estimates ranging from 10% to 55% in older adults.^{4 ­}Etiology is often multifactorial; causes may be neurogenic (mediated by autonomic failure as in Parkinson’s disease, multiple system atrophy, or diabetic neuropathy), non-­neurogenic (related to medications or hypovolemia), or idiopathic.

It’s important to identify OH because of its associated increase in morbidities, such as an increased risk of falls (hazard ratio [HR] = 1.5),⁵ coronary heart disease (HR = 1.3), stroke (HR = 1.2), and all-cause mortality (HR = 1.4).⁶ Treatments include physical maneuvers (getting up slowly, leg crossing, and muscle clenching), increased salt and water intake, compression stockings, the addition of medications (such as fludrocortisone or midodrine), and the avoidance of other medications (such as benzodiazepines and diuretics).

The guideline-recommended 3-minute delay in assessment can be impractical in a busy clinical setting. Using data from the Atherosclerosis Risk in Communities (ARIC) study, investigators correlated the timing of measurements of postural change in BP with long-term adverse outcomes.¹

STUDY SUMMARY

Early vs late OH assessment in middle-aged adults

The ARIC study is a longitudinal, prospective, cohort study of almost 16,000 adults followed since 1987. Juraschek et al¹ assessed the optimal time to identify OH and its association with the adverse clinical outcomes of fall, fracture, syncope, motor vehicle crash, and mortality. The researchers sought to discover whether BP measurements determined immediately after standing predict adverse events as well as BP measurements taken closer to 3 minutes.

Study participants were between the ages of 45 and 64 years (mean 54 years), and 26% were black and 54% were female. They lived in 4 different US communities. The researchers excluded patients with missing OH assessments or other relevant cohort or historical data, leaving a cohort of 11,429 subjects.

Continue to: As part of their...

As part of their enrollment into the ARIC study, subjects had their BP measurements taken 2 to 5 times in the lying position (90% of participants had ≥ 4 measurements) and after standing (91% participants had ≥ 4 measurements) using a programmable automatic BP cuff. All 5 standing BP measurements (taken at a mean of 28, 53, 76, 100, and 116 seconds after standing) were measured for 7385 out of 11,429 (64.6%) participants. Subjects were asked if he or she “usually gets dizzy on standing up.”

This study found that orthostatic hypotension identified within 1 minute of standing was more clinically meaningful than OH identified after 1 minute.

Researchers determined the association between OH and postural change in systolic BP or postural change in diastolic BP with history of dizziness after standing. They also determined the incidence of falls, fracture, syncope, motor vehicle crash, and mortality via a review of hospitalizations and billing for Medicaid and Medicare services. Subjects were followed for a median of 23 years.

Results

Of the entire cohort, 1138 (10%) reported dizziness on standing. Only OH identified at the first BP measurement (mean 28 secs) was associated with a history of dizziness upon standing (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.18-1.89). Also, it was associated with the highest incidence of fracture, syncope, and death (18.9, 17, and 31.4 per 1000 person-years, respectively).

After adjusting for age, sex, and multiple other cardiovascular risk factors, the risk of falls was significantly associated with OH at BP measurements 1 to 4, but was most strongly associated with BP measurement 2 (taken at a mean of 53 secs after standing) (HR = 1.29; 95% CI, 1.12-1.49), which translates to 13.2 falls per 1000 patient-years. Fracture was associated with OH at measurements 1 (HR = 1.16; 95% CI, 1.01-1.34) and 2 (HR = 1.14; 95% CI, 1.01-1.29). Motor vehicle crashes were associated only with BP measurement 2 (HR = 1.43; 95% CI, 1.04-1.96). Finally, risk of syncope and risk of death were statistically associated with the presence of OH at all 5 BP measurements.

WHAT’S NEW

Earlier OH assessments are more informative than late ones

This study found OH identified within 1 minute of standing to be more clinically meaningful than OH identified after 1 minute. Also, the findings reinforce the relationship between OH and adverse events, including injury and overall mortality. Evaluation for OH performed only at 3 minutes may miss symptomatic OH.

Continue to: CAVEATS

Could a healthy population skew the results?

The population in this study was relatively healthy, with a lower prevalence of diabetes and coronary artery disease than the general population. While there is no reason to expect detection of OH to differ in a population with more comorbidities, the possibility exists.

If OH is not identified in < 1 minute of standing, standard OH evaluation within 3 minutes after standing should be performed, as OH identified at any time point after standing is associated with adverse events and increased mortality.

This study did not address the effects of medical intervention for OH on injury or mortality. Also, whether OH is the direct cause of the adverse outcomes or a marker for other disease is unknown.

CHALLENGES TO IMPLEMENTATION

A change to protocols and guidelines

Although none were noted, any change in practice requires updating clinical protocols and guidelines, which can take time.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

THE CASE

Emily T,* a 30-year-old woman, visited her primary care physician as follow-up to reassess her grief over the loss of her father a year earlier. Emily was her father’s primary caretaker and still lived alone in his home. Emily had a history of chronic pain and major depressive disorder and had expressed feelings of worthlessness and hopelessness about her future since her father’s passing. In addition to her continuing grief response, she reported feeling worse on most days. She completed the Patient Health Questionnaire-9, and results indicated anhedonia, depressed mood, psychomotor retardation, hypersomnia, decreased appetite, decreased concentration, and thoughts that she would be better off dead.

• HOW WOULD YOU PROCEED WITH THIS PATIENT?

* The patient’s name has been changed to protect her identity.

In the United States, 1 suicide occurs on average every 12 minutes; lifetime prevalence of suicide attempts ranges from 1.9% to 8.7%.¹ Suicide is the 10th overall cause of death in the United States, and it is the second leading cause of death for adults 18 to 34 years of age.² In one study, nearly half of suicide victims had contact with primary care providers within 1 month of their suicide.³ Unfortunately, additional research suggests that primary care physicians appropriately screen for suicide in fewer than 40% of patient encounters.^4,5

Suicide is defined as “death caused by self-directed injurious behavior with any intent to die as a result of the behavior.”⁶ When screening for suicide, be aware of the many terms related to suicide evaluation (TABLE 1⁶). Be mindful, too, of the differences between suicidal and nonsuicidal ideation (death wish); the continuum of such thoughts ranges from those that lead to suicide to those that do not.

SUICIDE SCREENING RECOMMENDATIONS VARY

Although most health care providers would agree that intervening with a suicidal patient first requires competence in assessing suicide risk, regulating bodies differ on the use of routine screening and on appropriate screening tools for primary care. The Joint Commission recommends assessing suicide risk with all primary care patients,⁷ while the US Preventive Services Tasks Force (USPSTF) advises against universal suicide screening in primary care⁸ due to insufficient evidence that its benefit outweighs potential harm (TABLE 2^7-12). Instead, the USPSTF recommends screening primary care patients with known mental health disorders, recent inpatient psychiatric hospitalization, prior suicide or self-harm attempts, or increased emotional distress.⁸ USPSTF does support screening for depression with routine mental health measures that include items assessing suicidality.^8,13,14 The American Academy of Family Physicians supports the recommendations by USPSTF.¹³

When screening for suicide, a comprehensive suicide risk assessment is recommended by both the Joint Commission and USPSTF.^7,8 A comprehensive suicide risk assessment has 4 components: (1) identification of current suicide risk factors, (2) identification of protective factors, (3) inquiry about suicidal ideation, intent, and plan, and (4) primary care practitioner judgment of risk level and plan for clinical intervention.^9-11

Take into account both risks and protective factors

Unfortunately, there is no “typical” description of a patient at risk for suicide and no validated models to predict suicide risk.^8,10 A multitude of factors, both individual and societal, can increase or reduce risk of suicide.^11,15 Each patient’s unique history includes risk factors for suicide including precipitating events (eg, job loss, termination of a relationship, death of a loved one) and protective factors that may be evaluated to determine overall risk for suicide (TABLE 3^8,10,11,15). According to the Centers for Disease Control and Prevention (CDC), there are several warning signs for patients who may be at greater risk for suicide: isolation, increased anxiety or anger, obtaining lethal means (eg, guns, knives, ropes), frequent mood swings, sleep changes, feeling trapped or in pain, increased substance use, discussing plans for death or wishes of death, and feeling like a burden.¹⁶

CHOOSING FROM AMONG SUICIDE SCREENING TOOLS

Brief mental health screening tools such as the Patient Health Questionnaire-9 (PHQ-9) are commonly used as primary screening tools for suicidal ideation.¹⁷ However, to attain a fuller understanding of a patient’s suicidality, select a screening tool that specifically focuses on suicidal ideation, intent, or plan, and then interview the patient (TABLE 4^10,11,15).

Continue to: Several screening tools...

Several screening tools are available for exploring a patient’s suicidality. Unfortunately, most of them are supported by limited evidence of effectiveness in identifying suicide risk.^8-10 An exception is the well-researched and commonly used Columbia-Suicide Severity Rating Scale (C-SSRS).^18,19 In a comparative study conducted at 2 primary care clinics, researchers found that the suicide item included in the PHQ-9 provided poor sensitivity but moderate specificity (60% and 84%, respectively),²⁰ while the C-SSRS showed high sensitivity (100%) and specificity (96%-100%) in accurately identifying various suicidal self-injurious behaviors above and beyond what was identified through a structured clinical interview.²⁰ Free copies of the C-SSRS, training materials, and follow-up assessments in multiple languages can be obtained on The Columbia Lighthouse Project Web site (http://cssrs.columbia.edu/).¹⁹

RECOMMENDATIONS FOR INTERVENTION

While there is debate regarding whom to screen for suicide, the importance of intervention when a patient is revealed to be at risk is clear. After completing a comprehensive suicide risk assessment, designate the patient’s level of risk as high, moderate, or low, and follow a stepped approach to clinical care (see the Assessment and Interventions with Potentially Suicidal Patients table (page 31) at https://www.sprc.org/sites/default/files/Final%20National%20Suicide%20Prevention%20Toolkit%202.15.18%20FINAL.pdf).¹¹ Provide any patient at risk, regardless of level, with contact information for local crisis and peer support as well as national resources (National Suicide Prevention Lifeline, (800) 273-TALK (8255), https://suicidepreventionlifeline.org/; Crisis Text Line, Text HOME to 741741, https://www.crisistextline.org/).

The Columbia- Suicide Severity Rating Scale has higher sensitivity and specificity for suicide risk than the PHQ-9.

When a patient is at high risk for suicide and reports an imminent plan or intent, ensure their safety through inpatient psychiatric hospitalization and then close follow-up upon hospital discharge. First encourage voluntary hospitalization in a collaborative discussion with the patient; resort to involuntary hospitalization only if the patient resists.

What not to do. When the patient does not require immediate hospitalization, evidence recommends against contracting for patient safety via a written contract or requiring patients to verbally guarantee that they will not commit suicide upon leaving a provider’s office.²¹ Concerns about such contracts include a lack of evidence supporting their use, decreased vigilance by health care workers when such contracts are in place, and questions regarding informed consent and competence.²¹ Instead, engage a patient who is at moderate or low risk in safety planning, and meet with the patient frequently to discuss continued safety planning through close follow-up (or with a behavioral health provider if available).^10-12,22 With patients previously identified as at high risk for suicide who return from inpatient psychiatric hospitalization, continue to screen them for suicide at subsequent visits and engage them in collaborative safety planning.

Safety planning (TABLE 5¹²), also known as crisis response planning, is considered a best practice and effective suicide prevention intervention by the Suicide Prevention Resource Center and the American Foundation for Suicide Prevention Best Practices Registry for Suicide Prevention.²³ Safety planning involves a collaboration between patient and physician to identify risk factors and protective factors along with crisis resources and strategies to reduce engagement in suicide behaviors.^12,22

Continue to: THE CASE

THE CASE

Based on the concerning results from the ­PHQ-9 suicide item, Emily’s physician conducted a comprehensive suicide risk assessment using both clinical interview and the C-SSRS. Emily reported that she was experiencing daily suicidal ideations due to a lack of social support and longing to be with her deceased father. She had not previously attempted suicide and had no imminent intent to commit suicide. Emily did, however, have a plan to overdose on opioid medications she had been collecting for many months. Her physician determined that Emily was at moderate risk for suicide and consulted with the clinic’s behavioral health consultant, a psychologist, to confirm a treatment plan.

After a comprehensive suicide risk assessment, determine the patient’s level of risk and follow a stepped approach to clinical care.

Emily and her physician collaboratively developed a safety plan including means reduction. Emily agreed to have her physician contact a friend to assist with safety planning, and she brought her opioid medications to the primary care clinic for disposal. Follow-up appointments were scheduled with the physician for every other week. The psychologist was available at the time of the first biweekly appointment to consult with the physician if needed. This initial appointment was focused on Emily’s suicide risk and her ability to engage in safety planning. In addition, the physician recommended that Emily schedule time with the psychologist so that she could work on her grief and depressive symptoms.

After several weeks of the biweekly appointments with both the primary care provider and the psychologist, Emily was no longer reporting suicidal ideation and she was ready to engage in coping strategies to deal with her grief and depressive symptoms.

CORRESPONDENCE
Meredith L.C. Williamson, PhD, 2900 E. 29th Street, Suite 100, Bryan, TX 77802; [email protected].

THE CASE

Emily T,* a 30-year-old woman, visited her primary care physician as follow-up to reassess her grief over the loss of her father a year earlier. Emily was her father’s primary caretaker and still lived alone in his home. Emily had a history of chronic pain and major depressive disorder and had expressed feelings of worthlessness and hopelessness about her future since her father’s passing. In addition to her continuing grief response, she reported feeling worse on most days. She completed the Patient Health Questionnaire-9, and results indicated anhedonia, depressed mood, psychomotor retardation, hypersomnia, decreased appetite, decreased concentration, and thoughts that she would be better off dead.

• HOW WOULD YOU PROCEED WITH THIS PATIENT?

* The patient’s name has been changed to protect her identity.

In the United States, 1 suicide occurs on average every 12 minutes; lifetime prevalence of suicide attempts ranges from 1.9% to 8.7%.¹ Suicide is the 10th overall cause of death in the United States, and it is the second leading cause of death for adults 18 to 34 years of age.² In one study, nearly half of suicide victims had contact with primary care providers within 1 month of their suicide.³ Unfortunately, additional research suggests that primary care physicians appropriately screen for suicide in fewer than 40% of patient encounters.^4,5

Suicide is defined as “death caused by self-directed injurious behavior with any intent to die as a result of the behavior.”⁶ When screening for suicide, be aware of the many terms related to suicide evaluation (TABLE 1⁶). Be mindful, too, of the differences between suicidal and nonsuicidal ideation (death wish); the continuum of such thoughts ranges from those that lead to suicide to those that do not.

SUICIDE SCREENING RECOMMENDATIONS VARY

Although most health care providers would agree that intervening with a suicidal patient first requires competence in assessing suicide risk, regulating bodies differ on the use of routine screening and on appropriate screening tools for primary care. The Joint Commission recommends assessing suicide risk with all primary care patients,⁷ while the US Preventive Services Tasks Force (USPSTF) advises against universal suicide screening in primary care⁸ due to insufficient evidence that its benefit outweighs potential harm (TABLE 2^7-12). Instead, the USPSTF recommends screening primary care patients with known mental health disorders, recent inpatient psychiatric hospitalization, prior suicide or self-harm attempts, or increased emotional distress.⁸ USPSTF does support screening for depression with routine mental health measures that include items assessing suicidality.^8,13,14 The American Academy of Family Physicians supports the recommendations by USPSTF.¹³

When screening for suicide, a comprehensive suicide risk assessment is recommended by both the Joint Commission and USPSTF.^7,8 A comprehensive suicide risk assessment has 4 components: (1) identification of current suicide risk factors, (2) identification of protective factors, (3) inquiry about suicidal ideation, intent, and plan, and (4) primary care practitioner judgment of risk level and plan for clinical intervention.^9-11

Take into account both risks and protective factors

Unfortunately, there is no “typical” description of a patient at risk for suicide and no validated models to predict suicide risk.^8,10 A multitude of factors, both individual and societal, can increase or reduce risk of suicide.^11,15 Each patient’s unique history includes risk factors for suicide including precipitating events (eg, job loss, termination of a relationship, death of a loved one) and protective factors that may be evaluated to determine overall risk for suicide (TABLE 3^8,10,11,15). According to the Centers for Disease Control and Prevention (CDC), there are several warning signs for patients who may be at greater risk for suicide: isolation, increased anxiety or anger, obtaining lethal means (eg, guns, knives, ropes), frequent mood swings, sleep changes, feeling trapped or in pain, increased substance use, discussing plans for death or wishes of death, and feeling like a burden.¹⁶

CHOOSING FROM AMONG SUICIDE SCREENING TOOLS

Brief mental health screening tools such as the Patient Health Questionnaire-9 (PHQ-9) are commonly used as primary screening tools for suicidal ideation.¹⁷ However, to attain a fuller understanding of a patient’s suicidality, select a screening tool that specifically focuses on suicidal ideation, intent, or plan, and then interview the patient (TABLE 4^10,11,15).

Continue to: Several screening tools...

Several screening tools are available for exploring a patient’s suicidality. Unfortunately, most of them are supported by limited evidence of effectiveness in identifying suicide risk.^8-10 An exception is the well-researched and commonly used Columbia-Suicide Severity Rating Scale (C-SSRS).^18,19 In a comparative study conducted at 2 primary care clinics, researchers found that the suicide item included in the PHQ-9 provided poor sensitivity but moderate specificity (60% and 84%, respectively),²⁰ while the C-SSRS showed high sensitivity (100%) and specificity (96%-100%) in accurately identifying various suicidal self-injurious behaviors above and beyond what was identified through a structured clinical interview.²⁰ Free copies of the C-SSRS, training materials, and follow-up assessments in multiple languages can be obtained on The Columbia Lighthouse Project Web site (http://cssrs.columbia.edu/).¹⁹

RECOMMENDATIONS FOR INTERVENTION

While there is debate regarding whom to screen for suicide, the importance of intervention when a patient is revealed to be at risk is clear. After completing a comprehensive suicide risk assessment, designate the patient’s level of risk as high, moderate, or low, and follow a stepped approach to clinical care (see the Assessment and Interventions with Potentially Suicidal Patients table (page 31) at https://www.sprc.org/sites/default/files/Final%20National%20Suicide%20Prevention%20Toolkit%202.15.18%20FINAL.pdf).¹¹ Provide any patient at risk, regardless of level, with contact information for local crisis and peer support as well as national resources (National Suicide Prevention Lifeline, (800) 273-TALK (8255), https://suicidepreventionlifeline.org/; Crisis Text Line, Text HOME to 741741, https://www.crisistextline.org/).

The Columbia- Suicide Severity Rating Scale has higher sensitivity and specificity for suicide risk than the PHQ-9.

When a patient is at high risk for suicide and reports an imminent plan or intent, ensure their safety through inpatient psychiatric hospitalization and then close follow-up upon hospital discharge. First encourage voluntary hospitalization in a collaborative discussion with the patient; resort to involuntary hospitalization only if the patient resists.

What not to do. When the patient does not require immediate hospitalization, evidence recommends against contracting for patient safety via a written contract or requiring patients to verbally guarantee that they will not commit suicide upon leaving a provider’s office.²¹ Concerns about such contracts include a lack of evidence supporting their use, decreased vigilance by health care workers when such contracts are in place, and questions regarding informed consent and competence.²¹ Instead, engage a patient who is at moderate or low risk in safety planning, and meet with the patient frequently to discuss continued safety planning through close follow-up (or with a behavioral health provider if available).^10-12,22 With patients previously identified as at high risk for suicide who return from inpatient psychiatric hospitalization, continue to screen them for suicide at subsequent visits and engage them in collaborative safety planning.

Safety planning (TABLE 5¹²), also known as crisis response planning, is considered a best practice and effective suicide prevention intervention by the Suicide Prevention Resource Center and the American Foundation for Suicide Prevention Best Practices Registry for Suicide Prevention.²³ Safety planning involves a collaboration between patient and physician to identify risk factors and protective factors along with crisis resources and strategies to reduce engagement in suicide behaviors.^12,22

Continue to: THE CASE

THE CASE

Based on the concerning results from the ­PHQ-9 suicide item, Emily’s physician conducted a comprehensive suicide risk assessment using both clinical interview and the C-SSRS. Emily reported that she was experiencing daily suicidal ideations due to a lack of social support and longing to be with her deceased father. She had not previously attempted suicide and had no imminent intent to commit suicide. Emily did, however, have a plan to overdose on opioid medications she had been collecting for many months. Her physician determined that Emily was at moderate risk for suicide and consulted with the clinic’s behavioral health consultant, a psychologist, to confirm a treatment plan.

After a comprehensive suicide risk assessment, determine the patient’s level of risk and follow a stepped approach to clinical care.

Emily and her physician collaboratively developed a safety plan including means reduction. Emily agreed to have her physician contact a friend to assist with safety planning, and she brought her opioid medications to the primary care clinic for disposal. Follow-up appointments were scheduled with the physician for every other week. The psychologist was available at the time of the first biweekly appointment to consult with the physician if needed. This initial appointment was focused on Emily’s suicide risk and her ability to engage in safety planning. In addition, the physician recommended that Emily schedule time with the psychologist so that she could work on her grief and depressive symptoms.

After several weeks of the biweekly appointments with both the primary care provider and the psychologist, Emily was no longer reporting suicidal ideation and she was ready to engage in coping strategies to deal with her grief and depressive symptoms.

CORRESPONDENCE
Meredith L.C. Williamson, PhD, 2900 E. 29th Street, Suite 100, Bryan, TX 77802; [email protected].

THE CASE

Emily T,* a 30-year-old woman, visited her primary care physician as follow-up to reassess her grief over the loss of her father a year earlier. Emily was her father’s primary caretaker and still lived alone in his home. Emily had a history of chronic pain and major depressive disorder and had expressed feelings of worthlessness and hopelessness about her future since her father’s passing. In addition to her continuing grief response, she reported feeling worse on most days. She completed the Patient Health Questionnaire-9, and results indicated anhedonia, depressed mood, psychomotor retardation, hypersomnia, decreased appetite, decreased concentration, and thoughts that she would be better off dead.

• HOW WOULD YOU PROCEED WITH THIS PATIENT?

* The patient’s name has been changed to protect her identity.

In the United States, 1 suicide occurs on average every 12 minutes; lifetime prevalence of suicide attempts ranges from 1.9% to 8.7%.¹ Suicide is the 10th overall cause of death in the United States, and it is the second leading cause of death for adults 18 to 34 years of age.² In one study, nearly half of suicide victims had contact with primary care providers within 1 month of their suicide.³ Unfortunately, additional research suggests that primary care physicians appropriately screen for suicide in fewer than 40% of patient encounters.^4,5

Suicide is defined as “death caused by self-directed injurious behavior with any intent to die as a result of the behavior.”⁶ When screening for suicide, be aware of the many terms related to suicide evaluation (TABLE 1⁶). Be mindful, too, of the differences between suicidal and nonsuicidal ideation (death wish); the continuum of such thoughts ranges from those that lead to suicide to those that do not.

SUICIDE SCREENING RECOMMENDATIONS VARY

Although most health care providers would agree that intervening with a suicidal patient first requires competence in assessing suicide risk, regulating bodies differ on the use of routine screening and on appropriate screening tools for primary care. The Joint Commission recommends assessing suicide risk with all primary care patients,⁷ while the US Preventive Services Tasks Force (USPSTF) advises against universal suicide screening in primary care⁸ due to insufficient evidence that its benefit outweighs potential harm (TABLE 2^7-12). Instead, the USPSTF recommends screening primary care patients with known mental health disorders, recent inpatient psychiatric hospitalization, prior suicide or self-harm attempts, or increased emotional distress.⁸ USPSTF does support screening for depression with routine mental health measures that include items assessing suicidality.^8,13,14 The American Academy of Family Physicians supports the recommendations by USPSTF.¹³

When screening for suicide, a comprehensive suicide risk assessment is recommended by both the Joint Commission and USPSTF.^7,8 A comprehensive suicide risk assessment has 4 components: (1) identification of current suicide risk factors, (2) identification of protective factors, (3) inquiry about suicidal ideation, intent, and plan, and (4) primary care practitioner judgment of risk level and plan for clinical intervention.^9-11

Take into account both risks and protective factors

Unfortunately, there is no “typical” description of a patient at risk for suicide and no validated models to predict suicide risk.^8,10 A multitude of factors, both individual and societal, can increase or reduce risk of suicide.^11,15 Each patient’s unique history includes risk factors for suicide including precipitating events (eg, job loss, termination of a relationship, death of a loved one) and protective factors that may be evaluated to determine overall risk for suicide (TABLE 3^8,10,11,15). According to the Centers for Disease Control and Prevention (CDC), there are several warning signs for patients who may be at greater risk for suicide: isolation, increased anxiety or anger, obtaining lethal means (eg, guns, knives, ropes), frequent mood swings, sleep changes, feeling trapped or in pain, increased substance use, discussing plans for death or wishes of death, and feeling like a burden.¹⁶

CHOOSING FROM AMONG SUICIDE SCREENING TOOLS

Brief mental health screening tools such as the Patient Health Questionnaire-9 (PHQ-9) are commonly used as primary screening tools for suicidal ideation.¹⁷ However, to attain a fuller understanding of a patient’s suicidality, select a screening tool that specifically focuses on suicidal ideation, intent, or plan, and then interview the patient (TABLE 4^10,11,15).

Continue to: Several screening tools...

Several screening tools are available for exploring a patient’s suicidality. Unfortunately, most of them are supported by limited evidence of effectiveness in identifying suicide risk.^8-10 An exception is the well-researched and commonly used Columbia-Suicide Severity Rating Scale (C-SSRS).^18,19 In a comparative study conducted at 2 primary care clinics, researchers found that the suicide item included in the PHQ-9 provided poor sensitivity but moderate specificity (60% and 84%, respectively),²⁰ while the C-SSRS showed high sensitivity (100%) and specificity (96%-100%) in accurately identifying various suicidal self-injurious behaviors above and beyond what was identified through a structured clinical interview.²⁰ Free copies of the C-SSRS, training materials, and follow-up assessments in multiple languages can be obtained on The Columbia Lighthouse Project Web site (http://cssrs.columbia.edu/).¹⁹

RECOMMENDATIONS FOR INTERVENTION

While there is debate regarding whom to screen for suicide, the importance of intervention when a patient is revealed to be at risk is clear. After completing a comprehensive suicide risk assessment, designate the patient’s level of risk as high, moderate, or low, and follow a stepped approach to clinical care (see the Assessment and Interventions with Potentially Suicidal Patients table (page 31) at https://www.sprc.org/sites/default/files/Final%20National%20Suicide%20Prevention%20Toolkit%202.15.18%20FINAL.pdf).¹¹ Provide any patient at risk, regardless of level, with contact information for local crisis and peer support as well as national resources (National Suicide Prevention Lifeline, (800) 273-TALK (8255), https://suicidepreventionlifeline.org/; Crisis Text Line, Text HOME to 741741, https://www.crisistextline.org/).

The Columbia- Suicide Severity Rating Scale has higher sensitivity and specificity for suicide risk than the PHQ-9.

When a patient is at high risk for suicide and reports an imminent plan or intent, ensure their safety through inpatient psychiatric hospitalization and then close follow-up upon hospital discharge. First encourage voluntary hospitalization in a collaborative discussion with the patient; resort to involuntary hospitalization only if the patient resists.

What not to do. When the patient does not require immediate hospitalization, evidence recommends against contracting for patient safety via a written contract or requiring patients to verbally guarantee that they will not commit suicide upon leaving a provider’s office.²¹ Concerns about such contracts include a lack of evidence supporting their use, decreased vigilance by health care workers when such contracts are in place, and questions regarding informed consent and competence.²¹ Instead, engage a patient who is at moderate or low risk in safety planning, and meet with the patient frequently to discuss continued safety planning through close follow-up (or with a behavioral health provider if available).^10-12,22 With patients previously identified as at high risk for suicide who return from inpatient psychiatric hospitalization, continue to screen them for suicide at subsequent visits and engage them in collaborative safety planning.

Safety planning (TABLE 5¹²), also known as crisis response planning, is considered a best practice and effective suicide prevention intervention by the Suicide Prevention Resource Center and the American Foundation for Suicide Prevention Best Practices Registry for Suicide Prevention.²³ Safety planning involves a collaboration between patient and physician to identify risk factors and protective factors along with crisis resources and strategies to reduce engagement in suicide behaviors.^12,22

Continue to: THE CASE

THE CASE

Based on the concerning results from the ­PHQ-9 suicide item, Emily’s physician conducted a comprehensive suicide risk assessment using both clinical interview and the C-SSRS. Emily reported that she was experiencing daily suicidal ideations due to a lack of social support and longing to be with her deceased father. She had not previously attempted suicide and had no imminent intent to commit suicide. Emily did, however, have a plan to overdose on opioid medications she had been collecting for many months. Her physician determined that Emily was at moderate risk for suicide and consulted with the clinic’s behavioral health consultant, a psychologist, to confirm a treatment plan.

After a comprehensive suicide risk assessment, determine the patient’s level of risk and follow a stepped approach to clinical care.

Emily and her physician collaboratively developed a safety plan including means reduction. Emily agreed to have her physician contact a friend to assist with safety planning, and she brought her opioid medications to the primary care clinic for disposal. Follow-up appointments were scheduled with the physician for every other week. The psychologist was available at the time of the first biweekly appointment to consult with the physician if needed. This initial appointment was focused on Emily’s suicide risk and her ability to engage in safety planning. In addition, the physician recommended that Emily schedule time with the psychologist so that she could work on her grief and depressive symptoms.

After several weeks of the biweekly appointments with both the primary care provider and the psychologist, Emily was no longer reporting suicidal ideation and she was ready to engage in coping strategies to deal with her grief and depressive symptoms.

CORRESPONDENCE
Meredith L.C. Williamson, PhD, 2900 E. 29th Street, Suite 100, Bryan, TX 77802; [email protected].

Computer technology and artificial intelligence (AI) have come a long way in several decades:

• Between 1971 and 1996, access to the Medline database was primarily limited to university libraries and other institutions; in 1997, the database became universally available online as PubMed.¹
• In 2004, the President of the United States issued an executive order that launched a 10-year plan to put electronic health records (EHRs) in place nationwide; EHRs are now employed in nearly 9 of 10 (85.9%) medical offices.²

Over time, numerous online resources sprouted as well, including DxPlain, UpToDate, and Clinical Key, to name a few. These digital tools were impressive for their time, but many of them are now considered “old-school” AI-enabled clinical decision support.

In the past 2 to 3 years, innovative clinicians and technologists have pushed medicine into a new era that takes advantage of machine learning (ML)-enhanced diagnostic aids, software systems that predict disease progression, and advanced clinical pathways to help individualize treatment. Enthusiastic early adopters believe these resources are transforming patient care—although skeptics remain unconvinced, cautioning that they have yet to prove their worth in everyday clinical practice.

In this review, we first analyze the strengths and weaknesses of evidence supporting these tools, then propose a potential role for them in family medicine.

Machine learning takes on retinopathy

The term “artificial intelligence” has been with us for longer than a half century.³ In the broadest sense, AI refers to any computer system capable of automating a process usually performed manually by humans. But the latest innovations in AI take advantage of a subset of AI called “machine learning”: the ability of software systems to learn new functionality or insights on their own, without additional programming from human data engineers. Case in point: A software platform has been developed that is capable of diagnosing or screening for diabetic retinopathy without the involvement of an experienced ophthalmologist.

A software platform has been developed that is capable of diagnosing or screening for diabetic retinopathy without the involvement of an experienced ophthalmologist.

The landmark study that started clinicians and health care executives thinking seriously about the potential role of ML in medical practice was spearheaded by ­Varun Gulshan, PhD, at Google, and associates from several medical schools.⁴ Gulshan used an artificial neural network designed to mimic the functions of the human nervous system to analyze more than 128,000 retinal images, looking for evidence of diabetic retinopathy. (See “Deciphering artificial neural networks,” for an explanation of how such networks function.⁵) The algorithm they employed was compared with the diagnostic skills of several board-certified ophthalmologists.

[polldaddy:10453606]

Continue to: Deciperhing artificial neural networks

Using an area-under-the-receiver operating curve (AUROC) as a metric, and choosing an operating point for high specificity, the algorithm generated sensitivity of 87% and 90.3% and specificity of 98.1% and 98.5% for 2 validation data sets for detecting referable retinopathy, as defined by a panel of at least 7 ophthalmologists. When AUROC was set for high sensitivity, the algorithm generated sensitivity of 97.5% and 96.1% and specificity of 93.4% and 93.9% for the 2 data sets.

These results are impressive, but the researchers used a retrospective approach in their analysis. A prospective analysis would provide stronger evidence.

That shortcoming was addressed by a pivotal clinical trial that convinced the US Food and Drug Administration (FDA) to approve the technology. Michael Abramoff, MD, PhD, at the University of Iowa Department of Ophthalmology and Visual Sciences and his associates⁶ conducted a prospective study that compared the gold standard for detecting retinopathy, the Fundus Photograph Reading Center (of the University of Wisconsin School of Medicine and Public Health), to an ML-based algorithm, the commercialized IDx-DR. The IDx-DR is a software system that is used in combination with a fundal camera to capture retinal images. The researchers found that “the AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% ... [and] specificity of 90.7% ....”

Continue to: The FDA clearance statement...

The FDA clearance statement for this technology⁷ limits its use, emphasizing that it is intended only as a screening tool, not a stand-alone diagnostic system. Because ­IDx-DR is being used in primary care, the FDA states that patients who have a positive result should be referred to an eye care professional. The technology is contraindicated in patients who have a history of laser treatment, surgery, or injection in the eye or who have any of the following: persistent vision loss, blurred vision, floaters, previously diagnosed macular edema, severe nonproliferative retinopathy, proliferative retinopathy, radiation retinopathy, and retinal vein occlusion. It is also not intended for pregnant patients because their eye disease often progresses rapidly.

A large-scale validation study performed on data from Kaiser Permanente Northwest found that it is possible to estimate a person's risk of colorectal cancer by using age, gender, and complete blood count.

Additional caveats to keep in mind when evaluating this new technology include that, although the software can help detect retinopathy, it does not address other key issues for this patient population, including cataracts and glaucoma. The cost of the new technology also requires attention: Software must be used in conjunction with a specific retinal camera, the Topcon TRC-NW400, which is expensive (new, as much as $20,000).

IMAGE: ©GETTY IMAGES

Speaking of cost: Health care providers and insurers still question whether implementing AI-enabled systems is cost-­effective. It is too early to say definitively how AI and machine learning will have an impact on health care expenditures, because the most promising technological systems have yet to be fully implemented in hospitals and medical practices nationwide. Projections by Forbes suggest that private investment in health care AI will reach $6.6 billion by 2021; on a more confident note, an Accenture analysis predicts that the best possible application of AI might save the health care sector $150 billion annually by 2026.⁸

What role might this diabetic retinopathy technology play in family medicine? Physicians are constantly advising patients who have diabetes about the need to have a regular ophthalmic examination to check for early signs of retinopathy—advice that is often ignored. The American Academy of Ophthalmology points out that “6 out of 10 people with diabetes skip a sight-saving exam.”⁹ When a patient is screened with this type of device and found to be at high risk of eye disease, however, the advice to see an eye-care specialist might carry more weight.

Screening colonoscopy: Improving patient incentives

No responsible physician doubts the value of screening colonoscopy in patients 50 years and older, but many patients have yet to realize that the procedure just might save their life. Is there a way to incentivize resistant patients to have a colonoscopy performed? An ML-based software system that only requires access to a few readily available parameters might be the needed impetus for many patients.

Continue to: A large-scale validation...

A large-scale validation study performed on data from Kaiser Permanente Northwest found that it is possible to estimate a person’s risk of colorectal cancer by using age, gender, and complete blood count.¹⁰ This retrospective investigation analyzed more than 17,000 Kaiser Permanente patients, including 900 who already had colorectal cancer. The analysis generated a risk score for patients who did not have the malignancy to gauge their likelihood of developing it. The algorithms were more sensitive for detecting tumors of the cecum and ascending colon, and less sensitive for detection of tumors of the transverse and sigmoid colon and rectum.

To provide more definitive evidence to support the value of the software platform, a prospective study was subsequently conducted on more than 79,000 patients who had initially declined to undergo colorectal screening. The platform, called ColonFlag, was used to detect 688 patients at highest risk, who were then offered screening colonoscopy. In this subgroup, 254 agreed to the procedure; ColonFlag identified 19 malignancies (7.5%) among patients within the Maccabi Health System (Israel), and 15 more in patients outside that health system.¹¹ (In the United States, the same program is known as LGI Flag and has been cleared by the FDA.)

Although ColonFlag has the potential to reduce the incidence of colorectal cancer, other evidence-based screening modalities are highlighted in US Preventive Services Task Force guidelines, including the guaiac-based fecal occult blood test and the fecal immunochemical test.¹²

Beyond screening to applications in managing disease

The complex etiology of sepsis makes the condition difficult to treat. That complexity has also led to disagreement on the best course of management. Using an ML algorithm called an “Artificial Intelligence Clinician,” Komorowski and associates¹³ extracted data from a large data set from 2 nonoverlapping intensive care unit databases collected from US adults.The researchers’ analysis suggested a list of 48 variables that likely influence sepsis outcomes, including:

• demographics,
• Elixhauser premorbid status,
• vital signs,
• clinical laboratory data,
• intravenous fluids given, and
• vasopressors administered.

Komorowski and co-workers concluded that “… mortality was lowest in patients for whom clinicians’ actual doses matched the AI decisions. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.”

A randomized clinical trial has found that an ML program that uses only 6 common clinical markers—blood pressure, heart rate, temperature, respiratory rate, peripheral capillary oxygen saturation (SpO₂), and age—can improve clinical outcomes in patients with severe sepsis.¹⁴ The alerts generated by the algorithm were used to guide treatment. Average length of stay was 13 days in controls, compared with 10.3 days in those evaluated with the ML algorithm. The algorithm was also associated with a 12.4% drop in in-­hospital mortality.

Continue to: Addressing challenges, tapping resources

Advances in the management of diabetic retinopathy, colorectal cancer, and sepsis are the tip of the AI iceberg. There are now ML programs to distinguish melanoma from benign nevi; to improve insulin dosing for patients with type 1 diabetes; to predict which hospital patients are most likely to end up in the intensive care unit; and to mitigate the opioid epidemic.

An ML Web page on the JAMA Network (https://sites.jamanetwork.com/machine-learning/) features a long list of published research studies, reviews, and opinion papers suggesting that the future of medicine is closely tied to innovative developments in this area. This Web page also addresses the potential use of ML in detecting lymph node metastases in breast cancer, the need to temper AI with human intelligence, the role of AI in clinical decision support, and more.

The JAMA Network also discusses a few of the challenges that still need to be overcome in developing ML tools for clinical medicine—challenges that you will want to be cognizant of as you evaluate new research in the field.

Black-box dilemma. A challenge that technologists face as they introduce new programs that have the potential to improve diagnosis, treatment, and prognosis is a phenomenon called the “black-box dilemma,” which refers to the complex data science, advanced statistics, and mathematical equations that underpin ML algorithms. These complexities make it difficult to explain the mechanism of action upon which software is based, which, in turn, makes many clinicians skeptical about its worth.

A randomized clinical trial has found that an ML program that uses only 6 common clinical markers can improve clinical outcomes in patients with severe sepsis.

For example, the neural networks that are the backbone of the retinopathy algorithm discussed earlier might seem like voodoo science to those unfamiliar with the technology. It’s fortunate that several technology-savvy physicians have mastered these digital tools and have the teaching skills to explain them in plain-English tutorials. One such tutorial, “Understanding How Machine Learning Works,” is posted on the JAMA Network (https://sites.­jamanetwork.com/machine-learning/#multimedia). A more basic explanation was included in a recent Public Broadcasting System “Nova” episode, viewable at www.youtube.com/watch?v=xS2G0oolHpo.

Continue to: Limited analysis

Limited analysis. Another problem that plagues many ML-based algorithms is that they have been tested on only a single data set. (Typically, a data set refers to a collection of clinical parameters from a patient population.) For example, researchers developing an algorithm might collect their data from a single health care system.

Several investigators have addressed this shortcoming by testing their software on 2 completely independent patient populations. Banda and colleagues¹⁵ recently developed a software platform to improve the detection rate in familial hypercholesterolemia, a significant cause of premature cardiovascular disease and death that affects approximately 1 of every 250 people. Despite the urgency of identifying the disorder and providing potentially lifesaving treatment, only 10% of patients receive an accurate diagnosis.¹⁶ Banda and colleagues developed a deep-learning algorithm that is far more effective than the traditional screening approach now in use.

To address the generalizability of the algorithm, it was tested on EHR data from 2 independent health care systems: Stanford Health Care and Geisinger Health System. In Stanford patients, the positive predictive value of the algorithm was 88%, with a sensitivity of 75%; it identified 84% of affected patients at the highest probability threshold. In Geisinger patients, the classifier generated a positive predictive value of 85%.

The future of these technologies

AI and ML are not panaceas that will revolutionize medicine in the near future. Likewise, the digital tools discussed in this article are not going to solve multiple complex medical problems addressed during a single office visit. But physicians who ignore mounting evidence that supports these emerging technologies will be left behind by more forward-thinking colleagues.

The best possible application of AI might save the health care sector $150 billion annually by 2026, according to an economic analysis.

A recent commentary in Gastroenterology¹⁷ sums up the situation best: “It is now too conservative to suggest that CADe [computer-assisted detection] and CADx [computer-assisted diagnosis] carry the potential to revolutionize colonoscopy. The artificial intelligence revolution has already begun.”

CORRESPONDENCE
Paul Cerrato, MA, [email protected], [email protected]. John Halamka, MD, MS, [email protected].

Computer technology and artificial intelligence (AI) have come a long way in several decades:

• Between 1971 and 1996, access to the Medline database was primarily limited to university libraries and other institutions; in 1997, the database became universally available online as PubMed.¹
• In 2004, the President of the United States issued an executive order that launched a 10-year plan to put electronic health records (EHRs) in place nationwide; EHRs are now employed in nearly 9 of 10 (85.9%) medical offices.²

Over time, numerous online resources sprouted as well, including DxPlain, UpToDate, and Clinical Key, to name a few. These digital tools were impressive for their time, but many of them are now considered “old-school” AI-enabled clinical decision support.

In the past 2 to 3 years, innovative clinicians and technologists have pushed medicine into a new era that takes advantage of machine learning (ML)-enhanced diagnostic aids, software systems that predict disease progression, and advanced clinical pathways to help individualize treatment. Enthusiastic early adopters believe these resources are transforming patient care—although skeptics remain unconvinced, cautioning that they have yet to prove their worth in everyday clinical practice.

In this review, we first analyze the strengths and weaknesses of evidence supporting these tools, then propose a potential role for them in family medicine.

Machine learning takes on retinopathy

The term “artificial intelligence” has been with us for longer than a half century.³ In the broadest sense, AI refers to any computer system capable of automating a process usually performed manually by humans. But the latest innovations in AI take advantage of a subset of AI called “machine learning”: the ability of software systems to learn new functionality or insights on their own, without additional programming from human data engineers. Case in point: A software platform has been developed that is capable of diagnosing or screening for diabetic retinopathy without the involvement of an experienced ophthalmologist.

A software platform has been developed that is capable of diagnosing or screening for diabetic retinopathy without the involvement of an experienced ophthalmologist.

The landmark study that started clinicians and health care executives thinking seriously about the potential role of ML in medical practice was spearheaded by ­Varun Gulshan, PhD, at Google, and associates from several medical schools.⁴ Gulshan used an artificial neural network designed to mimic the functions of the human nervous system to analyze more than 128,000 retinal images, looking for evidence of diabetic retinopathy. (See “Deciphering artificial neural networks,” for an explanation of how such networks function.⁵) The algorithm they employed was compared with the diagnostic skills of several board-certified ophthalmologists.

[polldaddy:10453606]

Continue to: Deciperhing artificial neural networks

Using an area-under-the-receiver operating curve (AUROC) as a metric, and choosing an operating point for high specificity, the algorithm generated sensitivity of 87% and 90.3% and specificity of 98.1% and 98.5% for 2 validation data sets for detecting referable retinopathy, as defined by a panel of at least 7 ophthalmologists. When AUROC was set for high sensitivity, the algorithm generated sensitivity of 97.5% and 96.1% and specificity of 93.4% and 93.9% for the 2 data sets.

These results are impressive, but the researchers used a retrospective approach in their analysis. A prospective analysis would provide stronger evidence.

That shortcoming was addressed by a pivotal clinical trial that convinced the US Food and Drug Administration (FDA) to approve the technology. Michael Abramoff, MD, PhD, at the University of Iowa Department of Ophthalmology and Visual Sciences and his associates⁶ conducted a prospective study that compared the gold standard for detecting retinopathy, the Fundus Photograph Reading Center (of the University of Wisconsin School of Medicine and Public Health), to an ML-based algorithm, the commercialized IDx-DR. The IDx-DR is a software system that is used in combination with a fundal camera to capture retinal images. The researchers found that “the AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% ... [and] specificity of 90.7% ....”

Continue to: The FDA clearance statement...

The FDA clearance statement for this technology⁷ limits its use, emphasizing that it is intended only as a screening tool, not a stand-alone diagnostic system. Because ­IDx-DR is being used in primary care, the FDA states that patients who have a positive result should be referred to an eye care professional. The technology is contraindicated in patients who have a history of laser treatment, surgery, or injection in the eye or who have any of the following: persistent vision loss, blurred vision, floaters, previously diagnosed macular edema, severe nonproliferative retinopathy, proliferative retinopathy, radiation retinopathy, and retinal vein occlusion. It is also not intended for pregnant patients because their eye disease often progresses rapidly.

A large-scale validation study performed on data from Kaiser Permanente Northwest found that it is possible to estimate a person's risk of colorectal cancer by using age, gender, and complete blood count.

Additional caveats to keep in mind when evaluating this new technology include that, although the software can help detect retinopathy, it does not address other key issues for this patient population, including cataracts and glaucoma. The cost of the new technology also requires attention: Software must be used in conjunction with a specific retinal camera, the Topcon TRC-NW400, which is expensive (new, as much as $20,000).

IMAGE: ©GETTY IMAGES

Speaking of cost: Health care providers and insurers still question whether implementing AI-enabled systems is cost-­effective. It is too early to say definitively how AI and machine learning will have an impact on health care expenditures, because the most promising technological systems have yet to be fully implemented in hospitals and medical practices nationwide. Projections by Forbes suggest that private investment in health care AI will reach $6.6 billion by 2021; on a more confident note, an Accenture analysis predicts that the best possible application of AI might save the health care sector $150 billion annually by 2026.⁸

What role might this diabetic retinopathy technology play in family medicine? Physicians are constantly advising patients who have diabetes about the need to have a regular ophthalmic examination to check for early signs of retinopathy—advice that is often ignored. The American Academy of Ophthalmology points out that “6 out of 10 people with diabetes skip a sight-saving exam.”⁹ When a patient is screened with this type of device and found to be at high risk of eye disease, however, the advice to see an eye-care specialist might carry more weight.

Screening colonoscopy: Improving patient incentives

No responsible physician doubts the value of screening colonoscopy in patients 50 years and older, but many patients have yet to realize that the procedure just might save their life. Is there a way to incentivize resistant patients to have a colonoscopy performed? An ML-based software system that only requires access to a few readily available parameters might be the needed impetus for many patients.

Continue to: A large-scale validation...

A large-scale validation study performed on data from Kaiser Permanente Northwest found that it is possible to estimate a person’s risk of colorectal cancer by using age, gender, and complete blood count.¹⁰ This retrospective investigation analyzed more than 17,000 Kaiser Permanente patients, including 900 who already had colorectal cancer. The analysis generated a risk score for patients who did not have the malignancy to gauge their likelihood of developing it. The algorithms were more sensitive for detecting tumors of the cecum and ascending colon, and less sensitive for detection of tumors of the transverse and sigmoid colon and rectum.

To provide more definitive evidence to support the value of the software platform, a prospective study was subsequently conducted on more than 79,000 patients who had initially declined to undergo colorectal screening. The platform, called ColonFlag, was used to detect 688 patients at highest risk, who were then offered screening colonoscopy. In this subgroup, 254 agreed to the procedure; ColonFlag identified 19 malignancies (7.5%) among patients within the Maccabi Health System (Israel), and 15 more in patients outside that health system.¹¹ (In the United States, the same program is known as LGI Flag and has been cleared by the FDA.)

Although ColonFlag has the potential to reduce the incidence of colorectal cancer, other evidence-based screening modalities are highlighted in US Preventive Services Task Force guidelines, including the guaiac-based fecal occult blood test and the fecal immunochemical test.¹²

Beyond screening to applications in managing disease

The complex etiology of sepsis makes the condition difficult to treat. That complexity has also led to disagreement on the best course of management. Using an ML algorithm called an “Artificial Intelligence Clinician,” Komorowski and associates¹³ extracted data from a large data set from 2 nonoverlapping intensive care unit databases collected from US adults.The researchers’ analysis suggested a list of 48 variables that likely influence sepsis outcomes, including:

• demographics,
• Elixhauser premorbid status,
• vital signs,
• clinical laboratory data,
• intravenous fluids given, and
• vasopressors administered.

Komorowski and co-workers concluded that “… mortality was lowest in patients for whom clinicians’ actual doses matched the AI decisions. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.”

A randomized clinical trial has found that an ML program that uses only 6 common clinical markers—blood pressure, heart rate, temperature, respiratory rate, peripheral capillary oxygen saturation (SpO₂), and age—can improve clinical outcomes in patients with severe sepsis.¹⁴ The alerts generated by the algorithm were used to guide treatment. Average length of stay was 13 days in controls, compared with 10.3 days in those evaluated with the ML algorithm. The algorithm was also associated with a 12.4% drop in in-­hospital mortality.

Continue to: Addressing challenges, tapping resources

Advances in the management of diabetic retinopathy, colorectal cancer, and sepsis are the tip of the AI iceberg. There are now ML programs to distinguish melanoma from benign nevi; to improve insulin dosing for patients with type 1 diabetes; to predict which hospital patients are most likely to end up in the intensive care unit; and to mitigate the opioid epidemic.

An ML Web page on the JAMA Network (https://sites.jamanetwork.com/machine-learning/) features a long list of published research studies, reviews, and opinion papers suggesting that the future of medicine is closely tied to innovative developments in this area. This Web page also addresses the potential use of ML in detecting lymph node metastases in breast cancer, the need to temper AI with human intelligence, the role of AI in clinical decision support, and more.

The JAMA Network also discusses a few of the challenges that still need to be overcome in developing ML tools for clinical medicine—challenges that you will want to be cognizant of as you evaluate new research in the field.

Black-box dilemma. A challenge that technologists face as they introduce new programs that have the potential to improve diagnosis, treatment, and prognosis is a phenomenon called the “black-box dilemma,” which refers to the complex data science, advanced statistics, and mathematical equations that underpin ML algorithms. These complexities make it difficult to explain the mechanism of action upon which software is based, which, in turn, makes many clinicians skeptical about its worth.

A randomized clinical trial has found that an ML program that uses only 6 common clinical markers can improve clinical outcomes in patients with severe sepsis.

For example, the neural networks that are the backbone of the retinopathy algorithm discussed earlier might seem like voodoo science to those unfamiliar with the technology. It’s fortunate that several technology-savvy physicians have mastered these digital tools and have the teaching skills to explain them in plain-English tutorials. One such tutorial, “Understanding How Machine Learning Works,” is posted on the JAMA Network (https://sites.­jamanetwork.com/machine-learning/#multimedia). A more basic explanation was included in a recent Public Broadcasting System “Nova” episode, viewable at www.youtube.com/watch?v=xS2G0oolHpo.

Continue to: Limited analysis

Limited analysis. Another problem that plagues many ML-based algorithms is that they have been tested on only a single data set. (Typically, a data set refers to a collection of clinical parameters from a patient population.) For example, researchers developing an algorithm might collect their data from a single health care system.

Several investigators have addressed this shortcoming by testing their software on 2 completely independent patient populations. Banda and colleagues¹⁵ recently developed a software platform to improve the detection rate in familial hypercholesterolemia, a significant cause of premature cardiovascular disease and death that affects approximately 1 of every 250 people. Despite the urgency of identifying the disorder and providing potentially lifesaving treatment, only 10% of patients receive an accurate diagnosis.¹⁶ Banda and colleagues developed a deep-learning algorithm that is far more effective than the traditional screening approach now in use.

To address the generalizability of the algorithm, it was tested on EHR data from 2 independent health care systems: Stanford Health Care and Geisinger Health System. In Stanford patients, the positive predictive value of the algorithm was 88%, with a sensitivity of 75%; it identified 84% of affected patients at the highest probability threshold. In Geisinger patients, the classifier generated a positive predictive value of 85%.

The future of these technologies

AI and ML are not panaceas that will revolutionize medicine in the near future. Likewise, the digital tools discussed in this article are not going to solve multiple complex medical problems addressed during a single office visit. But physicians who ignore mounting evidence that supports these emerging technologies will be left behind by more forward-thinking colleagues.

The best possible application of AI might save the health care sector $150 billion annually by 2026, according to an economic analysis.

A recent commentary in Gastroenterology¹⁷ sums up the situation best: “It is now too conservative to suggest that CADe [computer-assisted detection] and CADx [computer-assisted diagnosis] carry the potential to revolutionize colonoscopy. The artificial intelligence revolution has already begun.”

CORRESPONDENCE
Paul Cerrato, MA, [email protected], [email protected]. John Halamka, MD, MS, [email protected].

Computer technology and artificial intelligence (AI) have come a long way in several decades:

• Between 1971 and 1996, access to the Medline database was primarily limited to university libraries and other institutions; in 1997, the database became universally available online as PubMed.¹
• In 2004, the President of the United States issued an executive order that launched a 10-year plan to put electronic health records (EHRs) in place nationwide; EHRs are now employed in nearly 9 of 10 (85.9%) medical offices.²

Over time, numerous online resources sprouted as well, including DxPlain, UpToDate, and Clinical Key, to name a few. These digital tools were impressive for their time, but many of them are now considered “old-school” AI-enabled clinical decision support.

In the past 2 to 3 years, innovative clinicians and technologists have pushed medicine into a new era that takes advantage of machine learning (ML)-enhanced diagnostic aids, software systems that predict disease progression, and advanced clinical pathways to help individualize treatment. Enthusiastic early adopters believe these resources are transforming patient care—although skeptics remain unconvinced, cautioning that they have yet to prove their worth in everyday clinical practice.

In this review, we first analyze the strengths and weaknesses of evidence supporting these tools, then propose a potential role for them in family medicine.

Machine learning takes on retinopathy

The term “artificial intelligence” has been with us for longer than a half century.³ In the broadest sense, AI refers to any computer system capable of automating a process usually performed manually by humans. But the latest innovations in AI take advantage of a subset of AI called “machine learning”: the ability of software systems to learn new functionality or insights on their own, without additional programming from human data engineers. Case in point: A software platform has been developed that is capable of diagnosing or screening for diabetic retinopathy without the involvement of an experienced ophthalmologist.

A software platform has been developed that is capable of diagnosing or screening for diabetic retinopathy without the involvement of an experienced ophthalmologist.

The landmark study that started clinicians and health care executives thinking seriously about the potential role of ML in medical practice was spearheaded by ­Varun Gulshan, PhD, at Google, and associates from several medical schools.⁴ Gulshan used an artificial neural network designed to mimic the functions of the human nervous system to analyze more than 128,000 retinal images, looking for evidence of diabetic retinopathy. (See “Deciphering artificial neural networks,” for an explanation of how such networks function.⁵) The algorithm they employed was compared with the diagnostic skills of several board-certified ophthalmologists.

[polldaddy:10453606]

Continue to: Deciperhing artificial neural networks

Using an area-under-the-receiver operating curve (AUROC) as a metric, and choosing an operating point for high specificity, the algorithm generated sensitivity of 87% and 90.3% and specificity of 98.1% and 98.5% for 2 validation data sets for detecting referable retinopathy, as defined by a panel of at least 7 ophthalmologists. When AUROC was set for high sensitivity, the algorithm generated sensitivity of 97.5% and 96.1% and specificity of 93.4% and 93.9% for the 2 data sets.

These results are impressive, but the researchers used a retrospective approach in their analysis. A prospective analysis would provide stronger evidence.

That shortcoming was addressed by a pivotal clinical trial that convinced the US Food and Drug Administration (FDA) to approve the technology. Michael Abramoff, MD, PhD, at the University of Iowa Department of Ophthalmology and Visual Sciences and his associates⁶ conducted a prospective study that compared the gold standard for detecting retinopathy, the Fundus Photograph Reading Center (of the University of Wisconsin School of Medicine and Public Health), to an ML-based algorithm, the commercialized IDx-DR. The IDx-DR is a software system that is used in combination with a fundal camera to capture retinal images. The researchers found that “the AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% ... [and] specificity of 90.7% ....”

Continue to: The FDA clearance statement...

The FDA clearance statement for this technology⁷ limits its use, emphasizing that it is intended only as a screening tool, not a stand-alone diagnostic system. Because ­IDx-DR is being used in primary care, the FDA states that patients who have a positive result should be referred to an eye care professional. The technology is contraindicated in patients who have a history of laser treatment, surgery, or injection in the eye or who have any of the following: persistent vision loss, blurred vision, floaters, previously diagnosed macular edema, severe nonproliferative retinopathy, proliferative retinopathy, radiation retinopathy, and retinal vein occlusion. It is also not intended for pregnant patients because their eye disease often progresses rapidly.

A large-scale validation study performed on data from Kaiser Permanente Northwest found that it is possible to estimate a person's risk of colorectal cancer by using age, gender, and complete blood count.

Additional caveats to keep in mind when evaluating this new technology include that, although the software can help detect retinopathy, it does not address other key issues for this patient population, including cataracts and glaucoma. The cost of the new technology also requires attention: Software must be used in conjunction with a specific retinal camera, the Topcon TRC-NW400, which is expensive (new, as much as $20,000).

IMAGE: ©GETTY IMAGES

Speaking of cost: Health care providers and insurers still question whether implementing AI-enabled systems is cost-­effective. It is too early to say definitively how AI and machine learning will have an impact on health care expenditures, because the most promising technological systems have yet to be fully implemented in hospitals and medical practices nationwide. Projections by Forbes suggest that private investment in health care AI will reach $6.6 billion by 2021; on a more confident note, an Accenture analysis predicts that the best possible application of AI might save the health care sector $150 billion annually by 2026.⁸

What role might this diabetic retinopathy technology play in family medicine? Physicians are constantly advising patients who have diabetes about the need to have a regular ophthalmic examination to check for early signs of retinopathy—advice that is often ignored. The American Academy of Ophthalmology points out that “6 out of 10 people with diabetes skip a sight-saving exam.”⁹ When a patient is screened with this type of device and found to be at high risk of eye disease, however, the advice to see an eye-care specialist might carry more weight.

Screening colonoscopy: Improving patient incentives

No responsible physician doubts the value of screening colonoscopy in patients 50 years and older, but many patients have yet to realize that the procedure just might save their life. Is there a way to incentivize resistant patients to have a colonoscopy performed? An ML-based software system that only requires access to a few readily available parameters might be the needed impetus for many patients.

Continue to: A large-scale validation...

A large-scale validation study performed on data from Kaiser Permanente Northwest found that it is possible to estimate a person’s risk of colorectal cancer by using age, gender, and complete blood count.¹⁰ This retrospective investigation analyzed more than 17,000 Kaiser Permanente patients, including 900 who already had colorectal cancer. The analysis generated a risk score for patients who did not have the malignancy to gauge their likelihood of developing it. The algorithms were more sensitive for detecting tumors of the cecum and ascending colon, and less sensitive for detection of tumors of the transverse and sigmoid colon and rectum.

To provide more definitive evidence to support the value of the software platform, a prospective study was subsequently conducted on more than 79,000 patients who had initially declined to undergo colorectal screening. The platform, called ColonFlag, was used to detect 688 patients at highest risk, who were then offered screening colonoscopy. In this subgroup, 254 agreed to the procedure; ColonFlag identified 19 malignancies (7.5%) among patients within the Maccabi Health System (Israel), and 15 more in patients outside that health system.¹¹ (In the United States, the same program is known as LGI Flag and has been cleared by the FDA.)

Although ColonFlag has the potential to reduce the incidence of colorectal cancer, other evidence-based screening modalities are highlighted in US Preventive Services Task Force guidelines, including the guaiac-based fecal occult blood test and the fecal immunochemical test.¹²

Beyond screening to applications in managing disease

The complex etiology of sepsis makes the condition difficult to treat. That complexity has also led to disagreement on the best course of management. Using an ML algorithm called an “Artificial Intelligence Clinician,” Komorowski and associates¹³ extracted data from a large data set from 2 nonoverlapping intensive care unit databases collected from US adults.The researchers’ analysis suggested a list of 48 variables that likely influence sepsis outcomes, including:

• demographics,
• Elixhauser premorbid status,
• vital signs,
• clinical laboratory data,
• intravenous fluids given, and
• vasopressors administered.

Komorowski and co-workers concluded that “… mortality was lowest in patients for whom clinicians’ actual doses matched the AI decisions. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.”

A randomized clinical trial has found that an ML program that uses only 6 common clinical markers—blood pressure, heart rate, temperature, respiratory rate, peripheral capillary oxygen saturation (SpO₂), and age—can improve clinical outcomes in patients with severe sepsis.¹⁴ The alerts generated by the algorithm were used to guide treatment. Average length of stay was 13 days in controls, compared with 10.3 days in those evaluated with the ML algorithm. The algorithm was also associated with a 12.4% drop in in-­hospital mortality.

Continue to: Addressing challenges, tapping resources

Advances in the management of diabetic retinopathy, colorectal cancer, and sepsis are the tip of the AI iceberg. There are now ML programs to distinguish melanoma from benign nevi; to improve insulin dosing for patients with type 1 diabetes; to predict which hospital patients are most likely to end up in the intensive care unit; and to mitigate the opioid epidemic.

An ML Web page on the JAMA Network (https://sites.jamanetwork.com/machine-learning/) features a long list of published research studies, reviews, and opinion papers suggesting that the future of medicine is closely tied to innovative developments in this area. This Web page also addresses the potential use of ML in detecting lymph node metastases in breast cancer, the need to temper AI with human intelligence, the role of AI in clinical decision support, and more.

The JAMA Network also discusses a few of the challenges that still need to be overcome in developing ML tools for clinical medicine—challenges that you will want to be cognizant of as you evaluate new research in the field.

Black-box dilemma. A challenge that technologists face as they introduce new programs that have the potential to improve diagnosis, treatment, and prognosis is a phenomenon called the “black-box dilemma,” which refers to the complex data science, advanced statistics, and mathematical equations that underpin ML algorithms. These complexities make it difficult to explain the mechanism of action upon which software is based, which, in turn, makes many clinicians skeptical about its worth.

A randomized clinical trial has found that an ML program that uses only 6 common clinical markers can improve clinical outcomes in patients with severe sepsis.

For example, the neural networks that are the backbone of the retinopathy algorithm discussed earlier might seem like voodoo science to those unfamiliar with the technology. It’s fortunate that several technology-savvy physicians have mastered these digital tools and have the teaching skills to explain them in plain-English tutorials. One such tutorial, “Understanding How Machine Learning Works,” is posted on the JAMA Network (https://sites.­jamanetwork.com/machine-learning/#multimedia). A more basic explanation was included in a recent Public Broadcasting System “Nova” episode, viewable at www.youtube.com/watch?v=xS2G0oolHpo.

Continue to: Limited analysis

Limited analysis. Another problem that plagues many ML-based algorithms is that they have been tested on only a single data set. (Typically, a data set refers to a collection of clinical parameters from a patient population.) For example, researchers developing an algorithm might collect their data from a single health care system.

Several investigators have addressed this shortcoming by testing their software on 2 completely independent patient populations. Banda and colleagues¹⁵ recently developed a software platform to improve the detection rate in familial hypercholesterolemia, a significant cause of premature cardiovascular disease and death that affects approximately 1 of every 250 people. Despite the urgency of identifying the disorder and providing potentially lifesaving treatment, only 10% of patients receive an accurate diagnosis.¹⁶ Banda and colleagues developed a deep-learning algorithm that is far more effective than the traditional screening approach now in use.

To address the generalizability of the algorithm, it was tested on EHR data from 2 independent health care systems: Stanford Health Care and Geisinger Health System. In Stanford patients, the positive predictive value of the algorithm was 88%, with a sensitivity of 75%; it identified 84% of affected patients at the highest probability threshold. In Geisinger patients, the classifier generated a positive predictive value of 85%.

The future of these technologies

AI and ML are not panaceas that will revolutionize medicine in the near future. Likewise, the digital tools discussed in this article are not going to solve multiple complex medical problems addressed during a single office visit. But physicians who ignore mounting evidence that supports these emerging technologies will be left behind by more forward-thinking colleagues.

The best possible application of AI might save the health care sector $150 billion annually by 2026, according to an economic analysis.

A recent commentary in Gastroenterology¹⁷ sums up the situation best: “It is now too conservative to suggest that CADe [computer-assisted detection] and CADx [computer-assisted diagnosis] carry the potential to revolutionize colonoscopy. The artificial intelligence revolution has already begun.”

CORRESPONDENCE
Paul Cerrato, MA, [email protected], [email protected]. John Halamka, MD, MS, [email protected].

Sleep vs. Netflix: the eternal struggle

Ladies and gentlemen, welcome to Livin’ on the MDedge World Championship Boxing! Tonight, we bring you a classic match-up in the endless battle for your valuable time.

jackscoldsweat/Getty Images

In the red corner, weighing in at a muscular 8 hours, is the defending champion: a good night’s sleep! And now for the challenger in the blue corner, coming in at a strong “just one more episode, I promise,” it’s binge watching!

Oh, sleep opens the match strong: According to a survey from the American Academy of Sleep Medicine, U.S. adults rank sleep as their second-most important priority, with only family beating it out. My goodness, that is a strong opening offensive.

But wait, binge watching is countering! According to the very same survey, 88% of Americans have admitted that they’d lost sleep because they’d stayed up late to watch extra episodes of a TV show or streaming series, a rate that rises to 95% in people aged 18-44 years. Oh dear, sleep looks like it’s in trouble.

Hang on, what’s binge watching doing? It’s unleashing a quick barrage of attacks: 72% of men aged 18-34 reported delaying sleep for video games, two-thirds of U.S. adults reported losing sleep to read a book, and nearly 60% of adults delayed sleep to watch sports. We feel slightly conflicted about our metaphor choice now.

And with a final haymaker from “guess I’ll watch ‘The Office’ for a sixth time,” binge watching has defeated the defending champion! Be sure to tune in next week, when alcohol takes on common sense. A true fight for the ages there.
 

Lead us not into temptation

Can anyone resist the temptation of binge watching? Can no one swim against the sleep-depriving, show-streaming current? Is resistance to an “Orange Is the New Black” bender futile?

spaxiax/Getty Images

University of Wyoming researchers say there’s hope. Those who would sleep svelte and sound in a world of streaming services and Krispy Kreme must plan ahead to tame temptation.

Proactive temptation management begins long before those chocolate iced glazed with sprinkles appear at the nurses’ station. Planning your response ahead of time increases the odds that the first episode of “Stranger Things” is also the evening’s last episode.

Using psychology’s human lab mice – undergraduate students – the researchers tested five temptation-proofing self-control strategies.

The first strategy: situation selection. If “Game of Thrones” is on in the den, avoid the room as if it were an unmucked House Lannister horse stall. Second: situation modification. Is your spouse hotboxing GoT on an iPad next to you in the bed? Politely suggest that GoT is even better when viewed on the living room sofa.

The third strategy: distraction. Enjoy the wholesome snap of a Finn Crisp while your coworkers destroy those Krispy Kremes like Daenerys leveling King’s Landing. Fourth: reappraisal. Tell yourself that season 2 of “Ozark” can’t surpass season 1, and will simply swindle you of your precious time. And fifth, the Nancy-Reagan, temptation-resistance classic: response inhibition. When offered the narcotic that is “Breaking Bad,” just say no!

Which temptation strategies worked best?

Planning ahead with one through four led fewer Cowboy State undergrads into temptation.

As for responding in the moment? Well, the Krispy Kremes would’ve never lasted past season 2 of “The Great British Baking Show.”
 

Stuck between a tongue and a hard place

There once was a 7-year-old boy who loved grape juice. He loved grape juice so much that he didn’t want to waste any after drinking a bottle of the stuff.

Shablon/Getty Images

To get every last drop, he tried to use his tongue to lick the inside of a grape juice bottle. One particular bottle, however, was evil and had other plans. It grabbed his tongue and wouldn’t let go, even after his mother tried to help him.

She took him to the great healing wizards at Auf der Bult Children’s Hospital in Hannover, Germany – which is quite surprising, because they live in New Jersey. [Just kidding, they’re from Hannover – just checking to see if you’re paying attention.]

When their magic wands didn’t work, doctors at the hospital mildly sedated the boy with midazolam and esketamine and then advanced a 70-mm plastic button cannula between the neck of the bottle and his tongue, hoping to release the presumed vacuum. No such luck.

It was at that point that the greatest of all the wizards, Dr. Christoph Eich, a pediatric anesthesiologist at the hospital, remembered having a similar problem with a particularly villainous bottle of “grape juice” during his magical training days some 20 years earlier.

The solution then, he discovered, was to connect the cannula to a syringe and inject air into the bottle to produce positive pressure and force out the foreign object.

Dr. Eich’s reinvention of BPAP (bottle positive airway pressure) worked on the child, who, once the purple discoloration of his tongue faded after 3 days, was none the worse for wear and lived happily ever after.

We’re just wondering if the good doctor told the child’s mother that the original situation involved a bottle of wine that couldn’t be opened because no one had a corkscrew. Well, maybe she reads the European Journal of Anaesthesiology.

Sleep vs. Netflix: the eternal struggle

Ladies and gentlemen, welcome to Livin’ on the MDedge World Championship Boxing! Tonight, we bring you a classic match-up in the endless battle for your valuable time.

jackscoldsweat/Getty Images

In the red corner, weighing in at a muscular 8 hours, is the defending champion: a good night’s sleep! And now for the challenger in the blue corner, coming in at a strong “just one more episode, I promise,” it’s binge watching!

Oh, sleep opens the match strong: According to a survey from the American Academy of Sleep Medicine, U.S. adults rank sleep as their second-most important priority, with only family beating it out. My goodness, that is a strong opening offensive.

But wait, binge watching is countering! According to the very same survey, 88% of Americans have admitted that they’d lost sleep because they’d stayed up late to watch extra episodes of a TV show or streaming series, a rate that rises to 95% in people aged 18-44 years. Oh dear, sleep looks like it’s in trouble.

Hang on, what’s binge watching doing? It’s unleashing a quick barrage of attacks: 72% of men aged 18-34 reported delaying sleep for video games, two-thirds of U.S. adults reported losing sleep to read a book, and nearly 60% of adults delayed sleep to watch sports. We feel slightly conflicted about our metaphor choice now.

And with a final haymaker from “guess I’ll watch ‘The Office’ for a sixth time,” binge watching has defeated the defending champion! Be sure to tune in next week, when alcohol takes on common sense. A true fight for the ages there.
 

Lead us not into temptation

Can anyone resist the temptation of binge watching? Can no one swim against the sleep-depriving, show-streaming current? Is resistance to an “Orange Is the New Black” bender futile?

spaxiax/Getty Images

University of Wyoming researchers say there’s hope. Those who would sleep svelte and sound in a world of streaming services and Krispy Kreme must plan ahead to tame temptation.

Proactive temptation management begins long before those chocolate iced glazed with sprinkles appear at the nurses’ station. Planning your response ahead of time increases the odds that the first episode of “Stranger Things” is also the evening’s last episode.

Using psychology’s human lab mice – undergraduate students – the researchers tested five temptation-proofing self-control strategies.

The first strategy: situation selection. If “Game of Thrones” is on in the den, avoid the room as if it were an unmucked House Lannister horse stall. Second: situation modification. Is your spouse hotboxing GoT on an iPad next to you in the bed? Politely suggest that GoT is even better when viewed on the living room sofa.

The third strategy: distraction. Enjoy the wholesome snap of a Finn Crisp while your coworkers destroy those Krispy Kremes like Daenerys leveling King’s Landing. Fourth: reappraisal. Tell yourself that season 2 of “Ozark” can’t surpass season 1, and will simply swindle you of your precious time. And fifth, the Nancy-Reagan, temptation-resistance classic: response inhibition. When offered the narcotic that is “Breaking Bad,” just say no!

Which temptation strategies worked best?

Planning ahead with one through four led fewer Cowboy State undergrads into temptation.

As for responding in the moment? Well, the Krispy Kremes would’ve never lasted past season 2 of “The Great British Baking Show.”
 

Stuck between a tongue and a hard place

There once was a 7-year-old boy who loved grape juice. He loved grape juice so much that he didn’t want to waste any after drinking a bottle of the stuff.

Shablon/Getty Images

To get every last drop, he tried to use his tongue to lick the inside of a grape juice bottle. One particular bottle, however, was evil and had other plans. It grabbed his tongue and wouldn’t let go, even after his mother tried to help him.

She took him to the great healing wizards at Auf der Bult Children’s Hospital in Hannover, Germany – which is quite surprising, because they live in New Jersey. [Just kidding, they’re from Hannover – just checking to see if you’re paying attention.]

When their magic wands didn’t work, doctors at the hospital mildly sedated the boy with midazolam and esketamine and then advanced a 70-mm plastic button cannula between the neck of the bottle and his tongue, hoping to release the presumed vacuum. No such luck.

It was at that point that the greatest of all the wizards, Dr. Christoph Eich, a pediatric anesthesiologist at the hospital, remembered having a similar problem with a particularly villainous bottle of “grape juice” during his magical training days some 20 years earlier.

The solution then, he discovered, was to connect the cannula to a syringe and inject air into the bottle to produce positive pressure and force out the foreign object.

Dr. Eich’s reinvention of BPAP (bottle positive airway pressure) worked on the child, who, once the purple discoloration of his tongue faded after 3 days, was none the worse for wear and lived happily ever after.

We’re just wondering if the good doctor told the child’s mother that the original situation involved a bottle of wine that couldn’t be opened because no one had a corkscrew. Well, maybe she reads the European Journal of Anaesthesiology.

Sleep vs. Netflix: the eternal struggle

Ladies and gentlemen, welcome to Livin’ on the MDedge World Championship Boxing! Tonight, we bring you a classic match-up in the endless battle for your valuable time.

jackscoldsweat/Getty Images

In the red corner, weighing in at a muscular 8 hours, is the defending champion: a good night’s sleep! And now for the challenger in the blue corner, coming in at a strong “just one more episode, I promise,” it’s binge watching!

Oh, sleep opens the match strong: According to a survey from the American Academy of Sleep Medicine, U.S. adults rank sleep as their second-most important priority, with only family beating it out. My goodness, that is a strong opening offensive.

But wait, binge watching is countering! According to the very same survey, 88% of Americans have admitted that they’d lost sleep because they’d stayed up late to watch extra episodes of a TV show or streaming series, a rate that rises to 95% in people aged 18-44 years. Oh dear, sleep looks like it’s in trouble.

Hang on, what’s binge watching doing? It’s unleashing a quick barrage of attacks: 72% of men aged 18-34 reported delaying sleep for video games, two-thirds of U.S. adults reported losing sleep to read a book, and nearly 60% of adults delayed sleep to watch sports. We feel slightly conflicted about our metaphor choice now.

And with a final haymaker from “guess I’ll watch ‘The Office’ for a sixth time,” binge watching has defeated the defending champion! Be sure to tune in next week, when alcohol takes on common sense. A true fight for the ages there.
 

Lead us not into temptation

Can anyone resist the temptation of binge watching? Can no one swim against the sleep-depriving, show-streaming current? Is resistance to an “Orange Is the New Black” bender futile?

spaxiax/Getty Images

University of Wyoming researchers say there’s hope. Those who would sleep svelte and sound in a world of streaming services and Krispy Kreme must plan ahead to tame temptation.

Proactive temptation management begins long before those chocolate iced glazed with sprinkles appear at the nurses’ station. Planning your response ahead of time increases the odds that the first episode of “Stranger Things” is also the evening’s last episode.

Using psychology’s human lab mice – undergraduate students – the researchers tested five temptation-proofing self-control strategies.

The first strategy: situation selection. If “Game of Thrones” is on in the den, avoid the room as if it were an unmucked House Lannister horse stall. Second: situation modification. Is your spouse hotboxing GoT on an iPad next to you in the bed? Politely suggest that GoT is even better when viewed on the living room sofa.

The third strategy: distraction. Enjoy the wholesome snap of a Finn Crisp while your coworkers destroy those Krispy Kremes like Daenerys leveling King’s Landing. Fourth: reappraisal. Tell yourself that season 2 of “Ozark” can’t surpass season 1, and will simply swindle you of your precious time. And fifth, the Nancy-Reagan, temptation-resistance classic: response inhibition. When offered the narcotic that is “Breaking Bad,” just say no!

Which temptation strategies worked best?

Planning ahead with one through four led fewer Cowboy State undergrads into temptation.

As for responding in the moment? Well, the Krispy Kremes would’ve never lasted past season 2 of “The Great British Baking Show.”
 

Stuck between a tongue and a hard place

There once was a 7-year-old boy who loved grape juice. He loved grape juice so much that he didn’t want to waste any after drinking a bottle of the stuff.

Shablon/Getty Images

To get every last drop, he tried to use his tongue to lick the inside of a grape juice bottle. One particular bottle, however, was evil and had other plans. It grabbed his tongue and wouldn’t let go, even after his mother tried to help him.

She took him to the great healing wizards at Auf der Bult Children’s Hospital in Hannover, Germany – which is quite surprising, because they live in New Jersey. [Just kidding, they’re from Hannover – just checking to see if you’re paying attention.]

When their magic wands didn’t work, doctors at the hospital mildly sedated the boy with midazolam and esketamine and then advanced a 70-mm plastic button cannula between the neck of the bottle and his tongue, hoping to release the presumed vacuum. No such luck.

It was at that point that the greatest of all the wizards, Dr. Christoph Eich, a pediatric anesthesiologist at the hospital, remembered having a similar problem with a particularly villainous bottle of “grape juice” during his magical training days some 20 years earlier.

The solution then, he discovered, was to connect the cannula to a syringe and inject air into the bottle to produce positive pressure and force out the foreign object.

Dr. Eich’s reinvention of BPAP (bottle positive airway pressure) worked on the child, who, once the purple discoloration of his tongue faded after 3 days, was none the worse for wear and lived happily ever after.

We’re just wondering if the good doctor told the child’s mother that the original situation involved a bottle of wine that couldn’t be opened because no one had a corkscrew. Well, maybe she reads the European Journal of Anaesthesiology.

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

[email protected]

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

[email protected]

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

[email protected]