Prurigo pigmentosa is an inflammatory disorder of uncertain etiology characterized by the eruption of erythematous, markedly pruritic, urticaria-like papules and vesicles on the posterior neck, mid- to upper back, and chest. Crops of papules appear rapidly and then involute within days, leaving behind postinflammatory hyperpigmentation in a netlike configuration. New papules may appear prior to resolution of hyperpigmented macules, resulting in a mixed presentation of erythematous papules overlying reticulated hyperpigmentation.¹

The condition was initially described in Japanese individuals, and to date, most cases have occurred in this population.² However, the incidence of prurigo pigmentosa is increasing worldwide, including in the United States, which has led to the identification of several metabolic risk factors including diabetes mellitus, fasting, and dieting, with the common etiologic endpoint of ketosis.³With the increasing popularity of diets with strict carbohydrate limits, often with the goal of ketosis, dermatologists should be aware of the clinical appearance and common history of this rash to facilitate prompt diagnosis and treatment.

Clinical exam with appropriate history is usually sufficient for diagnosis. However, biopsy with histopathologic analysis can be utilized to confirm atypical cases. Histopathologic findings depend on the stage of the lesion biopsied. The earliest finding is a shallow perivascular neutrophilic infiltrate, neutrophil exocytosis, and epidermal and superficial dermal edema. As lesions progress, the prominent findings include epidermal vesiculation with necrotic keratinocytes and a lichenoid infiltrate dominated by lymphocytes and eosinophils. In the final stages, lesions demonstrate variable parakeratosis and acanthosis, as well as prominent dermal melanophagia.¹

Treatment of prurigo pigmentosa includes modification of the patient’s underlying health issues to avoid ketosis, and in the case of diet-induced ketosis, reinstitution of a more balanced diet with sufficient carbohydrates. In the case of the patient presented here, rash resolved 1 week following instruction to include more carbohydrates in his diet. For recalcitrant cases or those without a clear precipitating factor, the addition of oral antibiotics is often helpful. Tetracyclines or dapsone are typically employed, usually in courses of 1-2 months.^3,4
 

Dr. Johnson is a PGY-4 dermatology resident at Carilion Clinic in Roanoke, Va. He provided the case and photos. Donna Bilu Martin, MD, is the editor of the column.

References

1. Boer A et al. Am J Dermatopathol. 2003 Apr;25(2):117-292.

2. Satter E et al. J Cutan Pathol. 2016 Oct;43(10):809-14.

3. Alshaya M et al. JAAD Case Rep. 2019 Jun 8;5(6):504-7.

4. Hartman M et al. Cutis. 2019 Mar;103(3):E10-3.

Prurigo pigmentosa is an inflammatory disorder of uncertain etiology characterized by the eruption of erythematous, markedly pruritic, urticaria-like papules and vesicles on the posterior neck, mid- to upper back, and chest. Crops of papules appear rapidly and then involute within days, leaving behind postinflammatory hyperpigmentation in a netlike configuration. New papules may appear prior to resolution of hyperpigmented macules, resulting in a mixed presentation of erythematous papules overlying reticulated hyperpigmentation.¹

The condition was initially described in Japanese individuals, and to date, most cases have occurred in this population.² However, the incidence of prurigo pigmentosa is increasing worldwide, including in the United States, which has led to the identification of several metabolic risk factors including diabetes mellitus, fasting, and dieting, with the common etiologic endpoint of ketosis.³With the increasing popularity of diets with strict carbohydrate limits, often with the goal of ketosis, dermatologists should be aware of the clinical appearance and common history of this rash to facilitate prompt diagnosis and treatment.

Clinical exam with appropriate history is usually sufficient for diagnosis. However, biopsy with histopathologic analysis can be utilized to confirm atypical cases. Histopathologic findings depend on the stage of the lesion biopsied. The earliest finding is a shallow perivascular neutrophilic infiltrate, neutrophil exocytosis, and epidermal and superficial dermal edema. As lesions progress, the prominent findings include epidermal vesiculation with necrotic keratinocytes and a lichenoid infiltrate dominated by lymphocytes and eosinophils. In the final stages, lesions demonstrate variable parakeratosis and acanthosis, as well as prominent dermal melanophagia.¹

Treatment of prurigo pigmentosa includes modification of the patient’s underlying health issues to avoid ketosis, and in the case of diet-induced ketosis, reinstitution of a more balanced diet with sufficient carbohydrates. In the case of the patient presented here, rash resolved 1 week following instruction to include more carbohydrates in his diet. For recalcitrant cases or those without a clear precipitating factor, the addition of oral antibiotics is often helpful. Tetracyclines or dapsone are typically employed, usually in courses of 1-2 months.^3,4
 

Dr. Johnson is a PGY-4 dermatology resident at Carilion Clinic in Roanoke, Va. He provided the case and photos. Donna Bilu Martin, MD, is the editor of the column.

References

1. Boer A et al. Am J Dermatopathol. 2003 Apr;25(2):117-292.

2. Satter E et al. J Cutan Pathol. 2016 Oct;43(10):809-14.

3. Alshaya M et al. JAAD Case Rep. 2019 Jun 8;5(6):504-7.

4. Hartman M et al. Cutis. 2019 Mar;103(3):E10-3.

Prurigo pigmentosa is an inflammatory disorder of uncertain etiology characterized by the eruption of erythematous, markedly pruritic, urticaria-like papules and vesicles on the posterior neck, mid- to upper back, and chest. Crops of papules appear rapidly and then involute within days, leaving behind postinflammatory hyperpigmentation in a netlike configuration. New papules may appear prior to resolution of hyperpigmented macules, resulting in a mixed presentation of erythematous papules overlying reticulated hyperpigmentation.¹

The condition was initially described in Japanese individuals, and to date, most cases have occurred in this population.² However, the incidence of prurigo pigmentosa is increasing worldwide, including in the United States, which has led to the identification of several metabolic risk factors including diabetes mellitus, fasting, and dieting, with the common etiologic endpoint of ketosis.³With the increasing popularity of diets with strict carbohydrate limits, often with the goal of ketosis, dermatologists should be aware of the clinical appearance and common history of this rash to facilitate prompt diagnosis and treatment.

Clinical exam with appropriate history is usually sufficient for diagnosis. However, biopsy with histopathologic analysis can be utilized to confirm atypical cases. Histopathologic findings depend on the stage of the lesion biopsied. The earliest finding is a shallow perivascular neutrophilic infiltrate, neutrophil exocytosis, and epidermal and superficial dermal edema. As lesions progress, the prominent findings include epidermal vesiculation with necrotic keratinocytes and a lichenoid infiltrate dominated by lymphocytes and eosinophils. In the final stages, lesions demonstrate variable parakeratosis and acanthosis, as well as prominent dermal melanophagia.¹

Treatment of prurigo pigmentosa includes modification of the patient’s underlying health issues to avoid ketosis, and in the case of diet-induced ketosis, reinstitution of a more balanced diet with sufficient carbohydrates. In the case of the patient presented here, rash resolved 1 week following instruction to include more carbohydrates in his diet. For recalcitrant cases or those without a clear precipitating factor, the addition of oral antibiotics is often helpful. Tetracyclines or dapsone are typically employed, usually in courses of 1-2 months.^3,4
 

Dr. Johnson is a PGY-4 dermatology resident at Carilion Clinic in Roanoke, Va. He provided the case and photos. Donna Bilu Martin, MD, is the editor of the column.

References

1. Boer A et al. Am J Dermatopathol. 2003 Apr;25(2):117-292.

2. Satter E et al. J Cutan Pathol. 2016 Oct;43(10):809-14.

3. Alshaya M et al. JAAD Case Rep. 2019 Jun 8;5(6):504-7.

4. Hartman M et al. Cutis. 2019 Mar;103(3):E10-3.

CASE

Jessica F is a new 23-year-old patient at your clinic who is seeing you to discuss her severe anxiety. She also has asthma and reports during your exploration of her family history that her father has been diagnosed with schizophrenia. She has been using 3 cartridges of cannabis vape daily to help “calm her mind” but has never tried other psychotropic medications and has never been referred to a psychiatrist.

How would you proceed with this patient?

Despite emerging evidence of the harmful effects of cannabis consumption, public perception of harm has steadily declined over the past 10 years.^1,2 More adults are using cannabis than before and using it more frequently. Among primary care patients who consume cannabis recreationally, about half report less than monthly consumption; 15% use it weekly, and 20% daily.³ The potency of cannabis products has also increased. In the past 2 decades, the average tetrahydrocannabinol (THC) content of recreational cannabis rose from 3% to 19%, and high-THC content delivery modalities such as vaporizer pens (“vapes”) were introduced.^4,5

Health hazards of cannabis use include gastrointestinal dysfunction (eg, cannabinoid hyperemesis syndrome), acute psychosis or exacerbation of an existing mood, anxiety, or psychotic disorder, and cardiovascular sequelae such as myocardial infarction or dysrhythmia.⁶ Potential long-term effects include neurocognitive impairment among adolescents who use cannabis,^7-9 worse outcomes in anxiety and mood disorders,¹⁰ schizophrenia,¹¹ cardiovascular sequelae,¹² chronic bronchitis,¹³ negative impact on reproductive function,¹⁴ and poor birth outcomes.^15-17

Hidden in plain sight. Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.¹⁸ Inadequate screening for cannabis can be attributed to time constraints, inconsistent definitions for problematic or risky cannabis use, and lack of guidance.^19,20 This article offers a more inclusive definition of “problematic cannabis use,” presents an up-to-date framework for evaluating it in the outpatient setting, and outlines potential interventions.

Your patient doesn’t meetthe DSM criteria, but …

Although it is important to identify cannabis use disorder (CUD) as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; TABLE 1^21,22), consider also the immediate and long-term consequences of cannabis use for individuals who do not meet criteria for CUD. “Problematic cannabis use,” as we define it, may also involve (a) high-risk behaviors or (b) contraindicating medical or psychiatric comorbidities (TABLE 2^6-9).

CASE

The patient in our case exhibited 4 factors indicative of problematic cannabis use: heavy vape use, cannabis use more than twice a week, asthma, and a family history of schizophrenia.

Continue to: Guidelines for screening and evaluation

All primary care patients should be screened for problematic cannabis use, but especially teenagers, young adults, pregnant women, and patients with a mental health or substance use history. A variation of the single question used to screen for alcohol use disorder can be applied to cannabis use.²³ We recommend asking the initial question, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?” Although some guidelines emphasize frequency of cannabis use when identifying problematic consumption,^24,25 duration of behavior and content of THC are also important indicators.¹⁹ Inquire about cannabis consumption over 1 month to differentiate sporadic use from longstanding persistent use.

Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.

Explore what types of cannabis the patient is ingesting and whether the patient uses cannabis heavily (4 or more times a week on average). Also determine the method of ingestion (eg, eating, vaping, smoking), THC-content (%, if known), and estimated weight of daily cannabis use in grams (TABLE 3²⁶). Although patients may not always be able to provide accurate answers, you can gain a sense of the quantity and forms of cannabis a patient is ingesting to inform future conversations on risk and harm reduction.²⁷

Assess a patient’s risk for harm

Cannabis use has the potential to cause immediate harm (linked to a single event of problematic cannabis use) and long-term harm (linked to a recurring pattern of problematic consumption). Cannabis can be especially harmful for patients with the following medical comorbidities or psychosocial factors, and should be avoided.

Cardiovascular disease. Cannabis is associated with an elevated risk for acute coronary syndrome and cardiovascular disease.²⁸ Long-term cannabis use is linked to increased frequency of anginal events, development of cardiac arrhythmias, peripheral arteritis, coronary vasospasms, and problems with platelet aggregation.^29,30 Strongly caution against cannabis use with patients who have a history of cardiovascular disease, orthostatic hypotension, tachyarrhythmia, or hypertension.

Pulmonary disease. Patients with pulmonary disease such as asthma may find cannabis helpful as a short-term bronchodilator.³¹ However, for patients with underlying pulmonary disease who also smoke cigarettes, strongly discourage the smoking of cannabis or hashish, as that may worsen asthma symptoms,³² increase risk of chronic bronchitis,³³ and increase cough, sputum production, and wheezing.³¹ There is currently insufficient evidence to suggest a positive association between cannabis use and the development of chronic obstructive pulmonary disease.³⁴

Continue to: Family history of psychotic disorders

Family history of psychotic disorders. Cannabis is associated with a dose-­dependent risk of schizophrenia, which is especially pronounced in patients with a family history of schizophrenia.³⁵ Among patients with a history of psychosis, heavy cannabis use has been associated with increased hospitalizations, increased positive symptoms, and more frequent relapses.^36-38

Pregnancy, current or planned. Some women turn to cannabis during pregnancy due to its antiemetic properties. However, perinatal exposure to cannabis is associated with significant risk to the offspring. Maternal cannabis use during the first and second trimesters of pregnancy is associated with decreased performance of the child on measures of function at 3 years of age.³⁹ In addition, cannabis consumption during pregnancy is linked to increased frequency of childhood behavioral issues, inattention, hyperactivity, and impulsivity.⁴⁰ Peripartum cannabis exposure can affect birth outcomes and is correlated with lower birth weight, incidence of preterm labor, and neonatal intensive care unit admission.^15-17,41 Of note, the THC concentration in breast milk peaks at 1 hour after the nursing mother inhales cannabis and typically dissipates after 4 hours.⁴²

Age < 25 years. Chronic heavy use of cannabis in those younger than 25 is associated with higher likelihood of developing CUD, lower IQ,⁹ lower level of educational attainment, lower income,⁴³ and decreased executive function.⁸

Substance use disorder history. Recreational cannabis use can hinder recovery from other substance use disorders.⁴⁴

Consider these 5 interventions

Physicians can address problematic cannabis use with a 5-pronged approach: (1) harm reduction, (2) motivational interviewing, (3) addressing underlying conditions, (4) mitigating withdrawal symptoms, and (5) referring to an addiction specialist (FIGURE).

Continue to: Harm reduction

Harm reduction applies to all individuals who use cannabis but especially to problematic cannabis users. Ask users to abstain from cannabis for limited periods of time to see how such abstinence affects other areas of their life. While abstinence is a goal, be prepared to perform non-abstinence-based interventions. The goal of harm reduction is to encourage behaviors that minimize health risks to which cannabis users are exposed. Encourage patients to:

Abstain from driving while intoxicated. Cannabis use while driving slows reaction time,⁴⁵ impairs road tracking (driving with correct road position),⁴⁶ increases weaving,⁴⁷ and causes a loss of anticipatory reactions learned in driving practice.⁴⁸ Risk of crashing is significantly increased with elevated levels of THC, and driving within 1 hour of cannabis ingestion nearly doubles the risk of a crash.^49-51

Abstain from vaping THC-containing products. The Centers for Disease Control and Prevention recommends that patients minimize the use of THC-containing e-cigarette or vaping products in light of the thousands of reports in the United States of product-associated lung injury, which in some cases have led to death.⁵²

Clarify serving sizes and recognize delayed effects. Inexperienced cannabis users often are confused by recommended serving sizes for edible cannabis products. A typical cannabis-infused brownie may contain 100 mg of THC when the recommended serving size typically is 10 mg. THC content is included on the label of cannabis edibles purchased in state-regulated stores; these products are tested regularly in laboratories designated by the state.

To screen, ask, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?”

Due to the delayed onset of THC’s effect, there have been numerous cases of patients taking a higher-than-intended dose of edible cannabis that caused acute intoxication and psychomedical sequelae leading to emergency hospital visits and, in some cases, death.^6,53 Individuals should start at a low dose and gradually work up to a higher dose as tolerated. Patients naïve to cannabis should be especially cautious when ingesting edible products.

Continue to: Abstain from cannabis with high THC content

Abstain from cannabis with high THC content. High-potency cannabis (> 10% THC) is associated with earlier onset of first-episode psychosis.^54,55

Motivational interviewing

Motivational interviewing (MI) is a psychosocial approach that emphasizes a patient’s self-efficacy and an interviewer’s positive feedback to collaboratively address substance use.⁵⁶ MI can be performed in short, discrete sessions. Such interventions can reduce the average number of days of cannabis use. One large-scale Cochrane review found that cognitive behavioral therapy (CBT), motivational enhancement therapy, or the 2 therapies combined most consistently reduced the frequency of cannabis use reported by patients at early follow-up.⁵⁷

Address underlying conditions

Some patients use cannabis to self-medicate for pain, insomnia, nausea, and anxiety. Identify these conditions and address them with first-line pharmacologic or psychotherapeutic interventions when possible. This is especially important for conditions in which long-term cannabis use may adversely impact outcomes, such as in posttraumatic stress disorder, anxiety, and mood disorders.^58-60 Little evidence exists for the use of cannabis as treatment of any primary psychiatric disorder.^61,62 Family physicians who are uncomfortable treating a specific underlying condition can consult specialists in pain management, sleep medicine, psychiatry, and neurology.

Mitigate withdrawal symptoms

Discontinuation of cannabis use may lead to withdrawal symptoms such as waxing and waning irritability, restlessness, sweating, aggression, anxiety, depressed mood, sleep disturbance, or changes in appetite.^63,64 These symptoms typically emerge within the first couple days of abstinence and can last up to 28 days.^63,64 Although the US Food and Drug Administration has not approved any medications for CUD treatment, and there are no established protocols for detoxification, there is evidence that CBT or medications such as gabapentin or zolpidem can reduce the intensity of withdrawal symptoms.^65,66

Refer to an addiction specialist

Consider referring patients with problematic cannabis use to an addiction specialist with expertise in psychopharmacologic and psychotherapeutic approaches to managing substance use.

Continue to: CASE

CASE

You renew Ms. F’s asthma medications, discuss her cannabis use, start her on a selective serotonin reuptake inhibitor, and refer her to an outpatient psychiatrist. Over the next few weeks, you and the outpatient psychiatrist employ brief motivational interviewing around cannabis use, and you provide psychoeducation around potential harms of use when driving and in light of the patient’s asthma.

Factors to consider in cannabis use include the method of ingestion, percentage of THC content, and times of day cannabis is used.

The patient’s anxiety symptoms decrease with up-titration of the SSRI by the outpatient psychiatrist and with enrollment in individual CBT. She is slowly able to taper off cannabis vaping with continued motivational interviewing and encouragement, despite withdrawal-induced anxiety and sleep disturbance.

CORRESPONDENCE
Michael Hsu, MD, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02215; [email protected].

CASE

Jessica F is a new 23-year-old patient at your clinic who is seeing you to discuss her severe anxiety. She also has asthma and reports during your exploration of her family history that her father has been diagnosed with schizophrenia. She has been using 3 cartridges of cannabis vape daily to help “calm her mind” but has never tried other psychotropic medications and has never been referred to a psychiatrist.

How would you proceed with this patient?

Despite emerging evidence of the harmful effects of cannabis consumption, public perception of harm has steadily declined over the past 10 years.^1,2 More adults are using cannabis than before and using it more frequently. Among primary care patients who consume cannabis recreationally, about half report less than monthly consumption; 15% use it weekly, and 20% daily.³ The potency of cannabis products has also increased. In the past 2 decades, the average tetrahydrocannabinol (THC) content of recreational cannabis rose from 3% to 19%, and high-THC content delivery modalities such as vaporizer pens (“vapes”) were introduced.^4,5

Health hazards of cannabis use include gastrointestinal dysfunction (eg, cannabinoid hyperemesis syndrome), acute psychosis or exacerbation of an existing mood, anxiety, or psychotic disorder, and cardiovascular sequelae such as myocardial infarction or dysrhythmia.⁶ Potential long-term effects include neurocognitive impairment among adolescents who use cannabis,^7-9 worse outcomes in anxiety and mood disorders,¹⁰ schizophrenia,¹¹ cardiovascular sequelae,¹² chronic bronchitis,¹³ negative impact on reproductive function,¹⁴ and poor birth outcomes.^15-17

Hidden in plain sight. Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.¹⁸ Inadequate screening for cannabis can be attributed to time constraints, inconsistent definitions for problematic or risky cannabis use, and lack of guidance.^19,20 This article offers a more inclusive definition of “problematic cannabis use,” presents an up-to-date framework for evaluating it in the outpatient setting, and outlines potential interventions.

Your patient doesn’t meetthe DSM criteria, but …

Although it is important to identify cannabis use disorder (CUD) as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; TABLE 1^21,22), consider also the immediate and long-term consequences of cannabis use for individuals who do not meet criteria for CUD. “Problematic cannabis use,” as we define it, may also involve (a) high-risk behaviors or (b) contraindicating medical or psychiatric comorbidities (TABLE 2^6-9).

CASE

The patient in our case exhibited 4 factors indicative of problematic cannabis use: heavy vape use, cannabis use more than twice a week, asthma, and a family history of schizophrenia.

Continue to: Guidelines for screening and evaluation

All primary care patients should be screened for problematic cannabis use, but especially teenagers, young adults, pregnant women, and patients with a mental health or substance use history. A variation of the single question used to screen for alcohol use disorder can be applied to cannabis use.²³ We recommend asking the initial question, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?” Although some guidelines emphasize frequency of cannabis use when identifying problematic consumption,^24,25 duration of behavior and content of THC are also important indicators.¹⁹ Inquire about cannabis consumption over 1 month to differentiate sporadic use from longstanding persistent use.

Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.

Explore what types of cannabis the patient is ingesting and whether the patient uses cannabis heavily (4 or more times a week on average). Also determine the method of ingestion (eg, eating, vaping, smoking), THC-content (%, if known), and estimated weight of daily cannabis use in grams (TABLE 3²⁶). Although patients may not always be able to provide accurate answers, you can gain a sense of the quantity and forms of cannabis a patient is ingesting to inform future conversations on risk and harm reduction.²⁷

Assess a patient’s risk for harm

Cannabis use has the potential to cause immediate harm (linked to a single event of problematic cannabis use) and long-term harm (linked to a recurring pattern of problematic consumption). Cannabis can be especially harmful for patients with the following medical comorbidities or psychosocial factors, and should be avoided.

Cardiovascular disease. Cannabis is associated with an elevated risk for acute coronary syndrome and cardiovascular disease.²⁸ Long-term cannabis use is linked to increased frequency of anginal events, development of cardiac arrhythmias, peripheral arteritis, coronary vasospasms, and problems with platelet aggregation.^29,30 Strongly caution against cannabis use with patients who have a history of cardiovascular disease, orthostatic hypotension, tachyarrhythmia, or hypertension.

Pulmonary disease. Patients with pulmonary disease such as asthma may find cannabis helpful as a short-term bronchodilator.³¹ However, for patients with underlying pulmonary disease who also smoke cigarettes, strongly discourage the smoking of cannabis or hashish, as that may worsen asthma symptoms,³² increase risk of chronic bronchitis,³³ and increase cough, sputum production, and wheezing.³¹ There is currently insufficient evidence to suggest a positive association between cannabis use and the development of chronic obstructive pulmonary disease.³⁴

Continue to: Family history of psychotic disorders

Family history of psychotic disorders. Cannabis is associated with a dose-­dependent risk of schizophrenia, which is especially pronounced in patients with a family history of schizophrenia.³⁵ Among patients with a history of psychosis, heavy cannabis use has been associated with increased hospitalizations, increased positive symptoms, and more frequent relapses.^36-38

Pregnancy, current or planned. Some women turn to cannabis during pregnancy due to its antiemetic properties. However, perinatal exposure to cannabis is associated with significant risk to the offspring. Maternal cannabis use during the first and second trimesters of pregnancy is associated with decreased performance of the child on measures of function at 3 years of age.³⁹ In addition, cannabis consumption during pregnancy is linked to increased frequency of childhood behavioral issues, inattention, hyperactivity, and impulsivity.⁴⁰ Peripartum cannabis exposure can affect birth outcomes and is correlated with lower birth weight, incidence of preterm labor, and neonatal intensive care unit admission.^15-17,41 Of note, the THC concentration in breast milk peaks at 1 hour after the nursing mother inhales cannabis and typically dissipates after 4 hours.⁴²

Age < 25 years. Chronic heavy use of cannabis in those younger than 25 is associated with higher likelihood of developing CUD, lower IQ,⁹ lower level of educational attainment, lower income,⁴³ and decreased executive function.⁸

Substance use disorder history. Recreational cannabis use can hinder recovery from other substance use disorders.⁴⁴

Consider these 5 interventions

Physicians can address problematic cannabis use with a 5-pronged approach: (1) harm reduction, (2) motivational interviewing, (3) addressing underlying conditions, (4) mitigating withdrawal symptoms, and (5) referring to an addiction specialist (FIGURE).

Continue to: Harm reduction

Harm reduction applies to all individuals who use cannabis but especially to problematic cannabis users. Ask users to abstain from cannabis for limited periods of time to see how such abstinence affects other areas of their life. While abstinence is a goal, be prepared to perform non-abstinence-based interventions. The goal of harm reduction is to encourage behaviors that minimize health risks to which cannabis users are exposed. Encourage patients to:

Abstain from driving while intoxicated. Cannabis use while driving slows reaction time,⁴⁵ impairs road tracking (driving with correct road position),⁴⁶ increases weaving,⁴⁷ and causes a loss of anticipatory reactions learned in driving practice.⁴⁸ Risk of crashing is significantly increased with elevated levels of THC, and driving within 1 hour of cannabis ingestion nearly doubles the risk of a crash.^49-51

Abstain from vaping THC-containing products. The Centers for Disease Control and Prevention recommends that patients minimize the use of THC-containing e-cigarette or vaping products in light of the thousands of reports in the United States of product-associated lung injury, which in some cases have led to death.⁵²

Clarify serving sizes and recognize delayed effects. Inexperienced cannabis users often are confused by recommended serving sizes for edible cannabis products. A typical cannabis-infused brownie may contain 100 mg of THC when the recommended serving size typically is 10 mg. THC content is included on the label of cannabis edibles purchased in state-regulated stores; these products are tested regularly in laboratories designated by the state.

To screen, ask, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?”

Due to the delayed onset of THC’s effect, there have been numerous cases of patients taking a higher-than-intended dose of edible cannabis that caused acute intoxication and psychomedical sequelae leading to emergency hospital visits and, in some cases, death.^6,53 Individuals should start at a low dose and gradually work up to a higher dose as tolerated. Patients naïve to cannabis should be especially cautious when ingesting edible products.

Continue to: Abstain from cannabis with high THC content

Abstain from cannabis with high THC content. High-potency cannabis (> 10% THC) is associated with earlier onset of first-episode psychosis.^54,55

Motivational interviewing

Motivational interviewing (MI) is a psychosocial approach that emphasizes a patient’s self-efficacy and an interviewer’s positive feedback to collaboratively address substance use.⁵⁶ MI can be performed in short, discrete sessions. Such interventions can reduce the average number of days of cannabis use. One large-scale Cochrane review found that cognitive behavioral therapy (CBT), motivational enhancement therapy, or the 2 therapies combined most consistently reduced the frequency of cannabis use reported by patients at early follow-up.⁵⁷

Address underlying conditions

Some patients use cannabis to self-medicate for pain, insomnia, nausea, and anxiety. Identify these conditions and address them with first-line pharmacologic or psychotherapeutic interventions when possible. This is especially important for conditions in which long-term cannabis use may adversely impact outcomes, such as in posttraumatic stress disorder, anxiety, and mood disorders.^58-60 Little evidence exists for the use of cannabis as treatment of any primary psychiatric disorder.^61,62 Family physicians who are uncomfortable treating a specific underlying condition can consult specialists in pain management, sleep medicine, psychiatry, and neurology.

Mitigate withdrawal symptoms

Discontinuation of cannabis use may lead to withdrawal symptoms such as waxing and waning irritability, restlessness, sweating, aggression, anxiety, depressed mood, sleep disturbance, or changes in appetite.^63,64 These symptoms typically emerge within the first couple days of abstinence and can last up to 28 days.^63,64 Although the US Food and Drug Administration has not approved any medications for CUD treatment, and there are no established protocols for detoxification, there is evidence that CBT or medications such as gabapentin or zolpidem can reduce the intensity of withdrawal symptoms.^65,66

Refer to an addiction specialist

Consider referring patients with problematic cannabis use to an addiction specialist with expertise in psychopharmacologic and psychotherapeutic approaches to managing substance use.

Continue to: CASE

CASE

You renew Ms. F’s asthma medications, discuss her cannabis use, start her on a selective serotonin reuptake inhibitor, and refer her to an outpatient psychiatrist. Over the next few weeks, you and the outpatient psychiatrist employ brief motivational interviewing around cannabis use, and you provide psychoeducation around potential harms of use when driving and in light of the patient’s asthma.

Factors to consider in cannabis use include the method of ingestion, percentage of THC content, and times of day cannabis is used.

The patient’s anxiety symptoms decrease with up-titration of the SSRI by the outpatient psychiatrist and with enrollment in individual CBT. She is slowly able to taper off cannabis vaping with continued motivational interviewing and encouragement, despite withdrawal-induced anxiety and sleep disturbance.

CORRESPONDENCE
Michael Hsu, MD, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02215; [email protected].

CASE

Jessica F is a new 23-year-old patient at your clinic who is seeing you to discuss her severe anxiety. She also has asthma and reports during your exploration of her family history that her father has been diagnosed with schizophrenia. She has been using 3 cartridges of cannabis vape daily to help “calm her mind” but has never tried other psychotropic medications and has never been referred to a psychiatrist.

How would you proceed with this patient?

Despite emerging evidence of the harmful effects of cannabis consumption, public perception of harm has steadily declined over the past 10 years.^1,2 More adults are using cannabis than before and using it more frequently. Among primary care patients who consume cannabis recreationally, about half report less than monthly consumption; 15% use it weekly, and 20% daily.³ The potency of cannabis products has also increased. In the past 2 decades, the average tetrahydrocannabinol (THC) content of recreational cannabis rose from 3% to 19%, and high-THC content delivery modalities such as vaporizer pens (“vapes”) were introduced.^4,5

Health hazards of cannabis use include gastrointestinal dysfunction (eg, cannabinoid hyperemesis syndrome), acute psychosis or exacerbation of an existing mood, anxiety, or psychotic disorder, and cardiovascular sequelae such as myocardial infarction or dysrhythmia.⁶ Potential long-term effects include neurocognitive impairment among adolescents who use cannabis,^7-9 worse outcomes in anxiety and mood disorders,¹⁰ schizophrenia,¹¹ cardiovascular sequelae,¹² chronic bronchitis,¹³ negative impact on reproductive function,¹⁴ and poor birth outcomes.^15-17

Hidden in plain sight. Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.¹⁸ Inadequate screening for cannabis can be attributed to time constraints, inconsistent definitions for problematic or risky cannabis use, and lack of guidance.^19,20 This article offers a more inclusive definition of “problematic cannabis use,” presents an up-to-date framework for evaluating it in the outpatient setting, and outlines potential interventions.

Your patient doesn’t meetthe DSM criteria, but …

Although it is important to identify cannabis use disorder (CUD) as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; TABLE 1^21,22), consider also the immediate and long-term consequences of cannabis use for individuals who do not meet criteria for CUD. “Problematic cannabis use,” as we define it, may also involve (a) high-risk behaviors or (b) contraindicating medical or psychiatric comorbidities (TABLE 2^6-9).

CASE

The patient in our case exhibited 4 factors indicative of problematic cannabis use: heavy vape use, cannabis use more than twice a week, asthma, and a family history of schizophrenia.

Continue to: Guidelines for screening and evaluation

All primary care patients should be screened for problematic cannabis use, but especially teenagers, young adults, pregnant women, and patients with a mental health or substance use history. A variation of the single question used to screen for alcohol use disorder can be applied to cannabis use.²³ We recommend asking the initial question, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?” Although some guidelines emphasize frequency of cannabis use when identifying problematic consumption,^24,25 duration of behavior and content of THC are also important indicators.¹⁹ Inquire about cannabis consumption over 1 month to differentiate sporadic use from longstanding persistent use.

Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.

Explore what types of cannabis the patient is ingesting and whether the patient uses cannabis heavily (4 or more times a week on average). Also determine the method of ingestion (eg, eating, vaping, smoking), THC-content (%, if known), and estimated weight of daily cannabis use in grams (TABLE 3²⁶). Although patients may not always be able to provide accurate answers, you can gain a sense of the quantity and forms of cannabis a patient is ingesting to inform future conversations on risk and harm reduction.²⁷

Assess a patient’s risk for harm

Cannabis use has the potential to cause immediate harm (linked to a single event of problematic cannabis use) and long-term harm (linked to a recurring pattern of problematic consumption). Cannabis can be especially harmful for patients with the following medical comorbidities or psychosocial factors, and should be avoided.

Cardiovascular disease. Cannabis is associated with an elevated risk for acute coronary syndrome and cardiovascular disease.²⁸ Long-term cannabis use is linked to increased frequency of anginal events, development of cardiac arrhythmias, peripheral arteritis, coronary vasospasms, and problems with platelet aggregation.^29,30 Strongly caution against cannabis use with patients who have a history of cardiovascular disease, orthostatic hypotension, tachyarrhythmia, or hypertension.

Pulmonary disease. Patients with pulmonary disease such as asthma may find cannabis helpful as a short-term bronchodilator.³¹ However, for patients with underlying pulmonary disease who also smoke cigarettes, strongly discourage the smoking of cannabis or hashish, as that may worsen asthma symptoms,³² increase risk of chronic bronchitis,³³ and increase cough, sputum production, and wheezing.³¹ There is currently insufficient evidence to suggest a positive association between cannabis use and the development of chronic obstructive pulmonary disease.³⁴

Continue to: Family history of psychotic disorders

Family history of psychotic disorders. Cannabis is associated with a dose-­dependent risk of schizophrenia, which is especially pronounced in patients with a family history of schizophrenia.³⁵ Among patients with a history of psychosis, heavy cannabis use has been associated with increased hospitalizations, increased positive symptoms, and more frequent relapses.^36-38

Pregnancy, current or planned. Some women turn to cannabis during pregnancy due to its antiemetic properties. However, perinatal exposure to cannabis is associated with significant risk to the offspring. Maternal cannabis use during the first and second trimesters of pregnancy is associated with decreased performance of the child on measures of function at 3 years of age.³⁹ In addition, cannabis consumption during pregnancy is linked to increased frequency of childhood behavioral issues, inattention, hyperactivity, and impulsivity.⁴⁰ Peripartum cannabis exposure can affect birth outcomes and is correlated with lower birth weight, incidence of preterm labor, and neonatal intensive care unit admission.^15-17,41 Of note, the THC concentration in breast milk peaks at 1 hour after the nursing mother inhales cannabis and typically dissipates after 4 hours.⁴²

Age < 25 years. Chronic heavy use of cannabis in those younger than 25 is associated with higher likelihood of developing CUD, lower IQ,⁹ lower level of educational attainment, lower income,⁴³ and decreased executive function.⁸

Substance use disorder history. Recreational cannabis use can hinder recovery from other substance use disorders.⁴⁴

Consider these 5 interventions

Physicians can address problematic cannabis use with a 5-pronged approach: (1) harm reduction, (2) motivational interviewing, (3) addressing underlying conditions, (4) mitigating withdrawal symptoms, and (5) referring to an addiction specialist (FIGURE).

Continue to: Harm reduction

Harm reduction applies to all individuals who use cannabis but especially to problematic cannabis users. Ask users to abstain from cannabis for limited periods of time to see how such abstinence affects other areas of their life. While abstinence is a goal, be prepared to perform non-abstinence-based interventions. The goal of harm reduction is to encourage behaviors that minimize health risks to which cannabis users are exposed. Encourage patients to:

Abstain from driving while intoxicated. Cannabis use while driving slows reaction time,⁴⁵ impairs road tracking (driving with correct road position),⁴⁶ increases weaving,⁴⁷ and causes a loss of anticipatory reactions learned in driving practice.⁴⁸ Risk of crashing is significantly increased with elevated levels of THC, and driving within 1 hour of cannabis ingestion nearly doubles the risk of a crash.^49-51

Abstain from vaping THC-containing products. The Centers for Disease Control and Prevention recommends that patients minimize the use of THC-containing e-cigarette or vaping products in light of the thousands of reports in the United States of product-associated lung injury, which in some cases have led to death.⁵²

Clarify serving sizes and recognize delayed effects. Inexperienced cannabis users often are confused by recommended serving sizes for edible cannabis products. A typical cannabis-infused brownie may contain 100 mg of THC when the recommended serving size typically is 10 mg. THC content is included on the label of cannabis edibles purchased in state-regulated stores; these products are tested regularly in laboratories designated by the state.

To screen, ask, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?”

Due to the delayed onset of THC’s effect, there have been numerous cases of patients taking a higher-than-intended dose of edible cannabis that caused acute intoxication and psychomedical sequelae leading to emergency hospital visits and, in some cases, death.^6,53 Individuals should start at a low dose and gradually work up to a higher dose as tolerated. Patients naïve to cannabis should be especially cautious when ingesting edible products.

Continue to: Abstain from cannabis with high THC content

Abstain from cannabis with high THC content. High-potency cannabis (> 10% THC) is associated with earlier onset of first-episode psychosis.^54,55

Motivational interviewing

Motivational interviewing (MI) is a psychosocial approach that emphasizes a patient’s self-efficacy and an interviewer’s positive feedback to collaboratively address substance use.⁵⁶ MI can be performed in short, discrete sessions. Such interventions can reduce the average number of days of cannabis use. One large-scale Cochrane review found that cognitive behavioral therapy (CBT), motivational enhancement therapy, or the 2 therapies combined most consistently reduced the frequency of cannabis use reported by patients at early follow-up.⁵⁷

Address underlying conditions

Some patients use cannabis to self-medicate for pain, insomnia, nausea, and anxiety. Identify these conditions and address them with first-line pharmacologic or psychotherapeutic interventions when possible. This is especially important for conditions in which long-term cannabis use may adversely impact outcomes, such as in posttraumatic stress disorder, anxiety, and mood disorders.^58-60 Little evidence exists for the use of cannabis as treatment of any primary psychiatric disorder.^61,62 Family physicians who are uncomfortable treating a specific underlying condition can consult specialists in pain management, sleep medicine, psychiatry, and neurology.

Mitigate withdrawal symptoms

Discontinuation of cannabis use may lead to withdrawal symptoms such as waxing and waning irritability, restlessness, sweating, aggression, anxiety, depressed mood, sleep disturbance, or changes in appetite.^63,64 These symptoms typically emerge within the first couple days of abstinence and can last up to 28 days.^63,64 Although the US Food and Drug Administration has not approved any medications for CUD treatment, and there are no established protocols for detoxification, there is evidence that CBT or medications such as gabapentin or zolpidem can reduce the intensity of withdrawal symptoms.^65,66

Refer to an addiction specialist

Consider referring patients with problematic cannabis use to an addiction specialist with expertise in psychopharmacologic and psychotherapeutic approaches to managing substance use.

Continue to: CASE

CASE

You renew Ms. F’s asthma medications, discuss her cannabis use, start her on a selective serotonin reuptake inhibitor, and refer her to an outpatient psychiatrist. Over the next few weeks, you and the outpatient psychiatrist employ brief motivational interviewing around cannabis use, and you provide psychoeducation around potential harms of use when driving and in light of the patient’s asthma.

Factors to consider in cannabis use include the method of ingestion, percentage of THC content, and times of day cannabis is used.

The patient’s anxiety symptoms decrease with up-titration of the SSRI by the outpatient psychiatrist and with enrollment in individual CBT. She is slowly able to taper off cannabis vaping with continued motivational interviewing and encouragement, despite withdrawal-induced anxiety and sleep disturbance.

CORRESPONDENCE
Michael Hsu, MD, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02215; [email protected].

The investigational agent MK-6482 demonstrated durable efficacy and a favorable safety profile in a phase 2 trial of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and nonrenal lesions, according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.

MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.

Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.

The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.

The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).

The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
 

Efficacy and safety

At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.

By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.

The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.

“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.

Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.

In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.

“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.

Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
 

Remaining questions and next steps

The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.

“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.

While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.

“These are the best response rates reported in non-RCC lesions,” she noted.

However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?

Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.

The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.

SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.

The investigational agent MK-6482 demonstrated durable efficacy and a favorable safety profile in a phase 2 trial of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and nonrenal lesions, according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.

MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.

Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.

The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.

The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).

The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
 

Efficacy and safety

At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.

By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.

The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.

“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.

Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.

In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.

“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.

Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
 

Remaining questions and next steps

The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.

“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.

While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.

“These are the best response rates reported in non-RCC lesions,” she noted.

However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?

Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.

The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.

SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.

The investigational agent MK-6482 demonstrated durable efficacy and a favorable safety profile in a phase 2 trial of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and nonrenal lesions, according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.

MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.

Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.

The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.

The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).

The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
 

Efficacy and safety

At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.

By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.

The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.

“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.

Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.

In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.

“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.

Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
 

Remaining questions and next steps

The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.

“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.

While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.

“These are the best response rates reported in non-RCC lesions,” she noted.

However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?

Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.

The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.

SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.

The year 2020 has brought the COVID-19 pandemic and civil unrest and protests, which have resulted in unprecedented health care challenges to hospitals and clinics. The daunting prospect of a fall influenza season has hospital staff and administrators looking ahead to still greater challenges.

This year of crisis has put even greater emphasis on leadership in hospitals, as patients, clinicians, and staff look for direction in the face of uncertainty and stress. But hospital leaders often arrive at their positions unprepared for their roles, according to Leonard Marcus, PhD, director of the Program for Health Care Negotiation and Conflict Resolution at Harvard T.H. Chan School of Public Health, Boston.

“Many times what happens in medicine is that someone with the greatest technical skills or greatest clinical skills emerges to be leader of a department, or a group, or a hospital, without having really paid attention to how they can build their leadership skills,” Dr. Marcus said during the 2020 Society of Hospital Medicine Leadership Virtual Seminar, held online Sept. 16-17.

Over 2 days, Dr. Marcus discussed the complex environments faced by hospital leaders, and some of the tools and strategies that can be used to maintain calm, problem-solve, and chart a course ahead.

He emphasized that hospitals and medical systems are complex, nonlinear organizations, which could be swept up by change in the form of mergers, financial policies, patient surges due to local emergencies, or pandemics.

“Complexity has to be central to how you think about leadership. If you think you can control everything, that doesn’t work that well,” said Dr. Marcus.

Most think of leadership as hierarchical, with a boss on top and underlings below, though this is starting to change. Dr. Marcus suggested a different view. Instead of just “leading down” to those who report to them, leaders should consider “leading up” to their own bosses or oversight committees, and across to other departments or even beyond to interlinked organizations such as nursing homes.

“Being able to build that connectivity not only within your hospital, but beyond your hospital, lets you see the chain that goes through the experience of any patient. You are looking at the problem from a much wider lens. We call this meta-leadership,” Dr. Marcus said.

A key focus of meta-leadership is to create a culture where individuals are working together to help one another succeed. Leadership in hospitals is often dominated by egos, with individual leaders battling one another in a win-lose effort, and this gets in the way of incorporating different perspectives into problem-solving.

Dr. Marcus used an example from previous seminars in which he instructed participants to arm wrestle the person sitting next to them. The goal was to attain as many pins as possible in 30 seconds. About half would fight as hard as they could, and achieve a few victories. The other half worked cooperatively, letting one person win, then the other, so that they could have 30 or 40 wins each. Dr. Marcus told the story of a young nurse who was paired up with a much stronger surgeon. She let him win twice, and when he asked her why she wasn’t resisting, she took his arm and placed it in a winning position, then a losing position, and then a winning position again, and he instantly understood that the cooperative approach could be more effective. Why didn’t she just tell him? She told Dr. Marcus that she knew he wouldn’t take instruction, so she let him win and then demonstrated an alternative. “We nurses learned how to do that a long time ago,” she told Dr. Marcus.

The idea is collaborative problem-solving. “How do you orient people looking to you for leadership so that we’re in this together and we can accomplish a whole lot more in 30 seconds if we’re working together instead of always battling one another? If we’re always battling one another, we’re putting all of our effort into the contest,” said Dr. Marcus. This sort of approach is all the more important when facing the complexity experienced by hospital systems, especially during crises such as COVID-19.

A critical element of meta-leadership is emotional intelligence, which includes elements such as self-awareness, self-regulation, empathy, determining motivation of yourself and others, and the social skills to portray yourself as caring, open, and interested.

Emotional intelligence also can help recognize when you’ve entered survival mode in reaction to a crisis or incident, or something as simple as losing your car keys – what Dr. Marcus terms “going to the basement.” Responses revolve around freeze, fight, or flight. It’s helpful in the wake of a car accident, but not when trying to make managerial decisions or respond to a complex situation. It’s vital for leaders to quickly get themselves out of the basement, said Dr. Marcus, and that they help other members of the team get out as well.

He recommended protocols designed in advance, both to recognize when you’re in the basement, and to lift yourself out. Dr. Marcus uses a trigger script, telling himself “I can do this,” and then when he’s working with other people, “we can do this.” He also speaks slowly, measuring every word. Whatever you do, “it has to be a pivot you do to get yourself out of the basement,” he said. It can be helpful to predict the kinds of situations that send you “to the basement” to help recognize it when it has happened.

It’s very important not to lead, negotiate, or make important decisions while in the basement, according to Dr. Marcus. If one thinks about some of the things they’ve said to others while under duress, they are often some of the statements they regret most.
 

Practical leadership skills

On the second day of the Leadership Seminar, Dr. Marcus moved his focus to using leadership skills and techniques. One important technique is to incorporate multiple perspectives. He gave the example of an opaque cube with a cone inside it, with a window on the side and one on top. Viewers from the side see the cone in profile, and see it as a triangle. Viewers from the top see an aerial perspective that looks like the circular base of the cone. The two groups could argue about what’s inside the cube, but they can only identify the object if they work together.

“When dealing with complex reality, you oftentimes find there are different people with different perspectives on a problem. They may have different experiences of what the problem is, and what often happens is that people get into an adversarial fight. Looking at the problem from different perspectives actually allows a much richer and more comprehensive view,” said Dr. Marcus.

The metaphor comes from a study of the tragic events at the Twin Towers in Manhattan on Sept. 11, 2001. The New York Fire Department had a command center at the base of the building, while the police had a helicopter flying around the buildings. The helicopter could see the steel girders beginning to melt and predicted a collapse, and therefore ordered their personnel out of the buildings. But they were unable to convey that information to the firefighters, who continued to send personnel into the buildings. In all, 343 firefighters lost their lives. The police force lost 32.

To best understand a problem, a key element is the “unknown knowns.” That is, information that is available, that someone has, but is unknown to you. It takes some imagination to conceive of what “unknown knowns” might be out there, but it’s worth the effort to identify possible knowledge sources. It’s vital to seek out this information, because a common leadership mistake is to assume you know something when you really don’t.

“In many ways what you’re doing is looking for obstacles. It could be you don’t have access to the information, that it’s beyond some sort of curtain you need to overcome, or it could be people in your own department who have the information and they’re not sharing it with you,” Dr. Marcus said.

He outlined a tool called the POP-DOC loop, which is a 6-step exercise designed to analyze problems and implement solutions. Step 1 is Perceiving the situation, determining knowns and unknowns, and incorporating multiple perspectives, emotions, and politics. Step 2 is to Orient oneself: examine patterns and how they may replicate themselves as long as conditions don’t change. For example, during COVID-19, physicians have begun to learn how the virus transmits and how it affects the immune system. Step 3, based on those patterns is to make Predictions. With COVID-19, it’s predictable that people who assemble without wearing masks are vulnerable to transmission. Step 4 is to use the predictions to begin to make Decisions. Step 5 is to begin Operationalizing those decisions, and step 6 is to Communicate those decisions effectively.

Dr. Marcus emphasized that POP-DOC is not a one-time exercise. Once decisions have been made and implemented, if they aren’t having the planned effect, it’s important to incorporate the results of those actions and start right back at the beginning of the POP-DOC loop.

“The POP side of the loop is perceiving, analysis. You get out of the basement and understand the situation that surrounds you. On the DOC side, you lead down, lead up, lead across and lead beyond. You’re bringing people into the action to get things done,” Dr. Marcus said.

Another tool Dr. Marcus described, aimed at problem-solving and negotiation, is the “Walk in the Woods.” The idea is to bring two parties together to help each other succeed. The first step is Self-Interest, where both parties articulate their objectives, perspectives, and fears. The second step, Enlarged Interests, requires each party to list their points of agreement, and only then should they focus on and list their points of disagreement. During conflict, people tend to focus on their disagreements. The parties often find that they agree on more than they realize, and this can frame the disagreements as more manageable. The third step, Enlightened Interest, is a free thinking period where both parties come up with potential solutions that had not been previously considered. In step 4, Aligned Interests, the parties discuss some of those ideas that can be explored further.

The Walk in the Woods is applicable to a wide range of situations, and negotiation is central to being a leader. “Being a clinician is all about negotiating – with patients, family members, with other clinicians, with the institution,” Dr. Marcus said. “We all want the patient to have the best possible care, and in the course of those conversations if we can better understand people, have empathy, and if there are new ideas or ways we can individualize our care, let’s do it, and then at the end of the day combine our motivations so that we’re providing the best possible care.”

In the end, meta-leadership is about creating a culture where individuals strive to help each other succeed, said Dr. Marcus. “That’s the essence: involving people, making them part of the solution, and if it’s a solution they’ve created together, everyone wants to make that solution a success.”

For more information, see the book “You’re It,” coauthored by Dr. Marcus, and available on Amazon for $16.99 in hardback, or $3.99 in Kindle format.

The year 2020 has brought the COVID-19 pandemic and civil unrest and protests, which have resulted in unprecedented health care challenges to hospitals and clinics. The daunting prospect of a fall influenza season has hospital staff and administrators looking ahead to still greater challenges.

This year of crisis has put even greater emphasis on leadership in hospitals, as patients, clinicians, and staff look for direction in the face of uncertainty and stress. But hospital leaders often arrive at their positions unprepared for their roles, according to Leonard Marcus, PhD, director of the Program for Health Care Negotiation and Conflict Resolution at Harvard T.H. Chan School of Public Health, Boston.

“Many times what happens in medicine is that someone with the greatest technical skills or greatest clinical skills emerges to be leader of a department, or a group, or a hospital, without having really paid attention to how they can build their leadership skills,” Dr. Marcus said during the 2020 Society of Hospital Medicine Leadership Virtual Seminar, held online Sept. 16-17.

Over 2 days, Dr. Marcus discussed the complex environments faced by hospital leaders, and some of the tools and strategies that can be used to maintain calm, problem-solve, and chart a course ahead.

He emphasized that hospitals and medical systems are complex, nonlinear organizations, which could be swept up by change in the form of mergers, financial policies, patient surges due to local emergencies, or pandemics.

“Complexity has to be central to how you think about leadership. If you think you can control everything, that doesn’t work that well,” said Dr. Marcus.

Most think of leadership as hierarchical, with a boss on top and underlings below, though this is starting to change. Dr. Marcus suggested a different view. Instead of just “leading down” to those who report to them, leaders should consider “leading up” to their own bosses or oversight committees, and across to other departments or even beyond to interlinked organizations such as nursing homes.

“Being able to build that connectivity not only within your hospital, but beyond your hospital, lets you see the chain that goes through the experience of any patient. You are looking at the problem from a much wider lens. We call this meta-leadership,” Dr. Marcus said.

A key focus of meta-leadership is to create a culture where individuals are working together to help one another succeed. Leadership in hospitals is often dominated by egos, with individual leaders battling one another in a win-lose effort, and this gets in the way of incorporating different perspectives into problem-solving.

Dr. Marcus used an example from previous seminars in which he instructed participants to arm wrestle the person sitting next to them. The goal was to attain as many pins as possible in 30 seconds. About half would fight as hard as they could, and achieve a few victories. The other half worked cooperatively, letting one person win, then the other, so that they could have 30 or 40 wins each. Dr. Marcus told the story of a young nurse who was paired up with a much stronger surgeon. She let him win twice, and when he asked her why she wasn’t resisting, she took his arm and placed it in a winning position, then a losing position, and then a winning position again, and he instantly understood that the cooperative approach could be more effective. Why didn’t she just tell him? She told Dr. Marcus that she knew he wouldn’t take instruction, so she let him win and then demonstrated an alternative. “We nurses learned how to do that a long time ago,” she told Dr. Marcus.

The idea is collaborative problem-solving. “How do you orient people looking to you for leadership so that we’re in this together and we can accomplish a whole lot more in 30 seconds if we’re working together instead of always battling one another? If we’re always battling one another, we’re putting all of our effort into the contest,” said Dr. Marcus. This sort of approach is all the more important when facing the complexity experienced by hospital systems, especially during crises such as COVID-19.

A critical element of meta-leadership is emotional intelligence, which includes elements such as self-awareness, self-regulation, empathy, determining motivation of yourself and others, and the social skills to portray yourself as caring, open, and interested.

Emotional intelligence also can help recognize when you’ve entered survival mode in reaction to a crisis or incident, or something as simple as losing your car keys – what Dr. Marcus terms “going to the basement.” Responses revolve around freeze, fight, or flight. It’s helpful in the wake of a car accident, but not when trying to make managerial decisions or respond to a complex situation. It’s vital for leaders to quickly get themselves out of the basement, said Dr. Marcus, and that they help other members of the team get out as well.

He recommended protocols designed in advance, both to recognize when you’re in the basement, and to lift yourself out. Dr. Marcus uses a trigger script, telling himself “I can do this,” and then when he’s working with other people, “we can do this.” He also speaks slowly, measuring every word. Whatever you do, “it has to be a pivot you do to get yourself out of the basement,” he said. It can be helpful to predict the kinds of situations that send you “to the basement” to help recognize it when it has happened.

It’s very important not to lead, negotiate, or make important decisions while in the basement, according to Dr. Marcus. If one thinks about some of the things they’ve said to others while under duress, they are often some of the statements they regret most.
 

Practical leadership skills

On the second day of the Leadership Seminar, Dr. Marcus moved his focus to using leadership skills and techniques. One important technique is to incorporate multiple perspectives. He gave the example of an opaque cube with a cone inside it, with a window on the side and one on top. Viewers from the side see the cone in profile, and see it as a triangle. Viewers from the top see an aerial perspective that looks like the circular base of the cone. The two groups could argue about what’s inside the cube, but they can only identify the object if they work together.

“When dealing with complex reality, you oftentimes find there are different people with different perspectives on a problem. They may have different experiences of what the problem is, and what often happens is that people get into an adversarial fight. Looking at the problem from different perspectives actually allows a much richer and more comprehensive view,” said Dr. Marcus.

The metaphor comes from a study of the tragic events at the Twin Towers in Manhattan on Sept. 11, 2001. The New York Fire Department had a command center at the base of the building, while the police had a helicopter flying around the buildings. The helicopter could see the steel girders beginning to melt and predicted a collapse, and therefore ordered their personnel out of the buildings. But they were unable to convey that information to the firefighters, who continued to send personnel into the buildings. In all, 343 firefighters lost their lives. The police force lost 32.

To best understand a problem, a key element is the “unknown knowns.” That is, information that is available, that someone has, but is unknown to you. It takes some imagination to conceive of what “unknown knowns” might be out there, but it’s worth the effort to identify possible knowledge sources. It’s vital to seek out this information, because a common leadership mistake is to assume you know something when you really don’t.

“In many ways what you’re doing is looking for obstacles. It could be you don’t have access to the information, that it’s beyond some sort of curtain you need to overcome, or it could be people in your own department who have the information and they’re not sharing it with you,” Dr. Marcus said.

He outlined a tool called the POP-DOC loop, which is a 6-step exercise designed to analyze problems and implement solutions. Step 1 is Perceiving the situation, determining knowns and unknowns, and incorporating multiple perspectives, emotions, and politics. Step 2 is to Orient oneself: examine patterns and how they may replicate themselves as long as conditions don’t change. For example, during COVID-19, physicians have begun to learn how the virus transmits and how it affects the immune system. Step 3, based on those patterns is to make Predictions. With COVID-19, it’s predictable that people who assemble without wearing masks are vulnerable to transmission. Step 4 is to use the predictions to begin to make Decisions. Step 5 is to begin Operationalizing those decisions, and step 6 is to Communicate those decisions effectively.

Dr. Marcus emphasized that POP-DOC is not a one-time exercise. Once decisions have been made and implemented, if they aren’t having the planned effect, it’s important to incorporate the results of those actions and start right back at the beginning of the POP-DOC loop.

“The POP side of the loop is perceiving, analysis. You get out of the basement and understand the situation that surrounds you. On the DOC side, you lead down, lead up, lead across and lead beyond. You’re bringing people into the action to get things done,” Dr. Marcus said.

Another tool Dr. Marcus described, aimed at problem-solving and negotiation, is the “Walk in the Woods.” The idea is to bring two parties together to help each other succeed. The first step is Self-Interest, where both parties articulate their objectives, perspectives, and fears. The second step, Enlarged Interests, requires each party to list their points of agreement, and only then should they focus on and list their points of disagreement. During conflict, people tend to focus on their disagreements. The parties often find that they agree on more than they realize, and this can frame the disagreements as more manageable. The third step, Enlightened Interest, is a free thinking period where both parties come up with potential solutions that had not been previously considered. In step 4, Aligned Interests, the parties discuss some of those ideas that can be explored further.

The Walk in the Woods is applicable to a wide range of situations, and negotiation is central to being a leader. “Being a clinician is all about negotiating – with patients, family members, with other clinicians, with the institution,” Dr. Marcus said. “We all want the patient to have the best possible care, and in the course of those conversations if we can better understand people, have empathy, and if there are new ideas or ways we can individualize our care, let’s do it, and then at the end of the day combine our motivations so that we’re providing the best possible care.”

In the end, meta-leadership is about creating a culture where individuals strive to help each other succeed, said Dr. Marcus. “That’s the essence: involving people, making them part of the solution, and if it’s a solution they’ve created together, everyone wants to make that solution a success.”

For more information, see the book “You’re It,” coauthored by Dr. Marcus, and available on Amazon for $16.99 in hardback, or $3.99 in Kindle format.

The year 2020 has brought the COVID-19 pandemic and civil unrest and protests, which have resulted in unprecedented health care challenges to hospitals and clinics. The daunting prospect of a fall influenza season has hospital staff and administrators looking ahead to still greater challenges.

This year of crisis has put even greater emphasis on leadership in hospitals, as patients, clinicians, and staff look for direction in the face of uncertainty and stress. But hospital leaders often arrive at their positions unprepared for their roles, according to Leonard Marcus, PhD, director of the Program for Health Care Negotiation and Conflict Resolution at Harvard T.H. Chan School of Public Health, Boston.

“Many times what happens in medicine is that someone with the greatest technical skills or greatest clinical skills emerges to be leader of a department, or a group, or a hospital, without having really paid attention to how they can build their leadership skills,” Dr. Marcus said during the 2020 Society of Hospital Medicine Leadership Virtual Seminar, held online Sept. 16-17.

Over 2 days, Dr. Marcus discussed the complex environments faced by hospital leaders, and some of the tools and strategies that can be used to maintain calm, problem-solve, and chart a course ahead.

He emphasized that hospitals and medical systems are complex, nonlinear organizations, which could be swept up by change in the form of mergers, financial policies, patient surges due to local emergencies, or pandemics.

“Complexity has to be central to how you think about leadership. If you think you can control everything, that doesn’t work that well,” said Dr. Marcus.

Most think of leadership as hierarchical, with a boss on top and underlings below, though this is starting to change. Dr. Marcus suggested a different view. Instead of just “leading down” to those who report to them, leaders should consider “leading up” to their own bosses or oversight committees, and across to other departments or even beyond to interlinked organizations such as nursing homes.

“Being able to build that connectivity not only within your hospital, but beyond your hospital, lets you see the chain that goes through the experience of any patient. You are looking at the problem from a much wider lens. We call this meta-leadership,” Dr. Marcus said.

A key focus of meta-leadership is to create a culture where individuals are working together to help one another succeed. Leadership in hospitals is often dominated by egos, with individual leaders battling one another in a win-lose effort, and this gets in the way of incorporating different perspectives into problem-solving.

Dr. Marcus used an example from previous seminars in which he instructed participants to arm wrestle the person sitting next to them. The goal was to attain as many pins as possible in 30 seconds. About half would fight as hard as they could, and achieve a few victories. The other half worked cooperatively, letting one person win, then the other, so that they could have 30 or 40 wins each. Dr. Marcus told the story of a young nurse who was paired up with a much stronger surgeon. She let him win twice, and when he asked her why she wasn’t resisting, she took his arm and placed it in a winning position, then a losing position, and then a winning position again, and he instantly understood that the cooperative approach could be more effective. Why didn’t she just tell him? She told Dr. Marcus that she knew he wouldn’t take instruction, so she let him win and then demonstrated an alternative. “We nurses learned how to do that a long time ago,” she told Dr. Marcus.

The idea is collaborative problem-solving. “How do you orient people looking to you for leadership so that we’re in this together and we can accomplish a whole lot more in 30 seconds if we’re working together instead of always battling one another? If we’re always battling one another, we’re putting all of our effort into the contest,” said Dr. Marcus. This sort of approach is all the more important when facing the complexity experienced by hospital systems, especially during crises such as COVID-19.

A critical element of meta-leadership is emotional intelligence, which includes elements such as self-awareness, self-regulation, empathy, determining motivation of yourself and others, and the social skills to portray yourself as caring, open, and interested.

Emotional intelligence also can help recognize when you’ve entered survival mode in reaction to a crisis or incident, or something as simple as losing your car keys – what Dr. Marcus terms “going to the basement.” Responses revolve around freeze, fight, or flight. It’s helpful in the wake of a car accident, but not when trying to make managerial decisions or respond to a complex situation. It’s vital for leaders to quickly get themselves out of the basement, said Dr. Marcus, and that they help other members of the team get out as well.

He recommended protocols designed in advance, both to recognize when you’re in the basement, and to lift yourself out. Dr. Marcus uses a trigger script, telling himself “I can do this,” and then when he’s working with other people, “we can do this.” He also speaks slowly, measuring every word. Whatever you do, “it has to be a pivot you do to get yourself out of the basement,” he said. It can be helpful to predict the kinds of situations that send you “to the basement” to help recognize it when it has happened.

It’s very important not to lead, negotiate, or make important decisions while in the basement, according to Dr. Marcus. If one thinks about some of the things they’ve said to others while under duress, they are often some of the statements they regret most.
 

Practical leadership skills

On the second day of the Leadership Seminar, Dr. Marcus moved his focus to using leadership skills and techniques. One important technique is to incorporate multiple perspectives. He gave the example of an opaque cube with a cone inside it, with a window on the side and one on top. Viewers from the side see the cone in profile, and see it as a triangle. Viewers from the top see an aerial perspective that looks like the circular base of the cone. The two groups could argue about what’s inside the cube, but they can only identify the object if they work together.

“When dealing with complex reality, you oftentimes find there are different people with different perspectives on a problem. They may have different experiences of what the problem is, and what often happens is that people get into an adversarial fight. Looking at the problem from different perspectives actually allows a much richer and more comprehensive view,” said Dr. Marcus.

The metaphor comes from a study of the tragic events at the Twin Towers in Manhattan on Sept. 11, 2001. The New York Fire Department had a command center at the base of the building, while the police had a helicopter flying around the buildings. The helicopter could see the steel girders beginning to melt and predicted a collapse, and therefore ordered their personnel out of the buildings. But they were unable to convey that information to the firefighters, who continued to send personnel into the buildings. In all, 343 firefighters lost their lives. The police force lost 32.

To best understand a problem, a key element is the “unknown knowns.” That is, information that is available, that someone has, but is unknown to you. It takes some imagination to conceive of what “unknown knowns” might be out there, but it’s worth the effort to identify possible knowledge sources. It’s vital to seek out this information, because a common leadership mistake is to assume you know something when you really don’t.

“In many ways what you’re doing is looking for obstacles. It could be you don’t have access to the information, that it’s beyond some sort of curtain you need to overcome, or it could be people in your own department who have the information and they’re not sharing it with you,” Dr. Marcus said.

He outlined a tool called the POP-DOC loop, which is a 6-step exercise designed to analyze problems and implement solutions. Step 1 is Perceiving the situation, determining knowns and unknowns, and incorporating multiple perspectives, emotions, and politics. Step 2 is to Orient oneself: examine patterns and how they may replicate themselves as long as conditions don’t change. For example, during COVID-19, physicians have begun to learn how the virus transmits and how it affects the immune system. Step 3, based on those patterns is to make Predictions. With COVID-19, it’s predictable that people who assemble without wearing masks are vulnerable to transmission. Step 4 is to use the predictions to begin to make Decisions. Step 5 is to begin Operationalizing those decisions, and step 6 is to Communicate those decisions effectively.

Dr. Marcus emphasized that POP-DOC is not a one-time exercise. Once decisions have been made and implemented, if they aren’t having the planned effect, it’s important to incorporate the results of those actions and start right back at the beginning of the POP-DOC loop.

“The POP side of the loop is perceiving, analysis. You get out of the basement and understand the situation that surrounds you. On the DOC side, you lead down, lead up, lead across and lead beyond. You’re bringing people into the action to get things done,” Dr. Marcus said.

Another tool Dr. Marcus described, aimed at problem-solving and negotiation, is the “Walk in the Woods.” The idea is to bring two parties together to help each other succeed. The first step is Self-Interest, where both parties articulate their objectives, perspectives, and fears. The second step, Enlarged Interests, requires each party to list their points of agreement, and only then should they focus on and list their points of disagreement. During conflict, people tend to focus on their disagreements. The parties often find that they agree on more than they realize, and this can frame the disagreements as more manageable. The third step, Enlightened Interest, is a free thinking period where both parties come up with potential solutions that had not been previously considered. In step 4, Aligned Interests, the parties discuss some of those ideas that can be explored further.

The Walk in the Woods is applicable to a wide range of situations, and negotiation is central to being a leader. “Being a clinician is all about negotiating – with patients, family members, with other clinicians, with the institution,” Dr. Marcus said. “We all want the patient to have the best possible care, and in the course of those conversations if we can better understand people, have empathy, and if there are new ideas or ways we can individualize our care, let’s do it, and then at the end of the day combine our motivations so that we’re providing the best possible care.”

In the end, meta-leadership is about creating a culture where individuals strive to help each other succeed, said Dr. Marcus. “That’s the essence: involving people, making them part of the solution, and if it’s a solution they’ve created together, everyone wants to make that solution a success.”

For more information, see the book “You’re It,” coauthored by Dr. Marcus, and available on Amazon for $16.99 in hardback, or $3.99 in Kindle format.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Increased high-density lipoprotein cholesterol (HDL-C) is associated with decreased gray matter and cortical atrophy in patients with multiple sclerosis (MS) after adjusting for baseline serum neurofilaments (sNfL).

Major finding: Gray matter volume and cortical volume had significant associations with percent change in HDL-C (P = .0024 and P less than .001, respectively) after adjusting for sNfL as a predictor.

Study details: This prospective longitudinal study assessed patients with relapsing-remitting MS (n = 75) and progressive multiple sclerosis (n = 37) over a 5-year follow-up period.

Disclosures: The study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health. B Weinstock-Guttman, J Kuhle, R Zivadinov and M Ramanathan reported ties with multiple pharmaceutical companies. The remaining authors declared no conflicts of interest.

Citation: McComb M et al. Mult Scler Relat Disord. 2020 Jul 11. doi: 10.1016/j.msard.2020.102389.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Early and continuous ocrelizumab treatment can provide sustained benefit on clinical and magnetic resonance imaging measures for disease progression in patients with relapsing multiple sclerosis (MS).

Major finding: At 5 years, the cumulative proportion of patients with 24-week confirmed disability progression was lower among those who continued ocrelizumab vs those who switched from interferon (IFN) β-1a to ocrelizumab (16.1% vs 21.3%; P = .014). Similarly, brain atrophy was significantly lower among those who continued ocrelizumab than in those who switched to ocrelizumab (P less than .01).

Study details: The OPERA open label extension study evaluated long-term efficacy and safety (5 years follow-up) of ocrelizumab (600 mg) in adults with relapsing MS. Patients previously assigned to INF β-1a  (n = 829) and ocrelizumab (n = 827) entered the open-label extension phase in this study, of which 623 switched to ocrelizumab and 702 continued ocrelizumab, respectively

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The lead author reporting receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. Some of his coinvestigators reported owning stock in, being an employee of, receiving support from, and/or serving on scientific advisory board for F. Hoffmann-La Roche Ltd.

Citation: Hauser SL et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010376.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Real-world data demonstrates effectiveness of rituximab in reducing disease activity and maintaining long-term treatment in patients with multiple sclerosis (MS).

Major finding: The odds for experiencing a clinical relapse, contrast-enhancing lesions (CEL), and/or new T2 lesions were greater with fingolimod  (adjusted odds ratio [aOR], 3.17; P less than .001)  and dimethyl fumarate (aOR, 2.68; P less than .001) compared with rituximab. Similarly, natalizimab vs rituximab showed higher odds for disease activity (aOR, 1.36; P = 0.216). The odds for discontinuation were higher for fingolimod (aOR, 2.02; P = .005) and dimethyl fumarate (aOR, 3.27; P less than .001) compared with rituximab.

Study details: A retrospective real-world study included MS patients who were initiated on rituximab (n = 182), natalizumab (n = 451), fingolimod (n = 271) or dimethyl fumarate (n = 342) and followed for 2 years.

Disclosures: This study received no funding. KV Nair, JR Corboy, T Vollmer and E Alvarez reported relationships with multiple pharmaceutical companies.

Citation: Vollmer BL et al. Ann Clin Transl Neurol. 2020 Aug 6. doi: 10.1002/acn3.51111.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

Key clinical point: Elevated blood lipid parameters in patients with multiple sclerosis (MS) may harm cognitive functions.

Major finding: A negative correlation was observed between cholesterol and general cognitive functioning score after rehabilitation and the Expanded Disability Status Scale scores (Cronbach alpha, 0.60 and 0.65, respectively). Triglyceride scores also has a negative correlation with working memory scores before and after rehabilitation (Cronbach alpha, 0.36 and 0.40, respectively). Furthermore, body mass index scores had a negative correlation with the visuospatial ability (Cronbach alpha, 0.59)

Study details: The study included 90 inpatients with relapsing remitting, primary and secondary progressive MS who underwent intense neurorehabilitation training.

Disclosures: The study received no funding. The authors reported no conflicts of interest.

Citation: Andaloro A et al. Int J Neurosci. 2020 Aug 7. doi: 10.1080/00207454.2020.1807980.

To say that the pandemic has dropped us into uncharted territory is an understatement of unmeasurable proportions. Every day we learn more about it, and every day that new information brings us new challenges. COVID-19 is playing by its own set of rules. To keep pace with it societies have been forced to adapt to them, and members of those societies have had to realize that these new rules must be obeyed or be prepared to suffer the consequences.

BananaStock/Thinkstock

I’m not sure exactly when it happened but gradually over my 7 and a half decades on this planet it appears that following the rules and understanding the value of “No” have become concepts to be ignored and left to gather dust in the attics and basements of our society. The tug of war between well-considered rules and the often misinterpreted concept of freedom has been ebbing and flowing since Eve plucked a forbidden apple off that tree.

In some parts of the world, the twin skills of saying and responding to “No” have become lost arts. I think it is not by chance that, of the four books I have written for parents, the one titled “How to Say No to Your Toddler” has become the most widely distributed, having been translated into Italian, Polish, and Russian. It is only slightly comforting to learn that at least some parents understand that creating rules can be important, but realize they aren’t quite sure how go about it.

As it has become clear that social distancing and mask wearing are associated with curtailing the spread of COVID-19, state and local governments have had to bone up on their long-forgotten No-saying skills. This relearning process has been particularly painful for school administrators who may have been warned that “You’ll never be able to get first and second graders to wear masks” or that “College students just won’t obey the rules.”

Both of these cautions are based on observations by educators with years of experience and certainly have a ring of truth to them. But could it be that these pessimistic predictions reflect a society in which parents and educators have lost the talent for crafting sensible rules and linking them to enforceable and rational consequences?

As colleges throughout the country have reopened using a variety of learning and residential strategies, there have been numerous incidents that validate the gloomy predictions of student misbehavior. Smaller schools seem to be having less difficulty, which is not surprising given their relative ease in fostering a sense of community. Many schools have been forced to rollback their plans for in-person learning because students have failed to follow some very simple but unpopular rules.

In a swift and decisive response to student misbehavior, Northeastern University in Boston dismissed 11 first-year students and will not refund their tuition when officials discovered a prohibited social gathering in one of the resident facilities (“Northeastern Dismisses 11 Students for Gathering in Violation of COVID-19 Policies,” by Ian Thomsen, News at Northwestern). This response seemed to have come as a surprise to many students and parents around the country who have become accustomed a diet of warnings and minor sanctions.

Whether this action by Northeastern will trigger similar responses by other universities remains to be seen. But we can hope that it sets an example of how learning about “No” can be an important part of one’s education.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

To say that the pandemic has dropped us into uncharted territory is an understatement of unmeasurable proportions. Every day we learn more about it, and every day that new information brings us new challenges. COVID-19 is playing by its own set of rules. To keep pace with it societies have been forced to adapt to them, and members of those societies have had to realize that these new rules must be obeyed or be prepared to suffer the consequences.

BananaStock/Thinkstock

I’m not sure exactly when it happened but gradually over my 7 and a half decades on this planet it appears that following the rules and understanding the value of “No” have become concepts to be ignored and left to gather dust in the attics and basements of our society. The tug of war between well-considered rules and the often misinterpreted concept of freedom has been ebbing and flowing since Eve plucked a forbidden apple off that tree.

In some parts of the world, the twin skills of saying and responding to “No” have become lost arts. I think it is not by chance that, of the four books I have written for parents, the one titled “How to Say No to Your Toddler” has become the most widely distributed, having been translated into Italian, Polish, and Russian. It is only slightly comforting to learn that at least some parents understand that creating rules can be important, but realize they aren’t quite sure how go about it.

As it has become clear that social distancing and mask wearing are associated with curtailing the spread of COVID-19, state and local governments have had to bone up on their long-forgotten No-saying skills. This relearning process has been particularly painful for school administrators who may have been warned that “You’ll never be able to get first and second graders to wear masks” or that “College students just won’t obey the rules.”

Both of these cautions are based on observations by educators with years of experience and certainly have a ring of truth to them. But could it be that these pessimistic predictions reflect a society in which parents and educators have lost the talent for crafting sensible rules and linking them to enforceable and rational consequences?

As colleges throughout the country have reopened using a variety of learning and residential strategies, there have been numerous incidents that validate the gloomy predictions of student misbehavior. Smaller schools seem to be having less difficulty, which is not surprising given their relative ease in fostering a sense of community. Many schools have been forced to rollback their plans for in-person learning because students have failed to follow some very simple but unpopular rules.

In a swift and decisive response to student misbehavior, Northeastern University in Boston dismissed 11 first-year students and will not refund their tuition when officials discovered a prohibited social gathering in one of the resident facilities (“Northeastern Dismisses 11 Students for Gathering in Violation of COVID-19 Policies,” by Ian Thomsen, News at Northwestern). This response seemed to have come as a surprise to many students and parents around the country who have become accustomed a diet of warnings and minor sanctions.

Whether this action by Northeastern will trigger similar responses by other universities remains to be seen. But we can hope that it sets an example of how learning about “No” can be an important part of one’s education.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

To say that the pandemic has dropped us into uncharted territory is an understatement of unmeasurable proportions. Every day we learn more about it, and every day that new information brings us new challenges. COVID-19 is playing by its own set of rules. To keep pace with it societies have been forced to adapt to them, and members of those societies have had to realize that these new rules must be obeyed or be prepared to suffer the consequences.

BananaStock/Thinkstock

I’m not sure exactly when it happened but gradually over my 7 and a half decades on this planet it appears that following the rules and understanding the value of “No” have become concepts to be ignored and left to gather dust in the attics and basements of our society. The tug of war between well-considered rules and the often misinterpreted concept of freedom has been ebbing and flowing since Eve plucked a forbidden apple off that tree.

In some parts of the world, the twin skills of saying and responding to “No” have become lost arts. I think it is not by chance that, of the four books I have written for parents, the one titled “How to Say No to Your Toddler” has become the most widely distributed, having been translated into Italian, Polish, and Russian. It is only slightly comforting to learn that at least some parents understand that creating rules can be important, but realize they aren’t quite sure how go about it.

As it has become clear that social distancing and mask wearing are associated with curtailing the spread of COVID-19, state and local governments have had to bone up on their long-forgotten No-saying skills. This relearning process has been particularly painful for school administrators who may have been warned that “You’ll never be able to get first and second graders to wear masks” or that “College students just won’t obey the rules.”

Both of these cautions are based on observations by educators with years of experience and certainly have a ring of truth to them. But could it be that these pessimistic predictions reflect a society in which parents and educators have lost the talent for crafting sensible rules and linking them to enforceable and rational consequences?

As colleges throughout the country have reopened using a variety of learning and residential strategies, there have been numerous incidents that validate the gloomy predictions of student misbehavior. Smaller schools seem to be having less difficulty, which is not surprising given their relative ease in fostering a sense of community. Many schools have been forced to rollback their plans for in-person learning because students have failed to follow some very simple but unpopular rules.

In a swift and decisive response to student misbehavior, Northeastern University in Boston dismissed 11 first-year students and will not refund their tuition when officials discovered a prohibited social gathering in one of the resident facilities (“Northeastern Dismisses 11 Students for Gathering in Violation of COVID-19 Policies,” by Ian Thomsen, News at Northwestern). This response seemed to have come as a surprise to many students and parents around the country who have become accustomed a diet of warnings and minor sanctions.

Whether this action by Northeastern will trigger similar responses by other universities remains to be seen. But we can hope that it sets an example of how learning about “No” can be an important part of one’s education.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

At a time when new evidence strongly suggests that roughly a fifth of patents with hypertension have primary aldosteronism as the cause, other recent findings suggest that many of these possibly tens of millions of patients with aldosterone-driven high blood pressure may as a consequence need an expensive and not-widely-available diagnostic test – adrenal vein sampling – to determine whether they are candidates for a definitive surgical cure to their aldosteronism.

SciePro/Shutterstock

Some endocrinologists worry the worldwide infrastructure for running adrenal vein sampling (AVS) isn’t close to being in place to deliver on this looming need for patients with primary aldosteronism (PA), especially given the burgeoning numbers now being cited for PA prevalence.

“The system could be overwhelmed,” warned Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville. “Right now, adrenal vein sampling [AVS] is the gold standard,” for distinguishing unilateral and bilateral excess aldosterone secretion, “but not every radiologist can do AVS. Until we find a surrogate biomarker that can distinguish unilateral and bilateral PA” many patients will need AVS, Dr. Carey said in an interview.

“AVS is important for accurate lateralization of aldosterone excess in patients, but it may not be feasible for all patients with PA to undergo AVS. If the prevalence of PA truly is on the order of 15% [of all patients with hypertension] then health systems would be stretched to offer all of them AVS, which is technically challenging and requires dedicated training and is therefore limited to expert centers,” commented Jun Yang, MBBS, a cardiovascular endocrinologist at the Hudson Institute of Medical Research and a hypertension researcher at Monash University, both in Melbourne. “At Monash, our interventional radiologists have increased their [AVS] success rate from 40% to more than 90% during the past 10 years, and our waiting list for patients scheduled for AVS is now 3-4 months long,” Dr. Yang said in an interview.

Finding a unilateral adrenal nodule as the cause of PA means that surgical removal is an option, a step that often fully resolves the PA and normalizes blood pressure. Patients with a bilateral source of the aldosterone are not candidates for surgical cure and must be managed with medical treatment, usually a mineralocorticoid receptor antagonist such as spironolactone that can neutralize or at least reduce the impact of hyperaldosteronism.
 

AVS finds unilateral adenomas when imaging can’t

The evidence that raised concerns about the reliability of imaging as an easier and noninvasive means to identify hypertensive patients with PA and a unilateral adrenal nodule that makes them candidates for surgical removal to resolve their PA and hypertension came out in May 2020 in a review of 174 PA patients who underwent AVS at a single center in Calgary, Alta., during 2006-2018.

The review included 366 patients with PA referred to the University of Calgary for assessment, of whom 179 had no adrenal nodule visible with either CT or MRI imaging, with 174 of these patients also undergoing successful AVS. The procedure revealed 70 patients (40%) had unilateral aldosterone secretion (Can J Cardiol. 2020 May 16. doi: 10.1016/j.cjca.2020.05.013).

In an editorial about this report that appeared a few weeks later, Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg, Man., said the finding was “amazing,” and “confirms that lateralization of aldosterone secretion in a patient with PA but without an identifiable mass on that side is not a zebra,” but instead a presentation that “occurs in almost half of patients with PA and no discernible adenoma on the side that lateralizes.” (Can J. Cardiol. 2020 Jul 3. doi: 10.1016/j.cjca.2020.06.022).

Although this was just one center’s experience, the authors are not alone in making this finding, although prior reports seem to have been largely forgotten or ignored until now.

“The discordance between AVS and adrenal imaging has been documented by numerous groups, and in our own experience [in Melbourne] around 40% of patients with unilateral aldosterone excess do not have a distinct unilateral adenoma on CT,” said Dr. Yang.

“Here’s the problem,” summed up Dr. Feldman in an interview. “Nearly half of patients with hyperaldosteronism don’t localize based on a CT or MRI, so you have to do AVS, but AVS is not generally available; it’s only at tertiary centers; and you have to do a lot of them,” to do them well. “It’s a half-day procedure, and you have to hit the correct adrenal vein.”
 

AVS for millions?

Compounding the challenge is the other bit of bombshell news recently dropped on the endocrinology and hypertension communities: PA may be much more prevalent that previously suspected, occurring in roughly 20% of patients with hypertension, according to study results that also came out in 2020 (Ann Int Med. 2020 Jul 7;173[1]:10-20).

The upshot, according to Dr. Feldman and others, is that researchers will need to find reliable criteria besides imaging for identifying PA patients with an increased likelihood of having a lateralized source for their excess aldosterone production. That’s “the only hope,” said Dr. Feldman, “so we won’t have to do AVS on 20 million Americans.”

Unfortunately, the path toward a successful screen to winnow down candidates for AVS has been long and not especially fruitful, with efforts dating back at least 50 years, and with one of the most recent efforts at stratifying PA patients by certain laboratory measures getting dismissed as producing a benefit that “might not be substantial,” wrote Michael Stowasser, MBBS, in a published commentary (J Hypertension. 2020 Jul;38[7]:1259-61).

In contrast to Dr. Feldman, Dr. Stowasser was more optimistic about the prospects for avoiding an immediate crisis in AVS assessment of PA patients, mostly because so few patients with PA are now identified by clinicians. Given the poor record clinicians have historically rung up diagnosing PA, “it would seem unlikely that we are going to be flooded with AVS requests any time soon,” he wrote. There is also reason to hope that increased demand for AVS will help broaden availability, and innovative testing methods promise to speed up the procedure, said Dr. Stowasser, a professor of medicine at the University of Queensland in Brisbane, Australia and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane, in an interview.

But regardless of whether AVS testing becomes more available or streamlined, recent events suggest there will be little way to avoid eventually having to run millions of these diagnostic procedures.

Patients with PA “who decide they will not want surgery do not need AVS. For all other patients with PA, you need AVS. The medical system will just have to respond,” Dr. Carey concluded.

Dr. Carey, Dr. Yang, Dr. Feldman, and Dr. Stowasser had no relevant disclosures.

[email protected]

At a time when new evidence strongly suggests that roughly a fifth of patents with hypertension have primary aldosteronism as the cause, other recent findings suggest that many of these possibly tens of millions of patients with aldosterone-driven high blood pressure may as a consequence need an expensive and not-widely-available diagnostic test – adrenal vein sampling – to determine whether they are candidates for a definitive surgical cure to their aldosteronism.

SciePro/Shutterstock

Some endocrinologists worry the worldwide infrastructure for running adrenal vein sampling (AVS) isn’t close to being in place to deliver on this looming need for patients with primary aldosteronism (PA), especially given the burgeoning numbers now being cited for PA prevalence.

“The system could be overwhelmed,” warned Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville. “Right now, adrenal vein sampling [AVS] is the gold standard,” for distinguishing unilateral and bilateral excess aldosterone secretion, “but not every radiologist can do AVS. Until we find a surrogate biomarker that can distinguish unilateral and bilateral PA” many patients will need AVS, Dr. Carey said in an interview.

“AVS is important for accurate lateralization of aldosterone excess in patients, but it may not be feasible for all patients with PA to undergo AVS. If the prevalence of PA truly is on the order of 15% [of all patients with hypertension] then health systems would be stretched to offer all of them AVS, which is technically challenging and requires dedicated training and is therefore limited to expert centers,” commented Jun Yang, MBBS, a cardiovascular endocrinologist at the Hudson Institute of Medical Research and a hypertension researcher at Monash University, both in Melbourne. “At Monash, our interventional radiologists have increased their [AVS] success rate from 40% to more than 90% during the past 10 years, and our waiting list for patients scheduled for AVS is now 3-4 months long,” Dr. Yang said in an interview.

Finding a unilateral adrenal nodule as the cause of PA means that surgical removal is an option, a step that often fully resolves the PA and normalizes blood pressure. Patients with a bilateral source of the aldosterone are not candidates for surgical cure and must be managed with medical treatment, usually a mineralocorticoid receptor antagonist such as spironolactone that can neutralize or at least reduce the impact of hyperaldosteronism.
 

AVS finds unilateral adenomas when imaging can’t

The evidence that raised concerns about the reliability of imaging as an easier and noninvasive means to identify hypertensive patients with PA and a unilateral adrenal nodule that makes them candidates for surgical removal to resolve their PA and hypertension came out in May 2020 in a review of 174 PA patients who underwent AVS at a single center in Calgary, Alta., during 2006-2018.

The review included 366 patients with PA referred to the University of Calgary for assessment, of whom 179 had no adrenal nodule visible with either CT or MRI imaging, with 174 of these patients also undergoing successful AVS. The procedure revealed 70 patients (40%) had unilateral aldosterone secretion (Can J Cardiol. 2020 May 16. doi: 10.1016/j.cjca.2020.05.013).

In an editorial about this report that appeared a few weeks later, Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg, Man., said the finding was “amazing,” and “confirms that lateralization of aldosterone secretion in a patient with PA but without an identifiable mass on that side is not a zebra,” but instead a presentation that “occurs in almost half of patients with PA and no discernible adenoma on the side that lateralizes.” (Can J. Cardiol. 2020 Jul 3. doi: 10.1016/j.cjca.2020.06.022).

Although this was just one center’s experience, the authors are not alone in making this finding, although prior reports seem to have been largely forgotten or ignored until now.

“The discordance between AVS and adrenal imaging has been documented by numerous groups, and in our own experience [in Melbourne] around 40% of patients with unilateral aldosterone excess do not have a distinct unilateral adenoma on CT,” said Dr. Yang.

“Here’s the problem,” summed up Dr. Feldman in an interview. “Nearly half of patients with hyperaldosteronism don’t localize based on a CT or MRI, so you have to do AVS, but AVS is not generally available; it’s only at tertiary centers; and you have to do a lot of them,” to do them well. “It’s a half-day procedure, and you have to hit the correct adrenal vein.”
 

AVS for millions?

Compounding the challenge is the other bit of bombshell news recently dropped on the endocrinology and hypertension communities: PA may be much more prevalent that previously suspected, occurring in roughly 20% of patients with hypertension, according to study results that also came out in 2020 (Ann Int Med. 2020 Jul 7;173[1]:10-20).

The upshot, according to Dr. Feldman and others, is that researchers will need to find reliable criteria besides imaging for identifying PA patients with an increased likelihood of having a lateralized source for their excess aldosterone production. That’s “the only hope,” said Dr. Feldman, “so we won’t have to do AVS on 20 million Americans.”

Unfortunately, the path toward a successful screen to winnow down candidates for AVS has been long and not especially fruitful, with efforts dating back at least 50 years, and with one of the most recent efforts at stratifying PA patients by certain laboratory measures getting dismissed as producing a benefit that “might not be substantial,” wrote Michael Stowasser, MBBS, in a published commentary (J Hypertension. 2020 Jul;38[7]:1259-61).

In contrast to Dr. Feldman, Dr. Stowasser was more optimistic about the prospects for avoiding an immediate crisis in AVS assessment of PA patients, mostly because so few patients with PA are now identified by clinicians. Given the poor record clinicians have historically rung up diagnosing PA, “it would seem unlikely that we are going to be flooded with AVS requests any time soon,” he wrote. There is also reason to hope that increased demand for AVS will help broaden availability, and innovative testing methods promise to speed up the procedure, said Dr. Stowasser, a professor of medicine at the University of Queensland in Brisbane, Australia and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane, in an interview.

But regardless of whether AVS testing becomes more available or streamlined, recent events suggest there will be little way to avoid eventually having to run millions of these diagnostic procedures.

Patients with PA “who decide they will not want surgery do not need AVS. For all other patients with PA, you need AVS. The medical system will just have to respond,” Dr. Carey concluded.

Dr. Carey, Dr. Yang, Dr. Feldman, and Dr. Stowasser had no relevant disclosures.

[email protected]

At a time when new evidence strongly suggests that roughly a fifth of patents with hypertension have primary aldosteronism as the cause, other recent findings suggest that many of these possibly tens of millions of patients with aldosterone-driven high blood pressure may as a consequence need an expensive and not-widely-available diagnostic test – adrenal vein sampling – to determine whether they are candidates for a definitive surgical cure to their aldosteronism.

SciePro/Shutterstock

Some endocrinologists worry the worldwide infrastructure for running adrenal vein sampling (AVS) isn’t close to being in place to deliver on this looming need for patients with primary aldosteronism (PA), especially given the burgeoning numbers now being cited for PA prevalence.

“The system could be overwhelmed,” warned Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville. “Right now, adrenal vein sampling [AVS] is the gold standard,” for distinguishing unilateral and bilateral excess aldosterone secretion, “but not every radiologist can do AVS. Until we find a surrogate biomarker that can distinguish unilateral and bilateral PA” many patients will need AVS, Dr. Carey said in an interview.

“AVS is important for accurate lateralization of aldosterone excess in patients, but it may not be feasible for all patients with PA to undergo AVS. If the prevalence of PA truly is on the order of 15% [of all patients with hypertension] then health systems would be stretched to offer all of them AVS, which is technically challenging and requires dedicated training and is therefore limited to expert centers,” commented Jun Yang, MBBS, a cardiovascular endocrinologist at the Hudson Institute of Medical Research and a hypertension researcher at Monash University, both in Melbourne. “At Monash, our interventional radiologists have increased their [AVS] success rate from 40% to more than 90% during the past 10 years, and our waiting list for patients scheduled for AVS is now 3-4 months long,” Dr. Yang said in an interview.

Finding a unilateral adrenal nodule as the cause of PA means that surgical removal is an option, a step that often fully resolves the PA and normalizes blood pressure. Patients with a bilateral source of the aldosterone are not candidates for surgical cure and must be managed with medical treatment, usually a mineralocorticoid receptor antagonist such as spironolactone that can neutralize or at least reduce the impact of hyperaldosteronism.
 

AVS finds unilateral adenomas when imaging can’t

The evidence that raised concerns about the reliability of imaging as an easier and noninvasive means to identify hypertensive patients with PA and a unilateral adrenal nodule that makes them candidates for surgical removal to resolve their PA and hypertension came out in May 2020 in a review of 174 PA patients who underwent AVS at a single center in Calgary, Alta., during 2006-2018.

The review included 366 patients with PA referred to the University of Calgary for assessment, of whom 179 had no adrenal nodule visible with either CT or MRI imaging, with 174 of these patients also undergoing successful AVS. The procedure revealed 70 patients (40%) had unilateral aldosterone secretion (Can J Cardiol. 2020 May 16. doi: 10.1016/j.cjca.2020.05.013).

In an editorial about this report that appeared a few weeks later, Ross D. Feldman, MD, a hypertension-management researcher and professor of medicine at the University of Manitoba in Winnipeg, Man., said the finding was “amazing,” and “confirms that lateralization of aldosterone secretion in a patient with PA but without an identifiable mass on that side is not a zebra,” but instead a presentation that “occurs in almost half of patients with PA and no discernible adenoma on the side that lateralizes.” (Can J. Cardiol. 2020 Jul 3. doi: 10.1016/j.cjca.2020.06.022).

Although this was just one center’s experience, the authors are not alone in making this finding, although prior reports seem to have been largely forgotten or ignored until now.

“The discordance between AVS and adrenal imaging has been documented by numerous groups, and in our own experience [in Melbourne] around 40% of patients with unilateral aldosterone excess do not have a distinct unilateral adenoma on CT,” said Dr. Yang.

“Here’s the problem,” summed up Dr. Feldman in an interview. “Nearly half of patients with hyperaldosteronism don’t localize based on a CT or MRI, so you have to do AVS, but AVS is not generally available; it’s only at tertiary centers; and you have to do a lot of them,” to do them well. “It’s a half-day procedure, and you have to hit the correct adrenal vein.”
 

AVS for millions?

Compounding the challenge is the other bit of bombshell news recently dropped on the endocrinology and hypertension communities: PA may be much more prevalent that previously suspected, occurring in roughly 20% of patients with hypertension, according to study results that also came out in 2020 (Ann Int Med. 2020 Jul 7;173[1]:10-20).

The upshot, according to Dr. Feldman and others, is that researchers will need to find reliable criteria besides imaging for identifying PA patients with an increased likelihood of having a lateralized source for their excess aldosterone production. That’s “the only hope,” said Dr. Feldman, “so we won’t have to do AVS on 20 million Americans.”

Unfortunately, the path toward a successful screen to winnow down candidates for AVS has been long and not especially fruitful, with efforts dating back at least 50 years, and with one of the most recent efforts at stratifying PA patients by certain laboratory measures getting dismissed as producing a benefit that “might not be substantial,” wrote Michael Stowasser, MBBS, in a published commentary (J Hypertension. 2020 Jul;38[7]:1259-61).

In contrast to Dr. Feldman, Dr. Stowasser was more optimistic about the prospects for avoiding an immediate crisis in AVS assessment of PA patients, mostly because so few patients with PA are now identified by clinicians. Given the poor record clinicians have historically rung up diagnosing PA, “it would seem unlikely that we are going to be flooded with AVS requests any time soon,” he wrote. There is also reason to hope that increased demand for AVS will help broaden availability, and innovative testing methods promise to speed up the procedure, said Dr. Stowasser, a professor of medicine at the University of Queensland in Brisbane, Australia and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane, in an interview.

But regardless of whether AVS testing becomes more available or streamlined, recent events suggest there will be little way to avoid eventually having to run millions of these diagnostic procedures.

Patients with PA “who decide they will not want surgery do not need AVS. For all other patients with PA, you need AVS. The medical system will just have to respond,” Dr. Carey concluded.

Dr. Carey, Dr. Yang, Dr. Feldman, and Dr. Stowasser had no relevant disclosures.

[email protected]