In the thick of a job search for this coming July, I fondly remember my first experience at the 47th Annual STS meeting in San Diego in 2011. The presidential address was delivered by Dr. Mathisen and focused nearly an entire hour on encouraging and mentoring young trainees to pursue a career in cardiothoracic surgery. Citing concerns about job availability and security, declining compensation, and increasing scrutiny on outcome measures, the president attempted to individually address these.

Most vividly I remember the emphasis on baby boomers getting older, median CT surgeon age approaching the retirement point, and the overall increased need for young, motivated, and highly skilled junior attendings. Until this year, the number of STS and CTSnet job posts was abysmally low. This led many new graduates to consider advanced fellowships or alternative avenues. Half a decade after Dr. Mathisen’s prediction at STS, the proverbial flood gates have opened.

This past year, I’ve seen at least a dozen quality academic positions looking for new graduates in thoracic surgery. Additionally, at least another dozen hybrid practice or private/community practice groups are looking to hire junior attendings. What is also interesting is the direction that many practices are headed: thoracic service lines, where volume is accrued from surrounding community practices and brought to centralized, multidisciplinary tertiary care institutions.

In many models, mentorship has been built in with involved senior partners, especially now that expertise in advanced techniques in bronchoscopy (EBUS, navigational bronchoscopy), endoscopy (RFA, EMR, and other ablative strategies) and minimally invasive surgery (VATS, MIS esophagectomy, robotic) are commonly expected by patients. These skills are initially learned in training and, with the right support structure, are perfected early in practice.

With more precise earlier stage screening and detection of esophageal and lung malignancies and the general stability or increase in the year-to-year incidence of these cancers, I expect the job market will continue to accommodate a growing need for thoracic surgeons in the United States. This should greatly help recruitment of the best young medical talent into what is truly an exciting and blossoming field of surgery.

Reference

Mathisen DJ. “It’s Not the Destination, It’s the Journey: Lessons Learned”. 47th Annual STS Presidential Address. San Diego, CA. January 2011. www.sts.org/news/mathisen-delivers-presidential-address.

Dr. Shersher is at Rush University Medical Center, Chicago.

In the thick of a job search for this coming July, I fondly remember my first experience at the 47th Annual STS meeting in San Diego in 2011. The presidential address was delivered by Dr. Mathisen and focused nearly an entire hour on encouraging and mentoring young trainees to pursue a career in cardiothoracic surgery. Citing concerns about job availability and security, declining compensation, and increasing scrutiny on outcome measures, the president attempted to individually address these.

Most vividly I remember the emphasis on baby boomers getting older, median CT surgeon age approaching the retirement point, and the overall increased need for young, motivated, and highly skilled junior attendings. Until this year, the number of STS and CTSnet job posts was abysmally low. This led many new graduates to consider advanced fellowships or alternative avenues. Half a decade after Dr. Mathisen’s prediction at STS, the proverbial flood gates have opened.

This past year, I’ve seen at least a dozen quality academic positions looking for new graduates in thoracic surgery. Additionally, at least another dozen hybrid practice or private/community practice groups are looking to hire junior attendings. What is also interesting is the direction that many practices are headed: thoracic service lines, where volume is accrued from surrounding community practices and brought to centralized, multidisciplinary tertiary care institutions.

In many models, mentorship has been built in with involved senior partners, especially now that expertise in advanced techniques in bronchoscopy (EBUS, navigational bronchoscopy), endoscopy (RFA, EMR, and other ablative strategies) and minimally invasive surgery (VATS, MIS esophagectomy, robotic) are commonly expected by patients. These skills are initially learned in training and, with the right support structure, are perfected early in practice.

With more precise earlier stage screening and detection of esophageal and lung malignancies and the general stability or increase in the year-to-year incidence of these cancers, I expect the job market will continue to accommodate a growing need for thoracic surgeons in the United States. This should greatly help recruitment of the best young medical talent into what is truly an exciting and blossoming field of surgery.

Reference

Mathisen DJ. “It’s Not the Destination, It’s the Journey: Lessons Learned”. 47th Annual STS Presidential Address. San Diego, CA. January 2011. www.sts.org/news/mathisen-delivers-presidential-address.

Dr. Shersher is at Rush University Medical Center, Chicago.

In the thick of a job search for this coming July, I fondly remember my first experience at the 47th Annual STS meeting in San Diego in 2011. The presidential address was delivered by Dr. Mathisen and focused nearly an entire hour on encouraging and mentoring young trainees to pursue a career in cardiothoracic surgery. Citing concerns about job availability and security, declining compensation, and increasing scrutiny on outcome measures, the president attempted to individually address these.

Most vividly I remember the emphasis on baby boomers getting older, median CT surgeon age approaching the retirement point, and the overall increased need for young, motivated, and highly skilled junior attendings. Until this year, the number of STS and CTSnet job posts was abysmally low. This led many new graduates to consider advanced fellowships or alternative avenues. Half a decade after Dr. Mathisen’s prediction at STS, the proverbial flood gates have opened.

This past year, I’ve seen at least a dozen quality academic positions looking for new graduates in thoracic surgery. Additionally, at least another dozen hybrid practice or private/community practice groups are looking to hire junior attendings. What is also interesting is the direction that many practices are headed: thoracic service lines, where volume is accrued from surrounding community practices and brought to centralized, multidisciplinary tertiary care institutions.

In many models, mentorship has been built in with involved senior partners, especially now that expertise in advanced techniques in bronchoscopy (EBUS, navigational bronchoscopy), endoscopy (RFA, EMR, and other ablative strategies) and minimally invasive surgery (VATS, MIS esophagectomy, robotic) are commonly expected by patients. These skills are initially learned in training and, with the right support structure, are perfected early in practice.

With more precise earlier stage screening and detection of esophageal and lung malignancies and the general stability or increase in the year-to-year incidence of these cancers, I expect the job market will continue to accommodate a growing need for thoracic surgeons in the United States. This should greatly help recruitment of the best young medical talent into what is truly an exciting and blossoming field of surgery.

Reference

Mathisen DJ. “It’s Not the Destination, It’s the Journey: Lessons Learned”. 47th Annual STS Presidential Address. San Diego, CA. January 2011. www.sts.org/news/mathisen-delivers-presidential-address.

Dr. Shersher is at Rush University Medical Center, Chicago.

The article “What Is Your Diagnosis? Tinea Corporis” (Cutis. 2015;96:297, 326) contained an error in the author affiliations. The text should have stated:

Ms. Gyurjyan is from the University of Virginia School of Medicine, Charlottesville. Dr. Wilson is from the Department of Dermatology, University of Virginia Health System, Charlottesville.

The staff of Cutis^® makes every possible effort to ensure accuracy in its articles and apologizes for the mistake.

The article “What Is Your Diagnosis? Tinea Corporis” (Cutis. 2015;96:297, 326) contained an error in the author affiliations. The text should have stated:

Ms. Gyurjyan is from the University of Virginia School of Medicine, Charlottesville. Dr. Wilson is from the Department of Dermatology, University of Virginia Health System, Charlottesville.

The staff of Cutis^® makes every possible effort to ensure accuracy in its articles and apologizes for the mistake.

The article “What Is Your Diagnosis? Tinea Corporis” (Cutis. 2015;96:297, 326) contained an error in the author affiliations. The text should have stated:

Ms. Gyurjyan is from the University of Virginia School of Medicine, Charlottesville. Dr. Wilson is from the Department of Dermatology, University of Virginia Health System, Charlottesville.

The staff of Cutis^® makes every possible effort to ensure accuracy in its articles and apologizes for the mistake.

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

SAN DIEGO – The prevalence of kidney stone disease appears to be rising in the United States.

According to an analysis of responses from the 2007-2012 National Health and Nutrition Examination Survey (NHANES), 8.8% of people in the United States have kidney stone disease (Eur Urol. 2012 Jul;62[1]:160-5), up from a prevalence of 5.2% observed in the 1988-1994 NHANES.

“There’s also been a marked increase in emergency room visits for kidney stones: 91% between 1994 and 2006,” Dr. Anna L. Zisman said at the meeting sponsored by the American Society of Nephrology.

“Unfortunately, it doesn’t only affect adults. There has been an increased incidence in ER visits for kids as well.” Though good national data on the incidence of kidney stone disease in children are lacking, one study conducted in South Carolina found that the incidence of ER visits in children rose from 8 per 100,000 in 1996 to more than 18 per 100,000 in 2007 (J Pediatr. 2010 Jul;157[1]:132-7).

What’s driving these increases? Dr. Zisman, a nephrologist at the University of Chicago, discussed a “recipe” for how to create a kidney stone, with heredity as the first step.

“Pick your parents well,” she said. “The familial clustering index is higher for nephrolithiasis than for diabetes and hypertension. A family history of stone disease is present in 16%-37% of stone formers, compared with 4%-12% of healthy controls. And the heritability estimates – how much of a given disease or trait can be attributable to genetic predisposition – is somewhere between 46% and 63%.”

According to Mayo Clinic researchers, heritable traits for kidney stone disease based on 24-hour urine measurements, adjusted for diet, include calcium, magnesium, pH, and citrate (Clin J Am Soc Nephrol. 2014 May;9[5]:943-50).

“Hypercalciuria is the most well-established risk factor for stone disease,” Dr. Zisman said. “Up to 50% of subjects with stones have a history of hypercalciuria, and 43% of first-degree relatives of hypercalciuric patients have hypercalciuria.”

Race and gender are two factors people can’t control in their risk for kidney stone disease. NHANES data suggest that non-Hispanic whites are at highest risk for stone formation, compared with Hispanics and non-Hispanic blacks. However, among whites and all of the racial categories, males have a higher risk than females.

Step two in the recipe for stone formation is timing: Age matters.

According to an analysis of 49,976 men who participated in the Health Professionals Follow-Up Study, the highest risk of stone formation was in male patients in their 40s (J Am Soc Nephrol. 2004 Dec;15[12]:3225-32). By the time white males reach their 70s, the prevalence is almost 19%, while the prevalence for white women in their 70s is 9.4% (Eur Urol. 2012 Jul;62[1]:160-5).

Step three in the recipe is location. According to Dr. Zisman, the prevalence of kidney stone disease across the world is quite varied. “That likely has to do with both genetic predispositions as well as environmental factors,” she noted. “For example, Iran, which has a pretty warm climate, has a prevalence of 5.7%, Greece 15.2%, whereas Argentina only 4%. In the United States, data suggest that the highest incidence of stone disease is in the south. It is suspected that this is due to more men working outside in manual labor in the heat, but that’s just a hypothesis.”

Step four in the recipe involves the role of certain nutrients. For example, a higher daily calcium intake is associated with a lower risk of kidney stone formation. “The theory is that with higher dietary calcium, your urine oxalate tends to drop,” she said. Increased intake of magnesium, protein, potassium, and fluid are also associated with decreased stone formation.

On the other hand, a higher daily vitamin C intake is associated with an increased risk of stone formation. Specifically, a daily intake of more than 1,000 mg confers a 41% increased risk, compared with a lower intake. “The theory there is that vitamin C intake, once absorbed, results in a higher urine oxalate,” Dr. Zisman said.

Current epidemiology literature draws no clear association between a high-sodium diet and the development of kidney stones. From a clinical standpoint, however, “I think everyone would recommend a low-sodium diet because of the physiologic mechanisms leading to higher urine calcium,” she said.

Higher body mass index and increased waist circumference also impact the risk of developing kidney stones, especially among women. “The higher [they are], the greater the risk,” Dr. Zisman said. “We know that as weight goes up, urinary pH drops. Another potential reason is that as body weight goes up, urinary oxalate goes up as well.”

Step five in the recipe for stone formation is occupation. A study from Israel found that lifeguards in that country faced about a 20-fold increased risk of kidney stones, compared with that of the general population (Adv Exp Med Biol. 1980;128:467-72). Meanwhile, a study of glass factory workers in Italy found that the prevalence of kidney stones was 8.5% among those exposed to blast furnace sites, compared with 2.4% among those who worked in ambient temperatures (P = .03) (J Urol 1993 Dec;150[6]:1757-60). A similar finding was observed in a more recent study of steel factory workers in Brazil (Urology 2005;65[5]:858-61).

Variations to the “recipe” for kidney stones include certain genetic diseases such as primary hyperoxaluria and Dent disease; anatomic variations such as horseshoe kidney and ileal conduits; coexisting disease such as inflammatory bowel disease and primary hyperparathyroidism; and effects from medication such as acetazolamide/topiramate and prednisone.

“Mix up genetic predisposition, environmental factors, and dietary/lifestyle factors and add the magic ingredient,” Dr. Zisman concluded. “There is something that is affecting some people and not others. We don’t know what that is, and we clearly need more research.”

Dr. Zisman reported having no financial disclosures.

[email protected]

SAN DIEGO – The prevalence of kidney stone disease appears to be rising in the United States.

According to an analysis of responses from the 2007-2012 National Health and Nutrition Examination Survey (NHANES), 8.8% of people in the United States have kidney stone disease (Eur Urol. 2012 Jul;62[1]:160-5), up from a prevalence of 5.2% observed in the 1988-1994 NHANES.

“There’s also been a marked increase in emergency room visits for kidney stones: 91% between 1994 and 2006,” Dr. Anna L. Zisman said at the meeting sponsored by the American Society of Nephrology.

“Unfortunately, it doesn’t only affect adults. There has been an increased incidence in ER visits for kids as well.” Though good national data on the incidence of kidney stone disease in children are lacking, one study conducted in South Carolina found that the incidence of ER visits in children rose from 8 per 100,000 in 1996 to more than 18 per 100,000 in 2007 (J Pediatr. 2010 Jul;157[1]:132-7).

What’s driving these increases? Dr. Zisman, a nephrologist at the University of Chicago, discussed a “recipe” for how to create a kidney stone, with heredity as the first step.

“Pick your parents well,” she said. “The familial clustering index is higher for nephrolithiasis than for diabetes and hypertension. A family history of stone disease is present in 16%-37% of stone formers, compared with 4%-12% of healthy controls. And the heritability estimates – how much of a given disease or trait can be attributable to genetic predisposition – is somewhere between 46% and 63%.”

According to Mayo Clinic researchers, heritable traits for kidney stone disease based on 24-hour urine measurements, adjusted for diet, include calcium, magnesium, pH, and citrate (Clin J Am Soc Nephrol. 2014 May;9[5]:943-50).

“Hypercalciuria is the most well-established risk factor for stone disease,” Dr. Zisman said. “Up to 50% of subjects with stones have a history of hypercalciuria, and 43% of first-degree relatives of hypercalciuric patients have hypercalciuria.”

Race and gender are two factors people can’t control in their risk for kidney stone disease. NHANES data suggest that non-Hispanic whites are at highest risk for stone formation, compared with Hispanics and non-Hispanic blacks. However, among whites and all of the racial categories, males have a higher risk than females.

Step two in the recipe for stone formation is timing: Age matters.

According to an analysis of 49,976 men who participated in the Health Professionals Follow-Up Study, the highest risk of stone formation was in male patients in their 40s (J Am Soc Nephrol. 2004 Dec;15[12]:3225-32). By the time white males reach their 70s, the prevalence is almost 19%, while the prevalence for white women in their 70s is 9.4% (Eur Urol. 2012 Jul;62[1]:160-5).

Step three in the recipe is location. According to Dr. Zisman, the prevalence of kidney stone disease across the world is quite varied. “That likely has to do with both genetic predispositions as well as environmental factors,” she noted. “For example, Iran, which has a pretty warm climate, has a prevalence of 5.7%, Greece 15.2%, whereas Argentina only 4%. In the United States, data suggest that the highest incidence of stone disease is in the south. It is suspected that this is due to more men working outside in manual labor in the heat, but that’s just a hypothesis.”

Step four in the recipe involves the role of certain nutrients. For example, a higher daily calcium intake is associated with a lower risk of kidney stone formation. “The theory is that with higher dietary calcium, your urine oxalate tends to drop,” she said. Increased intake of magnesium, protein, potassium, and fluid are also associated with decreased stone formation.

On the other hand, a higher daily vitamin C intake is associated with an increased risk of stone formation. Specifically, a daily intake of more than 1,000 mg confers a 41% increased risk, compared with a lower intake. “The theory there is that vitamin C intake, once absorbed, results in a higher urine oxalate,” Dr. Zisman said.

Current epidemiology literature draws no clear association between a high-sodium diet and the development of kidney stones. From a clinical standpoint, however, “I think everyone would recommend a low-sodium diet because of the physiologic mechanisms leading to higher urine calcium,” she said.

Higher body mass index and increased waist circumference also impact the risk of developing kidney stones, especially among women. “The higher [they are], the greater the risk,” Dr. Zisman said. “We know that as weight goes up, urinary pH drops. Another potential reason is that as body weight goes up, urinary oxalate goes up as well.”

Step five in the recipe for stone formation is occupation. A study from Israel found that lifeguards in that country faced about a 20-fold increased risk of kidney stones, compared with that of the general population (Adv Exp Med Biol. 1980;128:467-72). Meanwhile, a study of glass factory workers in Italy found that the prevalence of kidney stones was 8.5% among those exposed to blast furnace sites, compared with 2.4% among those who worked in ambient temperatures (P = .03) (J Urol 1993 Dec;150[6]:1757-60). A similar finding was observed in a more recent study of steel factory workers in Brazil (Urology 2005;65[5]:858-61).

Variations to the “recipe” for kidney stones include certain genetic diseases such as primary hyperoxaluria and Dent disease; anatomic variations such as horseshoe kidney and ileal conduits; coexisting disease such as inflammatory bowel disease and primary hyperparathyroidism; and effects from medication such as acetazolamide/topiramate and prednisone.

“Mix up genetic predisposition, environmental factors, and dietary/lifestyle factors and add the magic ingredient,” Dr. Zisman concluded. “There is something that is affecting some people and not others. We don’t know what that is, and we clearly need more research.”

Dr. Zisman reported having no financial disclosures.

[email protected]

SAN DIEGO – The prevalence of kidney stone disease appears to be rising in the United States.

According to an analysis of responses from the 2007-2012 National Health and Nutrition Examination Survey (NHANES), 8.8% of people in the United States have kidney stone disease (Eur Urol. 2012 Jul;62[1]:160-5), up from a prevalence of 5.2% observed in the 1988-1994 NHANES.

“There’s also been a marked increase in emergency room visits for kidney stones: 91% between 1994 and 2006,” Dr. Anna L. Zisman said at the meeting sponsored by the American Society of Nephrology.

“Unfortunately, it doesn’t only affect adults. There has been an increased incidence in ER visits for kids as well.” Though good national data on the incidence of kidney stone disease in children are lacking, one study conducted in South Carolina found that the incidence of ER visits in children rose from 8 per 100,000 in 1996 to more than 18 per 100,000 in 2007 (J Pediatr. 2010 Jul;157[1]:132-7).

What’s driving these increases? Dr. Zisman, a nephrologist at the University of Chicago, discussed a “recipe” for how to create a kidney stone, with heredity as the first step.

“Pick your parents well,” she said. “The familial clustering index is higher for nephrolithiasis than for diabetes and hypertension. A family history of stone disease is present in 16%-37% of stone formers, compared with 4%-12% of healthy controls. And the heritability estimates – how much of a given disease or trait can be attributable to genetic predisposition – is somewhere between 46% and 63%.”

According to Mayo Clinic researchers, heritable traits for kidney stone disease based on 24-hour urine measurements, adjusted for diet, include calcium, magnesium, pH, and citrate (Clin J Am Soc Nephrol. 2014 May;9[5]:943-50).

“Hypercalciuria is the most well-established risk factor for stone disease,” Dr. Zisman said. “Up to 50% of subjects with stones have a history of hypercalciuria, and 43% of first-degree relatives of hypercalciuric patients have hypercalciuria.”

Race and gender are two factors people can’t control in their risk for kidney stone disease. NHANES data suggest that non-Hispanic whites are at highest risk for stone formation, compared with Hispanics and non-Hispanic blacks. However, among whites and all of the racial categories, males have a higher risk than females.

Step two in the recipe for stone formation is timing: Age matters.

According to an analysis of 49,976 men who participated in the Health Professionals Follow-Up Study, the highest risk of stone formation was in male patients in their 40s (J Am Soc Nephrol. 2004 Dec;15[12]:3225-32). By the time white males reach their 70s, the prevalence is almost 19%, while the prevalence for white women in their 70s is 9.4% (Eur Urol. 2012 Jul;62[1]:160-5).

Step three in the recipe is location. According to Dr. Zisman, the prevalence of kidney stone disease across the world is quite varied. “That likely has to do with both genetic predispositions as well as environmental factors,” she noted. “For example, Iran, which has a pretty warm climate, has a prevalence of 5.7%, Greece 15.2%, whereas Argentina only 4%. In the United States, data suggest that the highest incidence of stone disease is in the south. It is suspected that this is due to more men working outside in manual labor in the heat, but that’s just a hypothesis.”

Step four in the recipe involves the role of certain nutrients. For example, a higher daily calcium intake is associated with a lower risk of kidney stone formation. “The theory is that with higher dietary calcium, your urine oxalate tends to drop,” she said. Increased intake of magnesium, protein, potassium, and fluid are also associated with decreased stone formation.

On the other hand, a higher daily vitamin C intake is associated with an increased risk of stone formation. Specifically, a daily intake of more than 1,000 mg confers a 41% increased risk, compared with a lower intake. “The theory there is that vitamin C intake, once absorbed, results in a higher urine oxalate,” Dr. Zisman said.

Current epidemiology literature draws no clear association between a high-sodium diet and the development of kidney stones. From a clinical standpoint, however, “I think everyone would recommend a low-sodium diet because of the physiologic mechanisms leading to higher urine calcium,” she said.

Higher body mass index and increased waist circumference also impact the risk of developing kidney stones, especially among women. “The higher [they are], the greater the risk,” Dr. Zisman said. “We know that as weight goes up, urinary pH drops. Another potential reason is that as body weight goes up, urinary oxalate goes up as well.”

Step five in the recipe for stone formation is occupation. A study from Israel found that lifeguards in that country faced about a 20-fold increased risk of kidney stones, compared with that of the general population (Adv Exp Med Biol. 1980;128:467-72). Meanwhile, a study of glass factory workers in Italy found that the prevalence of kidney stones was 8.5% among those exposed to blast furnace sites, compared with 2.4% among those who worked in ambient temperatures (P = .03) (J Urol 1993 Dec;150[6]:1757-60). A similar finding was observed in a more recent study of steel factory workers in Brazil (Urology 2005;65[5]:858-61).

Variations to the “recipe” for kidney stones include certain genetic diseases such as primary hyperoxaluria and Dent disease; anatomic variations such as horseshoe kidney and ileal conduits; coexisting disease such as inflammatory bowel disease and primary hyperparathyroidism; and effects from medication such as acetazolamide/topiramate and prednisone.

“Mix up genetic predisposition, environmental factors, and dietary/lifestyle factors and add the magic ingredient,” Dr. Zisman concluded. “There is something that is affecting some people and not others. We don’t know what that is, and we clearly need more research.”

Dr. Zisman reported having no financial disclosures.

[email protected]

There is a link between poor decision making and suicidal tendencies in patients with unipolar depressive disorder and bipolar disorder, according to Dr. Stéphane Richard-Devantoy and his associates.

In the first part of the study, suicide attempters with unipolar and bipolar disorders took the Iowa Gambling Task (IGT), as did a control group of non–suicide attempters with unipolar and bipolar disorders. IGT scores were significantly worse in the suicide-attempting group, compared with the control group, with most of the difference coming from patients with unipolar disorder. Women who attempted suicide also had significantly worse IGT scores than did male suicide attempters.

In a subsequent meta-analysis of 10 studies and 1,148 participants, impaired decision making in suicide attempters with unipolar and bipolar disorders, compared with nonattempters with unipolar and bipolar disorders was confirmed with a moderate effect size. The effect size was moderate between unipolar suicide attempters and a healthy control group, and large between bipolar suicide attempters and a healthy control group.

“Examination of sex differences in brain functioning appears to be necessary in [the] suicide field. Indeed, females consistently attempt suicide more than males,whereas males consistently die by suicide more frequently than females. In spite of the important role gender plays in the expression of suicidal behavior, the perspective of future tailor-made therapeutic modalities in suicide attempters is needed,” the investigators noted.

Find the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.10.001).

[email protected]

There is a link between poor decision making and suicidal tendencies in patients with unipolar depressive disorder and bipolar disorder, according to Dr. Stéphane Richard-Devantoy and his associates.

In the first part of the study, suicide attempters with unipolar and bipolar disorders took the Iowa Gambling Task (IGT), as did a control group of non–suicide attempters with unipolar and bipolar disorders. IGT scores were significantly worse in the suicide-attempting group, compared with the control group, with most of the difference coming from patients with unipolar disorder. Women who attempted suicide also had significantly worse IGT scores than did male suicide attempters.

In a subsequent meta-analysis of 10 studies and 1,148 participants, impaired decision making in suicide attempters with unipolar and bipolar disorders, compared with nonattempters with unipolar and bipolar disorders was confirmed with a moderate effect size. The effect size was moderate between unipolar suicide attempters and a healthy control group, and large between bipolar suicide attempters and a healthy control group.

“Examination of sex differences in brain functioning appears to be necessary in [the] suicide field. Indeed, females consistently attempt suicide more than males,whereas males consistently die by suicide more frequently than females. In spite of the important role gender plays in the expression of suicidal behavior, the perspective of future tailor-made therapeutic modalities in suicide attempters is needed,” the investigators noted.

Find the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.10.001).

[email protected]

There is a link between poor decision making and suicidal tendencies in patients with unipolar depressive disorder and bipolar disorder, according to Dr. Stéphane Richard-Devantoy and his associates.

In the first part of the study, suicide attempters with unipolar and bipolar disorders took the Iowa Gambling Task (IGT), as did a control group of non–suicide attempters with unipolar and bipolar disorders. IGT scores were significantly worse in the suicide-attempting group, compared with the control group, with most of the difference coming from patients with unipolar disorder. Women who attempted suicide also had significantly worse IGT scores than did male suicide attempters.

In a subsequent meta-analysis of 10 studies and 1,148 participants, impaired decision making in suicide attempters with unipolar and bipolar disorders, compared with nonattempters with unipolar and bipolar disorders was confirmed with a moderate effect size. The effect size was moderate between unipolar suicide attempters and a healthy control group, and large between bipolar suicide attempters and a healthy control group.

“Examination of sex differences in brain functioning appears to be necessary in [the] suicide field. Indeed, females consistently attempt suicide more than males,whereas males consistently die by suicide more frequently than females. In spite of the important role gender plays in the expression of suicidal behavior, the perspective of future tailor-made therapeutic modalities in suicide attempters is needed,” the investigators noted.

Find the full study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.10.001).

[email protected]

As the long 2016 presidential election season draws on, Republican hopefuls strive to stand out among their fellow party candidates; however, many in the running remain tacit about specific policies on issues ranging from immigration to gun control and healthcare.

“Many of these candidates … do not feel like getting involved in an extensive policy discussion will influence whether they win Iowa and New Hampshire,” says Robert Blendon, ScD, professor of health policy and political analysis at the Harvard School of Public Health and Harvard Kennedy School of Government in Cambridge, Mass. “They see it as a distraction, because the people voting are not asking them.”

For physicians and others passionate about healthcare, “it’s very frustrating,” Dr. Blendon says. “People who are on the Republican side want a replacement [for the Affordable Care Act], but they are not driven—I have seen the surveys—to want to really know the details of that replacement.”

GOP candidates share many common ideas about the U.S. health system. Most say they want to allow people under age 26 to remain on their parents’ health plans and believe people with preexisting conditions should have access to coverage, generally through the creation of state-based, high-risk insurance pools. They believe expanded health savings accounts will give patients more skin in the game, and, across the board, they have vowed to “repeal and replace Obamacare.”

Listen to more of our interview with Robert Blendon, ScD

However, “with more than 10 candidates, there is going to be variation,” Dr. Blendon adds.

For instance, former Florida Governor Jeb Bush has proposed the Conservative Plan for 21st Century Health, which aims to “lower costs,” “promote innovation,” and “return power to states.”

Neurosurgeon Ben Carson originally suggested he would “abolish” Medicare and instead provide seniors with a $2,000-a-year federal subsidy to purchase private insurance. He has backtracked that idea and, in December 2015, issued a report highlighting the pillars of his health plan, which include creating “health empowerment accounts” and raising the Medicare age to 70.

New Jersey Governor Chris Christie’s plan suggests a priority for veterans, including the formation of a federal Secretary of Veterans Affairs, while Carly Fiorina says that “every healthcare provider “ought to publish its costs, its prices, its outcomes” so patients know what they are buying.

“As the field on the Republican side narrows, I think we will start to see more pressure on them to flesh those principles out a little bit more,” says Joshua Lenchus, DO, RPh, FACP, SFHM, a hospitalist at the University of Miami (Fla.) Jackson Memorial Hospital and a member of SHM’s Public Policy Committee.

Some GOP candidates, like Kentucky Senator and ophthalmologist Rand Paul, have proposed reforming medical malpractice. Some wish to make insurance portable from one job to the next, like former Arkansas Governor Mike Huckabee, or across state lines, as Ohio Governor John Kasich has proposed.

Some of these ideas, says hospitalist and SHM Public Policy Committee member Bradley Flansbaum, DO, MPH, MHM, “have been adequately dismembered, and they’re not going to carry weight.

“Buying insurance across state lines, fixing malpractice—that is not going to fix the healthcare system,” says Dr. Flansbaum, clinical professor of medicine at NYU School of Medicine in New York City.

Overall, a Republican-sponsored healthcare system will not guarantee the same level of comprehensive benefits patients have now under the ACA, Dr. Blendon says, and, in general, subsidies and tax credits will be less generous than they are today, in turn reducing federal expenditures.

Most Republican candidates are in favor of some version of free market healthcare, but Dr. Flansbaum points out that “there are so many imperfections in the market, everything from people having asymmetric information—a physician knows a lot more than a patient does—to opaque pricing,” he says. “It’s not exchanging goods like we are used to.”

Republicans are generally committed to “less federal government, less expenditures, more choices, and less expensive benefits,” in healthcare, but Dr. Blendon says the system “would not go back to 2009.”

For hospitalists interested in election-year or other healthcare policy issues, Dr. Flansbaum suggests getting involved in the SHM committee, visiting the advocacy section of the SHM website, and reaching out to local representatives and others who write and vote on laws.

“How do you affect change?” he asks. “It’s not sitting in the breakfast lounge at the hospital bellyaching to your colleagues.” TH

Editor's note: update Jan. 4, 2016.

Kelly April Tyrrell is a freelance writer in Madison, Wis.

As the long 2016 presidential election season draws on, Republican hopefuls strive to stand out among their fellow party candidates; however, many in the running remain tacit about specific policies on issues ranging from immigration to gun control and healthcare.

“Many of these candidates … do not feel like getting involved in an extensive policy discussion will influence whether they win Iowa and New Hampshire,” says Robert Blendon, ScD, professor of health policy and political analysis at the Harvard School of Public Health and Harvard Kennedy School of Government in Cambridge, Mass. “They see it as a distraction, because the people voting are not asking them.”

For physicians and others passionate about healthcare, “it’s very frustrating,” Dr. Blendon says. “People who are on the Republican side want a replacement [for the Affordable Care Act], but they are not driven—I have seen the surveys—to want to really know the details of that replacement.”

GOP candidates share many common ideas about the U.S. health system. Most say they want to allow people under age 26 to remain on their parents’ health plans and believe people with preexisting conditions should have access to coverage, generally through the creation of state-based, high-risk insurance pools. They believe expanded health savings accounts will give patients more skin in the game, and, across the board, they have vowed to “repeal and replace Obamacare.”

Listen to more of our interview with Robert Blendon, ScD

However, “with more than 10 candidates, there is going to be variation,” Dr. Blendon adds.

For instance, former Florida Governor Jeb Bush has proposed the Conservative Plan for 21st Century Health, which aims to “lower costs,” “promote innovation,” and “return power to states.”

Neurosurgeon Ben Carson originally suggested he would “abolish” Medicare and instead provide seniors with a $2,000-a-year federal subsidy to purchase private insurance. He has backtracked that idea and, in December 2015, issued a report highlighting the pillars of his health plan, which include creating “health empowerment accounts” and raising the Medicare age to 70.

New Jersey Governor Chris Christie’s plan suggests a priority for veterans, including the formation of a federal Secretary of Veterans Affairs, while Carly Fiorina says that “every healthcare provider “ought to publish its costs, its prices, its outcomes” so patients know what they are buying.

“As the field on the Republican side narrows, I think we will start to see more pressure on them to flesh those principles out a little bit more,” says Joshua Lenchus, DO, RPh, FACP, SFHM, a hospitalist at the University of Miami (Fla.) Jackson Memorial Hospital and a member of SHM’s Public Policy Committee.

Some GOP candidates, like Kentucky Senator and ophthalmologist Rand Paul, have proposed reforming medical malpractice. Some wish to make insurance portable from one job to the next, like former Arkansas Governor Mike Huckabee, or across state lines, as Ohio Governor John Kasich has proposed.

Some of these ideas, says hospitalist and SHM Public Policy Committee member Bradley Flansbaum, DO, MPH, MHM, “have been adequately dismembered, and they’re not going to carry weight.

“Buying insurance across state lines, fixing malpractice—that is not going to fix the healthcare system,” says Dr. Flansbaum, clinical professor of medicine at NYU School of Medicine in New York City.

Overall, a Republican-sponsored healthcare system will not guarantee the same level of comprehensive benefits patients have now under the ACA, Dr. Blendon says, and, in general, subsidies and tax credits will be less generous than they are today, in turn reducing federal expenditures.

Most Republican candidates are in favor of some version of free market healthcare, but Dr. Flansbaum points out that “there are so many imperfections in the market, everything from people having asymmetric information—a physician knows a lot more than a patient does—to opaque pricing,” he says. “It’s not exchanging goods like we are used to.”

Republicans are generally committed to “less federal government, less expenditures, more choices, and less expensive benefits,” in healthcare, but Dr. Blendon says the system “would not go back to 2009.”

For hospitalists interested in election-year or other healthcare policy issues, Dr. Flansbaum suggests getting involved in the SHM committee, visiting the advocacy section of the SHM website, and reaching out to local representatives and others who write and vote on laws.

“How do you affect change?” he asks. “It’s not sitting in the breakfast lounge at the hospital bellyaching to your colleagues.” TH

Editor's note: update Jan. 4, 2016.

Kelly April Tyrrell is a freelance writer in Madison, Wis.

As the long 2016 presidential election season draws on, Republican hopefuls strive to stand out among their fellow party candidates; however, many in the running remain tacit about specific policies on issues ranging from immigration to gun control and healthcare.

“Many of these candidates … do not feel like getting involved in an extensive policy discussion will influence whether they win Iowa and New Hampshire,” says Robert Blendon, ScD, professor of health policy and political analysis at the Harvard School of Public Health and Harvard Kennedy School of Government in Cambridge, Mass. “They see it as a distraction, because the people voting are not asking them.”

For physicians and others passionate about healthcare, “it’s very frustrating,” Dr. Blendon says. “People who are on the Republican side want a replacement [for the Affordable Care Act], but they are not driven—I have seen the surveys—to want to really know the details of that replacement.”

GOP candidates share many common ideas about the U.S. health system. Most say they want to allow people under age 26 to remain on their parents’ health plans and believe people with preexisting conditions should have access to coverage, generally through the creation of state-based, high-risk insurance pools. They believe expanded health savings accounts will give patients more skin in the game, and, across the board, they have vowed to “repeal and replace Obamacare.”

Listen to more of our interview with Robert Blendon, ScD

However, “with more than 10 candidates, there is going to be variation,” Dr. Blendon adds.

For instance, former Florida Governor Jeb Bush has proposed the Conservative Plan for 21st Century Health, which aims to “lower costs,” “promote innovation,” and “return power to states.”

Neurosurgeon Ben Carson originally suggested he would “abolish” Medicare and instead provide seniors with a $2,000-a-year federal subsidy to purchase private insurance. He has backtracked that idea and, in December 2015, issued a report highlighting the pillars of his health plan, which include creating “health empowerment accounts” and raising the Medicare age to 70.

New Jersey Governor Chris Christie’s plan suggests a priority for veterans, including the formation of a federal Secretary of Veterans Affairs, while Carly Fiorina says that “every healthcare provider “ought to publish its costs, its prices, its outcomes” so patients know what they are buying.

“As the field on the Republican side narrows, I think we will start to see more pressure on them to flesh those principles out a little bit more,” says Joshua Lenchus, DO, RPh, FACP, SFHM, a hospitalist at the University of Miami (Fla.) Jackson Memorial Hospital and a member of SHM’s Public Policy Committee.

Some GOP candidates, like Kentucky Senator and ophthalmologist Rand Paul, have proposed reforming medical malpractice. Some wish to make insurance portable from one job to the next, like former Arkansas Governor Mike Huckabee, or across state lines, as Ohio Governor John Kasich has proposed.

Some of these ideas, says hospitalist and SHM Public Policy Committee member Bradley Flansbaum, DO, MPH, MHM, “have been adequately dismembered, and they’re not going to carry weight.

“Buying insurance across state lines, fixing malpractice—that is not going to fix the healthcare system,” says Dr. Flansbaum, clinical professor of medicine at NYU School of Medicine in New York City.

Overall, a Republican-sponsored healthcare system will not guarantee the same level of comprehensive benefits patients have now under the ACA, Dr. Blendon says, and, in general, subsidies and tax credits will be less generous than they are today, in turn reducing federal expenditures.

Most Republican candidates are in favor of some version of free market healthcare, but Dr. Flansbaum points out that “there are so many imperfections in the market, everything from people having asymmetric information—a physician knows a lot more than a patient does—to opaque pricing,” he says. “It’s not exchanging goods like we are used to.”

Republicans are generally committed to “less federal government, less expenditures, more choices, and less expensive benefits,” in healthcare, but Dr. Blendon says the system “would not go back to 2009.”

For hospitalists interested in election-year or other healthcare policy issues, Dr. Flansbaum suggests getting involved in the SHM committee, visiting the advocacy section of the SHM website, and reaching out to local representatives and others who write and vote on laws.

“How do you affect change?” he asks. “It’s not sitting in the breakfast lounge at the hospital bellyaching to your colleagues.” TH

Editor's note: update Jan. 4, 2016.

Kelly April Tyrrell is a freelance writer in Madison, Wis.

Attendees at ASH 2015

Photo courtesy of ASH

ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.

In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.

The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.

Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*

Study design and patient demographics

Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.

The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.

“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”

The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.

Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.

The patients received no prior therapies.

Results

The trial is currently ongoing.

The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.

In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.

Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.

Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”

Dr Lampson noted that toxicities resolved rapidly with steroids.

“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”

Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.

Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.

“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.

Comparison with earlier studies

The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).

They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.

Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.

The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.

The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.

“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”

He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.

Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.

Decrease in regulatory T cells

Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.

This, they say, could provide a possible explanation for the development of early hepatotoxicity.

The trial is investigator-initiated and funded by Gilead Sciences.

*Data in the presentation differs from the abstract.

Attendees at ASH 2015

Photo courtesy of ASH

ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.

In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.

The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.

Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*

Study design and patient demographics

Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.

The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.

“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”

The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.

Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.

The patients received no prior therapies.

Results

The trial is currently ongoing.

The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.

In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.

Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.

Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”

Dr Lampson noted that toxicities resolved rapidly with steroids.

“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”

Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.

Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.

“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.

Comparison with earlier studies

The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).

They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.

Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.

The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.

The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.

“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”

He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.

Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.

Decrease in regulatory T cells

Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.

This, they say, could provide a possible explanation for the development of early hepatotoxicity.

The trial is investigator-initiated and funded by Gilead Sciences.

*Data in the presentation differs from the abstract.

Attendees at ASH 2015

Photo courtesy of ASH

ORLANDO, FL—Investigators have observed early fulminant hepatotoxicity in a subset of primarily younger chronic lymphocytic leukemia (CLL) patients treated with idelalisib monotherapy in the frontline setting.

In a phase 2 study of idelalisib plus ofatumumab, 52% of the 24 patients enrolled experienced grade 3 or higher hepatotoxicity shortly after idelalisib was started.

The investigators say this may occur because a proportion of regulatory T cells in the peripheral blood decreases while patients are on idelalisib. The team believes this early hepatotoxicity is immune-mediated.

Benjamin Lampson, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, described these surprising findings at the 2015 ASH Annual Meeting as abstract 497.*

Study design and patient demographics

Patients received 150 mg of idelalisib twice daily as monotherapy on days 1 through 56. They then received combination therapy with idelalisib plus ofatumumab for 8 weekly infusions, followed by 4 monthly infusions through day 225, and then idelalisib monotherapy indefinitely.

The primary endpoint of overall response rate was assessed 2 months after the completion of combination therapy.

“This dosing strategy is slightly different than what has been previously used in trials combining these particular drugs,” Dr Lampson said. “Specifically, previously reported trials started these agents simultaneously without a lead-in period of monotherapy.”

The investigators monitored the patients weekly for toxicities during the 2-month monotherapy lead-in period.

Three-quarters of the patients are male. Their median age is 67.4 years (range, 57.6–84.9), 54% have unmutated IgHV, 17% have deletion 17p or TP53 mutation, 4% have deletion 11q, and 54% have deletion 13q.

The patients received no prior therapies.

Results

The trial is currently ongoing.

The 24 patients enrolled as of early November have been on therapy a median of 7.7 months, for a median follow-up time of 14.7 months.

“What we began to notice after enrolling just a few subjects on the trial was that severe hepatotoxicity was occurring shortly after initiating idelalisib,” Dr Lampson said.

In the first 2 months of therapy, 52% of patients developed transaminitis, and 13% developed colitis or diarrhea, all grade 3 or higher. Thirteen percent developed pneumonitis of any grade.

Younger age is a risk factor for early hepatotoxicity, Dr Lampson said, with a significance of P=0.02. All subjects age 65 or younger (n=7) required systemic steroids to treat their toxicities.

Hepatotoxicity developed in a median of 28 days, he said, “and the hepatotoxicity is typically occurring before the first dose of ofatumumab is administered at week 8, suggesting that idelalisib alone is the cause of the hepatotoxicity.”

Dr Lampson noted that toxicities resolved rapidly with steroids.

“I do want to point out that all subjects evaluable for a response have had a response,” he added. “Additionally, in all subjects where treatment has been discontinued, the discontinuation was due to adverse events rather than disease progression.”

Twelve patients with grade 2 or higher transaminitis were re-challenged with idelalisib after holding the drug for toxicity.

Five patients were re-challenged while off steroids, and 4 developed recurrent transaminitis within 4 days. Seven patients were re-challenged while on steroids, and 2 developed recurrent transaminitis within 4 days.

“In general, our experience has been, if idelalisib is resumed while the subject remains on steroids, the drug is more likely to be tolerated and the subject can eventually be taken off steroids,” Dr Lampson said.

Comparison with earlier studies

The investigators compared the frequency of toxicity in their trial to earlier studies of idelalisib (Brown, Blood 2014; Coutre, EHA 2015, abstr P588; O’Brien, Blood 2015).

They found that grade 3 or higher transaminitis (52%) and any grade pneumonitis (13%) were higher in their trial than in the 3 other trials.

Colitis/diarrhea was about the same in 2 of the 3 other trials. But in the paper by O’Brien et al, 42% of patients experienced grade 3 or greater colitis/diarrhea.

The lower rate of colitis in the present trial may be due to the shorter follow-up, Dr Lampson said, as colitis is a late adverse event.

The O’Brien trial was also an upfront study, so patients had no prior therapies. The investigators observed that toxicities appeared to be more common in less heavily pretreated patients.

“As the median number of prior therapies decreases,” Dr Lampson said, “the frequency of adverse events increases.”

He noted that, in the O’Brien trial, idelalisib was started simultaneously with the other drugs, perhaps accounting for its somewhat lower rate (21%) of grade 3 or higher transaminitis.

Additionally, the patient population in the O’Brien trial was older than the population in the current trial, which could account for the higher rate of transaminitis, as younger age is a risk factor.

Decrease in regulatory T cells

Investigators noted a decrease in regulatory T cells while patients were on therapy. Eleven of 15 patients (73%) with matched samples had a significant (P<0.05) decrease in the percentage of T cells over time.

This, they say, could provide a possible explanation for the development of early hepatotoxicity.

The trial is investigator-initiated and funded by Gilead Sciences.

*Data in the presentation differs from the abstract.

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

AML cells

Image by Lance Liotta

Two genes can stop the development of acute myeloid leukemia (AML), according to research published in the Journal of Experimental Medicine.

The work suggests that Hif-1α and Hif-2α work together to stop the formation of leukemic stem cells, and blocking either Hif-2α or both genes

accelerates AML development.

Investigators said these findings are surprising because previous research suggested that blocking Hif-1α or Hif-2α might stop AML progression.

But their study suggests that therapies designed to block these genes might worsen AML or at least have no impact on the disease.

Conversely, designing new therapies that promote the activity of Hif-1α and Hif-2α could help treat AML or stop relapse after chemotherapy.

“Our discovery that Hif-1α and Hif-2α molecules act together to stop leukemia development is a major milestone in our efforts to combat leukemia,” said study author Kamil R. Kranc, DPhil, of the University of Edinburgh in Scotland.

“We now intend to harness this knowledge to develop curative therapies that eliminate leukemic stem cells, which are the underlying cause of AML.”

AML cells

Image by Lance Liotta

Two genes can stop the development of acute myeloid leukemia (AML), according to research published in the Journal of Experimental Medicine.

The work suggests that Hif-1α and Hif-2α work together to stop the formation of leukemic stem cells, and blocking either Hif-2α or both genes

accelerates AML development.

Investigators said these findings are surprising because previous research suggested that blocking Hif-1α or Hif-2α might stop AML progression.

But their study suggests that therapies designed to block these genes might worsen AML or at least have no impact on the disease.

Conversely, designing new therapies that promote the activity of Hif-1α and Hif-2α could help treat AML or stop relapse after chemotherapy.

“Our discovery that Hif-1α and Hif-2α molecules act together to stop leukemia development is a major milestone in our efforts to combat leukemia,” said study author Kamil R. Kranc, DPhil, of the University of Edinburgh in Scotland.

“We now intend to harness this knowledge to develop curative therapies that eliminate leukemic stem cells, which are the underlying cause of AML.”

AML cells

Image by Lance Liotta

Two genes can stop the development of acute myeloid leukemia (AML), according to research published in the Journal of Experimental Medicine.

The work suggests that Hif-1α and Hif-2α work together to stop the formation of leukemic stem cells, and blocking either Hif-2α or both genes

accelerates AML development.

Investigators said these findings are surprising because previous research suggested that blocking Hif-1α or Hif-2α might stop AML progression.

But their study suggests that therapies designed to block these genes might worsen AML or at least have no impact on the disease.

Conversely, designing new therapies that promote the activity of Hif-1α and Hif-2α could help treat AML or stop relapse after chemotherapy.

“Our discovery that Hif-1α and Hif-2α molecules act together to stop leukemia development is a major milestone in our efforts to combat leukemia,” said study author Kamil R. Kranc, DPhil, of the University of Edinburgh in Scotland.

“We now intend to harness this knowledge to develop curative therapies that eliminate leukemic stem cells, which are the underlying cause of AML.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”