The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

[email protected]

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

[email protected]

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

[email protected]

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

Romosozumab is a novel osteoporosis treatment agent that stimulates bone formation and inhibits bone resorption. Due to concerns for adverse cardiovascular effects, this medication is generally reserved for patients with severe osteoporosis despite multiple previous treatments. However, the influence of previous osteoporosis pharmacotherapy on romosozumab’s skeletal efficacy remains poorly studied, especially in real world clinical scenarios. In a prospective non-randomized study of 130 patients treated with romosozumab in Japan, the effects of romosozumab treatment on bone turnover markers and bone mineral density (BMD) was assessed based on previous treatment with either no osteoporosis medication, bisphosphonates, denosumab, or teriparatide. In general, treatment-naïve individuals experienced superior spine BMD and bone turnover marker gains versus patients who had previously received osteoporosis pharmacotherapy. Notably, prior treatment with the potent anti-resorptive agent denosumab was associated with suboptimal spine BMD response to romosozumab. These results highlight the potential impact of previous anti-resorptive treatment on romosozumab efficacy and indicate that careful consideration of treatment sequence is warranted when deciding amongst the multiple osteoporosis agents that are currently available.

Denosumab is a potent anti-resorptive osteoporosis agent that works by neutralizing RANKL, the key cytokine that drives osteoclast differentiation. While effective at suppressing bone resorption, increasing BMD, and preventing fragility fractures when administered every 6 months, rapid discontinuation of denosumab has been associated with an increased risk of vertebral compression fractures. In routine clinical practice, denosumab injection delays are common. However, risks of vertebral fractures associated with such injection delays remain unknown. In this study of a UK population-based cohort of 2,594 patients, a large electronic database was used to assess the relationship between denosumab dosing intervals (defined as ‘on time’, ‘short delay’, and ‘long delay’) and fractures in the 6 month window after the recommended treatment date. Compared with ‘on time’ denosumab treatment, individuals who received delayed denosumab injections showed an increased risk of interval vertebral fractures. Notably, the delay time was associated with fracture risk. This powerful study design further underscores the importance of timely (every 6 months) denosumab injections. Given current health care delivery challenges associated with the COVID-19 pandemic, these results should be considered when selecting initial osteoporosis treatment agents and in management of patients currently receiving denosumab. 

Abaloparatide, a synthetic analog of parathyroid hormone related peptide (PTHrP) is a bone anabolic osteoporosis treatment agent. In the ACTIVE study, abaloparatide increased bone mineral density and reduced fracture risk compared to both placebo and teriparatide. Although abaloparatide is generally well-tolerated, non-serious adverse events have been reported such as dizziness and palpitations. PTHrP can act in a paracrine manner to cause vasodilation. Therefore, in this post hoc drug safety study, the effects of abaloparatide on blood pressure, pulse, and cardiovascular adverse events were assessed in detail in subjects from the ACTIVE study (one hour post treatment) plus an additional group of 55 subjects for more detailed hemodynamic assessment. Compared to placebo injection, both abaloparatide and teriparatide treatment caused mild and transient increases in pulse and decreases in systolic blood pressure. These mild hemodynamic changes were not associated with an increased risk of adverse cardiovascular events. In general, these data are reassuring and support the cardiac safety of PTH analogs for osteoporosis. However, the transient hemodynamic changes observed should be considered for patients with cardiovascular comorbidities or baseline problems with orthostasis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Romosozumab is a novel osteoporosis treatment agent that stimulates bone formation and inhibits bone resorption. Due to concerns for adverse cardiovascular effects, this medication is generally reserved for patients with severe osteoporosis despite multiple previous treatments. However, the influence of previous osteoporosis pharmacotherapy on romosozumab’s skeletal efficacy remains poorly studied, especially in real world clinical scenarios. In a prospective non-randomized study of 130 patients treated with romosozumab in Japan, the effects of romosozumab treatment on bone turnover markers and bone mineral density (BMD) was assessed based on previous treatment with either no osteoporosis medication, bisphosphonates, denosumab, or teriparatide. In general, treatment-naïve individuals experienced superior spine BMD and bone turnover marker gains versus patients who had previously received osteoporosis pharmacotherapy. Notably, prior treatment with the potent anti-resorptive agent denosumab was associated with suboptimal spine BMD response to romosozumab. These results highlight the potential impact of previous anti-resorptive treatment on romosozumab efficacy and indicate that careful consideration of treatment sequence is warranted when deciding amongst the multiple osteoporosis agents that are currently available.

Denosumab is a potent anti-resorptive osteoporosis agent that works by neutralizing RANKL, the key cytokine that drives osteoclast differentiation. While effective at suppressing bone resorption, increasing BMD, and preventing fragility fractures when administered every 6 months, rapid discontinuation of denosumab has been associated with an increased risk of vertebral compression fractures. In routine clinical practice, denosumab injection delays are common. However, risks of vertebral fractures associated with such injection delays remain unknown. In this study of a UK population-based cohort of 2,594 patients, a large electronic database was used to assess the relationship between denosumab dosing intervals (defined as ‘on time’, ‘short delay’, and ‘long delay’) and fractures in the 6 month window after the recommended treatment date. Compared with ‘on time’ denosumab treatment, individuals who received delayed denosumab injections showed an increased risk of interval vertebral fractures. Notably, the delay time was associated with fracture risk. This powerful study design further underscores the importance of timely (every 6 months) denosumab injections. Given current health care delivery challenges associated with the COVID-19 pandemic, these results should be considered when selecting initial osteoporosis treatment agents and in management of patients currently receiving denosumab. 

Abaloparatide, a synthetic analog of parathyroid hormone related peptide (PTHrP) is a bone anabolic osteoporosis treatment agent. In the ACTIVE study, abaloparatide increased bone mineral density and reduced fracture risk compared to both placebo and teriparatide. Although abaloparatide is generally well-tolerated, non-serious adverse events have been reported such as dizziness and palpitations. PTHrP can act in a paracrine manner to cause vasodilation. Therefore, in this post hoc drug safety study, the effects of abaloparatide on blood pressure, pulse, and cardiovascular adverse events were assessed in detail in subjects from the ACTIVE study (one hour post treatment) plus an additional group of 55 subjects for more detailed hemodynamic assessment. Compared to placebo injection, both abaloparatide and teriparatide treatment caused mild and transient increases in pulse and decreases in systolic blood pressure. These mild hemodynamic changes were not associated with an increased risk of adverse cardiovascular events. In general, these data are reassuring and support the cardiac safety of PTH analogs for osteoporosis. However, the transient hemodynamic changes observed should be considered for patients with cardiovascular comorbidities or baseline problems with orthostasis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Romosozumab is a novel osteoporosis treatment agent that stimulates bone formation and inhibits bone resorption. Due to concerns for adverse cardiovascular effects, this medication is generally reserved for patients with severe osteoporosis despite multiple previous treatments. However, the influence of previous osteoporosis pharmacotherapy on romosozumab’s skeletal efficacy remains poorly studied, especially in real world clinical scenarios. In a prospective non-randomized study of 130 patients treated with romosozumab in Japan, the effects of romosozumab treatment on bone turnover markers and bone mineral density (BMD) was assessed based on previous treatment with either no osteoporosis medication, bisphosphonates, denosumab, or teriparatide. In general, treatment-naïve individuals experienced superior spine BMD and bone turnover marker gains versus patients who had previously received osteoporosis pharmacotherapy. Notably, prior treatment with the potent anti-resorptive agent denosumab was associated with suboptimal spine BMD response to romosozumab. These results highlight the potential impact of previous anti-resorptive treatment on romosozumab efficacy and indicate that careful consideration of treatment sequence is warranted when deciding amongst the multiple osteoporosis agents that are currently available.

Denosumab is a potent anti-resorptive osteoporosis agent that works by neutralizing RANKL, the key cytokine that drives osteoclast differentiation. While effective at suppressing bone resorption, increasing BMD, and preventing fragility fractures when administered every 6 months, rapid discontinuation of denosumab has been associated with an increased risk of vertebral compression fractures. In routine clinical practice, denosumab injection delays are common. However, risks of vertebral fractures associated with such injection delays remain unknown. In this study of a UK population-based cohort of 2,594 patients, a large electronic database was used to assess the relationship between denosumab dosing intervals (defined as ‘on time’, ‘short delay’, and ‘long delay’) and fractures in the 6 month window after the recommended treatment date. Compared with ‘on time’ denosumab treatment, individuals who received delayed denosumab injections showed an increased risk of interval vertebral fractures. Notably, the delay time was associated with fracture risk. This powerful study design further underscores the importance of timely (every 6 months) denosumab injections. Given current health care delivery challenges associated with the COVID-19 pandemic, these results should be considered when selecting initial osteoporosis treatment agents and in management of patients currently receiving denosumab. 

Abaloparatide, a synthetic analog of parathyroid hormone related peptide (PTHrP) is a bone anabolic osteoporosis treatment agent. In the ACTIVE study, abaloparatide increased bone mineral density and reduced fracture risk compared to both placebo and teriparatide. Although abaloparatide is generally well-tolerated, non-serious adverse events have been reported such as dizziness and palpitations. PTHrP can act in a paracrine manner to cause vasodilation. Therefore, in this post hoc drug safety study, the effects of abaloparatide on blood pressure, pulse, and cardiovascular adverse events were assessed in detail in subjects from the ACTIVE study (one hour post treatment) plus an additional group of 55 subjects for more detailed hemodynamic assessment. Compared to placebo injection, both abaloparatide and teriparatide treatment caused mild and transient increases in pulse and decreases in systolic blood pressure. These mild hemodynamic changes were not associated with an increased risk of adverse cardiovascular events. In general, these data are reassuring and support the cardiac safety of PTH analogs for osteoporosis. However, the transient hemodynamic changes observed should be considered for patients with cardiovascular comorbidities or baseline problems with orthostasis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A systematic review of nine studies provided limited evidence that off-label oral nonselective beta-blockers can be an effective treatment for facial erythema and flushing in rosacea, while at the same time underscoring the paucity of evidence supporting their use, investigators reported.

“The evidence was highest for carvedilol and propranolol, two nonselective beta-blockers,” wrote the authors of the review, Jade G.M. Logger, MD, of the department of dermatology, Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. Their review is in the Journal of the American Academy of Dermatology.

The systematic review included a case control study of 53,927 patients and an equal number of controls that evaluated beta-blockers in general, but the remaining studies and case reports included only 106 patients in total. The largest was a prospective cohort study of propranolol in 63 patients. Other studies included a 15-patient randomized clinical trial of nadolol published 31 years ago and three single-patient case reports.

The studies included patients with a history of failed therapies; only a small number of beta-blockers were evaluated. Outcomes reported in the studies varied widely, which ruled out doing a meta-analysis. “Erythema and flushing were assessed by using a wide spectrum of mostly subjective clinical and patient-based scores, and method standardization was often missing,” the researchers stated.

“Most studies showed improved erythema and flushing after initiation of oral beta-blockers,” Dr. Logger and colleagues wrote. Treatment of facial erythema and flushing remains a clinical challenge despite approved therapies, for which poor response and reactivation are common. “Diminishing erythema and flushing in rosacea is challenging because it hardly responds to conventional anti-inflammatory treatment,” they noted.

“The study adds no new evidence to support the use of beta-blockers,” Diane M. Thiboutot, MD, professor of dermatology at Penn State University, Hershey, said in an interview. “As the authors point out, the nine studies reviewed were of low quality with a variety of outcome measures that precluded generation of a meta-analysis, which would have represented new information.”

Dr. Thiboutot is lead author of a 2019 update of management options for rosacea published by the National Rosacea Society Expert Committee last year.. Beta blockers are among the drugs that are sometimes prescribed off label to help rosacea-associated flushing, along with nonsteroidal anti-inflammatory drugs, antihistamines, and clonidine, according to the update.

Dr. Logger and coauthors noted that beta-blockers come with risks, and can aggravate asthma and psoriasis and are contraindicated in patients with heart failure, cardiogenic shock, and other cardiovascular diseases, along with hyperactive airway and Raynaud’s disease. “It is important to monitor patients for adverse effects, especially blood pressure and heart rate,” they stated. Carvedilol and propranolol may have more antioxidant and anti-inflammatory properties than other nonselective beta-blockers that may curtail rosacea manifestations, they wrote.

They called for large, prospective clinical trials to more accurately assess the efficacy of beta-blockers in rosacea patients. “Researchers should further focus on the determination of the optimal dosage, treatment duration, and long-term therapeutic effects for adequate treatment of erythema and flushing in rosacea,” they said.

Getting those trials is challenging, Dr. Thiboutot said. “Objective and even subjective measurement of transient and persistent facial erythema is extremely challenging, particularly in the setting of a prospective clinical trial.” The trials would have to control for a number of variables, including room conditions, patient diet, and timing of medication, and large trials require multiple sites,” which could add to the variability of the data,” she said in the interview. Funding such trials would be difficult because adding an indication for rosacea-related symptoms would have limited commercial potential, she added.

Nonetheless, the studies would be welcome, Dr. Thiboutot said. “If standardized outcome measures for facial erythema were to be developed, a study would be more feasible.”

Dr. Logger disclosed financial relationships with Galderma, AbbVie, Novartis, Janssen, and LEO Pharma; one author disclosed conducting clinical trials for AbbVie and Novartis; the third author disclosed relationships with Galderma, Cutanea Life Sciences, AbbVie, Novartis, and Janssen, with fees paid to his institution. Dr. Thiboutot disclosed a financial relationship with Galderma.
 

SOURCE: Logger JGM et al. J Am Acad Dermatol. 2020 Oct;83(4):1088-97.

A systematic review of nine studies provided limited evidence that off-label oral nonselective beta-blockers can be an effective treatment for facial erythema and flushing in rosacea, while at the same time underscoring the paucity of evidence supporting their use, investigators reported.

“The evidence was highest for carvedilol and propranolol, two nonselective beta-blockers,” wrote the authors of the review, Jade G.M. Logger, MD, of the department of dermatology, Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. Their review is in the Journal of the American Academy of Dermatology.

The systematic review included a case control study of 53,927 patients and an equal number of controls that evaluated beta-blockers in general, but the remaining studies and case reports included only 106 patients in total. The largest was a prospective cohort study of propranolol in 63 patients. Other studies included a 15-patient randomized clinical trial of nadolol published 31 years ago and three single-patient case reports.

The studies included patients with a history of failed therapies; only a small number of beta-blockers were evaluated. Outcomes reported in the studies varied widely, which ruled out doing a meta-analysis. “Erythema and flushing were assessed by using a wide spectrum of mostly subjective clinical and patient-based scores, and method standardization was often missing,” the researchers stated.

“Most studies showed improved erythema and flushing after initiation of oral beta-blockers,” Dr. Logger and colleagues wrote. Treatment of facial erythema and flushing remains a clinical challenge despite approved therapies, for which poor response and reactivation are common. “Diminishing erythema and flushing in rosacea is challenging because it hardly responds to conventional anti-inflammatory treatment,” they noted.

“The study adds no new evidence to support the use of beta-blockers,” Diane M. Thiboutot, MD, professor of dermatology at Penn State University, Hershey, said in an interview. “As the authors point out, the nine studies reviewed were of low quality with a variety of outcome measures that precluded generation of a meta-analysis, which would have represented new information.”

Dr. Thiboutot is lead author of a 2019 update of management options for rosacea published by the National Rosacea Society Expert Committee last year.. Beta blockers are among the drugs that are sometimes prescribed off label to help rosacea-associated flushing, along with nonsteroidal anti-inflammatory drugs, antihistamines, and clonidine, according to the update.

Dr. Logger and coauthors noted that beta-blockers come with risks, and can aggravate asthma and psoriasis and are contraindicated in patients with heart failure, cardiogenic shock, and other cardiovascular diseases, along with hyperactive airway and Raynaud’s disease. “It is important to monitor patients for adverse effects, especially blood pressure and heart rate,” they stated. Carvedilol and propranolol may have more antioxidant and anti-inflammatory properties than other nonselective beta-blockers that may curtail rosacea manifestations, they wrote.

They called for large, prospective clinical trials to more accurately assess the efficacy of beta-blockers in rosacea patients. “Researchers should further focus on the determination of the optimal dosage, treatment duration, and long-term therapeutic effects for adequate treatment of erythema and flushing in rosacea,” they said.

Getting those trials is challenging, Dr. Thiboutot said. “Objective and even subjective measurement of transient and persistent facial erythema is extremely challenging, particularly in the setting of a prospective clinical trial.” The trials would have to control for a number of variables, including room conditions, patient diet, and timing of medication, and large trials require multiple sites,” which could add to the variability of the data,” she said in the interview. Funding such trials would be difficult because adding an indication for rosacea-related symptoms would have limited commercial potential, she added.

Nonetheless, the studies would be welcome, Dr. Thiboutot said. “If standardized outcome measures for facial erythema were to be developed, a study would be more feasible.”

Dr. Logger disclosed financial relationships with Galderma, AbbVie, Novartis, Janssen, and LEO Pharma; one author disclosed conducting clinical trials for AbbVie and Novartis; the third author disclosed relationships with Galderma, Cutanea Life Sciences, AbbVie, Novartis, and Janssen, with fees paid to his institution. Dr. Thiboutot disclosed a financial relationship with Galderma.
 

SOURCE: Logger JGM et al. J Am Acad Dermatol. 2020 Oct;83(4):1088-97.

A systematic review of nine studies provided limited evidence that off-label oral nonselective beta-blockers can be an effective treatment for facial erythema and flushing in rosacea, while at the same time underscoring the paucity of evidence supporting their use, investigators reported.

“The evidence was highest for carvedilol and propranolol, two nonselective beta-blockers,” wrote the authors of the review, Jade G.M. Logger, MD, of the department of dermatology, Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. Their review is in the Journal of the American Academy of Dermatology.

The systematic review included a case control study of 53,927 patients and an equal number of controls that evaluated beta-blockers in general, but the remaining studies and case reports included only 106 patients in total. The largest was a prospective cohort study of propranolol in 63 patients. Other studies included a 15-patient randomized clinical trial of nadolol published 31 years ago and three single-patient case reports.

The studies included patients with a history of failed therapies; only a small number of beta-blockers were evaluated. Outcomes reported in the studies varied widely, which ruled out doing a meta-analysis. “Erythema and flushing were assessed by using a wide spectrum of mostly subjective clinical and patient-based scores, and method standardization was often missing,” the researchers stated.

“Most studies showed improved erythema and flushing after initiation of oral beta-blockers,” Dr. Logger and colleagues wrote. Treatment of facial erythema and flushing remains a clinical challenge despite approved therapies, for which poor response and reactivation are common. “Diminishing erythema and flushing in rosacea is challenging because it hardly responds to conventional anti-inflammatory treatment,” they noted.

“The study adds no new evidence to support the use of beta-blockers,” Diane M. Thiboutot, MD, professor of dermatology at Penn State University, Hershey, said in an interview. “As the authors point out, the nine studies reviewed were of low quality with a variety of outcome measures that precluded generation of a meta-analysis, which would have represented new information.”

Dr. Thiboutot is lead author of a 2019 update of management options for rosacea published by the National Rosacea Society Expert Committee last year.. Beta blockers are among the drugs that are sometimes prescribed off label to help rosacea-associated flushing, along with nonsteroidal anti-inflammatory drugs, antihistamines, and clonidine, according to the update.

Dr. Logger and coauthors noted that beta-blockers come with risks, and can aggravate asthma and psoriasis and are contraindicated in patients with heart failure, cardiogenic shock, and other cardiovascular diseases, along with hyperactive airway and Raynaud’s disease. “It is important to monitor patients for adverse effects, especially blood pressure and heart rate,” they stated. Carvedilol and propranolol may have more antioxidant and anti-inflammatory properties than other nonselective beta-blockers that may curtail rosacea manifestations, they wrote.

They called for large, prospective clinical trials to more accurately assess the efficacy of beta-blockers in rosacea patients. “Researchers should further focus on the determination of the optimal dosage, treatment duration, and long-term therapeutic effects for adequate treatment of erythema and flushing in rosacea,” they said.

Getting those trials is challenging, Dr. Thiboutot said. “Objective and even subjective measurement of transient and persistent facial erythema is extremely challenging, particularly in the setting of a prospective clinical trial.” The trials would have to control for a number of variables, including room conditions, patient diet, and timing of medication, and large trials require multiple sites,” which could add to the variability of the data,” she said in the interview. Funding such trials would be difficult because adding an indication for rosacea-related symptoms would have limited commercial potential, she added.

Nonetheless, the studies would be welcome, Dr. Thiboutot said. “If standardized outcome measures for facial erythema were to be developed, a study would be more feasible.”

Dr. Logger disclosed financial relationships with Galderma, AbbVie, Novartis, Janssen, and LEO Pharma; one author disclosed conducting clinical trials for AbbVie and Novartis; the third author disclosed relationships with Galderma, Cutanea Life Sciences, AbbVie, Novartis, and Janssen, with fees paid to his institution. Dr. Thiboutot disclosed a financial relationship with Galderma.
 

SOURCE: Logger JGM et al. J Am Acad Dermatol. 2020 Oct;83(4):1088-97.

Condom use among sexually active high school students rose slightly in 2019, but the longer-term trend has been one of decline since 2003, according to data from the Youth Risk Behavior Survey (YRBS).

Nonuse of birth control in this population dropped to 11.9% in 2019, but the overall trend is one of no significant change since 2003. Meanwhile, the use of birth control pills has taken a different path, with prevalence rising significantly from 16.0% in 2007 to 23.0% in 2019, the Centers for Disease Control and Prevention reported.

The prevalence of condom use among sexually active students was 54.3% in 2019, up from 53.8% in 2017 – the survey is conducted every 2 years – but down from a high of 63.0% in 2003, the YRBS data show.

Condoms were the most prevalent method of contraception, but the finding that “only approximately half of sexually active students reported any condom use at last sexual intercourse … is concerning given the high risk for STDs among this population,” Leigh E. Szucs, PhD, and associates said in the Morbidity and Mortality Weekly Report.

In 2019, White (55.8%) and Hispanic (56.2%) students were more likely than Blacks (48.2%) to have used a condom during their last sexual intercourse, but use of birth control pills was much higher among Whites (29.1%) than Hispanics (15.4%) or Blacks (12.9%).The Black respondents were much more likely (23.0%) to use no contraceptive method, compared with Whites (8.4%) or Hispanics (13.3%), they said.

“Meeting the unintended pregnancy and STD/HIV prevention needs of black and Hispanic youths is vital,” wrote Dr. Szucs of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and associates. “Understanding and addressing structural barriers that might contribute to the observed differences are important next steps.”

The high school students taking the YRBS were considered sexually active if they had intercourse with at least one person in the previous 3 months. Overall, 3,226 (27.4%) of respondents in 2019 reported being sexually active: 52.2% were female and 47.8% were male, the CDC said.

[email protected]

SOURCE: Szucs LE et al. MMWR. 2019 Aug 21;69(SS-01)11-8.

Condom use among sexually active high school students rose slightly in 2019, but the longer-term trend has been one of decline since 2003, according to data from the Youth Risk Behavior Survey (YRBS).

Nonuse of birth control in this population dropped to 11.9% in 2019, but the overall trend is one of no significant change since 2003. Meanwhile, the use of birth control pills has taken a different path, with prevalence rising significantly from 16.0% in 2007 to 23.0% in 2019, the Centers for Disease Control and Prevention reported.

The prevalence of condom use among sexually active students was 54.3% in 2019, up from 53.8% in 2017 – the survey is conducted every 2 years – but down from a high of 63.0% in 2003, the YRBS data show.

Condoms were the most prevalent method of contraception, but the finding that “only approximately half of sexually active students reported any condom use at last sexual intercourse … is concerning given the high risk for STDs among this population,” Leigh E. Szucs, PhD, and associates said in the Morbidity and Mortality Weekly Report.

In 2019, White (55.8%) and Hispanic (56.2%) students were more likely than Blacks (48.2%) to have used a condom during their last sexual intercourse, but use of birth control pills was much higher among Whites (29.1%) than Hispanics (15.4%) or Blacks (12.9%).The Black respondents were much more likely (23.0%) to use no contraceptive method, compared with Whites (8.4%) or Hispanics (13.3%), they said.

“Meeting the unintended pregnancy and STD/HIV prevention needs of black and Hispanic youths is vital,” wrote Dr. Szucs of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and associates. “Understanding and addressing structural barriers that might contribute to the observed differences are important next steps.”

The high school students taking the YRBS were considered sexually active if they had intercourse with at least one person in the previous 3 months. Overall, 3,226 (27.4%) of respondents in 2019 reported being sexually active: 52.2% were female and 47.8% were male, the CDC said.

[email protected]

SOURCE: Szucs LE et al. MMWR. 2019 Aug 21;69(SS-01)11-8.

Condom use among sexually active high school students rose slightly in 2019, but the longer-term trend has been one of decline since 2003, according to data from the Youth Risk Behavior Survey (YRBS).

Nonuse of birth control in this population dropped to 11.9% in 2019, but the overall trend is one of no significant change since 2003. Meanwhile, the use of birth control pills has taken a different path, with prevalence rising significantly from 16.0% in 2007 to 23.0% in 2019, the Centers for Disease Control and Prevention reported.

The prevalence of condom use among sexually active students was 54.3% in 2019, up from 53.8% in 2017 – the survey is conducted every 2 years – but down from a high of 63.0% in 2003, the YRBS data show.

Condoms were the most prevalent method of contraception, but the finding that “only approximately half of sexually active students reported any condom use at last sexual intercourse … is concerning given the high risk for STDs among this population,” Leigh E. Szucs, PhD, and associates said in the Morbidity and Mortality Weekly Report.

In 2019, White (55.8%) and Hispanic (56.2%) students were more likely than Blacks (48.2%) to have used a condom during their last sexual intercourse, but use of birth control pills was much higher among Whites (29.1%) than Hispanics (15.4%) or Blacks (12.9%).The Black respondents were much more likely (23.0%) to use no contraceptive method, compared with Whites (8.4%) or Hispanics (13.3%), they said.

“Meeting the unintended pregnancy and STD/HIV prevention needs of black and Hispanic youths is vital,” wrote Dr. Szucs of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and associates. “Understanding and addressing structural barriers that might contribute to the observed differences are important next steps.”

The high school students taking the YRBS were considered sexually active if they had intercourse with at least one person in the previous 3 months. Overall, 3,226 (27.4%) of respondents in 2019 reported being sexually active: 52.2% were female and 47.8% were male, the CDC said.

[email protected]

SOURCE: Szucs LE et al. MMWR. 2019 Aug 21;69(SS-01)11-8.

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

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

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

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

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

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

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

[email protected]

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

[email protected]

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

[email protected]

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The Diagnosis: Granular Parakeratosis 

Microscopic examination of a punch biopsy from the left axilla revealed verruciform epidermal hyperplasia with overlying parakeratosis and retention of keratohyalin granules in the stratum corneum (Figure). There was no evidence of acantholysis, dyskeratosis, epidermal neutrophils, or neutrophilic microabscesses. 

The patient's history and characteristic histopathologic findings confirmed the diagnosis of granular parakeratosis (GP). He was instructed to discontinue his current antiperspirant and began treatment with topical fluocinolone oil 0.01% every morning and urea cream 20% every night. Complete resolution was achieved within 2 weeks, and he reported no recurrence at a 2-year follow-up visit.  

Granular parakeratosis is a rare idiopathic skin condition characterized by hyperkeratotic papules and plaques, most often in intertriginous areas. Described by Northcutt et al¹ as a contact reaction to antiperspirant in the axillae, GP also has been reported in the submammary and inguinal creases² and rarely in nonintertriginous sites such as the abdomen.³ Although deodorants and antiperspirants in roll-on or stick form classically are implicated in GP, the condition also has been observed with exposure to laundry detergents containing benzalkonium chloride.⁴ Lesions with GP histology also have been incidentally observed in association with dermatophytosis,⁵ dermatomyositis,⁶ molluscum contagiosum,⁷ and carcinomas.⁸ Ding et al⁹ proposed that GP be reclassified as a reaction pattern observed in the skin as opposed to being a distinct disease entity.  

Clinically, GP presents as pruritic intertriginous papules and coalescent plaques that most commonly are seen in the axillae but also may involve the groin or other sites.^2,3 Both pruritus and disease burden can be aggravated by heat, sweating, or friction. There may be a history of a new irritant exposure prior to symptom onset, but GP has been observed in the absence of identifiable exposures and in the setting of long-term antiperspirant or deodorant use.³ Although a family history may be helpful, it can be difficult to distinguish GP from entities such as Hailey-Hailey disease or Darier disease based on history and examination alone; a biopsy often is necessary for definitive diagnosis. 

Histologically, GP demonstrates acanthosis with parakeratosis and retention of keratohyalin granules in the stratum corneum.¹ The stratum granulosum is preserved. On cursory examination, GP may resemble a psoriasiform dermatosis as can be seen in inverse psoriasis; however, neutrophilic microabscesses and infiltrates are not seen. Absence of acantholysis and dyskeratosis further differentiates GP from the clinically similar Hailey-Hailey disease and Darier disease. Spongiosis that is prominently found in allergic contact dermatitis also is absent. 

Although a benign disorder, GP warrants treatment to achieve symptomatic relief. A mainstay of treatment is to eliminate exposure to suspected aggravating or inciting factors such as antiperspirants or deodorants. A variety of treatments including laser therapy, corticosteroids, isotretinoin, and vitamin D analogs such as calcipotriene and calcitriol have been reported to be effective treatments of GP in case studies and series.^3,10 Large-scale clinical trials are not available because of the rarity of this condition. Our patient's clinical course suggests topical fluocinolone and urea in combination can be considered to achieve rapid resolution. 

The Diagnosis: Granular Parakeratosis 

Microscopic examination of a punch biopsy from the left axilla revealed verruciform epidermal hyperplasia with overlying parakeratosis and retention of keratohyalin granules in the stratum corneum (Figure). There was no evidence of acantholysis, dyskeratosis, epidermal neutrophils, or neutrophilic microabscesses. 

The patient's history and characteristic histopathologic findings confirmed the diagnosis of granular parakeratosis (GP). He was instructed to discontinue his current antiperspirant and began treatment with topical fluocinolone oil 0.01% every morning and urea cream 20% every night. Complete resolution was achieved within 2 weeks, and he reported no recurrence at a 2-year follow-up visit.  

Granular parakeratosis is a rare idiopathic skin condition characterized by hyperkeratotic papules and plaques, most often in intertriginous areas. Described by Northcutt et al¹ as a contact reaction to antiperspirant in the axillae, GP also has been reported in the submammary and inguinal creases² and rarely in nonintertriginous sites such as the abdomen.³ Although deodorants and antiperspirants in roll-on or stick form classically are implicated in GP, the condition also has been observed with exposure to laundry detergents containing benzalkonium chloride.⁴ Lesions with GP histology also have been incidentally observed in association with dermatophytosis,⁵ dermatomyositis,⁶ molluscum contagiosum,⁷ and carcinomas.⁸ Ding et al⁹ proposed that GP be reclassified as a reaction pattern observed in the skin as opposed to being a distinct disease entity.  

Clinically, GP presents as pruritic intertriginous papules and coalescent plaques that most commonly are seen in the axillae but also may involve the groin or other sites.^2,3 Both pruritus and disease burden can be aggravated by heat, sweating, or friction. There may be a history of a new irritant exposure prior to symptom onset, but GP has been observed in the absence of identifiable exposures and in the setting of long-term antiperspirant or deodorant use.³ Although a family history may be helpful, it can be difficult to distinguish GP from entities such as Hailey-Hailey disease or Darier disease based on history and examination alone; a biopsy often is necessary for definitive diagnosis. 

Histologically, GP demonstrates acanthosis with parakeratosis and retention of keratohyalin granules in the stratum corneum.¹ The stratum granulosum is preserved. On cursory examination, GP may resemble a psoriasiform dermatosis as can be seen in inverse psoriasis; however, neutrophilic microabscesses and infiltrates are not seen. Absence of acantholysis and dyskeratosis further differentiates GP from the clinically similar Hailey-Hailey disease and Darier disease. Spongiosis that is prominently found in allergic contact dermatitis also is absent. 

Although a benign disorder, GP warrants treatment to achieve symptomatic relief. A mainstay of treatment is to eliminate exposure to suspected aggravating or inciting factors such as antiperspirants or deodorants. A variety of treatments including laser therapy, corticosteroids, isotretinoin, and vitamin D analogs such as calcipotriene and calcitriol have been reported to be effective treatments of GP in case studies and series.^3,10 Large-scale clinical trials are not available because of the rarity of this condition. Our patient's clinical course suggests topical fluocinolone and urea in combination can be considered to achieve rapid resolution. 

The Diagnosis: Granular Parakeratosis 

Microscopic examination of a punch biopsy from the left axilla revealed verruciform epidermal hyperplasia with overlying parakeratosis and retention of keratohyalin granules in the stratum corneum (Figure). There was no evidence of acantholysis, dyskeratosis, epidermal neutrophils, or neutrophilic microabscesses. 

The patient's history and characteristic histopathologic findings confirmed the diagnosis of granular parakeratosis (GP). He was instructed to discontinue his current antiperspirant and began treatment with topical fluocinolone oil 0.01% every morning and urea cream 20% every night. Complete resolution was achieved within 2 weeks, and he reported no recurrence at a 2-year follow-up visit.  

Granular parakeratosis is a rare idiopathic skin condition characterized by hyperkeratotic papules and plaques, most often in intertriginous areas. Described by Northcutt et al¹ as a contact reaction to antiperspirant in the axillae, GP also has been reported in the submammary and inguinal creases² and rarely in nonintertriginous sites such as the abdomen.³ Although deodorants and antiperspirants in roll-on or stick form classically are implicated in GP, the condition also has been observed with exposure to laundry detergents containing benzalkonium chloride.⁴ Lesions with GP histology also have been incidentally observed in association with dermatophytosis,⁵ dermatomyositis,⁶ molluscum contagiosum,⁷ and carcinomas.⁸ Ding et al⁹ proposed that GP be reclassified as a reaction pattern observed in the skin as opposed to being a distinct disease entity.  

Clinically, GP presents as pruritic intertriginous papules and coalescent plaques that most commonly are seen in the axillae but also may involve the groin or other sites.^2,3 Both pruritus and disease burden can be aggravated by heat, sweating, or friction. There may be a history of a new irritant exposure prior to symptom onset, but GP has been observed in the absence of identifiable exposures and in the setting of long-term antiperspirant or deodorant use.³ Although a family history may be helpful, it can be difficult to distinguish GP from entities such as Hailey-Hailey disease or Darier disease based on history and examination alone; a biopsy often is necessary for definitive diagnosis. 

Histologically, GP demonstrates acanthosis with parakeratosis and retention of keratohyalin granules in the stratum corneum.¹ The stratum granulosum is preserved. On cursory examination, GP may resemble a psoriasiform dermatosis as can be seen in inverse psoriasis; however, neutrophilic microabscesses and infiltrates are not seen. Absence of acantholysis and dyskeratosis further differentiates GP from the clinically similar Hailey-Hailey disease and Darier disease. Spongiosis that is prominently found in allergic contact dermatitis also is absent. 

Although a benign disorder, GP warrants treatment to achieve symptomatic relief. A mainstay of treatment is to eliminate exposure to suspected aggravating or inciting factors such as antiperspirants or deodorants. A variety of treatments including laser therapy, corticosteroids, isotretinoin, and vitamin D analogs such as calcipotriene and calcitriol have been reported to be effective treatments of GP in case studies and series.^3,10 Large-scale clinical trials are not available because of the rarity of this condition. Our patient's clinical course suggests topical fluocinolone and urea in combination can be considered to achieve rapid resolution. 

Patients with higher intraoperative blood loss and those treated at lower-volume surgical centers had a greater risk of high-grade complications after undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC), according to an analysis of registry data.

Higher intraoperative blood loss was also associated with low-grade postoperative complications. Intraoperative complications were more likely in patients who had concurrent thrombectomy and surgery on adjacent organs.

Eduard Roussel, MD, of University Hospitals Leuven (Belgium) and colleagues reported these findings in European Urology Oncology.

The authors noted that the role of CN in metastatic RCC is controversial. The CARMENA trial, published in the New England Journal of Medicine, “shifted treatment paradigms” away from surgery by suggesting that sunitinib alone is noninferior to sunitinib after CN.

“Nonetheless, there is a general consensus that certain selected subgroups of patients with low-volume, single-site metastases and few adverse IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria would still benefit from the continued use of upfront CN,” the authors wrote.

They advised clinicians to weigh the risks and benefits of CN, particularly because “postoperative morbidity might preclude or delay the use of subsequent systemic therapies.” However, the risk/benefit calculation for CN has been difficult because past investigations have tended to focus only on survival outcomes, so there isn’t much data on morbidity, the authors wrote.

Patient characteristics and complications

To investigate morbidity associated with CN, Dr. Roussel and colleagues reviewed data from the Registry of Metastatic RCC (REMARCC). The team analyzed the clinical records of 736 patients who underwent nephrectomy for metastatic RCC during 1980-2019.

The patients’ median age was 63 years (range, 55-70 years), and about three-quarters were men. The majority had clear cell carcinoma, and the lungs were the most common site of metastases.

More than 97% of procedures were complete nephrectomies, and the rest were partial. The median estimated blood loss was 400 mL, and the median follow-up was 16.5 months.

There were 69 patients who had intraoperative complications, most commonly bleeding (n = 25), spleen laceration (n = 13), and vascular injury (n = 11).

There were 217 patients who had postoperative complications, including 45 patients with high-grade complications (grade 3-5) and 10 who died.

The most common postoperative complications were vascular/lymphatic in nature. These occurred in 67 patients and included 10 lymphoceles.

“[G]iven the relatively high rate of postoperative lymphoceles, which is probably attributable to the performance of lymph node dissections and the lack of proven oncological survival benefit thereof, surgeons might reconsider the performance of lymphadenectomy during CN,” the investigators wrote.

Other common postoperative complications included infectious and cardiopulmonary issues, which occurred in 42 and 39 patients, respectively.
 

Predictors of complications

Thrombectomy and adjacent organ removal were significant predictors of intraoperative complications on multivariable analysis. The odds ratios were 1.38 (P = .009) for thrombectomy and 2.71 (P = .004) for adjacent organ removal.

Estimated blood loss was a significant predictor of low- and high-grade postoperative complications. The OR for high-grade complications per 200 mL of blood lost was 1.06 (P = .007), and the OR for low-grade complications per 200 mL blood lost was 1.09 (P = .001).

There was a strong inverse correlation with CN case load at each center and high-grade postoperative complications, which highlights “the impact of centralization of care on postoperative outcomes in complex surgical scenarios,” the investigators wrote. The OR per 25 cases was 0.88 (P = .04).

Results were largely the same when the analysis was limited to the 560 subjects treated since 2006, in the targeted therapy era, except that adjacent organ removal as a predictor of intraoperative complications did not quite reach statistical significance (P = .06).

The presurgery risk factors identified in this study should assist with presurgical counseling, said Zachery Reichert, MD, PhD, a genitourinary medical oncologist and assistant professor at the University of Michigan, Ann Arbor, who was not involved in this study.

“This is especially important for patients who require thrombectomy or adjacent organ removal or do not have access to a surgeon with high cytoreductive nephrectomy caseloads,” he said.

Dr. Reichert reported having no disclosures. There was no external funding for this study, and the investigators didn’t have any disclosures.

[email protected]

SOURCE: Roussel E et al. Eur Urol Oncol. 2020 Aug;3(4):523-9.

Patients with higher intraoperative blood loss and those treated at lower-volume surgical centers had a greater risk of high-grade complications after undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC), according to an analysis of registry data.

Higher intraoperative blood loss was also associated with low-grade postoperative complications. Intraoperative complications were more likely in patients who had concurrent thrombectomy and surgery on adjacent organs.

Eduard Roussel, MD, of University Hospitals Leuven (Belgium) and colleagues reported these findings in European Urology Oncology.

The authors noted that the role of CN in metastatic RCC is controversial. The CARMENA trial, published in the New England Journal of Medicine, “shifted treatment paradigms” away from surgery by suggesting that sunitinib alone is noninferior to sunitinib after CN.

“Nonetheless, there is a general consensus that certain selected subgroups of patients with low-volume, single-site metastases and few adverse IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria would still benefit from the continued use of upfront CN,” the authors wrote.

They advised clinicians to weigh the risks and benefits of CN, particularly because “postoperative morbidity might preclude or delay the use of subsequent systemic therapies.” However, the risk/benefit calculation for CN has been difficult because past investigations have tended to focus only on survival outcomes, so there isn’t much data on morbidity, the authors wrote.

Patient characteristics and complications

To investigate morbidity associated with CN, Dr. Roussel and colleagues reviewed data from the Registry of Metastatic RCC (REMARCC). The team analyzed the clinical records of 736 patients who underwent nephrectomy for metastatic RCC during 1980-2019.

The patients’ median age was 63 years (range, 55-70 years), and about three-quarters were men. The majority had clear cell carcinoma, and the lungs were the most common site of metastases.

More than 97% of procedures were complete nephrectomies, and the rest were partial. The median estimated blood loss was 400 mL, and the median follow-up was 16.5 months.

There were 69 patients who had intraoperative complications, most commonly bleeding (n = 25), spleen laceration (n = 13), and vascular injury (n = 11).

There were 217 patients who had postoperative complications, including 45 patients with high-grade complications (grade 3-5) and 10 who died.

The most common postoperative complications were vascular/lymphatic in nature. These occurred in 67 patients and included 10 lymphoceles.

“[G]iven the relatively high rate of postoperative lymphoceles, which is probably attributable to the performance of lymph node dissections and the lack of proven oncological survival benefit thereof, surgeons might reconsider the performance of lymphadenectomy during CN,” the investigators wrote.

Other common postoperative complications included infectious and cardiopulmonary issues, which occurred in 42 and 39 patients, respectively.
 

Predictors of complications

Thrombectomy and adjacent organ removal were significant predictors of intraoperative complications on multivariable analysis. The odds ratios were 1.38 (P = .009) for thrombectomy and 2.71 (P = .004) for adjacent organ removal.

Estimated blood loss was a significant predictor of low- and high-grade postoperative complications. The OR for high-grade complications per 200 mL of blood lost was 1.06 (P = .007), and the OR for low-grade complications per 200 mL blood lost was 1.09 (P = .001).

There was a strong inverse correlation with CN case load at each center and high-grade postoperative complications, which highlights “the impact of centralization of care on postoperative outcomes in complex surgical scenarios,” the investigators wrote. The OR per 25 cases was 0.88 (P = .04).

Results were largely the same when the analysis was limited to the 560 subjects treated since 2006, in the targeted therapy era, except that adjacent organ removal as a predictor of intraoperative complications did not quite reach statistical significance (P = .06).

The presurgery risk factors identified in this study should assist with presurgical counseling, said Zachery Reichert, MD, PhD, a genitourinary medical oncologist and assistant professor at the University of Michigan, Ann Arbor, who was not involved in this study.

“This is especially important for patients who require thrombectomy or adjacent organ removal or do not have access to a surgeon with high cytoreductive nephrectomy caseloads,” he said.

Dr. Reichert reported having no disclosures. There was no external funding for this study, and the investigators didn’t have any disclosures.

[email protected]

SOURCE: Roussel E et al. Eur Urol Oncol. 2020 Aug;3(4):523-9.

Patients with higher intraoperative blood loss and those treated at lower-volume surgical centers had a greater risk of high-grade complications after undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC), according to an analysis of registry data.

Higher intraoperative blood loss was also associated with low-grade postoperative complications. Intraoperative complications were more likely in patients who had concurrent thrombectomy and surgery on adjacent organs.

Eduard Roussel, MD, of University Hospitals Leuven (Belgium) and colleagues reported these findings in European Urology Oncology.

The authors noted that the role of CN in metastatic RCC is controversial. The CARMENA trial, published in the New England Journal of Medicine, “shifted treatment paradigms” away from surgery by suggesting that sunitinib alone is noninferior to sunitinib after CN.

“Nonetheless, there is a general consensus that certain selected subgroups of patients with low-volume, single-site metastases and few adverse IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria would still benefit from the continued use of upfront CN,” the authors wrote.

They advised clinicians to weigh the risks and benefits of CN, particularly because “postoperative morbidity might preclude or delay the use of subsequent systemic therapies.” However, the risk/benefit calculation for CN has been difficult because past investigations have tended to focus only on survival outcomes, so there isn’t much data on morbidity, the authors wrote.

Patient characteristics and complications

To investigate morbidity associated with CN, Dr. Roussel and colleagues reviewed data from the Registry of Metastatic RCC (REMARCC). The team analyzed the clinical records of 736 patients who underwent nephrectomy for metastatic RCC during 1980-2019.

The patients’ median age was 63 years (range, 55-70 years), and about three-quarters were men. The majority had clear cell carcinoma, and the lungs were the most common site of metastases.

More than 97% of procedures were complete nephrectomies, and the rest were partial. The median estimated blood loss was 400 mL, and the median follow-up was 16.5 months.

There were 69 patients who had intraoperative complications, most commonly bleeding (n = 25), spleen laceration (n = 13), and vascular injury (n = 11).

There were 217 patients who had postoperative complications, including 45 patients with high-grade complications (grade 3-5) and 10 who died.

The most common postoperative complications were vascular/lymphatic in nature. These occurred in 67 patients and included 10 lymphoceles.

“[G]iven the relatively high rate of postoperative lymphoceles, which is probably attributable to the performance of lymph node dissections and the lack of proven oncological survival benefit thereof, surgeons might reconsider the performance of lymphadenectomy during CN,” the investigators wrote.

Other common postoperative complications included infectious and cardiopulmonary issues, which occurred in 42 and 39 patients, respectively.
 

Predictors of complications

Thrombectomy and adjacent organ removal were significant predictors of intraoperative complications on multivariable analysis. The odds ratios were 1.38 (P = .009) for thrombectomy and 2.71 (P = .004) for adjacent organ removal.

Estimated blood loss was a significant predictor of low- and high-grade postoperative complications. The OR for high-grade complications per 200 mL of blood lost was 1.06 (P = .007), and the OR for low-grade complications per 200 mL blood lost was 1.09 (P = .001).

There was a strong inverse correlation with CN case load at each center and high-grade postoperative complications, which highlights “the impact of centralization of care on postoperative outcomes in complex surgical scenarios,” the investigators wrote. The OR per 25 cases was 0.88 (P = .04).

Results were largely the same when the analysis was limited to the 560 subjects treated since 2006, in the targeted therapy era, except that adjacent organ removal as a predictor of intraoperative complications did not quite reach statistical significance (P = .06).

The presurgery risk factors identified in this study should assist with presurgical counseling, said Zachery Reichert, MD, PhD, a genitourinary medical oncologist and assistant professor at the University of Michigan, Ann Arbor, who was not involved in this study.

“This is especially important for patients who require thrombectomy or adjacent organ removal or do not have access to a surgeon with high cytoreductive nephrectomy caseloads,” he said.

Dr. Reichert reported having no disclosures. There was no external funding for this study, and the investigators didn’t have any disclosures.

[email protected]

SOURCE: Roussel E et al. Eur Urol Oncol. 2020 Aug;3(4):523-9.