SAN DIEGO – African Americans have higher mortality rates from pancreatic cancer compared with whites and Asians/American Indians, results from a large population-based study showed.

Doug Brunk/MDedge News

However, between 2013 and 2015, mortality rates began to fall among all ethnicities, for reasons that remain unclear. “There is still a significant disparity between the [white] and African American populations,” lead study author Mohamed M. Gad, MD, said at the annual Digestive Disease Week. “Trends for the Asian/American Indian populations were similar to that of the [white] population.”

While most patients diagnosed with pancreatic cancer are white men, the disparities among racial and ethnic groups have not been addressed on a large scale, said Dr. Gad, an internal medicine resident at the Cleveland Clinic. In an effort to investigate the racial disparities in mortality rates in patients with pancreatic cancer, he and colleagues collected data from the National Cancer Institute’s Surveillance, Epidemiology and End-Results Program (SEER) 9 database during 1973 to 2015. The researchers calculated mortality rates for all pancreatic cancer cases by race. Next, they calculated the Observed/Expected (O/E) ratio and the excess risk per 10,000 person-years to estimate the change of risk following the diagnosis in different ethnicities, when compared to the general population, using Joinpoint Regression software.

Dr. Gad reported results from 65,985 patients who died from pancreatic cancer between 1973 and 2015. The overall mortality rate was highest for African Americans (9.4%), followed by whites (6.4%), and Asians/American Indians (5.4%). The researchers observed that mortality rates of all racial groups continued to increase from 1973 until 2013. However, between 2013 and 2015, the mortality rates decreased by 20.5% for African Americans, by 27.1% for whites, and by 25.1% for Asians/American Indians (P less than .001 for all decreases). Socioeconomic status and access to health care have been hypothesized to play a role in these observed outcomes, Dr. Gad said, but more research is needed to understand the observed disparities and assess the need for intervention. For example, he said, one line of research would be to evaluate the difference between access to health care and the quality of health care delivery for African American patients compared with their white counterparts. “Once we identify that, how can we improve outcomes for the African American population?” Dr. Gad asked.

He reported having no financial disclosures.

[email protected]

SAN DIEGO – African Americans have higher mortality rates from pancreatic cancer compared with whites and Asians/American Indians, results from a large population-based study showed.

Doug Brunk/MDedge News

However, between 2013 and 2015, mortality rates began to fall among all ethnicities, for reasons that remain unclear. “There is still a significant disparity between the [white] and African American populations,” lead study author Mohamed M. Gad, MD, said at the annual Digestive Disease Week. “Trends for the Asian/American Indian populations were similar to that of the [white] population.”

While most patients diagnosed with pancreatic cancer are white men, the disparities among racial and ethnic groups have not been addressed on a large scale, said Dr. Gad, an internal medicine resident at the Cleveland Clinic. In an effort to investigate the racial disparities in mortality rates in patients with pancreatic cancer, he and colleagues collected data from the National Cancer Institute’s Surveillance, Epidemiology and End-Results Program (SEER) 9 database during 1973 to 2015. The researchers calculated mortality rates for all pancreatic cancer cases by race. Next, they calculated the Observed/Expected (O/E) ratio and the excess risk per 10,000 person-years to estimate the change of risk following the diagnosis in different ethnicities, when compared to the general population, using Joinpoint Regression software.

Dr. Gad reported results from 65,985 patients who died from pancreatic cancer between 1973 and 2015. The overall mortality rate was highest for African Americans (9.4%), followed by whites (6.4%), and Asians/American Indians (5.4%). The researchers observed that mortality rates of all racial groups continued to increase from 1973 until 2013. However, between 2013 and 2015, the mortality rates decreased by 20.5% for African Americans, by 27.1% for whites, and by 25.1% for Asians/American Indians (P less than .001 for all decreases). Socioeconomic status and access to health care have been hypothesized to play a role in these observed outcomes, Dr. Gad said, but more research is needed to understand the observed disparities and assess the need for intervention. For example, he said, one line of research would be to evaluate the difference between access to health care and the quality of health care delivery for African American patients compared with their white counterparts. “Once we identify that, how can we improve outcomes for the African American population?” Dr. Gad asked.

He reported having no financial disclosures.

[email protected]

SAN DIEGO – African Americans have higher mortality rates from pancreatic cancer compared with whites and Asians/American Indians, results from a large population-based study showed.

Doug Brunk/MDedge News

However, between 2013 and 2015, mortality rates began to fall among all ethnicities, for reasons that remain unclear. “There is still a significant disparity between the [white] and African American populations,” lead study author Mohamed M. Gad, MD, said at the annual Digestive Disease Week. “Trends for the Asian/American Indian populations were similar to that of the [white] population.”

While most patients diagnosed with pancreatic cancer are white men, the disparities among racial and ethnic groups have not been addressed on a large scale, said Dr. Gad, an internal medicine resident at the Cleveland Clinic. In an effort to investigate the racial disparities in mortality rates in patients with pancreatic cancer, he and colleagues collected data from the National Cancer Institute’s Surveillance, Epidemiology and End-Results Program (SEER) 9 database during 1973 to 2015. The researchers calculated mortality rates for all pancreatic cancer cases by race. Next, they calculated the Observed/Expected (O/E) ratio and the excess risk per 10,000 person-years to estimate the change of risk following the diagnosis in different ethnicities, when compared to the general population, using Joinpoint Regression software.

Dr. Gad reported results from 65,985 patients who died from pancreatic cancer between 1973 and 2015. The overall mortality rate was highest for African Americans (9.4%), followed by whites (6.4%), and Asians/American Indians (5.4%). The researchers observed that mortality rates of all racial groups continued to increase from 1973 until 2013. However, between 2013 and 2015, the mortality rates decreased by 20.5% for African Americans, by 27.1% for whites, and by 25.1% for Asians/American Indians (P less than .001 for all decreases). Socioeconomic status and access to health care have been hypothesized to play a role in these observed outcomes, Dr. Gad said, but more research is needed to understand the observed disparities and assess the need for intervention. For example, he said, one line of research would be to evaluate the difference between access to health care and the quality of health care delivery for African American patients compared with their white counterparts. “Once we identify that, how can we improve outcomes for the African American population?” Dr. Gad asked.

He reported having no financial disclosures.

[email protected]

The odds of surgical site infection were 5.77 times higher during the 90 days after revision vs. primary total joint replacement, according to the findings of a large cohort study.

©decade3d/Thinkstock

In absolute terms, these rates were 15.6% after revision total knee replacement and 8.6% after revision total hip replacement, vs. 2.1% and 2.1% after the respective primary surgeries, wrote Charles E. Edmiston Jr., PhD, and associates. “This result is consistent with results from several other studies that have reported an increased risk after revision procedures,” they added. Such information is essential for developing care bundles based on presenting risk factors, they wrote in a report published in the American Journal of Infection Control.

Population aging and comorbidities are fueling the need for primary and revision joint replacement surgery. “Such trends highlight the need for solutions to cost-effectively prevent and treat surgical site infections, one of the common complications after total joint replacement procedures,” the researchers wrote. Using IBM MarketScan and Medicare data, they studied 335,134 total knee replacements and 163,547 total hip replacements performed in the United States between 2009 and 2015.

After adjustment for potential confounders, the comorbidities that were most strongly linked to surgical site infections during the 90 days after primary or revision joint replacement were AIDS, paralysis, coagulopathy, metastatic cancer, heart failure, alcohol use disorder, obesity, fluid electrolyte disorders, and chronic pulmonary disorders. The estimated odds ratios for these correlates ranged from 1.33 to 1.58, and all confidence intervals reached statistical significance.

In general, these findings reflect those of smaller studies, the researchers noted. “The challenge for the future will be the development of evidence-based surgical care bundles that focus on the peri-, intra-, and postoperative components of orthopedic patient care, especially in patients undergoing periprosthetic revision.”

Johnson & Johnson Medical Device Companies provided funding. Three coinvestigators reported employment and stockholder ties to the company. In addition, Dr. Edmiston and one coinvestigator reported speaker fees for Ethicon, a Johnson & Johnson company.

SOURCE: Edmiston CE et al. Am J Infect Control. 2019 May 6. doi: 10.1016/j.ajic.2019.03.030.

The odds of surgical site infection were 5.77 times higher during the 90 days after revision vs. primary total joint replacement, according to the findings of a large cohort study.

©decade3d/Thinkstock

In absolute terms, these rates were 15.6% after revision total knee replacement and 8.6% after revision total hip replacement, vs. 2.1% and 2.1% after the respective primary surgeries, wrote Charles E. Edmiston Jr., PhD, and associates. “This result is consistent with results from several other studies that have reported an increased risk after revision procedures,” they added. Such information is essential for developing care bundles based on presenting risk factors, they wrote in a report published in the American Journal of Infection Control.

Population aging and comorbidities are fueling the need for primary and revision joint replacement surgery. “Such trends highlight the need for solutions to cost-effectively prevent and treat surgical site infections, one of the common complications after total joint replacement procedures,” the researchers wrote. Using IBM MarketScan and Medicare data, they studied 335,134 total knee replacements and 163,547 total hip replacements performed in the United States between 2009 and 2015.

After adjustment for potential confounders, the comorbidities that were most strongly linked to surgical site infections during the 90 days after primary or revision joint replacement were AIDS, paralysis, coagulopathy, metastatic cancer, heart failure, alcohol use disorder, obesity, fluid electrolyte disorders, and chronic pulmonary disorders. The estimated odds ratios for these correlates ranged from 1.33 to 1.58, and all confidence intervals reached statistical significance.

In general, these findings reflect those of smaller studies, the researchers noted. “The challenge for the future will be the development of evidence-based surgical care bundles that focus on the peri-, intra-, and postoperative components of orthopedic patient care, especially in patients undergoing periprosthetic revision.”

Johnson & Johnson Medical Device Companies provided funding. Three coinvestigators reported employment and stockholder ties to the company. In addition, Dr. Edmiston and one coinvestigator reported speaker fees for Ethicon, a Johnson & Johnson company.

SOURCE: Edmiston CE et al. Am J Infect Control. 2019 May 6. doi: 10.1016/j.ajic.2019.03.030.

The odds of surgical site infection were 5.77 times higher during the 90 days after revision vs. primary total joint replacement, according to the findings of a large cohort study.

©decade3d/Thinkstock

In absolute terms, these rates were 15.6% after revision total knee replacement and 8.6% after revision total hip replacement, vs. 2.1% and 2.1% after the respective primary surgeries, wrote Charles E. Edmiston Jr., PhD, and associates. “This result is consistent with results from several other studies that have reported an increased risk after revision procedures,” they added. Such information is essential for developing care bundles based on presenting risk factors, they wrote in a report published in the American Journal of Infection Control.

Population aging and comorbidities are fueling the need for primary and revision joint replacement surgery. “Such trends highlight the need for solutions to cost-effectively prevent and treat surgical site infections, one of the common complications after total joint replacement procedures,” the researchers wrote. Using IBM MarketScan and Medicare data, they studied 335,134 total knee replacements and 163,547 total hip replacements performed in the United States between 2009 and 2015.

After adjustment for potential confounders, the comorbidities that were most strongly linked to surgical site infections during the 90 days after primary or revision joint replacement were AIDS, paralysis, coagulopathy, metastatic cancer, heart failure, alcohol use disorder, obesity, fluid electrolyte disorders, and chronic pulmonary disorders. The estimated odds ratios for these correlates ranged from 1.33 to 1.58, and all confidence intervals reached statistical significance.

In general, these findings reflect those of smaller studies, the researchers noted. “The challenge for the future will be the development of evidence-based surgical care bundles that focus on the peri-, intra-, and postoperative components of orthopedic patient care, especially in patients undergoing periprosthetic revision.”

Johnson & Johnson Medical Device Companies provided funding. Three coinvestigators reported employment and stockholder ties to the company. In addition, Dr. Edmiston and one coinvestigator reported speaker fees for Ethicon, a Johnson & Johnson company.

SOURCE: Edmiston CE et al. Am J Infect Control. 2019 May 6. doi: 10.1016/j.ajic.2019.03.030.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

SAN DIEGO – Coffee, tea, and soda consumption are all associated with increased risk for gastroesophageal reflux disease (GERD), according to a new prospective cohort study presented at the annual Digestive Disease Week.

In an interview following the oral presentation, Raaj S. Mehta, MD, said that patients in his primary care panel at Massachusetts General Hospital, Boston, where he’s a senior resident, frequently came to him with GERD. In addition to questions about diet, patients frequently wanted to know which beverages might provoke or exacerbate their GERD.

In trying to help his patients, Dr. Mehta said he realized that there wasn’t a prospective evidence base to answer their questions about beverages and GERD, so he and his colleagues used data from the Nurses’ Health Study II (NHS II), a prospective cohort study, to look at the association between various beverages and the incidence of GERD.

“What’s exciting is that we were able to find that coffee, tea, and soda – all three – increase your risk for gastroesophageal reflux disease,” Dr. Mehta said in a video interview. “At the highest quintile level, so looking at people who consume six or more cups per day, you’re looking at maybe a 25%-35% increase in risk of reflux disease.”

There was a dose-response relationship as well: “You do see a slight increase as you go from one cup, to two, to three, and so on, all the way up to six cups” of the offending beverages, said Dr. Mehta.

Overall, the risk for GERD rose from 1.17 to 1.34 with coffee consumption as servings per day increased from less than one to six or more (P for trend less than .0001). Tea consumption was associated with increased GERD risk ranging from 1.08 to 1.26 as consumption rose (P for trend .001). For soda, the increased risk went from 1.12 at less than one serving daily, to 1.41 at four to five servings daily, and then fell to 1.29 at six or more daily servings (P for trend less than .0001).

Whether the beverages were caffeinated or not, said Dr. Mehta, only made a “minimal difference” in GERD risk.

“In contrast, we didn’t see an association for beverages like water, juice, and milk,” he said – reassuring findings in light of fruit juice’s anecdotal status as a GERD culprit.

The NHS II collected data every 2 years from 48,308 female nurses aged 42-62 years at the beginning of the study. Every 4 years dietary information was collected, and on the opposite 4-year cycle, participants answered questions about GERD. Medication use, including the incident use of proton pump inhibitors, was collected every 2 years.

Patients with baseline GERD or use of PPIs or H₂ receptor antagonists were excluded from participation.

The quantity and type of beverages were assessed by food frequency questionnaires; other demographic, dietary, and medication variables were also gathered and used to adjust the statistical analysis.

A substitution analysis answered the “what-if” question of the effect of substituting two glasses of plain water daily for either coffee, tea, or soda. Dr. Mehta and colleagues saw a modest reduction in risk for GERD with this strategy.

In addition to the prospective nature of the study (abstract 514, doi: 10.1016/S0016-5085(19)37044-1), the large sample size, high follow-up rates, and well validated dietary data were all strengths, said Dr. Mehta. However, the study’s population is relatively homogeneous, and residual confounding couldn’t be excluded. Also, GERD was defined by self-report, though participants were asked to respond to clear, validated criteria.

For Dr. Mehta, he’s glad to have a clear answer to a common clinic question. “I think that this is one additional thing that I can recommend as a primary care provider to my patients when they come into my office,” he said.

Dr. Mehta reported no conflicts of interest.

[email protected]

SAN DIEGO – Coffee, tea, and soda consumption are all associated with increased risk for gastroesophageal reflux disease (GERD), according to a new prospective cohort study presented at the annual Digestive Disease Week.

In an interview following the oral presentation, Raaj S. Mehta, MD, said that patients in his primary care panel at Massachusetts General Hospital, Boston, where he’s a senior resident, frequently came to him with GERD. In addition to questions about diet, patients frequently wanted to know which beverages might provoke or exacerbate their GERD.

In trying to help his patients, Dr. Mehta said he realized that there wasn’t a prospective evidence base to answer their questions about beverages and GERD, so he and his colleagues used data from the Nurses’ Health Study II (NHS II), a prospective cohort study, to look at the association between various beverages and the incidence of GERD.

“What’s exciting is that we were able to find that coffee, tea, and soda – all three – increase your risk for gastroesophageal reflux disease,” Dr. Mehta said in a video interview. “At the highest quintile level, so looking at people who consume six or more cups per day, you’re looking at maybe a 25%-35% increase in risk of reflux disease.”

There was a dose-response relationship as well: “You do see a slight increase as you go from one cup, to two, to three, and so on, all the way up to six cups” of the offending beverages, said Dr. Mehta.

Overall, the risk for GERD rose from 1.17 to 1.34 with coffee consumption as servings per day increased from less than one to six or more (P for trend less than .0001). Tea consumption was associated with increased GERD risk ranging from 1.08 to 1.26 as consumption rose (P for trend .001). For soda, the increased risk went from 1.12 at less than one serving daily, to 1.41 at four to five servings daily, and then fell to 1.29 at six or more daily servings (P for trend less than .0001).

Whether the beverages were caffeinated or not, said Dr. Mehta, only made a “minimal difference” in GERD risk.

“In contrast, we didn’t see an association for beverages like water, juice, and milk,” he said – reassuring findings in light of fruit juice’s anecdotal status as a GERD culprit.

The NHS II collected data every 2 years from 48,308 female nurses aged 42-62 years at the beginning of the study. Every 4 years dietary information was collected, and on the opposite 4-year cycle, participants answered questions about GERD. Medication use, including the incident use of proton pump inhibitors, was collected every 2 years.

Patients with baseline GERD or use of PPIs or H₂ receptor antagonists were excluded from participation.

The quantity and type of beverages were assessed by food frequency questionnaires; other demographic, dietary, and medication variables were also gathered and used to adjust the statistical analysis.

A substitution analysis answered the “what-if” question of the effect of substituting two glasses of plain water daily for either coffee, tea, or soda. Dr. Mehta and colleagues saw a modest reduction in risk for GERD with this strategy.

In addition to the prospective nature of the study (abstract 514, doi: 10.1016/S0016-5085(19)37044-1), the large sample size, high follow-up rates, and well validated dietary data were all strengths, said Dr. Mehta. However, the study’s population is relatively homogeneous, and residual confounding couldn’t be excluded. Also, GERD was defined by self-report, though participants were asked to respond to clear, validated criteria.

For Dr. Mehta, he’s glad to have a clear answer to a common clinic question. “I think that this is one additional thing that I can recommend as a primary care provider to my patients when they come into my office,” he said.

Dr. Mehta reported no conflicts of interest.

[email protected]

SAN DIEGO – Coffee, tea, and soda consumption are all associated with increased risk for gastroesophageal reflux disease (GERD), according to a new prospective cohort study presented at the annual Digestive Disease Week.

In an interview following the oral presentation, Raaj S. Mehta, MD, said that patients in his primary care panel at Massachusetts General Hospital, Boston, where he’s a senior resident, frequently came to him with GERD. In addition to questions about diet, patients frequently wanted to know which beverages might provoke or exacerbate their GERD.

In trying to help his patients, Dr. Mehta said he realized that there wasn’t a prospective evidence base to answer their questions about beverages and GERD, so he and his colleagues used data from the Nurses’ Health Study II (NHS II), a prospective cohort study, to look at the association between various beverages and the incidence of GERD.

“What’s exciting is that we were able to find that coffee, tea, and soda – all three – increase your risk for gastroesophageal reflux disease,” Dr. Mehta said in a video interview. “At the highest quintile level, so looking at people who consume six or more cups per day, you’re looking at maybe a 25%-35% increase in risk of reflux disease.”

There was a dose-response relationship as well: “You do see a slight increase as you go from one cup, to two, to three, and so on, all the way up to six cups” of the offending beverages, said Dr. Mehta.

Overall, the risk for GERD rose from 1.17 to 1.34 with coffee consumption as servings per day increased from less than one to six or more (P for trend less than .0001). Tea consumption was associated with increased GERD risk ranging from 1.08 to 1.26 as consumption rose (P for trend .001). For soda, the increased risk went from 1.12 at less than one serving daily, to 1.41 at four to five servings daily, and then fell to 1.29 at six or more daily servings (P for trend less than .0001).

Whether the beverages were caffeinated or not, said Dr. Mehta, only made a “minimal difference” in GERD risk.

“In contrast, we didn’t see an association for beverages like water, juice, and milk,” he said – reassuring findings in light of fruit juice’s anecdotal status as a GERD culprit.

The NHS II collected data every 2 years from 48,308 female nurses aged 42-62 years at the beginning of the study. Every 4 years dietary information was collected, and on the opposite 4-year cycle, participants answered questions about GERD. Medication use, including the incident use of proton pump inhibitors, was collected every 2 years.

Patients with baseline GERD or use of PPIs or H₂ receptor antagonists were excluded from participation.

The quantity and type of beverages were assessed by food frequency questionnaires; other demographic, dietary, and medication variables were also gathered and used to adjust the statistical analysis.

A substitution analysis answered the “what-if” question of the effect of substituting two glasses of plain water daily for either coffee, tea, or soda. Dr. Mehta and colleagues saw a modest reduction in risk for GERD with this strategy.

In addition to the prospective nature of the study (abstract 514, doi: 10.1016/S0016-5085(19)37044-1), the large sample size, high follow-up rates, and well validated dietary data were all strengths, said Dr. Mehta. However, the study’s population is relatively homogeneous, and residual confounding couldn’t be excluded. Also, GERD was defined by self-report, though participants were asked to respond to clear, validated criteria.

For Dr. Mehta, he’s glad to have a clear answer to a common clinic question. “I think that this is one additional thing that I can recommend as a primary care provider to my patients when they come into my office,” he said.

Dr. Mehta reported no conflicts of interest.

[email protected]

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

A Zika virus test initially authorized only for emergency use has now been approved for use in nonemergency situations, according to a statement from the Food and Drug Administration.

The ZIKV Detect 2.0 IgM Capture ELISA (enzyme-linked immunosorbent assay) is now authorized for use in patients with clinical signs and symptoms consistent with Zika virus infection, as well as those who meet the Centers for Disease Control and Prevention epidemiologic criteria, including residence in or travel to a region deemed high risk because of active Zika transmission.

The test is designed to identify Zika antibodies in the blood, and the FDA cited a review of clinical trial data and analytic data to support the test’s safety and effectiveness.

“Results of this test are intended to be used in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence to make patient management decisions,” the FDA stated.

The ZIKV Detect 2.0 IgM Capture ELISA, initially approved in 2016, had been authorized by the FDA only for emergency use, along with other tests for detecting Zika virus, under the under the FDA’s Emergency Use Authorization (EUA) authority.

The FDA granted marketing authorization to test manufacturer InBios International.

The FDA is communicating with four EUA holders to gather information to evaluate whether the FDA should revoke the EUAs for these specific tests. The marketing authorization of ZIKV Detect 2.0 IgM Capture ELISA does not impact the availability of the other 14 Zika nucleic acid diagnostics available under EUAs.

The Zika virus, typically transmitted by an infected mosquito, is especially a risk for pregnant women as the fetus may experience neurologic complications and microcephaly as a result of infection.

A Zika virus test initially authorized only for emergency use has now been approved for use in nonemergency situations, according to a statement from the Food and Drug Administration.

The ZIKV Detect 2.0 IgM Capture ELISA (enzyme-linked immunosorbent assay) is now authorized for use in patients with clinical signs and symptoms consistent with Zika virus infection, as well as those who meet the Centers for Disease Control and Prevention epidemiologic criteria, including residence in or travel to a region deemed high risk because of active Zika transmission.

The test is designed to identify Zika antibodies in the blood, and the FDA cited a review of clinical trial data and analytic data to support the test’s safety and effectiveness.

“Results of this test are intended to be used in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence to make patient management decisions,” the FDA stated.

The ZIKV Detect 2.0 IgM Capture ELISA, initially approved in 2016, had been authorized by the FDA only for emergency use, along with other tests for detecting Zika virus, under the under the FDA’s Emergency Use Authorization (EUA) authority.

The FDA granted marketing authorization to test manufacturer InBios International.

The FDA is communicating with four EUA holders to gather information to evaluate whether the FDA should revoke the EUAs for these specific tests. The marketing authorization of ZIKV Detect 2.0 IgM Capture ELISA does not impact the availability of the other 14 Zika nucleic acid diagnostics available under EUAs.

The Zika virus, typically transmitted by an infected mosquito, is especially a risk for pregnant women as the fetus may experience neurologic complications and microcephaly as a result of infection.

A Zika virus test initially authorized only for emergency use has now been approved for use in nonemergency situations, according to a statement from the Food and Drug Administration.

The ZIKV Detect 2.0 IgM Capture ELISA (enzyme-linked immunosorbent assay) is now authorized for use in patients with clinical signs and symptoms consistent with Zika virus infection, as well as those who meet the Centers for Disease Control and Prevention epidemiologic criteria, including residence in or travel to a region deemed high risk because of active Zika transmission.

The test is designed to identify Zika antibodies in the blood, and the FDA cited a review of clinical trial data and analytic data to support the test’s safety and effectiveness.

“Results of this test are intended to be used in conjunction with clinical observations, patient history, epidemiological information, and other laboratory evidence to make patient management decisions,” the FDA stated.

The ZIKV Detect 2.0 IgM Capture ELISA, initially approved in 2016, had been authorized by the FDA only for emergency use, along with other tests for detecting Zika virus, under the under the FDA’s Emergency Use Authorization (EUA) authority.

The FDA granted marketing authorization to test manufacturer InBios International.

The FDA is communicating with four EUA holders to gather information to evaluate whether the FDA should revoke the EUAs for these specific tests. The marketing authorization of ZIKV Detect 2.0 IgM Capture ELISA does not impact the availability of the other 14 Zika nucleic acid diagnostics available under EUAs.

The Zika virus, typically transmitted by an infected mosquito, is especially a risk for pregnant women as the fetus may experience neurologic complications and microcephaly as a result of infection.

Black men with newly diagnosed nonmetastatic prostate cancer had no significant difference in prostate cancer–specific mortality compared with white men when treated with a standardized approach and follow-up or at a health care system with standardized access, according to recent research published in JAMA Oncology.

Robert T. Dess, MD, from the department of radiation oncology at the University of Michigan, Ann Arbor, and colleagues examined data from 296,273 patients in the Surveillance, Epidemiology, and End Results (SEER) cohort, 3,972 patients from the Veterans Affairs (VA) health system, and 5,854 patients in four randomized controlled trials (RCTs) from the National Cancer Institute–sponsored Radiation Therapy Oncology Group between January 1992 and December 2013. Of these, 52,840 patients (17.8%) in the SEER cohort, 1,513 patients (38.1%) in the VA cohort, and 1,129 (19.3%) in the RCT cohort were black men. The mean age across all cohorts was 64.9 years, and the median follow-up was 75 months in the SEER cohort, 97 months in the VA cohort, and 104 months in the RCT cohort.

After adjustment for age in the SEER cohort, black men had a 30% increased risk of prostate cancer–specific mortality (PCSM) compared with white men (subdistribution hazard ratio, 1.30; 95% CI, 1.23-1.37; P less than .001). However, after the researchers performed inverse probability weighting (IPW) to adjust for race-based imbalances such as access to care and standardized treatment, there was a 0.5% increased risk over 10 years (sHR, 1.09; 95% CI, 1.04-1.15; P less than .001) after diagnosis.

In the VA cohort, IPW yielded no significant differences between black men and white men (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and there was a significantly lower risk for black men in the RCT cohort after IPW (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). With regard to other outcomes, other-cause mortality was significantly higher for black men in the SEER cohort (sHR, 1.30; 95% CI, 1.27-1.34; P less than .001) and in the RCT cohort (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) after IPW.

“Black race remains associated with many factors that negatively affect outcomes, and disparities persist at the population level,” Dr. Dess and colleagues wrote in their study. “Continued efforts are needed to address this clear racial health inequity driven by modifiable nonbiological risk factors.”

The researchers said some residual confounding may exist, but noted the strengths of the study included a diverse cohort with a large range of treatment approaches.

This study was funded in part by the Prostate Cancer Foundation, a grant from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, two grants from the Department of Defense, a grant from NIH, and a grant from the NIH Cancer Center. One or more of the authors reported relationships in the form of grants, personal fees, and consulting fees with numerous companies. The other authors report no relevant conflicts of interest.

SOURCE: Dess RT et al. JAMA Oncol. 2019 May 23. doi: 10.1001/jamaoncol.2019.0826.

Black men with newly diagnosed nonmetastatic prostate cancer had no significant difference in prostate cancer–specific mortality compared with white men when treated with a standardized approach and follow-up or at a health care system with standardized access, according to recent research published in JAMA Oncology.

Robert T. Dess, MD, from the department of radiation oncology at the University of Michigan, Ann Arbor, and colleagues examined data from 296,273 patients in the Surveillance, Epidemiology, and End Results (SEER) cohort, 3,972 patients from the Veterans Affairs (VA) health system, and 5,854 patients in four randomized controlled trials (RCTs) from the National Cancer Institute–sponsored Radiation Therapy Oncology Group between January 1992 and December 2013. Of these, 52,840 patients (17.8%) in the SEER cohort, 1,513 patients (38.1%) in the VA cohort, and 1,129 (19.3%) in the RCT cohort were black men. The mean age across all cohorts was 64.9 years, and the median follow-up was 75 months in the SEER cohort, 97 months in the VA cohort, and 104 months in the RCT cohort.

After adjustment for age in the SEER cohort, black men had a 30% increased risk of prostate cancer–specific mortality (PCSM) compared with white men (subdistribution hazard ratio, 1.30; 95% CI, 1.23-1.37; P less than .001). However, after the researchers performed inverse probability weighting (IPW) to adjust for race-based imbalances such as access to care and standardized treatment, there was a 0.5% increased risk over 10 years (sHR, 1.09; 95% CI, 1.04-1.15; P less than .001) after diagnosis.

In the VA cohort, IPW yielded no significant differences between black men and white men (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and there was a significantly lower risk for black men in the RCT cohort after IPW (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). With regard to other outcomes, other-cause mortality was significantly higher for black men in the SEER cohort (sHR, 1.30; 95% CI, 1.27-1.34; P less than .001) and in the RCT cohort (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) after IPW.

“Black race remains associated with many factors that negatively affect outcomes, and disparities persist at the population level,” Dr. Dess and colleagues wrote in their study. “Continued efforts are needed to address this clear racial health inequity driven by modifiable nonbiological risk factors.”

The researchers said some residual confounding may exist, but noted the strengths of the study included a diverse cohort with a large range of treatment approaches.

This study was funded in part by the Prostate Cancer Foundation, a grant from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, two grants from the Department of Defense, a grant from NIH, and a grant from the NIH Cancer Center. One or more of the authors reported relationships in the form of grants, personal fees, and consulting fees with numerous companies. The other authors report no relevant conflicts of interest.

SOURCE: Dess RT et al. JAMA Oncol. 2019 May 23. doi: 10.1001/jamaoncol.2019.0826.

Black men with newly diagnosed nonmetastatic prostate cancer had no significant difference in prostate cancer–specific mortality compared with white men when treated with a standardized approach and follow-up or at a health care system with standardized access, according to recent research published in JAMA Oncology.

Robert T. Dess, MD, from the department of radiation oncology at the University of Michigan, Ann Arbor, and colleagues examined data from 296,273 patients in the Surveillance, Epidemiology, and End Results (SEER) cohort, 3,972 patients from the Veterans Affairs (VA) health system, and 5,854 patients in four randomized controlled trials (RCTs) from the National Cancer Institute–sponsored Radiation Therapy Oncology Group between January 1992 and December 2013. Of these, 52,840 patients (17.8%) in the SEER cohort, 1,513 patients (38.1%) in the VA cohort, and 1,129 (19.3%) in the RCT cohort were black men. The mean age across all cohorts was 64.9 years, and the median follow-up was 75 months in the SEER cohort, 97 months in the VA cohort, and 104 months in the RCT cohort.

After adjustment for age in the SEER cohort, black men had a 30% increased risk of prostate cancer–specific mortality (PCSM) compared with white men (subdistribution hazard ratio, 1.30; 95% CI, 1.23-1.37; P less than .001). However, after the researchers performed inverse probability weighting (IPW) to adjust for race-based imbalances such as access to care and standardized treatment, there was a 0.5% increased risk over 10 years (sHR, 1.09; 95% CI, 1.04-1.15; P less than .001) after diagnosis.

In the VA cohort, IPW yielded no significant differences between black men and white men (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and there was a significantly lower risk for black men in the RCT cohort after IPW (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). With regard to other outcomes, other-cause mortality was significantly higher for black men in the SEER cohort (sHR, 1.30; 95% CI, 1.27-1.34; P less than .001) and in the RCT cohort (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) after IPW.

“Black race remains associated with many factors that negatively affect outcomes, and disparities persist at the population level,” Dr. Dess and colleagues wrote in their study. “Continued efforts are needed to address this clear racial health inequity driven by modifiable nonbiological risk factors.”

The researchers said some residual confounding may exist, but noted the strengths of the study included a diverse cohort with a large range of treatment approaches.

This study was funded in part by the Prostate Cancer Foundation, a grant from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, two grants from the Department of Defense, a grant from NIH, and a grant from the NIH Cancer Center. One or more of the authors reported relationships in the form of grants, personal fees, and consulting fees with numerous companies. The other authors report no relevant conflicts of interest.

SOURCE: Dess RT et al. JAMA Oncol. 2019 May 23. doi: 10.1001/jamaoncol.2019.0826.

TORONTO – The use of warfarin or related vitamin K antagonists was associated with a more than 100% increased risk of incident or progressive knee or hip osteoarthritis in the Rotterdam Study, Cindy G. Boer reported at the OARSI 2019 World Congress.

A biologically plausible mechanism exists for this relationship, added Ms. Boer, a PhD student with a special interest in the molecular genetics of OA at Erasmus University, Rotterdam, the Netherlands.

Bruce Jancin/MDedge News

About 80% of the OA endpoints in this analysis involved incident OA, defined radiographically as Kellgren-Lawrence grade 2. Progressive OA was defined as going from grade 2 at baseline to grade 3-4 during follow-up.

There was a signal of a treatment duration-related effect, with OA rates trending highest in individuals on warfarin for longer than 365 days, followed by those on the oral anticoagulant for more than 100 days, who in turn had higher rates than those on warfarin for less time.

Ms. Boer said an important next step in this research is to replicate the warfarin/OA association in an independent cohort. Also, she and her coworkers are now gathering OA incidence and progression data in patients on direct oral anticoagulants rather than warfarin to test the hypothesis that they will not have an increased rate of OA, compared with nonusers, since these newer agents don’t affect vitamin K. Of course, if they do turn out to have an elevated risk, it would point to one or more of the conditions for which oral anticoagulants are commonly prescribed as the explanation.

She reported having no financial conflicts regarding her study, sponsored by Erasmus University and the Dutch government.

[email protected]

TORONTO – The use of warfarin or related vitamin K antagonists was associated with a more than 100% increased risk of incident or progressive knee or hip osteoarthritis in the Rotterdam Study, Cindy G. Boer reported at the OARSI 2019 World Congress.

A biologically plausible mechanism exists for this relationship, added Ms. Boer, a PhD student with a special interest in the molecular genetics of OA at Erasmus University, Rotterdam, the Netherlands.

Bruce Jancin/MDedge News

About 80% of the OA endpoints in this analysis involved incident OA, defined radiographically as Kellgren-Lawrence grade 2. Progressive OA was defined as going from grade 2 at baseline to grade 3-4 during follow-up.

There was a signal of a treatment duration-related effect, with OA rates trending highest in individuals on warfarin for longer than 365 days, followed by those on the oral anticoagulant for more than 100 days, who in turn had higher rates than those on warfarin for less time.

Ms. Boer said an important next step in this research is to replicate the warfarin/OA association in an independent cohort. Also, she and her coworkers are now gathering OA incidence and progression data in patients on direct oral anticoagulants rather than warfarin to test the hypothesis that they will not have an increased rate of OA, compared with nonusers, since these newer agents don’t affect vitamin K. Of course, if they do turn out to have an elevated risk, it would point to one or more of the conditions for which oral anticoagulants are commonly prescribed as the explanation.

She reported having no financial conflicts regarding her study, sponsored by Erasmus University and the Dutch government.

[email protected]

TORONTO – The use of warfarin or related vitamin K antagonists was associated with a more than 100% increased risk of incident or progressive knee or hip osteoarthritis in the Rotterdam Study, Cindy G. Boer reported at the OARSI 2019 World Congress.

A biologically plausible mechanism exists for this relationship, added Ms. Boer, a PhD student with a special interest in the molecular genetics of OA at Erasmus University, Rotterdam, the Netherlands.

Bruce Jancin/MDedge News

About 80% of the OA endpoints in this analysis involved incident OA, defined radiographically as Kellgren-Lawrence grade 2. Progressive OA was defined as going from grade 2 at baseline to grade 3-4 during follow-up.

There was a signal of a treatment duration-related effect, with OA rates trending highest in individuals on warfarin for longer than 365 days, followed by those on the oral anticoagulant for more than 100 days, who in turn had higher rates than those on warfarin for less time.

Ms. Boer said an important next step in this research is to replicate the warfarin/OA association in an independent cohort. Also, she and her coworkers are now gathering OA incidence and progression data in patients on direct oral anticoagulants rather than warfarin to test the hypothesis that they will not have an increased rate of OA, compared with nonusers, since these newer agents don’t affect vitamin K. Of course, if they do turn out to have an elevated risk, it would point to one or more of the conditions for which oral anticoagulants are commonly prescribed as the explanation.

She reported having no financial conflicts regarding her study, sponsored by Erasmus University and the Dutch government.

[email protected]

Clinical question: Does using a restrictive transfusion strategy with patients undergoing cardiac surgery affect long-term outcomes?

Background: Using a restrictive transfusion strategy in patients undergoing cardiac surgery is known to use fewer units of allogeneic red cells, compared with a liberal strategy, while still having noninferior short-term clinical outcomes. At this time, little is known about such a strategy’s long-term effects.

Study design: Randomized, open-label, noninferiority trial.

Setting: 74 hospitals in 19 countries.

Synopsis: 5,243 adults undergoing nontransplant cardiac surgeries and having at least a moderate predicted risk for death were randomly divided into a liberal or restrictive transfusion strategy. Restrictive-­strategy participants received a transfusion when hemoglobin was less than 7.5 g/dL, compared with either a hemoglobin of 8.5 g/dL on the floor or 9.5 g/dL in the ICU for the liberal-strategy group. During the hospitalization, the restrictive group received fewer U of red cells and had a lower mean predischarge hemoglobin. At 6 months, the groups were compared for the primary outcomes of death, MI, stroke, or renal failure requiring dialysis, finding an occurrence of such in 402/2,317 in the restrictive-strategy group and 402/2,347 in the liberal-strategy group (P = .006 for noninferiority). Limitations include the study being a noninferiority trial and the very specific patient population selected.

Bottom line: In patients undergoing cardiac surgery, a restrictive transfusion strategy is noninferior to a liberal strategy with respect to death from any cause, MI, stroke, and new renal failure requiring dialysis at 6 months postop.

Citation: Mazer CD et al. Six-month outcomes after restrictive or liberal transfusion for cardiac surgery. N Eng J Med. 2018 Sep 27;379(13):1224-33.

Dr. Shaw is an assistant professor in the division of hospital medicine,University of New Mexico.

Clinical question: Does using a restrictive transfusion strategy with patients undergoing cardiac surgery affect long-term outcomes?

Background: Using a restrictive transfusion strategy in patients undergoing cardiac surgery is known to use fewer units of allogeneic red cells, compared with a liberal strategy, while still having noninferior short-term clinical outcomes. At this time, little is known about such a strategy’s long-term effects.

Study design: Randomized, open-label, noninferiority trial.

Setting: 74 hospitals in 19 countries.

Synopsis: 5,243 adults undergoing nontransplant cardiac surgeries and having at least a moderate predicted risk for death were randomly divided into a liberal or restrictive transfusion strategy. Restrictive-­strategy participants received a transfusion when hemoglobin was less than 7.5 g/dL, compared with either a hemoglobin of 8.5 g/dL on the floor or 9.5 g/dL in the ICU for the liberal-strategy group. During the hospitalization, the restrictive group received fewer U of red cells and had a lower mean predischarge hemoglobin. At 6 months, the groups were compared for the primary outcomes of death, MI, stroke, or renal failure requiring dialysis, finding an occurrence of such in 402/2,317 in the restrictive-strategy group and 402/2,347 in the liberal-strategy group (P = .006 for noninferiority). Limitations include the study being a noninferiority trial and the very specific patient population selected.

Bottom line: In patients undergoing cardiac surgery, a restrictive transfusion strategy is noninferior to a liberal strategy with respect to death from any cause, MI, stroke, and new renal failure requiring dialysis at 6 months postop.

Citation: Mazer CD et al. Six-month outcomes after restrictive or liberal transfusion for cardiac surgery. N Eng J Med. 2018 Sep 27;379(13):1224-33.

Dr. Shaw is an assistant professor in the division of hospital medicine,University of New Mexico.

Clinical question: Does using a restrictive transfusion strategy with patients undergoing cardiac surgery affect long-term outcomes?

Background: Using a restrictive transfusion strategy in patients undergoing cardiac surgery is known to use fewer units of allogeneic red cells, compared with a liberal strategy, while still having noninferior short-term clinical outcomes. At this time, little is known about such a strategy’s long-term effects.

Study design: Randomized, open-label, noninferiority trial.

Setting: 74 hospitals in 19 countries.

Synopsis: 5,243 adults undergoing nontransplant cardiac surgeries and having at least a moderate predicted risk for death were randomly divided into a liberal or restrictive transfusion strategy. Restrictive-­strategy participants received a transfusion when hemoglobin was less than 7.5 g/dL, compared with either a hemoglobin of 8.5 g/dL on the floor or 9.5 g/dL in the ICU for the liberal-strategy group. During the hospitalization, the restrictive group received fewer U of red cells and had a lower mean predischarge hemoglobin. At 6 months, the groups were compared for the primary outcomes of death, MI, stroke, or renal failure requiring dialysis, finding an occurrence of such in 402/2,317 in the restrictive-strategy group and 402/2,347 in the liberal-strategy group (P = .006 for noninferiority). Limitations include the study being a noninferiority trial and the very specific patient population selected.

Bottom line: In patients undergoing cardiac surgery, a restrictive transfusion strategy is noninferior to a liberal strategy with respect to death from any cause, MI, stroke, and new renal failure requiring dialysis at 6 months postop.

Citation: Mazer CD et al. Six-month outcomes after restrictive or liberal transfusion for cardiac surgery. N Eng J Med. 2018 Sep 27;379(13):1224-33.

Dr. Shaw is an assistant professor in the division of hospital medicine,University of New Mexico.

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