A nationwide survey of radiation oncologists showed a decline in the use of prophylactic cranial irradiation (PCI) for extensive-stage small cell lung cancer (ES-SCLC) after the release of phase 3 study results by Takahashi et al.

The recent study by Toshiaki Takahashi, MD, and colleagues (Lancet Oncol. 2017;18[5]:663-71) demonstrated no overall survival benefit when comparing active magnetic resonance imaging surveillance with PCI in patients with ES-SCLC. The results challenged the formerly accepted belief of the benefit of PCI for patients with ES-SCLC.

“We conducted a nationwide survey study of radiation oncologists to assess changes in the use of PCI for patients with ES-SCLC following publication of the trial by Takahashi et al.,” wrote Olsi Gjyshi, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. The findings were reported in a research letter published in JAMA Network Open.

Dr. Gjyshi and colleagues distributed the anonymous survey to 3,851 United States–based radiation oncologists registered with the American Society for Radiation Oncology (ASTRO). In total, 487 members (12.6%) completed the survey.

After analysis, the researchers found that 72% of respondents regularly offered PCI to patients before the publication of the study by Takahashi et al., while only 44% do so currently (difference, 28%; 95% confidence interval, 25%-31%; P less than .001).

With respect to radiation oncologists in private versus academic settings, no significant difference in practice patterns was observed (P = .71).

“Regression analysis showed no difference in likelihood of offering PCI based on practice setting, location, or size; volume of patients treated for lung cancer; or years in practice,” the researchers wrote.

In respondents unaware of the Takahashi et al. study, 85% continued to propose PCI, which was greater than those aware of the trial (odds ratio, 0.11; 95% CI, 0.04-0.32; P less than .001).

The researchers acknowledged a key limitation of the study was that radiation oncologists familiar with the study by Dr. Takahashi and colleagues may have been more apt to respond to the survey. As a result, participation bias could have influenced the results.

“These results highlight the continued lack of consensus for PCI in SCLC and support ongoing investigations,” they concluded.

No funding sources were reported. One co-author reported financial affiliations with Novocure, Inc. The other authors reported no conflicts of interest.

SOURCE: Gjyshi O et al. JAMA Netw Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9135.

A nationwide survey of radiation oncologists showed a decline in the use of prophylactic cranial irradiation (PCI) for extensive-stage small cell lung cancer (ES-SCLC) after the release of phase 3 study results by Takahashi et al.

The recent study by Toshiaki Takahashi, MD, and colleagues (Lancet Oncol. 2017;18[5]:663-71) demonstrated no overall survival benefit when comparing active magnetic resonance imaging surveillance with PCI in patients with ES-SCLC. The results challenged the formerly accepted belief of the benefit of PCI for patients with ES-SCLC.

“We conducted a nationwide survey study of radiation oncologists to assess changes in the use of PCI for patients with ES-SCLC following publication of the trial by Takahashi et al.,” wrote Olsi Gjyshi, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. The findings were reported in a research letter published in JAMA Network Open.

Dr. Gjyshi and colleagues distributed the anonymous survey to 3,851 United States–based radiation oncologists registered with the American Society for Radiation Oncology (ASTRO). In total, 487 members (12.6%) completed the survey.

After analysis, the researchers found that 72% of respondents regularly offered PCI to patients before the publication of the study by Takahashi et al., while only 44% do so currently (difference, 28%; 95% confidence interval, 25%-31%; P less than .001).

With respect to radiation oncologists in private versus academic settings, no significant difference in practice patterns was observed (P = .71).

“Regression analysis showed no difference in likelihood of offering PCI based on practice setting, location, or size; volume of patients treated for lung cancer; or years in practice,” the researchers wrote.

In respondents unaware of the Takahashi et al. study, 85% continued to propose PCI, which was greater than those aware of the trial (odds ratio, 0.11; 95% CI, 0.04-0.32; P less than .001).

The researchers acknowledged a key limitation of the study was that radiation oncologists familiar with the study by Dr. Takahashi and colleagues may have been more apt to respond to the survey. As a result, participation bias could have influenced the results.

“These results highlight the continued lack of consensus for PCI in SCLC and support ongoing investigations,” they concluded.

No funding sources were reported. One co-author reported financial affiliations with Novocure, Inc. The other authors reported no conflicts of interest.

SOURCE: Gjyshi O et al. JAMA Netw Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9135.

A nationwide survey of radiation oncologists showed a decline in the use of prophylactic cranial irradiation (PCI) for extensive-stage small cell lung cancer (ES-SCLC) after the release of phase 3 study results by Takahashi et al.

The recent study by Toshiaki Takahashi, MD, and colleagues (Lancet Oncol. 2017;18[5]:663-71) demonstrated no overall survival benefit when comparing active magnetic resonance imaging surveillance with PCI in patients with ES-SCLC. The results challenged the formerly accepted belief of the benefit of PCI for patients with ES-SCLC.

“We conducted a nationwide survey study of radiation oncologists to assess changes in the use of PCI for patients with ES-SCLC following publication of the trial by Takahashi et al.,” wrote Olsi Gjyshi, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. The findings were reported in a research letter published in JAMA Network Open.

Dr. Gjyshi and colleagues distributed the anonymous survey to 3,851 United States–based radiation oncologists registered with the American Society for Radiation Oncology (ASTRO). In total, 487 members (12.6%) completed the survey.

After analysis, the researchers found that 72% of respondents regularly offered PCI to patients before the publication of the study by Takahashi et al., while only 44% do so currently (difference, 28%; 95% confidence interval, 25%-31%; P less than .001).

With respect to radiation oncologists in private versus academic settings, no significant difference in practice patterns was observed (P = .71).

“Regression analysis showed no difference in likelihood of offering PCI based on practice setting, location, or size; volume of patients treated for lung cancer; or years in practice,” the researchers wrote.

In respondents unaware of the Takahashi et al. study, 85% continued to propose PCI, which was greater than those aware of the trial (odds ratio, 0.11; 95% CI, 0.04-0.32; P less than .001).

The researchers acknowledged a key limitation of the study was that radiation oncologists familiar with the study by Dr. Takahashi and colleagues may have been more apt to respond to the survey. As a result, participation bias could have influenced the results.

“These results highlight the continued lack of consensus for PCI in SCLC and support ongoing investigations,” they concluded.

No funding sources were reported. One co-author reported financial affiliations with Novocure, Inc. The other authors reported no conflicts of interest.

SOURCE: Gjyshi O et al. JAMA Netw Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9135.

Key clinical point: Data do not support an association between vaccination and increased risk of MS.

Major finding: The odds of MS were lower in participants who received vaccination, compared with participants without autoimmune disease (odds ratio, 0.870).

Study details: A systematic retrospective analysis of claims data for 12,262 patients with MS and 210,773 controls.

Disclosures: A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no relevant conflicts.

Citation: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.

Key clinical point: Data do not support an association between vaccination and increased risk of MS.

Major finding: The odds of MS were lower in participants who received vaccination, compared with participants without autoimmune disease (odds ratio, 0.870).

Study details: A systematic retrospective analysis of claims data for 12,262 patients with MS and 210,773 controls.

Disclosures: A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no relevant conflicts.

Citation: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.

Key clinical point: Data do not support an association between vaccination and increased risk of MS.

Major finding: The odds of MS were lower in participants who received vaccination, compared with participants without autoimmune disease (odds ratio, 0.870).

Study details: A systematic retrospective analysis of claims data for 12,262 patients with MS and 210,773 controls.

Disclosures: A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no relevant conflicts.

Citation: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.

Key clinical point: Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment.

Major finding: Mean Symbol Digit Modalities Test score was 49.0 in patients without a black hole and 42.9 in patients with at least one black hole.

Study details: A prospective study of 226 patients with MS.

Disclosures: The investigators had no disclosures and conducted their study without financial support.

Citation: Özakbas S et al. CMSC 2019, Abstract IMG02.

Key clinical point: Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment.

Major finding: Mean Symbol Digit Modalities Test score was 49.0 in patients without a black hole and 42.9 in patients with at least one black hole.

Study details: A prospective study of 226 patients with MS.

Disclosures: The investigators had no disclosures and conducted their study without financial support.

Citation: Özakbas S et al. CMSC 2019, Abstract IMG02.

Key clinical point: Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment.

Major finding: Mean Symbol Digit Modalities Test score was 49.0 in patients without a black hole and 42.9 in patients with at least one black hole.

Study details: A prospective study of 226 patients with MS.

Disclosures: The investigators had no disclosures and conducted their study without financial support.

Citation: Özakbas S et al. CMSC 2019, Abstract IMG02.

Key clinical point: Neutrophil levels may decline in patients with relapsing multiple sclerosis (MS) who have been on fingolimod for 2 or more years.

Major finding: In a cohort of patients continuously treated with fingolimod for at least 2 years, neutrophils declined over 6 months by about 9%, from an average of 3,698.56 cells per microliter to 3,336.13 cells per microliter.

Study details: Analysis of interim, 6-month data from the ongoing, open-label, phase 4 FLUENT study, which is a 12-month, prospective, multicenter, nonrandomized study to assess changes in the immune cell profiles of patients with relapsing MS who receive fingolimod. The interim results include data from 216 treatment-experienced patients and 166 treatment-naive patients.

Disclosures: Novartis funded the study, and four of the authors are Novartis employees. Dr. Cree disclosed consulting fees from Novartis and other pharmaceutical companies. His coauthors disclosed consulting fees, speaking fees, research support, and serving on advisory boards for pharmaceutical companies, including Novartis.

Citation: Mao-Draayer Y et al. CMSC 2019, Abstract DXM03.

Key clinical point: Neutrophil levels may decline in patients with relapsing multiple sclerosis (MS) who have been on fingolimod for 2 or more years.

Major finding: In a cohort of patients continuously treated with fingolimod for at least 2 years, neutrophils declined over 6 months by about 9%, from an average of 3,698.56 cells per microliter to 3,336.13 cells per microliter.

Study details: Analysis of interim, 6-month data from the ongoing, open-label, phase 4 FLUENT study, which is a 12-month, prospective, multicenter, nonrandomized study to assess changes in the immune cell profiles of patients with relapsing MS who receive fingolimod. The interim results include data from 216 treatment-experienced patients and 166 treatment-naive patients.

Disclosures: Novartis funded the study, and four of the authors are Novartis employees. Dr. Cree disclosed consulting fees from Novartis and other pharmaceutical companies. His coauthors disclosed consulting fees, speaking fees, research support, and serving on advisory boards for pharmaceutical companies, including Novartis.

Citation: Mao-Draayer Y et al. CMSC 2019, Abstract DXM03.

Key clinical point: Neutrophil levels may decline in patients with relapsing multiple sclerosis (MS) who have been on fingolimod for 2 or more years.

Major finding: In a cohort of patients continuously treated with fingolimod for at least 2 years, neutrophils declined over 6 months by about 9%, from an average of 3,698.56 cells per microliter to 3,336.13 cells per microliter.

Study details: Analysis of interim, 6-month data from the ongoing, open-label, phase 4 FLUENT study, which is a 12-month, prospective, multicenter, nonrandomized study to assess changes in the immune cell profiles of patients with relapsing MS who receive fingolimod. The interim results include data from 216 treatment-experienced patients and 166 treatment-naive patients.

Disclosures: Novartis funded the study, and four of the authors are Novartis employees. Dr. Cree disclosed consulting fees from Novartis and other pharmaceutical companies. His coauthors disclosed consulting fees, speaking fees, research support, and serving on advisory boards for pharmaceutical companies, including Novartis.

Citation: Mao-Draayer Y et al. CMSC 2019, Abstract DXM03.

The timing for adjuvant treatment following surgery for pancreatic cancer appears to have a sweet spot associated with the best survival outcomes, according to a study published in JAMA Network Open.

Researchers analyzed data from the National Cancer Database for 7,548 patients with stage I-II resected pancreatic cancer, 5,453 of whom had received adjuvant therapy and 2,095 who did not.

“While the benefit of adjuvant therapy to patients with resected pancreatic cancer is accepted, its optimal timing after surgery remains under investigation,” wrote Sung Jun Ma, MD, from the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and coauthors.

After a median overall follow-up of 38.6 months, they found the lowest mortality risk was in the reference cohort of patients who started adjuvant therapy 28-59 days after surgery. In comparison, patients who received early adjuvant therapy – within 28 days of surgery – had a 17% higher mortality (P = .03), and those who received adjuvant therapy late – 59 days or more after surgery – had a 9% higher mortality (P = .008)

The overall survival rate at 2 years was 45.2% for the early adjuvant therapy cohort and 52.5% for the reference cohort.

Despite the higher mortality among the early adjuvant therapy cohort, patients treated with adjuvant therapy more than 12 weeks after surgery still showed improved survival, compared with patient treated with surgery alone, particular those with node-positive disease.

“To our knowledge, it is the first study to suggest that patients who commence adjuvant therapy within 28-59 days after primary surgical resection of pancreatic adenocarcinoma have improved survival outcomes compared with those who waited for more than 59 days,” the authors wrote. “However, patients who recover slowly from surgery may still benefit from delayed adjuvant therapy initiated more than 12 weeks after surgery.”

No treatment interactions were seen for other variables such as age, comorbidity score, tumor size, pathologic T stages, surgical margin, duration of postoperative inpatient admission, unplanned readmission within 30 days after surgery, and time from diagnosis to surgery.

The analysis also revealed that patients with a primary tumor at the pancreatic body and tail and those receiving multiagent chemotherapy or radiation therapy were less likely to receive delayed adjuvant therapy, However, older or black patients, those with lower income, with postoperative inpatient admission longer than 1 week or with unplanned readmission within 30 days after surgery were more likely to have delayed initiation of adjuvant therapy.

No conflicts of interest were reported.

SOURCE: Ma SJ et al. JAMA Netw Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126.

The timing for adjuvant treatment following surgery for pancreatic cancer appears to have a sweet spot associated with the best survival outcomes, according to a study published in JAMA Network Open.

Researchers analyzed data from the National Cancer Database for 7,548 patients with stage I-II resected pancreatic cancer, 5,453 of whom had received adjuvant therapy and 2,095 who did not.

“While the benefit of adjuvant therapy to patients with resected pancreatic cancer is accepted, its optimal timing after surgery remains under investigation,” wrote Sung Jun Ma, MD, from the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and coauthors.

After a median overall follow-up of 38.6 months, they found the lowest mortality risk was in the reference cohort of patients who started adjuvant therapy 28-59 days after surgery. In comparison, patients who received early adjuvant therapy – within 28 days of surgery – had a 17% higher mortality (P = .03), and those who received adjuvant therapy late – 59 days or more after surgery – had a 9% higher mortality (P = .008)

The overall survival rate at 2 years was 45.2% for the early adjuvant therapy cohort and 52.5% for the reference cohort.

Despite the higher mortality among the early adjuvant therapy cohort, patients treated with adjuvant therapy more than 12 weeks after surgery still showed improved survival, compared with patient treated with surgery alone, particular those with node-positive disease.

“To our knowledge, it is the first study to suggest that patients who commence adjuvant therapy within 28-59 days after primary surgical resection of pancreatic adenocarcinoma have improved survival outcomes compared with those who waited for more than 59 days,” the authors wrote. “However, patients who recover slowly from surgery may still benefit from delayed adjuvant therapy initiated more than 12 weeks after surgery.”

No treatment interactions were seen for other variables such as age, comorbidity score, tumor size, pathologic T stages, surgical margin, duration of postoperative inpatient admission, unplanned readmission within 30 days after surgery, and time from diagnosis to surgery.

The analysis also revealed that patients with a primary tumor at the pancreatic body and tail and those receiving multiagent chemotherapy or radiation therapy were less likely to receive delayed adjuvant therapy, However, older or black patients, those with lower income, with postoperative inpatient admission longer than 1 week or with unplanned readmission within 30 days after surgery were more likely to have delayed initiation of adjuvant therapy.

No conflicts of interest were reported.

SOURCE: Ma SJ et al. JAMA Netw Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126.

The timing for adjuvant treatment following surgery for pancreatic cancer appears to have a sweet spot associated with the best survival outcomes, according to a study published in JAMA Network Open.

Researchers analyzed data from the National Cancer Database for 7,548 patients with stage I-II resected pancreatic cancer, 5,453 of whom had received adjuvant therapy and 2,095 who did not.

“While the benefit of adjuvant therapy to patients with resected pancreatic cancer is accepted, its optimal timing after surgery remains under investigation,” wrote Sung Jun Ma, MD, from the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and coauthors.

After a median overall follow-up of 38.6 months, they found the lowest mortality risk was in the reference cohort of patients who started adjuvant therapy 28-59 days after surgery. In comparison, patients who received early adjuvant therapy – within 28 days of surgery – had a 17% higher mortality (P = .03), and those who received adjuvant therapy late – 59 days or more after surgery – had a 9% higher mortality (P = .008)

The overall survival rate at 2 years was 45.2% for the early adjuvant therapy cohort and 52.5% for the reference cohort.

Despite the higher mortality among the early adjuvant therapy cohort, patients treated with adjuvant therapy more than 12 weeks after surgery still showed improved survival, compared with patient treated with surgery alone, particular those with node-positive disease.

“To our knowledge, it is the first study to suggest that patients who commence adjuvant therapy within 28-59 days after primary surgical resection of pancreatic adenocarcinoma have improved survival outcomes compared with those who waited for more than 59 days,” the authors wrote. “However, patients who recover slowly from surgery may still benefit from delayed adjuvant therapy initiated more than 12 weeks after surgery.”

No treatment interactions were seen for other variables such as age, comorbidity score, tumor size, pathologic T stages, surgical margin, duration of postoperative inpatient admission, unplanned readmission within 30 days after surgery, and time from diagnosis to surgery.

The analysis also revealed that patients with a primary tumor at the pancreatic body and tail and those receiving multiagent chemotherapy or radiation therapy were less likely to receive delayed adjuvant therapy, However, older or black patients, those with lower income, with postoperative inpatient admission longer than 1 week or with unplanned readmission within 30 days after surgery were more likely to have delayed initiation of adjuvant therapy.

No conflicts of interest were reported.

SOURCE: Ma SJ et al. JAMA Netw Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126.

The long-term benefit of adjuvant tamoxifen in lower-risk early breast cancer hinges on intrinsic molecular subtype, finds a secondary analysis of the Stockholm Tamoxifen (STO-3) trial.

“Patients with estrogen receptor (ER)–positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood,” noted the investigators, who conducted the research under senior investigator Linda Lindström, MSc, PhD, department of biosciences and nutrition, Karolinska Institutet, Stockholm.

The STO-3 trial spanned 1976 to 1990 and randomized postmenopausal patients with lymph node–negative breast cancer to receive at least 2 years of adjuvant tamoxifen or no endocrine therapy.

Dr. Lindström and coinvestigators used immunohistochemistry and Agilent microarrays to define tumor molecular subtype. Analyses were based on 462 patients with ER-positive disease: 336 with luminal A subtype tumors and 126 with luminal B subtype tumors.

Results reported in JAMA Oncology showed that the distant recurrence–free interval (DRFI) was significantly better with tamoxifen than with no endocrine therapy in both the luminal A group (P less than .001) and the luminal B group (P = .04).

Among patients given tamoxifen, the 25-year DRFI rate was 87% (95% confidence interval, 82%-93%) for those with luminal A tumors vs. 67% (95% CI, 56%-82%) for those with luminal B tumors. Among patients not given any endocrine therapy, it was 70% (95% CI, 62%-79%) vs. 54% (95% CI, 42%-70%), respectively.

Tamoxifen had a significant DRFI benefit for 15 years after diagnosis in the luminal A group (hazard ratio, 0.57; 95% CI, 0.35-0.94). In contrast, the benefit was significant for only 5 years in the luminal B group (HR, 0.38; 95% CI, 0.24-0.59).

“We conclude that tamoxifen appears to confer a long-term benefit for patients with lymph node–negative, ER-positive, luminal A subtype tumors, and a short-term benefit for patients with luminal B subtype tumors. Given that the risk of distant metastatic disease is low for patients with the luminal A subtype but persists in the long term, whereas the risk for patients with luminal B subtype is higher initially but decreases after 5 years, tamoxifen treatment is beneficial for patients with luminal A or luminal B subtype tumors,” Dr. Lindström and coinvestigators maintained.

“In patients with luminal B subtype, up-front chemotherapy should be discussed and endocrine therapy potentially extended for up to 10 years, particularly in those in the higher risk strata according to other tumor characteristics,” they recommended.

Dr. Lindström disclosed no conflicts of interest. The study was supported by the Swedish Research Council, FORTE, The Gösta Milton Donation Fund, the California Breast Cancer Research Program, The Iris, Stig och Gerry Castenbäcks Stiftelse för Cancerforskning, and Konung Gustaf V:s Jubileumsfond from Radiumhemmets Forskningsfonder.

SOURCE: Yu NY et al. JAMA Oncol. 2019 Aug 8. doi: 10.1001/jamaoncol.2019.1856.

The long-term benefit of adjuvant tamoxifen in lower-risk early breast cancer hinges on intrinsic molecular subtype, finds a secondary analysis of the Stockholm Tamoxifen (STO-3) trial.

“Patients with estrogen receptor (ER)–positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood,” noted the investigators, who conducted the research under senior investigator Linda Lindström, MSc, PhD, department of biosciences and nutrition, Karolinska Institutet, Stockholm.

The STO-3 trial spanned 1976 to 1990 and randomized postmenopausal patients with lymph node–negative breast cancer to receive at least 2 years of adjuvant tamoxifen or no endocrine therapy.

Dr. Lindström and coinvestigators used immunohistochemistry and Agilent microarrays to define tumor molecular subtype. Analyses were based on 462 patients with ER-positive disease: 336 with luminal A subtype tumors and 126 with luminal B subtype tumors.

Results reported in JAMA Oncology showed that the distant recurrence–free interval (DRFI) was significantly better with tamoxifen than with no endocrine therapy in both the luminal A group (P less than .001) and the luminal B group (P = .04).

Among patients given tamoxifen, the 25-year DRFI rate was 87% (95% confidence interval, 82%-93%) for those with luminal A tumors vs. 67% (95% CI, 56%-82%) for those with luminal B tumors. Among patients not given any endocrine therapy, it was 70% (95% CI, 62%-79%) vs. 54% (95% CI, 42%-70%), respectively.

Tamoxifen had a significant DRFI benefit for 15 years after diagnosis in the luminal A group (hazard ratio, 0.57; 95% CI, 0.35-0.94). In contrast, the benefit was significant for only 5 years in the luminal B group (HR, 0.38; 95% CI, 0.24-0.59).

“We conclude that tamoxifen appears to confer a long-term benefit for patients with lymph node–negative, ER-positive, luminal A subtype tumors, and a short-term benefit for patients with luminal B subtype tumors. Given that the risk of distant metastatic disease is low for patients with the luminal A subtype but persists in the long term, whereas the risk for patients with luminal B subtype is higher initially but decreases after 5 years, tamoxifen treatment is beneficial for patients with luminal A or luminal B subtype tumors,” Dr. Lindström and coinvestigators maintained.

“In patients with luminal B subtype, up-front chemotherapy should be discussed and endocrine therapy potentially extended for up to 10 years, particularly in those in the higher risk strata according to other tumor characteristics,” they recommended.

Dr. Lindström disclosed no conflicts of interest. The study was supported by the Swedish Research Council, FORTE, The Gösta Milton Donation Fund, the California Breast Cancer Research Program, The Iris, Stig och Gerry Castenbäcks Stiftelse för Cancerforskning, and Konung Gustaf V:s Jubileumsfond from Radiumhemmets Forskningsfonder.

SOURCE: Yu NY et al. JAMA Oncol. 2019 Aug 8. doi: 10.1001/jamaoncol.2019.1856.

The long-term benefit of adjuvant tamoxifen in lower-risk early breast cancer hinges on intrinsic molecular subtype, finds a secondary analysis of the Stockholm Tamoxifen (STO-3) trial.

“Patients with estrogen receptor (ER)–positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood,” noted the investigators, who conducted the research under senior investigator Linda Lindström, MSc, PhD, department of biosciences and nutrition, Karolinska Institutet, Stockholm.

The STO-3 trial spanned 1976 to 1990 and randomized postmenopausal patients with lymph node–negative breast cancer to receive at least 2 years of adjuvant tamoxifen or no endocrine therapy.

Dr. Lindström and coinvestigators used immunohistochemistry and Agilent microarrays to define tumor molecular subtype. Analyses were based on 462 patients with ER-positive disease: 336 with luminal A subtype tumors and 126 with luminal B subtype tumors.

Results reported in JAMA Oncology showed that the distant recurrence–free interval (DRFI) was significantly better with tamoxifen than with no endocrine therapy in both the luminal A group (P less than .001) and the luminal B group (P = .04).

Among patients given tamoxifen, the 25-year DRFI rate was 87% (95% confidence interval, 82%-93%) for those with luminal A tumors vs. 67% (95% CI, 56%-82%) for those with luminal B tumors. Among patients not given any endocrine therapy, it was 70% (95% CI, 62%-79%) vs. 54% (95% CI, 42%-70%), respectively.

Tamoxifen had a significant DRFI benefit for 15 years after diagnosis in the luminal A group (hazard ratio, 0.57; 95% CI, 0.35-0.94). In contrast, the benefit was significant for only 5 years in the luminal B group (HR, 0.38; 95% CI, 0.24-0.59).

“We conclude that tamoxifen appears to confer a long-term benefit for patients with lymph node–negative, ER-positive, luminal A subtype tumors, and a short-term benefit for patients with luminal B subtype tumors. Given that the risk of distant metastatic disease is low for patients with the luminal A subtype but persists in the long term, whereas the risk for patients with luminal B subtype is higher initially but decreases after 5 years, tamoxifen treatment is beneficial for patients with luminal A or luminal B subtype tumors,” Dr. Lindström and coinvestigators maintained.

“In patients with luminal B subtype, up-front chemotherapy should be discussed and endocrine therapy potentially extended for up to 10 years, particularly in those in the higher risk strata according to other tumor characteristics,” they recommended.

Dr. Lindström disclosed no conflicts of interest. The study was supported by the Swedish Research Council, FORTE, The Gösta Milton Donation Fund, the California Breast Cancer Research Program, The Iris, Stig och Gerry Castenbäcks Stiftelse för Cancerforskning, and Konung Gustaf V:s Jubileumsfond from Radiumhemmets Forskningsfonder.

SOURCE: Yu NY et al. JAMA Oncol. 2019 Aug 8. doi: 10.1001/jamaoncol.2019.1856.

Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.¹ Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT₃ receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in a commentary published in 2013.

Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.¹ Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.

There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).²

A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).³ No cases of cleft palate were reported among exposed cases in that study.

In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.⁴ The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (Fejzo et al. 2016 Jul;62:87-91; Einarson et al. 2004Aug 23. doi: 10.1111/j.1471-0528.2004.00236.x).

Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no conflicts of interest to disclose related to this column.

References:

1. Taylor LG et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017 May;26(5):592-6.

2. Anderka M et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):22-30.

3. Danielsson B et al. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7.

4. Pasternak B et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.

Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.¹ Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT₃ receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in a commentary published in 2013.

Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.¹ Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.

There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).²

A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).³ No cases of cleft palate were reported among exposed cases in that study.

In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.⁴ The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (Fejzo et al. 2016 Jul;62:87-91; Einarson et al. 2004Aug 23. doi: 10.1111/j.1471-0528.2004.00236.x).

Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no conflicts of interest to disclose related to this column.

References:

1. Taylor LG et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017 May;26(5):592-6.

2. Anderka M et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):22-30.

3. Danielsson B et al. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7.

4. Pasternak B et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.

Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.¹ Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT₃ receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in a commentary published in 2013.

Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.¹ Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.

There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).²

A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).³ No cases of cleft palate were reported among exposed cases in that study.

In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.⁴ The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (Fejzo et al. 2016 Jul;62:87-91; Einarson et al. 2004Aug 23. doi: 10.1111/j.1471-0528.2004.00236.x).

Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no conflicts of interest to disclose related to this column.

References:

1. Taylor LG et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017 May;26(5):592-6.

2. Anderka M et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):22-30.

3. Danielsson B et al. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7.

4. Pasternak B et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.

The Diagnosis: Nodular Kaposi Sarcoma 

Epidemic Kaposi sarcoma (KS) primarily affects patients with human immunodeficiency virus (HIV) infection. Kaposi sarcoma can appear as brown, red, or blue-black macules, plaques, patches, nodules, or tumors, and it often is observed as multifocal cutaneous lesions located on the head, neck, and upper aspects of the trunk in a fulminant manner. Kaposi sarcoma portends a poor prognosis and is an AIDS-defining malignancy.^1-3 Importantly, antiretroviral therapy does not preclude its consideration in those without AIDS-defining CD4 cell counts and undetectable HIV viremia presenting with cutaneous manifestations.^2,3 A retrospective review by Daly et al⁴ reported KS lesions in patients with CD4 lymphocyte counts greater than 300 cells/µL, most of whom were antiretroviral therapy-naïve patients. Also, those with higher CD4 counts tended to have a solitary KS lesion at presentation, while those with CD4 counts less than 300 cells/µL tended to present with multiple foci.⁴ Epidemic KS lesions are clinically indistinguishable from other common cutaneous conditions in the differential diagnosis of KS, necessitating biopsy for histopathologic examination. Light microscopy findings help to delineate the diagnosis of KS. Immunohistochemical staining to the latent nuclear antigen 1 of human herpesvirus 8 (HHV-8) confirms the KS diagnosis.^5,6 Our patient's presentation as a solitary acral lesion was atypical for KS.  

Light microscopy of our patient's biopsy demonstrated a large tumor on the acral surface of the right hand. Dermal collections of basophilic spindled cells clustered with small slitlike vascular spaces with abundant erythrocyte extravasation and numerous large ectatic vessels at the periphery were seen (Figure, A). At higher magnification, interlaced bundles of spindle cells with slitlike vessels with scattered lymphocytes and plasma cells were seen (Figure, B). An immunohistochemical stain for HHV-8 was positive and largely confined to spindle cells (Figure, C). These findings confirmed KS and met AIDS-defining criteria. Awareness of these histopathologic features is key in differentiating KS from other conditions in the differential diagnosis.  

The patient's history of late latent syphilis coinfected with HIV and persistently elevated rapid plasma reagin that was recalcitrant to therapy placed an atypical nodular presentation within reason for the differential diagnosis. Deviations from the typical papulosquamous presentation with acral involvement in an immunocompromised patient mandates a consideration for syphilis with an atypical presentation. Atypical presentations include nodular, annular, pustular, lues maligna, frambesiform, corymbose, and photosensitive distributions.^7,8 Notably, coinfection with HIV modifies the clinical presentation, serology, and efficacy of treatment.^7-10 Atypical presentations are more common in coinfected HIV-positive patients, mandating a high degree of suspicion. Nodular secondary syphilis and the noduloulcerative form (lues maligna) often spare the palmar and plantar surfaces, and patients often have constitutional symptoms accompanying the cutaneous eruptions. In questionable cases, a biopsy lends clarification. Light microscopy on hematoxylin and eosin (H&E) staining may display acanthosis, superficial and deep perivascular swelling, plasma, histiocyte infiltrates, dermoepidermal junction changes, mixed patterns, epidermal hyperplasia, and dermal vascular thickening.^7-9,11 Spirochetes may be observed on Warthin-Starry stain; however, artifact obscuration from melanin granules and reticular fibers or paucity of organisms can make identification difficult. Immunohistochemical staining may prove useful when H&E stains are atypical or have a paucity of organisms or plasma cells or when silver stains have artifactual obscuration.⁹ Our patient's solitary palmar lesion without constitutional symptoms made an atypical nodular secondary syphilis presentation less likely. Ultimately, the histopathologic findings were consistent with KS.  

Bacillary angiomatosis (BA) is caused by Bartonella species and results in vascular proliferation with cutaneous manifestation. It frequently is observed in patients with HIV or other immunosuppressive conditions as well as patients with exposure to mammals or their vectors. Protean cutaneous manifestations and distributions of BA exist. The number of lesions can be singular to thousands. Solitary superficial pyogenic granuloma-like lesions can be clinically indistinguishable from both KS and pyogenic granuloma (PG). Superficial lesions often begin as red, violaceous, or flesh-colored papules that hemorrhage easily with trauma. The morphology of the papule can progress to be exophytic with dome-shaped or ulcerative surface features and is rubbery on palpation.¹² Biopsy is required to differentiate BA from KS. Bacillary angiomatosis on light microscopy with H&E shows protuberant, lobulated, round vessels with plump endothelial cells with or without necrosis. A neutrophil infiltrate in close proximity to bacilli may be noted. Warthin-Starry stain demonstrates numerous bacilli juxtaposed to these endothelial cells. The lack of immunohistochemical staining for HHV-8 also differentiates BA from KS.^12,13  

Pyogenic granuloma is resultant from proliferation of endothelial cells with a lobular architecture. Pyogenic granulomas are benign, rapidly progressive, acquired lesions presenting in the skin and mucous membranes. Pyogenic granuloma often presents as a single painless papule or nodule with a glistening red-violaceous color that occasionally appears with a perilesional collarette. The lesions are friable and easily hemorrhage. Pyogenic granuloma has been associated with local skin trauma and estrogen hormones. Histopathologic examination of PG assists with differentiation from other nodular lesions. Light microscopy with standard H&E staining demonstrates a network of capillaries arranged into a lobule surrounded by a fibrous matrix. Endothelial cells appear round and protrude into the vascular lamina. Mitotic activity is increased. Lack of findings on Warthin-Starry stain assists with differentiating PG from BA, while the microscopy architecture and immunohistochemical staining differentiates PG from KS.^6,13,14 

Squamous cell carcinoma (SCC) is the primary malignant cancer of the hand. The dorsal aspect of the hand is the most common location; SCC less commonly is located on the palmar surface, fingers, nail bed, or intertriginous areas.^15-17 Chakrabarti et al¹⁶ found that these lesions were invasive SCC when located on the palmar surface. Morphologically, SCC takes an exophytic papular, nodular, or scaly appearance with a red to flesh-colored appearance and poor demarcation of the borders. Progression to large ulcerated or secondarily infected lesions also can occur. The inflammatory reaction may cause tenderness to palpation and hemorrhage with trauma. Histopathologic examination of invasive SCC reveals atypical keratinocytes violating the basement membrane and abundant cytoplasm. Our patient's clinical presentation placed invasive SCC low on the differential diagnosis, and the histopathologic and immunohistochemical results eliminated SCC as the diagnosis. 

The Diagnosis: Nodular Kaposi Sarcoma 

Epidemic Kaposi sarcoma (KS) primarily affects patients with human immunodeficiency virus (HIV) infection. Kaposi sarcoma can appear as brown, red, or blue-black macules, plaques, patches, nodules, or tumors, and it often is observed as multifocal cutaneous lesions located on the head, neck, and upper aspects of the trunk in a fulminant manner. Kaposi sarcoma portends a poor prognosis and is an AIDS-defining malignancy.^1-3 Importantly, antiretroviral therapy does not preclude its consideration in those without AIDS-defining CD4 cell counts and undetectable HIV viremia presenting with cutaneous manifestations.^2,3 A retrospective review by Daly et al⁴ reported KS lesions in patients with CD4 lymphocyte counts greater than 300 cells/µL, most of whom were antiretroviral therapy-naïve patients. Also, those with higher CD4 counts tended to have a solitary KS lesion at presentation, while those with CD4 counts less than 300 cells/µL tended to present with multiple foci.⁴ Epidemic KS lesions are clinically indistinguishable from other common cutaneous conditions in the differential diagnosis of KS, necessitating biopsy for histopathologic examination. Light microscopy findings help to delineate the diagnosis of KS. Immunohistochemical staining to the latent nuclear antigen 1 of human herpesvirus 8 (HHV-8) confirms the KS diagnosis.^5,6 Our patient's presentation as a solitary acral lesion was atypical for KS.  

Light microscopy of our patient's biopsy demonstrated a large tumor on the acral surface of the right hand. Dermal collections of basophilic spindled cells clustered with small slitlike vascular spaces with abundant erythrocyte extravasation and numerous large ectatic vessels at the periphery were seen (Figure, A). At higher magnification, interlaced bundles of spindle cells with slitlike vessels with scattered lymphocytes and plasma cells were seen (Figure, B). An immunohistochemical stain for HHV-8 was positive and largely confined to spindle cells (Figure, C). These findings confirmed KS and met AIDS-defining criteria. Awareness of these histopathologic features is key in differentiating KS from other conditions in the differential diagnosis.  

The patient's history of late latent syphilis coinfected with HIV and persistently elevated rapid plasma reagin that was recalcitrant to therapy placed an atypical nodular presentation within reason for the differential diagnosis. Deviations from the typical papulosquamous presentation with acral involvement in an immunocompromised patient mandates a consideration for syphilis with an atypical presentation. Atypical presentations include nodular, annular, pustular, lues maligna, frambesiform, corymbose, and photosensitive distributions.^7,8 Notably, coinfection with HIV modifies the clinical presentation, serology, and efficacy of treatment.^7-10 Atypical presentations are more common in coinfected HIV-positive patients, mandating a high degree of suspicion. Nodular secondary syphilis and the noduloulcerative form (lues maligna) often spare the palmar and plantar surfaces, and patients often have constitutional symptoms accompanying the cutaneous eruptions. In questionable cases, a biopsy lends clarification. Light microscopy on hematoxylin and eosin (H&E) staining may display acanthosis, superficial and deep perivascular swelling, plasma, histiocyte infiltrates, dermoepidermal junction changes, mixed patterns, epidermal hyperplasia, and dermal vascular thickening.^7-9,11 Spirochetes may be observed on Warthin-Starry stain; however, artifact obscuration from melanin granules and reticular fibers or paucity of organisms can make identification difficult. Immunohistochemical staining may prove useful when H&E stains are atypical or have a paucity of organisms or plasma cells or when silver stains have artifactual obscuration.⁹ Our patient's solitary palmar lesion without constitutional symptoms made an atypical nodular secondary syphilis presentation less likely. Ultimately, the histopathologic findings were consistent with KS.  

Bacillary angiomatosis (BA) is caused by Bartonella species and results in vascular proliferation with cutaneous manifestation. It frequently is observed in patients with HIV or other immunosuppressive conditions as well as patients with exposure to mammals or their vectors. Protean cutaneous manifestations and distributions of BA exist. The number of lesions can be singular to thousands. Solitary superficial pyogenic granuloma-like lesions can be clinically indistinguishable from both KS and pyogenic granuloma (PG). Superficial lesions often begin as red, violaceous, or flesh-colored papules that hemorrhage easily with trauma. The morphology of the papule can progress to be exophytic with dome-shaped or ulcerative surface features and is rubbery on palpation.¹² Biopsy is required to differentiate BA from KS. Bacillary angiomatosis on light microscopy with H&E shows protuberant, lobulated, round vessels with plump endothelial cells with or without necrosis. A neutrophil infiltrate in close proximity to bacilli may be noted. Warthin-Starry stain demonstrates numerous bacilli juxtaposed to these endothelial cells. The lack of immunohistochemical staining for HHV-8 also differentiates BA from KS.^12,13  

Pyogenic granuloma is resultant from proliferation of endothelial cells with a lobular architecture. Pyogenic granulomas are benign, rapidly progressive, acquired lesions presenting in the skin and mucous membranes. Pyogenic granuloma often presents as a single painless papule or nodule with a glistening red-violaceous color that occasionally appears with a perilesional collarette. The lesions are friable and easily hemorrhage. Pyogenic granuloma has been associated with local skin trauma and estrogen hormones. Histopathologic examination of PG assists with differentiation from other nodular lesions. Light microscopy with standard H&E staining demonstrates a network of capillaries arranged into a lobule surrounded by a fibrous matrix. Endothelial cells appear round and protrude into the vascular lamina. Mitotic activity is increased. Lack of findings on Warthin-Starry stain assists with differentiating PG from BA, while the microscopy architecture and immunohistochemical staining differentiates PG from KS.^6,13,14 

Squamous cell carcinoma (SCC) is the primary malignant cancer of the hand. The dorsal aspect of the hand is the most common location; SCC less commonly is located on the palmar surface, fingers, nail bed, or intertriginous areas.^15-17 Chakrabarti et al¹⁶ found that these lesions were invasive SCC when located on the palmar surface. Morphologically, SCC takes an exophytic papular, nodular, or scaly appearance with a red to flesh-colored appearance and poor demarcation of the borders. Progression to large ulcerated or secondarily infected lesions also can occur. The inflammatory reaction may cause tenderness to palpation and hemorrhage with trauma. Histopathologic examination of invasive SCC reveals atypical keratinocytes violating the basement membrane and abundant cytoplasm. Our patient's clinical presentation placed invasive SCC low on the differential diagnosis, and the histopathologic and immunohistochemical results eliminated SCC as the diagnosis. 

The Diagnosis: Nodular Kaposi Sarcoma 

Epidemic Kaposi sarcoma (KS) primarily affects patients with human immunodeficiency virus (HIV) infection. Kaposi sarcoma can appear as brown, red, or blue-black macules, plaques, patches, nodules, or tumors, and it often is observed as multifocal cutaneous lesions located on the head, neck, and upper aspects of the trunk in a fulminant manner. Kaposi sarcoma portends a poor prognosis and is an AIDS-defining malignancy.^1-3 Importantly, antiretroviral therapy does not preclude its consideration in those without AIDS-defining CD4 cell counts and undetectable HIV viremia presenting with cutaneous manifestations.^2,3 A retrospective review by Daly et al⁴ reported KS lesions in patients with CD4 lymphocyte counts greater than 300 cells/µL, most of whom were antiretroviral therapy-naïve patients. Also, those with higher CD4 counts tended to have a solitary KS lesion at presentation, while those with CD4 counts less than 300 cells/µL tended to present with multiple foci.⁴ Epidemic KS lesions are clinically indistinguishable from other common cutaneous conditions in the differential diagnosis of KS, necessitating biopsy for histopathologic examination. Light microscopy findings help to delineate the diagnosis of KS. Immunohistochemical staining to the latent nuclear antigen 1 of human herpesvirus 8 (HHV-8) confirms the KS diagnosis.^5,6 Our patient's presentation as a solitary acral lesion was atypical for KS.  

Light microscopy of our patient's biopsy demonstrated a large tumor on the acral surface of the right hand. Dermal collections of basophilic spindled cells clustered with small slitlike vascular spaces with abundant erythrocyte extravasation and numerous large ectatic vessels at the periphery were seen (Figure, A). At higher magnification, interlaced bundles of spindle cells with slitlike vessels with scattered lymphocytes and plasma cells were seen (Figure, B). An immunohistochemical stain for HHV-8 was positive and largely confined to spindle cells (Figure, C). These findings confirmed KS and met AIDS-defining criteria. Awareness of these histopathologic features is key in differentiating KS from other conditions in the differential diagnosis.  

The patient's history of late latent syphilis coinfected with HIV and persistently elevated rapid plasma reagin that was recalcitrant to therapy placed an atypical nodular presentation within reason for the differential diagnosis. Deviations from the typical papulosquamous presentation with acral involvement in an immunocompromised patient mandates a consideration for syphilis with an atypical presentation. Atypical presentations include nodular, annular, pustular, lues maligna, frambesiform, corymbose, and photosensitive distributions.^7,8 Notably, coinfection with HIV modifies the clinical presentation, serology, and efficacy of treatment.^7-10 Atypical presentations are more common in coinfected HIV-positive patients, mandating a high degree of suspicion. Nodular secondary syphilis and the noduloulcerative form (lues maligna) often spare the palmar and plantar surfaces, and patients often have constitutional symptoms accompanying the cutaneous eruptions. In questionable cases, a biopsy lends clarification. Light microscopy on hematoxylin and eosin (H&E) staining may display acanthosis, superficial and deep perivascular swelling, plasma, histiocyte infiltrates, dermoepidermal junction changes, mixed patterns, epidermal hyperplasia, and dermal vascular thickening.^7-9,11 Spirochetes may be observed on Warthin-Starry stain; however, artifact obscuration from melanin granules and reticular fibers or paucity of organisms can make identification difficult. Immunohistochemical staining may prove useful when H&E stains are atypical or have a paucity of organisms or plasma cells or when silver stains have artifactual obscuration.⁹ Our patient's solitary palmar lesion without constitutional symptoms made an atypical nodular secondary syphilis presentation less likely. Ultimately, the histopathologic findings were consistent with KS.  

Bacillary angiomatosis (BA) is caused by Bartonella species and results in vascular proliferation with cutaneous manifestation. It frequently is observed in patients with HIV or other immunosuppressive conditions as well as patients with exposure to mammals or their vectors. Protean cutaneous manifestations and distributions of BA exist. The number of lesions can be singular to thousands. Solitary superficial pyogenic granuloma-like lesions can be clinically indistinguishable from both KS and pyogenic granuloma (PG). Superficial lesions often begin as red, violaceous, or flesh-colored papules that hemorrhage easily with trauma. The morphology of the papule can progress to be exophytic with dome-shaped or ulcerative surface features and is rubbery on palpation.¹² Biopsy is required to differentiate BA from KS. Bacillary angiomatosis on light microscopy with H&E shows protuberant, lobulated, round vessels with plump endothelial cells with or without necrosis. A neutrophil infiltrate in close proximity to bacilli may be noted. Warthin-Starry stain demonstrates numerous bacilli juxtaposed to these endothelial cells. The lack of immunohistochemical staining for HHV-8 also differentiates BA from KS.^12,13  

Pyogenic granuloma is resultant from proliferation of endothelial cells with a lobular architecture. Pyogenic granulomas are benign, rapidly progressive, acquired lesions presenting in the skin and mucous membranes. Pyogenic granuloma often presents as a single painless papule or nodule with a glistening red-violaceous color that occasionally appears with a perilesional collarette. The lesions are friable and easily hemorrhage. Pyogenic granuloma has been associated with local skin trauma and estrogen hormones. Histopathologic examination of PG assists with differentiation from other nodular lesions. Light microscopy with standard H&E staining demonstrates a network of capillaries arranged into a lobule surrounded by a fibrous matrix. Endothelial cells appear round and protrude into the vascular lamina. Mitotic activity is increased. Lack of findings on Warthin-Starry stain assists with differentiating PG from BA, while the microscopy architecture and immunohistochemical staining differentiates PG from KS.^6,13,14 

Squamous cell carcinoma (SCC) is the primary malignant cancer of the hand. The dorsal aspect of the hand is the most common location; SCC less commonly is located on the palmar surface, fingers, nail bed, or intertriginous areas.^15-17 Chakrabarti et al¹⁶ found that these lesions were invasive SCC when located on the palmar surface. Morphologically, SCC takes an exophytic papular, nodular, or scaly appearance with a red to flesh-colored appearance and poor demarcation of the borders. Progression to large ulcerated or secondarily infected lesions also can occur. The inflammatory reaction may cause tenderness to palpation and hemorrhage with trauma. Histopathologic examination of invasive SCC reveals atypical keratinocytes violating the basement membrane and abundant cytoplasm. Our patient's clinical presentation placed invasive SCC low on the differential diagnosis, and the histopathologic and immunohistochemical results eliminated SCC as the diagnosis. 

BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.

Bruce Jancin/MDedge News

This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.

“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.

Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.


 

KDT best practice guidelines

The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).

“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.

The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.

Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).

The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
 

KDT benefits beyond seizure control

“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.

That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).

More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).

There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
 

The use of KDT in critical care settings

Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).

“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.

Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
 

The future: nonketogenic diet therapies

KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.

Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).

Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).

“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.

She reported having no financial conflicts regarding her presentation.

[email protected]

BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.

Bruce Jancin/MDedge News

This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.

“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.

Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.


 

KDT best practice guidelines

The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).

“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.

The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.

Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).

The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
 

KDT benefits beyond seizure control

“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.

That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).

More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).

There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
 

The use of KDT in critical care settings

Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).

“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.

Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
 

The future: nonketogenic diet therapies

KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.

Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).

Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).

“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.

She reported having no financial conflicts regarding her presentation.

[email protected]

BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.

Bruce Jancin/MDedge News

This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.

“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.

Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.


 

KDT best practice guidelines

The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).

“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.

The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.

Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).

The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
 

KDT benefits beyond seizure control

“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.

That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).

More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).

There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
 

The use of KDT in critical care settings

Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).

“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.

Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
 

The future: nonketogenic diet therapies

KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.

Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).

Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).

“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.

She reported having no financial conflicts regarding her presentation.

[email protected]

PHILADELPHIA – U.S. children and teens who were hospitalized because of asthma had twice the rate of migraine headache when compared with a similar pediatric population without asthma. The finding is based on an analysis of more than 11 million U.S. pediatric hospitalizations over the course of a decade.

Among children and adolescents aged 3-21 years who were hospitalized for asthma, migraine rates were significantly higher among girls, adolescents, and whites, compared with boys, children aged 12 years or younger, and nonwhites, respectively, in a trio of adjusted analyses, Riddhiben S. Patel, MD, and associates reported in a poster at the annual meeting of the American Headache Society.

“Our hope is that, by establishing an association between childhood asthma and migraine, [these children] may be more easily screened for, diagnosed, and treated early by providers,” wrote Dr. Patel, a pediatric neurologist and headache specialist at the University of Mississippi, Jackson, and associates.

Their analysis used administrative billing data collected by the Kids’ Inpatient Database, maintained by the U.S. Healthcare Cost and Utilization Project. The project includes a representative national sample of about 3 million pediatric hospital discharges every 3 years. The study used data from 11,483,103 hospitalizations of children and adolescents aged 3-21 years during 2003, 2006, 2009, and 2012, and found an overall hospitalization rate of 0.8% billed for migraine. For patients also hospitalized with a billing code for asthma, the rate jumped to 1.36%, a 120% statistically significant relative increase in migraine hospitalizations after adjustment for baseline demographic differences, the researchers said.

Among the children and adolescents hospitalized with an asthma billing code, the relative rate of also having a billing code for migraine after adjustment was a statistically significant 80% higher in girls, compared with boys, a statistically significant 7% higher in adolescents, compared with children 12 years or younger, and was significantly reduced by a relative 45% rate in nonwhites, compared with whites.

The mechanisms behind these associations are not known, but could involve mast-cell degranulation, autonomic dysfunction, or shared genetic or environmental etiologic factors, the authors said.

Dr. Patel reported no relevant disclosures.

[email protected]

SOURCE: Patel RS et al. Headache. 2019 June;59[S1]:1-208, Abstract P78.

PHILADELPHIA – U.S. children and teens who were hospitalized because of asthma had twice the rate of migraine headache when compared with a similar pediatric population without asthma. The finding is based on an analysis of more than 11 million U.S. pediatric hospitalizations over the course of a decade.

Among children and adolescents aged 3-21 years who were hospitalized for asthma, migraine rates were significantly higher among girls, adolescents, and whites, compared with boys, children aged 12 years or younger, and nonwhites, respectively, in a trio of adjusted analyses, Riddhiben S. Patel, MD, and associates reported in a poster at the annual meeting of the American Headache Society.

“Our hope is that, by establishing an association between childhood asthma and migraine, [these children] may be more easily screened for, diagnosed, and treated early by providers,” wrote Dr. Patel, a pediatric neurologist and headache specialist at the University of Mississippi, Jackson, and associates.

Their analysis used administrative billing data collected by the Kids’ Inpatient Database, maintained by the U.S. Healthcare Cost and Utilization Project. The project includes a representative national sample of about 3 million pediatric hospital discharges every 3 years. The study used data from 11,483,103 hospitalizations of children and adolescents aged 3-21 years during 2003, 2006, 2009, and 2012, and found an overall hospitalization rate of 0.8% billed for migraine. For patients also hospitalized with a billing code for asthma, the rate jumped to 1.36%, a 120% statistically significant relative increase in migraine hospitalizations after adjustment for baseline demographic differences, the researchers said.

Among the children and adolescents hospitalized with an asthma billing code, the relative rate of also having a billing code for migraine after adjustment was a statistically significant 80% higher in girls, compared with boys, a statistically significant 7% higher in adolescents, compared with children 12 years or younger, and was significantly reduced by a relative 45% rate in nonwhites, compared with whites.

The mechanisms behind these associations are not known, but could involve mast-cell degranulation, autonomic dysfunction, or shared genetic or environmental etiologic factors, the authors said.

Dr. Patel reported no relevant disclosures.

[email protected]

SOURCE: Patel RS et al. Headache. 2019 June;59[S1]:1-208, Abstract P78.

PHILADELPHIA – U.S. children and teens who were hospitalized because of asthma had twice the rate of migraine headache when compared with a similar pediatric population without asthma. The finding is based on an analysis of more than 11 million U.S. pediatric hospitalizations over the course of a decade.

Among children and adolescents aged 3-21 years who were hospitalized for asthma, migraine rates were significantly higher among girls, adolescents, and whites, compared with boys, children aged 12 years or younger, and nonwhites, respectively, in a trio of adjusted analyses, Riddhiben S. Patel, MD, and associates reported in a poster at the annual meeting of the American Headache Society.

“Our hope is that, by establishing an association between childhood asthma and migraine, [these children] may be more easily screened for, diagnosed, and treated early by providers,” wrote Dr. Patel, a pediatric neurologist and headache specialist at the University of Mississippi, Jackson, and associates.

Their analysis used administrative billing data collected by the Kids’ Inpatient Database, maintained by the U.S. Healthcare Cost and Utilization Project. The project includes a representative national sample of about 3 million pediatric hospital discharges every 3 years. The study used data from 11,483,103 hospitalizations of children and adolescents aged 3-21 years during 2003, 2006, 2009, and 2012, and found an overall hospitalization rate of 0.8% billed for migraine. For patients also hospitalized with a billing code for asthma, the rate jumped to 1.36%, a 120% statistically significant relative increase in migraine hospitalizations after adjustment for baseline demographic differences, the researchers said.

Among the children and adolescents hospitalized with an asthma billing code, the relative rate of also having a billing code for migraine after adjustment was a statistically significant 80% higher in girls, compared with boys, a statistically significant 7% higher in adolescents, compared with children 12 years or younger, and was significantly reduced by a relative 45% rate in nonwhites, compared with whites.

The mechanisms behind these associations are not known, but could involve mast-cell degranulation, autonomic dysfunction, or shared genetic or environmental etiologic factors, the authors said.

Dr. Patel reported no relevant disclosures.

[email protected]

SOURCE: Patel RS et al. Headache. 2019 June;59[S1]:1-208, Abstract P78.