Hepatocellular carcinoma (HCC) has a poor prognosis and remains an important cause of cancer-related morbidity and mortality.^1,2 Potentially curative interventions include surgical resection, radiofrequency ablation, and liver transplantation. However, the majority of patients are not eligible for these procedures because they are diagnosed at an advanced stage, when locoregional therapies are much more limited.^3,4 Although the kinase inhibitors sorafenib and lenvatinib are approved as first-line systemic treatment, at the US Department of Veterans Affairs (VA) Kansas City VA Medical Center (KCVAMC) in Missouri, nivolumab was used instead because of concerns for the tolerability of the kinase inhibitors. Locoregional therapies, resection, and transplantation options were either not appropriate or had been exhausted for these patients. The objective of this retrospective study was to determine the outcomes of those veteran patients in a small cohort.

Methods

The KCVAMC Institutional Review Board approved this retrospective chart review. Patients were selected from pharmacy records at KCVAMC. We identified all patients with a diagnosis of HCC who received nivolumab from January 2016 to December 2019. We then included only the patients that had nivolumab in the front-line setting for our final analysis. At the time of initiation of treatment, all patients were informed that immunotherapy was not approved for front-line treatment, but available evidence suggested that it would be easier to tolerate than sorafenib or lenvatinib. These patients were determined to be either ineligible for sorafenib or lenvatinib therapy or expected to tolerate it poorly, and hence they consented to the use of nivolumab. Tumor response and progression were assessed by the investigator according to iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria.⁵ Data were obtained from retrospective health record review.

Results

Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.

Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.

The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.

Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.

Discussion

Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,^6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.^8,9

Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.¹⁰ The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.¹¹ This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.¹²

The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.^11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.^13,14

Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.¹⁵

Limitations

We acknowledge several limitations to our study, such as the small number of patients and the retrospective single center nature of this study. Patients were older men with multiple psychosocial comorbitities like mental illness, substance abuse, and homelessness. This cohort may not represent the non-VA population, but is an excellent representation of a frail, real-world veteran population.

Conclusions

Despite clinical trials showing the promise of immunotherapy as an attractive front-line systemic treatment option for HCC, our results show poor outcomes in a frail real-world population. In a cohort of patients who received immunotherapy as a front-line systemic treatment for HCC, results were poor with a response rate of 14.3%, a median PFS of 4 months, and a median OS of 8 months. We noted a significantly higher number of adverse effects, including 21% incidence of grade 5 hepatotoxicity. There remains an urgent need to develop more effective and safer therapies for this patient population as well as validation from larger real-world studies.

Hepatocellular carcinoma (HCC) has a poor prognosis and remains an important cause of cancer-related morbidity and mortality.^1,2 Potentially curative interventions include surgical resection, radiofrequency ablation, and liver transplantation. However, the majority of patients are not eligible for these procedures because they are diagnosed at an advanced stage, when locoregional therapies are much more limited.^3,4 Although the kinase inhibitors sorafenib and lenvatinib are approved as first-line systemic treatment, at the US Department of Veterans Affairs (VA) Kansas City VA Medical Center (KCVAMC) in Missouri, nivolumab was used instead because of concerns for the tolerability of the kinase inhibitors. Locoregional therapies, resection, and transplantation options were either not appropriate or had been exhausted for these patients. The objective of this retrospective study was to determine the outcomes of those veteran patients in a small cohort.

Methods

The KCVAMC Institutional Review Board approved this retrospective chart review. Patients were selected from pharmacy records at KCVAMC. We identified all patients with a diagnosis of HCC who received nivolumab from January 2016 to December 2019. We then included only the patients that had nivolumab in the front-line setting for our final analysis. At the time of initiation of treatment, all patients were informed that immunotherapy was not approved for front-line treatment, but available evidence suggested that it would be easier to tolerate than sorafenib or lenvatinib. These patients were determined to be either ineligible for sorafenib or lenvatinib therapy or expected to tolerate it poorly, and hence they consented to the use of nivolumab. Tumor response and progression were assessed by the investigator according to iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria.⁵ Data were obtained from retrospective health record review.

Results

Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.

Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.

The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.

Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.

Discussion

Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,^6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.^8,9

Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.¹⁰ The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.¹¹ This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.¹²

The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.^11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.^13,14

Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.¹⁵

Limitations

We acknowledge several limitations to our study, such as the small number of patients and the retrospective single center nature of this study. Patients were older men with multiple psychosocial comorbitities like mental illness, substance abuse, and homelessness. This cohort may not represent the non-VA population, but is an excellent representation of a frail, real-world veteran population.

Conclusions

Despite clinical trials showing the promise of immunotherapy as an attractive front-line systemic treatment option for HCC, our results show poor outcomes in a frail real-world population. In a cohort of patients who received immunotherapy as a front-line systemic treatment for HCC, results were poor with a response rate of 14.3%, a median PFS of 4 months, and a median OS of 8 months. We noted a significantly higher number of adverse effects, including 21% incidence of grade 5 hepatotoxicity. There remains an urgent need to develop more effective and safer therapies for this patient population as well as validation from larger real-world studies.

Hepatocellular carcinoma (HCC) has a poor prognosis and remains an important cause of cancer-related morbidity and mortality.^1,2 Potentially curative interventions include surgical resection, radiofrequency ablation, and liver transplantation. However, the majority of patients are not eligible for these procedures because they are diagnosed at an advanced stage, when locoregional therapies are much more limited.^3,4 Although the kinase inhibitors sorafenib and lenvatinib are approved as first-line systemic treatment, at the US Department of Veterans Affairs (VA) Kansas City VA Medical Center (KCVAMC) in Missouri, nivolumab was used instead because of concerns for the tolerability of the kinase inhibitors. Locoregional therapies, resection, and transplantation options were either not appropriate or had been exhausted for these patients. The objective of this retrospective study was to determine the outcomes of those veteran patients in a small cohort.

Methods

The KCVAMC Institutional Review Board approved this retrospective chart review. Patients were selected from pharmacy records at KCVAMC. We identified all patients with a diagnosis of HCC who received nivolumab from January 2016 to December 2019. We then included only the patients that had nivolumab in the front-line setting for our final analysis. At the time of initiation of treatment, all patients were informed that immunotherapy was not approved for front-line treatment, but available evidence suggested that it would be easier to tolerate than sorafenib or lenvatinib. These patients were determined to be either ineligible for sorafenib or lenvatinib therapy or expected to tolerate it poorly, and hence they consented to the use of nivolumab. Tumor response and progression were assessed by the investigator according to iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria.⁵ Data were obtained from retrospective health record review.

Results

Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.

Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.

The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.

Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.

Discussion

Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,^6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.^8,9

Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.¹⁰ The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.¹¹ This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.¹²

The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.^11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.^13,14

Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.¹⁵

Limitations

We acknowledge several limitations to our study, such as the small number of patients and the retrospective single center nature of this study. Patients were older men with multiple psychosocial comorbitities like mental illness, substance abuse, and homelessness. This cohort may not represent the non-VA population, but is an excellent representation of a frail, real-world veteran population.

Conclusions

Despite clinical trials showing the promise of immunotherapy as an attractive front-line systemic treatment option for HCC, our results show poor outcomes in a frail real-world population. In a cohort of patients who received immunotherapy as a front-line systemic treatment for HCC, results were poor with a response rate of 14.3%, a median PFS of 4 months, and a median OS of 8 months. We noted a significantly higher number of adverse effects, including 21% incidence of grade 5 hepatotoxicity. There remains an urgent need to develop more effective and safer therapies for this patient population as well as validation from larger real-world studies.

There were more new cases of COVID-19 reported in children during the week ending Oct. 29 than any other week during the pandemic, the American Academy of Pediatrics announced Nov. 2.

For the week, over 61,000 cases were reported in children, bringing the number of COVID-19 cases for the month of October to nearly 200,000 and the total since the start of the pandemic to over 853,000, the AAP and the Children’s Hospital Association said in their weekly report.

“These numbers reflect a disturbing increase in cases throughout most of the United States in all populations, especially among young adults,” Yvonne Maldonado, MD, chair of the AAP Committee on Infectious Diseases, said in a separate statement. “We are entering a heightened wave of infections around the country. We would encourage family holiday gatherings to be avoided if possible, especially if there are high-risk individuals in the household.”

For the week ending Oct. 29, children represented 13.3% of all cases, possibly constituting a minitrend of stability over the past 3 weeks. For the full length of the pandemic, 11.1% of all COVID-19 cases have occurred in children, although severe illness is much less common: 1.7% of all hospitalizations (data from 24 states and New York City) and 0.06% of all deaths (data from 42 states and New York City), the AAP and CHA report said.

Other data show that 1,134 per 100,000 children in the United States have been infected by the coronavirus, up from 1,053 the previous week, with state rates ranging from 221 per 100,000 in Vermont to 3,321 in North Dakota. In Wyoming, 25.5% of all COVID-19 cases have occurred in children, the highest of any state, while New Jersey has the lowest rate at 4.9%, the AAP/CHA report showed.

In the 10 states making testing data available, children represent the lowest percentage of tests in Iowa (5.0%) and the highest in Indiana (16.9%). Iowa, however, has the highest positivity rate for children at 14.6%, along with Nevada, while West Virginia has the lowest at 3.6%, the AAP and CHA said in the report.

These numbers, however, may not be telling the whole story. “The number of reported COVID-19 cases in children is likely an undercount because children’s symptoms are often mild and they may not be tested for every illness,” the AAP said in its statement.

“We urge policy makers to listen to doctors and public health experts rather than level baseless accusations against them. Physicians, nurses and other health care professionals have put their lives on the line to protect our communities. We can all do our part to protect them, and our communities, by wearing masks, practicing physical distancing, and getting our flu immunizations,” AAP President Sally Goza, MD, said in the AAP statement.

[email protected]

There were more new cases of COVID-19 reported in children during the week ending Oct. 29 than any other week during the pandemic, the American Academy of Pediatrics announced Nov. 2.

For the week, over 61,000 cases were reported in children, bringing the number of COVID-19 cases for the month of October to nearly 200,000 and the total since the start of the pandemic to over 853,000, the AAP and the Children’s Hospital Association said in their weekly report.

“These numbers reflect a disturbing increase in cases throughout most of the United States in all populations, especially among young adults,” Yvonne Maldonado, MD, chair of the AAP Committee on Infectious Diseases, said in a separate statement. “We are entering a heightened wave of infections around the country. We would encourage family holiday gatherings to be avoided if possible, especially if there are high-risk individuals in the household.”

For the week ending Oct. 29, children represented 13.3% of all cases, possibly constituting a minitrend of stability over the past 3 weeks. For the full length of the pandemic, 11.1% of all COVID-19 cases have occurred in children, although severe illness is much less common: 1.7% of all hospitalizations (data from 24 states and New York City) and 0.06% of all deaths (data from 42 states and New York City), the AAP and CHA report said.

Other data show that 1,134 per 100,000 children in the United States have been infected by the coronavirus, up from 1,053 the previous week, with state rates ranging from 221 per 100,000 in Vermont to 3,321 in North Dakota. In Wyoming, 25.5% of all COVID-19 cases have occurred in children, the highest of any state, while New Jersey has the lowest rate at 4.9%, the AAP/CHA report showed.

In the 10 states making testing data available, children represent the lowest percentage of tests in Iowa (5.0%) and the highest in Indiana (16.9%). Iowa, however, has the highest positivity rate for children at 14.6%, along with Nevada, while West Virginia has the lowest at 3.6%, the AAP and CHA said in the report.

These numbers, however, may not be telling the whole story. “The number of reported COVID-19 cases in children is likely an undercount because children’s symptoms are often mild and they may not be tested for every illness,” the AAP said in its statement.

“We urge policy makers to listen to doctors and public health experts rather than level baseless accusations against them. Physicians, nurses and other health care professionals have put their lives on the line to protect our communities. We can all do our part to protect them, and our communities, by wearing masks, practicing physical distancing, and getting our flu immunizations,” AAP President Sally Goza, MD, said in the AAP statement.

[email protected]

There were more new cases of COVID-19 reported in children during the week ending Oct. 29 than any other week during the pandemic, the American Academy of Pediatrics announced Nov. 2.

For the week, over 61,000 cases were reported in children, bringing the number of COVID-19 cases for the month of October to nearly 200,000 and the total since the start of the pandemic to over 853,000, the AAP and the Children’s Hospital Association said in their weekly report.

“These numbers reflect a disturbing increase in cases throughout most of the United States in all populations, especially among young adults,” Yvonne Maldonado, MD, chair of the AAP Committee on Infectious Diseases, said in a separate statement. “We are entering a heightened wave of infections around the country. We would encourage family holiday gatherings to be avoided if possible, especially if there are high-risk individuals in the household.”

For the week ending Oct. 29, children represented 13.3% of all cases, possibly constituting a minitrend of stability over the past 3 weeks. For the full length of the pandemic, 11.1% of all COVID-19 cases have occurred in children, although severe illness is much less common: 1.7% of all hospitalizations (data from 24 states and New York City) and 0.06% of all deaths (data from 42 states and New York City), the AAP and CHA report said.

Other data show that 1,134 per 100,000 children in the United States have been infected by the coronavirus, up from 1,053 the previous week, with state rates ranging from 221 per 100,000 in Vermont to 3,321 in North Dakota. In Wyoming, 25.5% of all COVID-19 cases have occurred in children, the highest of any state, while New Jersey has the lowest rate at 4.9%, the AAP/CHA report showed.

In the 10 states making testing data available, children represent the lowest percentage of tests in Iowa (5.0%) and the highest in Indiana (16.9%). Iowa, however, has the highest positivity rate for children at 14.6%, along with Nevada, while West Virginia has the lowest at 3.6%, the AAP and CHA said in the report.

These numbers, however, may not be telling the whole story. “The number of reported COVID-19 cases in children is likely an undercount because children’s symptoms are often mild and they may not be tested for every illness,” the AAP said in its statement.

“We urge policy makers to listen to doctors and public health experts rather than level baseless accusations against them. Physicians, nurses and other health care professionals have put their lives on the line to protect our communities. We can all do our part to protect them, and our communities, by wearing masks, practicing physical distancing, and getting our flu immunizations,” AAP President Sally Goza, MD, said in the AAP statement.

[email protected]

For women who receive radiotherapy after undergoing hysterectomy for high-risk cervical cancer, image-guided intensity-modulated radiotherapy (IG-IMRT) is superior to three-dimensional conformal radiotherapy (3D-CRT) at reducing late gastrointestinal (GI) toxicity and is similarly efficacious, according to new findings.

“IG-IMRT should represent the new standard of care for postoperative pelvic radiation therapy in women with gynecological cancers,” said study lead author Supriya Chopra, MD, of the Tata Memorial Center in Mumbai, India.

She noted that the study, known as PARCER, is the first in gynecologic cancer to show the impact of advanced technology in reducing long-term morbidity and thus improving the experience of survivors.

At 4 years, rates of late GI toxicity of grade 2 or higher in the IG-IMRT and 3D-CRT arms were 19.2% and 36.2%, respectively (P = .005). Rates of toxicity of grade 3 or higher were 2.0% and 8.7%, respectively (P < .01).

Chopra presented the results at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online.

Postoperative radiotherapy is indicated for women with cervical and endometrial cancers who have high-risk features, but long-term follow-up has shown an increase in GI symptom burden and toxicity in long-term survivors after adjuvant radiotherapy.

“The uptake of IMRT has been relatively slow in gynecological cancers,” said Chopra. She explained that previous data suggested a benefit with the use of IMRT, but long-term postoperative effects were unclear.

The new data amount to a “practice-change use” of IMRT for this indication, said Sue Yom, MD, PhD, of the University of California, San Francisco, who was not involved with the study. “I see this as having potentially important future impacts on clinical practice.”

Yom explained that, although there have been studies in the United States on the use of postoperative IMRT for pelvic cancer, “this is the first phase 3 study that has shown definite long-term advantages with the use of IMRT, and I would consider it confirmatory.”

In 2015, the preliminary results of PARCER were presented at the plenary session at ASTRO. The results showed that patients treated with IG-IMRT had fewer late GI toxicities at a median follow-up of 20 months. However, the difference between groups was not statistically significant in this earlier analysis.
 

Now at 49 months’ follow-up

The study was conducted in three clinical sites of Tata Memorial Center and included a total of 300 patients with cervical cancer. The patients had undergone type III hysterectomy and had intermediate- or high-risk features, or they had undergone type I/II hysterectomy necessitating adjuvant chemoradiotherapy. They were randomly assigned to IG-IMRT (n = 151) or 3D-CRT (n = 149). Most patients (117 in the IG-IMRT arm and 114 in the 3D-CRT arm) received concurrent chemotherapy.

The primary endpoint was late GI toxicity of grade 2 or higher. Follow-up included clinical and quality-of-life evaluations, which were conducted every 3 months for 2 years and then every 6 months for years 2 to 5.

Chopra and colleagues evaluated 11 different GI-related side effects. Differences emerged over time between the two groups. Among the group that received IG-IMRT, significantly fewer patients reported moderate to severe acute diarrhea (17% in the IG-IMRT arm vs 27% in the 3D-CRT arm), late abdominal bloating (14% vs 28%), bowel obstruction (1% vs 7%), and anorexia/appetite loss (1% vs 7%).

Overall, for patients treated with IG-IMRT, grade 2 toxicity–free survival rates were significantly higher (78% with IG-IMRT vs 57% with 3D-CRT; P = .0009), as were grade 3 toxicity–free survival rates (97.6% vs 81.6%; P = .001).

As noted above, rates of disease-free survival were similar for both groups (73% with image-guided IMRT vs 68% with 3D-CRT; P = .30).

Funding for the study was provided by the Department of Science and Technology and the Department of Atomic Energy, Clinical Trials Center, in India, and by Varian International and the Terry Fox Foundation. Chopra and Yom have disclosed no relevant financial relationships.


This article first appeared on Medscape.com.

For women who receive radiotherapy after undergoing hysterectomy for high-risk cervical cancer, image-guided intensity-modulated radiotherapy (IG-IMRT) is superior to three-dimensional conformal radiotherapy (3D-CRT) at reducing late gastrointestinal (GI) toxicity and is similarly efficacious, according to new findings.

“IG-IMRT should represent the new standard of care for postoperative pelvic radiation therapy in women with gynecological cancers,” said study lead author Supriya Chopra, MD, of the Tata Memorial Center in Mumbai, India.

She noted that the study, known as PARCER, is the first in gynecologic cancer to show the impact of advanced technology in reducing long-term morbidity and thus improving the experience of survivors.

At 4 years, rates of late GI toxicity of grade 2 or higher in the IG-IMRT and 3D-CRT arms were 19.2% and 36.2%, respectively (P = .005). Rates of toxicity of grade 3 or higher were 2.0% and 8.7%, respectively (P < .01).

Chopra presented the results at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online.

Postoperative radiotherapy is indicated for women with cervical and endometrial cancers who have high-risk features, but long-term follow-up has shown an increase in GI symptom burden and toxicity in long-term survivors after adjuvant radiotherapy.

“The uptake of IMRT has been relatively slow in gynecological cancers,” said Chopra. She explained that previous data suggested a benefit with the use of IMRT, but long-term postoperative effects were unclear.

The new data amount to a “practice-change use” of IMRT for this indication, said Sue Yom, MD, PhD, of the University of California, San Francisco, who was not involved with the study. “I see this as having potentially important future impacts on clinical practice.”

Yom explained that, although there have been studies in the United States on the use of postoperative IMRT for pelvic cancer, “this is the first phase 3 study that has shown definite long-term advantages with the use of IMRT, and I would consider it confirmatory.”

In 2015, the preliminary results of PARCER were presented at the plenary session at ASTRO. The results showed that patients treated with IG-IMRT had fewer late GI toxicities at a median follow-up of 20 months. However, the difference between groups was not statistically significant in this earlier analysis.
 

Now at 49 months’ follow-up

The study was conducted in three clinical sites of Tata Memorial Center and included a total of 300 patients with cervical cancer. The patients had undergone type III hysterectomy and had intermediate- or high-risk features, or they had undergone type I/II hysterectomy necessitating adjuvant chemoradiotherapy. They were randomly assigned to IG-IMRT (n = 151) or 3D-CRT (n = 149). Most patients (117 in the IG-IMRT arm and 114 in the 3D-CRT arm) received concurrent chemotherapy.

The primary endpoint was late GI toxicity of grade 2 or higher. Follow-up included clinical and quality-of-life evaluations, which were conducted every 3 months for 2 years and then every 6 months for years 2 to 5.

Chopra and colleagues evaluated 11 different GI-related side effects. Differences emerged over time between the two groups. Among the group that received IG-IMRT, significantly fewer patients reported moderate to severe acute diarrhea (17% in the IG-IMRT arm vs 27% in the 3D-CRT arm), late abdominal bloating (14% vs 28%), bowel obstruction (1% vs 7%), and anorexia/appetite loss (1% vs 7%).

Overall, for patients treated with IG-IMRT, grade 2 toxicity–free survival rates were significantly higher (78% with IG-IMRT vs 57% with 3D-CRT; P = .0009), as were grade 3 toxicity–free survival rates (97.6% vs 81.6%; P = .001).

As noted above, rates of disease-free survival were similar for both groups (73% with image-guided IMRT vs 68% with 3D-CRT; P = .30).

Funding for the study was provided by the Department of Science and Technology and the Department of Atomic Energy, Clinical Trials Center, in India, and by Varian International and the Terry Fox Foundation. Chopra and Yom have disclosed no relevant financial relationships.


This article first appeared on Medscape.com.

For women who receive radiotherapy after undergoing hysterectomy for high-risk cervical cancer, image-guided intensity-modulated radiotherapy (IG-IMRT) is superior to three-dimensional conformal radiotherapy (3D-CRT) at reducing late gastrointestinal (GI) toxicity and is similarly efficacious, according to new findings.

“IG-IMRT should represent the new standard of care for postoperative pelvic radiation therapy in women with gynecological cancers,” said study lead author Supriya Chopra, MD, of the Tata Memorial Center in Mumbai, India.

She noted that the study, known as PARCER, is the first in gynecologic cancer to show the impact of advanced technology in reducing long-term morbidity and thus improving the experience of survivors.

At 4 years, rates of late GI toxicity of grade 2 or higher in the IG-IMRT and 3D-CRT arms were 19.2% and 36.2%, respectively (P = .005). Rates of toxicity of grade 3 or higher were 2.0% and 8.7%, respectively (P < .01).

Chopra presented the results at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online.

Postoperative radiotherapy is indicated for women with cervical and endometrial cancers who have high-risk features, but long-term follow-up has shown an increase in GI symptom burden and toxicity in long-term survivors after adjuvant radiotherapy.

“The uptake of IMRT has been relatively slow in gynecological cancers,” said Chopra. She explained that previous data suggested a benefit with the use of IMRT, but long-term postoperative effects were unclear.

The new data amount to a “practice-change use” of IMRT for this indication, said Sue Yom, MD, PhD, of the University of California, San Francisco, who was not involved with the study. “I see this as having potentially important future impacts on clinical practice.”

Yom explained that, although there have been studies in the United States on the use of postoperative IMRT for pelvic cancer, “this is the first phase 3 study that has shown definite long-term advantages with the use of IMRT, and I would consider it confirmatory.”

In 2015, the preliminary results of PARCER were presented at the plenary session at ASTRO. The results showed that patients treated with IG-IMRT had fewer late GI toxicities at a median follow-up of 20 months. However, the difference between groups was not statistically significant in this earlier analysis.
 

Now at 49 months’ follow-up

The study was conducted in three clinical sites of Tata Memorial Center and included a total of 300 patients with cervical cancer. The patients had undergone type III hysterectomy and had intermediate- or high-risk features, or they had undergone type I/II hysterectomy necessitating adjuvant chemoradiotherapy. They were randomly assigned to IG-IMRT (n = 151) or 3D-CRT (n = 149). Most patients (117 in the IG-IMRT arm and 114 in the 3D-CRT arm) received concurrent chemotherapy.

The primary endpoint was late GI toxicity of grade 2 or higher. Follow-up included clinical and quality-of-life evaluations, which were conducted every 3 months for 2 years and then every 6 months for years 2 to 5.

Chopra and colleagues evaluated 11 different GI-related side effects. Differences emerged over time between the two groups. Among the group that received IG-IMRT, significantly fewer patients reported moderate to severe acute diarrhea (17% in the IG-IMRT arm vs 27% in the 3D-CRT arm), late abdominal bloating (14% vs 28%), bowel obstruction (1% vs 7%), and anorexia/appetite loss (1% vs 7%).

Overall, for patients treated with IG-IMRT, grade 2 toxicity–free survival rates were significantly higher (78% with IG-IMRT vs 57% with 3D-CRT; P = .0009), as were grade 3 toxicity–free survival rates (97.6% vs 81.6%; P = .001).

As noted above, rates of disease-free survival were similar for both groups (73% with image-guided IMRT vs 68% with 3D-CRT; P = .30).

Funding for the study was provided by the Department of Science and Technology and the Department of Atomic Energy, Clinical Trials Center, in India, and by Varian International and the Terry Fox Foundation. Chopra and Yom have disclosed no relevant financial relationships.


This article first appeared on Medscape.com.

A gel derived from birch bark is the first topical medication ever tested in the treatment of epidermolysis bullosa (EB) to heal wounds faster than placebo. The results come from the largest double-blind, randomized trial performed in this patient population.

Dr. Dedee Murrell

More than 41% of EB target wounds that were treated with Oleogel-S10 healed within 45 days, compared with about 29% of target wounds treated with placebo, in the EASE phase 3 trial, conducted at 58 sites in 28 countries.

A group of rare genetic disorders, EB “is described as the worst disease you’ve never heard of,” explained lead investigator Dedee Murrell, MD, director of dermatology, St. George Hospital at the University of New South Wales, Sydney. “It starts in children and is like having burns that heal with scars, and no treatment has been approved for it” by the Food and Drug Administration.

“This is the first large clinical trial with placebo of a topical treatment that’s worked for this terrible disease,” Dr. Murrell said in an interview. She noted that standard EB treatment currently consists of applying nonstick dressings to wounds to protect skin from trauma and infection.

Dr. Murrell, who has focused her work on EB patients since 1990, presented the findings at the virtual annual Congress of the European Academy of Dermatology and Venereology.

The trial enrolled 223 patients (average age, 12 years, but ages ranged to 81 years) with three types of EB, including dystrophic and junctional EB and Kindler syndrome. For each participant, a target wound was selected for use as the primary efficacy endpoint. Those wounds had a partial thickness of between 10 cm² and 50 cm² and lasted between 21 days and 9 months. Patients were stratified into groups depending on type of EB and size of target wound.

Participants were randomly assigned to receive either Oleogel-S10 (n = 109) or placebo (n = 114). All applied the blinded-study gel to all their wounds at least every 4 days at the time dressings were changed.

The primary endpoint was the percentage of patients whose target wounds completely closed within 45 days. Key secondary endpoints included time to wound healing and percentage of target wounds that healed within 90 days of treatment; incidence and severity of target wound infection; change in total body wound burden, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index skin activity subscore; change in itching, as measured by the Itch Man Scale and the Leuven Itch Scale; and adverse events.

Nearly 92% of patients who were treated with Oleogel-S10 completed the double-blind phase of the trial, compared with nearly 87% who received placebo. As noted, the primary endpoint was met, with 41.3% of Oleogel-S10 patients achieving target wound closure within 45 days, compared with 28.9% of the patients who received placebo (P = .013).

But the difference in time to wound healing by day 90 between the two patient groups was not statistically significant (P = .302), with 50.5% of Oleogel-S10 patients achieving wound closure vs. 43.9% of control patients.

Target-wound infection occurred in eight participants, including three who used Oleogel-S10 and five who received placebo; all moderate or severe infections occurred in patients who received placebo. Total wound burden was reduced to a greater extent among Oleogel-S10 patients by day 60, but there was no apparent difference at day 90.

Both treatment groups reported qualitative improvements in itch, with no significant differences between groups. The prevalence of adverse events was also similar between groups (Oleogel-S10, 81.7%; placebo, 80.7%). The most frequently reported adverse events among Oleogel-S10 patients, compared with patients who received placebo, were wound complications, pyrexia, wound infection, pruritus, and anemia; only 4.5% of adverse events were deemed severe.

Dr. Murrell said that, on the basis of the trial results, she expects the FDA to fast-track approval of Oleogel-S10, which contains triterpene extract and sunflower oil.

The gel is “a treatment patients will be able to put under their dressings, added to normal treatment, which will accelerate their wound healing, with no significant increase in any side effects,” she added.

Jemima Mellerio, MD, of St. Thomas’ Hospital in London who sees about 400 EB patients each year, agreed with Dr. Murrell that the results are “very exciting.” Dr. Mellerio was not involved in the study.

“Practicing dermatologists seeing people with EB will have something to offer that appears to speed up wound healing in chronic wounds,” Dr. Mellerio said in an interview. “It’s a positive option rather than just supportive treatment, something that makes a difference to the natural history of wounds.”

She said the trial’s biggest strength was including “such a large cohort of patients.

“It’s extremely difficult to do that kind of study, especially with a placebo-controlled arm and especially in a rare disease,” Dr. Mellerio said. “If you think about the product itself, it’s easy to apply, so it’s not particularly onerous for people to add to their daily regimen of dressings.”

The study was funded by Amryt Pharma. Dr. Murrell is an advisory board member for Amryt Pharma. Dr. Mellerio is a consultant for Amryt Pharma.

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

A gel derived from birch bark is the first topical medication ever tested in the treatment of epidermolysis bullosa (EB) to heal wounds faster than placebo. The results come from the largest double-blind, randomized trial performed in this patient population.

Dr. Dedee Murrell

More than 41% of EB target wounds that were treated with Oleogel-S10 healed within 45 days, compared with about 29% of target wounds treated with placebo, in the EASE phase 3 trial, conducted at 58 sites in 28 countries.

A group of rare genetic disorders, EB “is described as the worst disease you’ve never heard of,” explained lead investigator Dedee Murrell, MD, director of dermatology, St. George Hospital at the University of New South Wales, Sydney. “It starts in children and is like having burns that heal with scars, and no treatment has been approved for it” by the Food and Drug Administration.

“This is the first large clinical trial with placebo of a topical treatment that’s worked for this terrible disease,” Dr. Murrell said in an interview. She noted that standard EB treatment currently consists of applying nonstick dressings to wounds to protect skin from trauma and infection.

Dr. Murrell, who has focused her work on EB patients since 1990, presented the findings at the virtual annual Congress of the European Academy of Dermatology and Venereology.

The trial enrolled 223 patients (average age, 12 years, but ages ranged to 81 years) with three types of EB, including dystrophic and junctional EB and Kindler syndrome. For each participant, a target wound was selected for use as the primary efficacy endpoint. Those wounds had a partial thickness of between 10 cm² and 50 cm² and lasted between 21 days and 9 months. Patients were stratified into groups depending on type of EB and size of target wound.

Participants were randomly assigned to receive either Oleogel-S10 (n = 109) or placebo (n = 114). All applied the blinded-study gel to all their wounds at least every 4 days at the time dressings were changed.

The primary endpoint was the percentage of patients whose target wounds completely closed within 45 days. Key secondary endpoints included time to wound healing and percentage of target wounds that healed within 90 days of treatment; incidence and severity of target wound infection; change in total body wound burden, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index skin activity subscore; change in itching, as measured by the Itch Man Scale and the Leuven Itch Scale; and adverse events.

Nearly 92% of patients who were treated with Oleogel-S10 completed the double-blind phase of the trial, compared with nearly 87% who received placebo. As noted, the primary endpoint was met, with 41.3% of Oleogel-S10 patients achieving target wound closure within 45 days, compared with 28.9% of the patients who received placebo (P = .013).

But the difference in time to wound healing by day 90 between the two patient groups was not statistically significant (P = .302), with 50.5% of Oleogel-S10 patients achieving wound closure vs. 43.9% of control patients.

Target-wound infection occurred in eight participants, including three who used Oleogel-S10 and five who received placebo; all moderate or severe infections occurred in patients who received placebo. Total wound burden was reduced to a greater extent among Oleogel-S10 patients by day 60, but there was no apparent difference at day 90.

Both treatment groups reported qualitative improvements in itch, with no significant differences between groups. The prevalence of adverse events was also similar between groups (Oleogel-S10, 81.7%; placebo, 80.7%). The most frequently reported adverse events among Oleogel-S10 patients, compared with patients who received placebo, were wound complications, pyrexia, wound infection, pruritus, and anemia; only 4.5% of adverse events were deemed severe.

Dr. Murrell said that, on the basis of the trial results, she expects the FDA to fast-track approval of Oleogel-S10, which contains triterpene extract and sunflower oil.

The gel is “a treatment patients will be able to put under their dressings, added to normal treatment, which will accelerate their wound healing, with no significant increase in any side effects,” she added.

Jemima Mellerio, MD, of St. Thomas’ Hospital in London who sees about 400 EB patients each year, agreed with Dr. Murrell that the results are “very exciting.” Dr. Mellerio was not involved in the study.

“Practicing dermatologists seeing people with EB will have something to offer that appears to speed up wound healing in chronic wounds,” Dr. Mellerio said in an interview. “It’s a positive option rather than just supportive treatment, something that makes a difference to the natural history of wounds.”

She said the trial’s biggest strength was including “such a large cohort of patients.

“It’s extremely difficult to do that kind of study, especially with a placebo-controlled arm and especially in a rare disease,” Dr. Mellerio said. “If you think about the product itself, it’s easy to apply, so it’s not particularly onerous for people to add to their daily regimen of dressings.”

The study was funded by Amryt Pharma. Dr. Murrell is an advisory board member for Amryt Pharma. Dr. Mellerio is a consultant for Amryt Pharma.

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

A gel derived from birch bark is the first topical medication ever tested in the treatment of epidermolysis bullosa (EB) to heal wounds faster than placebo. The results come from the largest double-blind, randomized trial performed in this patient population.

Dr. Dedee Murrell

More than 41% of EB target wounds that were treated with Oleogel-S10 healed within 45 days, compared with about 29% of target wounds treated with placebo, in the EASE phase 3 trial, conducted at 58 sites in 28 countries.

A group of rare genetic disorders, EB “is described as the worst disease you’ve never heard of,” explained lead investigator Dedee Murrell, MD, director of dermatology, St. George Hospital at the University of New South Wales, Sydney. “It starts in children and is like having burns that heal with scars, and no treatment has been approved for it” by the Food and Drug Administration.

“This is the first large clinical trial with placebo of a topical treatment that’s worked for this terrible disease,” Dr. Murrell said in an interview. She noted that standard EB treatment currently consists of applying nonstick dressings to wounds to protect skin from trauma and infection.

Dr. Murrell, who has focused her work on EB patients since 1990, presented the findings at the virtual annual Congress of the European Academy of Dermatology and Venereology.

The trial enrolled 223 patients (average age, 12 years, but ages ranged to 81 years) with three types of EB, including dystrophic and junctional EB and Kindler syndrome. For each participant, a target wound was selected for use as the primary efficacy endpoint. Those wounds had a partial thickness of between 10 cm² and 50 cm² and lasted between 21 days and 9 months. Patients were stratified into groups depending on type of EB and size of target wound.

Participants were randomly assigned to receive either Oleogel-S10 (n = 109) or placebo (n = 114). All applied the blinded-study gel to all their wounds at least every 4 days at the time dressings were changed.

The primary endpoint was the percentage of patients whose target wounds completely closed within 45 days. Key secondary endpoints included time to wound healing and percentage of target wounds that healed within 90 days of treatment; incidence and severity of target wound infection; change in total body wound burden, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index skin activity subscore; change in itching, as measured by the Itch Man Scale and the Leuven Itch Scale; and adverse events.

Nearly 92% of patients who were treated with Oleogel-S10 completed the double-blind phase of the trial, compared with nearly 87% who received placebo. As noted, the primary endpoint was met, with 41.3% of Oleogel-S10 patients achieving target wound closure within 45 days, compared with 28.9% of the patients who received placebo (P = .013).

But the difference in time to wound healing by day 90 between the two patient groups was not statistically significant (P = .302), with 50.5% of Oleogel-S10 patients achieving wound closure vs. 43.9% of control patients.

Target-wound infection occurred in eight participants, including three who used Oleogel-S10 and five who received placebo; all moderate or severe infections occurred in patients who received placebo. Total wound burden was reduced to a greater extent among Oleogel-S10 patients by day 60, but there was no apparent difference at day 90.

Both treatment groups reported qualitative improvements in itch, with no significant differences between groups. The prevalence of adverse events was also similar between groups (Oleogel-S10, 81.7%; placebo, 80.7%). The most frequently reported adverse events among Oleogel-S10 patients, compared with patients who received placebo, were wound complications, pyrexia, wound infection, pruritus, and anemia; only 4.5% of adverse events were deemed severe.

Dr. Murrell said that, on the basis of the trial results, she expects the FDA to fast-track approval of Oleogel-S10, which contains triterpene extract and sunflower oil.

The gel is “a treatment patients will be able to put under their dressings, added to normal treatment, which will accelerate their wound healing, with no significant increase in any side effects,” she added.

Jemima Mellerio, MD, of St. Thomas’ Hospital in London who sees about 400 EB patients each year, agreed with Dr. Murrell that the results are “very exciting.” Dr. Mellerio was not involved in the study.

“Practicing dermatologists seeing people with EB will have something to offer that appears to speed up wound healing in chronic wounds,” Dr. Mellerio said in an interview. “It’s a positive option rather than just supportive treatment, something that makes a difference to the natural history of wounds.”

She said the trial’s biggest strength was including “such a large cohort of patients.

“It’s extremely difficult to do that kind of study, especially with a placebo-controlled arm and especially in a rare disease,” Dr. Mellerio said. “If you think about the product itself, it’s easy to apply, so it’s not particularly onerous for people to add to their daily regimen of dressings.”

The study was funded by Amryt Pharma. Dr. Murrell is an advisory board member for Amryt Pharma. Dr. Mellerio is a consultant for Amryt Pharma.

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

Background: AMA discharges are common (1%-2% of all U.S. discharges) and disproportionately affect vulnerable patient populations, specifically those of lower socioeconomic status and the uninsured. Previous studies have been insufficiently powered to assess the effects of AMA discharge on 30-day readmission rates at a national level.

Patients who were discharged AMA had almost 20 times the odds of undergoing repeat AMA discharge at readmission (OR, 18.41; 95% CI, 17.46-19.41; P less than .001) and twice the odds of presenting to a different hospital (OR, 2.35; 95% CI, 2.22-2.49; P less than .001). The study did not capture readmissions in a different state than that of the index hospital and was limited to the 22 states participating in the 2014 Readmissions Database.

Bottom line: Discharge AMA is associated with significantly higher odds of 30-day readmission, subsequent AMA discharge and presentation to another hospital, compared with routine discharge.

Citation: Kumar N. Burden of 30-day readmissions associated with discharge against medical advice among inpatients in the United States. Am J Med. 2019 Jun;132(6):708-17.

Dr. Webber is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.

Background: AMA discharges are common (1%-2% of all U.S. discharges) and disproportionately affect vulnerable patient populations, specifically those of lower socioeconomic status and the uninsured. Previous studies have been insufficiently powered to assess the effects of AMA discharge on 30-day readmission rates at a national level.

Patients who were discharged AMA had almost 20 times the odds of undergoing repeat AMA discharge at readmission (OR, 18.41; 95% CI, 17.46-19.41; P less than .001) and twice the odds of presenting to a different hospital (OR, 2.35; 95% CI, 2.22-2.49; P less than .001). The study did not capture readmissions in a different state than that of the index hospital and was limited to the 22 states participating in the 2014 Readmissions Database.

Bottom line: Discharge AMA is associated with significantly higher odds of 30-day readmission, subsequent AMA discharge and presentation to another hospital, compared with routine discharge.

Citation: Kumar N. Burden of 30-day readmissions associated with discharge against medical advice among inpatients in the United States. Am J Med. 2019 Jun;132(6):708-17.

Dr. Webber is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.

Background: AMA discharges are common (1%-2% of all U.S. discharges) and disproportionately affect vulnerable patient populations, specifically those of lower socioeconomic status and the uninsured. Previous studies have been insufficiently powered to assess the effects of AMA discharge on 30-day readmission rates at a national level.

Patients who were discharged AMA had almost 20 times the odds of undergoing repeat AMA discharge at readmission (OR, 18.41; 95% CI, 17.46-19.41; P less than .001) and twice the odds of presenting to a different hospital (OR, 2.35; 95% CI, 2.22-2.49; P less than .001). The study did not capture readmissions in a different state than that of the index hospital and was limited to the 22 states participating in the 2014 Readmissions Database.

Bottom line: Discharge AMA is associated with significantly higher odds of 30-day readmission, subsequent AMA discharge and presentation to another hospital, compared with routine discharge.

Citation: Kumar N. Burden of 30-day readmissions associated with discharge against medical advice among inpatients in the United States. Am J Med. 2019 Jun;132(6):708-17.

Dr. Webber is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.

Antibiotics may not significantly improve clinical outcomes in patients with colon ischemia (CI), regardless of severity level, based on a retrospective study involving more than 800 patients.

Given these findings, clinicians “should consider not giving antibiotics to patients with CI,” reported lead author Paul Feuerstadt, MD, of Yale University, New Haven , Conn., and colleagues.

“CI is the most common ischemic injury to the GI tract,” the investigators wrote in their abstract, which was presented at the annual meeting of the American College of Gastroenterology. “The clinical utility of antibiotic treatment in CI is unclear and the literature is limited.”

Dr. Feuerstadt and colleagues analyzed data from 838 patients with biopsy-proven CI who were hospitalized between 2005 and 2017, of whom 413 and 425 had moderate and severe disease, respectively.

Across all patients, 67.7% received antibiotics. While there were no significant intergroup differences in age, Charlson Comorbidity Index, or sex, patients who received antibiotics were more likely to have severe CI (54.4% vs. 42.2%; P = .001), small-bowel involvement (12.0% vs. 5.7%; P = .04), and peritonitis (11.3% vs. 4.5%; P = 002), as well as require intensive care (26.1% vs. 19.9%; P = .04).

After adjusting for severity of CI, small-bowel involvement, and comorbidities, analysis revealed no significant associations between antibiotic use and 30-day mortality, 90-day mortality, 30-day colectomy, 90-day recurrence, 90-day readmission, or length of stay. The primary outcome, 30-day mortality, remained insignificant in subgroup analyses based on CI severity and age.

Patients were most frequently prescribed ciprofloxacin-metronidazole (57.1%), followed by piperacillin-tazobactam (13.2%), ceftriaxone-metronidazole (11.1%), and other antibiotics (18.5%).

When each of these antimicrobials was compared with no antibiotic usage, only piperacillin-tazobactam correlated with a higher rate of 30-day mortality, based on an adjusted odds ratio of 3.4 (95% CI, 1.5-8.0; P = .0003). But most patients who received piperacillin-tazobactam underwent colectomy, which prompted independent analyses of patients who underwent colectomy and those who did not undergo colectomy. These findings showed no difference in 30-day mortality based on the type of antibiotic used.

During an oral presentation at the meeting, coauthor Karthik Gnanapandithan, MD, of the Mayo Clinic in Jacksonville, Fla, said, “In practice, it is reasonable to still use antibiotics in patients with small bowel ischemia and those with severe CI with a high risk of poor outcomes pending prospective studies.”

According to John F. Valentine, MD, of the University of Utah, Salt Lake City, the present study “adds to the literature that questions the role of antibiotics in CI.”

Dr. Valentine noted that, even among patients with CI who have severe inflammation, “sepsis rarely occurs without frank perforation.”

Still, like Dr. Gnanapandithan, Dr. Valentine concluded that antibiotics are still a reasonable treatment option for certain patients with CI.

“The risks and potential benefits of antibiotics must be considered,” he said. “Until prospective studies are available, use of antibiotics in colon ischemia is reasonable in the setting of severe disease with peritoneal signs, signs of sepsis, pneumatosis, or portal venous gas.”

Dr. Feuerstadt disclosed relationships with Ferring/Rebiotix, Merck, and Roche. Dr. Valentine reported no relevant conflicts of interest.

Antibiotics may not significantly improve clinical outcomes in patients with colon ischemia (CI), regardless of severity level, based on a retrospective study involving more than 800 patients.

Given these findings, clinicians “should consider not giving antibiotics to patients with CI,” reported lead author Paul Feuerstadt, MD, of Yale University, New Haven , Conn., and colleagues.

“CI is the most common ischemic injury to the GI tract,” the investigators wrote in their abstract, which was presented at the annual meeting of the American College of Gastroenterology. “The clinical utility of antibiotic treatment in CI is unclear and the literature is limited.”

Dr. Feuerstadt and colleagues analyzed data from 838 patients with biopsy-proven CI who were hospitalized between 2005 and 2017, of whom 413 and 425 had moderate and severe disease, respectively.

Across all patients, 67.7% received antibiotics. While there were no significant intergroup differences in age, Charlson Comorbidity Index, or sex, patients who received antibiotics were more likely to have severe CI (54.4% vs. 42.2%; P = .001), small-bowel involvement (12.0% vs. 5.7%; P = .04), and peritonitis (11.3% vs. 4.5%; P = 002), as well as require intensive care (26.1% vs. 19.9%; P = .04).

After adjusting for severity of CI, small-bowel involvement, and comorbidities, analysis revealed no significant associations between antibiotic use and 30-day mortality, 90-day mortality, 30-day colectomy, 90-day recurrence, 90-day readmission, or length of stay. The primary outcome, 30-day mortality, remained insignificant in subgroup analyses based on CI severity and age.

Patients were most frequently prescribed ciprofloxacin-metronidazole (57.1%), followed by piperacillin-tazobactam (13.2%), ceftriaxone-metronidazole (11.1%), and other antibiotics (18.5%).

When each of these antimicrobials was compared with no antibiotic usage, only piperacillin-tazobactam correlated with a higher rate of 30-day mortality, based on an adjusted odds ratio of 3.4 (95% CI, 1.5-8.0; P = .0003). But most patients who received piperacillin-tazobactam underwent colectomy, which prompted independent analyses of patients who underwent colectomy and those who did not undergo colectomy. These findings showed no difference in 30-day mortality based on the type of antibiotic used.

During an oral presentation at the meeting, coauthor Karthik Gnanapandithan, MD, of the Mayo Clinic in Jacksonville, Fla, said, “In practice, it is reasonable to still use antibiotics in patients with small bowel ischemia and those with severe CI with a high risk of poor outcomes pending prospective studies.”

According to John F. Valentine, MD, of the University of Utah, Salt Lake City, the present study “adds to the literature that questions the role of antibiotics in CI.”

Dr. Valentine noted that, even among patients with CI who have severe inflammation, “sepsis rarely occurs without frank perforation.”

Still, like Dr. Gnanapandithan, Dr. Valentine concluded that antibiotics are still a reasonable treatment option for certain patients with CI.

“The risks and potential benefits of antibiotics must be considered,” he said. “Until prospective studies are available, use of antibiotics in colon ischemia is reasonable in the setting of severe disease with peritoneal signs, signs of sepsis, pneumatosis, or portal venous gas.”

Dr. Feuerstadt disclosed relationships with Ferring/Rebiotix, Merck, and Roche. Dr. Valentine reported no relevant conflicts of interest.

Antibiotics may not significantly improve clinical outcomes in patients with colon ischemia (CI), regardless of severity level, based on a retrospective study involving more than 800 patients.

Given these findings, clinicians “should consider not giving antibiotics to patients with CI,” reported lead author Paul Feuerstadt, MD, of Yale University, New Haven , Conn., and colleagues.

“CI is the most common ischemic injury to the GI tract,” the investigators wrote in their abstract, which was presented at the annual meeting of the American College of Gastroenterology. “The clinical utility of antibiotic treatment in CI is unclear and the literature is limited.”

Dr. Feuerstadt and colleagues analyzed data from 838 patients with biopsy-proven CI who were hospitalized between 2005 and 2017, of whom 413 and 425 had moderate and severe disease, respectively.

Across all patients, 67.7% received antibiotics. While there were no significant intergroup differences in age, Charlson Comorbidity Index, or sex, patients who received antibiotics were more likely to have severe CI (54.4% vs. 42.2%; P = .001), small-bowel involvement (12.0% vs. 5.7%; P = .04), and peritonitis (11.3% vs. 4.5%; P = 002), as well as require intensive care (26.1% vs. 19.9%; P = .04).

After adjusting for severity of CI, small-bowel involvement, and comorbidities, analysis revealed no significant associations between antibiotic use and 30-day mortality, 90-day mortality, 30-day colectomy, 90-day recurrence, 90-day readmission, or length of stay. The primary outcome, 30-day mortality, remained insignificant in subgroup analyses based on CI severity and age.

Patients were most frequently prescribed ciprofloxacin-metronidazole (57.1%), followed by piperacillin-tazobactam (13.2%), ceftriaxone-metronidazole (11.1%), and other antibiotics (18.5%).

When each of these antimicrobials was compared with no antibiotic usage, only piperacillin-tazobactam correlated with a higher rate of 30-day mortality, based on an adjusted odds ratio of 3.4 (95% CI, 1.5-8.0; P = .0003). But most patients who received piperacillin-tazobactam underwent colectomy, which prompted independent analyses of patients who underwent colectomy and those who did not undergo colectomy. These findings showed no difference in 30-day mortality based on the type of antibiotic used.

During an oral presentation at the meeting, coauthor Karthik Gnanapandithan, MD, of the Mayo Clinic in Jacksonville, Fla, said, “In practice, it is reasonable to still use antibiotics in patients with small bowel ischemia and those with severe CI with a high risk of poor outcomes pending prospective studies.”

According to John F. Valentine, MD, of the University of Utah, Salt Lake City, the present study “adds to the literature that questions the role of antibiotics in CI.”

Dr. Valentine noted that, even among patients with CI who have severe inflammation, “sepsis rarely occurs without frank perforation.”

Still, like Dr. Gnanapandithan, Dr. Valentine concluded that antibiotics are still a reasonable treatment option for certain patients with CI.

“The risks and potential benefits of antibiotics must be considered,” he said. “Until prospective studies are available, use of antibiotics in colon ischemia is reasonable in the setting of severe disease with peritoneal signs, signs of sepsis, pneumatosis, or portal venous gas.”

Dr. Feuerstadt disclosed relationships with Ferring/Rebiotix, Merck, and Roche. Dr. Valentine reported no relevant conflicts of interest.

Many female radiation oncologists find their career choice strongly influences when they start a family, and some deal with infertility and pregnancy-related discrimination, a U.S. cross-sectional survey suggests.

Courtesy MD Anderson Cancer Center

Results from the survey were reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Female radiation oncologists often spend their childbearing years in training and establishing careers,” commented lead investigator Anna Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Currently, physician fertility and family planning are rarely discussed or taught in medical school or postgraduate training,” Dr. Lee said.

Dr. Lee and colleagues conducted a national anonymous cross-sectional online survey of female oncologists of all types and all career levels (including trainees). The team circulated a 39-item questionnaire exploring attitudes toward and experiences related to family planning and assisted reproductive technology (ART) by email and social media channels.

A total of 351 radiation oncologists participated, representing one-fifth of the specialty’s entire female workforce nationally and making this study the largest to date on family planning among these physicians.

Most respondents were aged 31-40 years (60%) and married (79%), had children (68%), and were in training (26%) or academic practice (48%).
 

Survey results

Fully 74% of respondents reported that their career plans strongly influenced the timing of when to start a family, and 29% said family planning considerations influenced their decision regarding their choice of academia versus private practice, Dr. Lee reported.

Overall, 24% of respondents indicated that they had difficulty with infertility or required fertility counseling/treatment, 66% said they wished fertility preservation was discussed at some point during their training, and 22% said either that ART would have benefited them if it had been available or that they were planning to or had already used fertility preservation.

On the topic of maternity leave, some respondents reported that their institution either had no formal leave policy during training or provided less than 1 month of leave (23%) and that they felt pressure to take less time off than was policy (15%).

“Of note, 32 women in our survey were not offered non–radiation-exposing assignments during pregnancy, and an additional 57 had to specifically ask for them,” Dr. Lee remarked.

About one-third of respondents each reported that they did not feel supported during training for issues related to fertility and/or pregnancy (33%) and that they experienced discrimination for being pregnant (32%) and taking maternity leave (30%).

“Systemic changes are necessary early in medical education and training to ensure women are supported and able to advance equitably in the field. As less than a third of the current radiation oncology workforce are women, improvement upon these issues will be necessary to draw more women into the field,” Dr. Lee commented. “Education on ART risks, benefits, and success rates can help physicians and those in training in their family planning, while the lack of education and structured policy can exacerbate the emotional, physical, and financial impact of infertility.

“Until recently, there has been a dearth of policy at the programmatic, institutional, and national level allowing time and protection for pregnancy and maternity leave,” she added. “Thankfully, this summer, the American Board of Medical Specialties announced a progressive leave policy for residents and fellows.”

The new policy, which goes into effect July 2021, allows a minimum of 6 weeks away without exhausting time allowed for vacation or sick leave and without requiring an extension in training.
 

When career and biology collide

“The collision of professional and biological clocks for women in medicine is an important issue highlighted by this study,” Reshma Jagsi, MD, DPhil, of the University of Michigan in Ann Arbor, said in an interview.

“Prior work focused on women in medicine more generally. A deeper dive into the experiences of women in a specific field may be even more compelling to drive change on the part of professional societies and organizations,” Dr. Jagsi added.

The infertility rate observed in the study could have potentially been skewed by the preponderance of younger respondents (resulting in underestimation) or by greater participation of those interested in the subject (resulting in overestimation), she noted. However, it aligns well with the rate in a study Dr. Jagsi and colleagues conducted among female physicians generally using somewhat different methods. That study was published in the Journal of Women’s Health.

Concern about radiation exposure and its potential reproductive health effects should not deter women from choosing radiation oncology as a specialty, according to Dr. Jagsi.

“Radiation exposure is actually very low in radiation oncology, much lower than in specialties like interventional cardiology, where physicians are in the room where fluoroscopy is being used. It is actually an important misconception about this field that merits correction,” she stressed. “Rather, the fertility concerns are related to the expectations of training and demands of work during the prime childbearing years more generally that can lead women to delay pregnancy, which is an issue common to all medical specialties.”

“The investigators’ conclusions are very reasonable,” Dr. Jagsi said. “Although one might quibble whether the exact proportions reflect the experiences of all women in the field perfectly due to the possibility of selection bias, one cannot question whether a substantial number of women are experiencing these challenges and that they merit intervention.”

The study did not receive specific funding. Dr. Lee and Dr. Jagsi disclosed no relevant conflicts of interest.

SOURCE: Lee A et al. ASTRO 2020, Abstract LBA 6.

Many female radiation oncologists find their career choice strongly influences when they start a family, and some deal with infertility and pregnancy-related discrimination, a U.S. cross-sectional survey suggests.

Courtesy MD Anderson Cancer Center

Results from the survey were reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Female radiation oncologists often spend their childbearing years in training and establishing careers,” commented lead investigator Anna Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Currently, physician fertility and family planning are rarely discussed or taught in medical school or postgraduate training,” Dr. Lee said.

Dr. Lee and colleagues conducted a national anonymous cross-sectional online survey of female oncologists of all types and all career levels (including trainees). The team circulated a 39-item questionnaire exploring attitudes toward and experiences related to family planning and assisted reproductive technology (ART) by email and social media channels.

A total of 351 radiation oncologists participated, representing one-fifth of the specialty’s entire female workforce nationally and making this study the largest to date on family planning among these physicians.

Most respondents were aged 31-40 years (60%) and married (79%), had children (68%), and were in training (26%) or academic practice (48%).
 

Survey results

Fully 74% of respondents reported that their career plans strongly influenced the timing of when to start a family, and 29% said family planning considerations influenced their decision regarding their choice of academia versus private practice, Dr. Lee reported.

Overall, 24% of respondents indicated that they had difficulty with infertility or required fertility counseling/treatment, 66% said they wished fertility preservation was discussed at some point during their training, and 22% said either that ART would have benefited them if it had been available or that they were planning to or had already used fertility preservation.

On the topic of maternity leave, some respondents reported that their institution either had no formal leave policy during training or provided less than 1 month of leave (23%) and that they felt pressure to take less time off than was policy (15%).

“Of note, 32 women in our survey were not offered non–radiation-exposing assignments during pregnancy, and an additional 57 had to specifically ask for them,” Dr. Lee remarked.

About one-third of respondents each reported that they did not feel supported during training for issues related to fertility and/or pregnancy (33%) and that they experienced discrimination for being pregnant (32%) and taking maternity leave (30%).

“Systemic changes are necessary early in medical education and training to ensure women are supported and able to advance equitably in the field. As less than a third of the current radiation oncology workforce are women, improvement upon these issues will be necessary to draw more women into the field,” Dr. Lee commented. “Education on ART risks, benefits, and success rates can help physicians and those in training in their family planning, while the lack of education and structured policy can exacerbate the emotional, physical, and financial impact of infertility.

“Until recently, there has been a dearth of policy at the programmatic, institutional, and national level allowing time and protection for pregnancy and maternity leave,” she added. “Thankfully, this summer, the American Board of Medical Specialties announced a progressive leave policy for residents and fellows.”

The new policy, which goes into effect July 2021, allows a minimum of 6 weeks away without exhausting time allowed for vacation or sick leave and without requiring an extension in training.
 

When career and biology collide

“The collision of professional and biological clocks for women in medicine is an important issue highlighted by this study,” Reshma Jagsi, MD, DPhil, of the University of Michigan in Ann Arbor, said in an interview.

“Prior work focused on women in medicine more generally. A deeper dive into the experiences of women in a specific field may be even more compelling to drive change on the part of professional societies and organizations,” Dr. Jagsi added.

The infertility rate observed in the study could have potentially been skewed by the preponderance of younger respondents (resulting in underestimation) or by greater participation of those interested in the subject (resulting in overestimation), she noted. However, it aligns well with the rate in a study Dr. Jagsi and colleagues conducted among female physicians generally using somewhat different methods. That study was published in the Journal of Women’s Health.

Concern about radiation exposure and its potential reproductive health effects should not deter women from choosing radiation oncology as a specialty, according to Dr. Jagsi.

“Radiation exposure is actually very low in radiation oncology, much lower than in specialties like interventional cardiology, where physicians are in the room where fluoroscopy is being used. It is actually an important misconception about this field that merits correction,” she stressed. “Rather, the fertility concerns are related to the expectations of training and demands of work during the prime childbearing years more generally that can lead women to delay pregnancy, which is an issue common to all medical specialties.”

“The investigators’ conclusions are very reasonable,” Dr. Jagsi said. “Although one might quibble whether the exact proportions reflect the experiences of all women in the field perfectly due to the possibility of selection bias, one cannot question whether a substantial number of women are experiencing these challenges and that they merit intervention.”

The study did not receive specific funding. Dr. Lee and Dr. Jagsi disclosed no relevant conflicts of interest.

SOURCE: Lee A et al. ASTRO 2020, Abstract LBA 6.

Many female radiation oncologists find their career choice strongly influences when they start a family, and some deal with infertility and pregnancy-related discrimination, a U.S. cross-sectional survey suggests.

Courtesy MD Anderson Cancer Center

Results from the survey were reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Female radiation oncologists often spend their childbearing years in training and establishing careers,” commented lead investigator Anna Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Currently, physician fertility and family planning are rarely discussed or taught in medical school or postgraduate training,” Dr. Lee said.

Dr. Lee and colleagues conducted a national anonymous cross-sectional online survey of female oncologists of all types and all career levels (including trainees). The team circulated a 39-item questionnaire exploring attitudes toward and experiences related to family planning and assisted reproductive technology (ART) by email and social media channels.

A total of 351 radiation oncologists participated, representing one-fifth of the specialty’s entire female workforce nationally and making this study the largest to date on family planning among these physicians.

Most respondents were aged 31-40 years (60%) and married (79%), had children (68%), and were in training (26%) or academic practice (48%).
 

Survey results

Fully 74% of respondents reported that their career plans strongly influenced the timing of when to start a family, and 29% said family planning considerations influenced their decision regarding their choice of academia versus private practice, Dr. Lee reported.

Overall, 24% of respondents indicated that they had difficulty with infertility or required fertility counseling/treatment, 66% said they wished fertility preservation was discussed at some point during their training, and 22% said either that ART would have benefited them if it had been available or that they were planning to or had already used fertility preservation.

On the topic of maternity leave, some respondents reported that their institution either had no formal leave policy during training or provided less than 1 month of leave (23%) and that they felt pressure to take less time off than was policy (15%).

“Of note, 32 women in our survey were not offered non–radiation-exposing assignments during pregnancy, and an additional 57 had to specifically ask for them,” Dr. Lee remarked.

About one-third of respondents each reported that they did not feel supported during training for issues related to fertility and/or pregnancy (33%) and that they experienced discrimination for being pregnant (32%) and taking maternity leave (30%).

“Systemic changes are necessary early in medical education and training to ensure women are supported and able to advance equitably in the field. As less than a third of the current radiation oncology workforce are women, improvement upon these issues will be necessary to draw more women into the field,” Dr. Lee commented. “Education on ART risks, benefits, and success rates can help physicians and those in training in their family planning, while the lack of education and structured policy can exacerbate the emotional, physical, and financial impact of infertility.

“Until recently, there has been a dearth of policy at the programmatic, institutional, and national level allowing time and protection for pregnancy and maternity leave,” she added. “Thankfully, this summer, the American Board of Medical Specialties announced a progressive leave policy for residents and fellows.”

The new policy, which goes into effect July 2021, allows a minimum of 6 weeks away without exhausting time allowed for vacation or sick leave and without requiring an extension in training.
 

When career and biology collide

“The collision of professional and biological clocks for women in medicine is an important issue highlighted by this study,” Reshma Jagsi, MD, DPhil, of the University of Michigan in Ann Arbor, said in an interview.

“Prior work focused on women in medicine more generally. A deeper dive into the experiences of women in a specific field may be even more compelling to drive change on the part of professional societies and organizations,” Dr. Jagsi added.

The infertility rate observed in the study could have potentially been skewed by the preponderance of younger respondents (resulting in underestimation) or by greater participation of those interested in the subject (resulting in overestimation), she noted. However, it aligns well with the rate in a study Dr. Jagsi and colleagues conducted among female physicians generally using somewhat different methods. That study was published in the Journal of Women’s Health.

Concern about radiation exposure and its potential reproductive health effects should not deter women from choosing radiation oncology as a specialty, according to Dr. Jagsi.

“Radiation exposure is actually very low in radiation oncology, much lower than in specialties like interventional cardiology, where physicians are in the room where fluoroscopy is being used. It is actually an important misconception about this field that merits correction,” she stressed. “Rather, the fertility concerns are related to the expectations of training and demands of work during the prime childbearing years more generally that can lead women to delay pregnancy, which is an issue common to all medical specialties.”

“The investigators’ conclusions are very reasonable,” Dr. Jagsi said. “Although one might quibble whether the exact proportions reflect the experiences of all women in the field perfectly due to the possibility of selection bias, one cannot question whether a substantial number of women are experiencing these challenges and that they merit intervention.”

The study did not receive specific funding. Dr. Lee and Dr. Jagsi disclosed no relevant conflicts of interest.

SOURCE: Lee A et al. ASTRO 2020, Abstract LBA 6.

Choosing the most effective treatment for patients with obsessive-compulsive disorder requires flexibility and agility on the part of clinicians, according to Wayne K. Goodman, MD.

“There are no data at this point to suggest that one SSRI is superior to another. It’s really dealer’s choice, and it has to do with really picking medications based upon side effects,” Dr. Goodman said at the Psychopharmacology Update, presented by Current Psychiatry and Global Academy for Medical Education. Clinicians can use family history as a guide, he noted, but pharmacogenetic testing has not been helpful in his experience for selection or dosing of an SSRI.

SSRIs, such as fluvoxamine, are one of two mainstays of treatment for patients with obsessive-compulsive disorder (OCD). The other drug class is serotonin reuptake inhibitors, which include medications such clomipramine. Cognitive-behavioral therapy options, such as Exposure and Response Prevention therapy, also has some, albeit limited, efficacy.

Meanwhile, Dr. Goodman said, antidepressant classes other than SRIs and SSRIs have not been effective in treating obsessive-compulsive symptoms, and some patients do not adhere well to cognitive-behavioral therapy, said Dr. Goodman, who is the D.C. and Irene Ellwood Professor in the department of psychiatry and behavioral sciences at Baylor College of Medicine, Houston.

Choosing the most effective treatment for patients with obsessive-compulsive disorder requires flexibility and agility on the part of clinicians, according to Wayne K. Goodman, MD.

“There are no data at this point to suggest that one SSRI is superior to another. It’s really dealer’s choice, and it has to do with really picking medications based upon side effects,” Dr. Goodman said at the Psychopharmacology Update, presented by Current Psychiatry and Global Academy for Medical Education. Clinicians can use family history as a guide, he noted, but pharmacogenetic testing has not been helpful in his experience for selection or dosing of an SSRI.

SSRIs, such as fluvoxamine, are one of two mainstays of treatment for patients with obsessive-compulsive disorder (OCD). The other drug class is serotonin reuptake inhibitors, which include medications such clomipramine. Cognitive-behavioral therapy options, such as Exposure and Response Prevention therapy, also has some, albeit limited, efficacy.

Meanwhile, Dr. Goodman said, antidepressant classes other than SRIs and SSRIs have not been effective in treating obsessive-compulsive symptoms, and some patients do not adhere well to cognitive-behavioral therapy, said Dr. Goodman, who is the D.C. and Irene Ellwood Professor in the department of psychiatry and behavioral sciences at Baylor College of Medicine, Houston.

Choosing the most effective treatment for patients with obsessive-compulsive disorder requires flexibility and agility on the part of clinicians, according to Wayne K. Goodman, MD.

“There are no data at this point to suggest that one SSRI is superior to another. It’s really dealer’s choice, and it has to do with really picking medications based upon side effects,” Dr. Goodman said at the Psychopharmacology Update, presented by Current Psychiatry and Global Academy for Medical Education. Clinicians can use family history as a guide, he noted, but pharmacogenetic testing has not been helpful in his experience for selection or dosing of an SSRI.

SSRIs, such as fluvoxamine, are one of two mainstays of treatment for patients with obsessive-compulsive disorder (OCD). The other drug class is serotonin reuptake inhibitors, which include medications such clomipramine. Cognitive-behavioral therapy options, such as Exposure and Response Prevention therapy, also has some, albeit limited, efficacy.

Meanwhile, Dr. Goodman said, antidepressant classes other than SRIs and SSRIs have not been effective in treating obsessive-compulsive symptoms, and some patients do not adhere well to cognitive-behavioral therapy, said Dr. Goodman, who is the D.C. and Irene Ellwood Professor in the department of psychiatry and behavioral sciences at Baylor College of Medicine, Houston.

CASE Heart rate tracing suggests fetal distress

Ms. M. presents for elective induction of labor at 39 weeks’ gestation. During the course of her labor, a Category II fetal heart rate (FHR) tracing is noted, and maternal oxygen is administered as part of the intrauterine resuscitative efforts. Her infant ultimately was delivered vaginally with an arterial cord blood pH of 7.1 and Apgar scores of 5 and 7.

Should intrauterine resuscitation include maternal oxygen administration?

It is a common sight on labor and delivery: An FHR monitoring strip is noted to be a Category II tracing. There may be fetal tachycardia, late decelerations, or perhaps decreased variability. The nurse or physician goes to the laboring mother’s room, checks cervical dilation, changes the patient’s position, and puts an oxygen mask over her face.

The American College of Obstetricians and Gynecologists (ACOG) lists maternal oxygen administration, most commonly at 10 L/min via a nonrebreather face mask, as an intrauterine resuscitative measure for Category II or Category III FHR tracings.¹ Maternal oxygen is used to treat abnormal FHR tracings in approximately half of all births in the United States.² Despite these recommendations and the frequency of its use, however, evidence is limited that maternal oxygenation improves neonatal outcome. In fact, there is emerging evidence of potential harm.

Why use oxygen?

The use of maternal oxygen supplementation intuitively makes sense. We know that certain abnormalities in FHR tracings can signal fetal hypoxia. Left untreated, the hypoxia could lead to fetal acidemia and associated neonatal sequelae. Theoretically, the administration of maternal oxygen should lead to improved fetal oxygenation and improved fetal outcome. This is supported by studies from the 1960s that demonstrate improved FHR tracings after maternal oxygen administration.³

This idea was further supported by studies that demonstrated an increase in fetal oxygen levels when maternal oxygen is administered. Haydon and colleagues evaluated the administration of maternal oxygen in women with nonreassuring FHR tracings.⁴ Their data showed that maternal oxygen administration increased fetal oxygen as measured by fetal pulse oximetry. The lower the initial fetal oxygen levels prior to oxygen administration, the greater the increase.

Despite these findings, evidence for improved neonatal outcomes is lacking.⁵ While heart rate tracings and fetal oxygen saturation may be improved with maternal oxygen supplementation, neonatal morbidity appears to remain unchanged (FIGURE). In fact, newer research suggests potential harm. Although an improved FHR tracing may be comforting to the clinician, the end result may be less so. Given these findings on maternal oxygen supplementation, it is time to break this practice habit.

Maternal cardiovascular effects

Most of the literature on maternal hyperoxygenation focuses on fetal response. Before examining the effects on the fetus, however, we must consider the effect on the mother. Cardiovascular changes occur during and after maternal oxygen administration that should be taken into account.

McHugh and colleagues measured the hemodynamic changes in 46 pregnant and 20 nonpregnant women before, immediately, and 10 minutes after a 30-minute period of high-flow oxygen administration.⁶ While there were no changes in the nonpregnant women’s parameters, in the pregnant women heart rate and stroke volume were decreased after oxygen administration. Additionally, systemic vascular resistance increased and did not return to baseline by 10 minutes postadministration.

Since the purpose of the maternal oxygen administration is to increase oxygen to the fetus, this decrease in cardiac output and increase in systemic vascular resistance is concerning. These results may negate the intended effect of increased oxygen delivery to the fetus.

Continue to: Maternal and fetal oxidative stress...

Maternal and fetal oxidative stress

Assuming that the abnormal FHR tracing in our case patient is actually due to fetal hypoxia, it would seem prudent to increase fetal oxygenation. However, fetal hyperoxygenation may lead to free radical damage that could worsen neonatal outcomes. Oxidative stress, which can be caused by both hypoxia and hyperoxia, can lead to endothelial and cell receptor damage. This is known to contribute to the cerebral damage of hypoxic-ischemic encephalopathy.

In a randomized trial, Khaw and colleagues measured lipid peroxidases as a “free radical footprint” in women undergoing elective cesarean delivery who were administered oxygen or room air.⁷ Maternal and fetal oxygen levels were higher in the oxygen-supplementation group, but lipid peroxidases also were elevated. This finding suggests that the excess oxygen results in free radical formation and potentially negative effects on the neonate.

Although maternal oxygen supplementation frequently is viewed as harmless, this research shows that free radical damage may occur in the mother as well.

Additional research shows that longer durations of oxygen administration are correlated with worsening neonatal outcomes. In a study of liberal versus indicated oxygen use, the average time was approximately 90 minutes.⁸ Use for longer than 176 minutes was associated with lower oxygen levels in fetal blood. A proposed mechanism for this response is placental vasoconstriction thought to protect the fetus from free radical damage.

Again, if the goal is to increase oxygenation, prolonged maternal oxygen supplementation appears to produce the opposite effect.

Fetal acidemia and neonatal morbidity

If a fetus with an abnormal FHR tracing is thought to be hypoxic or acidemic, adding the potentially harmful effects of free radicals could worsen this condition. This is exactly what Raghuraman and colleagues demonstrated in a large prospective cohort analysis.⁹ While there was no difference in neonatal morbidity between those receiving oxygen and those on room air, there was a significant difference among infants with acidemia and hyperoxia. Composite morbidity (mechanical ventilation, hypothermic therapy, meconium aspiration, and death) was significantly increased in neonates with both hyperoxia and acidemia compared with nonacidemic hyperoxic infants.⁹ This is further supported by reports of an increased need for neonatal resuscitation and a fourfold increase in umbilical cord pH of less than 7.2.¹⁰

While intrauterine and extrauterine life certainly differ, these findings align with the pediatric literature that supports neonatal resuscitation with room air rather than 100% oxygen.¹¹ Additionally, the intrauterine environment is relatively hypoxic, which may make free radical damage more severe.

Continue to: Oxygen use during the COVID-19 pandemic...

While high-flow oxygen by mask is not considered an aerosol-generating procedure according to the Centers for Disease Control and Prevention, data are limited regarding the cleaning and filtering of oxygen. It is unknown if high-flow oxygen by mask increases the risk of infectious disease transmission to care providers. Therefore, in the midst of the COVID-19 pandemic, ACOG currently recommends against using supplemental oxygen for Category II and Category III tracings, since the benefits are not well established and the possibility of harm to providers may be increased.¹² Oxygen supplementation still should be used in mothers with hypoxia.

Other intrauterine resuscitation options

Maternal oxygen administration does not appear beneficial for neonatal outcomes, but other methods can be used. An intravenous fluid bolus and lateral positioning of the mother, for example, are both associated with increased fetal oxygenation. Reducing uterine activity by discontinuing oxytocin or cervical ripening agents or by administering a tocolytic also can improve FHR abnormalities. Oxygen use should be reserved for patients with maternal hypoxia.

The bottom line

The liberal use of maternal oxygenation for the management of abnormal FHR tracings should be stopped. Clear evidence of its benefit is lacking, and the real possibility of fetal and maternal harm remains. This may be especially true during the COVID-19 pandemic. ●

CASE Heart rate tracing suggests fetal distress

Ms. M. presents for elective induction of labor at 39 weeks’ gestation. During the course of her labor, a Category II fetal heart rate (FHR) tracing is noted, and maternal oxygen is administered as part of the intrauterine resuscitative efforts. Her infant ultimately was delivered vaginally with an arterial cord blood pH of 7.1 and Apgar scores of 5 and 7.

Should intrauterine resuscitation include maternal oxygen administration?

It is a common sight on labor and delivery: An FHR monitoring strip is noted to be a Category II tracing. There may be fetal tachycardia, late decelerations, or perhaps decreased variability. The nurse or physician goes to the laboring mother’s room, checks cervical dilation, changes the patient’s position, and puts an oxygen mask over her face.

The American College of Obstetricians and Gynecologists (ACOG) lists maternal oxygen administration, most commonly at 10 L/min via a nonrebreather face mask, as an intrauterine resuscitative measure for Category II or Category III FHR tracings.¹ Maternal oxygen is used to treat abnormal FHR tracings in approximately half of all births in the United States.² Despite these recommendations and the frequency of its use, however, evidence is limited that maternal oxygenation improves neonatal outcome. In fact, there is emerging evidence of potential harm.

Why use oxygen?

The use of maternal oxygen supplementation intuitively makes sense. We know that certain abnormalities in FHR tracings can signal fetal hypoxia. Left untreated, the hypoxia could lead to fetal acidemia and associated neonatal sequelae. Theoretically, the administration of maternal oxygen should lead to improved fetal oxygenation and improved fetal outcome. This is supported by studies from the 1960s that demonstrate improved FHR tracings after maternal oxygen administration.³

This idea was further supported by studies that demonstrated an increase in fetal oxygen levels when maternal oxygen is administered. Haydon and colleagues evaluated the administration of maternal oxygen in women with nonreassuring FHR tracings.⁴ Their data showed that maternal oxygen administration increased fetal oxygen as measured by fetal pulse oximetry. The lower the initial fetal oxygen levels prior to oxygen administration, the greater the increase.

Despite these findings, evidence for improved neonatal outcomes is lacking.⁵ While heart rate tracings and fetal oxygen saturation may be improved with maternal oxygen supplementation, neonatal morbidity appears to remain unchanged (FIGURE). In fact, newer research suggests potential harm. Although an improved FHR tracing may be comforting to the clinician, the end result may be less so. Given these findings on maternal oxygen supplementation, it is time to break this practice habit.

Maternal cardiovascular effects

Most of the literature on maternal hyperoxygenation focuses on fetal response. Before examining the effects on the fetus, however, we must consider the effect on the mother. Cardiovascular changes occur during and after maternal oxygen administration that should be taken into account.

McHugh and colleagues measured the hemodynamic changes in 46 pregnant and 20 nonpregnant women before, immediately, and 10 minutes after a 30-minute period of high-flow oxygen administration.⁶ While there were no changes in the nonpregnant women’s parameters, in the pregnant women heart rate and stroke volume were decreased after oxygen administration. Additionally, systemic vascular resistance increased and did not return to baseline by 10 minutes postadministration.

Since the purpose of the maternal oxygen administration is to increase oxygen to the fetus, this decrease in cardiac output and increase in systemic vascular resistance is concerning. These results may negate the intended effect of increased oxygen delivery to the fetus.

Continue to: Maternal and fetal oxidative stress...

Maternal and fetal oxidative stress

Assuming that the abnormal FHR tracing in our case patient is actually due to fetal hypoxia, it would seem prudent to increase fetal oxygenation. However, fetal hyperoxygenation may lead to free radical damage that could worsen neonatal outcomes. Oxidative stress, which can be caused by both hypoxia and hyperoxia, can lead to endothelial and cell receptor damage. This is known to contribute to the cerebral damage of hypoxic-ischemic encephalopathy.

In a randomized trial, Khaw and colleagues measured lipid peroxidases as a “free radical footprint” in women undergoing elective cesarean delivery who were administered oxygen or room air.⁷ Maternal and fetal oxygen levels were higher in the oxygen-supplementation group, but lipid peroxidases also were elevated. This finding suggests that the excess oxygen results in free radical formation and potentially negative effects on the neonate.

Although maternal oxygen supplementation frequently is viewed as harmless, this research shows that free radical damage may occur in the mother as well.

Additional research shows that longer durations of oxygen administration are correlated with worsening neonatal outcomes. In a study of liberal versus indicated oxygen use, the average time was approximately 90 minutes.⁸ Use for longer than 176 minutes was associated with lower oxygen levels in fetal blood. A proposed mechanism for this response is placental vasoconstriction thought to protect the fetus from free radical damage.

Again, if the goal is to increase oxygenation, prolonged maternal oxygen supplementation appears to produce the opposite effect.

Fetal acidemia and neonatal morbidity

If a fetus with an abnormal FHR tracing is thought to be hypoxic or acidemic, adding the potentially harmful effects of free radicals could worsen this condition. This is exactly what Raghuraman and colleagues demonstrated in a large prospective cohort analysis.⁹ While there was no difference in neonatal morbidity between those receiving oxygen and those on room air, there was a significant difference among infants with acidemia and hyperoxia. Composite morbidity (mechanical ventilation, hypothermic therapy, meconium aspiration, and death) was significantly increased in neonates with both hyperoxia and acidemia compared with nonacidemic hyperoxic infants.⁹ This is further supported by reports of an increased need for neonatal resuscitation and a fourfold increase in umbilical cord pH of less than 7.2.¹⁰

While intrauterine and extrauterine life certainly differ, these findings align with the pediatric literature that supports neonatal resuscitation with room air rather than 100% oxygen.¹¹ Additionally, the intrauterine environment is relatively hypoxic, which may make free radical damage more severe.

Continue to: Oxygen use during the COVID-19 pandemic...

While high-flow oxygen by mask is not considered an aerosol-generating procedure according to the Centers for Disease Control and Prevention, data are limited regarding the cleaning and filtering of oxygen. It is unknown if high-flow oxygen by mask increases the risk of infectious disease transmission to care providers. Therefore, in the midst of the COVID-19 pandemic, ACOG currently recommends against using supplemental oxygen for Category II and Category III tracings, since the benefits are not well established and the possibility of harm to providers may be increased.¹² Oxygen supplementation still should be used in mothers with hypoxia.

Other intrauterine resuscitation options

Maternal oxygen administration does not appear beneficial for neonatal outcomes, but other methods can be used. An intravenous fluid bolus and lateral positioning of the mother, for example, are both associated with increased fetal oxygenation. Reducing uterine activity by discontinuing oxytocin or cervical ripening agents or by administering a tocolytic also can improve FHR abnormalities. Oxygen use should be reserved for patients with maternal hypoxia.

The bottom line

The liberal use of maternal oxygenation for the management of abnormal FHR tracings should be stopped. Clear evidence of its benefit is lacking, and the real possibility of fetal and maternal harm remains. This may be especially true during the COVID-19 pandemic. ●

CASE Heart rate tracing suggests fetal distress

Ms. M. presents for elective induction of labor at 39 weeks’ gestation. During the course of her labor, a Category II fetal heart rate (FHR) tracing is noted, and maternal oxygen is administered as part of the intrauterine resuscitative efforts. Her infant ultimately was delivered vaginally with an arterial cord blood pH of 7.1 and Apgar scores of 5 and 7.

Should intrauterine resuscitation include maternal oxygen administration?

It is a common sight on labor and delivery: An FHR monitoring strip is noted to be a Category II tracing. There may be fetal tachycardia, late decelerations, or perhaps decreased variability. The nurse or physician goes to the laboring mother’s room, checks cervical dilation, changes the patient’s position, and puts an oxygen mask over her face.

The American College of Obstetricians and Gynecologists (ACOG) lists maternal oxygen administration, most commonly at 10 L/min via a nonrebreather face mask, as an intrauterine resuscitative measure for Category II or Category III FHR tracings.¹ Maternal oxygen is used to treat abnormal FHR tracings in approximately half of all births in the United States.² Despite these recommendations and the frequency of its use, however, evidence is limited that maternal oxygenation improves neonatal outcome. In fact, there is emerging evidence of potential harm.

Why use oxygen?

The use of maternal oxygen supplementation intuitively makes sense. We know that certain abnormalities in FHR tracings can signal fetal hypoxia. Left untreated, the hypoxia could lead to fetal acidemia and associated neonatal sequelae. Theoretically, the administration of maternal oxygen should lead to improved fetal oxygenation and improved fetal outcome. This is supported by studies from the 1960s that demonstrate improved FHR tracings after maternal oxygen administration.³

This idea was further supported by studies that demonstrated an increase in fetal oxygen levels when maternal oxygen is administered. Haydon and colleagues evaluated the administration of maternal oxygen in women with nonreassuring FHR tracings.⁴ Their data showed that maternal oxygen administration increased fetal oxygen as measured by fetal pulse oximetry. The lower the initial fetal oxygen levels prior to oxygen administration, the greater the increase.

Despite these findings, evidence for improved neonatal outcomes is lacking.⁵ While heart rate tracings and fetal oxygen saturation may be improved with maternal oxygen supplementation, neonatal morbidity appears to remain unchanged (FIGURE). In fact, newer research suggests potential harm. Although an improved FHR tracing may be comforting to the clinician, the end result may be less so. Given these findings on maternal oxygen supplementation, it is time to break this practice habit.

Maternal cardiovascular effects

Most of the literature on maternal hyperoxygenation focuses on fetal response. Before examining the effects on the fetus, however, we must consider the effect on the mother. Cardiovascular changes occur during and after maternal oxygen administration that should be taken into account.

McHugh and colleagues measured the hemodynamic changes in 46 pregnant and 20 nonpregnant women before, immediately, and 10 minutes after a 30-minute period of high-flow oxygen administration.⁶ While there were no changes in the nonpregnant women’s parameters, in the pregnant women heart rate and stroke volume were decreased after oxygen administration. Additionally, systemic vascular resistance increased and did not return to baseline by 10 minutes postadministration.

Since the purpose of the maternal oxygen administration is to increase oxygen to the fetus, this decrease in cardiac output and increase in systemic vascular resistance is concerning. These results may negate the intended effect of increased oxygen delivery to the fetus.

Continue to: Maternal and fetal oxidative stress...

Maternal and fetal oxidative stress

Assuming that the abnormal FHR tracing in our case patient is actually due to fetal hypoxia, it would seem prudent to increase fetal oxygenation. However, fetal hyperoxygenation may lead to free radical damage that could worsen neonatal outcomes. Oxidative stress, which can be caused by both hypoxia and hyperoxia, can lead to endothelial and cell receptor damage. This is known to contribute to the cerebral damage of hypoxic-ischemic encephalopathy.

In a randomized trial, Khaw and colleagues measured lipid peroxidases as a “free radical footprint” in women undergoing elective cesarean delivery who were administered oxygen or room air.⁷ Maternal and fetal oxygen levels were higher in the oxygen-supplementation group, but lipid peroxidases also were elevated. This finding suggests that the excess oxygen results in free radical formation and potentially negative effects on the neonate.

Although maternal oxygen supplementation frequently is viewed as harmless, this research shows that free radical damage may occur in the mother as well.

Additional research shows that longer durations of oxygen administration are correlated with worsening neonatal outcomes. In a study of liberal versus indicated oxygen use, the average time was approximately 90 minutes.⁸ Use for longer than 176 minutes was associated with lower oxygen levels in fetal blood. A proposed mechanism for this response is placental vasoconstriction thought to protect the fetus from free radical damage.

Again, if the goal is to increase oxygenation, prolonged maternal oxygen supplementation appears to produce the opposite effect.

Fetal acidemia and neonatal morbidity

If a fetus with an abnormal FHR tracing is thought to be hypoxic or acidemic, adding the potentially harmful effects of free radicals could worsen this condition. This is exactly what Raghuraman and colleagues demonstrated in a large prospective cohort analysis.⁹ While there was no difference in neonatal morbidity between those receiving oxygen and those on room air, there was a significant difference among infants with acidemia and hyperoxia. Composite morbidity (mechanical ventilation, hypothermic therapy, meconium aspiration, and death) was significantly increased in neonates with both hyperoxia and acidemia compared with nonacidemic hyperoxic infants.⁹ This is further supported by reports of an increased need for neonatal resuscitation and a fourfold increase in umbilical cord pH of less than 7.2.¹⁰

While intrauterine and extrauterine life certainly differ, these findings align with the pediatric literature that supports neonatal resuscitation with room air rather than 100% oxygen.¹¹ Additionally, the intrauterine environment is relatively hypoxic, which may make free radical damage more severe.

Continue to: Oxygen use during the COVID-19 pandemic...

While high-flow oxygen by mask is not considered an aerosol-generating procedure according to the Centers for Disease Control and Prevention, data are limited regarding the cleaning and filtering of oxygen. It is unknown if high-flow oxygen by mask increases the risk of infectious disease transmission to care providers. Therefore, in the midst of the COVID-19 pandemic, ACOG currently recommends against using supplemental oxygen for Category II and Category III tracings, since the benefits are not well established and the possibility of harm to providers may be increased.¹² Oxygen supplementation still should be used in mothers with hypoxia.

Other intrauterine resuscitation options

Maternal oxygen administration does not appear beneficial for neonatal outcomes, but other methods can be used. An intravenous fluid bolus and lateral positioning of the mother, for example, are both associated with increased fetal oxygenation. Reducing uterine activity by discontinuing oxytocin or cervical ripening agents or by administering a tocolytic also can improve FHR abnormalities. Oxygen use should be reserved for patients with maternal hypoxia.

The bottom line

The liberal use of maternal oxygenation for the management of abnormal FHR tracings should be stopped. Clear evidence of its benefit is lacking, and the real possibility of fetal and maternal harm remains. This may be especially true during the COVID-19 pandemic. ●

Chimeric antigen receptor natural killer T (CAR NKT) cells can expand in vivo and localize to tumors in patients with relapsed/refractory neuroblastoma, according to results of an ongoing phase 1 trial.

In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.

Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.

The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.

NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.

The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
 

‘A significant advance’ if confirmed

Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.

However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.

“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.

Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
 

Treatment, safety, and efficacy details

NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.

The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.

After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 10⁶ CAR NKT cells/m².

The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.

NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.

Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.

The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.

This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.

[email protected]

SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.

Chimeric antigen receptor natural killer T (CAR NKT) cells can expand in vivo and localize to tumors in patients with relapsed/refractory neuroblastoma, according to results of an ongoing phase 1 trial.

In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.

Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.

The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.

NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.

The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
 

‘A significant advance’ if confirmed

Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.

However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.

“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.

Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
 

Treatment, safety, and efficacy details

NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.

The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.

After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 10⁶ CAR NKT cells/m².

The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.

NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.

Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.

The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.

This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.

[email protected]

SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.

Chimeric antigen receptor natural killer T (CAR NKT) cells can expand in vivo and localize to tumors in patients with relapsed/refractory neuroblastoma, according to results of an ongoing phase 1 trial.

In one of three patients treated thus far, the CAR NKT cells induced an objective response with regression of a metastatic bone lesion.

Andras Heczey, MD, of Baylor College of Medicine, Houston, and colleagues reported outcomes for the first three patients in Nature Medicine.

The three boys – two 12-year-olds and one 6-year-old – had relapsed/refractory neuroblastoma.

NKT cells were collected from the patients, then genetically engineered to express a CAR to recognize the GD2-ganglioside expressed in neuroblastomas and also to express interleukin-15, which supports NKT cell survival. The cells were expanded and reinfused back into the patients.

The initial results suggest that CAR NKT cells can be used safely to treat neuroblastomas and perhaps other solid tumors, investigators said.
 

‘A significant advance’ if confirmed

Treating solid tumors with CAR T cells has been a challenge, in part because of inefficient trafficking into tumors.

However, NKT cells naturally migrate to tumors in response to tumor-derived chemokines, Dr. Heczey and colleagues noted. NKT cells kill macrophages associated with tumor growth and promote NK- and T-cell–mediated antitumor responses.

“We decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet – the so-called CAR – to further potentiate their capacity to destroy the tumor,” investigator Gianpietro Dotti, MD, of the University of North Carolina Lindberger Comprehensive Cancer Center in Chapel Hill, said in a press release.

Overall, the “results are very encouraging and, if confirmed in a larger cohort of patients, present a significant advance in the cell therapy field for solid tumors,” said CAR-T researcher Stephen Gottschalk, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn., when asked for comment.
 

Treatment, safety, and efficacy details

NKT cells are infrequent in human peripheral blood, so the investigators stimulated the NKT cells collected from patients with alpha-galactosylceramide–pulsed irradiated peripheral blood mononuclear cells.

The final products reached a mean NKT cell purity of 95%. The proportion of cells positive for the GD2-CAR ranged from 20% to 70% across the three patients.

After lymphodepletion with cyclophosphamide/fludarabine, the patients were infused with 3 × 10⁶ CAR NKT cells/m².

The cells were well tolerated, with no dose-limiting toxicities. There were grade 3/4 adverse events, but they occurred before CAR NKT-cell infusion and were thought to be related to lymphodepletion.

NKT-cell frequency and absolute numbers increased in the peripheral blood over baseline and remained elevated at the week 4 assessment.

Two patients had stable disease at 4 weeks, but one had a partial response and a change in Curie score from 2 to 1. The patient’s SPECT- and MIBG-merged scans “revealed a dramatic reduction in the size and MIBG uptake of a bone metastasis. The patient consequently received salvage therapy and achieved a complete response that lasted approximately 6 months,” the investigators noted.

The team found higher percentages of CAR NKT cells in primary tumor and metastatic bone marrow biopsies than in peripheral blood. A high percentage of CAR NKT cells from the tumor specimen, but only a small fraction from the bone metastasis, expressed the GD2-CAR.

This research was funded by Kuur Therapeutics, Alex’s Lemonade Stand Foundation for Childhood Cancer, the American Cancer Society, Cookies for Kids’ Cancer Foundation, and the Cancer Prevention and Research Institute of Texas. Dr. Heczey, Dr. Dotti, and two other researchers are coinventors on pending patent applications for NKT cells in cancer immunotherapy that have been licensed to Kuur Therapeutics for commercial development. Dr. Gottschalk has patent applications in the fields of T-cell and/or gene therapy for cancer. He has relationships with TESSA Therapeutics, Immatics, and Tidal.

[email protected]

SOURCE: Heczey A et al. Nat Med. 2020 Oct 12. doi: 10.1038/s41591-020-1074-2.