Will Pass

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

A recently updated guideline for idiopathic pulmonary fibrosis (IPF) provides refined diagnostic criteria in an effort to improve clinical application and diagnostic accuracy.

©Sergey Nivens/thinkstockphotos

Of note, the guideline recommends that high-resolution CT (HRCT) patterns be used to dictate management course. The guideline also calls for detailed medical history, serological testing to exclude connective tissue disease, and multidisciplinary discussion. Serum biomarkers are recommended against as a means of distinguishing between IPF and other interstitial lung diseases (ILDs).

“Diagnosing IPF is challenging because these symptoms are nonspecific: They occur with all other interstitial lung diseases and with other respiratory problems,” Ganesh Raghu, MD, chair of the guideline committee and professor of medicine and director of the Center for Interstitial Lung Disease at the University of Washington, Seattle, said in a written statement. “Because drugs may slow the progression of IPF, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.”

The 2018 guideline represents a second collaborative effort from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The guideline committee consisted of 29 clinicians, scientists, and a patient with IPF. They evaluated all IPF-related evidence and rated the quality of findings with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The first IPF guideline was published 7 years ago; the intervening time has revealed some clinical limitations that the 2018 guideline aims to fix.

“The 2011 guideline provided the first evidence-based, formal criteria for diagnosis of IPF and allowed patients with a well-defined diagnosis of IPF to participate in numerous clinical studies and randomized controlled trials that enhanced our understanding of the disease,” Dr. Raghu said. “However, it became clear that there were significant challenges in ascertaining the diagnosis per the 2011 criteria, and abundant evidence accumulated since then allowed the committee to refine the diagnostic criteria now.”

“This [updated] guideline is intended to help clinicians make an accurate diagnosis of IPF,” the authors wrote in the American Journal of Respiratory and Critical Care Medicine, “and to empower them to implement recommended courses of action in the context of individual patient values and preferences, particularly decisions regarding which diagnostic interventions to pursue.”

While the 2011 guideline did not distinguish between patients with different HRCT patterns, the 2018 guideline emphasizes the use of HRCT. It is now recommended that patients undergo HRCT to determine the pattern of usual interstitial pneumonia (UIP). Broadly, patients exhibit the UIP pattern or one of three possible non-UIP patterns (probable UIP, indeterminate UIP, or an alternative diagnosis). Recommendations are specific for UIP and non-UIP.

Patients with probable UIP, indeterminate UIP, or an alternative diagnosis should undergo bronchoalveolar lavage (BAL) and surgical lung biopsy (SLB). Transbronchial lung biopsy (TBBx) and lung cryobiopsy recommendations were not described in these patients because of a lack of evidence. However, patients with UIP should not undergo BAL, SLB, TBBx, or cryobiopsy.

For all patients, the 2018 guideline recommends that medical histories include environmental exposure and medication use, and that serological testing is performed to exclude connective tissue disease. Multidisciplinary discussion is conditionally recommended for diagnostic decision making, particularly when a patient has probable UIP, indeterminate UIP, or an alternative diagnosis.

Finally, the guideline recommends against the use of serum biomarkers as a means of distinguishing between IPF and other ILDs because of weak data on this point. “For the time being, the guideline panel dismissed serum biomarker measurement as an approach to distinguishing IPF from other ILDs because of the high false-positive and false-negative result rates,” the panel wrote.

“Our hope is that this new guideline will bridge the gap between the experienced IPF experts and general pulmonologists in making a prompt and accurate diagnosis of IPF for the individual unfortunately confronted with the disease,” Dr. Raghu said. “This will allow patients to make well-informed decisions about treatment options and participation in clinical trials.”

Looking to the future, the panel described an “urgent need to refine and validate diagnostic approaches to ILD. These needs can be roughly categorized as investigations into the roles of clinical observations, HRCT, bronchoscopy, histopathology, and biomarkers.” The authors also emphasized “the need to refine prognostic approaches, identify risk factors for the development of IPF, and determine the impact and approach to the diagnosis of comorbid illness in the patient with IPF.”

The authors reported funding from Bellerophon, Gilead, Roche, Sanofi, and others.
 

SOURCE: Raghu G et al. Am J Respir Crit Care Med. 2018 Sep 1. doi: 10.1164/rccm.201807-1255ST.

A recently updated guideline for idiopathic pulmonary fibrosis (IPF) provides refined diagnostic criteria in an effort to improve clinical application and diagnostic accuracy.

©Sergey Nivens/thinkstockphotos

Of note, the guideline recommends that high-resolution CT (HRCT) patterns be used to dictate management course. The guideline also calls for detailed medical history, serological testing to exclude connective tissue disease, and multidisciplinary discussion. Serum biomarkers are recommended against as a means of distinguishing between IPF and other interstitial lung diseases (ILDs).

“Diagnosing IPF is challenging because these symptoms are nonspecific: They occur with all other interstitial lung diseases and with other respiratory problems,” Ganesh Raghu, MD, chair of the guideline committee and professor of medicine and director of the Center for Interstitial Lung Disease at the University of Washington, Seattle, said in a written statement. “Because drugs may slow the progression of IPF, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.”

The 2018 guideline represents a second collaborative effort from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The guideline committee consisted of 29 clinicians, scientists, and a patient with IPF. They evaluated all IPF-related evidence and rated the quality of findings with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The first IPF guideline was published 7 years ago; the intervening time has revealed some clinical limitations that the 2018 guideline aims to fix.

“The 2011 guideline provided the first evidence-based, formal criteria for diagnosis of IPF and allowed patients with a well-defined diagnosis of IPF to participate in numerous clinical studies and randomized controlled trials that enhanced our understanding of the disease,” Dr. Raghu said. “However, it became clear that there were significant challenges in ascertaining the diagnosis per the 2011 criteria, and abundant evidence accumulated since then allowed the committee to refine the diagnostic criteria now.”

“This [updated] guideline is intended to help clinicians make an accurate diagnosis of IPF,” the authors wrote in the American Journal of Respiratory and Critical Care Medicine, “and to empower them to implement recommended courses of action in the context of individual patient values and preferences, particularly decisions regarding which diagnostic interventions to pursue.”

While the 2011 guideline did not distinguish between patients with different HRCT patterns, the 2018 guideline emphasizes the use of HRCT. It is now recommended that patients undergo HRCT to determine the pattern of usual interstitial pneumonia (UIP). Broadly, patients exhibit the UIP pattern or one of three possible non-UIP patterns (probable UIP, indeterminate UIP, or an alternative diagnosis). Recommendations are specific for UIP and non-UIP.

Patients with probable UIP, indeterminate UIP, or an alternative diagnosis should undergo bronchoalveolar lavage (BAL) and surgical lung biopsy (SLB). Transbronchial lung biopsy (TBBx) and lung cryobiopsy recommendations were not described in these patients because of a lack of evidence. However, patients with UIP should not undergo BAL, SLB, TBBx, or cryobiopsy.

For all patients, the 2018 guideline recommends that medical histories include environmental exposure and medication use, and that serological testing is performed to exclude connective tissue disease. Multidisciplinary discussion is conditionally recommended for diagnostic decision making, particularly when a patient has probable UIP, indeterminate UIP, or an alternative diagnosis.

Finally, the guideline recommends against the use of serum biomarkers as a means of distinguishing between IPF and other ILDs because of weak data on this point. “For the time being, the guideline panel dismissed serum biomarker measurement as an approach to distinguishing IPF from other ILDs because of the high false-positive and false-negative result rates,” the panel wrote.

“Our hope is that this new guideline will bridge the gap between the experienced IPF experts and general pulmonologists in making a prompt and accurate diagnosis of IPF for the individual unfortunately confronted with the disease,” Dr. Raghu said. “This will allow patients to make well-informed decisions about treatment options and participation in clinical trials.”

Looking to the future, the panel described an “urgent need to refine and validate diagnostic approaches to ILD. These needs can be roughly categorized as investigations into the roles of clinical observations, HRCT, bronchoscopy, histopathology, and biomarkers.” The authors also emphasized “the need to refine prognostic approaches, identify risk factors for the development of IPF, and determine the impact and approach to the diagnosis of comorbid illness in the patient with IPF.”

The authors reported funding from Bellerophon, Gilead, Roche, Sanofi, and others.
 

SOURCE: Raghu G et al. Am J Respir Crit Care Med. 2018 Sep 1. doi: 10.1164/rccm.201807-1255ST.

A recently updated guideline for idiopathic pulmonary fibrosis (IPF) provides refined diagnostic criteria in an effort to improve clinical application and diagnostic accuracy.

©Sergey Nivens/thinkstockphotos

Of note, the guideline recommends that high-resolution CT (HRCT) patterns be used to dictate management course. The guideline also calls for detailed medical history, serological testing to exclude connective tissue disease, and multidisciplinary discussion. Serum biomarkers are recommended against as a means of distinguishing between IPF and other interstitial lung diseases (ILDs).

“Diagnosing IPF is challenging because these symptoms are nonspecific: They occur with all other interstitial lung diseases and with other respiratory problems,” Ganesh Raghu, MD, chair of the guideline committee and professor of medicine and director of the Center for Interstitial Lung Disease at the University of Washington, Seattle, said in a written statement. “Because drugs may slow the progression of IPF, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.”

The 2018 guideline represents a second collaborative effort from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The guideline committee consisted of 29 clinicians, scientists, and a patient with IPF. They evaluated all IPF-related evidence and rated the quality of findings with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The first IPF guideline was published 7 years ago; the intervening time has revealed some clinical limitations that the 2018 guideline aims to fix.

“The 2011 guideline provided the first evidence-based, formal criteria for diagnosis of IPF and allowed patients with a well-defined diagnosis of IPF to participate in numerous clinical studies and randomized controlled trials that enhanced our understanding of the disease,” Dr. Raghu said. “However, it became clear that there were significant challenges in ascertaining the diagnosis per the 2011 criteria, and abundant evidence accumulated since then allowed the committee to refine the diagnostic criteria now.”

“This [updated] guideline is intended to help clinicians make an accurate diagnosis of IPF,” the authors wrote in the American Journal of Respiratory and Critical Care Medicine, “and to empower them to implement recommended courses of action in the context of individual patient values and preferences, particularly decisions regarding which diagnostic interventions to pursue.”

While the 2011 guideline did not distinguish between patients with different HRCT patterns, the 2018 guideline emphasizes the use of HRCT. It is now recommended that patients undergo HRCT to determine the pattern of usual interstitial pneumonia (UIP). Broadly, patients exhibit the UIP pattern or one of three possible non-UIP patterns (probable UIP, indeterminate UIP, or an alternative diagnosis). Recommendations are specific for UIP and non-UIP.

Patients with probable UIP, indeterminate UIP, or an alternative diagnosis should undergo bronchoalveolar lavage (BAL) and surgical lung biopsy (SLB). Transbronchial lung biopsy (TBBx) and lung cryobiopsy recommendations were not described in these patients because of a lack of evidence. However, patients with UIP should not undergo BAL, SLB, TBBx, or cryobiopsy.

For all patients, the 2018 guideline recommends that medical histories include environmental exposure and medication use, and that serological testing is performed to exclude connective tissue disease. Multidisciplinary discussion is conditionally recommended for diagnostic decision making, particularly when a patient has probable UIP, indeterminate UIP, or an alternative diagnosis.

Finally, the guideline recommends against the use of serum biomarkers as a means of distinguishing between IPF and other ILDs because of weak data on this point. “For the time being, the guideline panel dismissed serum biomarker measurement as an approach to distinguishing IPF from other ILDs because of the high false-positive and false-negative result rates,” the panel wrote.

“Our hope is that this new guideline will bridge the gap between the experienced IPF experts and general pulmonologists in making a prompt and accurate diagnosis of IPF for the individual unfortunately confronted with the disease,” Dr. Raghu said. “This will allow patients to make well-informed decisions about treatment options and participation in clinical trials.”

Looking to the future, the panel described an “urgent need to refine and validate diagnostic approaches to ILD. These needs can be roughly categorized as investigations into the roles of clinical observations, HRCT, bronchoscopy, histopathology, and biomarkers.” The authors also emphasized “the need to refine prognostic approaches, identify risk factors for the development of IPF, and determine the impact and approach to the diagnosis of comorbid illness in the patient with IPF.”

The authors reported funding from Bellerophon, Gilead, Roche, Sanofi, and others.
 

SOURCE: Raghu G et al. Am J Respir Crit Care Med. 2018 Sep 1. doi: 10.1164/rccm.201807-1255ST.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.

Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.

These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.

“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.

The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.

Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.

In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).

Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.

The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”

The authors reported no conflicts of interest.

SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.

Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.

These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.

“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.

The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.

Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.

In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).

Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.

The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”

The authors reported no conflicts of interest.

SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.

Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.

These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.

“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.

The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.

Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.

In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).

Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.

The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”

The authors reported no conflicts of interest.

SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.

Patients with chronic back pain suspected of having axial spondyloarthritis (axSpA) should not undergo follow-up MRI of the sacroiliac joint (MRI-SI) within a year if they had a negative baseline MRI-SI, according to investigators.

It is very unlikely that a follow-up MRI-SI will yield new results, reported Pauline A. Bakker, MD, of the department of rheumatology at Leiden University Medical Centre, the Netherlands, and her colleagues.

Since gender and HLA-B27 status were closely associated with MRI-SI positivity, these factors should be considered when deciding to repeat an MRI-SI.

“Over the last decade, MRI rapidly gained ground and proved to be an important imaging technique in the diagnostic process of [nonradiographic] axial spondyloarthritis,” the investigators wrote in Arthritis and Rheumatology. “It has been shown that MRI can detect the early inflammatory stages of sacroiliitis months to years before structural damage can be detected on a conventional radiograph.”

Although MRI represents a diagnostic leap forward, questions of clinical application remain. “For example… if an MRI is completely normal and there is still a clinical suspicion of axSpA, should the MRI be repeated? And if so, after what period of follow-up? Or does this not contribute to the diagnostic process?”

To answer these questions, the investigators observed the “evolution of MRI lesions over a 3-month and 1-year time frame” in patients with early chronic back pain and suspected axSpA.

The prospective study involved 188 patients from the Spondyloarthritis Caught Early (SPACE) cohort. The authors commented that this is “an ideal cohort… since it includes a population of patients with back pain of short duration referred to rheumatologists with a suspicion of SpA [but without the mandatory presence of a single or multiple SpA features].”

Gender and HLA-B27 status were independently associated with a positive MRI-SI at any point in time. About 43% of HLA-B27-positive men had a positive MRI-SI, compared with just 7% of HLA-B27-negative women. The investigators advised that these associations be considered when deciding upon repeat MRI-SI.

“If a clinical suspicion [of axSpA] remains [for example, a patient develops other SpA features] it might be worthwhile to consider redoing an MRI in HLA-B27 positive patients,” the investigators wrote. “Likewise, there is a statistically significant difference between male and female patients with a negative baseline MRI, namely that in male patients more often a positive MRI at follow-up is seen [difference: 12% in men, 3% in women].”

The researchers reported having no conflicts of interest.

SOURCE: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.

Patients with chronic back pain suspected of having axial spondyloarthritis (axSpA) should not undergo follow-up MRI of the sacroiliac joint (MRI-SI) within a year if they had a negative baseline MRI-SI, according to investigators.

It is very unlikely that a follow-up MRI-SI will yield new results, reported Pauline A. Bakker, MD, of the department of rheumatology at Leiden University Medical Centre, the Netherlands, and her colleagues.

Since gender and HLA-B27 status were closely associated with MRI-SI positivity, these factors should be considered when deciding to repeat an MRI-SI.

“Over the last decade, MRI rapidly gained ground and proved to be an important imaging technique in the diagnostic process of [nonradiographic] axial spondyloarthritis,” the investigators wrote in Arthritis and Rheumatology. “It has been shown that MRI can detect the early inflammatory stages of sacroiliitis months to years before structural damage can be detected on a conventional radiograph.”

Although MRI represents a diagnostic leap forward, questions of clinical application remain. “For example… if an MRI is completely normal and there is still a clinical suspicion of axSpA, should the MRI be repeated? And if so, after what period of follow-up? Or does this not contribute to the diagnostic process?”

To answer these questions, the investigators observed the “evolution of MRI lesions over a 3-month and 1-year time frame” in patients with early chronic back pain and suspected axSpA.

The prospective study involved 188 patients from the Spondyloarthritis Caught Early (SPACE) cohort. The authors commented that this is “an ideal cohort… since it includes a population of patients with back pain of short duration referred to rheumatologists with a suspicion of SpA [but without the mandatory presence of a single or multiple SpA features].”

Gender and HLA-B27 status were independently associated with a positive MRI-SI at any point in time. About 43% of HLA-B27-positive men had a positive MRI-SI, compared with just 7% of HLA-B27-negative women. The investigators advised that these associations be considered when deciding upon repeat MRI-SI.

“If a clinical suspicion [of axSpA] remains [for example, a patient develops other SpA features] it might be worthwhile to consider redoing an MRI in HLA-B27 positive patients,” the investigators wrote. “Likewise, there is a statistically significant difference between male and female patients with a negative baseline MRI, namely that in male patients more often a positive MRI at follow-up is seen [difference: 12% in men, 3% in women].”

The researchers reported having no conflicts of interest.

SOURCE: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.

Patients with chronic back pain suspected of having axial spondyloarthritis (axSpA) should not undergo follow-up MRI of the sacroiliac joint (MRI-SI) within a year if they had a negative baseline MRI-SI, according to investigators.

It is very unlikely that a follow-up MRI-SI will yield new results, reported Pauline A. Bakker, MD, of the department of rheumatology at Leiden University Medical Centre, the Netherlands, and her colleagues.

Since gender and HLA-B27 status were closely associated with MRI-SI positivity, these factors should be considered when deciding to repeat an MRI-SI.

“Over the last decade, MRI rapidly gained ground and proved to be an important imaging technique in the diagnostic process of [nonradiographic] axial spondyloarthritis,” the investigators wrote in Arthritis and Rheumatology. “It has been shown that MRI can detect the early inflammatory stages of sacroiliitis months to years before structural damage can be detected on a conventional radiograph.”

Although MRI represents a diagnostic leap forward, questions of clinical application remain. “For example… if an MRI is completely normal and there is still a clinical suspicion of axSpA, should the MRI be repeated? And if so, after what period of follow-up? Or does this not contribute to the diagnostic process?”

To answer these questions, the investigators observed the “evolution of MRI lesions over a 3-month and 1-year time frame” in patients with early chronic back pain and suspected axSpA.

The prospective study involved 188 patients from the Spondyloarthritis Caught Early (SPACE) cohort. The authors commented that this is “an ideal cohort… since it includes a population of patients with back pain of short duration referred to rheumatologists with a suspicion of SpA [but without the mandatory presence of a single or multiple SpA features].”

Gender and HLA-B27 status were independently associated with a positive MRI-SI at any point in time. About 43% of HLA-B27-positive men had a positive MRI-SI, compared with just 7% of HLA-B27-negative women. The investigators advised that these associations be considered when deciding upon repeat MRI-SI.

“If a clinical suspicion [of axSpA] remains [for example, a patient develops other SpA features] it might be worthwhile to consider redoing an MRI in HLA-B27 positive patients,” the investigators wrote. “Likewise, there is a statistically significant difference between male and female patients with a negative baseline MRI, namely that in male patients more often a positive MRI at follow-up is seen [difference: 12% in men, 3% in women].”

The researchers reported having no conflicts of interest.

SOURCE: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.

The average cost of outpatient care for Medicare recipients with chronic hepatitis B (CH-B) rose by 400% from 2005 to 2014, according to investigators.

utah778/Thinkstock

Inpatient costs also increased, although less dramatically, reported lead author Min Kim, MD, of the Inova Fairfax Hospital Center for Liver Diseases in Falls Church, Virginia, and her colleagues. The causes of these spending hikes may range from policy changes and expanded screening to an aging immigrant population.

“According to the National Health and Nutrition Examination Survey, from 1988 to 2012 most people with CH-B in the United States were foreign born and accounted for up to 70% of all CH-B infections,” the authors wrote in the Journal of Clinical Gastroenterology. “The Centers for Disease Control [and Prevention] estimates that Asians, who comprise 5% of the U.S. population, account for 50% of all chronic CH-B infections.” Despite these statistics, the clinical and economic impacts of an aging immigrant population are unknown. The investigators therefore assessed patient characteristics associated with increased 1-year mortality and the impact of demographic changes on Medicare costs.

The retrospective study began with a random sample of Medicare beneficiaries from 2005 to 2014. From this group, 18,603 patients with CH-B were identified by ICD-9 codes V02.61, 070.2, 070.3, 070.42, and 070.52. Patients with ICD-9-CM codes of 197.7, 155.1, or 155.2 were excluded, as were records containing insufficient information about year, region, or race. Patients were analyzed collectively and as inpatients (n = 6,550) or outpatients (n = 13,648).

Cost of care (per patient, per year) and 1-year mortality were evaluated. Patient characteristics included age, sex, race/ethnicity, geographic region, type of Medicare eligibility, length of stay, Charlson comorbidity index, presence of decompensated cirrhosis, and/or hepatocellular carcinoma (HCC).

Most dramatically, outpatient charges rose more than 400% during the study period, from $9,257 in 2005 to $47,864 in 2014 (P less than .001). Inpatient charges increased by almost 50%, from $66,610 to $94,221 (P less than .001). (All values converted to 2016 dollars.)

Although the increase in outpatient costs appears seismic, the authors noted that costs held steady from 2005 to 2010 before spiking dramatically, reaching a peak of $58,450 in 2013 before settling down to $47,864 the following year. This spike may be caused by changes in screening measures and policies. In 2009, the American Association for the Study of Liver Diseases expanded screening guidelines to include previously ineligible patients with CH-B, and in 2010, the Centers for Medicare & Medicaid Services expanded ICD-9 and ICD-10 codes for CH-B from 9 to 25.

“It seems plausible that the increase in CH-B prevalence, and its associated costs, might actually be a reflection of [these factors],” the authors noted. Still, “additional studies are needed to clarify this observation.”

Turning to patient characteristics, the authors reported that 1-year mortality was independently associated most strongly with decompensated cirrhosis (odds ratio, 3.02) and hepatocellular carcinoma (OR, 2.64). In comparison with white patients, Asians were less likely to die (OR, 0.47).

“It is possible that this can be explained through differences in transmission mode and disease progression of CH-B between these two demographics,” the authors wrote. “A majority of Asian Medicare recipients with CH-B likely acquired it perinatally and did not develop significant liver disease. In contrast, whites with CH-B generally acquired it in adulthood, increasing the chance of developing liver disease.”

Over the 10-year study period, Medicare beneficiaries with CH-B became more frequently Asian and less frequently male. While the number of outpatient visits and average Charlson comorbidity index increased, decreases were reported for length of stay, rates of 1-year mortality, hospitalization, and HCC – the latter of which is most closely associated with higher costs of care.

The investigators suggested that the decreased incidence of HCC was caused by “better screening programs for HCC and/or more widespread use of antiviral treatment for CH-B.”

“Although advances in antiviral treatment have effectively reduced hospitalization and disease progression,” the authors wrote, “vulnerable groups – especially immigrants and individuals living in poverty – present an important challenge for better identification of infected individuals and their linkage to care. In this context, it is vital to target these cohorts to reduce further mortality and resource utilization, as well as optimize long-term public health and financial benefits.”

Study funding was provided by Seattle Genetics. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.

SOURCE: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.

The average cost of outpatient care for Medicare recipients with chronic hepatitis B (CH-B) rose by 400% from 2005 to 2014, according to investigators.

utah778/Thinkstock

Inpatient costs also increased, although less dramatically, reported lead author Min Kim, MD, of the Inova Fairfax Hospital Center for Liver Diseases in Falls Church, Virginia, and her colleagues. The causes of these spending hikes may range from policy changes and expanded screening to an aging immigrant population.

“According to the National Health and Nutrition Examination Survey, from 1988 to 2012 most people with CH-B in the United States were foreign born and accounted for up to 70% of all CH-B infections,” the authors wrote in the Journal of Clinical Gastroenterology. “The Centers for Disease Control [and Prevention] estimates that Asians, who comprise 5% of the U.S. population, account for 50% of all chronic CH-B infections.” Despite these statistics, the clinical and economic impacts of an aging immigrant population are unknown. The investigators therefore assessed patient characteristics associated with increased 1-year mortality and the impact of demographic changes on Medicare costs.

The retrospective study began with a random sample of Medicare beneficiaries from 2005 to 2014. From this group, 18,603 patients with CH-B were identified by ICD-9 codes V02.61, 070.2, 070.3, 070.42, and 070.52. Patients with ICD-9-CM codes of 197.7, 155.1, or 155.2 were excluded, as were records containing insufficient information about year, region, or race. Patients were analyzed collectively and as inpatients (n = 6,550) or outpatients (n = 13,648).

Cost of care (per patient, per year) and 1-year mortality were evaluated. Patient characteristics included age, sex, race/ethnicity, geographic region, type of Medicare eligibility, length of stay, Charlson comorbidity index, presence of decompensated cirrhosis, and/or hepatocellular carcinoma (HCC).

Most dramatically, outpatient charges rose more than 400% during the study period, from $9,257 in 2005 to $47,864 in 2014 (P less than .001). Inpatient charges increased by almost 50%, from $66,610 to $94,221 (P less than .001). (All values converted to 2016 dollars.)

Although the increase in outpatient costs appears seismic, the authors noted that costs held steady from 2005 to 2010 before spiking dramatically, reaching a peak of $58,450 in 2013 before settling down to $47,864 the following year. This spike may be caused by changes in screening measures and policies. In 2009, the American Association for the Study of Liver Diseases expanded screening guidelines to include previously ineligible patients with CH-B, and in 2010, the Centers for Medicare & Medicaid Services expanded ICD-9 and ICD-10 codes for CH-B from 9 to 25.

“It seems plausible that the increase in CH-B prevalence, and its associated costs, might actually be a reflection of [these factors],” the authors noted. Still, “additional studies are needed to clarify this observation.”

Turning to patient characteristics, the authors reported that 1-year mortality was independently associated most strongly with decompensated cirrhosis (odds ratio, 3.02) and hepatocellular carcinoma (OR, 2.64). In comparison with white patients, Asians were less likely to die (OR, 0.47).

“It is possible that this can be explained through differences in transmission mode and disease progression of CH-B between these two demographics,” the authors wrote. “A majority of Asian Medicare recipients with CH-B likely acquired it perinatally and did not develop significant liver disease. In contrast, whites with CH-B generally acquired it in adulthood, increasing the chance of developing liver disease.”

Over the 10-year study period, Medicare beneficiaries with CH-B became more frequently Asian and less frequently male. While the number of outpatient visits and average Charlson comorbidity index increased, decreases were reported for length of stay, rates of 1-year mortality, hospitalization, and HCC – the latter of which is most closely associated with higher costs of care.

The investigators suggested that the decreased incidence of HCC was caused by “better screening programs for HCC and/or more widespread use of antiviral treatment for CH-B.”

“Although advances in antiviral treatment have effectively reduced hospitalization and disease progression,” the authors wrote, “vulnerable groups – especially immigrants and individuals living in poverty – present an important challenge for better identification of infected individuals and their linkage to care. In this context, it is vital to target these cohorts to reduce further mortality and resource utilization, as well as optimize long-term public health and financial benefits.”

Study funding was provided by Seattle Genetics. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.

SOURCE: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.

The average cost of outpatient care for Medicare recipients with chronic hepatitis B (CH-B) rose by 400% from 2005 to 2014, according to investigators.

utah778/Thinkstock

Inpatient costs also increased, although less dramatically, reported lead author Min Kim, MD, of the Inova Fairfax Hospital Center for Liver Diseases in Falls Church, Virginia, and her colleagues. The causes of these spending hikes may range from policy changes and expanded screening to an aging immigrant population.

“According to the National Health and Nutrition Examination Survey, from 1988 to 2012 most people with CH-B in the United States were foreign born and accounted for up to 70% of all CH-B infections,” the authors wrote in the Journal of Clinical Gastroenterology. “The Centers for Disease Control [and Prevention] estimates that Asians, who comprise 5% of the U.S. population, account for 50% of all chronic CH-B infections.” Despite these statistics, the clinical and economic impacts of an aging immigrant population are unknown. The investigators therefore assessed patient characteristics associated with increased 1-year mortality and the impact of demographic changes on Medicare costs.

The retrospective study began with a random sample of Medicare beneficiaries from 2005 to 2014. From this group, 18,603 patients with CH-B were identified by ICD-9 codes V02.61, 070.2, 070.3, 070.42, and 070.52. Patients with ICD-9-CM codes of 197.7, 155.1, or 155.2 were excluded, as were records containing insufficient information about year, region, or race. Patients were analyzed collectively and as inpatients (n = 6,550) or outpatients (n = 13,648).

Cost of care (per patient, per year) and 1-year mortality were evaluated. Patient characteristics included age, sex, race/ethnicity, geographic region, type of Medicare eligibility, length of stay, Charlson comorbidity index, presence of decompensated cirrhosis, and/or hepatocellular carcinoma (HCC).

Most dramatically, outpatient charges rose more than 400% during the study period, from $9,257 in 2005 to $47,864 in 2014 (P less than .001). Inpatient charges increased by almost 50%, from $66,610 to $94,221 (P less than .001). (All values converted to 2016 dollars.)

Although the increase in outpatient costs appears seismic, the authors noted that costs held steady from 2005 to 2010 before spiking dramatically, reaching a peak of $58,450 in 2013 before settling down to $47,864 the following year. This spike may be caused by changes in screening measures and policies. In 2009, the American Association for the Study of Liver Diseases expanded screening guidelines to include previously ineligible patients with CH-B, and in 2010, the Centers for Medicare & Medicaid Services expanded ICD-9 and ICD-10 codes for CH-B from 9 to 25.

“It seems plausible that the increase in CH-B prevalence, and its associated costs, might actually be a reflection of [these factors],” the authors noted. Still, “additional studies are needed to clarify this observation.”

Turning to patient characteristics, the authors reported that 1-year mortality was independently associated most strongly with decompensated cirrhosis (odds ratio, 3.02) and hepatocellular carcinoma (OR, 2.64). In comparison with white patients, Asians were less likely to die (OR, 0.47).

“It is possible that this can be explained through differences in transmission mode and disease progression of CH-B between these two demographics,” the authors wrote. “A majority of Asian Medicare recipients with CH-B likely acquired it perinatally and did not develop significant liver disease. In contrast, whites with CH-B generally acquired it in adulthood, increasing the chance of developing liver disease.”

Over the 10-year study period, Medicare beneficiaries with CH-B became more frequently Asian and less frequently male. While the number of outpatient visits and average Charlson comorbidity index increased, decreases were reported for length of stay, rates of 1-year mortality, hospitalization, and HCC – the latter of which is most closely associated with higher costs of care.

The investigators suggested that the decreased incidence of HCC was caused by “better screening programs for HCC and/or more widespread use of antiviral treatment for CH-B.”

“Although advances in antiviral treatment have effectively reduced hospitalization and disease progression,” the authors wrote, “vulnerable groups – especially immigrants and individuals living in poverty – present an important challenge for better identification of infected individuals and their linkage to care. In this context, it is vital to target these cohorts to reduce further mortality and resource utilization, as well as optimize long-term public health and financial benefits.”

Study funding was provided by Seattle Genetics. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.

SOURCE: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.

Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.

Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.

“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.

The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.

Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.

Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.

“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”

Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.

SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.

Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.

Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.

“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.

The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.

Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.

Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.

“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”

Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.

SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.

Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.

Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.

“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.

The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.

Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.

Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.

“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”

Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.

SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.

Peroral endoscopic myotomy (POEM) is safe and effective for several nonachalasia esophageal motility disorders, according to a retrospective study.

The procedure was clinically successful and relieved chest pain in most patients, reported Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Hospital in Baltimore.

POEM was introduced in 2008 as a less invasive alternative to laparoscopic Heller myotomy. During the procedure, submucosal tunneling is performed through the lower esophageal sphincter to the gastric cardia, thereby weakening the lower esophageal sphincter to allow passage of food.

POEM is clinically successful in 80%-90% of patients with achalasia. Although the procedure is regarded as safe and effective for achalasia, it has not been thoroughly researched for treatment of other esophageal motility disorders, including junction outflow obstruction (EGJOO), jackhammer esophagus (JE), or esophagogastric distal esophageal spasm (DES). EGJOO is similar to achalasia, but with peristalsis and a mean integrated relaxation pressure (IRP) greater than 15 mm Hg. Both JE and DES are spastic esophageal disorders. Patients with JE exhibit extreme esophageal hypercontractility, whereas patients with DES have a normal mean IRP and at least 20% premature contractions.

“The role POEM plays in management of these disorders is not clear, mainly due to scarcity of studies on this topic,” the authors wrote in Endoscopy International Open. “A previous multicenter study investigated the role of POEM in 73 patients with spastic esophageal disorders. However, the vast majority of patients (n = 54) in that study had type III (spastic) achalasia.” Since therapies such as botulinum toxin injections and calcium channel blockers are ineffective for many patients with nonachalasia esophageal motility disorders, “POEM is potentially an ideal treatment.”

The international, multicenter study involved 11 treatment centers and 50 patients. Patients with JE (n = 18), EGJOO (n = 15), and DES (n = 17) were included, each diagnosed according to the Chicago classification of esophageal motility disorders. Patients with type III achalasia were excluded.

Outcomes included technical success (completion of myotomy) and clinical success (Eckardt score at least 3 and symptom improvement). Prior to the procedure, the mean Eckardt score was 6.9 and chest pain was reported by almost three-quarters of the patients (72%).

Technical success was achieved in all patients. Myotomy thickness varied between cases; approximately half had a selective inner circular myotomy (48%), slightly less had a full-thickness myotomy (44%), and several were undefined (8%). Mean esophageal myotomy length was 12.5 cm and mean gastric myotomy length was 2.5 cm. Mean procedure time was approximately 90 minutes. Median duration of hospital stay was 2 days.

Nine adverse events (AEs) occurred in 8 patients, including submucosal hematoma, aspiration pneumonia, inadvertent mucosotomy, postprocedure pain, esophageal leak, bleed, and symptomatic capno-thorax/peritoneum.

“Although AEs occurred in 18% of patients,” the authors noted, “55.6% were rated as mild and 44.4% as moderate with no severe events. Most AEs can be managed intraprocedurally.”

Median follow-up time was approximately 8 months, during which 42 patients (87.5%) achieved clinical success, with many dramatically improved; over half of the patients (52%) had Eckardt scores of 0 or 1. From the group of patients who had chest pain prior to the procedure, 87% had resolution of chest pain. Although reflux developed in almost a quarter of the patients (22.2%), this was successfully managed with proton pump inhibitors in all instances. Most patients (82.9%) who underwent postoperative manometry had resolution of preoperative abnormalities.

Subgroup analysis was also performed. Clinical success was achieved in 94.1% of patients with DES, 93.3% of patients with EGJOO, and 75.0% with JE. Collectively, the spastic disorders (DES/JE) had a lower numerical response than EGJOO. However, the authors noted that “the difference was not statistically significant (P = .41), likely a type II error due to the relatively small number of included patients.” In all subgroups, postprocedural mean Eckardt scores decreased to less than 2. Patients with EGJOO were most likely to achieve Eckardt scores of 0 or 1. AEs were similar between subgroups.

“Remarkably, chest pain improved in more than 85% of patients,” the authors wrote. “Chest pain is frequently the major presenting symptom in these disorders and is difficult to treat.”

“It is important to mention that a long esophageal myotomy is essential to ensure that proximal esophageal spasms are effectively covered and treated,” the authors wrote. “Mean length of esophageal myotomy in patients with DES and JE in the current study was about 14 cm, which is more than twice the length of a typical endoscopic or surgical myotomy performed in achalasia patients.”

Even with the need for an extended myotomy, “results from the current study along with published data suggest POEM as an effective technique” for nonachalasia esophageal motility disorders, the authors concluded.

Since retrospective studies are inherently limited by design, the authors encouraged randomized trials to clarify the primary role of POEM in the management of nonachalasia esophageal motility disorders.

The authors reported compensation from Olympus, Boston Scientific, and Cook Medical.

SOURCE: Khashab MA et al. Endosc Int Open. 2018 Aug 10. doi: 10.1055/a-0625-6288.

Peroral endoscopic myotomy (POEM) is safe and effective for several nonachalasia esophageal motility disorders, according to a retrospective study.

The procedure was clinically successful and relieved chest pain in most patients, reported Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Hospital in Baltimore.

POEM was introduced in 2008 as a less invasive alternative to laparoscopic Heller myotomy. During the procedure, submucosal tunneling is performed through the lower esophageal sphincter to the gastric cardia, thereby weakening the lower esophageal sphincter to allow passage of food.

POEM is clinically successful in 80%-90% of patients with achalasia. Although the procedure is regarded as safe and effective for achalasia, it has not been thoroughly researched for treatment of other esophageal motility disorders, including junction outflow obstruction (EGJOO), jackhammer esophagus (JE), or esophagogastric distal esophageal spasm (DES). EGJOO is similar to achalasia, but with peristalsis and a mean integrated relaxation pressure (IRP) greater than 15 mm Hg. Both JE and DES are spastic esophageal disorders. Patients with JE exhibit extreme esophageal hypercontractility, whereas patients with DES have a normal mean IRP and at least 20% premature contractions.

“The role POEM plays in management of these disorders is not clear, mainly due to scarcity of studies on this topic,” the authors wrote in Endoscopy International Open. “A previous multicenter study investigated the role of POEM in 73 patients with spastic esophageal disorders. However, the vast majority of patients (n = 54) in that study had type III (spastic) achalasia.” Since therapies such as botulinum toxin injections and calcium channel blockers are ineffective for many patients with nonachalasia esophageal motility disorders, “POEM is potentially an ideal treatment.”

The international, multicenter study involved 11 treatment centers and 50 patients. Patients with JE (n = 18), EGJOO (n = 15), and DES (n = 17) were included, each diagnosed according to the Chicago classification of esophageal motility disorders. Patients with type III achalasia were excluded.

Outcomes included technical success (completion of myotomy) and clinical success (Eckardt score at least 3 and symptom improvement). Prior to the procedure, the mean Eckardt score was 6.9 and chest pain was reported by almost three-quarters of the patients (72%).

Technical success was achieved in all patients. Myotomy thickness varied between cases; approximately half had a selective inner circular myotomy (48%), slightly less had a full-thickness myotomy (44%), and several were undefined (8%). Mean esophageal myotomy length was 12.5 cm and mean gastric myotomy length was 2.5 cm. Mean procedure time was approximately 90 minutes. Median duration of hospital stay was 2 days.

Nine adverse events (AEs) occurred in 8 patients, including submucosal hematoma, aspiration pneumonia, inadvertent mucosotomy, postprocedure pain, esophageal leak, bleed, and symptomatic capno-thorax/peritoneum.

“Although AEs occurred in 18% of patients,” the authors noted, “55.6% were rated as mild and 44.4% as moderate with no severe events. Most AEs can be managed intraprocedurally.”

Median follow-up time was approximately 8 months, during which 42 patients (87.5%) achieved clinical success, with many dramatically improved; over half of the patients (52%) had Eckardt scores of 0 or 1. From the group of patients who had chest pain prior to the procedure, 87% had resolution of chest pain. Although reflux developed in almost a quarter of the patients (22.2%), this was successfully managed with proton pump inhibitors in all instances. Most patients (82.9%) who underwent postoperative manometry had resolution of preoperative abnormalities.

Subgroup analysis was also performed. Clinical success was achieved in 94.1% of patients with DES, 93.3% of patients with EGJOO, and 75.0% with JE. Collectively, the spastic disorders (DES/JE) had a lower numerical response than EGJOO. However, the authors noted that “the difference was not statistically significant (P = .41), likely a type II error due to the relatively small number of included patients.” In all subgroups, postprocedural mean Eckardt scores decreased to less than 2. Patients with EGJOO were most likely to achieve Eckardt scores of 0 or 1. AEs were similar between subgroups.

“Remarkably, chest pain improved in more than 85% of patients,” the authors wrote. “Chest pain is frequently the major presenting symptom in these disorders and is difficult to treat.”

“It is important to mention that a long esophageal myotomy is essential to ensure that proximal esophageal spasms are effectively covered and treated,” the authors wrote. “Mean length of esophageal myotomy in patients with DES and JE in the current study was about 14 cm, which is more than twice the length of a typical endoscopic or surgical myotomy performed in achalasia patients.”

Even with the need for an extended myotomy, “results from the current study along with published data suggest POEM as an effective technique” for nonachalasia esophageal motility disorders, the authors concluded.

Since retrospective studies are inherently limited by design, the authors encouraged randomized trials to clarify the primary role of POEM in the management of nonachalasia esophageal motility disorders.

The authors reported compensation from Olympus, Boston Scientific, and Cook Medical.

SOURCE: Khashab MA et al. Endosc Int Open. 2018 Aug 10. doi: 10.1055/a-0625-6288.

Peroral endoscopic myotomy (POEM) is safe and effective for several nonachalasia esophageal motility disorders, according to a retrospective study.

The procedure was clinically successful and relieved chest pain in most patients, reported Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Hospital in Baltimore.

POEM was introduced in 2008 as a less invasive alternative to laparoscopic Heller myotomy. During the procedure, submucosal tunneling is performed through the lower esophageal sphincter to the gastric cardia, thereby weakening the lower esophageal sphincter to allow passage of food.

POEM is clinically successful in 80%-90% of patients with achalasia. Although the procedure is regarded as safe and effective for achalasia, it has not been thoroughly researched for treatment of other esophageal motility disorders, including junction outflow obstruction (EGJOO), jackhammer esophagus (JE), or esophagogastric distal esophageal spasm (DES). EGJOO is similar to achalasia, but with peristalsis and a mean integrated relaxation pressure (IRP) greater than 15 mm Hg. Both JE and DES are spastic esophageal disorders. Patients with JE exhibit extreme esophageal hypercontractility, whereas patients with DES have a normal mean IRP and at least 20% premature contractions.

“The role POEM plays in management of these disorders is not clear, mainly due to scarcity of studies on this topic,” the authors wrote in Endoscopy International Open. “A previous multicenter study investigated the role of POEM in 73 patients with spastic esophageal disorders. However, the vast majority of patients (n = 54) in that study had type III (spastic) achalasia.” Since therapies such as botulinum toxin injections and calcium channel blockers are ineffective for many patients with nonachalasia esophageal motility disorders, “POEM is potentially an ideal treatment.”

The international, multicenter study involved 11 treatment centers and 50 patients. Patients with JE (n = 18), EGJOO (n = 15), and DES (n = 17) were included, each diagnosed according to the Chicago classification of esophageal motility disorders. Patients with type III achalasia were excluded.

Outcomes included technical success (completion of myotomy) and clinical success (Eckardt score at least 3 and symptom improvement). Prior to the procedure, the mean Eckardt score was 6.9 and chest pain was reported by almost three-quarters of the patients (72%).

Technical success was achieved in all patients. Myotomy thickness varied between cases; approximately half had a selective inner circular myotomy (48%), slightly less had a full-thickness myotomy (44%), and several were undefined (8%). Mean esophageal myotomy length was 12.5 cm and mean gastric myotomy length was 2.5 cm. Mean procedure time was approximately 90 minutes. Median duration of hospital stay was 2 days.

Nine adverse events (AEs) occurred in 8 patients, including submucosal hematoma, aspiration pneumonia, inadvertent mucosotomy, postprocedure pain, esophageal leak, bleed, and symptomatic capno-thorax/peritoneum.

“Although AEs occurred in 18% of patients,” the authors noted, “55.6% were rated as mild and 44.4% as moderate with no severe events. Most AEs can be managed intraprocedurally.”

Median follow-up time was approximately 8 months, during which 42 patients (87.5%) achieved clinical success, with many dramatically improved; over half of the patients (52%) had Eckardt scores of 0 or 1. From the group of patients who had chest pain prior to the procedure, 87% had resolution of chest pain. Although reflux developed in almost a quarter of the patients (22.2%), this was successfully managed with proton pump inhibitors in all instances. Most patients (82.9%) who underwent postoperative manometry had resolution of preoperative abnormalities.

Subgroup analysis was also performed. Clinical success was achieved in 94.1% of patients with DES, 93.3% of patients with EGJOO, and 75.0% with JE. Collectively, the spastic disorders (DES/JE) had a lower numerical response than EGJOO. However, the authors noted that “the difference was not statistically significant (P = .41), likely a type II error due to the relatively small number of included patients.” In all subgroups, postprocedural mean Eckardt scores decreased to less than 2. Patients with EGJOO were most likely to achieve Eckardt scores of 0 or 1. AEs were similar between subgroups.

“Remarkably, chest pain improved in more than 85% of patients,” the authors wrote. “Chest pain is frequently the major presenting symptom in these disorders and is difficult to treat.”

“It is important to mention that a long esophageal myotomy is essential to ensure that proximal esophageal spasms are effectively covered and treated,” the authors wrote. “Mean length of esophageal myotomy in patients with DES and JE in the current study was about 14 cm, which is more than twice the length of a typical endoscopic or surgical myotomy performed in achalasia patients.”

Even with the need for an extended myotomy, “results from the current study along with published data suggest POEM as an effective technique” for nonachalasia esophageal motility disorders, the authors concluded.

Since retrospective studies are inherently limited by design, the authors encouraged randomized trials to clarify the primary role of POEM in the management of nonachalasia esophageal motility disorders.

The authors reported compensation from Olympus, Boston Scientific, and Cook Medical.

SOURCE: Khashab MA et al. Endosc Int Open. 2018 Aug 10. doi: 10.1055/a-0625-6288.

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.

For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.

“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.

Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).

The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.

Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).

More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).

The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.

“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.

The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.

SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.

In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.

For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.

“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.

Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).

The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.

Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).

More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).

The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.

“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.

The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.

SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.

In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.

For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.

“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.

Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).

The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.

Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).

More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).

The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.

“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.

The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.

SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.