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What Ascites Might Mean in a Patient With HIV
A 53-year-old man presented to the hospital after gaining weight for 6 months and had developed peripheral edema and abdominal distension. He also had HIV for 32 years, had undergone a renal cadaveric transplant 2 years earlier, and had type 2 diabetes, coronary artery disease, and dyslipidemia. The patient was taking > 10 medications, including immunosuppressants and antiretrovirals.
Based on the physical examination and abdominal ultrasonography, the clinicians diagnosed the patient with ascites but could not confirm the cause. Although nonhepatic causes account for only about 15% of all ascites cases, the differential diagnosis includes malignant disease, lymphatic obstruction, and infections. But samples of ascitic fluid were negative for malignant disease and mycobacteria, and there was no evidence of lymphadenopathy. Lacking a definitive diagnosis, the clinicians decided on watchful waiting, with large-volume paracentesis every 2 to 3 weeks.
However, the patient returned to the hospital 1 week later with shortness of breath, nonproductive cough, and fever. Computed tomography (CT) scan showed small pleural effusions and consolidation in the lower lung. This time, a mycobacterial culture was positive for Mycobacterium avium (M avium ) complex.
Antimycobacterial drugs were added to his regimen, and his symptoms rapidly resolved. A CT scan confirmed improvement. Six months later, he was doing well, without recurrence.
The clinicians note that their patient was at increased risk because of the double toll HIV infection and the transplant had taken on his immune system. But the diagnosis was challenging because contrary to the school of thought that M avium complex infections are usually seen with CD4 count < 50 cells/µL, their patient’s count was 141 cells/µL at diagnosis.
When mycobacterial infections are suspected, patients may need extensive testing and close monitoring before the diagnosis can be made, the clinicians say. They suggest counseling patients about the potential need for invasive testing and the risks of possible diagnostic delay. Wherever possible, the clinicians add, patients with M avium complex should be overseen by infectious disease specialists and pharmacists to reduce the risk of harmful drug-drug interactions.
Source:
Auguste BL, Patel AD, Siemieniuk RA. CMAJ. 2018;190:E394-E387.
doi: 10.1503/cmaj.170823.
A 53-year-old man presented to the hospital after gaining weight for 6 months and had developed peripheral edema and abdominal distension. He also had HIV for 32 years, had undergone a renal cadaveric transplant 2 years earlier, and had type 2 diabetes, coronary artery disease, and dyslipidemia. The patient was taking > 10 medications, including immunosuppressants and antiretrovirals.
Based on the physical examination and abdominal ultrasonography, the clinicians diagnosed the patient with ascites but could not confirm the cause. Although nonhepatic causes account for only about 15% of all ascites cases, the differential diagnosis includes malignant disease, lymphatic obstruction, and infections. But samples of ascitic fluid were negative for malignant disease and mycobacteria, and there was no evidence of lymphadenopathy. Lacking a definitive diagnosis, the clinicians decided on watchful waiting, with large-volume paracentesis every 2 to 3 weeks.
However, the patient returned to the hospital 1 week later with shortness of breath, nonproductive cough, and fever. Computed tomography (CT) scan showed small pleural effusions and consolidation in the lower lung. This time, a mycobacterial culture was positive for Mycobacterium avium (M avium ) complex.
Antimycobacterial drugs were added to his regimen, and his symptoms rapidly resolved. A CT scan confirmed improvement. Six months later, he was doing well, without recurrence.
The clinicians note that their patient was at increased risk because of the double toll HIV infection and the transplant had taken on his immune system. But the diagnosis was challenging because contrary to the school of thought that M avium complex infections are usually seen with CD4 count < 50 cells/µL, their patient’s count was 141 cells/µL at diagnosis.
When mycobacterial infections are suspected, patients may need extensive testing and close monitoring before the diagnosis can be made, the clinicians say. They suggest counseling patients about the potential need for invasive testing and the risks of possible diagnostic delay. Wherever possible, the clinicians add, patients with M avium complex should be overseen by infectious disease specialists and pharmacists to reduce the risk of harmful drug-drug interactions.
Source:
Auguste BL, Patel AD, Siemieniuk RA. CMAJ. 2018;190:E394-E387.
doi: 10.1503/cmaj.170823.
A 53-year-old man presented to the hospital after gaining weight for 6 months and had developed peripheral edema and abdominal distension. He also had HIV for 32 years, had undergone a renal cadaveric transplant 2 years earlier, and had type 2 diabetes, coronary artery disease, and dyslipidemia. The patient was taking > 10 medications, including immunosuppressants and antiretrovirals.
Based on the physical examination and abdominal ultrasonography, the clinicians diagnosed the patient with ascites but could not confirm the cause. Although nonhepatic causes account for only about 15% of all ascites cases, the differential diagnosis includes malignant disease, lymphatic obstruction, and infections. But samples of ascitic fluid were negative for malignant disease and mycobacteria, and there was no evidence of lymphadenopathy. Lacking a definitive diagnosis, the clinicians decided on watchful waiting, with large-volume paracentesis every 2 to 3 weeks.
However, the patient returned to the hospital 1 week later with shortness of breath, nonproductive cough, and fever. Computed tomography (CT) scan showed small pleural effusions and consolidation in the lower lung. This time, a mycobacterial culture was positive for Mycobacterium avium (M avium ) complex.
Antimycobacterial drugs were added to his regimen, and his symptoms rapidly resolved. A CT scan confirmed improvement. Six months later, he was doing well, without recurrence.
The clinicians note that their patient was at increased risk because of the double toll HIV infection and the transplant had taken on his immune system. But the diagnosis was challenging because contrary to the school of thought that M avium complex infections are usually seen with CD4 count < 50 cells/µL, their patient’s count was 141 cells/µL at diagnosis.
When mycobacterial infections are suspected, patients may need extensive testing and close monitoring before the diagnosis can be made, the clinicians say. They suggest counseling patients about the potential need for invasive testing and the risks of possible diagnostic delay. Wherever possible, the clinicians add, patients with M avium complex should be overseen by infectious disease specialists and pharmacists to reduce the risk of harmful drug-drug interactions.
Source:
Auguste BL, Patel AD, Siemieniuk RA. CMAJ. 2018;190:E394-E387.
doi: 10.1503/cmaj.170823.
MSC product can treat refractory GVHD
MONTRÉAL—Results from a phase 3 trial suggest a mesenchymal stem cell (MSC) product can treat steroid-refractory, acute graft-versus-host disease (GVHD) in children.
The product, remestemcel-L (MSC-100-IV), produced an overall response rate of 69% at day 28, with complete resolution of GVHD in 29% of patients.
Adverse events (AEs) in this trial were consistent with the known safety profile of remestemcel-L.
Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina, presented these results at ISCT 2018.
The trial was sponsored by Mesoblast International Sàrl, the company developing remestemcel-L.
Remestemcel-L consists of human MSCs derived from donor bone marrow and expanded in culture.
Patients
The trial enrolled 55 patients who had acute GVHD and had failed to respond to steroid treatment. This was defined as progression within 3 days or no improvement within 7 days of consecutive treatment with at least 2 mg/kg/day of methylprednisolone or an equivalent product.
The patients had a median age of 7.6 years (range, 0.6 years to 17.9 years) at baseline, and 64% were male. Underlying diseases include acute myeloid leukemia (32.7%), acute lymphoblastic leukemia (21.8%), anemia (9.1%), chronic myeloid leukemia (7.3%), sickle cell disease (5.5%), juvenile myelomonocytic leukemia (3.6%), myelodysplastic syndromes (3.6%), and “other” disease (16.4%).
Most patients (87%) had received myeloablative conditioning, most (76%) had an unrelated donor, and roughly half (51%) received an HLA-mismatched transplant.
Fifty-five percent of patients received a bone marrow transplant, 25% received peripheral blood stem cells, and 20% received cord blood.
Forty-seven percent of patients had grade D GVHD at baseline, 42% had grade C, and 11% had grade B. Thirty-six percent of patients had multi-organ involvement (all with lower gastrointestinal), 38% had lower gastrointestinal involvement only, and 26% had skin involvement only.
Results
Fifty-four patients were treated with remestemcel-L. They received 8 injections over 4 weeks (twice weekly), consisting of 2 million cells per kg per injection.
The overall response rate at day 28 was 69%. Twenty-nine percent of patients achieved a complete response, defined as resolution of acute GVHD in all involved organs.
Forty percent of patients achieved a partial response, defined as organ-level improvement of at least one stage without worsening of any other organ.
All patients reported at least one treatment-emergent AE, and 61% had serious treatment-emergent AEs. The most common of these were infection (33%) and respiratory events (20%).
Four patients withdrew from the trial before day 100. One patient couldn’t receive treatment, 1 withdrew due to an AE (somnolence), 1 had parental consent withdrawn, and 1 was taken off study by the principal investigator.
There were 11 on-study deaths, but none were considered related to remestemcel-L. Eight deaths were due to infection, 1 due to GVHD progression, and 2 due to primary cancer relapse.
The day-100 survival analysis is pending.
MONTRÉAL—Results from a phase 3 trial suggest a mesenchymal stem cell (MSC) product can treat steroid-refractory, acute graft-versus-host disease (GVHD) in children.
The product, remestemcel-L (MSC-100-IV), produced an overall response rate of 69% at day 28, with complete resolution of GVHD in 29% of patients.
Adverse events (AEs) in this trial were consistent with the known safety profile of remestemcel-L.
Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina, presented these results at ISCT 2018.
The trial was sponsored by Mesoblast International Sàrl, the company developing remestemcel-L.
Remestemcel-L consists of human MSCs derived from donor bone marrow and expanded in culture.
Patients
The trial enrolled 55 patients who had acute GVHD and had failed to respond to steroid treatment. This was defined as progression within 3 days or no improvement within 7 days of consecutive treatment with at least 2 mg/kg/day of methylprednisolone or an equivalent product.
The patients had a median age of 7.6 years (range, 0.6 years to 17.9 years) at baseline, and 64% were male. Underlying diseases include acute myeloid leukemia (32.7%), acute lymphoblastic leukemia (21.8%), anemia (9.1%), chronic myeloid leukemia (7.3%), sickle cell disease (5.5%), juvenile myelomonocytic leukemia (3.6%), myelodysplastic syndromes (3.6%), and “other” disease (16.4%).
Most patients (87%) had received myeloablative conditioning, most (76%) had an unrelated donor, and roughly half (51%) received an HLA-mismatched transplant.
Fifty-five percent of patients received a bone marrow transplant, 25% received peripheral blood stem cells, and 20% received cord blood.
Forty-seven percent of patients had grade D GVHD at baseline, 42% had grade C, and 11% had grade B. Thirty-six percent of patients had multi-organ involvement (all with lower gastrointestinal), 38% had lower gastrointestinal involvement only, and 26% had skin involvement only.
Results
Fifty-four patients were treated with remestemcel-L. They received 8 injections over 4 weeks (twice weekly), consisting of 2 million cells per kg per injection.
The overall response rate at day 28 was 69%. Twenty-nine percent of patients achieved a complete response, defined as resolution of acute GVHD in all involved organs.
Forty percent of patients achieved a partial response, defined as organ-level improvement of at least one stage without worsening of any other organ.
All patients reported at least one treatment-emergent AE, and 61% had serious treatment-emergent AEs. The most common of these were infection (33%) and respiratory events (20%).
Four patients withdrew from the trial before day 100. One patient couldn’t receive treatment, 1 withdrew due to an AE (somnolence), 1 had parental consent withdrawn, and 1 was taken off study by the principal investigator.
There were 11 on-study deaths, but none were considered related to remestemcel-L. Eight deaths were due to infection, 1 due to GVHD progression, and 2 due to primary cancer relapse.
The day-100 survival analysis is pending.
MONTRÉAL—Results from a phase 3 trial suggest a mesenchymal stem cell (MSC) product can treat steroid-refractory, acute graft-versus-host disease (GVHD) in children.
The product, remestemcel-L (MSC-100-IV), produced an overall response rate of 69% at day 28, with complete resolution of GVHD in 29% of patients.
Adverse events (AEs) in this trial were consistent with the known safety profile of remestemcel-L.
Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina, presented these results at ISCT 2018.
The trial was sponsored by Mesoblast International Sàrl, the company developing remestemcel-L.
Remestemcel-L consists of human MSCs derived from donor bone marrow and expanded in culture.
Patients
The trial enrolled 55 patients who had acute GVHD and had failed to respond to steroid treatment. This was defined as progression within 3 days or no improvement within 7 days of consecutive treatment with at least 2 mg/kg/day of methylprednisolone or an equivalent product.
The patients had a median age of 7.6 years (range, 0.6 years to 17.9 years) at baseline, and 64% were male. Underlying diseases include acute myeloid leukemia (32.7%), acute lymphoblastic leukemia (21.8%), anemia (9.1%), chronic myeloid leukemia (7.3%), sickle cell disease (5.5%), juvenile myelomonocytic leukemia (3.6%), myelodysplastic syndromes (3.6%), and “other” disease (16.4%).
Most patients (87%) had received myeloablative conditioning, most (76%) had an unrelated donor, and roughly half (51%) received an HLA-mismatched transplant.
Fifty-five percent of patients received a bone marrow transplant, 25% received peripheral blood stem cells, and 20% received cord blood.
Forty-seven percent of patients had grade D GVHD at baseline, 42% had grade C, and 11% had grade B. Thirty-six percent of patients had multi-organ involvement (all with lower gastrointestinal), 38% had lower gastrointestinal involvement only, and 26% had skin involvement only.
Results
Fifty-four patients were treated with remestemcel-L. They received 8 injections over 4 weeks (twice weekly), consisting of 2 million cells per kg per injection.
The overall response rate at day 28 was 69%. Twenty-nine percent of patients achieved a complete response, defined as resolution of acute GVHD in all involved organs.
Forty percent of patients achieved a partial response, defined as organ-level improvement of at least one stage without worsening of any other organ.
All patients reported at least one treatment-emergent AE, and 61% had serious treatment-emergent AEs. The most common of these were infection (33%) and respiratory events (20%).
Four patients withdrew from the trial before day 100. One patient couldn’t receive treatment, 1 withdrew due to an AE (somnolence), 1 had parental consent withdrawn, and 1 was taken off study by the principal investigator.
There were 11 on-study deaths, but none were considered related to remestemcel-L. Eight deaths were due to infection, 1 due to GVHD progression, and 2 due to primary cancer relapse.
The day-100 survival analysis is pending.
Galinpepimut-S receives orphan designation for MM
The US Food and Drug Administration (FDA) has granted orphan drug designation to galinpepimut-S (GPS) as a treatment for multiple myeloma (MM).
GPS is an immunotherapeutic that targets malignancies characterized by overexpression of the Wilms tumor 1 (WT1) antigen.
GPS consists of 4 peptide chains, 2 of which are modified chains that induce an innate immune response (CD4+/CD8+) against the WT1 antigen and access a range of HLA types.
When GPS is administered to a patient, the induced immune response has the potential to recognize and destroy cancer cells and provide ongoing support to the immune system so it can continue to target and destroy residual cancer cells.
GPS also has orphan designation from the FDA for the treatment of acute myeloid leukemia and malignant plural mesothelioma.
Phase 2 trial
GPS has been investigated in a phase 2 trial of MM patients. Results from this trial were recently presented at the 44th Annual Meeting of the EBMT.
Researchers evaluated GPS in combination with lenalidomide as maintenance therapy in MM patients who received an autologous stem cell transplant (ASCT).
The study enrolled 19 patients who began receiving GPS within 22 days of ASCT. They received 6 doses every 2 weeks. (Injection sites were pre-stimulated with granulocyte-macrophage colony-stimulating factor.)
Patients received 6 additional monthly doses of GPS as well as lenalidomide maintenance (10 mg daily) starting on day 100 post-ASCT.
Twelve patients received all 12 doses of GPS. Eleven patients achieved a complete response or very good partial response. All of these patients had CD4 immune responses, and 9 of them had CD8 immune responses.
The progression-free survival was 81% at 12 months and 62% at 18 months. The median progression-free survival was 23.6 months (range, 15.2 to not reached).
The overall survival was 88% at 18 months, and the median overall survival was not reached.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to galinpepimut-S (GPS) as a treatment for multiple myeloma (MM).
GPS is an immunotherapeutic that targets malignancies characterized by overexpression of the Wilms tumor 1 (WT1) antigen.
GPS consists of 4 peptide chains, 2 of which are modified chains that induce an innate immune response (CD4+/CD8+) against the WT1 antigen and access a range of HLA types.
When GPS is administered to a patient, the induced immune response has the potential to recognize and destroy cancer cells and provide ongoing support to the immune system so it can continue to target and destroy residual cancer cells.
GPS also has orphan designation from the FDA for the treatment of acute myeloid leukemia and malignant plural mesothelioma.
Phase 2 trial
GPS has been investigated in a phase 2 trial of MM patients. Results from this trial were recently presented at the 44th Annual Meeting of the EBMT.
Researchers evaluated GPS in combination with lenalidomide as maintenance therapy in MM patients who received an autologous stem cell transplant (ASCT).
The study enrolled 19 patients who began receiving GPS within 22 days of ASCT. They received 6 doses every 2 weeks. (Injection sites were pre-stimulated with granulocyte-macrophage colony-stimulating factor.)
Patients received 6 additional monthly doses of GPS as well as lenalidomide maintenance (10 mg daily) starting on day 100 post-ASCT.
Twelve patients received all 12 doses of GPS. Eleven patients achieved a complete response or very good partial response. All of these patients had CD4 immune responses, and 9 of them had CD8 immune responses.
The progression-free survival was 81% at 12 months and 62% at 18 months. The median progression-free survival was 23.6 months (range, 15.2 to not reached).
The overall survival was 88% at 18 months, and the median overall survival was not reached.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to galinpepimut-S (GPS) as a treatment for multiple myeloma (MM).
GPS is an immunotherapeutic that targets malignancies characterized by overexpression of the Wilms tumor 1 (WT1) antigen.
GPS consists of 4 peptide chains, 2 of which are modified chains that induce an innate immune response (CD4+/CD8+) against the WT1 antigen and access a range of HLA types.
When GPS is administered to a patient, the induced immune response has the potential to recognize and destroy cancer cells and provide ongoing support to the immune system so it can continue to target and destroy residual cancer cells.
GPS also has orphan designation from the FDA for the treatment of acute myeloid leukemia and malignant plural mesothelioma.
Phase 2 trial
GPS has been investigated in a phase 2 trial of MM patients. Results from this trial were recently presented at the 44th Annual Meeting of the EBMT.
Researchers evaluated GPS in combination with lenalidomide as maintenance therapy in MM patients who received an autologous stem cell transplant (ASCT).
The study enrolled 19 patients who began receiving GPS within 22 days of ASCT. They received 6 doses every 2 weeks. (Injection sites were pre-stimulated with granulocyte-macrophage colony-stimulating factor.)
Patients received 6 additional monthly doses of GPS as well as lenalidomide maintenance (10 mg daily) starting on day 100 post-ASCT.
Twelve patients received all 12 doses of GPS. Eleven patients achieved a complete response or very good partial response. All of these patients had CD4 immune responses, and 9 of them had CD8 immune responses.
The progression-free survival was 81% at 12 months and 62% at 18 months. The median progression-free survival was 23.6 months (range, 15.2 to not reached).
The overall survival was 88% at 18 months, and the median overall survival was not reached.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Gender equity in surgery: It’s complicated
For most of my professional life I have avoided writing about gender inequity in the field of surgery – not because I believe it does not exist, but because the reasons it does exist are manifold and complicated.
To be sure, implicit and explicit bias remain important reasons why only a minority of female medical students still choose surgery as a career in 2018, why female surgeons still earn only 82% of the salary of their male counterparts, and why women occupy only 12% of the chairs in academic surgical departments in the United States. It has long been tempting to lay the blame for those inequities on a stereotypical macho surgical culture that prevailed as the 20th century came to a close. But the factors that perpetuate male/female imbalance in our profession are complicated and run deep in the psyches of both men and women. We are all products of our generations, our culture, upbringing, and environment – men as well as women. Correcting the imbalance requires much more than simply passing laws that require equitable pay or treatment.
I realized how deeply ingrained biases are in all of us while still in my surgical residency in the 1970s. On a rare occasion when neither my husband (also a surgical resident) nor I was on call, we had a dinner party with friends at our house. The telephone rang (no iPhones, just a land line), and I ran to answer our only telephone in another room. It was the hospital operator, who asked, “Is Dr. Deveney there?” Without thinking, I answered, “Just a moment, I’ll get him!” I had taken only three steps away from the phone when it occurred to me what I had just said. I turned back, picked up the phone, and asked, “Which Dr. Deveney were you looking for?”
If even I had been conditioned to think automatically of “doctor” being a man after all of my effort to earn a place in the ranks, was there any hope that equality could be achieved? When I finished my residency and was offered a surgery position at our VA, I asked no questions about salary or other particulars; I was simply grateful that I had been given a job.
That was 1978 – a different time, a different generation. Since then, women have made dramatic progress toward equity in our profession, as in many others. The support, mentoring, and consciousness-raising efforts of the Association of Women Surgeons (AWS) are responsible for much of this progress. The American College of Surgeons was very supportive of the AWS early on and continues to encourage female medical students to choose surgery as a career and to help the advancement of women into leadership roles in surgery. Many surgical residency programs have 50% women in their ranks; half of our residents in Oregon have been women for over a decade. Our program director is a woman, as are 28% of the faculty; not 50%, but definitely progress, since I was the lone woman on the faculty when I arrived in 1987.
Although women occupy only 12% of the surgical chairs in U.S. surgical departments, this number has soared in the past 2 years from 7 in 2016 to 21 this year after languishing in the low single digits since 1987, when the late Olga Jonasson, MD, FACS, became the first female chair at Ohio State University. And yet, women have not reached full equality with men across the United States in surgical training, leadership, or pay. Why not?
Multiple factors have played roles in impeding the progress of women in achieving equality in surgery. Traditional cultural expectations of male and female roles in society affect both genders as they grow up, even when their parents make deliberate efforts to raise their children in as “gender-neutral” a way as possible and encourage their daughters to strive for success to the same degree as their sons. Explicit bias against women remains easier to recognize and combat than implicit or unconscious bias, to which we are all subject.
We have only recently begun to acknowledge and attempt to dispel implicit bias and much work remains to be done if we are to reach a level playing field that is gender neutral. The book, “Why So Slow?” by Virginia Valian (Cambridge, Mass.: The MIT Press, 1998) offered valuable insights that helped me understand why we behave as we do and how our departments and institutions might become more equitable to all. Women tend to underrate their abilities and attribute their success to luck rather than superior performance, to believe that they are less qualified for higher pay or promotion than men are, and to be less assertive than men in negotiations. It will require conscious vigilance and effort by both sexes as well as by institutions themselves to educate all about the criteria necessary for advancement. Institutions need to develop training for all in recognizing and eliminating implicit bias, and in implementing clear and explicit criteria for compensation and promotion, making sure that all faculty are educated to understand what those criteria are.
Dr. Deveney is professor of surgery and vice chair of education in the department of surgery, Oregon Health & Science University, Portland. She is the coeditor of ACS Surgery News.
For most of my professional life I have avoided writing about gender inequity in the field of surgery – not because I believe it does not exist, but because the reasons it does exist are manifold and complicated.
To be sure, implicit and explicit bias remain important reasons why only a minority of female medical students still choose surgery as a career in 2018, why female surgeons still earn only 82% of the salary of their male counterparts, and why women occupy only 12% of the chairs in academic surgical departments in the United States. It has long been tempting to lay the blame for those inequities on a stereotypical macho surgical culture that prevailed as the 20th century came to a close. But the factors that perpetuate male/female imbalance in our profession are complicated and run deep in the psyches of both men and women. We are all products of our generations, our culture, upbringing, and environment – men as well as women. Correcting the imbalance requires much more than simply passing laws that require equitable pay or treatment.
I realized how deeply ingrained biases are in all of us while still in my surgical residency in the 1970s. On a rare occasion when neither my husband (also a surgical resident) nor I was on call, we had a dinner party with friends at our house. The telephone rang (no iPhones, just a land line), and I ran to answer our only telephone in another room. It was the hospital operator, who asked, “Is Dr. Deveney there?” Without thinking, I answered, “Just a moment, I’ll get him!” I had taken only three steps away from the phone when it occurred to me what I had just said. I turned back, picked up the phone, and asked, “Which Dr. Deveney were you looking for?”
If even I had been conditioned to think automatically of “doctor” being a man after all of my effort to earn a place in the ranks, was there any hope that equality could be achieved? When I finished my residency and was offered a surgery position at our VA, I asked no questions about salary or other particulars; I was simply grateful that I had been given a job.
That was 1978 – a different time, a different generation. Since then, women have made dramatic progress toward equity in our profession, as in many others. The support, mentoring, and consciousness-raising efforts of the Association of Women Surgeons (AWS) are responsible for much of this progress. The American College of Surgeons was very supportive of the AWS early on and continues to encourage female medical students to choose surgery as a career and to help the advancement of women into leadership roles in surgery. Many surgical residency programs have 50% women in their ranks; half of our residents in Oregon have been women for over a decade. Our program director is a woman, as are 28% of the faculty; not 50%, but definitely progress, since I was the lone woman on the faculty when I arrived in 1987.
Although women occupy only 12% of the surgical chairs in U.S. surgical departments, this number has soared in the past 2 years from 7 in 2016 to 21 this year after languishing in the low single digits since 1987, when the late Olga Jonasson, MD, FACS, became the first female chair at Ohio State University. And yet, women have not reached full equality with men across the United States in surgical training, leadership, or pay. Why not?
Multiple factors have played roles in impeding the progress of women in achieving equality in surgery. Traditional cultural expectations of male and female roles in society affect both genders as they grow up, even when their parents make deliberate efforts to raise their children in as “gender-neutral” a way as possible and encourage their daughters to strive for success to the same degree as their sons. Explicit bias against women remains easier to recognize and combat than implicit or unconscious bias, to which we are all subject.
We have only recently begun to acknowledge and attempt to dispel implicit bias and much work remains to be done if we are to reach a level playing field that is gender neutral. The book, “Why So Slow?” by Virginia Valian (Cambridge, Mass.: The MIT Press, 1998) offered valuable insights that helped me understand why we behave as we do and how our departments and institutions might become more equitable to all. Women tend to underrate their abilities and attribute their success to luck rather than superior performance, to believe that they are less qualified for higher pay or promotion than men are, and to be less assertive than men in negotiations. It will require conscious vigilance and effort by both sexes as well as by institutions themselves to educate all about the criteria necessary for advancement. Institutions need to develop training for all in recognizing and eliminating implicit bias, and in implementing clear and explicit criteria for compensation and promotion, making sure that all faculty are educated to understand what those criteria are.
Dr. Deveney is professor of surgery and vice chair of education in the department of surgery, Oregon Health & Science University, Portland. She is the coeditor of ACS Surgery News.
For most of my professional life I have avoided writing about gender inequity in the field of surgery – not because I believe it does not exist, but because the reasons it does exist are manifold and complicated.
To be sure, implicit and explicit bias remain important reasons why only a minority of female medical students still choose surgery as a career in 2018, why female surgeons still earn only 82% of the salary of their male counterparts, and why women occupy only 12% of the chairs in academic surgical departments in the United States. It has long been tempting to lay the blame for those inequities on a stereotypical macho surgical culture that prevailed as the 20th century came to a close. But the factors that perpetuate male/female imbalance in our profession are complicated and run deep in the psyches of both men and women. We are all products of our generations, our culture, upbringing, and environment – men as well as women. Correcting the imbalance requires much more than simply passing laws that require equitable pay or treatment.
I realized how deeply ingrained biases are in all of us while still in my surgical residency in the 1970s. On a rare occasion when neither my husband (also a surgical resident) nor I was on call, we had a dinner party with friends at our house. The telephone rang (no iPhones, just a land line), and I ran to answer our only telephone in another room. It was the hospital operator, who asked, “Is Dr. Deveney there?” Without thinking, I answered, “Just a moment, I’ll get him!” I had taken only three steps away from the phone when it occurred to me what I had just said. I turned back, picked up the phone, and asked, “Which Dr. Deveney were you looking for?”
If even I had been conditioned to think automatically of “doctor” being a man after all of my effort to earn a place in the ranks, was there any hope that equality could be achieved? When I finished my residency and was offered a surgery position at our VA, I asked no questions about salary or other particulars; I was simply grateful that I had been given a job.
That was 1978 – a different time, a different generation. Since then, women have made dramatic progress toward equity in our profession, as in many others. The support, mentoring, and consciousness-raising efforts of the Association of Women Surgeons (AWS) are responsible for much of this progress. The American College of Surgeons was very supportive of the AWS early on and continues to encourage female medical students to choose surgery as a career and to help the advancement of women into leadership roles in surgery. Many surgical residency programs have 50% women in their ranks; half of our residents in Oregon have been women for over a decade. Our program director is a woman, as are 28% of the faculty; not 50%, but definitely progress, since I was the lone woman on the faculty when I arrived in 1987.
Although women occupy only 12% of the surgical chairs in U.S. surgical departments, this number has soared in the past 2 years from 7 in 2016 to 21 this year after languishing in the low single digits since 1987, when the late Olga Jonasson, MD, FACS, became the first female chair at Ohio State University. And yet, women have not reached full equality with men across the United States in surgical training, leadership, or pay. Why not?
Multiple factors have played roles in impeding the progress of women in achieving equality in surgery. Traditional cultural expectations of male and female roles in society affect both genders as they grow up, even when their parents make deliberate efforts to raise their children in as “gender-neutral” a way as possible and encourage their daughters to strive for success to the same degree as their sons. Explicit bias against women remains easier to recognize and combat than implicit or unconscious bias, to which we are all subject.
We have only recently begun to acknowledge and attempt to dispel implicit bias and much work remains to be done if we are to reach a level playing field that is gender neutral. The book, “Why So Slow?” by Virginia Valian (Cambridge, Mass.: The MIT Press, 1998) offered valuable insights that helped me understand why we behave as we do and how our departments and institutions might become more equitable to all. Women tend to underrate their abilities and attribute their success to luck rather than superior performance, to believe that they are less qualified for higher pay or promotion than men are, and to be less assertive than men in negotiations. It will require conscious vigilance and effort by both sexes as well as by institutions themselves to educate all about the criteria necessary for advancement. Institutions need to develop training for all in recognizing and eliminating implicit bias, and in implementing clear and explicit criteria for compensation and promotion, making sure that all faculty are educated to understand what those criteria are.
Dr. Deveney is professor of surgery and vice chair of education in the department of surgery, Oregon Health & Science University, Portland. She is the coeditor of ACS Surgery News.
Upping the game of surgical researchers
Many are submitted, but few are chosen.
Concerned about the quality of submitted research papers based on large surgical databases that are not accepted for publication, the editorial board of JAMA Surgery has taken the initiative by giving some pointers to would-be authors. The journal editors have published a 10-point checklist of dos and don’ts to address commonly seen problems with submitted manuscripts. In addition, JAMA Surgery collaborated with the Surgical Outcomes Club to commission a series of practical guides on the most widely used data sets in an effort to improve the quality of surgical database research. The Surgical Outcomes Club is a consortium of surgeons and scientists who work to advance health services and outcomes research in surgery that was launched in 2005 at the American College of Surgeons Clinical Congress.
The authors noted that, although JAMA Surgery receives hundreds of submissions of retrospective studies of large surgical databases each year, most of these studies have flaws in the data analysis or use a hypothesis that the data sets cannot address. Hence, the editors do not send most of them out for peer review. “Of those that are sent out for peer review, many are recommended to be rejected by expert peer reviewers as they find major methodological flaws in the use of these otherwise powerful data sets,” the team wrote.
“Research using data sets can be very powerful as the research can address questions and hypotheses using large populations of people. However, the research can have many weaknesses. First, the research is only as good as the data collection for each data set. Second, the investigator needs to be familiar with the types of research questions and hypotheses that can be addressed with each data set. Third, the statistical methodology used to analyze the data is also imperative,” said Dr. Kibbe in an interview.
The checklist begins with a recommendation that the researchers develop a clear, concise hypothesis using established criteria – either FINER (for feasible, interesting, novel, ethical, relevant) or PICO (patient, population, or problem; intervention, prognostic factor, or exposure; comparison or intervention; outcome); the checklist then goes on to include compliance with institutional review board and data use agreements and to emphasize the importance of a clear take-home message that addresses policy or clinical implications.
The series comprises 11 two-page articles that aim to serve as practical guides for using each of the most widely used surgical data sets, starting with the National Inpatient Sample and ending with the Society of Thoracic Surgeons data set. Each article includes a bulleted list of the data set’s attributes, an explanation of its limitations, a history of the data set, an explanation of how the data is collected and what is unique about the set’s features, and statistical considerations researchers should take into account when analyzing the data.
The series concludes with tips from the statistical editors of JAMA Surgery – Amy H. Kaji, MD, PhD, of Harbor–University of California Los Angeles Medical Center in Torrance; Alfred W. Rademaker, PhD, of Northwestern University, Chicago; and Terry Hyslop, PhD, of Duke University, Durham, N.C. – for performing statistical analysis of large data sets: “With bigger data, random signals may denote statistical significance, and precision may be incorrectly inferred because of narrow confidence intervals,” the statistical editors noted. “While many principles apply to all studies, the importance of these methodological issues is amplified in large, complex data sets.”
However, they noted that large data sets are prone to bias and measurement errors. “It is important to respect and acknowledge the limitations of the data,” the statistical team wrote. They also reprise the introductory editorial’s call for a clear hypothesis and take-home message. “The challenge with Big Data is that it requires a carefully thought-out research question and a transparent analytic strategy,” the statistical editors said.
And there are pitfalls. Dr. Bilimoria noted, “We shouldn’t let the database define our research. We should instead be asking interesting questions and then seeking out a database that fits best to answer the question.” He said one particular problem that comes up often for reviewers is trying to discern how researchers arrived at the population of interest in a study. “A lot of inclusion and exclusions criteria are applied, and unless [the reviewer] can see the decisions that were made in the process, some fairly important biases can be introduced unintentionally. We as reviewers would like to be able to follow that exclusion pathway.”
He said, “A problem we frequently see is that these databases change the variable definitions over time – in fact, change the variables over time. So if researchers aren’t checking to see if that variable was reported the same every year of the study and in the same way, they will get spurious results. Similarly, the number of hospitals reporting is important as well since hospitals come in and out of these data sets.”
In their introductory editorial, the JAMA Surgery team noted that the checklist, practical guides, and statistical tips are a three-pronged approach that authors should consult before submitting their manuscripts. “We hope that by following these simple guides, authors can benefit from the collective wisdom of so many colleagues who have successfully completed similar analyses in the past,” they wrote.
Dr. Bilimoria sees great strengths in database research, such as giving researchers a population-level view of how care is being delivered, insights into the outcomes of care, indications of the effects of policy decisions, and data on rare diseases and operations.
Big Data of all kinds will be increasingly available for researchers. Dr. Kibbe commented that, “In the future, having a comprehensive (not sampling) country- or worldwide electronic medical record that will allow for robust inclusion of all medical data at the individual as well as cohort level will greatly contribute to the era of personalized medicine. In my opinion, this would be a real-time inclusive medical database that would allow for individual as well as population-based prospective studies.”
Dr. Haider receives support from the Henry M. Jackson Foundation of the Department of Defense, the Orthopaedic Research and Education Foundation, and the National Institutes of Health, and nonfinancial research support the Centers for Medicare and Medicaid Services Office of Minority Health. Dr. Bilimoria was the president of the Surgical Outcomes Club from 2016 to 2017.
Many are submitted, but few are chosen.
Concerned about the quality of submitted research papers based on large surgical databases that are not accepted for publication, the editorial board of JAMA Surgery has taken the initiative by giving some pointers to would-be authors. The journal editors have published a 10-point checklist of dos and don’ts to address commonly seen problems with submitted manuscripts. In addition, JAMA Surgery collaborated with the Surgical Outcomes Club to commission a series of practical guides on the most widely used data sets in an effort to improve the quality of surgical database research. The Surgical Outcomes Club is a consortium of surgeons and scientists who work to advance health services and outcomes research in surgery that was launched in 2005 at the American College of Surgeons Clinical Congress.
The authors noted that, although JAMA Surgery receives hundreds of submissions of retrospective studies of large surgical databases each year, most of these studies have flaws in the data analysis or use a hypothesis that the data sets cannot address. Hence, the editors do not send most of them out for peer review. “Of those that are sent out for peer review, many are recommended to be rejected by expert peer reviewers as they find major methodological flaws in the use of these otherwise powerful data sets,” the team wrote.
“Research using data sets can be very powerful as the research can address questions and hypotheses using large populations of people. However, the research can have many weaknesses. First, the research is only as good as the data collection for each data set. Second, the investigator needs to be familiar with the types of research questions and hypotheses that can be addressed with each data set. Third, the statistical methodology used to analyze the data is also imperative,” said Dr. Kibbe in an interview.
The checklist begins with a recommendation that the researchers develop a clear, concise hypothesis using established criteria – either FINER (for feasible, interesting, novel, ethical, relevant) or PICO (patient, population, or problem; intervention, prognostic factor, or exposure; comparison or intervention; outcome); the checklist then goes on to include compliance with institutional review board and data use agreements and to emphasize the importance of a clear take-home message that addresses policy or clinical implications.
The series comprises 11 two-page articles that aim to serve as practical guides for using each of the most widely used surgical data sets, starting with the National Inpatient Sample and ending with the Society of Thoracic Surgeons data set. Each article includes a bulleted list of the data set’s attributes, an explanation of its limitations, a history of the data set, an explanation of how the data is collected and what is unique about the set’s features, and statistical considerations researchers should take into account when analyzing the data.
The series concludes with tips from the statistical editors of JAMA Surgery – Amy H. Kaji, MD, PhD, of Harbor–University of California Los Angeles Medical Center in Torrance; Alfred W. Rademaker, PhD, of Northwestern University, Chicago; and Terry Hyslop, PhD, of Duke University, Durham, N.C. – for performing statistical analysis of large data sets: “With bigger data, random signals may denote statistical significance, and precision may be incorrectly inferred because of narrow confidence intervals,” the statistical editors noted. “While many principles apply to all studies, the importance of these methodological issues is amplified in large, complex data sets.”
However, they noted that large data sets are prone to bias and measurement errors. “It is important to respect and acknowledge the limitations of the data,” the statistical team wrote. They also reprise the introductory editorial’s call for a clear hypothesis and take-home message. “The challenge with Big Data is that it requires a carefully thought-out research question and a transparent analytic strategy,” the statistical editors said.
And there are pitfalls. Dr. Bilimoria noted, “We shouldn’t let the database define our research. We should instead be asking interesting questions and then seeking out a database that fits best to answer the question.” He said one particular problem that comes up often for reviewers is trying to discern how researchers arrived at the population of interest in a study. “A lot of inclusion and exclusions criteria are applied, and unless [the reviewer] can see the decisions that were made in the process, some fairly important biases can be introduced unintentionally. We as reviewers would like to be able to follow that exclusion pathway.”
He said, “A problem we frequently see is that these databases change the variable definitions over time – in fact, change the variables over time. So if researchers aren’t checking to see if that variable was reported the same every year of the study and in the same way, they will get spurious results. Similarly, the number of hospitals reporting is important as well since hospitals come in and out of these data sets.”
In their introductory editorial, the JAMA Surgery team noted that the checklist, practical guides, and statistical tips are a three-pronged approach that authors should consult before submitting their manuscripts. “We hope that by following these simple guides, authors can benefit from the collective wisdom of so many colleagues who have successfully completed similar analyses in the past,” they wrote.
Dr. Bilimoria sees great strengths in database research, such as giving researchers a population-level view of how care is being delivered, insights into the outcomes of care, indications of the effects of policy decisions, and data on rare diseases and operations.
Big Data of all kinds will be increasingly available for researchers. Dr. Kibbe commented that, “In the future, having a comprehensive (not sampling) country- or worldwide electronic medical record that will allow for robust inclusion of all medical data at the individual as well as cohort level will greatly contribute to the era of personalized medicine. In my opinion, this would be a real-time inclusive medical database that would allow for individual as well as population-based prospective studies.”
Dr. Haider receives support from the Henry M. Jackson Foundation of the Department of Defense, the Orthopaedic Research and Education Foundation, and the National Institutes of Health, and nonfinancial research support the Centers for Medicare and Medicaid Services Office of Minority Health. Dr. Bilimoria was the president of the Surgical Outcomes Club from 2016 to 2017.
Many are submitted, but few are chosen.
Concerned about the quality of submitted research papers based on large surgical databases that are not accepted for publication, the editorial board of JAMA Surgery has taken the initiative by giving some pointers to would-be authors. The journal editors have published a 10-point checklist of dos and don’ts to address commonly seen problems with submitted manuscripts. In addition, JAMA Surgery collaborated with the Surgical Outcomes Club to commission a series of practical guides on the most widely used data sets in an effort to improve the quality of surgical database research. The Surgical Outcomes Club is a consortium of surgeons and scientists who work to advance health services and outcomes research in surgery that was launched in 2005 at the American College of Surgeons Clinical Congress.
The authors noted that, although JAMA Surgery receives hundreds of submissions of retrospective studies of large surgical databases each year, most of these studies have flaws in the data analysis or use a hypothesis that the data sets cannot address. Hence, the editors do not send most of them out for peer review. “Of those that are sent out for peer review, many are recommended to be rejected by expert peer reviewers as they find major methodological flaws in the use of these otherwise powerful data sets,” the team wrote.
“Research using data sets can be very powerful as the research can address questions and hypotheses using large populations of people. However, the research can have many weaknesses. First, the research is only as good as the data collection for each data set. Second, the investigator needs to be familiar with the types of research questions and hypotheses that can be addressed with each data set. Third, the statistical methodology used to analyze the data is also imperative,” said Dr. Kibbe in an interview.
The checklist begins with a recommendation that the researchers develop a clear, concise hypothesis using established criteria – either FINER (for feasible, interesting, novel, ethical, relevant) or PICO (patient, population, or problem; intervention, prognostic factor, or exposure; comparison or intervention; outcome); the checklist then goes on to include compliance with institutional review board and data use agreements and to emphasize the importance of a clear take-home message that addresses policy or clinical implications.
The series comprises 11 two-page articles that aim to serve as practical guides for using each of the most widely used surgical data sets, starting with the National Inpatient Sample and ending with the Society of Thoracic Surgeons data set. Each article includes a bulleted list of the data set’s attributes, an explanation of its limitations, a history of the data set, an explanation of how the data is collected and what is unique about the set’s features, and statistical considerations researchers should take into account when analyzing the data.
The series concludes with tips from the statistical editors of JAMA Surgery – Amy H. Kaji, MD, PhD, of Harbor–University of California Los Angeles Medical Center in Torrance; Alfred W. Rademaker, PhD, of Northwestern University, Chicago; and Terry Hyslop, PhD, of Duke University, Durham, N.C. – for performing statistical analysis of large data sets: “With bigger data, random signals may denote statistical significance, and precision may be incorrectly inferred because of narrow confidence intervals,” the statistical editors noted. “While many principles apply to all studies, the importance of these methodological issues is amplified in large, complex data sets.”
However, they noted that large data sets are prone to bias and measurement errors. “It is important to respect and acknowledge the limitations of the data,” the statistical team wrote. They also reprise the introductory editorial’s call for a clear hypothesis and take-home message. “The challenge with Big Data is that it requires a carefully thought-out research question and a transparent analytic strategy,” the statistical editors said.
And there are pitfalls. Dr. Bilimoria noted, “We shouldn’t let the database define our research. We should instead be asking interesting questions and then seeking out a database that fits best to answer the question.” He said one particular problem that comes up often for reviewers is trying to discern how researchers arrived at the population of interest in a study. “A lot of inclusion and exclusions criteria are applied, and unless [the reviewer] can see the decisions that were made in the process, some fairly important biases can be introduced unintentionally. We as reviewers would like to be able to follow that exclusion pathway.”
He said, “A problem we frequently see is that these databases change the variable definitions over time – in fact, change the variables over time. So if researchers aren’t checking to see if that variable was reported the same every year of the study and in the same way, they will get spurious results. Similarly, the number of hospitals reporting is important as well since hospitals come in and out of these data sets.”
In their introductory editorial, the JAMA Surgery team noted that the checklist, practical guides, and statistical tips are a three-pronged approach that authors should consult before submitting their manuscripts. “We hope that by following these simple guides, authors can benefit from the collective wisdom of so many colleagues who have successfully completed similar analyses in the past,” they wrote.
Dr. Bilimoria sees great strengths in database research, such as giving researchers a population-level view of how care is being delivered, insights into the outcomes of care, indications of the effects of policy decisions, and data on rare diseases and operations.
Big Data of all kinds will be increasingly available for researchers. Dr. Kibbe commented that, “In the future, having a comprehensive (not sampling) country- or worldwide electronic medical record that will allow for robust inclusion of all medical data at the individual as well as cohort level will greatly contribute to the era of personalized medicine. In my opinion, this would be a real-time inclusive medical database that would allow for individual as well as population-based prospective studies.”
Dr. Haider receives support from the Henry M. Jackson Foundation of the Department of Defense, the Orthopaedic Research and Education Foundation, and the National Institutes of Health, and nonfinancial research support the Centers for Medicare and Medicaid Services Office of Minority Health. Dr. Bilimoria was the president of the Surgical Outcomes Club from 2016 to 2017.
FDA advisory committee recommends volanesorsen for rare triglyceride disorder
SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”
FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.
Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.
The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH, COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.
APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.
All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.
Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.
The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.
Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).
Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.
COMPASS
The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71% in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
APPROACH OPEN LABEL
The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”
The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.
SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”
FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.
Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.
The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH, COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.
APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.
All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.
Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.
The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.
Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).
Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.
COMPASS
The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71% in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
APPROACH OPEN LABEL
The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”
The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.
SILVER SPRING, Md. – A novel drug to treat a rare metabolic disorder was recommended for approval by the Endocrinologic and Metabolic Drugs Advisory Committee in a May 10 meeting.
Advisors voted 12 to 8 to recommend volanesorsen, a novel antisense drug, as an adjunct to diet for the treatment of familial chylomicronemia syndrome (FCS).
“The sponsor provided compelling evidence that the drug lowers triglyceride levels, substantially,” said panelist Jean-Pierre Raufman, MD, of the University of Maryland. I think that there is clearly a group of patients with this disease that can benefit from this agent.”
FCS is an extremely rare genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis caused by a deficiency in lipoprotein lipase. Pancreatitis in the setting of hypertriglyceridemia is particularly severe, often leading to multi-organ failure, pancreatic necrosis, and death.
Volanesorsen targets apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance.
Because of the small number of patients affected, estimated at just 3,000-5,000 patients worldwide, the FDA considers FCS to be an orphan disease.
The application, submitted by Akcea Pharmaceuticals, was based on the results of several phase 3 clinical trials conducted both in FCS patients and, because of the rarity of the disorder, patients with high triglycerides. The APPROACH study looked at patients with FCS. The COMPASS study examined patients with hypertriglyceridemia. Additionally, an ongoing, open-label extension of the APPROACH study examined patients with FCS who had completed APPROACH, COMPASS, and FCS patients who had not participated in a previous volanesorsen trial.
APPROACH APPROACH was a phase 3, double-blind clinical trial to assess the safety and efficacy of volanesorsen in patients with FCS. Because of the extremely small number of patients affected by FCS, non-FCS patients with hypertriglyceridemia were included in the trial.
All patients who had completed a 6 week diet, lifestyle, and medication stabilization period were enrolled in the study. In total, 67 patients were randomized to receive a weekly, subcutaneous 300 mg dose of volanesorsen or a placebo for 52 weeks. Due to the risk of platelet reduction, the study allowed for dosing schedule interruptions or pauses, if needed. To assess efficacy, the study looked at the percent change in fasting triglycerides at month 3 of the study in all randomized patients who received at least one dose of the study drug and who had baseline fasting plasma trigylcerides recorded.
Volanesorsen proved quite effective in reducing fasting triglyceride levels, with a 94% (P < 0.0001) reduction in plasma concentrations at 3 months, compared with placebo.
The effectiveness of volanesorsen extended beyond month 3, with statistically significant reductions in triglyceride concentrations at both month 6 and month 12 compared with placebo. Patients taking volanesorsen had 53% and 40% reductions at month 6 and 12 compared to baseline. Conversely, patients taking placebo experienced increases of 25% and 9%, respectively. The differences between volanesorsen and placebo patients at month 6 (–78%) and month 12 (–49%) were both statistically significant.
Another important finding from this study was that 77% of patients responded to treatment, evidenced by a reduction of triglyceride levels greater than 750 mg/dL, a much better response than the 10% of placebo patients (P =.0001).
Nine patients (27%) discontinued the study due to adverse events (AE). Five of the discontinuations were related to platelet reductions with the other four related to nonplatelet-related adverse events.
COMPASS
The COMPASS study primarily looked at patients without FCS, but severe hypertriglyceridemia, to evaluate the safety and efficacy of volanesorsen in a similarly ill, but less severe, population over a 6 month study period. Patients with FCS had baseline fasting plasma triglyceride levels of 2,644 mg/dL and 2,134 mg/dL in the placebo and volanesorsen groups, respectively. This is nearly double what was seen in non-FCS patients in the study, and is 14-17 higher than the upper limit of normal (ULN).
Researchers enrolled 114 patients and randomized them 2:1 to receive volanesorsen or placebo. This led to 75 patients taking volanesorsen and 34 placebo.
The efficacy results were similar to those in the FCS-focused APPROACH trial, with volanesorsen treatment leading to reductions in triglyceride levels after 3 months, with further reductions over the 6-month study treatment.
Weekly treatment with volanesorsen reduced triglycerides by nearly 71% in the total patient population, compared to placebo, which only achieved a 0.9% decrease in triglycerides. These reductions were conserved at the end of week 26 in patients who had to reduce their dosing to biweekly (62%) and patients who maintained weekly dosing treatments (78%). Overall, a greater than 40% reduction of fasting triglyceride levels after 3 months of treatment was achieved in 87% of volanesorsen-treated patients, compared to 13% of placebo-treated patients (P < 0.0001).
Serious adverse events (SAEs) occurred in nine patients (8%). In the placebo group, two patients (5%) reported acute pancreatitis. Apart from the bouts of pancreatitis, some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
APPROACH OPEN LABEL
The open label portion of the APPROACH study is ongoing and was designed to assess the safety and efficacy of extended treatment with volanesorsen in patients with FCS who had previously completed APPROACH or COMPASS studies or had never received volanesorsen treatment. Patients received 300 mg of volanesorsen once weekly for 52 weeks. Patients who completed the trial were eligible to continue treatment for an additional 52 weeks or until a product is available. As of August 31, 2017, after the data cutoff, 60 patients were enrolled.
The results of this open label portion of the APPROACH trial were similar to that of the APPROACH trial itself. Patients who transitioned from APPROACH or COMPASS showed decreases in their open label extension (OLE) baseline triglyceride measurements to OLE month 3 of 48.1% and 52.1%, respectively. Treatment-naive patients displayed a nearly 60% decrease in their triglyceride levels 3 months.
Of the 60 patients who started the study, 12 have discontinued the study prematurely. The majority of patients, eight, who discontinued did so because of adverse events and four withdrew voluntarily.
Adverse events were not uncommon, with 56 patients (93%) experiencing an AE during the course of the study. Some of the most common AEs were decreased platelet count, thrombocytopenia, and nasopharyngitis.
Akcea has developed a Risk Evaluation and Mitigation program to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS.
Panelist Susan Z. Yanovksi, MD, of the National Institutes of Health, said she voted no over safety concerns, but felt conflicted.
“There’s no question that volanesorsen is effective in dramatically reducing triglycerides, but I had a lot of concerns whether the data presented by the sponsor actually established favorable risk-benefit ratio.”
The FDA is expected to decide on the application by August 30. The FDA usually follows the recommendations of its advisory panels, which are not binding.
REPORTING FROM an fda advisory committee meeting
Managing agitation in outpatient dementia
NEW ORLEANS – A reasonable stepwise approach to pharmacotherapy for agitation in outpatient dementia begins with a judiciously chosen SSRI as first-line therapy, with the second-line consisting of augmentation with a benzodiazepine, M. Philip Luber, MD, said at the annual meeting of the American College of Physicians.
If this combination doesn’t provide satisfactory improvement after adequate dosing for sufficient duration, only then is it time to turn to an atypical antipsychotic agent as a higher-risk/higher-reward third-line therapy, added Dr. Luber, professor of psychiatry and associate dean for graduate medical education at the University of Texas, San Antonio.
He emphasized, however, that medications are not the first-line therapy for agitation in outpatients with dementia. That distinction belongs to psychosocial interventions.
“Utilize a social worker to assist the family in modifying the environment: family settings and people, regular routines, consistently orienting the patient, keeping stimulation at a low to moderate level. When that’s done right, it can really dampen down a lot of agitation,” he said.
Dr. Luber noted that the formal randomized trial evidence base for SSRIs as first-line pharmacotherapy and benzodiazepines as second-line is quite limited. But in conversations with geriatric psychiatrists and other health care professionals around the country who are working in this area, he has found broad agreement that this is a good strategy.
“A lot of folks don’t realize that [SSRIs] are actually very useful in the treatment of agitation in dementia. But you want to choose one with fewer side effects and drug-drug interactions,” Dr. Luber said.
Two SSRIs that fit the bill are escitalopram (Lexapro) and sertraline (Zoloft). Start low and increase the dose slowly, provided circumstances allow. Expect a therapeutic response to emerge in weeks, not days. And, in this elderly population, be sure to monitor for hyponatremia.
When considering augmentation, remember that “using benzodiazepines in the elderly is controversial, particularly with agitation in dementia. There is very little randomized clinical trial data on benzodiazepines in dementia. Actually, though, there are lots of clinical trials of benzodiazepines in dementia that feature benzodiazepines as rescue medication. So, clinically, there’s an awareness that the drugs work, but they haven’t been studied except as rescue medication,” he explained.
The phenomenon of paradoxical agitation occurring in elderly patients on benzodiazepines “is something to be careful about, but in fact it’s pretty uncommon. Just watch for it,” he added.
Dr. Luber is among many geriatric psychiatrists who preferentially turn to clonazepam (Klonopin) because its relatively long half-life allows for twice-daily administration.
“Think about using it regularly rather than PRN. You want to stay ahead of the agitation rather than behind it,” he advised.
Patients with liver disease are better served by a shorter-acting benzodiazepine such as lorazepam (Ativan), which is not oxidized in the liver.
Also controversial is use of atypical antipsychotics as third-line pharmacotherapy, “but many geriatric psychiatrists would agree with me that the next step if the patient is still agitated despite an SSRI augmented with a benzodiazepine is to consider a trial of an atypical antipsychotic,” Dr. Luber said.
He pointed to risperidone (Risperdal) and aripiprazole (Abilify) as agents with a good track record for treatment of agitation in dementia. He urged primary care physicians to be familiar with the risk of serious and even potentially fatal side effects as described in the black box warning.
“There are tough choices involved in treating patients with this disorder. Use shared decision making with the patient or family,” Dr. Luber said.
He reported having no financial conflicts of interest regarding his presentation.
NEW ORLEANS – A reasonable stepwise approach to pharmacotherapy for agitation in outpatient dementia begins with a judiciously chosen SSRI as first-line therapy, with the second-line consisting of augmentation with a benzodiazepine, M. Philip Luber, MD, said at the annual meeting of the American College of Physicians.
If this combination doesn’t provide satisfactory improvement after adequate dosing for sufficient duration, only then is it time to turn to an atypical antipsychotic agent as a higher-risk/higher-reward third-line therapy, added Dr. Luber, professor of psychiatry and associate dean for graduate medical education at the University of Texas, San Antonio.
He emphasized, however, that medications are not the first-line therapy for agitation in outpatients with dementia. That distinction belongs to psychosocial interventions.
“Utilize a social worker to assist the family in modifying the environment: family settings and people, regular routines, consistently orienting the patient, keeping stimulation at a low to moderate level. When that’s done right, it can really dampen down a lot of agitation,” he said.
Dr. Luber noted that the formal randomized trial evidence base for SSRIs as first-line pharmacotherapy and benzodiazepines as second-line is quite limited. But in conversations with geriatric psychiatrists and other health care professionals around the country who are working in this area, he has found broad agreement that this is a good strategy.
“A lot of folks don’t realize that [SSRIs] are actually very useful in the treatment of agitation in dementia. But you want to choose one with fewer side effects and drug-drug interactions,” Dr. Luber said.
Two SSRIs that fit the bill are escitalopram (Lexapro) and sertraline (Zoloft). Start low and increase the dose slowly, provided circumstances allow. Expect a therapeutic response to emerge in weeks, not days. And, in this elderly population, be sure to monitor for hyponatremia.
When considering augmentation, remember that “using benzodiazepines in the elderly is controversial, particularly with agitation in dementia. There is very little randomized clinical trial data on benzodiazepines in dementia. Actually, though, there are lots of clinical trials of benzodiazepines in dementia that feature benzodiazepines as rescue medication. So, clinically, there’s an awareness that the drugs work, but they haven’t been studied except as rescue medication,” he explained.
The phenomenon of paradoxical agitation occurring in elderly patients on benzodiazepines “is something to be careful about, but in fact it’s pretty uncommon. Just watch for it,” he added.
Dr. Luber is among many geriatric psychiatrists who preferentially turn to clonazepam (Klonopin) because its relatively long half-life allows for twice-daily administration.
“Think about using it regularly rather than PRN. You want to stay ahead of the agitation rather than behind it,” he advised.
Patients with liver disease are better served by a shorter-acting benzodiazepine such as lorazepam (Ativan), which is not oxidized in the liver.
Also controversial is use of atypical antipsychotics as third-line pharmacotherapy, “but many geriatric psychiatrists would agree with me that the next step if the patient is still agitated despite an SSRI augmented with a benzodiazepine is to consider a trial of an atypical antipsychotic,” Dr. Luber said.
He pointed to risperidone (Risperdal) and aripiprazole (Abilify) as agents with a good track record for treatment of agitation in dementia. He urged primary care physicians to be familiar with the risk of serious and even potentially fatal side effects as described in the black box warning.
“There are tough choices involved in treating patients with this disorder. Use shared decision making with the patient or family,” Dr. Luber said.
He reported having no financial conflicts of interest regarding his presentation.
NEW ORLEANS – A reasonable stepwise approach to pharmacotherapy for agitation in outpatient dementia begins with a judiciously chosen SSRI as first-line therapy, with the second-line consisting of augmentation with a benzodiazepine, M. Philip Luber, MD, said at the annual meeting of the American College of Physicians.
If this combination doesn’t provide satisfactory improvement after adequate dosing for sufficient duration, only then is it time to turn to an atypical antipsychotic agent as a higher-risk/higher-reward third-line therapy, added Dr. Luber, professor of psychiatry and associate dean for graduate medical education at the University of Texas, San Antonio.
He emphasized, however, that medications are not the first-line therapy for agitation in outpatients with dementia. That distinction belongs to psychosocial interventions.
“Utilize a social worker to assist the family in modifying the environment: family settings and people, regular routines, consistently orienting the patient, keeping stimulation at a low to moderate level. When that’s done right, it can really dampen down a lot of agitation,” he said.
Dr. Luber noted that the formal randomized trial evidence base for SSRIs as first-line pharmacotherapy and benzodiazepines as second-line is quite limited. But in conversations with geriatric psychiatrists and other health care professionals around the country who are working in this area, he has found broad agreement that this is a good strategy.
“A lot of folks don’t realize that [SSRIs] are actually very useful in the treatment of agitation in dementia. But you want to choose one with fewer side effects and drug-drug interactions,” Dr. Luber said.
Two SSRIs that fit the bill are escitalopram (Lexapro) and sertraline (Zoloft). Start low and increase the dose slowly, provided circumstances allow. Expect a therapeutic response to emerge in weeks, not days. And, in this elderly population, be sure to monitor for hyponatremia.
When considering augmentation, remember that “using benzodiazepines in the elderly is controversial, particularly with agitation in dementia. There is very little randomized clinical trial data on benzodiazepines in dementia. Actually, though, there are lots of clinical trials of benzodiazepines in dementia that feature benzodiazepines as rescue medication. So, clinically, there’s an awareness that the drugs work, but they haven’t been studied except as rescue medication,” he explained.
The phenomenon of paradoxical agitation occurring in elderly patients on benzodiazepines “is something to be careful about, but in fact it’s pretty uncommon. Just watch for it,” he added.
Dr. Luber is among many geriatric psychiatrists who preferentially turn to clonazepam (Klonopin) because its relatively long half-life allows for twice-daily administration.
“Think about using it regularly rather than PRN. You want to stay ahead of the agitation rather than behind it,” he advised.
Patients with liver disease are better served by a shorter-acting benzodiazepine such as lorazepam (Ativan), which is not oxidized in the liver.
Also controversial is use of atypical antipsychotics as third-line pharmacotherapy, “but many geriatric psychiatrists would agree with me that the next step if the patient is still agitated despite an SSRI augmented with a benzodiazepine is to consider a trial of an atypical antipsychotic,” Dr. Luber said.
He pointed to risperidone (Risperdal) and aripiprazole (Abilify) as agents with a good track record for treatment of agitation in dementia. He urged primary care physicians to be familiar with the risk of serious and even potentially fatal side effects as described in the black box warning.
“There are tough choices involved in treating patients with this disorder. Use shared decision making with the patient or family,” Dr. Luber said.
He reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM ACP INTERNAL MEDICINE
Implanted pulse generator ups exercise tolerance in HF
BOSTON – Cardiac contractility modulation (CCM), an electrical device–based modality, may improve exercise tolerance and quality of life in heart failure patients with ejection fraction between 25% and 45%, results of a randomized, controlled trial suggested.
Notably, clinical effectiveness appeared to be even greater in the subset of patient with ejection fractions between 35% and 45%, according to results presented at the annual scientific sessions of the Heart Rhythm Society.
The CCM approach was designed to treat chronic heart failure patients with reduced and midrange ejection fractions. It involves the delivery of electrical signals during the cardiac absolute refractory period to enhance contraction strength. Key components include an atrial lead used for sensing and two ventricular leads used for sensing local electrical activity and delivery of CCM signals.
The device was previously evaluated in FIX-HF-5, a 428-patient randomized trial of CCM in patients with New York Heart Association functional class III/IV and reduced ejection fraction. That study failed to meet its primary efficacy end point, but a subgroup analysis showed significant treatment effects in patients with ejection fractions between 25% and 45%.
Consequently, Dr. Abraham initiated the FIX-HF-5 confirmatory study (FIX-HF-5C) to prospectively evaluate CCM in patients with ejection fractions in that range.
The study included 160 with NYHA class III/IV heart failure, QRS duration less than 130 ms, and ejection fractions of 25%-45% who were randomized either to CCM or to continued optimal medical therapy. The control arm included 86 patients, and the CCM arm included 74 patients, of whom 68 received device implantation.
For evaluating peak VO2, the primary end point of this confirmatory study, investigators used a Bayesian model that allowed them incorporate some data from the corresponding subgroup of patients with ejection fractions between 25% and 45% in the previous FIX-HF-5 randomized trial.
Using this model, they found the mean difference between CCM and medical therapy groups at week 24 was 0.836 mL O2/kg per minute (95% Bayesian credible interval, 0.123-1.552). The probability of CCM treatment’s superiority to control was 0.989, according to investigators, which exceeded the 0.975 threshold for statistical significance.
Dr. Abraham and his coinvestigators found that CCM implantation was safe, with a 90% complication-free rate, and that it improved both quality of life and functional status.
All efficacy endpoints were better in patients with ejection fractions of 35% or greater, confirming the subgroup analysis findings of the previous randomized trial, according to Dr. Abraham and his coinvestigators.
Survival free of cardiac death and heart failure hospitalization at 24 weeks was 97.1% in the CCM arm versus 89.2% in controls, which was a secondary finding that reached statistical significance in favor of CCM (P = .048) in one analysis of Kaplan-Meier estimates, investigators said in their report.
The CCM device could fulfill an unmet need for patients who have persistent heart failure despite optimal, guideline-based medical therapy, according to the investigators.
“Although ICDs are applicable to the broad population of patients with ejection fraction [at least] 35%, they do not deliver a therapy for improving exercise tolerance or quality of life,” they said in their report.
Research grant support for the study came from Impulse Dynamics. Dr. Abraham and several coauthors reported serving as consultants to the company.
SOURCE: Abraham WT et al. JACC Heart Fail. 2018 May 10. doi: 10.1016/j.jchf.2018.04.010.
BOSTON – Cardiac contractility modulation (CCM), an electrical device–based modality, may improve exercise tolerance and quality of life in heart failure patients with ejection fraction between 25% and 45%, results of a randomized, controlled trial suggested.
Notably, clinical effectiveness appeared to be even greater in the subset of patient with ejection fractions between 35% and 45%, according to results presented at the annual scientific sessions of the Heart Rhythm Society.
The CCM approach was designed to treat chronic heart failure patients with reduced and midrange ejection fractions. It involves the delivery of electrical signals during the cardiac absolute refractory period to enhance contraction strength. Key components include an atrial lead used for sensing and two ventricular leads used for sensing local electrical activity and delivery of CCM signals.
The device was previously evaluated in FIX-HF-5, a 428-patient randomized trial of CCM in patients with New York Heart Association functional class III/IV and reduced ejection fraction. That study failed to meet its primary efficacy end point, but a subgroup analysis showed significant treatment effects in patients with ejection fractions between 25% and 45%.
Consequently, Dr. Abraham initiated the FIX-HF-5 confirmatory study (FIX-HF-5C) to prospectively evaluate CCM in patients with ejection fractions in that range.
The study included 160 with NYHA class III/IV heart failure, QRS duration less than 130 ms, and ejection fractions of 25%-45% who were randomized either to CCM or to continued optimal medical therapy. The control arm included 86 patients, and the CCM arm included 74 patients, of whom 68 received device implantation.
For evaluating peak VO2, the primary end point of this confirmatory study, investigators used a Bayesian model that allowed them incorporate some data from the corresponding subgroup of patients with ejection fractions between 25% and 45% in the previous FIX-HF-5 randomized trial.
Using this model, they found the mean difference between CCM and medical therapy groups at week 24 was 0.836 mL O2/kg per minute (95% Bayesian credible interval, 0.123-1.552). The probability of CCM treatment’s superiority to control was 0.989, according to investigators, which exceeded the 0.975 threshold for statistical significance.
Dr. Abraham and his coinvestigators found that CCM implantation was safe, with a 90% complication-free rate, and that it improved both quality of life and functional status.
All efficacy endpoints were better in patients with ejection fractions of 35% or greater, confirming the subgroup analysis findings of the previous randomized trial, according to Dr. Abraham and his coinvestigators.
Survival free of cardiac death and heart failure hospitalization at 24 weeks was 97.1% in the CCM arm versus 89.2% in controls, which was a secondary finding that reached statistical significance in favor of CCM (P = .048) in one analysis of Kaplan-Meier estimates, investigators said in their report.
The CCM device could fulfill an unmet need for patients who have persistent heart failure despite optimal, guideline-based medical therapy, according to the investigators.
“Although ICDs are applicable to the broad population of patients with ejection fraction [at least] 35%, they do not deliver a therapy for improving exercise tolerance or quality of life,” they said in their report.
Research grant support for the study came from Impulse Dynamics. Dr. Abraham and several coauthors reported serving as consultants to the company.
SOURCE: Abraham WT et al. JACC Heart Fail. 2018 May 10. doi: 10.1016/j.jchf.2018.04.010.
BOSTON – Cardiac contractility modulation (CCM), an electrical device–based modality, may improve exercise tolerance and quality of life in heart failure patients with ejection fraction between 25% and 45%, results of a randomized, controlled trial suggested.
Notably, clinical effectiveness appeared to be even greater in the subset of patient with ejection fractions between 35% and 45%, according to results presented at the annual scientific sessions of the Heart Rhythm Society.
The CCM approach was designed to treat chronic heart failure patients with reduced and midrange ejection fractions. It involves the delivery of electrical signals during the cardiac absolute refractory period to enhance contraction strength. Key components include an atrial lead used for sensing and two ventricular leads used for sensing local electrical activity and delivery of CCM signals.
The device was previously evaluated in FIX-HF-5, a 428-patient randomized trial of CCM in patients with New York Heart Association functional class III/IV and reduced ejection fraction. That study failed to meet its primary efficacy end point, but a subgroup analysis showed significant treatment effects in patients with ejection fractions between 25% and 45%.
Consequently, Dr. Abraham initiated the FIX-HF-5 confirmatory study (FIX-HF-5C) to prospectively evaluate CCM in patients with ejection fractions in that range.
The study included 160 with NYHA class III/IV heart failure, QRS duration less than 130 ms, and ejection fractions of 25%-45% who were randomized either to CCM or to continued optimal medical therapy. The control arm included 86 patients, and the CCM arm included 74 patients, of whom 68 received device implantation.
For evaluating peak VO2, the primary end point of this confirmatory study, investigators used a Bayesian model that allowed them incorporate some data from the corresponding subgroup of patients with ejection fractions between 25% and 45% in the previous FIX-HF-5 randomized trial.
Using this model, they found the mean difference between CCM and medical therapy groups at week 24 was 0.836 mL O2/kg per minute (95% Bayesian credible interval, 0.123-1.552). The probability of CCM treatment’s superiority to control was 0.989, according to investigators, which exceeded the 0.975 threshold for statistical significance.
Dr. Abraham and his coinvestigators found that CCM implantation was safe, with a 90% complication-free rate, and that it improved both quality of life and functional status.
All efficacy endpoints were better in patients with ejection fractions of 35% or greater, confirming the subgroup analysis findings of the previous randomized trial, according to Dr. Abraham and his coinvestigators.
Survival free of cardiac death and heart failure hospitalization at 24 weeks was 97.1% in the CCM arm versus 89.2% in controls, which was a secondary finding that reached statistical significance in favor of CCM (P = .048) in one analysis of Kaplan-Meier estimates, investigators said in their report.
The CCM device could fulfill an unmet need for patients who have persistent heart failure despite optimal, guideline-based medical therapy, according to the investigators.
“Although ICDs are applicable to the broad population of patients with ejection fraction [at least] 35%, they do not deliver a therapy for improving exercise tolerance or quality of life,” they said in their report.
Research grant support for the study came from Impulse Dynamics. Dr. Abraham and several coauthors reported serving as consultants to the company.
SOURCE: Abraham WT et al. JACC Heart Fail. 2018 May 10. doi: 10.1016/j.jchf.2018.04.010.
REPORTING FROM HEART RHYTHM 2018
Key clinical point: Compared with continued medical therapy, cardiac contractility modulation (CCM) improved exercise tolerance and quality of life in heart failure patients with ejection fraction between 25% and 45%.
Major finding: The difference in peak VO2 between study arms was 0.836 mL O2/kg per minute (95% Bayesian credible interval, 0.123-1.552).
Study details: A randomized controlled trial including 160 patients with NYHA class III/IV heart failure and ejection fraction between 25% and 45%.
Disclosures: Research grant support for the study came from Impulse Dynamics. Several study authors reported serving as consultants to Impulse Dynamics.
Source: Abraham WT et al. JACC Heart Fail. 2018 May 10. doi: 10.1016/j.jchf.2018.04.010.
Pain relievers, bed rest may be sufficient to manage PEH
Although skin biopsy and the “presence of deep dermal mixed infiltrate with abundant neutrophils surrounding eccrine sweat glands” is considered the preferred method for diagnosing palmoplantar eccrine hidradenitis (PEH), Paola Piccini, MD, and her colleagues at the University of Florence (Italy) caution that biopsy frequently is not needed.
In the days prior to the appearance of erythematous and painful nodules on the soles of his feet, a healthy 8-year-old boy sustained “thermal and mechanical trauma playing football and cycling,” that made walking difficult. The week prior to the injury, he had complained of diarrhea in the absence of fever.
Given results of testing and the patient’s overall good health, he received a diagnosis of PEH. Dr. Piccini and her colleagues chose not to biopsy the nodules because they typically resolve on their own within a few weeks. Instead, he was prescribed pain relievers and bed rest. Within 2 weeks, the nodules were completely healed, and no further relapse was reported, the authors noted in the Journal of Pediatrics.
All previous case studies cited in the literature reported complete resolution without treatment within 4 weeks, said Dr. Piccini and her colleagues. They added that correct diagnosis is key to avoiding inappropriate medical treatments given the benign course of PEH.
Common presenting risk factors tend to include local thermal and mechanical trauma plus intense physical activity and recent infection. It is these risk factors that cause rupture of the eccrine gland and resulting infiltration of neutrophils to the site.
Conditions that share common symptoms with PEH include erythema multiforme, nodular erythema, cellulitis, and viral infections.
No disclosures were noted.
SOURCE: Piccini, P et al. J. Pediatr. 2018. doi: 10.1016/j.peds.2018.03.017.
Although skin biopsy and the “presence of deep dermal mixed infiltrate with abundant neutrophils surrounding eccrine sweat glands” is considered the preferred method for diagnosing palmoplantar eccrine hidradenitis (PEH), Paola Piccini, MD, and her colleagues at the University of Florence (Italy) caution that biopsy frequently is not needed.
In the days prior to the appearance of erythematous and painful nodules on the soles of his feet, a healthy 8-year-old boy sustained “thermal and mechanical trauma playing football and cycling,” that made walking difficult. The week prior to the injury, he had complained of diarrhea in the absence of fever.
Given results of testing and the patient’s overall good health, he received a diagnosis of PEH. Dr. Piccini and her colleagues chose not to biopsy the nodules because they typically resolve on their own within a few weeks. Instead, he was prescribed pain relievers and bed rest. Within 2 weeks, the nodules were completely healed, and no further relapse was reported, the authors noted in the Journal of Pediatrics.
All previous case studies cited in the literature reported complete resolution without treatment within 4 weeks, said Dr. Piccini and her colleagues. They added that correct diagnosis is key to avoiding inappropriate medical treatments given the benign course of PEH.
Common presenting risk factors tend to include local thermal and mechanical trauma plus intense physical activity and recent infection. It is these risk factors that cause rupture of the eccrine gland and resulting infiltration of neutrophils to the site.
Conditions that share common symptoms with PEH include erythema multiforme, nodular erythema, cellulitis, and viral infections.
No disclosures were noted.
SOURCE: Piccini, P et al. J. Pediatr. 2018. doi: 10.1016/j.peds.2018.03.017.
Although skin biopsy and the “presence of deep dermal mixed infiltrate with abundant neutrophils surrounding eccrine sweat glands” is considered the preferred method for diagnosing palmoplantar eccrine hidradenitis (PEH), Paola Piccini, MD, and her colleagues at the University of Florence (Italy) caution that biopsy frequently is not needed.
In the days prior to the appearance of erythematous and painful nodules on the soles of his feet, a healthy 8-year-old boy sustained “thermal and mechanical trauma playing football and cycling,” that made walking difficult. The week prior to the injury, he had complained of diarrhea in the absence of fever.
Given results of testing and the patient’s overall good health, he received a diagnosis of PEH. Dr. Piccini and her colleagues chose not to biopsy the nodules because they typically resolve on their own within a few weeks. Instead, he was prescribed pain relievers and bed rest. Within 2 weeks, the nodules were completely healed, and no further relapse was reported, the authors noted in the Journal of Pediatrics.
All previous case studies cited in the literature reported complete resolution without treatment within 4 weeks, said Dr. Piccini and her colleagues. They added that correct diagnosis is key to avoiding inappropriate medical treatments given the benign course of PEH.
Common presenting risk factors tend to include local thermal and mechanical trauma plus intense physical activity and recent infection. It is these risk factors that cause rupture of the eccrine gland and resulting infiltration of neutrophils to the site.
Conditions that share common symptoms with PEH include erythema multiforme, nodular erythema, cellulitis, and viral infections.
No disclosures were noted.
SOURCE: Piccini, P et al. J. Pediatr. 2018. doi: 10.1016/j.peds.2018.03.017.
FROM THE JOURNAL OF PEDIATRICS
Key clinical point: Complete resolution within 4 weeks is common without treatment.
Major finding: .
Study details: Case study.
Disclosures: No disclosures were noted.
Source: Lund, E et al. Ped. Dermatol. 2018. doi: 10.1111/pde.13508.
Delay of NSCLC surgery can lead to worse prognosis
SAN DIEGO – Delaying
“There is significant upstaging with time from completion of clinical staging to surgical resection, with a 4% increase of upstaging per week for the overall study population,” said study coauthor Harmik J. Soukiasian, MD, FACS, of Cedars-Sinai Medical Center, Los Angeles, in an interview. “Upstaging impacts lung cancer prognosis as more advanced stages portend to a poorer prognosis.”
An estimated 80%-85% of lung cancer patients have NSCLC, according to the American Cancer Society, and Dr. Soukiasian said surgery offers a chance at a cure for those diagnosed at stage I.
“National Cancer Comprehensive Network (NCCN) Guidelines recommend surgery within 8 weeks of completed clinical staging for NSCLC to limit cancer progression or upstaging,” Dr. Soukiasian said. “Although these guidelines are well established and widely adopted, our study performs a more granular analysis, studying time as a predictor of upstaging for those patients diagnosed with stage I NSCLC.”
For the new study, Dr. Soukiasian and colleagues tracked 52,406 patients in a cancer database who had stage I NSCLC but had not undergone preoperative chemotherapy. The researchers tracked their clinical stages for up to 12 weeks from initial staging.
Researchers found that, while staging levels rose with each successive week, just 25% of patients underwent surgery by 1 week, and only 79% had surgery in accordance with NSCLC guidelines by week 8. At 12 weeks, 9% had still not undergone surgery.
Upstaging was common: 22% at 1 week, 32% after 8 weeks, and 33% after 12 weeks.
“We demonstrate that patients diagnosed with stage I NSCLC benefit from surgery sooner than the 8-week window recommended by the NCCN guidelines,” Dr. Soukiasian said. “Exclusive of the rate of progression and in addition to time to surgery, our study also demonstrated academic centers, higher lymph node yield during surgery, and left-sided tumors to be independent predictors of upstaging.”
The study design doesn’t provide insight into why surgery is often delayed. However, “we can theorize factors associated with delays to surgery may be due to patient factors (personal scheduling, availability of support systems, etc.), delays in follow up, operating room availability or scheduling, and issues with insurance approval,” Dr. Soukiasian said.
In his presentation, Dr. Soukiasian emphasized the role of the mediastinum. “Given the clinical impact of stage III disease, we analyzed upstaging rates of stage I NSCLC to stage IIIA and revealed a 1.3% increase per week of upstaging specifically to stage IIIA. Additionally, almost 5% of patients initially diagnosed with stage I NSCLC upstaged to IIIA disease. The significant rate of upstaging to IIIA disease makes the case for more accurate and aggressive mediastinal staging prior to surgical resection.”
No disclosures and no study funding are reported.
SOURCE: Soukiasian HJ et al. AATS 2018, Abstract 67.
SAN DIEGO – Delaying
“There is significant upstaging with time from completion of clinical staging to surgical resection, with a 4% increase of upstaging per week for the overall study population,” said study coauthor Harmik J. Soukiasian, MD, FACS, of Cedars-Sinai Medical Center, Los Angeles, in an interview. “Upstaging impacts lung cancer prognosis as more advanced stages portend to a poorer prognosis.”
An estimated 80%-85% of lung cancer patients have NSCLC, according to the American Cancer Society, and Dr. Soukiasian said surgery offers a chance at a cure for those diagnosed at stage I.
“National Cancer Comprehensive Network (NCCN) Guidelines recommend surgery within 8 weeks of completed clinical staging for NSCLC to limit cancer progression or upstaging,” Dr. Soukiasian said. “Although these guidelines are well established and widely adopted, our study performs a more granular analysis, studying time as a predictor of upstaging for those patients diagnosed with stage I NSCLC.”
For the new study, Dr. Soukiasian and colleagues tracked 52,406 patients in a cancer database who had stage I NSCLC but had not undergone preoperative chemotherapy. The researchers tracked their clinical stages for up to 12 weeks from initial staging.
Researchers found that, while staging levels rose with each successive week, just 25% of patients underwent surgery by 1 week, and only 79% had surgery in accordance with NSCLC guidelines by week 8. At 12 weeks, 9% had still not undergone surgery.
Upstaging was common: 22% at 1 week, 32% after 8 weeks, and 33% after 12 weeks.
“We demonstrate that patients diagnosed with stage I NSCLC benefit from surgery sooner than the 8-week window recommended by the NCCN guidelines,” Dr. Soukiasian said. “Exclusive of the rate of progression and in addition to time to surgery, our study also demonstrated academic centers, higher lymph node yield during surgery, and left-sided tumors to be independent predictors of upstaging.”
The study design doesn’t provide insight into why surgery is often delayed. However, “we can theorize factors associated with delays to surgery may be due to patient factors (personal scheduling, availability of support systems, etc.), delays in follow up, operating room availability or scheduling, and issues with insurance approval,” Dr. Soukiasian said.
In his presentation, Dr. Soukiasian emphasized the role of the mediastinum. “Given the clinical impact of stage III disease, we analyzed upstaging rates of stage I NSCLC to stage IIIA and revealed a 1.3% increase per week of upstaging specifically to stage IIIA. Additionally, almost 5% of patients initially diagnosed with stage I NSCLC upstaged to IIIA disease. The significant rate of upstaging to IIIA disease makes the case for more accurate and aggressive mediastinal staging prior to surgical resection.”
No disclosures and no study funding are reported.
SOURCE: Soukiasian HJ et al. AATS 2018, Abstract 67.
SAN DIEGO – Delaying
“There is significant upstaging with time from completion of clinical staging to surgical resection, with a 4% increase of upstaging per week for the overall study population,” said study coauthor Harmik J. Soukiasian, MD, FACS, of Cedars-Sinai Medical Center, Los Angeles, in an interview. “Upstaging impacts lung cancer prognosis as more advanced stages portend to a poorer prognosis.”
An estimated 80%-85% of lung cancer patients have NSCLC, according to the American Cancer Society, and Dr. Soukiasian said surgery offers a chance at a cure for those diagnosed at stage I.
“National Cancer Comprehensive Network (NCCN) Guidelines recommend surgery within 8 weeks of completed clinical staging for NSCLC to limit cancer progression or upstaging,” Dr. Soukiasian said. “Although these guidelines are well established and widely adopted, our study performs a more granular analysis, studying time as a predictor of upstaging for those patients diagnosed with stage I NSCLC.”
For the new study, Dr. Soukiasian and colleagues tracked 52,406 patients in a cancer database who had stage I NSCLC but had not undergone preoperative chemotherapy. The researchers tracked their clinical stages for up to 12 weeks from initial staging.
Researchers found that, while staging levels rose with each successive week, just 25% of patients underwent surgery by 1 week, and only 79% had surgery in accordance with NSCLC guidelines by week 8. At 12 weeks, 9% had still not undergone surgery.
Upstaging was common: 22% at 1 week, 32% after 8 weeks, and 33% after 12 weeks.
“We demonstrate that patients diagnosed with stage I NSCLC benefit from surgery sooner than the 8-week window recommended by the NCCN guidelines,” Dr. Soukiasian said. “Exclusive of the rate of progression and in addition to time to surgery, our study also demonstrated academic centers, higher lymph node yield during surgery, and left-sided tumors to be independent predictors of upstaging.”
The study design doesn’t provide insight into why surgery is often delayed. However, “we can theorize factors associated with delays to surgery may be due to patient factors (personal scheduling, availability of support systems, etc.), delays in follow up, operating room availability or scheduling, and issues with insurance approval,” Dr. Soukiasian said.
In his presentation, Dr. Soukiasian emphasized the role of the mediastinum. “Given the clinical impact of stage III disease, we analyzed upstaging rates of stage I NSCLC to stage IIIA and revealed a 1.3% increase per week of upstaging specifically to stage IIIA. Additionally, almost 5% of patients initially diagnosed with stage I NSCLC upstaged to IIIA disease. The significant rate of upstaging to IIIA disease makes the case for more accurate and aggressive mediastinal staging prior to surgical resection.”
No disclosures and no study funding are reported.
SOURCE: Soukiasian HJ et al. AATS 2018, Abstract 67.
AT THE AATS ANNUAL MEETING
Key clinical point: Clinical staging levels worsen in each successive surgery-free week after initial staging in certain NSCLC patients.
Major finding: There was a 1.3% increase per week of upstaging to stage IIIA.
Study details: Analysis of 52,406 patients with stage I NSCLC who were tracked for up to 12 weeks.
Disclosures: No disclosures and no funding were reported.
Source: Soukiasian HJ et al. AATS 2018, Abstract 67.