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Refractory immune-mediated colitis: Fecal transplant may be the answer
WASHINGTON – , according to Yinghong Wang, MD.
In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.
Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.
A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.
Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.
“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.
Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.
However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.
“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.
Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.
“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”
Dr. Wang reported having no disclosures.
SOURCE: Wang Y et al. SITC 2018, Abstract P194.
WASHINGTON – , according to Yinghong Wang, MD.
In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.
Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.
A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.
Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.
“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.
Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.
However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.
“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.
Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.
“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”
Dr. Wang reported having no disclosures.
SOURCE: Wang Y et al. SITC 2018, Abstract P194.
WASHINGTON – , according to Yinghong Wang, MD.
In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.
Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.
A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.
Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.
“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.
Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.
However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.
“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.
Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.
“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”
Dr. Wang reported having no disclosures.
SOURCE: Wang Y et al. SITC 2018, Abstract P194.
REPORTING FROM SITC 2018
Key clinical point: FMT lead to recovery in two patients with refractory IMC.
Major finding: FMT was effective for the treatment of IMC in two patients.
Study details: Two case reports.
Disclosures: Dr. Wang reported having no disclosures.
Source: Wang Y et al. SITC 2018, Abstract P194.
PIONEER-HF called “practice changing” for acute decompensated heart failure
CHICAGO – Initiation of angiotensin-neprilysin inhibition using sacubitril/valsartan during hospitalization for acute decompensated heart failure, instead of relying upon enalapril, resulted in a substantially greater reduction in N-terminal of the prohormone brain natriuretic peptide concentration and a markedly lower rate of rehospitalization with no safety downside in the PIONEER-HF trial, Eric J. Velazquez, MD, reported at the American Heart Association scientific sessions.
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB [angiotensin II receptor blocker] use or prior diagnosis of heart failure,” said Dr. Velazquez, a professor of medicine and chief of the section of cardiovascular medicine at Yale University, New Haven, Conn., and physician in chief of the Heart and Vascular Center for the Yale-New Haven Health System.
Sacubitril/valsartan (Entresto) has a class I indication for treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) in the AHA/American College of Cardiology guidelines. This strong recommendation is based largely upon the impressive results of the PARADIGM-HF trial, which in ambulatory outpatients demonstrated a lower risk of cardiovascular mortality or hospitalization for heart failure than enalapril (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
However, since patients with acute decompensated heart failure (ADHF) were excluded from PARADIGM-HF, the safety and effectiveness of starting such patients on the drug while hospitalized for acute decompensation was unknown.
PIONEER-HF was carried out to shed light on that issue and thereby address a major unmet need for better treatments for ADHF. Even though this condition accounts for more than 1 million hospitalizations annually in the United States, short-term rehospitalization and mortality rates in affected patients remain unacceptably high at 21% and 12%, respectively. And the standard-of-care treatment – decongestion with intravenous diuretics and hemodynamic support with inotropes and vasodilators – hasn’t changed in nearly half a century, Dr. Velazquez noted.
The trial included 881 patients hospitalized for acute decompensated HFrEF at 129 U.S. centers. The study population was diverse: 36% of participants were black and one-third of subjects had no diagnosis of heart failure prior to their hospitalization. After achieving hemodynamic stabilization, patients were randomized to receive sacubitril/valsartan or enalapril.
Key outcomes
The primary endpoint was change in N-terminal of the prohormone brain natriuretic peptide concentration from baseline to week 8. There was a 25% reduction in the enalapril group and a 45% reduction with sacubitril/valsartan. This translated to a highly significant 29% greater relative risk reduction with sacubitril/valsartan.
More eye opening was the between-group difference in the prespecified composite clinical endpoint comprising death, rehospitalization for heart failure, implantation of a left ventricular assist device, or listing for heart transplant during the 8-week study.
The rate was 16.8% in the enalapril group and 9.3% with sacubitril/valsartan. This worked out to a 46% relative risk reduction, with a number needed to treat of 13.
The composite result was driven by a 44% reduction in risk of heart failure rehospitalization in the sacubitril/valsartan group: 8.0% versus 13.8%. The sacubitril/valsartan group also had a numerically lower mortality rate: 2.3% versus 3.4%, although the number of fatalities was small and this 34% relative risk reduction didn’t achieve statistical significance.
Rates of the key safety outcomes – symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema – didn’t differ between the two study arms. Of interest, however, all six cases of angioedema in the enalapril group occurred in black patients, while the only case in the sacubitril/valsartan group was in a white patient.
PIONEER-HF treatment strategy
Hemodynamic stabilization as a prelude to randomization to sacubitril/valsartan or enalapril required maintaining a systolic blood pressure of at least 100 mm Hg in the previous 6 hours, with no symptomatic hypotension, intensification of intravenous diuretics, or use of intravenous vasodilators during that time period, and no intravenous inotropes in the previous 24 hours.
Enalapril was titrated to a target dose of 10 mg twice daily. Sacubitril/valsartan was titrated to a target dose of 97/103 mg twice daily. Titration was carried out using an algorithm based upon systolic BP. If the SBP was at least 100 and less than 120 mm Hg at baseline, sacubitril/valsartan was initiated at 24/26 mg twice daily, enalapril at 2.5 mg b.i.d. If the SBP at randomization was 120 mm Hg or higher, the initial dosing was sacubitril/valsartan at 49/51 mm Hg b.i.d. or enalapril at 5 mg b.i.d. Up-titration occurred after 1 week, then biweekly through week 8.
PIONEER in perspective
Discussant Larry A. Allen, MD, a heart failure specialist at the University of Colorado at Denver, Aurora, predicted that this will be a practice-changing study.
“There has been a need for a study like PIONEER in heart failure,” he observed. While multiple randomized trials have advanced the treatment of ambulatory HFrEF patients, demonstrating benefit for initiation and intensification of treatment with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, the treatment of patients with ADHF has remained relatively static, marked by failed trials of once-promising novel agents including tolvaptan, nesiritide, and serelaxin.
“All the data is in ambulatory patients, but the action for the care of heart failure patients actually occurs largely in the hospital. Seventy percent of care provided in the U.S. to patients with heart failure occurs in the hospital setting. These patients are a captive audience at that time, and the transitions from inpatient to outpatient care are fragile,” Dr. Allen said.
He noted that the use of sacubitril/valsartan in routine practice as reflected in national registries has been “extremely low” – less than 15% among eligible patients – despite the drug having been approved more than 3 years ago. One major reason for the low uptake, in his view, is clinical inertia. That should melt away in what he termed “the post-PIONEER world.”
“I think one of the great things about this study is it keeps it simple. We now have a simpler algorithm for inpatient and subsequent outpatient management of heart failure with reduced ejection fraction. It’s easier for us to start with the treatment we want patients to be on, and it’s better for patients, too. Most importantly, this study reinforces the importance and safety of aggressive guideline-directed medical therapy starting from the beginning in most patients,” Dr. Allen said.
The study findings were published simultaneously in the New England Journal of Medicine (2018 Nov 11. doi: 10.1056/NEJMoa1812851).
PIONEER-HF was sponsored by Novartis. Dr. Velazquez reported receiving research grants from and serving as a consultant to that company and others. Dr. Allen reported having no financial conflicts.
CHICAGO – Initiation of angiotensin-neprilysin inhibition using sacubitril/valsartan during hospitalization for acute decompensated heart failure, instead of relying upon enalapril, resulted in a substantially greater reduction in N-terminal of the prohormone brain natriuretic peptide concentration and a markedly lower rate of rehospitalization with no safety downside in the PIONEER-HF trial, Eric J. Velazquez, MD, reported at the American Heart Association scientific sessions.
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB [angiotensin II receptor blocker] use or prior diagnosis of heart failure,” said Dr. Velazquez, a professor of medicine and chief of the section of cardiovascular medicine at Yale University, New Haven, Conn., and physician in chief of the Heart and Vascular Center for the Yale-New Haven Health System.
Sacubitril/valsartan (Entresto) has a class I indication for treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) in the AHA/American College of Cardiology guidelines. This strong recommendation is based largely upon the impressive results of the PARADIGM-HF trial, which in ambulatory outpatients demonstrated a lower risk of cardiovascular mortality or hospitalization for heart failure than enalapril (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
However, since patients with acute decompensated heart failure (ADHF) were excluded from PARADIGM-HF, the safety and effectiveness of starting such patients on the drug while hospitalized for acute decompensation was unknown.
PIONEER-HF was carried out to shed light on that issue and thereby address a major unmet need for better treatments for ADHF. Even though this condition accounts for more than 1 million hospitalizations annually in the United States, short-term rehospitalization and mortality rates in affected patients remain unacceptably high at 21% and 12%, respectively. And the standard-of-care treatment – decongestion with intravenous diuretics and hemodynamic support with inotropes and vasodilators – hasn’t changed in nearly half a century, Dr. Velazquez noted.
The trial included 881 patients hospitalized for acute decompensated HFrEF at 129 U.S. centers. The study population was diverse: 36% of participants were black and one-third of subjects had no diagnosis of heart failure prior to their hospitalization. After achieving hemodynamic stabilization, patients were randomized to receive sacubitril/valsartan or enalapril.
Key outcomes
The primary endpoint was change in N-terminal of the prohormone brain natriuretic peptide concentration from baseline to week 8. There was a 25% reduction in the enalapril group and a 45% reduction with sacubitril/valsartan. This translated to a highly significant 29% greater relative risk reduction with sacubitril/valsartan.
More eye opening was the between-group difference in the prespecified composite clinical endpoint comprising death, rehospitalization for heart failure, implantation of a left ventricular assist device, or listing for heart transplant during the 8-week study.
The rate was 16.8% in the enalapril group and 9.3% with sacubitril/valsartan. This worked out to a 46% relative risk reduction, with a number needed to treat of 13.
The composite result was driven by a 44% reduction in risk of heart failure rehospitalization in the sacubitril/valsartan group: 8.0% versus 13.8%. The sacubitril/valsartan group also had a numerically lower mortality rate: 2.3% versus 3.4%, although the number of fatalities was small and this 34% relative risk reduction didn’t achieve statistical significance.
Rates of the key safety outcomes – symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema – didn’t differ between the two study arms. Of interest, however, all six cases of angioedema in the enalapril group occurred in black patients, while the only case in the sacubitril/valsartan group was in a white patient.
PIONEER-HF treatment strategy
Hemodynamic stabilization as a prelude to randomization to sacubitril/valsartan or enalapril required maintaining a systolic blood pressure of at least 100 mm Hg in the previous 6 hours, with no symptomatic hypotension, intensification of intravenous diuretics, or use of intravenous vasodilators during that time period, and no intravenous inotropes in the previous 24 hours.
Enalapril was titrated to a target dose of 10 mg twice daily. Sacubitril/valsartan was titrated to a target dose of 97/103 mg twice daily. Titration was carried out using an algorithm based upon systolic BP. If the SBP was at least 100 and less than 120 mm Hg at baseline, sacubitril/valsartan was initiated at 24/26 mg twice daily, enalapril at 2.5 mg b.i.d. If the SBP at randomization was 120 mm Hg or higher, the initial dosing was sacubitril/valsartan at 49/51 mm Hg b.i.d. or enalapril at 5 mg b.i.d. Up-titration occurred after 1 week, then biweekly through week 8.
PIONEER in perspective
Discussant Larry A. Allen, MD, a heart failure specialist at the University of Colorado at Denver, Aurora, predicted that this will be a practice-changing study.
“There has been a need for a study like PIONEER in heart failure,” he observed. While multiple randomized trials have advanced the treatment of ambulatory HFrEF patients, demonstrating benefit for initiation and intensification of treatment with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, the treatment of patients with ADHF has remained relatively static, marked by failed trials of once-promising novel agents including tolvaptan, nesiritide, and serelaxin.
“All the data is in ambulatory patients, but the action for the care of heart failure patients actually occurs largely in the hospital. Seventy percent of care provided in the U.S. to patients with heart failure occurs in the hospital setting. These patients are a captive audience at that time, and the transitions from inpatient to outpatient care are fragile,” Dr. Allen said.
He noted that the use of sacubitril/valsartan in routine practice as reflected in national registries has been “extremely low” – less than 15% among eligible patients – despite the drug having been approved more than 3 years ago. One major reason for the low uptake, in his view, is clinical inertia. That should melt away in what he termed “the post-PIONEER world.”
“I think one of the great things about this study is it keeps it simple. We now have a simpler algorithm for inpatient and subsequent outpatient management of heart failure with reduced ejection fraction. It’s easier for us to start with the treatment we want patients to be on, and it’s better for patients, too. Most importantly, this study reinforces the importance and safety of aggressive guideline-directed medical therapy starting from the beginning in most patients,” Dr. Allen said.
The study findings were published simultaneously in the New England Journal of Medicine (2018 Nov 11. doi: 10.1056/NEJMoa1812851).
PIONEER-HF was sponsored by Novartis. Dr. Velazquez reported receiving research grants from and serving as a consultant to that company and others. Dr. Allen reported having no financial conflicts.
CHICAGO – Initiation of angiotensin-neprilysin inhibition using sacubitril/valsartan during hospitalization for acute decompensated heart failure, instead of relying upon enalapril, resulted in a substantially greater reduction in N-terminal of the prohormone brain natriuretic peptide concentration and a markedly lower rate of rehospitalization with no safety downside in the PIONEER-HF trial, Eric J. Velazquez, MD, reported at the American Heart Association scientific sessions.
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB [angiotensin II receptor blocker] use or prior diagnosis of heart failure,” said Dr. Velazquez, a professor of medicine and chief of the section of cardiovascular medicine at Yale University, New Haven, Conn., and physician in chief of the Heart and Vascular Center for the Yale-New Haven Health System.
Sacubitril/valsartan (Entresto) has a class I indication for treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) in the AHA/American College of Cardiology guidelines. This strong recommendation is based largely upon the impressive results of the PARADIGM-HF trial, which in ambulatory outpatients demonstrated a lower risk of cardiovascular mortality or hospitalization for heart failure than enalapril (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
However, since patients with acute decompensated heart failure (ADHF) were excluded from PARADIGM-HF, the safety and effectiveness of starting such patients on the drug while hospitalized for acute decompensation was unknown.
PIONEER-HF was carried out to shed light on that issue and thereby address a major unmet need for better treatments for ADHF. Even though this condition accounts for more than 1 million hospitalizations annually in the United States, short-term rehospitalization and mortality rates in affected patients remain unacceptably high at 21% and 12%, respectively. And the standard-of-care treatment – decongestion with intravenous diuretics and hemodynamic support with inotropes and vasodilators – hasn’t changed in nearly half a century, Dr. Velazquez noted.
The trial included 881 patients hospitalized for acute decompensated HFrEF at 129 U.S. centers. The study population was diverse: 36% of participants were black and one-third of subjects had no diagnosis of heart failure prior to their hospitalization. After achieving hemodynamic stabilization, patients were randomized to receive sacubitril/valsartan or enalapril.
Key outcomes
The primary endpoint was change in N-terminal of the prohormone brain natriuretic peptide concentration from baseline to week 8. There was a 25% reduction in the enalapril group and a 45% reduction with sacubitril/valsartan. This translated to a highly significant 29% greater relative risk reduction with sacubitril/valsartan.
More eye opening was the between-group difference in the prespecified composite clinical endpoint comprising death, rehospitalization for heart failure, implantation of a left ventricular assist device, or listing for heart transplant during the 8-week study.
The rate was 16.8% in the enalapril group and 9.3% with sacubitril/valsartan. This worked out to a 46% relative risk reduction, with a number needed to treat of 13.
The composite result was driven by a 44% reduction in risk of heart failure rehospitalization in the sacubitril/valsartan group: 8.0% versus 13.8%. The sacubitril/valsartan group also had a numerically lower mortality rate: 2.3% versus 3.4%, although the number of fatalities was small and this 34% relative risk reduction didn’t achieve statistical significance.
Rates of the key safety outcomes – symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema – didn’t differ between the two study arms. Of interest, however, all six cases of angioedema in the enalapril group occurred in black patients, while the only case in the sacubitril/valsartan group was in a white patient.
PIONEER-HF treatment strategy
Hemodynamic stabilization as a prelude to randomization to sacubitril/valsartan or enalapril required maintaining a systolic blood pressure of at least 100 mm Hg in the previous 6 hours, with no symptomatic hypotension, intensification of intravenous diuretics, or use of intravenous vasodilators during that time period, and no intravenous inotropes in the previous 24 hours.
Enalapril was titrated to a target dose of 10 mg twice daily. Sacubitril/valsartan was titrated to a target dose of 97/103 mg twice daily. Titration was carried out using an algorithm based upon systolic BP. If the SBP was at least 100 and less than 120 mm Hg at baseline, sacubitril/valsartan was initiated at 24/26 mg twice daily, enalapril at 2.5 mg b.i.d. If the SBP at randomization was 120 mm Hg or higher, the initial dosing was sacubitril/valsartan at 49/51 mm Hg b.i.d. or enalapril at 5 mg b.i.d. Up-titration occurred after 1 week, then biweekly through week 8.
PIONEER in perspective
Discussant Larry A. Allen, MD, a heart failure specialist at the University of Colorado at Denver, Aurora, predicted that this will be a practice-changing study.
“There has been a need for a study like PIONEER in heart failure,” he observed. While multiple randomized trials have advanced the treatment of ambulatory HFrEF patients, demonstrating benefit for initiation and intensification of treatment with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, the treatment of patients with ADHF has remained relatively static, marked by failed trials of once-promising novel agents including tolvaptan, nesiritide, and serelaxin.
“All the data is in ambulatory patients, but the action for the care of heart failure patients actually occurs largely in the hospital. Seventy percent of care provided in the U.S. to patients with heart failure occurs in the hospital setting. These patients are a captive audience at that time, and the transitions from inpatient to outpatient care are fragile,” Dr. Allen said.
He noted that the use of sacubitril/valsartan in routine practice as reflected in national registries has been “extremely low” – less than 15% among eligible patients – despite the drug having been approved more than 3 years ago. One major reason for the low uptake, in his view, is clinical inertia. That should melt away in what he termed “the post-PIONEER world.”
“I think one of the great things about this study is it keeps it simple. We now have a simpler algorithm for inpatient and subsequent outpatient management of heart failure with reduced ejection fraction. It’s easier for us to start with the treatment we want patients to be on, and it’s better for patients, too. Most importantly, this study reinforces the importance and safety of aggressive guideline-directed medical therapy starting from the beginning in most patients,” Dr. Allen said.
The study findings were published simultaneously in the New England Journal of Medicine (2018 Nov 11. doi: 10.1056/NEJMoa1812851).
PIONEER-HF was sponsored by Novartis. Dr. Velazquez reported receiving research grants from and serving as a consultant to that company and others. Dr. Allen reported having no financial conflicts.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The rate of rehospitalization for heart failure during the next 2 months after initiation of sacubitril/valsartan during hospitalization for acute decompensated heart failure was 44% lower than with enalapril.
Study details: A randomized, multicenter trial involving 881 patients hospitalized for acute decompensated heart failure.
Disclosures: The PIONEER-HF trial was sponsored by Novartis. The presenter reported receiving research grants from and serving as a consultant to that company and others.
‘Organoid technology’ poised to transform cancer care
BOSTON– Imagine being able to .
The implications are nearly endless. To start, chemotherapy and radiation options could be screened in vitro, much like culture and sensitivity testing of bacteria, to find a patient’s best option. Tumor cultures could be banked for mass screening of new cytotoxic candidates.
It’s already beginning to happen in a few research labs around the world, and it might foretell a breakthrough in cancer treatment.
After decades of failure, the trick to growing tumor cells in culture has finally been figured out. When stem cells are fished out of healthy tissue – from the crypts of the gastrointestinal lining, for instance – and put into a three-dimensional matrix culture with growth factors, they grow into little replications of the organs they came from, called “organoids;” when stem cells are pulled from cancers, they replicate the primary tumor, growing into “tumoroids” ready to be tested against cytotoxic drugs and radiation.
Philip B. Paty, MD, FACS, a colorectal surgeon and organoid researcher at Memorial Sloan Kettering Cancer Center, New York, said he is certain that the person who led the team that figured out the right culture condition – Hans Clevers, MD, PhD, a molecular genetics professor at the University of Utrecht (the Netherlands) – is destined for a Nobel Prize.
Dr. Paty took a few minutes at the annual clinical congress of the American College of Surgeons to explain in an interview why, and what ‘organoid technology’ will likely mean for cancer treatment in a few years.
“The ability to grow and sustain cancer means that we now can start doing real science on human tissues. We could never do this before. We’ve been treating cancer without being able to grow tumors and study them.” The breakthrough opens the door to “clinical trials in a dish,” and will likely take personalized cancer treatment to a new level, he said.
“It remains to be proven that “organoid technology “can change outcomes for patients, but those studies are likely coming,” said Dr. Paty, who investigates tumoroid response to radiation in his own lab work.
BOSTON– Imagine being able to .
The implications are nearly endless. To start, chemotherapy and radiation options could be screened in vitro, much like culture and sensitivity testing of bacteria, to find a patient’s best option. Tumor cultures could be banked for mass screening of new cytotoxic candidates.
It’s already beginning to happen in a few research labs around the world, and it might foretell a breakthrough in cancer treatment.
After decades of failure, the trick to growing tumor cells in culture has finally been figured out. When stem cells are fished out of healthy tissue – from the crypts of the gastrointestinal lining, for instance – and put into a three-dimensional matrix culture with growth factors, they grow into little replications of the organs they came from, called “organoids;” when stem cells are pulled from cancers, they replicate the primary tumor, growing into “tumoroids” ready to be tested against cytotoxic drugs and radiation.
Philip B. Paty, MD, FACS, a colorectal surgeon and organoid researcher at Memorial Sloan Kettering Cancer Center, New York, said he is certain that the person who led the team that figured out the right culture condition – Hans Clevers, MD, PhD, a molecular genetics professor at the University of Utrecht (the Netherlands) – is destined for a Nobel Prize.
Dr. Paty took a few minutes at the annual clinical congress of the American College of Surgeons to explain in an interview why, and what ‘organoid technology’ will likely mean for cancer treatment in a few years.
“The ability to grow and sustain cancer means that we now can start doing real science on human tissues. We could never do this before. We’ve been treating cancer without being able to grow tumors and study them.” The breakthrough opens the door to “clinical trials in a dish,” and will likely take personalized cancer treatment to a new level, he said.
“It remains to be proven that “organoid technology “can change outcomes for patients, but those studies are likely coming,” said Dr. Paty, who investigates tumoroid response to radiation in his own lab work.
BOSTON– Imagine being able to .
The implications are nearly endless. To start, chemotherapy and radiation options could be screened in vitro, much like culture and sensitivity testing of bacteria, to find a patient’s best option. Tumor cultures could be banked for mass screening of new cytotoxic candidates.
It’s already beginning to happen in a few research labs around the world, and it might foretell a breakthrough in cancer treatment.
After decades of failure, the trick to growing tumor cells in culture has finally been figured out. When stem cells are fished out of healthy tissue – from the crypts of the gastrointestinal lining, for instance – and put into a three-dimensional matrix culture with growth factors, they grow into little replications of the organs they came from, called “organoids;” when stem cells are pulled from cancers, they replicate the primary tumor, growing into “tumoroids” ready to be tested against cytotoxic drugs and radiation.
Philip B. Paty, MD, FACS, a colorectal surgeon and organoid researcher at Memorial Sloan Kettering Cancer Center, New York, said he is certain that the person who led the team that figured out the right culture condition – Hans Clevers, MD, PhD, a molecular genetics professor at the University of Utrecht (the Netherlands) – is destined for a Nobel Prize.
Dr. Paty took a few minutes at the annual clinical congress of the American College of Surgeons to explain in an interview why, and what ‘organoid technology’ will likely mean for cancer treatment in a few years.
“The ability to grow and sustain cancer means that we now can start doing real science on human tissues. We could never do this before. We’ve been treating cancer without being able to grow tumors and study them.” The breakthrough opens the door to “clinical trials in a dish,” and will likely take personalized cancer treatment to a new level, he said.
“It remains to be proven that “organoid technology “can change outcomes for patients, but those studies are likely coming,” said Dr. Paty, who investigates tumoroid response to radiation in his own lab work.
REPORTING FROM THE ACS CLINICAL CONGRESS
MIS for cervical cancer: Is it not for anyone or not for everyone?
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
References
1. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.
2. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1804923.
3. J Clin Oncol. 2012 Mar 1;30(7):695-700.
4. Med Sci Monit. 2014 Dec 1;20:2497-503.
5. Surg Endosc. 2006 Oct;20(10):1556-9.
6. Gynecol Oncol. 2011 Aug;122(2):264-8.
7. Surgery. 2016 Mar;159(3):736-48.
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
References
1. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.
2. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1804923.
3. J Clin Oncol. 2012 Mar 1;30(7):695-700.
4. Med Sci Monit. 2014 Dec 1;20:2497-503.
5. Surg Endosc. 2006 Oct;20(10):1556-9.
6. Gynecol Oncol. 2011 Aug;122(2):264-8.
7. Surgery. 2016 Mar;159(3):736-48.
Shock waves moved through the gynecologic oncology world on Oct. 31, 2018, when the New England Journal of Medicine published two papers on survival outcomes for women undergoing surgery for early stage cervical cancer.
The first was a randomized controlled trial of laparotomy and minimally invasive surgery (MIS) for radical hysterectomy called the LACC trial.1 In the multicenter, international trial of 631 women, the primary objective was disease-specific survival (cervical cancer–related deaths) and was powered to detect noninferiority of the MIS approach when compared with laparotomy. The trial was closed early when investigators noted a lower than expected rate of 3-year, disease-free survival (91% vs. 97%) from cervical cancer in the MIS group, which was made up of 84% laparoscopic and 16% robotic approaches, versus laparotomy. There were 19 deaths in the MIS group observed versus three in the laparotomy group. The conclusions of the trial were that MIS surgery is associated with inferior cervical cancer survival.
In the second study, authors analyzed data from large U.S. databases – the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program – to collect all-cause mortality for patients with early-stage cervical cancer who had undergone radical hysterectomy during 2010-2013.2 Among 2,461 observed results, 1,225 had undergone MIS surgery with the majority (79.8%) via robotic-assistance. Women undergoing MIS approaches had smaller, lower grade tumors; were more likely to be white, privately insured, and of a higher income; and had surgery later in the cohort and by nonacademic centers. The researchers adjusted for risk factors with an analytic process called propensity-score weighting, which matched the groups more closely in an attempt to minimize confounders. They identified higher all-cause mortality among women who were treated with an MIS approach, compared with those treated with laparotomy (hazard ratio, 1.65). They also observed a significant decline in the survival from cervical cancer annually that corresponded to the uptake of MIS radical hysterectomies.
In the wake of these publications, many concluded that gynecologic oncologists should no longer offer a minimally invasive approach for radical hysterectomy. Certainly level I evidence published in a highly influential journal is compelling, and the consistency in findings over two studies adds further weight to the results. However, was this the correct conclusion to draw from these results? Surgeons who had been performing MIS radical hysterectomies for many years with favorable outcomes are challenging this and are raising questions about external generalizability and whether these findings were driven by the surgery itself or by the surgeon.
The studies’ authors proposed hypotheses for their results that implicate the surgical route rather than the surgeon; however, these seem ad hoc and not well supported by data, including the authors’ own data. The first was the hypothesis that cervical tumors were being disrupted and disseminated through the use of uterine manipulators in MIS approaches. However, cervical cancers are fairly routinely “disrupted” by preoperative cone biopsies, loop electrosurgical excision procedures (LEEP), and sharp biopsies, which are arguably more invasive than placement of a manipulator. Uterine manipulators routinely are used in endometrial cancer surgeries, in which the manipulator is embedded within the tumor, without an associated negative survival effect in randomized trials.3 Additionally, not all surgeons utilize manipulators for radical hysterectomies, and these studies did not measure or report on their use; therefore, it is impossible to know whether, and by what magnitude, manipulators played a role. Finally, if uterine manipulators are the explanation for inferior survival, surely the recommendation should be to discourage their use, rather than abandon the MIS approach all together.
The other explanation offered was exposure of the tumor to CO2 gas. This seems an even less plausible explanation because CO2 gas is routinely used in MIS cancer surgeries for endometrial, prostate, gastric, and colorectal surgeries and is used as insufflation for malignant interventional endoscopies without a significant deleterious effect. Additionally, the cervix is not exposed to CO2 until colpotomy at the procedure’s end – and only briefly. The in vitro studies implicating a negative effect of simulated CO2 pneumoperitoneum are neither compelling nor consistent.4,5
I would like to propose another hypothesis for the results: surgical proficiency. Surgery, unlike medical interventions, is not a simple variable that is dichotomous – performed or not. Surgeons do not randomly select operative approaches for patients. We select surgical approaches based on patients’ circumstances and surgeon factors, including our own mastery of the various techniques. and any surgeon recognizes this if he or she has observed more than one surgeon or has attempted a procedure via different routes. While some procedures, such as extrafascial hysterectomy for endometrial cancer, are relatively straightforward and surgeon capabilities are more equitable across different approaches, cervical cancer surgery is quite different.
Early-stage cervical cancer primarily exerts radial growth into the cervical stroma and parametria. Curative surgical excision requires broadly negative margins through this tissue, a so called “radical hysterectomy.” The radicality of hysterectomy has been categorized in stages, acknowledging that different sized lesions require different volumes of parametrial resection to achieve adequate clearance from the tumor.6 In doing so, the surgeon must skeletonize and mobilize the distal ureters, cardinal ligament webs, and uterosacral ligaments. These structures are in close proximity to major vascular and neural structures. Hence, the radical hysterectomy is, without dispute, a technically challenging procedure.
Minimally invasive surgery further handicaps the surgeon by eliminating manual contact with tissue, and relying on complex instrumentation, electrosurgical modalities, and loss of haptics. The learning curve for MIS radical hysterectomy is further attenuated by their relative infrequency. Therefore, it makes sense that, when the MIS approach is randomly assigned to surgeons (such as in the LACC trial) or broadly and independently applied (as in the retrospective series), one might see variations in skill, quality, and outcomes, including oncologic outcomes.
The retrospective study by Melamed et al. acknowledged that surgeon skill and volume may contribute to their findings but stated that, because of the nature of their source data, they were unable to explain why they observed their results. The LACC trial attempted to overcome the issue of surgeon skill by ensuring all surgeons were from high-volume sites and had videos reviewed of their cases. However, the videos were chosen by the surgeons themselves and not available for audit in the study’s supplemental material. The LACC trial was conducted over a 9-year period across 33 sites and enrolled a total of 631 subjects. This equates to an enrollment of approximately two patients per site per year and either reflects extremely low-volume sites or highly selective patient enrollment. If the latter, what was different about the unenrolled patients and what was the preferred chosen route of surgery for them?
All 34 recurrences occurred in patients from just 14 of the 33 sites in the LACC trial. That means that less than half of the sites contributed to all of the recurrences. The authors provided no details on the specific sites, surgeons, or accrual rates in their manuscript or supplemental materials. Therefore, readers are unable to know what was different about those sites; whether they contributed the most patients and, therefore, the most recurrences; or whether they were low-volume sites with lower quality.
While margin status, positive or negative, was reported, there was no data captured regarding volume of resected parametrial tissue, or relative distance from tumor to margin, both of which might provide the reader with a better appraisal of surgeon proficiency and consistency in radicality of the two approaches. The incidence of locoregional (pelvic) recurrences were higher in the MIS arm, which is expected if there were inadequate margins around the laparoscopically resected tumors.
Finally, the authors of the LACC trial observed equivalent rates of postoperative complications between the laparotomy and MIS groups. The main virtue for MIS approaches is the reduction in perioperative morbidity. To observe no perioperative morbidity benefit in the MIS group is a red flag suggesting that these surgeons may not have achieved proficiency with the MIS approach.
Despite these arguments, the results of these studies should be taken seriously. Clearly, it is apparent that preservation of oncologic outcomes is not guaranteed with MIS radical hysterectomy, and it should not be the chosen approach for all patients and all surgeons. However, rather than entirely abandoning this less morbid approach, I would argue that it is a call to arms for gynecologic oncologists to self-evaluate. We should know our own data with respect to case volumes, perioperative complications, and cancer-related recurrence and death.
Perhaps MIS radical hysterectomies should be consolidated among high-volume surgeons with demonstrated good outcomes? Just as has been done for rectal cancer surgery with positive effect, we should establish accredited centers of excellence.7 We also need to improve the training of surgeons in novel, difficult techniques, as well as enhance the sophistication of MIS equipment such as improved instrumentation, haptics, and vision-guided surgery (for example, real-time intraoperative assessment of the tumor margins).
Let’s not take a wholesale step backwards to the surgical approaches of a 100 years ago just because they are more straightforward. Let’s do a better job of advancing the quality of what we do for our patients in the future.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at [email protected].
References
1. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.
2. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1804923.
3. J Clin Oncol. 2012 Mar 1;30(7):695-700.
4. Med Sci Monit. 2014 Dec 1;20:2497-503.
5. Surg Endosc. 2006 Oct;20(10):1556-9.
6. Gynecol Oncol. 2011 Aug;122(2):264-8.
7. Surgery. 2016 Mar;159(3):736-48.
Burden of atrial fibrillation associated with stroke risk
Background: Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke; however, it is unclear if atrial fibrillation burden in patients with PAF is correlated with increased stroke risk.
Study design: Retrospective cohort chart review study during October 2011–October 2016.
Setting: Outpatients in two Kaiser Permanente California health systems.
Synopsis: Among 1,965 adult patients with PAF not on anticoagulation therapy, PAF burden was defined as the percentage time spent in AF during 14-day ECG monitoring. Outcomes included hospitalization for ischemic stroke or arterial thromboembolism while not taking anticoagulants.
Patients in the highest tertile of PAF burden (less than 11%) had 215% higher risk of thromboembolic events, compared with those with lower PAF burden (less than 11%), yielding a hazard ratio of 3.15 (95% confidence interval, 1.51-6.61), even after adjustment.
This study was limited by short ECG monitoring period (14 days), low total number of events (29 total events, 17 in the highest tertile), and no minimum follow-up time. Further, with all patients insured in a single health care system, and excluded on disenrollment from the health plan, selection bias could have affected the results.
Bottom line: In patients with PAF, a larger AF burden (greater than 11%) is associated with increased risk of ischemic stroke. Assessment of AF burden may help determine the need for anticoagulation for stroke prevention.
Citation: Go AS et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM study. JAMA Cardiol. 2018 Jul 1;3(7):601-8.
Dr. Hanna is an assistant professor in the division of hospital medicine, University of Colorado, Denver.
Background: Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke; however, it is unclear if atrial fibrillation burden in patients with PAF is correlated with increased stroke risk.
Study design: Retrospective cohort chart review study during October 2011–October 2016.
Setting: Outpatients in two Kaiser Permanente California health systems.
Synopsis: Among 1,965 adult patients with PAF not on anticoagulation therapy, PAF burden was defined as the percentage time spent in AF during 14-day ECG monitoring. Outcomes included hospitalization for ischemic stroke or arterial thromboembolism while not taking anticoagulants.
Patients in the highest tertile of PAF burden (less than 11%) had 215% higher risk of thromboembolic events, compared with those with lower PAF burden (less than 11%), yielding a hazard ratio of 3.15 (95% confidence interval, 1.51-6.61), even after adjustment.
This study was limited by short ECG monitoring period (14 days), low total number of events (29 total events, 17 in the highest tertile), and no minimum follow-up time. Further, with all patients insured in a single health care system, and excluded on disenrollment from the health plan, selection bias could have affected the results.
Bottom line: In patients with PAF, a larger AF burden (greater than 11%) is associated with increased risk of ischemic stroke. Assessment of AF burden may help determine the need for anticoagulation for stroke prevention.
Citation: Go AS et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM study. JAMA Cardiol. 2018 Jul 1;3(7):601-8.
Dr. Hanna is an assistant professor in the division of hospital medicine, University of Colorado, Denver.
Background: Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke; however, it is unclear if atrial fibrillation burden in patients with PAF is correlated with increased stroke risk.
Study design: Retrospective cohort chart review study during October 2011–October 2016.
Setting: Outpatients in two Kaiser Permanente California health systems.
Synopsis: Among 1,965 adult patients with PAF not on anticoagulation therapy, PAF burden was defined as the percentage time spent in AF during 14-day ECG monitoring. Outcomes included hospitalization for ischemic stroke or arterial thromboembolism while not taking anticoagulants.
Patients in the highest tertile of PAF burden (less than 11%) had 215% higher risk of thromboembolic events, compared with those with lower PAF burden (less than 11%), yielding a hazard ratio of 3.15 (95% confidence interval, 1.51-6.61), even after adjustment.
This study was limited by short ECG monitoring period (14 days), low total number of events (29 total events, 17 in the highest tertile), and no minimum follow-up time. Further, with all patients insured in a single health care system, and excluded on disenrollment from the health plan, selection bias could have affected the results.
Bottom line: In patients with PAF, a larger AF burden (greater than 11%) is associated with increased risk of ischemic stroke. Assessment of AF burden may help determine the need for anticoagulation for stroke prevention.
Citation: Go AS et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM study. JAMA Cardiol. 2018 Jul 1;3(7):601-8.
Dr. Hanna is an assistant professor in the division of hospital medicine, University of Colorado, Denver.
Is prehospital cooling in cardiac arrest ready for prime time?
CHICAGO – Starting transnasal evaporative cooling before patients in cardiac arrest arrive at the hospital has been found to be safe, according to study results presented at the American Heart Association scientific sessions.
The European trial didn’t determine any benefit in the out-of-hospital approach, compared with in-hospital cooling across all study patients. But it did suggest that patients with ventricular fibrillation may achieve higher rates of complete neurologic recovery with the prehospital cooling approach.
“Transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe,” said Per Nordberg, MD, PhD, of Karolinska Institute in Stockholm, reporting for the Prehospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study (PRINCESS). “I think this an important message, because guidelines state at the moment that you shouldn’t cool patients outside the hospital. We have shown that this is possible with this new method.”
Transnasal evaporative cooling (RhinoChill) is a noninvasive method that involves cooling of the brain and provides continuous cooling without volume loading.
Centers in seven European countries participated in the trial, randomizing 677 patients to the transnasal, early cooling protocol or standard in-hospital hypothermia. The final analysis evaluated 671 patients: 337 in the intervention group and 334 in the control group. In the intervention group, the transnasal cooling technique was started on patients during CPR in their homes or in the ambulance.
The study found that the rate of 90-day survival with good neurological outcome was 16.6% in the intervention group, compared with 13.5% in the control group, a nonsignificant difference (P = .26).
“However, we could see a signal or a clinical trend toward an improved neurologic outcome in patients with ventricular fibrillation,” Dr. Nordberg said: 34.8% vs. 25.9% for the intervention vs. control populations, a relative, nonsignificant difference of 25% (P = .11).
In terms of complete neurologic recovery, the differences between the treatment groups among those with ventricular fibrillation were even more profound, and significant: 32.6% vs. 20% (P = .002).
Rates of cardiovascular complications – ventricular fibrillation, cardiogenic shock, pulmonary edema, and need for vasopressor – were similar between both groups, although the intervention group had low rates of nasal-related problems such as nose bleed and white nose tip that the control group didn’t have.
Transnasal evaporative cooling “could significantly shorten the time to the target temperature; we have shown that in previous safety feasibility trials,” Dr. Nordberg said. “Now, we can confirm that this method is effective to cool patients with cardiac arrest outside the hospital.”
In his discussion of the trial, Christopher B. Granger, MD, of Duke University, Durham, N.C., noted that the trial was well conducted and that it confirmed that patients can be rapidly cooled during or immediately after cardiac arrest. “But we still do not know if this has meaningful improvement in clinical outcomes,” he cautioned. A strength of the trial is its size, particularly “in a very challenging setting,” Dr. Granger added.
But he questioned the potential for neurological benefit in patients with ventricular fibrillation, particularly because the finding conflicts with a previously published trial (Crit Care Med. 2009 Dec;37[12]:3062-9). “With the primary outcome not significantly reduced, the subgroup analysis may not be reliable,” he said.
What’s needed next? “This trial provides some suggestion of the benefit of early rapid cooling in the ventricular fibrillation population,” Dr. Granger said, “but another trial is needed to justify a widespread change in practice.”
He reported receiving funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Dr. Granger reported financial relationships with AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic and the Medtronic Foundation, Merck, National Institutes of Health, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, and Verseon.
SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
CHICAGO – Starting transnasal evaporative cooling before patients in cardiac arrest arrive at the hospital has been found to be safe, according to study results presented at the American Heart Association scientific sessions.
The European trial didn’t determine any benefit in the out-of-hospital approach, compared with in-hospital cooling across all study patients. But it did suggest that patients with ventricular fibrillation may achieve higher rates of complete neurologic recovery with the prehospital cooling approach.
“Transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe,” said Per Nordberg, MD, PhD, of Karolinska Institute in Stockholm, reporting for the Prehospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study (PRINCESS). “I think this an important message, because guidelines state at the moment that you shouldn’t cool patients outside the hospital. We have shown that this is possible with this new method.”
Transnasal evaporative cooling (RhinoChill) is a noninvasive method that involves cooling of the brain and provides continuous cooling without volume loading.
Centers in seven European countries participated in the trial, randomizing 677 patients to the transnasal, early cooling protocol or standard in-hospital hypothermia. The final analysis evaluated 671 patients: 337 in the intervention group and 334 in the control group. In the intervention group, the transnasal cooling technique was started on patients during CPR in their homes or in the ambulance.
The study found that the rate of 90-day survival with good neurological outcome was 16.6% in the intervention group, compared with 13.5% in the control group, a nonsignificant difference (P = .26).
“However, we could see a signal or a clinical trend toward an improved neurologic outcome in patients with ventricular fibrillation,” Dr. Nordberg said: 34.8% vs. 25.9% for the intervention vs. control populations, a relative, nonsignificant difference of 25% (P = .11).
In terms of complete neurologic recovery, the differences between the treatment groups among those with ventricular fibrillation were even more profound, and significant: 32.6% vs. 20% (P = .002).
Rates of cardiovascular complications – ventricular fibrillation, cardiogenic shock, pulmonary edema, and need for vasopressor – were similar between both groups, although the intervention group had low rates of nasal-related problems such as nose bleed and white nose tip that the control group didn’t have.
Transnasal evaporative cooling “could significantly shorten the time to the target temperature; we have shown that in previous safety feasibility trials,” Dr. Nordberg said. “Now, we can confirm that this method is effective to cool patients with cardiac arrest outside the hospital.”
In his discussion of the trial, Christopher B. Granger, MD, of Duke University, Durham, N.C., noted that the trial was well conducted and that it confirmed that patients can be rapidly cooled during or immediately after cardiac arrest. “But we still do not know if this has meaningful improvement in clinical outcomes,” he cautioned. A strength of the trial is its size, particularly “in a very challenging setting,” Dr. Granger added.
But he questioned the potential for neurological benefit in patients with ventricular fibrillation, particularly because the finding conflicts with a previously published trial (Crit Care Med. 2009 Dec;37[12]:3062-9). “With the primary outcome not significantly reduced, the subgroup analysis may not be reliable,” he said.
What’s needed next? “This trial provides some suggestion of the benefit of early rapid cooling in the ventricular fibrillation population,” Dr. Granger said, “but another trial is needed to justify a widespread change in practice.”
He reported receiving funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Dr. Granger reported financial relationships with AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic and the Medtronic Foundation, Merck, National Institutes of Health, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, and Verseon.
SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
CHICAGO – Starting transnasal evaporative cooling before patients in cardiac arrest arrive at the hospital has been found to be safe, according to study results presented at the American Heart Association scientific sessions.
The European trial didn’t determine any benefit in the out-of-hospital approach, compared with in-hospital cooling across all study patients. But it did suggest that patients with ventricular fibrillation may achieve higher rates of complete neurologic recovery with the prehospital cooling approach.
“Transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe,” said Per Nordberg, MD, PhD, of Karolinska Institute in Stockholm, reporting for the Prehospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study (PRINCESS). “I think this an important message, because guidelines state at the moment that you shouldn’t cool patients outside the hospital. We have shown that this is possible with this new method.”
Transnasal evaporative cooling (RhinoChill) is a noninvasive method that involves cooling of the brain and provides continuous cooling without volume loading.
Centers in seven European countries participated in the trial, randomizing 677 patients to the transnasal, early cooling protocol or standard in-hospital hypothermia. The final analysis evaluated 671 patients: 337 in the intervention group and 334 in the control group. In the intervention group, the transnasal cooling technique was started on patients during CPR in their homes or in the ambulance.
The study found that the rate of 90-day survival with good neurological outcome was 16.6% in the intervention group, compared with 13.5% in the control group, a nonsignificant difference (P = .26).
“However, we could see a signal or a clinical trend toward an improved neurologic outcome in patients with ventricular fibrillation,” Dr. Nordberg said: 34.8% vs. 25.9% for the intervention vs. control populations, a relative, nonsignificant difference of 25% (P = .11).
In terms of complete neurologic recovery, the differences between the treatment groups among those with ventricular fibrillation were even more profound, and significant: 32.6% vs. 20% (P = .002).
Rates of cardiovascular complications – ventricular fibrillation, cardiogenic shock, pulmonary edema, and need for vasopressor – were similar between both groups, although the intervention group had low rates of nasal-related problems such as nose bleed and white nose tip that the control group didn’t have.
Transnasal evaporative cooling “could significantly shorten the time to the target temperature; we have shown that in previous safety feasibility trials,” Dr. Nordberg said. “Now, we can confirm that this method is effective to cool patients with cardiac arrest outside the hospital.”
In his discussion of the trial, Christopher B. Granger, MD, of Duke University, Durham, N.C., noted that the trial was well conducted and that it confirmed that patients can be rapidly cooled during or immediately after cardiac arrest. “But we still do not know if this has meaningful improvement in clinical outcomes,” he cautioned. A strength of the trial is its size, particularly “in a very challenging setting,” Dr. Granger added.
But he questioned the potential for neurological benefit in patients with ventricular fibrillation, particularly because the finding conflicts with a previously published trial (Crit Care Med. 2009 Dec;37[12]:3062-9). “With the primary outcome not significantly reduced, the subgroup analysis may not be reliable,” he said.
What’s needed next? “This trial provides some suggestion of the benefit of early rapid cooling in the ventricular fibrillation population,” Dr. Granger said, “but another trial is needed to justify a widespread change in practice.”
He reported receiving funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Dr. Granger reported financial relationships with AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic and the Medtronic Foundation, Merck, National Institutes of Health, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, and Verseon.
SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: Prehospital hypothermia therapy for cardiac arrest patients is safe.
Major finding: Ninety-day survival was 16.6% in the intervention group vs. 13.5% in controls (P = .26).
Study details: A randomized clinical trial of 677 patients who had cardiac arrest outside the hospital.
Disclosures: Dr. Nordberg receives funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Source: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
‘Watch and wait’ good for most – but not all – rectal cancers
BOSTON –
was established over a decade ago, and widely adopted since then. The idea is to hold off on surgery after a complete response to chemotherapy and radiation, to see if the patient really needs it.
While most do not, tumors regrow in 20%-30%, and when they come back, they tend to be aggressive, with poor outcomes. Patients in those situations would have been better off with upfront surgery.
The problem right now is that there’s no way to predict who will be cured by neoadjuvant therapy and whose tumor will come back, said Philip Paty, MD. FACS, a colorectal surgeon at Memorial Sloan Kettering Cancer Center, New York.
“There are some who are probably harmed by the watch-and-wait paradigm. The risk of local regrowth is hardbaked into [the model]; we haven’t been able to eliminate it,” he said at the annual clinical congress of the American College of Surgeons..
Dr. Paty is one of many investigators working to identify those at risk. In the meantime, watch-and-wait patients need to be followed closely, particularly in the first 2 years. Surgery is the best option at the first sign of regrowth. Dr. Paty explained his follow-up protocol, as well as the current state of watch and wait for low rectal cancer, in an interview at the meeting.
He also talked about overcoming hurdles. The risk of surgery, including permanent bowel and sexual dysfunction, is so great “that many patients latch onto watch and wait and won’t let go. They don’t come back for follow-up, or resist the idea of surgery even if it’s needed,” he said.
BOSTON –
was established over a decade ago, and widely adopted since then. The idea is to hold off on surgery after a complete response to chemotherapy and radiation, to see if the patient really needs it.
While most do not, tumors regrow in 20%-30%, and when they come back, they tend to be aggressive, with poor outcomes. Patients in those situations would have been better off with upfront surgery.
The problem right now is that there’s no way to predict who will be cured by neoadjuvant therapy and whose tumor will come back, said Philip Paty, MD. FACS, a colorectal surgeon at Memorial Sloan Kettering Cancer Center, New York.
“There are some who are probably harmed by the watch-and-wait paradigm. The risk of local regrowth is hardbaked into [the model]; we haven’t been able to eliminate it,” he said at the annual clinical congress of the American College of Surgeons..
Dr. Paty is one of many investigators working to identify those at risk. In the meantime, watch-and-wait patients need to be followed closely, particularly in the first 2 years. Surgery is the best option at the first sign of regrowth. Dr. Paty explained his follow-up protocol, as well as the current state of watch and wait for low rectal cancer, in an interview at the meeting.
He also talked about overcoming hurdles. The risk of surgery, including permanent bowel and sexual dysfunction, is so great “that many patients latch onto watch and wait and won’t let go. They don’t come back for follow-up, or resist the idea of surgery even if it’s needed,” he said.
BOSTON –
was established over a decade ago, and widely adopted since then. The idea is to hold off on surgery after a complete response to chemotherapy and radiation, to see if the patient really needs it.
While most do not, tumors regrow in 20%-30%, and when they come back, they tend to be aggressive, with poor outcomes. Patients in those situations would have been better off with upfront surgery.
The problem right now is that there’s no way to predict who will be cured by neoadjuvant therapy and whose tumor will come back, said Philip Paty, MD. FACS, a colorectal surgeon at Memorial Sloan Kettering Cancer Center, New York.
“There are some who are probably harmed by the watch-and-wait paradigm. The risk of local regrowth is hardbaked into [the model]; we haven’t been able to eliminate it,” he said at the annual clinical congress of the American College of Surgeons..
Dr. Paty is one of many investigators working to identify those at risk. In the meantime, watch-and-wait patients need to be followed closely, particularly in the first 2 years. Surgery is the best option at the first sign of regrowth. Dr. Paty explained his follow-up protocol, as well as the current state of watch and wait for low rectal cancer, in an interview at the meeting.
He also talked about overcoming hurdles. The risk of surgery, including permanent bowel and sexual dysfunction, is so great “that many patients latch onto watch and wait and won’t let go. They don’t come back for follow-up, or resist the idea of surgery even if it’s needed,” he said.
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
How to slash colorectal surgery infection rates
BOSTON – driven mostly by a reduction in deep organ space infections from 5.5% to 1.7%.
It was a remarkable finding that got the attention of attendees at the annual clinical congress of the American College of Surgeons. The Cleveland Clinic had been an outlier, in the wrong direction, compared with other centers, and administrators wanted a solution.
I. Emre Gorgun, MD, FACS, a colorectal surgeon and quality improvement officer at Cleveland Clinic, led the search for evidence-based interventions. Eventually, big changes were made to perioperative antibiotics, mechanical bowel prep, preop shower routines, and intraoperative procedures. The efforts paid off (Dis Colon Rectum. 2018 Jan;61[1]:89-98).
To help surgeons lower their own infection rates, Dr. Gorgun agreed to an interview at the meeting to explain exactly what was done.
There was resistance at first from surgeons who wanted to stick with their routines, but they came around once they were shown the data backing the changes. Eventually, “everyone was on board. We believe in this,” Dr. Gorgun said.
BOSTON – driven mostly by a reduction in deep organ space infections from 5.5% to 1.7%.
It was a remarkable finding that got the attention of attendees at the annual clinical congress of the American College of Surgeons. The Cleveland Clinic had been an outlier, in the wrong direction, compared with other centers, and administrators wanted a solution.
I. Emre Gorgun, MD, FACS, a colorectal surgeon and quality improvement officer at Cleveland Clinic, led the search for evidence-based interventions. Eventually, big changes were made to perioperative antibiotics, mechanical bowel prep, preop shower routines, and intraoperative procedures. The efforts paid off (Dis Colon Rectum. 2018 Jan;61[1]:89-98).
To help surgeons lower their own infection rates, Dr. Gorgun agreed to an interview at the meeting to explain exactly what was done.
There was resistance at first from surgeons who wanted to stick with their routines, but they came around once they were shown the data backing the changes. Eventually, “everyone was on board. We believe in this,” Dr. Gorgun said.
BOSTON – driven mostly by a reduction in deep organ space infections from 5.5% to 1.7%.
It was a remarkable finding that got the attention of attendees at the annual clinical congress of the American College of Surgeons. The Cleveland Clinic had been an outlier, in the wrong direction, compared with other centers, and administrators wanted a solution.
I. Emre Gorgun, MD, FACS, a colorectal surgeon and quality improvement officer at Cleveland Clinic, led the search for evidence-based interventions. Eventually, big changes were made to perioperative antibiotics, mechanical bowel prep, preop shower routines, and intraoperative procedures. The efforts paid off (Dis Colon Rectum. 2018 Jan;61[1]:89-98).
To help surgeons lower their own infection rates, Dr. Gorgun agreed to an interview at the meeting to explain exactly what was done.
There was resistance at first from surgeons who wanted to stick with their routines, but they came around once they were shown the data backing the changes. Eventually, “everyone was on board. We believe in this,” Dr. Gorgun said.
REPORTING FROM THE ACS CLINICAL CONGRESS
How, and when, to use fat grafting for scars
BOSTON – according to Benjamin Levi, MD, director of the burn/wound and regenerative medicine laboratory at the University of Michigan, Ann Arbor.
Some corners of the Internet tout it as “some sort of magic stem cell surgery,” Dr. Levi said, but in reality, for scar surgeons, it’s just another useful tool in the armamentarium, one that excels at filling skin depressions due to underlying tissue loss, whether from burns, trauma, or surgery. Unlike hyaluronic acid and other options, fat grafts last; about half of injected adipocytes remain indefinitely. Fat grafting might also help soften scars, he said.
To get the most out of the procedure, of course, it has to be done correctly, so Dr. Levi took a few minutes at the annual clinical congress of the American College of Surgeons to share his tips on harvesting and spinning down fat grafts, injecting adipocytes, and other matters. Although the concepts of fat grafting are straightforward, the techniques are a bit tricky. Dr. Levi hoped his treatment pearls would help other physicians, especially those considering adding fat grafting to their practice.
BOSTON – according to Benjamin Levi, MD, director of the burn/wound and regenerative medicine laboratory at the University of Michigan, Ann Arbor.
Some corners of the Internet tout it as “some sort of magic stem cell surgery,” Dr. Levi said, but in reality, for scar surgeons, it’s just another useful tool in the armamentarium, one that excels at filling skin depressions due to underlying tissue loss, whether from burns, trauma, or surgery. Unlike hyaluronic acid and other options, fat grafts last; about half of injected adipocytes remain indefinitely. Fat grafting might also help soften scars, he said.
To get the most out of the procedure, of course, it has to be done correctly, so Dr. Levi took a few minutes at the annual clinical congress of the American College of Surgeons to share his tips on harvesting and spinning down fat grafts, injecting adipocytes, and other matters. Although the concepts of fat grafting are straightforward, the techniques are a bit tricky. Dr. Levi hoped his treatment pearls would help other physicians, especially those considering adding fat grafting to their practice.
BOSTON – according to Benjamin Levi, MD, director of the burn/wound and regenerative medicine laboratory at the University of Michigan, Ann Arbor.
Some corners of the Internet tout it as “some sort of magic stem cell surgery,” Dr. Levi said, but in reality, for scar surgeons, it’s just another useful tool in the armamentarium, one that excels at filling skin depressions due to underlying tissue loss, whether from burns, trauma, or surgery. Unlike hyaluronic acid and other options, fat grafts last; about half of injected adipocytes remain indefinitely. Fat grafting might also help soften scars, he said.
To get the most out of the procedure, of course, it has to be done correctly, so Dr. Levi took a few minutes at the annual clinical congress of the American College of Surgeons to share his tips on harvesting and spinning down fat grafts, injecting adipocytes, and other matters. Although the concepts of fat grafting are straightforward, the techniques are a bit tricky. Dr. Levi hoped his treatment pearls would help other physicians, especially those considering adding fat grafting to their practice.
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
Transcription factor plays key role in AML gene regulatory networks
The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.
This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.
Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.
The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.
Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.
“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.
Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.
In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.
“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.
Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.
To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.
For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.
“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.
They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.
SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.
The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.
This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.
Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.
The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.
Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.
“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.
Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.
In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.
“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.
Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.
To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.
For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.
“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.
They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.
SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.
The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.
This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.
Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.
The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.
Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.
“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.
Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.
In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.
“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.
Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.
To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.
For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.
“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.
They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.
SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.
FROM NATURE GENETICS
Key clinical point:
Major finding: The AP-1 factor family gene regulatory network was of high regulatory relevance in multiple subtypes of AML with defined mutations.
Study details: Analysis of normal CD34+ cells and cells from AML subjects.
Disclosures: Funding came from Bloodwise and Cancer Research UK, among other sources. The researchers reported having no competing financial interests.
Source: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.