SEATTLE – Children who are suicidal and victims of trauma, especially those with PTSD, pose an especially difficult challenge for psychiatrists. Trauma, suicidality, and self-harm often present together, and they might heighten the risk of treatment.

“It becomes a dilemma to know in what order to treat those symptoms, because sometimes it feels like one will not get better without treating the other,” said Michele Berk, PhD. “But there’s also some question around when it’s safe to do exposure-based treatments – which are the key ingredient to resolving PTSD symptoms,” Dr. Berk said during a session focused on trauma and suicidality in youth at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Dialectical behavior therapy, or DBT, is an option. DBT was developed by Marsha M. Linehan, PhD, to treat chronic suicidality comorbid with borderline personality disorder. In addition to PTSD, newer work has shown DBT as efficacious for treating substance use disorders, depression, and eating disorders.

DBT is based on the idea that self-harm occurs, at least in some cases, because the patient is predisposed to experiencing heightened emotional reactions. When the patient is exposed to an invalidating environment, such as when a parent or caregiver tells them to “just get over it; you’re overreacting,” this can lead patients to question their emotions. Most importantly, patients never learn effective strategies to that manage their emotions, according to Dr. Berk, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University.

In addition, Dr. Berk said, traumatized youth sometimes present with the most extreme form of invalidation, in which the patient’s entire being is violated through physical violence.

“So you have people who have these really intense negative emotions but don’t know how to help themselves manage them, and that is where DBT believes suicidal and self-harm behavior comes in,” Dr. Berk said. “We know that self-harm, though not suicidal self-injury, does in fact reduce emotion.”

DBT aims to counter suicidality by assisting the patient to build a life worth living. It encompasses five modes, including skills training, individual psychotherapy, in-the-moment coaching, case management, and a DBT consultation team to support the therapist.

The program prioritizes life-threatening behaviors in stage I and saving any exposure or PTSD therapy for stage II, which might begin up to 12 months later.

Also in stage I, after life-threatening behaviors have been resolved, the therapist addresses symptoms or factors that potentially interfere with further therapy. That’s important, because patients usually have comorbid symptoms and might be acutely distressed. “DBT has developed a clear hierarchy of how to target those things so that the sessions don’t get chaotic or off track,” Dr. Berk said.

Trauma symptoms might be tackled in stage I if they’re directly linked to suicidality or interfere with treatment, through reluctance to share information or because they might lead to dissociation during a session. After that, the program addresses quality of life, since its goal is to help patients create lives they deem worth living.

The skills training component of DBT includes mindfulness to help ground patients in the present moment. It also fosters skills that can be used to address trauma, including distress tolerance. Distress tolerance incorporates actions such as distraction and self-soothing. Emotional regulation seeks to help patients alter their emotions when possible. Interpersonal relationship skills help the patients ask for what they want and how to say “no” effectively.

Exposure therapy does not begin until patients have gone at least 2 months without any self-harming behavior, and it is interrupted if the patients exhibit self-harming behavior after it starts.

DBT remains a subject of continuing research. One avenue would be to more directly integrate exposure therapy with DBT in adolescents, but a protocol has not yet been developed. Prolonged exposure is typically used in adult PTSD patients, but trauma-focused cognitive-behavioral therapy more often is the choice for adolescents.

Whatever the choice, involvement of caring adults would be key. “In adolescents, there’s a need to involve parents and caregivers in whatever the trauma treatment is going to be,” Dr. Berk said.

Dr. Berk disclosed no conflicts of interest.

SEATTLE – Children who are suicidal and victims of trauma, especially those with PTSD, pose an especially difficult challenge for psychiatrists. Trauma, suicidality, and self-harm often present together, and they might heighten the risk of treatment.

“It becomes a dilemma to know in what order to treat those symptoms, because sometimes it feels like one will not get better without treating the other,” said Michele Berk, PhD. “But there’s also some question around when it’s safe to do exposure-based treatments – which are the key ingredient to resolving PTSD symptoms,” Dr. Berk said during a session focused on trauma and suicidality in youth at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Dialectical behavior therapy, or DBT, is an option. DBT was developed by Marsha M. Linehan, PhD, to treat chronic suicidality comorbid with borderline personality disorder. In addition to PTSD, newer work has shown DBT as efficacious for treating substance use disorders, depression, and eating disorders.

DBT is based on the idea that self-harm occurs, at least in some cases, because the patient is predisposed to experiencing heightened emotional reactions. When the patient is exposed to an invalidating environment, such as when a parent or caregiver tells them to “just get over it; you’re overreacting,” this can lead patients to question their emotions. Most importantly, patients never learn effective strategies to that manage their emotions, according to Dr. Berk, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University.

In addition, Dr. Berk said, traumatized youth sometimes present with the most extreme form of invalidation, in which the patient’s entire being is violated through physical violence.

“So you have people who have these really intense negative emotions but don’t know how to help themselves manage them, and that is where DBT believes suicidal and self-harm behavior comes in,” Dr. Berk said. “We know that self-harm, though not suicidal self-injury, does in fact reduce emotion.”

DBT aims to counter suicidality by assisting the patient to build a life worth living. It encompasses five modes, including skills training, individual psychotherapy, in-the-moment coaching, case management, and a DBT consultation team to support the therapist.

The program prioritizes life-threatening behaviors in stage I and saving any exposure or PTSD therapy for stage II, which might begin up to 12 months later.

Also in stage I, after life-threatening behaviors have been resolved, the therapist addresses symptoms or factors that potentially interfere with further therapy. That’s important, because patients usually have comorbid symptoms and might be acutely distressed. “DBT has developed a clear hierarchy of how to target those things so that the sessions don’t get chaotic or off track,” Dr. Berk said.

Trauma symptoms might be tackled in stage I if they’re directly linked to suicidality or interfere with treatment, through reluctance to share information or because they might lead to dissociation during a session. After that, the program addresses quality of life, since its goal is to help patients create lives they deem worth living.

The skills training component of DBT includes mindfulness to help ground patients in the present moment. It also fosters skills that can be used to address trauma, including distress tolerance. Distress tolerance incorporates actions such as distraction and self-soothing. Emotional regulation seeks to help patients alter their emotions when possible. Interpersonal relationship skills help the patients ask for what they want and how to say “no” effectively.

Exposure therapy does not begin until patients have gone at least 2 months without any self-harming behavior, and it is interrupted if the patients exhibit self-harming behavior after it starts.

DBT remains a subject of continuing research. One avenue would be to more directly integrate exposure therapy with DBT in adolescents, but a protocol has not yet been developed. Prolonged exposure is typically used in adult PTSD patients, but trauma-focused cognitive-behavioral therapy more often is the choice for adolescents.

Whatever the choice, involvement of caring adults would be key. “In adolescents, there’s a need to involve parents and caregivers in whatever the trauma treatment is going to be,” Dr. Berk said.

Dr. Berk disclosed no conflicts of interest.

SEATTLE – Children who are suicidal and victims of trauma, especially those with PTSD, pose an especially difficult challenge for psychiatrists. Trauma, suicidality, and self-harm often present together, and they might heighten the risk of treatment.

“It becomes a dilemma to know in what order to treat those symptoms, because sometimes it feels like one will not get better without treating the other,” said Michele Berk, PhD. “But there’s also some question around when it’s safe to do exposure-based treatments – which are the key ingredient to resolving PTSD symptoms,” Dr. Berk said during a session focused on trauma and suicidality in youth at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Dialectical behavior therapy, or DBT, is an option. DBT was developed by Marsha M. Linehan, PhD, to treat chronic suicidality comorbid with borderline personality disorder. In addition to PTSD, newer work has shown DBT as efficacious for treating substance use disorders, depression, and eating disorders.

DBT is based on the idea that self-harm occurs, at least in some cases, because the patient is predisposed to experiencing heightened emotional reactions. When the patient is exposed to an invalidating environment, such as when a parent or caregiver tells them to “just get over it; you’re overreacting,” this can lead patients to question their emotions. Most importantly, patients never learn effective strategies to that manage their emotions, according to Dr. Berk, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University.

In addition, Dr. Berk said, traumatized youth sometimes present with the most extreme form of invalidation, in which the patient’s entire being is violated through physical violence.

“So you have people who have these really intense negative emotions but don’t know how to help themselves manage them, and that is where DBT believes suicidal and self-harm behavior comes in,” Dr. Berk said. “We know that self-harm, though not suicidal self-injury, does in fact reduce emotion.”

DBT aims to counter suicidality by assisting the patient to build a life worth living. It encompasses five modes, including skills training, individual psychotherapy, in-the-moment coaching, case management, and a DBT consultation team to support the therapist.

The program prioritizes life-threatening behaviors in stage I and saving any exposure or PTSD therapy for stage II, which might begin up to 12 months later.

Also in stage I, after life-threatening behaviors have been resolved, the therapist addresses symptoms or factors that potentially interfere with further therapy. That’s important, because patients usually have comorbid symptoms and might be acutely distressed. “DBT has developed a clear hierarchy of how to target those things so that the sessions don’t get chaotic or off track,” Dr. Berk said.

Trauma symptoms might be tackled in stage I if they’re directly linked to suicidality or interfere with treatment, through reluctance to share information or because they might lead to dissociation during a session. After that, the program addresses quality of life, since its goal is to help patients create lives they deem worth living.

The skills training component of DBT includes mindfulness to help ground patients in the present moment. It also fosters skills that can be used to address trauma, including distress tolerance. Distress tolerance incorporates actions such as distraction and self-soothing. Emotional regulation seeks to help patients alter their emotions when possible. Interpersonal relationship skills help the patients ask for what they want and how to say “no” effectively.

Exposure therapy does not begin until patients have gone at least 2 months without any self-harming behavior, and it is interrupted if the patients exhibit self-harming behavior after it starts.

DBT remains a subject of continuing research. One avenue would be to more directly integrate exposure therapy with DBT in adolescents, but a protocol has not yet been developed. Prolonged exposure is typically used in adult PTSD patients, but trauma-focused cognitive-behavioral therapy more often is the choice for adolescents.

Whatever the choice, involvement of caring adults would be key. “In adolescents, there’s a need to involve parents and caregivers in whatever the trauma treatment is going to be,” Dr. Berk said.

Dr. Berk disclosed no conflicts of interest.

SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.

The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.

The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.

Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.

Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.

In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.

The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.

To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.

Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.

Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.

The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.

SOURCE: Liu J. AASLD 2018, Abstract 0040.

SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.

The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.

The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.

Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.

Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.

In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.

The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.

To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.

Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.

Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.

The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.

SOURCE: Liu J. AASLD 2018, Abstract 0040.

SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.

The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.

The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.

Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.

Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.

In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.

The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.

To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.

Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.

Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.

The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.

SOURCE: Liu J. AASLD 2018, Abstract 0040.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, 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 – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, 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 – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, 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.

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.

Bruce Jancin/MDedge News

“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

Bruce Jancin/MDedge News

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.

[email protected]

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.

Bruce Jancin/MDedge News

“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

Bruce Jancin/MDedge News

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.

[email protected]

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.

Bruce Jancin/MDedge News

“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

Bruce Jancin/MDedge News

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.

[email protected]

BOSTON– Imagine being able to biopsy a tumor and grow it in a lab.
 

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.

[email protected]

BOSTON– Imagine being able to biopsy a tumor and grow it in a lab.
 

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.

[email protected]

BOSTON– Imagine being able to biopsy a tumor and grow it in a lab.
 

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.

[email protected]

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. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, 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.

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. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, 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.

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. Randomized surgical trials rely on the notion that a surgeon is equally skilled in both or all approaches offered, but this is clearly not the case, 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.

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.

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.

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.

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.

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.

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).

Janice Carr, CDC

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).

Janice Carr, CDC

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).

Janice Carr, CDC

SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.

BOSTON – Chemotherapy and radiation cure 70%-80% of patients with low rectal cancer.

It’s for them that the watch-and-wait paradigm 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.

[email protected]

BOSTON – Chemotherapy and radiation cure 70%-80% of patients with low rectal cancer.

It’s for them that the watch-and-wait paradigm 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.

[email protected]

BOSTON – Chemotherapy and radiation cure 70%-80% of patients with low rectal cancer.

It’s for them that the watch-and-wait paradigm 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.

[email protected]

BOSTON – A quality improvement project conducted at the Cleveland Clinic dropped the 30-day colorectal surgery infection rate from 11.8% to 6.6%, 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.

[email protected]

BOSTON – A quality improvement project conducted at the Cleveland Clinic dropped the 30-day colorectal surgery infection rate from 11.8% to 6.6%, 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.

[email protected]

BOSTON – A quality improvement project conducted at the Cleveland Clinic dropped the 30-day colorectal surgery infection rate from 11.8% to 6.6%, 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.

[email protected]