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Endoscopic full-thickness resection of colorectal lesions appears safe and effective
Endoscopic full-thickness resection (eFTR) of complex colorectal lesions appears safe and effective, based on prospective data from 20 Dutch hospitals.
Macroscopic complete en bloc resection was achieved in 83.9% of procedures with an adverse event rate of 9.3%, reported lead author Liselotte W. Zwager, a PhD candidate at the University of Amsterdam, and colleagues.
“With the advantage of enabling a transmural resection, eFTR offers an alternative to radical surgery in lesions considered incurable with current resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD),” the investigators wrote in Endoscopy.
But more data are needed for widespread adoption, they noted. “Several studies have reported encouraging results on the short-term safety and efficacy of eFTR for numerous indications. However, firm conclusions on clinical results will require analysis of large prospective series of patients in everyday clinical practice.”
The present study provided data from 362 patients who underwent 367 procedures at 5 academic and 15 nonacademic centers in the Netherlands.
Patients were eligible for eFTR if polyps were nonlifting or in difficult-to-reach locations, or if T1 colorectal cancer (CRC) was suspected. In addition, eFTR was performed for subepithelial tumors, and as secondary completion treatment after incomplete endoscopic resection of T1 CRC with a positive or nonassessable resection margin. Lesions greater than 30 mm were excluded because of device diameter constraints.
The primary outcome was macroscopic complete en bloc resection. Secondary outcomes included adverse events, full-thickness resection rate, and clinical success, the latter of which was defined by tumor-free resection margins (R0).
Out of 367 procedures, eFTR was most frequently conducted because of incomplete resection of T1 CRC (41%), followed by nonlifting or difficult-to-reach polyps (36%), suspected T1 CRC (19%), and least often, subepithelial tumors (4%).
Complete en bloc resection was achieved in 83.9% of procedures. Excluding 21 procedures in which eFTR was not performed because of inaccessibility of the lesion (n = 7) or immobility of tissue prohibiting retraction of the lesion into the cap (n = 14), R0 was achieved in 82.4% of cases. Among the same group, full-thickness resection rate was comparable, at 83.2%.
Adverse events occurred in 34 patients (9.3%), among whom 10 (2.7%) underwent emergency surgery for perforations or appendicitis.
“In conclusion,” the investigators wrote, “eFTR is an exciting, innovative resection technique that is clinically feasible and safe for complex colorectal lesions, with the potential to obviate the need for surgical resection. Further efficacy studies on eFTR as a primary and secondary treatment option for T1 CRC are needed, focusing on both the short- and long-term oncologic results.”
Peter V. Draganov, MD, of the University of Florida, Gainesville, called the R0 resection rate “respectable,” and suggested that the study “reconfirms on a larger scale that eFTR with the full-thickness resection device is successful in the majority of cases.”
“The full-thickness resection device expands our armamentarium to remove difficult polyps and early CRC,” he said.
Still, Dr. Draganov, who has previously advised careful patient selection for eFTR, noted certain drawbacks of the technique. “The presented data highlight some of the limitations of the full-thickness resection device, including the relatively small size of the lesion [median diameter, 23 mm] that can be resected, and challenges related to accessing and capturing the lesion due to the limited visibility and maneuverability of the device.”
Ultimately, Dr. Draganov supported the investigators’ call for more data. “Before eFTR becomes a primary modality for management of T1 CRC, we do need follow-up data on long-term cancer-related outcomes,” he said.
The study was supported by Ovesco Endoscopy. The investigators disclosed additional relationships with Cook, Ethicon, Olympus, and others.
SOURCE: Zwager LW et al. Endoscopy. 2020 Jun 4. doi: 10.1055/a-1176-1107.
Endoscopic full-thickness resection (eFTR) of complex colorectal lesions appears safe and effective, based on prospective data from 20 Dutch hospitals.
Macroscopic complete en bloc resection was achieved in 83.9% of procedures with an adverse event rate of 9.3%, reported lead author Liselotte W. Zwager, a PhD candidate at the University of Amsterdam, and colleagues.
“With the advantage of enabling a transmural resection, eFTR offers an alternative to radical surgery in lesions considered incurable with current resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD),” the investigators wrote in Endoscopy.
But more data are needed for widespread adoption, they noted. “Several studies have reported encouraging results on the short-term safety and efficacy of eFTR for numerous indications. However, firm conclusions on clinical results will require analysis of large prospective series of patients in everyday clinical practice.”
The present study provided data from 362 patients who underwent 367 procedures at 5 academic and 15 nonacademic centers in the Netherlands.
Patients were eligible for eFTR if polyps were nonlifting or in difficult-to-reach locations, or if T1 colorectal cancer (CRC) was suspected. In addition, eFTR was performed for subepithelial tumors, and as secondary completion treatment after incomplete endoscopic resection of T1 CRC with a positive or nonassessable resection margin. Lesions greater than 30 mm were excluded because of device diameter constraints.
The primary outcome was macroscopic complete en bloc resection. Secondary outcomes included adverse events, full-thickness resection rate, and clinical success, the latter of which was defined by tumor-free resection margins (R0).
Out of 367 procedures, eFTR was most frequently conducted because of incomplete resection of T1 CRC (41%), followed by nonlifting or difficult-to-reach polyps (36%), suspected T1 CRC (19%), and least often, subepithelial tumors (4%).
Complete en bloc resection was achieved in 83.9% of procedures. Excluding 21 procedures in which eFTR was not performed because of inaccessibility of the lesion (n = 7) or immobility of tissue prohibiting retraction of the lesion into the cap (n = 14), R0 was achieved in 82.4% of cases. Among the same group, full-thickness resection rate was comparable, at 83.2%.
Adverse events occurred in 34 patients (9.3%), among whom 10 (2.7%) underwent emergency surgery for perforations or appendicitis.
“In conclusion,” the investigators wrote, “eFTR is an exciting, innovative resection technique that is clinically feasible and safe for complex colorectal lesions, with the potential to obviate the need for surgical resection. Further efficacy studies on eFTR as a primary and secondary treatment option for T1 CRC are needed, focusing on both the short- and long-term oncologic results.”
Peter V. Draganov, MD, of the University of Florida, Gainesville, called the R0 resection rate “respectable,” and suggested that the study “reconfirms on a larger scale that eFTR with the full-thickness resection device is successful in the majority of cases.”
“The full-thickness resection device expands our armamentarium to remove difficult polyps and early CRC,” he said.
Still, Dr. Draganov, who has previously advised careful patient selection for eFTR, noted certain drawbacks of the technique. “The presented data highlight some of the limitations of the full-thickness resection device, including the relatively small size of the lesion [median diameter, 23 mm] that can be resected, and challenges related to accessing and capturing the lesion due to the limited visibility and maneuverability of the device.”
Ultimately, Dr. Draganov supported the investigators’ call for more data. “Before eFTR becomes a primary modality for management of T1 CRC, we do need follow-up data on long-term cancer-related outcomes,” he said.
The study was supported by Ovesco Endoscopy. The investigators disclosed additional relationships with Cook, Ethicon, Olympus, and others.
SOURCE: Zwager LW et al. Endoscopy. 2020 Jun 4. doi: 10.1055/a-1176-1107.
Endoscopic full-thickness resection (eFTR) of complex colorectal lesions appears safe and effective, based on prospective data from 20 Dutch hospitals.
Macroscopic complete en bloc resection was achieved in 83.9% of procedures with an adverse event rate of 9.3%, reported lead author Liselotte W. Zwager, a PhD candidate at the University of Amsterdam, and colleagues.
“With the advantage of enabling a transmural resection, eFTR offers an alternative to radical surgery in lesions considered incurable with current resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD),” the investigators wrote in Endoscopy.
But more data are needed for widespread adoption, they noted. “Several studies have reported encouraging results on the short-term safety and efficacy of eFTR for numerous indications. However, firm conclusions on clinical results will require analysis of large prospective series of patients in everyday clinical practice.”
The present study provided data from 362 patients who underwent 367 procedures at 5 academic and 15 nonacademic centers in the Netherlands.
Patients were eligible for eFTR if polyps were nonlifting or in difficult-to-reach locations, or if T1 colorectal cancer (CRC) was suspected. In addition, eFTR was performed for subepithelial tumors, and as secondary completion treatment after incomplete endoscopic resection of T1 CRC with a positive or nonassessable resection margin. Lesions greater than 30 mm were excluded because of device diameter constraints.
The primary outcome was macroscopic complete en bloc resection. Secondary outcomes included adverse events, full-thickness resection rate, and clinical success, the latter of which was defined by tumor-free resection margins (R0).
Out of 367 procedures, eFTR was most frequently conducted because of incomplete resection of T1 CRC (41%), followed by nonlifting or difficult-to-reach polyps (36%), suspected T1 CRC (19%), and least often, subepithelial tumors (4%).
Complete en bloc resection was achieved in 83.9% of procedures. Excluding 21 procedures in which eFTR was not performed because of inaccessibility of the lesion (n = 7) or immobility of tissue prohibiting retraction of the lesion into the cap (n = 14), R0 was achieved in 82.4% of cases. Among the same group, full-thickness resection rate was comparable, at 83.2%.
Adverse events occurred in 34 patients (9.3%), among whom 10 (2.7%) underwent emergency surgery for perforations or appendicitis.
“In conclusion,” the investigators wrote, “eFTR is an exciting, innovative resection technique that is clinically feasible and safe for complex colorectal lesions, with the potential to obviate the need for surgical resection. Further efficacy studies on eFTR as a primary and secondary treatment option for T1 CRC are needed, focusing on both the short- and long-term oncologic results.”
Peter V. Draganov, MD, of the University of Florida, Gainesville, called the R0 resection rate “respectable,” and suggested that the study “reconfirms on a larger scale that eFTR with the full-thickness resection device is successful in the majority of cases.”
“The full-thickness resection device expands our armamentarium to remove difficult polyps and early CRC,” he said.
Still, Dr. Draganov, who has previously advised careful patient selection for eFTR, noted certain drawbacks of the technique. “The presented data highlight some of the limitations of the full-thickness resection device, including the relatively small size of the lesion [median diameter, 23 mm] that can be resected, and challenges related to accessing and capturing the lesion due to the limited visibility and maneuverability of the device.”
Ultimately, Dr. Draganov supported the investigators’ call for more data. “Before eFTR becomes a primary modality for management of T1 CRC, we do need follow-up data on long-term cancer-related outcomes,” he said.
The study was supported by Ovesco Endoscopy. The investigators disclosed additional relationships with Cook, Ethicon, Olympus, and others.
SOURCE: Zwager LW et al. Endoscopy. 2020 Jun 4. doi: 10.1055/a-1176-1107.
FROM ENDOSCOPY
COVID-associated pancreatitis may disproportionately affect young, overweight men
Patients with COVID-19 develop a distinct subset of pancreatitis hallmarked by duodenal and periduodenal inflammation, according to a recent case series.
Although all five patients presented with multiple predictive markers of severe pancreatitis, the subsequent clinical pathway “was much more benign than anticipated,” reported lead author Peter Szatmary, MB, BChir, PhD, of the University of Liverpool (England) and colleagues. Still, they noted prolonged hospital stays because of persistent inflammation and poor diabetic control.
“As the global pandemic of SARS-CoV-2 continues, nuances of the disease it precipitates in humans continue to emerge,” the investigators wrote in Gastroenterology. “[A] group from Wuhan reported a series of 9 patients with purported pancreatic injury in the context of SARS-CoV-2 infection, but did not provide robust evidence for pancreatitis relying on mild hyperamylasemia alone.”
For the present series, Dr. Szatmary and colleagues restricted diagnosis of pancreatitis to international consensus guidelines, which require “abdominal pain consistent with pancreatitis, serum amylase/lipase greater than three times the upper limit of normal, and characteristic findings on cross-sectional imaging.”
From middle of March to late April, the investigators identified 35 patients with acute pancreatitis at Royal Liverpool (England) University Hospital, 25 of whom tested negative for SARS-CoV-2, which resulted in study exclusion. An additional five patients were excluded from the series as another etiology for pancreatitis was clearly present, such as gallstones.
“The remaining 5 patients, all with SARS-CoV-2, presented atypically yet homogenously with a distinct metabolic-pancreatitis phenotype,” the investigators wrote.
All five patients were obese or overweight young men with a median body mass index of 30 kg/m2 and age of 42 years. On presentation, all patients had elevated, but nondiagnostic, levels of amylase (median, 149 U/L). Contrast-enhanced abdominal CT revealed moderate to severe hepatic steatosis (less than 104 HU), which rapidly regressed within a week among patients who underwent repeat imaging.
“The pattern of pancreatic inflammation was similarly unusual in these patients,” the investigators wrote, going on to describe “mild pancreatic edema without significant pancreatic or peripancreatic necrosis, with distinct duodenal/periduodenal inflammation involving the second and third part of the duodenum.”
According to Dr. Szatmary and colleagues, these findings were “accompanied by a profound systemic inflammatory response,” including 1-2 criteria for systemic inflammatory response syndrome that increased to 2-4 criteria within 48 hours. During hospitalization, patients also exhibited a “dramatic elevation” of C-reactive protein, from a median of 31 mg/L upon admission to 485 mg/L within 48 hours.
Although these markers predicted severe disease, all cases followed a clinical course similar to “a typical attack of moderate pancreatitis,” the investigators wrote.
All patients were treated with IV fluids, four out of five received broad-spectrum IV antibiotics for pneumonitis, three out of five received fibrate and/or insulin therapy, and two out of five received pancreatic enzyme replacement therapy. No patients required corticosteroids, organ support, or respiratory support beyond low-flow oxygen. Median hospital stay was 14 days.
“We ... propose the combination of male sex, abdominal pain, metabolic stress, and CT-findings of predominantly pancreatico-duodenal inflammation with steatosis represent a distinct subset of pancreatitis in patients infected with SARS-CoV-2,” the investigators wrote.
They suggested that the endocrine pancreas may be “particularly vulnerable to this infection,” citing prolonged hospital stays because of poor diabetic control.
“[T]ransient dyslipidemias and impaired glucose tolerance may be common in SARS-CoV-2 patients and warrant further investigation,” they concluded.
Oscar J. Hines, MD, chief of the division of general surgery at UCLA Medical Center and leader in the field of pancreatitis management, said that the case series has a limited impact.
“The findings are unlikely to change practice and only call attention for physicians to the possibility of pancreatitis in COVID-positive patients,” Dr. Hines said.
The investigators reported grants from NIHR, Wellcome Trust, Mylan, and others.
SOURCE: Szatmary P et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.05.069.
Patients with COVID-19 develop a distinct subset of pancreatitis hallmarked by duodenal and periduodenal inflammation, according to a recent case series.
Although all five patients presented with multiple predictive markers of severe pancreatitis, the subsequent clinical pathway “was much more benign than anticipated,” reported lead author Peter Szatmary, MB, BChir, PhD, of the University of Liverpool (England) and colleagues. Still, they noted prolonged hospital stays because of persistent inflammation and poor diabetic control.
“As the global pandemic of SARS-CoV-2 continues, nuances of the disease it precipitates in humans continue to emerge,” the investigators wrote in Gastroenterology. “[A] group from Wuhan reported a series of 9 patients with purported pancreatic injury in the context of SARS-CoV-2 infection, but did not provide robust evidence for pancreatitis relying on mild hyperamylasemia alone.”
For the present series, Dr. Szatmary and colleagues restricted diagnosis of pancreatitis to international consensus guidelines, which require “abdominal pain consistent with pancreatitis, serum amylase/lipase greater than three times the upper limit of normal, and characteristic findings on cross-sectional imaging.”
From middle of March to late April, the investigators identified 35 patients with acute pancreatitis at Royal Liverpool (England) University Hospital, 25 of whom tested negative for SARS-CoV-2, which resulted in study exclusion. An additional five patients were excluded from the series as another etiology for pancreatitis was clearly present, such as gallstones.
“The remaining 5 patients, all with SARS-CoV-2, presented atypically yet homogenously with a distinct metabolic-pancreatitis phenotype,” the investigators wrote.
All five patients were obese or overweight young men with a median body mass index of 30 kg/m2 and age of 42 years. On presentation, all patients had elevated, but nondiagnostic, levels of amylase (median, 149 U/L). Contrast-enhanced abdominal CT revealed moderate to severe hepatic steatosis (less than 104 HU), which rapidly regressed within a week among patients who underwent repeat imaging.
“The pattern of pancreatic inflammation was similarly unusual in these patients,” the investigators wrote, going on to describe “mild pancreatic edema without significant pancreatic or peripancreatic necrosis, with distinct duodenal/periduodenal inflammation involving the second and third part of the duodenum.”
According to Dr. Szatmary and colleagues, these findings were “accompanied by a profound systemic inflammatory response,” including 1-2 criteria for systemic inflammatory response syndrome that increased to 2-4 criteria within 48 hours. During hospitalization, patients also exhibited a “dramatic elevation” of C-reactive protein, from a median of 31 mg/L upon admission to 485 mg/L within 48 hours.
Although these markers predicted severe disease, all cases followed a clinical course similar to “a typical attack of moderate pancreatitis,” the investigators wrote.
All patients were treated with IV fluids, four out of five received broad-spectrum IV antibiotics for pneumonitis, three out of five received fibrate and/or insulin therapy, and two out of five received pancreatic enzyme replacement therapy. No patients required corticosteroids, organ support, or respiratory support beyond low-flow oxygen. Median hospital stay was 14 days.
“We ... propose the combination of male sex, abdominal pain, metabolic stress, and CT-findings of predominantly pancreatico-duodenal inflammation with steatosis represent a distinct subset of pancreatitis in patients infected with SARS-CoV-2,” the investigators wrote.
They suggested that the endocrine pancreas may be “particularly vulnerable to this infection,” citing prolonged hospital stays because of poor diabetic control.
“[T]ransient dyslipidemias and impaired glucose tolerance may be common in SARS-CoV-2 patients and warrant further investigation,” they concluded.
Oscar J. Hines, MD, chief of the division of general surgery at UCLA Medical Center and leader in the field of pancreatitis management, said that the case series has a limited impact.
“The findings are unlikely to change practice and only call attention for physicians to the possibility of pancreatitis in COVID-positive patients,” Dr. Hines said.
The investigators reported grants from NIHR, Wellcome Trust, Mylan, and others.
SOURCE: Szatmary P et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.05.069.
Patients with COVID-19 develop a distinct subset of pancreatitis hallmarked by duodenal and periduodenal inflammation, according to a recent case series.
Although all five patients presented with multiple predictive markers of severe pancreatitis, the subsequent clinical pathway “was much more benign than anticipated,” reported lead author Peter Szatmary, MB, BChir, PhD, of the University of Liverpool (England) and colleagues. Still, they noted prolonged hospital stays because of persistent inflammation and poor diabetic control.
“As the global pandemic of SARS-CoV-2 continues, nuances of the disease it precipitates in humans continue to emerge,” the investigators wrote in Gastroenterology. “[A] group from Wuhan reported a series of 9 patients with purported pancreatic injury in the context of SARS-CoV-2 infection, but did not provide robust evidence for pancreatitis relying on mild hyperamylasemia alone.”
For the present series, Dr. Szatmary and colleagues restricted diagnosis of pancreatitis to international consensus guidelines, which require “abdominal pain consistent with pancreatitis, serum amylase/lipase greater than three times the upper limit of normal, and characteristic findings on cross-sectional imaging.”
From middle of March to late April, the investigators identified 35 patients with acute pancreatitis at Royal Liverpool (England) University Hospital, 25 of whom tested negative for SARS-CoV-2, which resulted in study exclusion. An additional five patients were excluded from the series as another etiology for pancreatitis was clearly present, such as gallstones.
“The remaining 5 patients, all with SARS-CoV-2, presented atypically yet homogenously with a distinct metabolic-pancreatitis phenotype,” the investigators wrote.
All five patients were obese or overweight young men with a median body mass index of 30 kg/m2 and age of 42 years. On presentation, all patients had elevated, but nondiagnostic, levels of amylase (median, 149 U/L). Contrast-enhanced abdominal CT revealed moderate to severe hepatic steatosis (less than 104 HU), which rapidly regressed within a week among patients who underwent repeat imaging.
“The pattern of pancreatic inflammation was similarly unusual in these patients,” the investigators wrote, going on to describe “mild pancreatic edema without significant pancreatic or peripancreatic necrosis, with distinct duodenal/periduodenal inflammation involving the second and third part of the duodenum.”
According to Dr. Szatmary and colleagues, these findings were “accompanied by a profound systemic inflammatory response,” including 1-2 criteria for systemic inflammatory response syndrome that increased to 2-4 criteria within 48 hours. During hospitalization, patients also exhibited a “dramatic elevation” of C-reactive protein, from a median of 31 mg/L upon admission to 485 mg/L within 48 hours.
Although these markers predicted severe disease, all cases followed a clinical course similar to “a typical attack of moderate pancreatitis,” the investigators wrote.
All patients were treated with IV fluids, four out of five received broad-spectrum IV antibiotics for pneumonitis, three out of five received fibrate and/or insulin therapy, and two out of five received pancreatic enzyme replacement therapy. No patients required corticosteroids, organ support, or respiratory support beyond low-flow oxygen. Median hospital stay was 14 days.
“We ... propose the combination of male sex, abdominal pain, metabolic stress, and CT-findings of predominantly pancreatico-duodenal inflammation with steatosis represent a distinct subset of pancreatitis in patients infected with SARS-CoV-2,” the investigators wrote.
They suggested that the endocrine pancreas may be “particularly vulnerable to this infection,” citing prolonged hospital stays because of poor diabetic control.
“[T]ransient dyslipidemias and impaired glucose tolerance may be common in SARS-CoV-2 patients and warrant further investigation,” they concluded.
Oscar J. Hines, MD, chief of the division of general surgery at UCLA Medical Center and leader in the field of pancreatitis management, said that the case series has a limited impact.
“The findings are unlikely to change practice and only call attention for physicians to the possibility of pancreatitis in COVID-positive patients,” Dr. Hines said.
The investigators reported grants from NIHR, Wellcome Trust, Mylan, and others.
SOURCE: Szatmary P et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.05.069.
FROM GASTROENTEROLOGY
Organoid model unveils response to Shiga toxin
The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.
Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
But little is known about the underlying biological processes driving Shiga-induced disease.
“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”
To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.
For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.
First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”
Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.
In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.
In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.
With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.
“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.
Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.
Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.
Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.
“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.
More generally, the study supports the use of HIOs as a disease model for future investigations.
“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.
The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.
SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.
Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.
Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.
Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.
Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.
Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.
Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.
The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.
Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
But little is known about the underlying biological processes driving Shiga-induced disease.
“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”
To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.
For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.
First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”
Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.
In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.
In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.
With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.
“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.
Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.
Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.
Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.
“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.
More generally, the study supports the use of HIOs as a disease model for future investigations.
“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.
The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.
SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.
The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.
Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
But little is known about the underlying biological processes driving Shiga-induced disease.
“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”
To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.
For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.
First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”
Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.
In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.
In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.
With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.
“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.
Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.
Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.
Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.
“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.
More generally, the study supports the use of HIOs as a disease model for future investigations.
“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.
The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.
SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Many COVID patients shed virus in feces, even without GI symptoms
Even without GI symptoms, many patients with COVID-19 shed viral RNA in feces, suggesting that stool testing and prevention of fecal-oral transmission may be needed to combat the ongoing pandemic, according to investigators.
A meta-analysis of 29 studies showed that 12% of patients with COVID-19 developed nausea, diarrhea, or vomiting, while 41% shed viral RNA in feces, reported lead author Sravanthi Parasa, MD, of Swedish Medical Center, Seattle.Writing in JAMA Network Open, Dr. Parasa and colleagues emphasized that respiratory symptoms remain the predominant form of disease; however, GI symptoms can occur.
“In fact, the first reported patient with COVID-19 in the U.S. reported GI symptoms of loose bowel movements and abdominal discomfort,” the investigators wrote, noting that the patient went on to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both respiratory and stool specimens.
“This raises the question of inadvertent human-to-human transmission via the fecal route despite public health emphasis on droplet transmission and precautions for contact with respiratory secretions,” the investigators wrote.
To address this question, the investigators conducted a systematic review and meta-analysis involving 23 published and 6 preprint studies involving a total of 4,805 patients, all of whom tested positive for SARS-CoV-2 based on PCR results from nasopharyngeal swabs. Dr. Parasa and colleagues noted that most of the studies “scored between 8 and 10 on the MINORS quality assessment,” suggesting moderate quality.
Pooled data from these studies showed that 4.6% of patients reported nausea or vomiting, while 7.4% reported diarrhea. Such symptoms may serve as an early warning flag for clinicians, the investigators noted.
“[T]he presence of GI symptoms may portend a worse outcome for patients infected with SARS-CoV-2,” they wrote, citing a study by Pan and colleagues, which found that GI symptoms were associated with lower rates of recovery and hospital discharge.
Regardless of GI symptoms, 40.5% of patients in the meta-analysis tested positive for viral RNA in feces (95% confidence interval, 27.4%-55.1%). Duration of viral shedding in feces lasted up to 11 days after symptom onset, or in a single-patient case study, 18 days after hospitalization.
The investigators called these duration figures “particularly concerning,” especially in light of a study published by Xiao and colleagues, which showed that 23.3% of patients with negative respiratory tests were still shedding live virus in feces.
“[T]he fecal-oral route of transmission could be an additional potential source of infection spread,” wrote Dr. Parasa and colleagues. “Our results also suggest that testing of the virus in feces ... could be helpful in disease monitoring and surveillance.”
David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said that the findings confirm what has been suspected for some time: GI disease is relatively common with COVID-19.
“The evidence is clear now that a sizable percentage of patients have GI symptoms,” Dr. Johnson said in an interview.
GI issues may precede respiratory signs, he added, so clinicians should be aware that nausea, vomiting, or diarrhea could be early indicators of COVID-19, and possibly, a worse outcome.
“The other highlight of this study is that stool shedding may be extended beyond respiratory shedding,” Dr. Johnson said.
He suggested that this finding could influence current CDC criteria, which define absence of infectious risk by two consecutive, negative nasopharyngeal swabs. Instead, fecal testing may be needed, he said, along with measures to prevent fecal-oral transmission.
Dr. Johnson expressed particular concern for risk of infection via toilet plume, in which toilet flushing aerosolizes viral particles.
“As much as people try to social distance by 6 feet – you can do that when you walk into a store, or a building, but you can’t necessarily do that when you walk into a public toilet, where the plume may have been expansive for a period of time,” he said. “That toilet may never really get cleaned to a high level of disinfection, and those droplets set up potential for fecal-oral spread.”
Dr. Sharma disclosed relationships with Medtronic, Fujifilm, Boston Scientific, and others. Dr. Johnson disclosed no relevant conflicts of interest.
SOURCE: Parasa S et al. JAMA Network Open. 2020 Jun 11. doi: 10.1001/jamanetworkopen.2020.11335.
Even without GI symptoms, many patients with COVID-19 shed viral RNA in feces, suggesting that stool testing and prevention of fecal-oral transmission may be needed to combat the ongoing pandemic, according to investigators.
A meta-analysis of 29 studies showed that 12% of patients with COVID-19 developed nausea, diarrhea, or vomiting, while 41% shed viral RNA in feces, reported lead author Sravanthi Parasa, MD, of Swedish Medical Center, Seattle.Writing in JAMA Network Open, Dr. Parasa and colleagues emphasized that respiratory symptoms remain the predominant form of disease; however, GI symptoms can occur.
“In fact, the first reported patient with COVID-19 in the U.S. reported GI symptoms of loose bowel movements and abdominal discomfort,” the investigators wrote, noting that the patient went on to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both respiratory and stool specimens.
“This raises the question of inadvertent human-to-human transmission via the fecal route despite public health emphasis on droplet transmission and precautions for contact with respiratory secretions,” the investigators wrote.
To address this question, the investigators conducted a systematic review and meta-analysis involving 23 published and 6 preprint studies involving a total of 4,805 patients, all of whom tested positive for SARS-CoV-2 based on PCR results from nasopharyngeal swabs. Dr. Parasa and colleagues noted that most of the studies “scored between 8 and 10 on the MINORS quality assessment,” suggesting moderate quality.
Pooled data from these studies showed that 4.6% of patients reported nausea or vomiting, while 7.4% reported diarrhea. Such symptoms may serve as an early warning flag for clinicians, the investigators noted.
“[T]he presence of GI symptoms may portend a worse outcome for patients infected with SARS-CoV-2,” they wrote, citing a study by Pan and colleagues, which found that GI symptoms were associated with lower rates of recovery and hospital discharge.
Regardless of GI symptoms, 40.5% of patients in the meta-analysis tested positive for viral RNA in feces (95% confidence interval, 27.4%-55.1%). Duration of viral shedding in feces lasted up to 11 days after symptom onset, or in a single-patient case study, 18 days after hospitalization.
The investigators called these duration figures “particularly concerning,” especially in light of a study published by Xiao and colleagues, which showed that 23.3% of patients with negative respiratory tests were still shedding live virus in feces.
“[T]he fecal-oral route of transmission could be an additional potential source of infection spread,” wrote Dr. Parasa and colleagues. “Our results also suggest that testing of the virus in feces ... could be helpful in disease monitoring and surveillance.”
David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said that the findings confirm what has been suspected for some time: GI disease is relatively common with COVID-19.
“The evidence is clear now that a sizable percentage of patients have GI symptoms,” Dr. Johnson said in an interview.
GI issues may precede respiratory signs, he added, so clinicians should be aware that nausea, vomiting, or diarrhea could be early indicators of COVID-19, and possibly, a worse outcome.
“The other highlight of this study is that stool shedding may be extended beyond respiratory shedding,” Dr. Johnson said.
He suggested that this finding could influence current CDC criteria, which define absence of infectious risk by two consecutive, negative nasopharyngeal swabs. Instead, fecal testing may be needed, he said, along with measures to prevent fecal-oral transmission.
Dr. Johnson expressed particular concern for risk of infection via toilet plume, in which toilet flushing aerosolizes viral particles.
“As much as people try to social distance by 6 feet – you can do that when you walk into a store, or a building, but you can’t necessarily do that when you walk into a public toilet, where the plume may have been expansive for a period of time,” he said. “That toilet may never really get cleaned to a high level of disinfection, and those droplets set up potential for fecal-oral spread.”
Dr. Sharma disclosed relationships with Medtronic, Fujifilm, Boston Scientific, and others. Dr. Johnson disclosed no relevant conflicts of interest.
SOURCE: Parasa S et al. JAMA Network Open. 2020 Jun 11. doi: 10.1001/jamanetworkopen.2020.11335.
Even without GI symptoms, many patients with COVID-19 shed viral RNA in feces, suggesting that stool testing and prevention of fecal-oral transmission may be needed to combat the ongoing pandemic, according to investigators.
A meta-analysis of 29 studies showed that 12% of patients with COVID-19 developed nausea, diarrhea, or vomiting, while 41% shed viral RNA in feces, reported lead author Sravanthi Parasa, MD, of Swedish Medical Center, Seattle.Writing in JAMA Network Open, Dr. Parasa and colleagues emphasized that respiratory symptoms remain the predominant form of disease; however, GI symptoms can occur.
“In fact, the first reported patient with COVID-19 in the U.S. reported GI symptoms of loose bowel movements and abdominal discomfort,” the investigators wrote, noting that the patient went on to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both respiratory and stool specimens.
“This raises the question of inadvertent human-to-human transmission via the fecal route despite public health emphasis on droplet transmission and precautions for contact with respiratory secretions,” the investigators wrote.
To address this question, the investigators conducted a systematic review and meta-analysis involving 23 published and 6 preprint studies involving a total of 4,805 patients, all of whom tested positive for SARS-CoV-2 based on PCR results from nasopharyngeal swabs. Dr. Parasa and colleagues noted that most of the studies “scored between 8 and 10 on the MINORS quality assessment,” suggesting moderate quality.
Pooled data from these studies showed that 4.6% of patients reported nausea or vomiting, while 7.4% reported diarrhea. Such symptoms may serve as an early warning flag for clinicians, the investigators noted.
“[T]he presence of GI symptoms may portend a worse outcome for patients infected with SARS-CoV-2,” they wrote, citing a study by Pan and colleagues, which found that GI symptoms were associated with lower rates of recovery and hospital discharge.
Regardless of GI symptoms, 40.5% of patients in the meta-analysis tested positive for viral RNA in feces (95% confidence interval, 27.4%-55.1%). Duration of viral shedding in feces lasted up to 11 days after symptom onset, or in a single-patient case study, 18 days after hospitalization.
The investigators called these duration figures “particularly concerning,” especially in light of a study published by Xiao and colleagues, which showed that 23.3% of patients with negative respiratory tests were still shedding live virus in feces.
“[T]he fecal-oral route of transmission could be an additional potential source of infection spread,” wrote Dr. Parasa and colleagues. “Our results also suggest that testing of the virus in feces ... could be helpful in disease monitoring and surveillance.”
David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said that the findings confirm what has been suspected for some time: GI disease is relatively common with COVID-19.
“The evidence is clear now that a sizable percentage of patients have GI symptoms,” Dr. Johnson said in an interview.
GI issues may precede respiratory signs, he added, so clinicians should be aware that nausea, vomiting, or diarrhea could be early indicators of COVID-19, and possibly, a worse outcome.
“The other highlight of this study is that stool shedding may be extended beyond respiratory shedding,” Dr. Johnson said.
He suggested that this finding could influence current CDC criteria, which define absence of infectious risk by two consecutive, negative nasopharyngeal swabs. Instead, fecal testing may be needed, he said, along with measures to prevent fecal-oral transmission.
Dr. Johnson expressed particular concern for risk of infection via toilet plume, in which toilet flushing aerosolizes viral particles.
“As much as people try to social distance by 6 feet – you can do that when you walk into a store, or a building, but you can’t necessarily do that when you walk into a public toilet, where the plume may have been expansive for a period of time,” he said. “That toilet may never really get cleaned to a high level of disinfection, and those droplets set up potential for fecal-oral spread.”
Dr. Sharma disclosed relationships with Medtronic, Fujifilm, Boston Scientific, and others. Dr. Johnson disclosed no relevant conflicts of interest.
SOURCE: Parasa S et al. JAMA Network Open. 2020 Jun 11. doi: 10.1001/jamanetworkopen.2020.11335.
FROM JAMA NETWORK OPEN
Electrosurgical choices lead to similar results
For endoscopists performing electrosurgical snare resection of large colorectal polyps, choosing between the blue foot pedal and the yellow foot pedal may be the least important step of the day, according to data from almost 1,000 patients.
Risks of severe adverse events and polyp recurrence were similar between cases in which blended current (yellow pedal) was used and those in which coagulation current (blue pedal) was used, reported lead author Heiko Pohl, MD, of Geisel School of Medicine at Dartmouth, Hanover, N.H., and colleagues.
“Although electrosurgical application is a fundamental aspect of polypectomy, various currents and settings are clinically used, and there are no accepted standards of practice,” the investigators wrote in Gastroenterology.
According to Dr. Pohl and colleagues, a 2004 study showed that the split between endoscopists using coagulation current and those using blended current was about 50-50 (46% vs. 46%), but no studies to date have tested the relative safety or efficacy of these approaches.
The investigators aimed to address this knowledge gap with a single-blinded study involving 928 patients who underwent endoscopic mucosal resection of nonpedunculated, large (20 mm or larger) colorectal polyps with an Erbe Vio® 300D electrosurgical unit (Erbe USA Inc., Marietta, Ga.) at 18 medical centers.
Patients were randomized in 2x2 factorial design involving clip closure versus no clip closure, and blended current (Endocut Q) versus pure coagulation current (Forced Coagulation). Although electrosurgical setting was initially a secondary intervention in the trial, post hoc analysis showed that interaction between the interventions was not significant (P = .957), allowing for the present, independent analysis of current type.
For this analysis, the primary outcome was severe adverse event rate, both during the procedure, and after the procedure for up to 30 days. Secondary outcomes included proportion of polyps completely excised and recurrence rate at time of first surveillance endoscopy.
Out of 928 patients randomized, 919 completed 30-day follow-up, and 675 underwent first surveillance colonoscopy. Baseline characteristics were similar between groups, apart from the proportion of individuals with more than one large polyp, which was significantly greater in the Endocut Q group (8.6% vs. 4.5%; P = .012), although the investigators noted that this imbalance did not affect main outcomes.
Rates of severe adverse events were similar between groups: 7.2% for the Endocut Q group and 7.9% for the Forced Coagulation group (P = .762). Groups also had similar rates of intra- and postprocedure adverse events, and types of adverse events.
Efficacy measures also revealed high similarity between cutting techniques. Endoscopists using Endocut achieved complete polyp removal 96% of the time, compared with 95% of the time when using Forced Coagulation (P = .267). Piecemeal resection rates were similar, at 90% and 87% for Endocut Q and Forced Coagulation, respectively (P = .270).
Although Endocut Q less frequently resulted in small residual tissue islands after initial snare resection (35% vs. 41%; P = .041), it more often caused intraprocedural bleeding that required treatment (17% vs. 11%; P = .006).
According to Dr. Pohl and colleagues, previous discussions have included concerns that such bleeding may impair visualization and therefore lead to higher rates of polyp recurrence; but surveillance colonoscopy, which was performed in 79% of patients, revealed a polyp recurrence rate of 17% for each group.
“Although we did not find a difference in recurrence between the two groups, our study cannot completely exclude this possibility,” the investigators added.
They also noted that six perforations occurred in the Endocut Q group, compared with three in the Forced Coagulation group, and suggested that this risk may be real, yet statistically unsupported by the present analysis because of sample size.
“Endoscopists using Endocut should therefore be aware of this potential risk and [ensure] that no muscularis propria is entrapped in the snare before electrosurgery is applied,” the investigators wrote.
Still, the investigators’ final conclusion supported the existing method of decision-making: personal choice.
“Overall, polyp resection with Endocut or Forced Coagulation did not differ with respect to severe adverse events, complete resection rate, or polyp recurrence,” they wrote. “This study therefore supports an individual approach based on endoscopist preference.”
The study was funded by Boston Scientific and the American College of Gastroenterology. The investigators disclosed additional relationships with Medtronic, Olympus, Cook Endoscopy, and others.
SOURCE: Pohl H et al. Gastroenterology. 2020 Mar 12. doi: 10.1053/j.gastro.2020.03.014.
There has long been a debate over which type of electrosurgical setting is best for colon polyp resection. Endoscopists can use either a blended current (yellow pedal) or a coagulation current (blue pedal). The choice is based on the endoscopists’ preference. However, few data have been available to support one setting versus the other. This study by Pohl et al. pursued the burning question of yellow or blue pedal? This single-blind randomized multicenter trial compared the two commonly used electrosurgical settings (Blended Current/Endocut Q vs. Forced Coagulation) for the resection of large colorectal polyps and found no difference in the risk of serious adverse events, complete resection rate, or polyp recurrence, thus supporting the current practice that electrosurgical settings can be selected based on endoscopist expertise and preference.
A few important highlights from this well designed study are worth mentioning. Although there was no significant difference in perforation, it should be noted that fewer patients had a perforation event in the Forced Coagulation group than in the Endocut Q group (3 vs. 6 patients; P = .320). In addition, the study demonstrated that the rate of polyp recurrence did not differ significantly between the two groups (17.4% vs. 16.5%; P = .762). while the rate of macroscopically visible recurrence was not statistically different, a histologic recurrence without visible polyp tissue was found slightly less frequent in the Forced Coagulation group than in the Endocut Q group (3.1% vs. 6.0%; P = .07). Finally, another important observation, intraprocedural bleeding requiring treatment, occurred less frequently during resection with Forced Coagulation than with Endocut Q (11% vs. 17%, P = .006); however, this difference did not affect overall safety and efficacy. This is an important finding since bleeding can affect the field of view during polypectomy, which that can potentially increase the risk of other serious adverse events such as perforation or increase the risk of recurrence because the endoscopist may not completely resect the polyp.
This study provides important insights into the potential risks associated with blended vs. coagulation currents. It further shows there is no difference in safety and efficacy of polypectomy using either a blended current or coagulation current, thus supporting current practice. However, the authors make it clear that a larger study will be needed to better answer such questions as polyp recurrence and perforation more definitively.
Frank G. Gress, MD, MBA, is senior faculty at the Icahn School of Medicine at Mount Sinai, New York; chief, division of gastroenterology and hepatology, and director of the Center for Interventional Endoscopy at Mount Sinai Hospital South Nassau. He has no conflicts.
There has long been a debate over which type of electrosurgical setting is best for colon polyp resection. Endoscopists can use either a blended current (yellow pedal) or a coagulation current (blue pedal). The choice is based on the endoscopists’ preference. However, few data have been available to support one setting versus the other. This study by Pohl et al. pursued the burning question of yellow or blue pedal? This single-blind randomized multicenter trial compared the two commonly used electrosurgical settings (Blended Current/Endocut Q vs. Forced Coagulation) for the resection of large colorectal polyps and found no difference in the risk of serious adverse events, complete resection rate, or polyp recurrence, thus supporting the current practice that electrosurgical settings can be selected based on endoscopist expertise and preference.
A few important highlights from this well designed study are worth mentioning. Although there was no significant difference in perforation, it should be noted that fewer patients had a perforation event in the Forced Coagulation group than in the Endocut Q group (3 vs. 6 patients; P = .320). In addition, the study demonstrated that the rate of polyp recurrence did not differ significantly between the two groups (17.4% vs. 16.5%; P = .762). while the rate of macroscopically visible recurrence was not statistically different, a histologic recurrence without visible polyp tissue was found slightly less frequent in the Forced Coagulation group than in the Endocut Q group (3.1% vs. 6.0%; P = .07). Finally, another important observation, intraprocedural bleeding requiring treatment, occurred less frequently during resection with Forced Coagulation than with Endocut Q (11% vs. 17%, P = .006); however, this difference did not affect overall safety and efficacy. This is an important finding since bleeding can affect the field of view during polypectomy, which that can potentially increase the risk of other serious adverse events such as perforation or increase the risk of recurrence because the endoscopist may not completely resect the polyp.
This study provides important insights into the potential risks associated with blended vs. coagulation currents. It further shows there is no difference in safety and efficacy of polypectomy using either a blended current or coagulation current, thus supporting current practice. However, the authors make it clear that a larger study will be needed to better answer such questions as polyp recurrence and perforation more definitively.
Frank G. Gress, MD, MBA, is senior faculty at the Icahn School of Medicine at Mount Sinai, New York; chief, division of gastroenterology and hepatology, and director of the Center for Interventional Endoscopy at Mount Sinai Hospital South Nassau. He has no conflicts.
There has long been a debate over which type of electrosurgical setting is best for colon polyp resection. Endoscopists can use either a blended current (yellow pedal) or a coagulation current (blue pedal). The choice is based on the endoscopists’ preference. However, few data have been available to support one setting versus the other. This study by Pohl et al. pursued the burning question of yellow or blue pedal? This single-blind randomized multicenter trial compared the two commonly used electrosurgical settings (Blended Current/Endocut Q vs. Forced Coagulation) for the resection of large colorectal polyps and found no difference in the risk of serious adverse events, complete resection rate, or polyp recurrence, thus supporting the current practice that electrosurgical settings can be selected based on endoscopist expertise and preference.
A few important highlights from this well designed study are worth mentioning. Although there was no significant difference in perforation, it should be noted that fewer patients had a perforation event in the Forced Coagulation group than in the Endocut Q group (3 vs. 6 patients; P = .320). In addition, the study demonstrated that the rate of polyp recurrence did not differ significantly between the two groups (17.4% vs. 16.5%; P = .762). while the rate of macroscopically visible recurrence was not statistically different, a histologic recurrence without visible polyp tissue was found slightly less frequent in the Forced Coagulation group than in the Endocut Q group (3.1% vs. 6.0%; P = .07). Finally, another important observation, intraprocedural bleeding requiring treatment, occurred less frequently during resection with Forced Coagulation than with Endocut Q (11% vs. 17%, P = .006); however, this difference did not affect overall safety and efficacy. This is an important finding since bleeding can affect the field of view during polypectomy, which that can potentially increase the risk of other serious adverse events such as perforation or increase the risk of recurrence because the endoscopist may not completely resect the polyp.
This study provides important insights into the potential risks associated with blended vs. coagulation currents. It further shows there is no difference in safety and efficacy of polypectomy using either a blended current or coagulation current, thus supporting current practice. However, the authors make it clear that a larger study will be needed to better answer such questions as polyp recurrence and perforation more definitively.
Frank G. Gress, MD, MBA, is senior faculty at the Icahn School of Medicine at Mount Sinai, New York; chief, division of gastroenterology and hepatology, and director of the Center for Interventional Endoscopy at Mount Sinai Hospital South Nassau. He has no conflicts.
For endoscopists performing electrosurgical snare resection of large colorectal polyps, choosing between the blue foot pedal and the yellow foot pedal may be the least important step of the day, according to data from almost 1,000 patients.
Risks of severe adverse events and polyp recurrence were similar between cases in which blended current (yellow pedal) was used and those in which coagulation current (blue pedal) was used, reported lead author Heiko Pohl, MD, of Geisel School of Medicine at Dartmouth, Hanover, N.H., and colleagues.
“Although electrosurgical application is a fundamental aspect of polypectomy, various currents and settings are clinically used, and there are no accepted standards of practice,” the investigators wrote in Gastroenterology.
According to Dr. Pohl and colleagues, a 2004 study showed that the split between endoscopists using coagulation current and those using blended current was about 50-50 (46% vs. 46%), but no studies to date have tested the relative safety or efficacy of these approaches.
The investigators aimed to address this knowledge gap with a single-blinded study involving 928 patients who underwent endoscopic mucosal resection of nonpedunculated, large (20 mm or larger) colorectal polyps with an Erbe Vio® 300D electrosurgical unit (Erbe USA Inc., Marietta, Ga.) at 18 medical centers.
Patients were randomized in 2x2 factorial design involving clip closure versus no clip closure, and blended current (Endocut Q) versus pure coagulation current (Forced Coagulation). Although electrosurgical setting was initially a secondary intervention in the trial, post hoc analysis showed that interaction between the interventions was not significant (P = .957), allowing for the present, independent analysis of current type.
For this analysis, the primary outcome was severe adverse event rate, both during the procedure, and after the procedure for up to 30 days. Secondary outcomes included proportion of polyps completely excised and recurrence rate at time of first surveillance endoscopy.
Out of 928 patients randomized, 919 completed 30-day follow-up, and 675 underwent first surveillance colonoscopy. Baseline characteristics were similar between groups, apart from the proportion of individuals with more than one large polyp, which was significantly greater in the Endocut Q group (8.6% vs. 4.5%; P = .012), although the investigators noted that this imbalance did not affect main outcomes.
Rates of severe adverse events were similar between groups: 7.2% for the Endocut Q group and 7.9% for the Forced Coagulation group (P = .762). Groups also had similar rates of intra- and postprocedure adverse events, and types of adverse events.
Efficacy measures also revealed high similarity between cutting techniques. Endoscopists using Endocut achieved complete polyp removal 96% of the time, compared with 95% of the time when using Forced Coagulation (P = .267). Piecemeal resection rates were similar, at 90% and 87% for Endocut Q and Forced Coagulation, respectively (P = .270).
Although Endocut Q less frequently resulted in small residual tissue islands after initial snare resection (35% vs. 41%; P = .041), it more often caused intraprocedural bleeding that required treatment (17% vs. 11%; P = .006).
According to Dr. Pohl and colleagues, previous discussions have included concerns that such bleeding may impair visualization and therefore lead to higher rates of polyp recurrence; but surveillance colonoscopy, which was performed in 79% of patients, revealed a polyp recurrence rate of 17% for each group.
“Although we did not find a difference in recurrence between the two groups, our study cannot completely exclude this possibility,” the investigators added.
They also noted that six perforations occurred in the Endocut Q group, compared with three in the Forced Coagulation group, and suggested that this risk may be real, yet statistically unsupported by the present analysis because of sample size.
“Endoscopists using Endocut should therefore be aware of this potential risk and [ensure] that no muscularis propria is entrapped in the snare before electrosurgery is applied,” the investigators wrote.
Still, the investigators’ final conclusion supported the existing method of decision-making: personal choice.
“Overall, polyp resection with Endocut or Forced Coagulation did not differ with respect to severe adverse events, complete resection rate, or polyp recurrence,” they wrote. “This study therefore supports an individual approach based on endoscopist preference.”
The study was funded by Boston Scientific and the American College of Gastroenterology. The investigators disclosed additional relationships with Medtronic, Olympus, Cook Endoscopy, and others.
SOURCE: Pohl H et al. Gastroenterology. 2020 Mar 12. doi: 10.1053/j.gastro.2020.03.014.
For endoscopists performing electrosurgical snare resection of large colorectal polyps, choosing between the blue foot pedal and the yellow foot pedal may be the least important step of the day, according to data from almost 1,000 patients.
Risks of severe adverse events and polyp recurrence were similar between cases in which blended current (yellow pedal) was used and those in which coagulation current (blue pedal) was used, reported lead author Heiko Pohl, MD, of Geisel School of Medicine at Dartmouth, Hanover, N.H., and colleagues.
“Although electrosurgical application is a fundamental aspect of polypectomy, various currents and settings are clinically used, and there are no accepted standards of practice,” the investigators wrote in Gastroenterology.
According to Dr. Pohl and colleagues, a 2004 study showed that the split between endoscopists using coagulation current and those using blended current was about 50-50 (46% vs. 46%), but no studies to date have tested the relative safety or efficacy of these approaches.
The investigators aimed to address this knowledge gap with a single-blinded study involving 928 patients who underwent endoscopic mucosal resection of nonpedunculated, large (20 mm or larger) colorectal polyps with an Erbe Vio® 300D electrosurgical unit (Erbe USA Inc., Marietta, Ga.) at 18 medical centers.
Patients were randomized in 2x2 factorial design involving clip closure versus no clip closure, and blended current (Endocut Q) versus pure coagulation current (Forced Coagulation). Although electrosurgical setting was initially a secondary intervention in the trial, post hoc analysis showed that interaction between the interventions was not significant (P = .957), allowing for the present, independent analysis of current type.
For this analysis, the primary outcome was severe adverse event rate, both during the procedure, and after the procedure for up to 30 days. Secondary outcomes included proportion of polyps completely excised and recurrence rate at time of first surveillance endoscopy.
Out of 928 patients randomized, 919 completed 30-day follow-up, and 675 underwent first surveillance colonoscopy. Baseline characteristics were similar between groups, apart from the proportion of individuals with more than one large polyp, which was significantly greater in the Endocut Q group (8.6% vs. 4.5%; P = .012), although the investigators noted that this imbalance did not affect main outcomes.
Rates of severe adverse events were similar between groups: 7.2% for the Endocut Q group and 7.9% for the Forced Coagulation group (P = .762). Groups also had similar rates of intra- and postprocedure adverse events, and types of adverse events.
Efficacy measures also revealed high similarity between cutting techniques. Endoscopists using Endocut achieved complete polyp removal 96% of the time, compared with 95% of the time when using Forced Coagulation (P = .267). Piecemeal resection rates were similar, at 90% and 87% for Endocut Q and Forced Coagulation, respectively (P = .270).
Although Endocut Q less frequently resulted in small residual tissue islands after initial snare resection (35% vs. 41%; P = .041), it more often caused intraprocedural bleeding that required treatment (17% vs. 11%; P = .006).
According to Dr. Pohl and colleagues, previous discussions have included concerns that such bleeding may impair visualization and therefore lead to higher rates of polyp recurrence; but surveillance colonoscopy, which was performed in 79% of patients, revealed a polyp recurrence rate of 17% for each group.
“Although we did not find a difference in recurrence between the two groups, our study cannot completely exclude this possibility,” the investigators added.
They also noted that six perforations occurred in the Endocut Q group, compared with three in the Forced Coagulation group, and suggested that this risk may be real, yet statistically unsupported by the present analysis because of sample size.
“Endoscopists using Endocut should therefore be aware of this potential risk and [ensure] that no muscularis propria is entrapped in the snare before electrosurgery is applied,” the investigators wrote.
Still, the investigators’ final conclusion supported the existing method of decision-making: personal choice.
“Overall, polyp resection with Endocut or Forced Coagulation did not differ with respect to severe adverse events, complete resection rate, or polyp recurrence,” they wrote. “This study therefore supports an individual approach based on endoscopist preference.”
The study was funded by Boston Scientific and the American College of Gastroenterology. The investigators disclosed additional relationships with Medtronic, Olympus, Cook Endoscopy, and others.
SOURCE: Pohl H et al. Gastroenterology. 2020 Mar 12. doi: 10.1053/j.gastro.2020.03.014.
FROM GASTROENTEROLOGY
FibroScan: M probe underestimates hepatic fat content
When performing transient elastography (FibroScan) to evaluate patients for hepatic steatosis, using an M probe instead of an XL probe may significantly underestimate hepatic fat content, according to investigators.
The findings, which were independent of body weight, suggest that probe-specific controlled attenuation parameter (CAP) thresholds are needed to accurately interpret FibroScan results, reported lead author Cyrielle Caussy, MD, PhD, of the University of California, San Diego, and colleagues.
“We have previously determined the optimal threshold of CAP using either [an] M or XL probe for the detection of ... nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, head-to-head comparison of consecutive measurements of CAP with both the M and XL probes versus MRI-PDFF [proton density fat fraction] ... has not been reported yet.”
Dr. Caussy and colleagues set out to do just that. They enrolled 105 individuals with and without NAFLD who had a mean body mass index (BMI) of 30.6 kg/m2, as this represented a typical population screened for NAFLD. After evaluation for other causes of hepatic steatosis and liver disease, participants underwent MRI-PDFF, which served as a gold standard, followed by FibroScan using both M and XL probes on the same day.
The primary outcome was hepatic steatosis (MRI-PDFF of at least 5%), while the secondary outcome was MRI-PDFF–detected hepatic fat content of at least 10%, the latter of which has been “used in several therapeutic trials as inclusion criteria,” the investigators noted.
A total of 100 participants were included in the final analysis, of whom two-thirds (66%) underwent MRI and FibroScan on the same day, with a mean interval between test types of 11 days. Most participants (68%) had an MRI-PDFF of at least 5%, while almost half (48%) exceeded an MRI-PDFF of 10%.
The mean CAP measurement with the M probe was 310 dB/m, which was significantly lower than the mean value detected by the XL probe, which was 317 dB/m (P = .007). In participants with hepatic steatosis, when the M probe was used for those with a BMI of less than 30, and the XL probe was used for those with a BMI of 30 or more, the M probe still provided a significantly lower measure of hepatic fat content (312 vs. 345 dB/m; P = .0035).
“[T]hese results have direct application in routine clinical practice,” the investigators wrote, “as [they] will help clinicians interpreting CAP measurements depending on the type of probe used.”
Dr. Caussy and colleagues went on to offer a diagnostic algorithm involving optimal probe-specific thresholds for CAP based on hepatic fat content. Individuals screened with an M probe who have a CAP of 294 dB/m or more should be considered positive for NAFLD, while patients screened with an XL probe need to have a CAP of at least 307 dB/m to be NAFLD positive.
For the XL probe, but not the M probe, diagnostic accuracy depended upon an interquartile range of less than 30 dB/m. The investigators noted that this finding should alter the interpretation of a 2019 study by Eddowes and colleagues, which concluded that interquartile range was unrelated to diagnostic accuracy.
“As Eddowes et al. did not perform head-to-head comparison of CAP measurement with both the M and XL probes, this important difference could not have been observed,” the investigators wrote, noting that “an interquartile range of CAP below 30 dB/m should be considered as a quality indicator that significantly improves the diagnostic performance of CAP using the XL probe for the detection of hepatic steatosis in NAFLD.”
The investigators concluded by suggesting that their findings will drive research forward.
“The use of these new thresholds will help to further assess the clinical utility of CAP for the detection of hepatic steatosis and its cost-effectiveness, compared with other modalities, to develop optimal strategies for the screening of NAFLD,” they wrote.
The study was funded by Atlantic Philanthropies, the John A. Hartford Foundation, the American Gastroenterological Association, and others. The investigators disclosed no conflicts of interest.
SOURCE: Caussy C et al. Clin Gastro Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.060.
When performing transient elastography (FibroScan) to evaluate patients for hepatic steatosis, using an M probe instead of an XL probe may significantly underestimate hepatic fat content, according to investigators.
The findings, which were independent of body weight, suggest that probe-specific controlled attenuation parameter (CAP) thresholds are needed to accurately interpret FibroScan results, reported lead author Cyrielle Caussy, MD, PhD, of the University of California, San Diego, and colleagues.
“We have previously determined the optimal threshold of CAP using either [an] M or XL probe for the detection of ... nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, head-to-head comparison of consecutive measurements of CAP with both the M and XL probes versus MRI-PDFF [proton density fat fraction] ... has not been reported yet.”
Dr. Caussy and colleagues set out to do just that. They enrolled 105 individuals with and without NAFLD who had a mean body mass index (BMI) of 30.6 kg/m2, as this represented a typical population screened for NAFLD. After evaluation for other causes of hepatic steatosis and liver disease, participants underwent MRI-PDFF, which served as a gold standard, followed by FibroScan using both M and XL probes on the same day.
The primary outcome was hepatic steatosis (MRI-PDFF of at least 5%), while the secondary outcome was MRI-PDFF–detected hepatic fat content of at least 10%, the latter of which has been “used in several therapeutic trials as inclusion criteria,” the investigators noted.
A total of 100 participants were included in the final analysis, of whom two-thirds (66%) underwent MRI and FibroScan on the same day, with a mean interval between test types of 11 days. Most participants (68%) had an MRI-PDFF of at least 5%, while almost half (48%) exceeded an MRI-PDFF of 10%.
The mean CAP measurement with the M probe was 310 dB/m, which was significantly lower than the mean value detected by the XL probe, which was 317 dB/m (P = .007). In participants with hepatic steatosis, when the M probe was used for those with a BMI of less than 30, and the XL probe was used for those with a BMI of 30 or more, the M probe still provided a significantly lower measure of hepatic fat content (312 vs. 345 dB/m; P = .0035).
“[T]hese results have direct application in routine clinical practice,” the investigators wrote, “as [they] will help clinicians interpreting CAP measurements depending on the type of probe used.”
Dr. Caussy and colleagues went on to offer a diagnostic algorithm involving optimal probe-specific thresholds for CAP based on hepatic fat content. Individuals screened with an M probe who have a CAP of 294 dB/m or more should be considered positive for NAFLD, while patients screened with an XL probe need to have a CAP of at least 307 dB/m to be NAFLD positive.
For the XL probe, but not the M probe, diagnostic accuracy depended upon an interquartile range of less than 30 dB/m. The investigators noted that this finding should alter the interpretation of a 2019 study by Eddowes and colleagues, which concluded that interquartile range was unrelated to diagnostic accuracy.
“As Eddowes et al. did not perform head-to-head comparison of CAP measurement with both the M and XL probes, this important difference could not have been observed,” the investigators wrote, noting that “an interquartile range of CAP below 30 dB/m should be considered as a quality indicator that significantly improves the diagnostic performance of CAP using the XL probe for the detection of hepatic steatosis in NAFLD.”
The investigators concluded by suggesting that their findings will drive research forward.
“The use of these new thresholds will help to further assess the clinical utility of CAP for the detection of hepatic steatosis and its cost-effectiveness, compared with other modalities, to develop optimal strategies for the screening of NAFLD,” they wrote.
The study was funded by Atlantic Philanthropies, the John A. Hartford Foundation, the American Gastroenterological Association, and others. The investigators disclosed no conflicts of interest.
SOURCE: Caussy C et al. Clin Gastro Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.060.
When performing transient elastography (FibroScan) to evaluate patients for hepatic steatosis, using an M probe instead of an XL probe may significantly underestimate hepatic fat content, according to investigators.
The findings, which were independent of body weight, suggest that probe-specific controlled attenuation parameter (CAP) thresholds are needed to accurately interpret FibroScan results, reported lead author Cyrielle Caussy, MD, PhD, of the University of California, San Diego, and colleagues.
“We have previously determined the optimal threshold of CAP using either [an] M or XL probe for the detection of ... nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, head-to-head comparison of consecutive measurements of CAP with both the M and XL probes versus MRI-PDFF [proton density fat fraction] ... has not been reported yet.”
Dr. Caussy and colleagues set out to do just that. They enrolled 105 individuals with and without NAFLD who had a mean body mass index (BMI) of 30.6 kg/m2, as this represented a typical population screened for NAFLD. After evaluation for other causes of hepatic steatosis and liver disease, participants underwent MRI-PDFF, which served as a gold standard, followed by FibroScan using both M and XL probes on the same day.
The primary outcome was hepatic steatosis (MRI-PDFF of at least 5%), while the secondary outcome was MRI-PDFF–detected hepatic fat content of at least 10%, the latter of which has been “used in several therapeutic trials as inclusion criteria,” the investigators noted.
A total of 100 participants were included in the final analysis, of whom two-thirds (66%) underwent MRI and FibroScan on the same day, with a mean interval between test types of 11 days. Most participants (68%) had an MRI-PDFF of at least 5%, while almost half (48%) exceeded an MRI-PDFF of 10%.
The mean CAP measurement with the M probe was 310 dB/m, which was significantly lower than the mean value detected by the XL probe, which was 317 dB/m (P = .007). In participants with hepatic steatosis, when the M probe was used for those with a BMI of less than 30, and the XL probe was used for those with a BMI of 30 or more, the M probe still provided a significantly lower measure of hepatic fat content (312 vs. 345 dB/m; P = .0035).
“[T]hese results have direct application in routine clinical practice,” the investigators wrote, “as [they] will help clinicians interpreting CAP measurements depending on the type of probe used.”
Dr. Caussy and colleagues went on to offer a diagnostic algorithm involving optimal probe-specific thresholds for CAP based on hepatic fat content. Individuals screened with an M probe who have a CAP of 294 dB/m or more should be considered positive for NAFLD, while patients screened with an XL probe need to have a CAP of at least 307 dB/m to be NAFLD positive.
For the XL probe, but not the M probe, diagnostic accuracy depended upon an interquartile range of less than 30 dB/m. The investigators noted that this finding should alter the interpretation of a 2019 study by Eddowes and colleagues, which concluded that interquartile range was unrelated to diagnostic accuracy.
“As Eddowes et al. did not perform head-to-head comparison of CAP measurement with both the M and XL probes, this important difference could not have been observed,” the investigators wrote, noting that “an interquartile range of CAP below 30 dB/m should be considered as a quality indicator that significantly improves the diagnostic performance of CAP using the XL probe for the detection of hepatic steatosis in NAFLD.”
The investigators concluded by suggesting that their findings will drive research forward.
“The use of these new thresholds will help to further assess the clinical utility of CAP for the detection of hepatic steatosis and its cost-effectiveness, compared with other modalities, to develop optimal strategies for the screening of NAFLD,” they wrote.
The study was funded by Atlantic Philanthropies, the John A. Hartford Foundation, the American Gastroenterological Association, and others. The investigators disclosed no conflicts of interest.
SOURCE: Caussy C et al. Clin Gastro Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.060.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Meta-analysis: For large proximal polyps, clipping prevents bleeding
Prophylactically clipping large proximal colorectal lesions after resection may reduce risk of postprocedural bleeding, according to a meta-analysis involving nine randomized controlled trials.
Across all lesions, prophylactic clipping had no significant benefit, but when considering only large proximal lesions, clipping reduced bleeding risk by 63%, reported lead author Marco Spadaccini, MD, of Humanitas University, Rozzano, Italy, and colleagues.
According to the investigators, these findings emphasize the relevance of polyp size and location when assessing bleeding risk, which may influence future clinical guidance.
“Despite lack of high-quality evidence, prophylactic clipping has been advocated as a technique to reduce the risk of postprocedural bleeding,” the investigators wrote in Gastroenterology, referring to the European Society of Gastrointestinal Endoscopy recommendation that is based on patient risk factors.
Although previous meta-analyses reported that prophylactic clipping had no protective effect, these studies were “at high risk of bias” and predominantly evaluated lesions less than 20 mm in diameter, the investigators wrote.
Dr. Spadaccini and colleagues suggested that data from more recent, high-quality, randomized controlled trials could be used to identify subgroups that may benefit from clipping. This knowledge is particularly valuable considering the “costs and technical complexity” involved in the procedure, they noted.
The present meta-analysis comprised nine trials that included 7,197 colorectal lesions, of which 49.2% were proximally located and 22.5% were large (at least 20 mm in diameter).
Across all lesions, postprocedural bleeding occurred in 2.2% of clipped lesions and 3.3% of nonclipped lesions, a difference that was not statistically significant (P = .072). But for lesions 20 mm or larger, clipping was associated with a significantly lower rate of bleeding (4.3% vs. 7.6%; relative risk, 0.51; 95% CI, 0.33-0.78; P = .020). Similarly, clipping in the proximal location was independently associated with reduced bleeding risk (3.0% vs. 6.2%; RR, 0.53; 95% CI, 0.35-0.81; P less than .001). A multilevel meta-regression added further clarity by combining both size and location; it showed that clipping had a significant protective effect for large proximal lesions (RR, 0.37; 95% CI, 0.22-0.61; P = .021), but not for those that were small and proximal (RR, 0.88; 95% CI, 0.48-1.62; P = .581).
“According to our meta-analysis, routine practice of endoscopic clipping as a prophylactic intervention does not reduce the risk of postpolypectomy bleeding,” the investigators wrote. “However, clipping was effective in reducing the risk of postprocedural bleeding by nearly 50% for large lesions. If such lesions do not undergo endoscopic clipping, there was fourfold increase in the baseline risk of post-procedural bleeding as compared with those less than 20 mm.”
While the present analysis suggested that clipping was beneficial only for large lesions in the proximal colon, the investigators noted that the protective effect of clipping large lesions in the distal colon (RR, 0.70; 95% CI, 0.22-2.27) was “somewhat intermediate ... albeit not statistically significant” and driven by data from one trial.
“[T]his was not confirmed by other studies generating some uncertainty on the benefit of prophylactic clipping for large distal lesions,” the investigators wrote. “Thus, the decision for large and distal lesions should be tailored, especially taking into consideration other patient- and polyp-risk factors for postprocedural bleeding, such as the use of anti-thrombotic agents or intraprocedural bleeding.”
In contrast, the findings indicated that clipping is unnecessary for lesions less than 20 mm, the investigators wrote.
They went on to explain that clinical application of these findings could result in “significant cost savings” because one bleeding event would be prevented for every 23 large lesions clipped.
“Considering that clips are expensive and their placement might be technically demanding, prophylactic clipping tailored for a subgroup of higher-risk lesions/patients would decrease in parallel both adverse events and costs,” the investigators concluded.
The investigators reported no external funding or conflicts of interest.
SOURCE: Spadaccini M et al. Gastroenterology. 2020 Apr 1. doi: 10.1053/j.gastro.2020.03.051.
Prophylactically clipping large proximal colorectal lesions after resection may reduce risk of postprocedural bleeding, according to a meta-analysis involving nine randomized controlled trials.
Across all lesions, prophylactic clipping had no significant benefit, but when considering only large proximal lesions, clipping reduced bleeding risk by 63%, reported lead author Marco Spadaccini, MD, of Humanitas University, Rozzano, Italy, and colleagues.
According to the investigators, these findings emphasize the relevance of polyp size and location when assessing bleeding risk, which may influence future clinical guidance.
“Despite lack of high-quality evidence, prophylactic clipping has been advocated as a technique to reduce the risk of postprocedural bleeding,” the investigators wrote in Gastroenterology, referring to the European Society of Gastrointestinal Endoscopy recommendation that is based on patient risk factors.
Although previous meta-analyses reported that prophylactic clipping had no protective effect, these studies were “at high risk of bias” and predominantly evaluated lesions less than 20 mm in diameter, the investigators wrote.
Dr. Spadaccini and colleagues suggested that data from more recent, high-quality, randomized controlled trials could be used to identify subgroups that may benefit from clipping. This knowledge is particularly valuable considering the “costs and technical complexity” involved in the procedure, they noted.
The present meta-analysis comprised nine trials that included 7,197 colorectal lesions, of which 49.2% were proximally located and 22.5% were large (at least 20 mm in diameter).
Across all lesions, postprocedural bleeding occurred in 2.2% of clipped lesions and 3.3% of nonclipped lesions, a difference that was not statistically significant (P = .072). But for lesions 20 mm or larger, clipping was associated with a significantly lower rate of bleeding (4.3% vs. 7.6%; relative risk, 0.51; 95% CI, 0.33-0.78; P = .020). Similarly, clipping in the proximal location was independently associated with reduced bleeding risk (3.0% vs. 6.2%; RR, 0.53; 95% CI, 0.35-0.81; P less than .001). A multilevel meta-regression added further clarity by combining both size and location; it showed that clipping had a significant protective effect for large proximal lesions (RR, 0.37; 95% CI, 0.22-0.61; P = .021), but not for those that were small and proximal (RR, 0.88; 95% CI, 0.48-1.62; P = .581).
“According to our meta-analysis, routine practice of endoscopic clipping as a prophylactic intervention does not reduce the risk of postpolypectomy bleeding,” the investigators wrote. “However, clipping was effective in reducing the risk of postprocedural bleeding by nearly 50% for large lesions. If such lesions do not undergo endoscopic clipping, there was fourfold increase in the baseline risk of post-procedural bleeding as compared with those less than 20 mm.”
While the present analysis suggested that clipping was beneficial only for large lesions in the proximal colon, the investigators noted that the protective effect of clipping large lesions in the distal colon (RR, 0.70; 95% CI, 0.22-2.27) was “somewhat intermediate ... albeit not statistically significant” and driven by data from one trial.
“[T]his was not confirmed by other studies generating some uncertainty on the benefit of prophylactic clipping for large distal lesions,” the investigators wrote. “Thus, the decision for large and distal lesions should be tailored, especially taking into consideration other patient- and polyp-risk factors for postprocedural bleeding, such as the use of anti-thrombotic agents or intraprocedural bleeding.”
In contrast, the findings indicated that clipping is unnecessary for lesions less than 20 mm, the investigators wrote.
They went on to explain that clinical application of these findings could result in “significant cost savings” because one bleeding event would be prevented for every 23 large lesions clipped.
“Considering that clips are expensive and their placement might be technically demanding, prophylactic clipping tailored for a subgroup of higher-risk lesions/patients would decrease in parallel both adverse events and costs,” the investigators concluded.
The investigators reported no external funding or conflicts of interest.
SOURCE: Spadaccini M et al. Gastroenterology. 2020 Apr 1. doi: 10.1053/j.gastro.2020.03.051.
Prophylactically clipping large proximal colorectal lesions after resection may reduce risk of postprocedural bleeding, according to a meta-analysis involving nine randomized controlled trials.
Across all lesions, prophylactic clipping had no significant benefit, but when considering only large proximal lesions, clipping reduced bleeding risk by 63%, reported lead author Marco Spadaccini, MD, of Humanitas University, Rozzano, Italy, and colleagues.
According to the investigators, these findings emphasize the relevance of polyp size and location when assessing bleeding risk, which may influence future clinical guidance.
“Despite lack of high-quality evidence, prophylactic clipping has been advocated as a technique to reduce the risk of postprocedural bleeding,” the investigators wrote in Gastroenterology, referring to the European Society of Gastrointestinal Endoscopy recommendation that is based on patient risk factors.
Although previous meta-analyses reported that prophylactic clipping had no protective effect, these studies were “at high risk of bias” and predominantly evaluated lesions less than 20 mm in diameter, the investigators wrote.
Dr. Spadaccini and colleagues suggested that data from more recent, high-quality, randomized controlled trials could be used to identify subgroups that may benefit from clipping. This knowledge is particularly valuable considering the “costs and technical complexity” involved in the procedure, they noted.
The present meta-analysis comprised nine trials that included 7,197 colorectal lesions, of which 49.2% were proximally located and 22.5% were large (at least 20 mm in diameter).
Across all lesions, postprocedural bleeding occurred in 2.2% of clipped lesions and 3.3% of nonclipped lesions, a difference that was not statistically significant (P = .072). But for lesions 20 mm or larger, clipping was associated with a significantly lower rate of bleeding (4.3% vs. 7.6%; relative risk, 0.51; 95% CI, 0.33-0.78; P = .020). Similarly, clipping in the proximal location was independently associated with reduced bleeding risk (3.0% vs. 6.2%; RR, 0.53; 95% CI, 0.35-0.81; P less than .001). A multilevel meta-regression added further clarity by combining both size and location; it showed that clipping had a significant protective effect for large proximal lesions (RR, 0.37; 95% CI, 0.22-0.61; P = .021), but not for those that were small and proximal (RR, 0.88; 95% CI, 0.48-1.62; P = .581).
“According to our meta-analysis, routine practice of endoscopic clipping as a prophylactic intervention does not reduce the risk of postpolypectomy bleeding,” the investigators wrote. “However, clipping was effective in reducing the risk of postprocedural bleeding by nearly 50% for large lesions. If such lesions do not undergo endoscopic clipping, there was fourfold increase in the baseline risk of post-procedural bleeding as compared with those less than 20 mm.”
While the present analysis suggested that clipping was beneficial only for large lesions in the proximal colon, the investigators noted that the protective effect of clipping large lesions in the distal colon (RR, 0.70; 95% CI, 0.22-2.27) was “somewhat intermediate ... albeit not statistically significant” and driven by data from one trial.
“[T]his was not confirmed by other studies generating some uncertainty on the benefit of prophylactic clipping for large distal lesions,” the investigators wrote. “Thus, the decision for large and distal lesions should be tailored, especially taking into consideration other patient- and polyp-risk factors for postprocedural bleeding, such as the use of anti-thrombotic agents or intraprocedural bleeding.”
In contrast, the findings indicated that clipping is unnecessary for lesions less than 20 mm, the investigators wrote.
They went on to explain that clinical application of these findings could result in “significant cost savings” because one bleeding event would be prevented for every 23 large lesions clipped.
“Considering that clips are expensive and their placement might be technically demanding, prophylactic clipping tailored for a subgroup of higher-risk lesions/patients would decrease in parallel both adverse events and costs,” the investigators concluded.
The investigators reported no external funding or conflicts of interest.
SOURCE: Spadaccini M et al. Gastroenterology. 2020 Apr 1. doi: 10.1053/j.gastro.2020.03.051.
FROM GASTROENTEROLOGY
Liposomal bupivacaine excreted in breast milk, but levels appear safe
based on a prospective cohort study.
Over the course of 4 days, relative neonatal dosages of bupivacaine were less than 1%, remaining below the 10% threshold of concern, reported Hiba J. Mustafa, MD, of the University of Minnesota, Minneapolis, and colleagues.
Liposomal bupivacaine can achieve up to 4 days of postcesarean pain control, which is significantly longer than the 8 hours provided by standard bupivacaine, the investigators wrote in Obstetrics & Gynecology. But usage of the liposomal formulation has not been widespread, they noted, partly because of a lack of clinical studies evaluating breast milk transfer and neonatal safety.
To address this knowledge gap, Dr. Mustafa and colleagues enrolled 30 healthy pregnant women scheduled to undergo cesarean birth at full term. All patients were aged 18-40 years, with an American Society of Anesthesiologists physical status of I or II. Exclusion criteria included a number of maternal and neonatal health concerns, such as sensitivity to local anesthetics, metabolic disorders, fetal anomaly, fetal growth restriction, and others.
The day of surgery, before the procedure, maternal blood samples were collected and used for baseline measurements.
Each woman received a spinal anesthetic including 150 mcg of morphine, 15 mcg of intrathecal fentanyl, and 1.4-1.6 mL of 0.75% hyperbaric bupivacaine hydrochloride. Within 30 minutes after birth, a bilateral transversus abdominus plane block was performed using 266 mg of 1.3% liposomal bupivacaine and 52 mg of 0.25% bupivacaine hydrochloride.
Using the block as time point zero, maternal blood and breast milk samples were collected at hour 2, 6, 12, 24, 48, 72, and 96. Sparse sampling was employed, such that participants were randomly assigned in a 1:1 ratio to provide paired blood and milk samples at hour 2, 12, and 48; or hour 6, 24, 72, and 96. Bupivacaine was quantified in samples by liquid chromatography–tandem mass spectrometry.
Using these data, the investigators determined bupivacaine concentrations in plasma and milk, milk/plasma area under the curve (AUC) ratios, neonatal dosage, and relative neonatal dosage. In addition, adverse events in both mothers and neonates were recorded for 2 weeks post partum.
Mean bupivacaine concentrations peaked in breast milk at 6 hours, at 58 ng/mL. This peak was followed by a steady reduction to an “almost undetectable” level of 5.2 ng/mL at 96 hours. Maternal plasma levels peaked first at hour 6 (155.9 ng/mL), then again at hour 48 (225.8 ng/mL), followed by a steady decline until hour 96, when the level reached 80.6 ng/mL.
Relative mean concentrations of milk to plasma were 44%, 36%, 28%, and 18% at hour 2, 6, 12, and 24, respectively. AUC ratios were used to represent exposure across various time intervals. For instance, the AUC ratio for milk/plasma from hour 0 to hour 2 was 0.45. The AUC findings declined steadily until the final ratio, which spanned hour 0 to hour 96, at 0.15.
These AUC ratios allowed for calculation of neonatal dosage and relative neonatal dosage using an average daily milk intake of 150 mL/kg per day. For the longest range, spanning from hour 0 to hour 96, the neonatal dosage was 15,155.4 ng/kg, which translated to a relative neonatal dosage of 0.396%.
No mothers or neonates experienced adverse events.
“Bupivacaine was transferred into mother’s milk such that an exclusively breastfeeding neonate would ingest less than 1% (relative neonatal dosage) of the maternal dose,” the investigators wrote, noting that this falls safely below the acceptable threshold of 10%.
“Because bupivacaine is metabolized primarily in the liver, a neonate’s absorption will likely be even lower [than modeled] given the first-pass effect,” they added.
Based on these findings, Dr. Mustafa and colleagues concluded that “the level of bupivacaine ingested by the sucking neonate is acceptable and compatible with breastfeeding.”
Michael G. Ross MD, MPH, Distinguished Professor of Obstetrics and Gynecology and Public Health at Geffen School of Medicine at the University of California, Los Angeles, commented that, this study adds to the literature of drug excretion into breast milk. “For the vast majority of drugs with passive transfer from maternal plasma to breast milk, the effective dosages of exclusive breastfeeding neonates are approximately 5% of the maternal (oral) dose. In the present study, the authors demonstrated a relative neonatal dosage of less than 1%. This low value results from consequences of minimal maternal plasma absorption (in the present case from transversus abdominis injection), maternal volume of distribution, transfer into breast milk, and the volume of milk ingestion. These results should provide reassurance for the safety of breastfeeding term infants under the conditions of the study.
“There are a number of study concerns, including the inability to differentiate absorption of the spinal bupivacaine from the liposomal bupivacaine, the lack of paired maternal plasma and breast milk sample, and the lack of detail as to how much milk was expressed for each sample. Importantly, breast milk composition varies from foremilk to hindmilk. Thus, a single sample may not accurately reflect the composition ingested by the infant. The suggestion of two peaks in maternal plasma concentration was not demonstrated statistically and may be an artifact of the timing of spinal and liposomal injections, or the fact that different patients were studied at each time period.
“Most importantly, despite the demonstrated safety, the authors acknowledge conflicting results of clinical benefits of liposomal bupivacaine injection. As such, I recommend that postcesarean transversus abdominis blocks be performed only under institutional review board-approved study protocols,” said Dr. Ross, codirector of the Institute for Women’ and Children’s Health at the Lundquist Institute, Torrance, Calif.*
The study was funded by the Thrasher Research Fund. The investigators reported no conflicts of interest. Dr. Ross had no relevant financial disclosures.
SOURCE: Mustafa et al. Obstet Gynecol. 2020 Jun 6. doi: 10.1097/AOG.0000000000003886.
*This article was updated 6/16/2020.
based on a prospective cohort study.
Over the course of 4 days, relative neonatal dosages of bupivacaine were less than 1%, remaining below the 10% threshold of concern, reported Hiba J. Mustafa, MD, of the University of Minnesota, Minneapolis, and colleagues.
Liposomal bupivacaine can achieve up to 4 days of postcesarean pain control, which is significantly longer than the 8 hours provided by standard bupivacaine, the investigators wrote in Obstetrics & Gynecology. But usage of the liposomal formulation has not been widespread, they noted, partly because of a lack of clinical studies evaluating breast milk transfer and neonatal safety.
To address this knowledge gap, Dr. Mustafa and colleagues enrolled 30 healthy pregnant women scheduled to undergo cesarean birth at full term. All patients were aged 18-40 years, with an American Society of Anesthesiologists physical status of I or II. Exclusion criteria included a number of maternal and neonatal health concerns, such as sensitivity to local anesthetics, metabolic disorders, fetal anomaly, fetal growth restriction, and others.
The day of surgery, before the procedure, maternal blood samples were collected and used for baseline measurements.
Each woman received a spinal anesthetic including 150 mcg of morphine, 15 mcg of intrathecal fentanyl, and 1.4-1.6 mL of 0.75% hyperbaric bupivacaine hydrochloride. Within 30 minutes after birth, a bilateral transversus abdominus plane block was performed using 266 mg of 1.3% liposomal bupivacaine and 52 mg of 0.25% bupivacaine hydrochloride.
Using the block as time point zero, maternal blood and breast milk samples were collected at hour 2, 6, 12, 24, 48, 72, and 96. Sparse sampling was employed, such that participants were randomly assigned in a 1:1 ratio to provide paired blood and milk samples at hour 2, 12, and 48; or hour 6, 24, 72, and 96. Bupivacaine was quantified in samples by liquid chromatography–tandem mass spectrometry.
Using these data, the investigators determined bupivacaine concentrations in plasma and milk, milk/plasma area under the curve (AUC) ratios, neonatal dosage, and relative neonatal dosage. In addition, adverse events in both mothers and neonates were recorded for 2 weeks post partum.
Mean bupivacaine concentrations peaked in breast milk at 6 hours, at 58 ng/mL. This peak was followed by a steady reduction to an “almost undetectable” level of 5.2 ng/mL at 96 hours. Maternal plasma levels peaked first at hour 6 (155.9 ng/mL), then again at hour 48 (225.8 ng/mL), followed by a steady decline until hour 96, when the level reached 80.6 ng/mL.
Relative mean concentrations of milk to plasma were 44%, 36%, 28%, and 18% at hour 2, 6, 12, and 24, respectively. AUC ratios were used to represent exposure across various time intervals. For instance, the AUC ratio for milk/plasma from hour 0 to hour 2 was 0.45. The AUC findings declined steadily until the final ratio, which spanned hour 0 to hour 96, at 0.15.
These AUC ratios allowed for calculation of neonatal dosage and relative neonatal dosage using an average daily milk intake of 150 mL/kg per day. For the longest range, spanning from hour 0 to hour 96, the neonatal dosage was 15,155.4 ng/kg, which translated to a relative neonatal dosage of 0.396%.
No mothers or neonates experienced adverse events.
“Bupivacaine was transferred into mother’s milk such that an exclusively breastfeeding neonate would ingest less than 1% (relative neonatal dosage) of the maternal dose,” the investigators wrote, noting that this falls safely below the acceptable threshold of 10%.
“Because bupivacaine is metabolized primarily in the liver, a neonate’s absorption will likely be even lower [than modeled] given the first-pass effect,” they added.
Based on these findings, Dr. Mustafa and colleagues concluded that “the level of bupivacaine ingested by the sucking neonate is acceptable and compatible with breastfeeding.”
Michael G. Ross MD, MPH, Distinguished Professor of Obstetrics and Gynecology and Public Health at Geffen School of Medicine at the University of California, Los Angeles, commented that, this study adds to the literature of drug excretion into breast milk. “For the vast majority of drugs with passive transfer from maternal plasma to breast milk, the effective dosages of exclusive breastfeeding neonates are approximately 5% of the maternal (oral) dose. In the present study, the authors demonstrated a relative neonatal dosage of less than 1%. This low value results from consequences of minimal maternal plasma absorption (in the present case from transversus abdominis injection), maternal volume of distribution, transfer into breast milk, and the volume of milk ingestion. These results should provide reassurance for the safety of breastfeeding term infants under the conditions of the study.
“There are a number of study concerns, including the inability to differentiate absorption of the spinal bupivacaine from the liposomal bupivacaine, the lack of paired maternal plasma and breast milk sample, and the lack of detail as to how much milk was expressed for each sample. Importantly, breast milk composition varies from foremilk to hindmilk. Thus, a single sample may not accurately reflect the composition ingested by the infant. The suggestion of two peaks in maternal plasma concentration was not demonstrated statistically and may be an artifact of the timing of spinal and liposomal injections, or the fact that different patients were studied at each time period.
“Most importantly, despite the demonstrated safety, the authors acknowledge conflicting results of clinical benefits of liposomal bupivacaine injection. As such, I recommend that postcesarean transversus abdominis blocks be performed only under institutional review board-approved study protocols,” said Dr. Ross, codirector of the Institute for Women’ and Children’s Health at the Lundquist Institute, Torrance, Calif.*
The study was funded by the Thrasher Research Fund. The investigators reported no conflicts of interest. Dr. Ross had no relevant financial disclosures.
SOURCE: Mustafa et al. Obstet Gynecol. 2020 Jun 6. doi: 10.1097/AOG.0000000000003886.
*This article was updated 6/16/2020.
based on a prospective cohort study.
Over the course of 4 days, relative neonatal dosages of bupivacaine were less than 1%, remaining below the 10% threshold of concern, reported Hiba J. Mustafa, MD, of the University of Minnesota, Minneapolis, and colleagues.
Liposomal bupivacaine can achieve up to 4 days of postcesarean pain control, which is significantly longer than the 8 hours provided by standard bupivacaine, the investigators wrote in Obstetrics & Gynecology. But usage of the liposomal formulation has not been widespread, they noted, partly because of a lack of clinical studies evaluating breast milk transfer and neonatal safety.
To address this knowledge gap, Dr. Mustafa and colleagues enrolled 30 healthy pregnant women scheduled to undergo cesarean birth at full term. All patients were aged 18-40 years, with an American Society of Anesthesiologists physical status of I or II. Exclusion criteria included a number of maternal and neonatal health concerns, such as sensitivity to local anesthetics, metabolic disorders, fetal anomaly, fetal growth restriction, and others.
The day of surgery, before the procedure, maternal blood samples were collected and used for baseline measurements.
Each woman received a spinal anesthetic including 150 mcg of morphine, 15 mcg of intrathecal fentanyl, and 1.4-1.6 mL of 0.75% hyperbaric bupivacaine hydrochloride. Within 30 minutes after birth, a bilateral transversus abdominus plane block was performed using 266 mg of 1.3% liposomal bupivacaine and 52 mg of 0.25% bupivacaine hydrochloride.
Using the block as time point zero, maternal blood and breast milk samples were collected at hour 2, 6, 12, 24, 48, 72, and 96. Sparse sampling was employed, such that participants were randomly assigned in a 1:1 ratio to provide paired blood and milk samples at hour 2, 12, and 48; or hour 6, 24, 72, and 96. Bupivacaine was quantified in samples by liquid chromatography–tandem mass spectrometry.
Using these data, the investigators determined bupivacaine concentrations in plasma and milk, milk/plasma area under the curve (AUC) ratios, neonatal dosage, and relative neonatal dosage. In addition, adverse events in both mothers and neonates were recorded for 2 weeks post partum.
Mean bupivacaine concentrations peaked in breast milk at 6 hours, at 58 ng/mL. This peak was followed by a steady reduction to an “almost undetectable” level of 5.2 ng/mL at 96 hours. Maternal plasma levels peaked first at hour 6 (155.9 ng/mL), then again at hour 48 (225.8 ng/mL), followed by a steady decline until hour 96, when the level reached 80.6 ng/mL.
Relative mean concentrations of milk to plasma were 44%, 36%, 28%, and 18% at hour 2, 6, 12, and 24, respectively. AUC ratios were used to represent exposure across various time intervals. For instance, the AUC ratio for milk/plasma from hour 0 to hour 2 was 0.45. The AUC findings declined steadily until the final ratio, which spanned hour 0 to hour 96, at 0.15.
These AUC ratios allowed for calculation of neonatal dosage and relative neonatal dosage using an average daily milk intake of 150 mL/kg per day. For the longest range, spanning from hour 0 to hour 96, the neonatal dosage was 15,155.4 ng/kg, which translated to a relative neonatal dosage of 0.396%.
No mothers or neonates experienced adverse events.
“Bupivacaine was transferred into mother’s milk such that an exclusively breastfeeding neonate would ingest less than 1% (relative neonatal dosage) of the maternal dose,” the investigators wrote, noting that this falls safely below the acceptable threshold of 10%.
“Because bupivacaine is metabolized primarily in the liver, a neonate’s absorption will likely be even lower [than modeled] given the first-pass effect,” they added.
Based on these findings, Dr. Mustafa and colleagues concluded that “the level of bupivacaine ingested by the sucking neonate is acceptable and compatible with breastfeeding.”
Michael G. Ross MD, MPH, Distinguished Professor of Obstetrics and Gynecology and Public Health at Geffen School of Medicine at the University of California, Los Angeles, commented that, this study adds to the literature of drug excretion into breast milk. “For the vast majority of drugs with passive transfer from maternal plasma to breast milk, the effective dosages of exclusive breastfeeding neonates are approximately 5% of the maternal (oral) dose. In the present study, the authors demonstrated a relative neonatal dosage of less than 1%. This low value results from consequences of minimal maternal plasma absorption (in the present case from transversus abdominis injection), maternal volume of distribution, transfer into breast milk, and the volume of milk ingestion. These results should provide reassurance for the safety of breastfeeding term infants under the conditions of the study.
“There are a number of study concerns, including the inability to differentiate absorption of the spinal bupivacaine from the liposomal bupivacaine, the lack of paired maternal plasma and breast milk sample, and the lack of detail as to how much milk was expressed for each sample. Importantly, breast milk composition varies from foremilk to hindmilk. Thus, a single sample may not accurately reflect the composition ingested by the infant. The suggestion of two peaks in maternal plasma concentration was not demonstrated statistically and may be an artifact of the timing of spinal and liposomal injections, or the fact that different patients were studied at each time period.
“Most importantly, despite the demonstrated safety, the authors acknowledge conflicting results of clinical benefits of liposomal bupivacaine injection. As such, I recommend that postcesarean transversus abdominis blocks be performed only under institutional review board-approved study protocols,” said Dr. Ross, codirector of the Institute for Women’ and Children’s Health at the Lundquist Institute, Torrance, Calif.*
The study was funded by the Thrasher Research Fund. The investigators reported no conflicts of interest. Dr. Ross had no relevant financial disclosures.
SOURCE: Mustafa et al. Obstet Gynecol. 2020 Jun 6. doi: 10.1097/AOG.0000000000003886.
*This article was updated 6/16/2020.
FROM OBSTETRICS & GYNECOLOGY
EBV may worsen immune checkpoint inhibitor–induced colitis
For patients with immune checkpoint inhibitor–induced colitis, Epstein-Barr virus (EBV) infection may increase risks of steroid-refractory disease and ulcers that contribute to colonic perforation, according to investigators.
Pending further research, routine monitoring of EBV status may be needed for patients undergoing checkpoint inhibitor therapy, reported lead author Matthew R. Pugh, FRCPath, of University Hospital of Wales, Cardiff, and colleagues.
“Few studies have investigated the role of viruses in the pathogenesis of immune-related colitis,” the investigators wrote. Their report is in Clinical Gastroenterology and Hepatology. While cytomegalovirus has been linked with worse disease, no studies to date have evaluated the role of EBV, they noted, despite theoretical concerns.
“A spectrum of EBV-positive lymphoproliferations shows a predilection for the GI tract, ranging from indolent lesions to aggressive lymphomas,” the investigators wrote. “One such proliferation, EBV-positive mucocutaneous ulcer (EBVMCU), is an indolent, ulcerating process associated with immunosuppression,” they added, referring to studies involving patients with inflammatory bowel disease.
To determine if EBV could be playing a similar role in cancer immunotherapy, the investigators retrospectively analyzed colon tissue samples from 16 patients who developed colitis after undergoing immune checkpoint inhibitor therapy between 2010 and 2018. Thirteen patients received an anti-CTLA-4 agent, three were treated with a PD-1 inhibitor, and four received both types of therapy. Most patients had advanced-stage melanoma (n = 14), while the remaining two patients had prostate and renal carcinoma, respectively. Ten samples were biopsies, whereas four specimens were collected from surgical repair of colon perforation.
EBV status was determined by chromogenic in situ hybridization for EBV-encoded small RNA, with positive samples further characterized by immunohistochemistry for CD3, CD15, CD20, CD30, CD138, MUM1, and PAX5. In addition, all samples were immunostained for cytomegalovirus, and PCR was used to assess B cell and T cell clonality.
The median time from induction of therapy to colitis onset was approximately 1 month (32.5 days), with symptoms typically lasting 3 weeks (22.5 days). Macroscopically, 10 patients had ulceration, and 6 displayed signs of hemorrhage.
EBVMCUs were found in four patients, of whom three had received anti-CTLA-4 therapy, one had received both anti-CTLA-4 and anti-PD-1 therapy, and all had undergone colonic resection. One case also tested positive for cytomegalovirus.
Immunostaining showed that EBVMCUs had underlying B cell and linear plasma cell infiltrates, with “a rim of small T lymphocytes at the base.” EBV-encoded small RNA expression was found in both plasma cells and small B cells.
The presence of EBVMCUs was significantly associated with more severe colitis.
All four EBV-positive patients had steroid-refractory colitis, compared with only two (12.5%) of the EBV-negative patients (P = .008), a difference that was echoed by the rate of colonic resection (100% vs. 12.5%; P .008). Furthermore, colon perforation occurred in all EBV-positive patients, versus none of the EBV-negative patients (P = .001).
For three EBV-positive patients, preresection biopsy samples were available, allowing for temporal analysis of EBV-encoded small RNA. Earlier samples had reduced or absent EBV-positive lymphoid cells, which offered some etiologic insight.
“The apparent absence or paucity of EBV-positive lymphoid cells in biopsies taken before resection suggests that EBVMCU is arising within preexisting immune-mediated inflammation rather than EBV driving the initial inflammatory insult,” the investigators wrote.
They suggested that EBVMCUs “likely contribute directly to colonic perforation,” since lesions are characterized by a form of localized tissue destruction that has been previously associated with colonic perforation in Crohn’s disease and intestinal perforation in rheumatoid arthritis.
Still, mechanisms of action remain unknown. “It is unclear why EBVMCUs should arise in the context of immune checkpoint regulator therapy, which, in contrast to conventional immunosuppressants, results in immune activation,” the investigators wrote. “It is possible that these patients may harbor residual immunosuppression resulting from their disease burden, advanced age, and prior immunosuppression.”
While more work is needed, Dr. Pugh and colleagues suggested that EBV testing may be valuable for some patients.
“The findings support the need for further studies investigating the role of EBV monitoring in immune checkpoint regulator therapy, which is not currently part of routine protocols.”
The study was funded by All Wales Lymphoma Panel. The investigators disclosed no conflicts of interest.
SOURCE: Pugh et al. Clin Gastroenterol Hepatol. 2019 Oct 11. doi: 10.1016/j.cgh.2019.09.031.
Immune checkpoint regulators (iCRs) have become common in the treatment for various cancers. Immune-related colitis (irColitis) is among the most common side effects of iCRs, as well as one of the most common etiologies of fatal toxicities from iCRs. However, much is still unknown on the pathophysiology behind irColitis or its complications. Pugh et al. performed detailed analyses of the potential role of Epstein-Barr virus (EBV) in irColitis. Rather than depend on serologies for EBV, the investigators utilized robust evaluation for colonic mucosal EBV with in situ hybridization, immunohistochemistry, and polymerase chain reaction. Interestingly, in the EBV-positive patients with endoscopic biopsies performed prior to perforation, EBV RNA were minimal or absent on endoscopic biopsies. This finding suggests EBV may be related to the immunosuppression used to treat the colitis rather than the primary driver of irColitis. This observation could have important clinical implications in using steroids for irColitis; we may be increasing the risk of perforation related to EBV by using steroids or other immunosuppression. While we need to interpret these findings with caution given the small sample size and comparisons between endoscopic biopsies and surgical specimens for EBV, this study highlights the potential role of EBV in steroid-refractory irColitis. An additional clinical implication from this study is that endoscopic biopsies did not identify patients who would eventually develop colonic perforation. We therefore cannot assume a patient with negative colonic biopsies for EBV is truly negative. Better means for assessing EBV status and predicting complications are still needed.
Jason K. Hou, MD, is assistant professor of medicine and gastroenterology; director of the GI and hepatology fellowship program; and director of research and IBD at Baylor College of Medicine, Houston. He is a staff physician in the department of gastroenterology, and medical director, IBD, at Michael E. DeBakey VA Medical Center, Houston. He has no conflicts of interest.
Immune checkpoint regulators (iCRs) have become common in the treatment for various cancers. Immune-related colitis (irColitis) is among the most common side effects of iCRs, as well as one of the most common etiologies of fatal toxicities from iCRs. However, much is still unknown on the pathophysiology behind irColitis or its complications. Pugh et al. performed detailed analyses of the potential role of Epstein-Barr virus (EBV) in irColitis. Rather than depend on serologies for EBV, the investigators utilized robust evaluation for colonic mucosal EBV with in situ hybridization, immunohistochemistry, and polymerase chain reaction. Interestingly, in the EBV-positive patients with endoscopic biopsies performed prior to perforation, EBV RNA were minimal or absent on endoscopic biopsies. This finding suggests EBV may be related to the immunosuppression used to treat the colitis rather than the primary driver of irColitis. This observation could have important clinical implications in using steroids for irColitis; we may be increasing the risk of perforation related to EBV by using steroids or other immunosuppression. While we need to interpret these findings with caution given the small sample size and comparisons between endoscopic biopsies and surgical specimens for EBV, this study highlights the potential role of EBV in steroid-refractory irColitis. An additional clinical implication from this study is that endoscopic biopsies did not identify patients who would eventually develop colonic perforation. We therefore cannot assume a patient with negative colonic biopsies for EBV is truly negative. Better means for assessing EBV status and predicting complications are still needed.
Jason K. Hou, MD, is assistant professor of medicine and gastroenterology; director of the GI and hepatology fellowship program; and director of research and IBD at Baylor College of Medicine, Houston. He is a staff physician in the department of gastroenterology, and medical director, IBD, at Michael E. DeBakey VA Medical Center, Houston. He has no conflicts of interest.
Immune checkpoint regulators (iCRs) have become common in the treatment for various cancers. Immune-related colitis (irColitis) is among the most common side effects of iCRs, as well as one of the most common etiologies of fatal toxicities from iCRs. However, much is still unknown on the pathophysiology behind irColitis or its complications. Pugh et al. performed detailed analyses of the potential role of Epstein-Barr virus (EBV) in irColitis. Rather than depend on serologies for EBV, the investigators utilized robust evaluation for colonic mucosal EBV with in situ hybridization, immunohistochemistry, and polymerase chain reaction. Interestingly, in the EBV-positive patients with endoscopic biopsies performed prior to perforation, EBV RNA were minimal or absent on endoscopic biopsies. This finding suggests EBV may be related to the immunosuppression used to treat the colitis rather than the primary driver of irColitis. This observation could have important clinical implications in using steroids for irColitis; we may be increasing the risk of perforation related to EBV by using steroids or other immunosuppression. While we need to interpret these findings with caution given the small sample size and comparisons between endoscopic biopsies and surgical specimens for EBV, this study highlights the potential role of EBV in steroid-refractory irColitis. An additional clinical implication from this study is that endoscopic biopsies did not identify patients who would eventually develop colonic perforation. We therefore cannot assume a patient with negative colonic biopsies for EBV is truly negative. Better means for assessing EBV status and predicting complications are still needed.
Jason K. Hou, MD, is assistant professor of medicine and gastroenterology; director of the GI and hepatology fellowship program; and director of research and IBD at Baylor College of Medicine, Houston. He is a staff physician in the department of gastroenterology, and medical director, IBD, at Michael E. DeBakey VA Medical Center, Houston. He has no conflicts of interest.
For patients with immune checkpoint inhibitor–induced colitis, Epstein-Barr virus (EBV) infection may increase risks of steroid-refractory disease and ulcers that contribute to colonic perforation, according to investigators.
Pending further research, routine monitoring of EBV status may be needed for patients undergoing checkpoint inhibitor therapy, reported lead author Matthew R. Pugh, FRCPath, of University Hospital of Wales, Cardiff, and colleagues.
“Few studies have investigated the role of viruses in the pathogenesis of immune-related colitis,” the investigators wrote. Their report is in Clinical Gastroenterology and Hepatology. While cytomegalovirus has been linked with worse disease, no studies to date have evaluated the role of EBV, they noted, despite theoretical concerns.
“A spectrum of EBV-positive lymphoproliferations shows a predilection for the GI tract, ranging from indolent lesions to aggressive lymphomas,” the investigators wrote. “One such proliferation, EBV-positive mucocutaneous ulcer (EBVMCU), is an indolent, ulcerating process associated with immunosuppression,” they added, referring to studies involving patients with inflammatory bowel disease.
To determine if EBV could be playing a similar role in cancer immunotherapy, the investigators retrospectively analyzed colon tissue samples from 16 patients who developed colitis after undergoing immune checkpoint inhibitor therapy between 2010 and 2018. Thirteen patients received an anti-CTLA-4 agent, three were treated with a PD-1 inhibitor, and four received both types of therapy. Most patients had advanced-stage melanoma (n = 14), while the remaining two patients had prostate and renal carcinoma, respectively. Ten samples were biopsies, whereas four specimens were collected from surgical repair of colon perforation.
EBV status was determined by chromogenic in situ hybridization for EBV-encoded small RNA, with positive samples further characterized by immunohistochemistry for CD3, CD15, CD20, CD30, CD138, MUM1, and PAX5. In addition, all samples were immunostained for cytomegalovirus, and PCR was used to assess B cell and T cell clonality.
The median time from induction of therapy to colitis onset was approximately 1 month (32.5 days), with symptoms typically lasting 3 weeks (22.5 days). Macroscopically, 10 patients had ulceration, and 6 displayed signs of hemorrhage.
EBVMCUs were found in four patients, of whom three had received anti-CTLA-4 therapy, one had received both anti-CTLA-4 and anti-PD-1 therapy, and all had undergone colonic resection. One case also tested positive for cytomegalovirus.
Immunostaining showed that EBVMCUs had underlying B cell and linear plasma cell infiltrates, with “a rim of small T lymphocytes at the base.” EBV-encoded small RNA expression was found in both plasma cells and small B cells.
The presence of EBVMCUs was significantly associated with more severe colitis.
All four EBV-positive patients had steroid-refractory colitis, compared with only two (12.5%) of the EBV-negative patients (P = .008), a difference that was echoed by the rate of colonic resection (100% vs. 12.5%; P .008). Furthermore, colon perforation occurred in all EBV-positive patients, versus none of the EBV-negative patients (P = .001).
For three EBV-positive patients, preresection biopsy samples were available, allowing for temporal analysis of EBV-encoded small RNA. Earlier samples had reduced or absent EBV-positive lymphoid cells, which offered some etiologic insight.
“The apparent absence or paucity of EBV-positive lymphoid cells in biopsies taken before resection suggests that EBVMCU is arising within preexisting immune-mediated inflammation rather than EBV driving the initial inflammatory insult,” the investigators wrote.
They suggested that EBVMCUs “likely contribute directly to colonic perforation,” since lesions are characterized by a form of localized tissue destruction that has been previously associated with colonic perforation in Crohn’s disease and intestinal perforation in rheumatoid arthritis.
Still, mechanisms of action remain unknown. “It is unclear why EBVMCUs should arise in the context of immune checkpoint regulator therapy, which, in contrast to conventional immunosuppressants, results in immune activation,” the investigators wrote. “It is possible that these patients may harbor residual immunosuppression resulting from their disease burden, advanced age, and prior immunosuppression.”
While more work is needed, Dr. Pugh and colleagues suggested that EBV testing may be valuable for some patients.
“The findings support the need for further studies investigating the role of EBV monitoring in immune checkpoint regulator therapy, which is not currently part of routine protocols.”
The study was funded by All Wales Lymphoma Panel. The investigators disclosed no conflicts of interest.
SOURCE: Pugh et al. Clin Gastroenterol Hepatol. 2019 Oct 11. doi: 10.1016/j.cgh.2019.09.031.
For patients with immune checkpoint inhibitor–induced colitis, Epstein-Barr virus (EBV) infection may increase risks of steroid-refractory disease and ulcers that contribute to colonic perforation, according to investigators.
Pending further research, routine monitoring of EBV status may be needed for patients undergoing checkpoint inhibitor therapy, reported lead author Matthew R. Pugh, FRCPath, of University Hospital of Wales, Cardiff, and colleagues.
“Few studies have investigated the role of viruses in the pathogenesis of immune-related colitis,” the investigators wrote. Their report is in Clinical Gastroenterology and Hepatology. While cytomegalovirus has been linked with worse disease, no studies to date have evaluated the role of EBV, they noted, despite theoretical concerns.
“A spectrum of EBV-positive lymphoproliferations shows a predilection for the GI tract, ranging from indolent lesions to aggressive lymphomas,” the investigators wrote. “One such proliferation, EBV-positive mucocutaneous ulcer (EBVMCU), is an indolent, ulcerating process associated with immunosuppression,” they added, referring to studies involving patients with inflammatory bowel disease.
To determine if EBV could be playing a similar role in cancer immunotherapy, the investigators retrospectively analyzed colon tissue samples from 16 patients who developed colitis after undergoing immune checkpoint inhibitor therapy between 2010 and 2018. Thirteen patients received an anti-CTLA-4 agent, three were treated with a PD-1 inhibitor, and four received both types of therapy. Most patients had advanced-stage melanoma (n = 14), while the remaining two patients had prostate and renal carcinoma, respectively. Ten samples were biopsies, whereas four specimens were collected from surgical repair of colon perforation.
EBV status was determined by chromogenic in situ hybridization for EBV-encoded small RNA, with positive samples further characterized by immunohistochemistry for CD3, CD15, CD20, CD30, CD138, MUM1, and PAX5. In addition, all samples were immunostained for cytomegalovirus, and PCR was used to assess B cell and T cell clonality.
The median time from induction of therapy to colitis onset was approximately 1 month (32.5 days), with symptoms typically lasting 3 weeks (22.5 days). Macroscopically, 10 patients had ulceration, and 6 displayed signs of hemorrhage.
EBVMCUs were found in four patients, of whom three had received anti-CTLA-4 therapy, one had received both anti-CTLA-4 and anti-PD-1 therapy, and all had undergone colonic resection. One case also tested positive for cytomegalovirus.
Immunostaining showed that EBVMCUs had underlying B cell and linear plasma cell infiltrates, with “a rim of small T lymphocytes at the base.” EBV-encoded small RNA expression was found in both plasma cells and small B cells.
The presence of EBVMCUs was significantly associated with more severe colitis.
All four EBV-positive patients had steroid-refractory colitis, compared with only two (12.5%) of the EBV-negative patients (P = .008), a difference that was echoed by the rate of colonic resection (100% vs. 12.5%; P .008). Furthermore, colon perforation occurred in all EBV-positive patients, versus none of the EBV-negative patients (P = .001).
For three EBV-positive patients, preresection biopsy samples were available, allowing for temporal analysis of EBV-encoded small RNA. Earlier samples had reduced or absent EBV-positive lymphoid cells, which offered some etiologic insight.
“The apparent absence or paucity of EBV-positive lymphoid cells in biopsies taken before resection suggests that EBVMCU is arising within preexisting immune-mediated inflammation rather than EBV driving the initial inflammatory insult,” the investigators wrote.
They suggested that EBVMCUs “likely contribute directly to colonic perforation,” since lesions are characterized by a form of localized tissue destruction that has been previously associated with colonic perforation in Crohn’s disease and intestinal perforation in rheumatoid arthritis.
Still, mechanisms of action remain unknown. “It is unclear why EBVMCUs should arise in the context of immune checkpoint regulator therapy, which, in contrast to conventional immunosuppressants, results in immune activation,” the investigators wrote. “It is possible that these patients may harbor residual immunosuppression resulting from their disease burden, advanced age, and prior immunosuppression.”
While more work is needed, Dr. Pugh and colleagues suggested that EBV testing may be valuable for some patients.
“The findings support the need for further studies investigating the role of EBV monitoring in immune checkpoint regulator therapy, which is not currently part of routine protocols.”
The study was funded by All Wales Lymphoma Panel. The investigators disclosed no conflicts of interest.
SOURCE: Pugh et al. Clin Gastroenterol Hepatol. 2019 Oct 11. doi: 10.1016/j.cgh.2019.09.031.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Tandem transplantation, long-term maintenance may extend MM remission
Tandem autologous hematopoietic stem cell transplantation (HSCT) could extend progression-free survival (PFS) for some patients with newly diagnosed multiple myeloma, based on long-term data from the phase 3 STaMINA trial.
While the intent-to-treat analysis showed no difference in 6-year PFS rate between single versus tandem HSCT, the as-treated analysis showed that patients who received two transplants had a 6-year PFS rate that was approximately 10% higher than those who received just one transplant, reported lead author Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
The STaMINA trial, also known as BMT CTN 0702, involved 758 patients who were randomized to receive one of three treatment regimens followed by 3 years of maintenance lenalidomide: tandem HSCT (auto/auto), single HSCT plus consolidation with lenalidomide/bortezomib/dexamethasone (auto/RVD), and single HSCT (auto/len).
“At the time, we intended the study to stop approximately 38 months from randomization, allowing for the time for transplant, and then 3 years of maintenance,” Dr. Hari said. However, as the results of lenalidomide maintenance in CALGB 00104 study were reported, they allowed for a follow-on protocol, which provided patients who are progression-free at the completion of the original STaMINA trial to go on to a second follow-on trial, which allowed lenalidomide maintenance on an indefinite basis, he added.
The present analysis looked at the long-term results of this follow-on trial, including the impact of discontinuing lenalidomide.
Aligning with the original study, the present intent-to-treat analysis showed no significant difference between treatment arms for 6-year PFS rate or overall survival. Respectively, PFS rates for auto/auto, auto/RVD, and auto/len were 43.9%, 39.7%, and 40.9% (P = .6).
But 32% of patients in the tandem group never underwent second HSCT, Dr. Hari noted, prompting the as-treated analysis. Although overall survival remained similar between groups, the 6-year PFS was significantly higher for patients who underwent tandem HSCT, at 49.4%, compared with 39.7% for auto/RVD and 38.6% for auto/len (P = .03).
Subgroup analysis showed the statistical benefit of tandem HSCT was driven by high-risk patients, who had a significantly better PFS after tandem transplant, compared with standard-risk patients, who showed no significant benefit.
Dr. Hari called the findings “provocative.”
“The tandem auto approach may still be relevant in high-risk multiple myeloma patients,” he said.
Dr. Hari and his colleagues also found that patients who stayed on maintenance lenalidomide after 38 months had a better 5-year PFS rate than those who discontinued maintenance therapy (79.5% vs. 61%; P = .0004). Subgroup analysis showed this benefit was statistically significant among patients with standard-risk disease (86.3% vs. 66%; P less than .001) but not among those in the high-risk subgroup (86.7% vs. 67.8%; P = .2).
However, Dr. Hari suggested that, based on the similarity of proportions between subgroups, the lack of significance in the high-risk subgroup was likely because of small sample size, suggesting the benefit of maintenance was actually shared across risk strata.
“Lenalidomide maintenance becomes a significant factor for preventing patients from progression,” Dr. Hari said, noting that the tandem transplant approach requires further study, and that he and his colleagues would soon publish minimal residual disease data.
He finished his presentation with a clear clinical recommendation. “Preplanned lenalidomide discontinuation at 3 years is not recommended based on inferior progression-free survival among those who stopped such therapy,” he said.
Invited discussant Joshua R. Richter, MD, of the Icahn School of Medicine at Mount Sinai, New York, said the findings encourage high-dose maintenance therapy, and for some, tandem HSCT.
“The STaMINA study presented today supports the notion that some patients with high-risk disease still may benefit and have further tumor burden reduction with the second transplant that leads to deeper remissions and hopefully abrogates diminished outcomes,” Dr. Richter said during a virtual presentation.
But improvements are needed to better identify such patients, Dr. Richter added. He highlighted a lack of standardization in risk modeling, with various factors currently employed, such as patient characteristics and genomic markers, among several others.
“Better definitions will allow us to cross compare and make true analyses about how to manage these patients,” Dr. Richter said. “Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena. And patients continue to suffer from worse outcomes, despite all of the other advances.”
The study was funded by the National Institutes of Health. The investigators disclosed additional relationships with Amgen, Celgene, Novartis, and others. Dr. Richter disclosed affiliations with Takeda, Sanofi, Janssen, and others.
SOURCE: Hari et al. ASCO 2020. Abstract 8506.
Tandem autologous hematopoietic stem cell transplantation (HSCT) could extend progression-free survival (PFS) for some patients with newly diagnosed multiple myeloma, based on long-term data from the phase 3 STaMINA trial.
While the intent-to-treat analysis showed no difference in 6-year PFS rate between single versus tandem HSCT, the as-treated analysis showed that patients who received two transplants had a 6-year PFS rate that was approximately 10% higher than those who received just one transplant, reported lead author Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
The STaMINA trial, also known as BMT CTN 0702, involved 758 patients who were randomized to receive one of three treatment regimens followed by 3 years of maintenance lenalidomide: tandem HSCT (auto/auto), single HSCT plus consolidation with lenalidomide/bortezomib/dexamethasone (auto/RVD), and single HSCT (auto/len).
“At the time, we intended the study to stop approximately 38 months from randomization, allowing for the time for transplant, and then 3 years of maintenance,” Dr. Hari said. However, as the results of lenalidomide maintenance in CALGB 00104 study were reported, they allowed for a follow-on protocol, which provided patients who are progression-free at the completion of the original STaMINA trial to go on to a second follow-on trial, which allowed lenalidomide maintenance on an indefinite basis, he added.
The present analysis looked at the long-term results of this follow-on trial, including the impact of discontinuing lenalidomide.
Aligning with the original study, the present intent-to-treat analysis showed no significant difference between treatment arms for 6-year PFS rate or overall survival. Respectively, PFS rates for auto/auto, auto/RVD, and auto/len were 43.9%, 39.7%, and 40.9% (P = .6).
But 32% of patients in the tandem group never underwent second HSCT, Dr. Hari noted, prompting the as-treated analysis. Although overall survival remained similar between groups, the 6-year PFS was significantly higher for patients who underwent tandem HSCT, at 49.4%, compared with 39.7% for auto/RVD and 38.6% for auto/len (P = .03).
Subgroup analysis showed the statistical benefit of tandem HSCT was driven by high-risk patients, who had a significantly better PFS after tandem transplant, compared with standard-risk patients, who showed no significant benefit.
Dr. Hari called the findings “provocative.”
“The tandem auto approach may still be relevant in high-risk multiple myeloma patients,” he said.
Dr. Hari and his colleagues also found that patients who stayed on maintenance lenalidomide after 38 months had a better 5-year PFS rate than those who discontinued maintenance therapy (79.5% vs. 61%; P = .0004). Subgroup analysis showed this benefit was statistically significant among patients with standard-risk disease (86.3% vs. 66%; P less than .001) but not among those in the high-risk subgroup (86.7% vs. 67.8%; P = .2).
However, Dr. Hari suggested that, based on the similarity of proportions between subgroups, the lack of significance in the high-risk subgroup was likely because of small sample size, suggesting the benefit of maintenance was actually shared across risk strata.
“Lenalidomide maintenance becomes a significant factor for preventing patients from progression,” Dr. Hari said, noting that the tandem transplant approach requires further study, and that he and his colleagues would soon publish minimal residual disease data.
He finished his presentation with a clear clinical recommendation. “Preplanned lenalidomide discontinuation at 3 years is not recommended based on inferior progression-free survival among those who stopped such therapy,” he said.
Invited discussant Joshua R. Richter, MD, of the Icahn School of Medicine at Mount Sinai, New York, said the findings encourage high-dose maintenance therapy, and for some, tandem HSCT.
“The STaMINA study presented today supports the notion that some patients with high-risk disease still may benefit and have further tumor burden reduction with the second transplant that leads to deeper remissions and hopefully abrogates diminished outcomes,” Dr. Richter said during a virtual presentation.
But improvements are needed to better identify such patients, Dr. Richter added. He highlighted a lack of standardization in risk modeling, with various factors currently employed, such as patient characteristics and genomic markers, among several others.
“Better definitions will allow us to cross compare and make true analyses about how to manage these patients,” Dr. Richter said. “Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena. And patients continue to suffer from worse outcomes, despite all of the other advances.”
The study was funded by the National Institutes of Health. The investigators disclosed additional relationships with Amgen, Celgene, Novartis, and others. Dr. Richter disclosed affiliations with Takeda, Sanofi, Janssen, and others.
SOURCE: Hari et al. ASCO 2020. Abstract 8506.
Tandem autologous hematopoietic stem cell transplantation (HSCT) could extend progression-free survival (PFS) for some patients with newly diagnosed multiple myeloma, based on long-term data from the phase 3 STaMINA trial.
While the intent-to-treat analysis showed no difference in 6-year PFS rate between single versus tandem HSCT, the as-treated analysis showed that patients who received two transplants had a 6-year PFS rate that was approximately 10% higher than those who received just one transplant, reported lead author Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
The STaMINA trial, also known as BMT CTN 0702, involved 758 patients who were randomized to receive one of three treatment regimens followed by 3 years of maintenance lenalidomide: tandem HSCT (auto/auto), single HSCT plus consolidation with lenalidomide/bortezomib/dexamethasone (auto/RVD), and single HSCT (auto/len).
“At the time, we intended the study to stop approximately 38 months from randomization, allowing for the time for transplant, and then 3 years of maintenance,” Dr. Hari said. However, as the results of lenalidomide maintenance in CALGB 00104 study were reported, they allowed for a follow-on protocol, which provided patients who are progression-free at the completion of the original STaMINA trial to go on to a second follow-on trial, which allowed lenalidomide maintenance on an indefinite basis, he added.
The present analysis looked at the long-term results of this follow-on trial, including the impact of discontinuing lenalidomide.
Aligning with the original study, the present intent-to-treat analysis showed no significant difference between treatment arms for 6-year PFS rate or overall survival. Respectively, PFS rates for auto/auto, auto/RVD, and auto/len were 43.9%, 39.7%, and 40.9% (P = .6).
But 32% of patients in the tandem group never underwent second HSCT, Dr. Hari noted, prompting the as-treated analysis. Although overall survival remained similar between groups, the 6-year PFS was significantly higher for patients who underwent tandem HSCT, at 49.4%, compared with 39.7% for auto/RVD and 38.6% for auto/len (P = .03).
Subgroup analysis showed the statistical benefit of tandem HSCT was driven by high-risk patients, who had a significantly better PFS after tandem transplant, compared with standard-risk patients, who showed no significant benefit.
Dr. Hari called the findings “provocative.”
“The tandem auto approach may still be relevant in high-risk multiple myeloma patients,” he said.
Dr. Hari and his colleagues also found that patients who stayed on maintenance lenalidomide after 38 months had a better 5-year PFS rate than those who discontinued maintenance therapy (79.5% vs. 61%; P = .0004). Subgroup analysis showed this benefit was statistically significant among patients with standard-risk disease (86.3% vs. 66%; P less than .001) but not among those in the high-risk subgroup (86.7% vs. 67.8%; P = .2).
However, Dr. Hari suggested that, based on the similarity of proportions between subgroups, the lack of significance in the high-risk subgroup was likely because of small sample size, suggesting the benefit of maintenance was actually shared across risk strata.
“Lenalidomide maintenance becomes a significant factor for preventing patients from progression,” Dr. Hari said, noting that the tandem transplant approach requires further study, and that he and his colleagues would soon publish minimal residual disease data.
He finished his presentation with a clear clinical recommendation. “Preplanned lenalidomide discontinuation at 3 years is not recommended based on inferior progression-free survival among those who stopped such therapy,” he said.
Invited discussant Joshua R. Richter, MD, of the Icahn School of Medicine at Mount Sinai, New York, said the findings encourage high-dose maintenance therapy, and for some, tandem HSCT.
“The STaMINA study presented today supports the notion that some patients with high-risk disease still may benefit and have further tumor burden reduction with the second transplant that leads to deeper remissions and hopefully abrogates diminished outcomes,” Dr. Richter said during a virtual presentation.
But improvements are needed to better identify such patients, Dr. Richter added. He highlighted a lack of standardization in risk modeling, with various factors currently employed, such as patient characteristics and genomic markers, among several others.
“Better definitions will allow us to cross compare and make true analyses about how to manage these patients,” Dr. Richter said. “Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena. And patients continue to suffer from worse outcomes, despite all of the other advances.”
The study was funded by the National Institutes of Health. The investigators disclosed additional relationships with Amgen, Celgene, Novartis, and others. Dr. Richter disclosed affiliations with Takeda, Sanofi, Janssen, and others.
SOURCE: Hari et al. ASCO 2020. Abstract 8506.
FROM ASCO 2020