One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.

“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).

All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.

Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.

It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.

Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.

The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.

Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.

The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.

[email protected]

One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.

“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).

All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.

Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.

It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.

Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.

The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.

Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.

The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.

[email protected]

One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.

“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).

All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.

Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.

It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.

Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.

The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.

Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.

The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.

[email protected]

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

CT scan showing PE

Image from Medical

College of Georgia

Suffering from obstructive sleep apnea (OSA) increases a person’s risk of pulmonary embolism (PE) recurrence, according to a study published in CHEST.

It has been hypothesized that OSA may promote the formation of blood clots.

Because venous thromboembolism is a chronic condition, researchers wanted to examine how OSA affected the rate of repeat PE occurrence.

They found that, after the first PE, OSA increases the risk for recurrence.

“There is growing evidence from cross-sectional and longitudinal studies that obstructive sleep apnea is a risk factor for pulmonary embolism,” explained study author Alberto Alonso-Fernández, MD, PhD, of Hospital Universitario Son Espases, Palma de Mallorca, Spain.

“This association represents a major public health burden, given the high prevalence of both disorders and the mortality rates of PE. However, to our knowledge, no longitudinal studies to date have explored the role of OSA as a risk factor for recurrent thromboembolic events.”

Therefore, Dr Alonso-Fernández and his colleagues followed 120 patients for 5 to 8 years after their first occurrence of PE. The patients were not taking oral anticoagulants at the start of the study.

The patients’ sleep was monitored for signs of OSA. A patient was classified as having OSA when the obstructive component was dominant and the apnea hypopnea index (AHI) was ≥ 10 per hour (10 h^–1).

Nineteen of the patients had recurrent PE during the follow-up period, and 16 of them suffered from OSA.

Multivariate analysis revealed several independent risk factors for recurrent PE, including:

• AHI ≥ 10 h^–1—hazard ratio (HR)=20.7
• Mean nocturnal oxygen saturation (nSaO2)—HR=0.39
• Time with SaO2 < 90% (CT90%)—HR=0.90
• D-dimer level—HR=1.001.

“The main finding in this study is that, after a first episode of PE, patients with OSA had a higher risk of recurrent PE than those without OSA,” Dr Alonso-Fernández said.

“Moreover, AHI and nocturnal hypoxemia, assessed by the mean nocturnal oxygen saturation and percentage of total time the patient spent with their oxygen saturation below 90%, are independent risk factors for PE recurrence and for resuming anticoagulation because of a new thromboembolic event.”

Twenty-four patients resumed oral anticoagulation. Independent risk factors for resuming anticoagulation included:

• AHI ≥ 10 h^–1—HR=20.66
• Mean nSaO2—HR=0.54
• Epworth Sleepiness Scale—HR=0.73.

Explaining the findings

Addressing why OSA may make people more susceptible to subsequent PE events, Dr Alonso-Fernández said, “PE is the result of Virchow’s classic risk triad—namely, vascular endothelial impairment, stasis of blood flow, and/or increased coagulability. OSA could hypothetically affect all 3 mechanistic pathways.”

“Intermittent hypoxia increases oxidative stress and inflammatory response that impairs endothelial function. OSA-related hemodynamic alterations and sedentarism may slow intravenous flow, and lastly, increased coagulability, platelet activity, and decreased fibrinolytic capacity in OSA may be improved after CPAP [continuous positive airway pressure].”

Several factors have been identified as playing a role in recurrent PE, including cancer, continued estrogen use, vena cava filters, high post-anticoagulation D-dimer, male gender, and obesity.

The current study suggested that OSA is an independent risk factor for recurrent PE, even after adjusting for several factors, including body mass index. OSA is a common problem among obese people, and the researchers assert that the risk of recurrent PE that is attributed to obesity might be partially related to OSA.

“Obesity is associated with sedentarism and venous stasis, and it has also been related to impaired fibrinolysis and high concentrations of clotting factors that might lead to a prothrombotic state that can further increase because obesity is associated with high estrogen levels and chronic low-grade inflammation,” Dr Alonso-Fernández said.

“It is tempting to speculate that OSA and obesity may additively or synergistically lead to upregulation of procoagulant activity that may intensify the risk of PE recurrence.”

Dr Alonso-Fernández and his colleagues believe that knowing OSA is an independent risk factor for recurrent PE can help physicians better understand treatment options. CPAP use is a proven intervention for OSA, and patients with OSA may need to stay on anticoagulation therapy longer to reduce their risk for another PE.

“Given the high prevalence of OSA in patients with PE, the procoagulable state induced by the intermittent hypoxia, and the risk for PE recurrence, the potential of CPAP and/or extend oral anticoagulation to reduce PE recurrence and mortality in patients with PE and OSA clearly warrants further study,” Dr Alonso-Fernández concluded.

CT scan showing PE

Image from Medical

College of Georgia

Suffering from obstructive sleep apnea (OSA) increases a person’s risk of pulmonary embolism (PE) recurrence, according to a study published in CHEST.

It has been hypothesized that OSA may promote the formation of blood clots.

Because venous thromboembolism is a chronic condition, researchers wanted to examine how OSA affected the rate of repeat PE occurrence.

They found that, after the first PE, OSA increases the risk for recurrence.

“There is growing evidence from cross-sectional and longitudinal studies that obstructive sleep apnea is a risk factor for pulmonary embolism,” explained study author Alberto Alonso-Fernández, MD, PhD, of Hospital Universitario Son Espases, Palma de Mallorca, Spain.

“This association represents a major public health burden, given the high prevalence of both disorders and the mortality rates of PE. However, to our knowledge, no longitudinal studies to date have explored the role of OSA as a risk factor for recurrent thromboembolic events.”

Therefore, Dr Alonso-Fernández and his colleagues followed 120 patients for 5 to 8 years after their first occurrence of PE. The patients were not taking oral anticoagulants at the start of the study.

The patients’ sleep was monitored for signs of OSA. A patient was classified as having OSA when the obstructive component was dominant and the apnea hypopnea index (AHI) was ≥ 10 per hour (10 h^–1).

Nineteen of the patients had recurrent PE during the follow-up period, and 16 of them suffered from OSA.

Multivariate analysis revealed several independent risk factors for recurrent PE, including:

• AHI ≥ 10 h^–1—hazard ratio (HR)=20.7
• Mean nocturnal oxygen saturation (nSaO2)—HR=0.39
• Time with SaO2 < 90% (CT90%)—HR=0.90
• D-dimer level—HR=1.001.

“The main finding in this study is that, after a first episode of PE, patients with OSA had a higher risk of recurrent PE than those without OSA,” Dr Alonso-Fernández said.

“Moreover, AHI and nocturnal hypoxemia, assessed by the mean nocturnal oxygen saturation and percentage of total time the patient spent with their oxygen saturation below 90%, are independent risk factors for PE recurrence and for resuming anticoagulation because of a new thromboembolic event.”

Twenty-four patients resumed oral anticoagulation. Independent risk factors for resuming anticoagulation included:

• AHI ≥ 10 h^–1—HR=20.66
• Mean nSaO2—HR=0.54
• Epworth Sleepiness Scale—HR=0.73.

Explaining the findings

Addressing why OSA may make people more susceptible to subsequent PE events, Dr Alonso-Fernández said, “PE is the result of Virchow’s classic risk triad—namely, vascular endothelial impairment, stasis of blood flow, and/or increased coagulability. OSA could hypothetically affect all 3 mechanistic pathways.”

“Intermittent hypoxia increases oxidative stress and inflammatory response that impairs endothelial function. OSA-related hemodynamic alterations and sedentarism may slow intravenous flow, and lastly, increased coagulability, platelet activity, and decreased fibrinolytic capacity in OSA may be improved after CPAP [continuous positive airway pressure].”

Several factors have been identified as playing a role in recurrent PE, including cancer, continued estrogen use, vena cava filters, high post-anticoagulation D-dimer, male gender, and obesity.

The current study suggested that OSA is an independent risk factor for recurrent PE, even after adjusting for several factors, including body mass index. OSA is a common problem among obese people, and the researchers assert that the risk of recurrent PE that is attributed to obesity might be partially related to OSA.

“Obesity is associated with sedentarism and venous stasis, and it has also been related to impaired fibrinolysis and high concentrations of clotting factors that might lead to a prothrombotic state that can further increase because obesity is associated with high estrogen levels and chronic low-grade inflammation,” Dr Alonso-Fernández said.

“It is tempting to speculate that OSA and obesity may additively or synergistically lead to upregulation of procoagulant activity that may intensify the risk of PE recurrence.”

Dr Alonso-Fernández and his colleagues believe that knowing OSA is an independent risk factor for recurrent PE can help physicians better understand treatment options. CPAP use is a proven intervention for OSA, and patients with OSA may need to stay on anticoagulation therapy longer to reduce their risk for another PE.

“Given the high prevalence of OSA in patients with PE, the procoagulable state induced by the intermittent hypoxia, and the risk for PE recurrence, the potential of CPAP and/or extend oral anticoagulation to reduce PE recurrence and mortality in patients with PE and OSA clearly warrants further study,” Dr Alonso-Fernández concluded.

CT scan showing PE

Image from Medical

College of Georgia

Suffering from obstructive sleep apnea (OSA) increases a person’s risk of pulmonary embolism (PE) recurrence, according to a study published in CHEST.

It has been hypothesized that OSA may promote the formation of blood clots.

Because venous thromboembolism is a chronic condition, researchers wanted to examine how OSA affected the rate of repeat PE occurrence.

They found that, after the first PE, OSA increases the risk for recurrence.

“There is growing evidence from cross-sectional and longitudinal studies that obstructive sleep apnea is a risk factor for pulmonary embolism,” explained study author Alberto Alonso-Fernández, MD, PhD, of Hospital Universitario Son Espases, Palma de Mallorca, Spain.

“This association represents a major public health burden, given the high prevalence of both disorders and the mortality rates of PE. However, to our knowledge, no longitudinal studies to date have explored the role of OSA as a risk factor for recurrent thromboembolic events.”

Therefore, Dr Alonso-Fernández and his colleagues followed 120 patients for 5 to 8 years after their first occurrence of PE. The patients were not taking oral anticoagulants at the start of the study.

The patients’ sleep was monitored for signs of OSA. A patient was classified as having OSA when the obstructive component was dominant and the apnea hypopnea index (AHI) was ≥ 10 per hour (10 h^–1).

Nineteen of the patients had recurrent PE during the follow-up period, and 16 of them suffered from OSA.

Multivariate analysis revealed several independent risk factors for recurrent PE, including:

• AHI ≥ 10 h^–1—hazard ratio (HR)=20.7
• Mean nocturnal oxygen saturation (nSaO2)—HR=0.39
• Time with SaO2 < 90% (CT90%)—HR=0.90
• D-dimer level—HR=1.001.

“The main finding in this study is that, after a first episode of PE, patients with OSA had a higher risk of recurrent PE than those without OSA,” Dr Alonso-Fernández said.

“Moreover, AHI and nocturnal hypoxemia, assessed by the mean nocturnal oxygen saturation and percentage of total time the patient spent with their oxygen saturation below 90%, are independent risk factors for PE recurrence and for resuming anticoagulation because of a new thromboembolic event.”

Twenty-four patients resumed oral anticoagulation. Independent risk factors for resuming anticoagulation included:

• AHI ≥ 10 h^–1—HR=20.66
• Mean nSaO2—HR=0.54
• Epworth Sleepiness Scale—HR=0.73.

Explaining the findings

Addressing why OSA may make people more susceptible to subsequent PE events, Dr Alonso-Fernández said, “PE is the result of Virchow’s classic risk triad—namely, vascular endothelial impairment, stasis of blood flow, and/or increased coagulability. OSA could hypothetically affect all 3 mechanistic pathways.”

“Intermittent hypoxia increases oxidative stress and inflammatory response that impairs endothelial function. OSA-related hemodynamic alterations and sedentarism may slow intravenous flow, and lastly, increased coagulability, platelet activity, and decreased fibrinolytic capacity in OSA may be improved after CPAP [continuous positive airway pressure].”

Several factors have been identified as playing a role in recurrent PE, including cancer, continued estrogen use, vena cava filters, high post-anticoagulation D-dimer, male gender, and obesity.

The current study suggested that OSA is an independent risk factor for recurrent PE, even after adjusting for several factors, including body mass index. OSA is a common problem among obese people, and the researchers assert that the risk of recurrent PE that is attributed to obesity might be partially related to OSA.

“Obesity is associated with sedentarism and venous stasis, and it has also been related to impaired fibrinolysis and high concentrations of clotting factors that might lead to a prothrombotic state that can further increase because obesity is associated with high estrogen levels and chronic low-grade inflammation,” Dr Alonso-Fernández said.

“It is tempting to speculate that OSA and obesity may additively or synergistically lead to upregulation of procoagulant activity that may intensify the risk of PE recurrence.”

Dr Alonso-Fernández and his colleagues believe that knowing OSA is an independent risk factor for recurrent PE can help physicians better understand treatment options. CPAP use is a proven intervention for OSA, and patients with OSA may need to stay on anticoagulation therapy longer to reduce their risk for another PE.

“Given the high prevalence of OSA in patients with PE, the procoagulable state induced by the intermittent hypoxia, and the risk for PE recurrence, the potential of CPAP and/or extend oral anticoagulation to reduce PE recurrence and mortality in patients with PE and OSA clearly warrants further study,” Dr Alonso-Fernández concluded.

Red blood cells

Having iron deficiency anemia (IDA) may increase a person’s risk of hearing loss, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.

The study indicated that adults with IDA had nearly twice the risk of sensorineural hearing loss and more than twice the risk of combined hearing loss as adults without IDA.

Researchers said the goals of future studies will be to better understand the association between IDA and hearing loss and determine whether promptly diagnosing and treating IDA may have a positive effect on the overall health of adults with hearing loss.

For this study, Kathleen M. Schieffer, of the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, and her colleagues examined data from deidentified electronic medical records.

The data encompassed 305,339 adults. They had a mean age of 50.1 (range, 21 to 90), and 43% were male.

The prevalence of IDA in this population was 0.7%.

There was a 1.6% prevalence of combined hearing loss, which was defined as any combination of conductive hearing loss (due to problems with the bones of the middle ear), sensorineural hearing loss (when there is damage to the cochlea or to the nerve pathways from the inner ear to the brain), deafness, and unspecified hearing loss.

Both sensorineural hearing loss and combined hearing loss were significantly associated with IDA.

Sensorineural hearing loss was present in 1.1% of individuals with IDA (P=0.005), and combined hearing loss was present in 3.4% of individuals with IDA (P<0.001).

Logistic regression analysis showed increased odds of sensorineural hearing loss and combined hearing loss among adults with IDA.

The odds ratio (adjusted for sex) was 1.82 for sensorineural hearing loss and 2.41 for combined hearing loss.

Red blood cells

Having iron deficiency anemia (IDA) may increase a person’s risk of hearing loss, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.

The study indicated that adults with IDA had nearly twice the risk of sensorineural hearing loss and more than twice the risk of combined hearing loss as adults without IDA.

Researchers said the goals of future studies will be to better understand the association between IDA and hearing loss and determine whether promptly diagnosing and treating IDA may have a positive effect on the overall health of adults with hearing loss.

For this study, Kathleen M. Schieffer, of the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, and her colleagues examined data from deidentified electronic medical records.

The data encompassed 305,339 adults. They had a mean age of 50.1 (range, 21 to 90), and 43% were male.

The prevalence of IDA in this population was 0.7%.

There was a 1.6% prevalence of combined hearing loss, which was defined as any combination of conductive hearing loss (due to problems with the bones of the middle ear), sensorineural hearing loss (when there is damage to the cochlea or to the nerve pathways from the inner ear to the brain), deafness, and unspecified hearing loss.

Both sensorineural hearing loss and combined hearing loss were significantly associated with IDA.

Sensorineural hearing loss was present in 1.1% of individuals with IDA (P=0.005), and combined hearing loss was present in 3.4% of individuals with IDA (P<0.001).

Logistic regression analysis showed increased odds of sensorineural hearing loss and combined hearing loss among adults with IDA.

The odds ratio (adjusted for sex) was 1.82 for sensorineural hearing loss and 2.41 for combined hearing loss.

Red blood cells

Having iron deficiency anemia (IDA) may increase a person’s risk of hearing loss, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.

The study indicated that adults with IDA had nearly twice the risk of sensorineural hearing loss and more than twice the risk of combined hearing loss as adults without IDA.

Researchers said the goals of future studies will be to better understand the association between IDA and hearing loss and determine whether promptly diagnosing and treating IDA may have a positive effect on the overall health of adults with hearing loss.

For this study, Kathleen M. Schieffer, of the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, and her colleagues examined data from deidentified electronic medical records.

The data encompassed 305,339 adults. They had a mean age of 50.1 (range, 21 to 90), and 43% were male.

The prevalence of IDA in this population was 0.7%.

There was a 1.6% prevalence of combined hearing loss, which was defined as any combination of conductive hearing loss (due to problems with the bones of the middle ear), sensorineural hearing loss (when there is damage to the cochlea or to the nerve pathways from the inner ear to the brain), deafness, and unspecified hearing loss.

Both sensorineural hearing loss and combined hearing loss were significantly associated with IDA.

Sensorineural hearing loss was present in 1.1% of individuals with IDA (P=0.005), and combined hearing loss was present in 3.4% of individuals with IDA (P<0.001).

Logistic regression analysis showed increased odds of sensorineural hearing loss and combined hearing loss among adults with IDA.

The odds ratio (adjusted for sex) was 1.82 for sensorineural hearing loss and 2.41 for combined hearing loss.

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Since 2011, HIV incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015, according to the European Centre for Disease Prevention and Control.

A study in the journal AIDS found that smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Since 2011, HIV incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015, according to the European Centre for Disease Prevention and Control.

A study in the journal AIDS found that smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Since 2011, HIV incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015, according to the European Centre for Disease Prevention and Control.

A study in the journal AIDS found that smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

NEW ORLEANS – A significant reduction in 30-day all-cause hospital readmissions after sleeve gastrectomy was accomplished through the first-ever joint national quality improvement collaboration between the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery, John M. Morton, MD, reported at Obesity Week 2016.

The quality improvement program, known as DROP, for Decreasing Readmissions through Opportunities Provided, was developed by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP). It was put to the test in a year-long study conducted in 128 nationally representative U.S. hospitals. The study involved a comparison of the participating hospitals’ 30-day all-cause readmission rates following bariatric surgery in the year prior to vs. the year after launch of the DROP project.

Bruce Jancin/Frontline Medical News

Of particular interest was the finding that the readmission rate following laparoscopic sleeve gastrectomy decreased from 4.02% to 3.54%, a 12% reduction. That’s an important finding, because sleeve gastrectomy is now by far the most frequently performed type of bariatric surgery in the United States. Indeed, it accounted for 54% of the estimated 196,000 bariatric surgery procedures performed in the country in 2015. Roux-en-Y gastric bypass was a distant second at 23%, followed by surgical revisions at 13.6%.

Moreover, the impact of the DROP initiative appeared to accelerate over time. The initiative as tested consisted of a comprehensive bundle of numerous components addressing preoperative, in-hospital, and postoperative care, and it took a while for hospitals to implement. The 30-day readmission rate following laparoscopic sleeve gastrectomy actually increased by 9.2% in the first 3 months following launch of the DROP initiative. But the readmission rate then took a U-turn, declining by 13.2% in the second quarter compared to the year-before rate, by 16.9% in the third quarter, and falling by 27.1% in the final 3 months of the study.

Mean length of stay for patients undergoing laparoscopic sleeve gastrectomy fell significantly, from 1.9 days pre-DROP to 1.79 days. The DROP intervention also achieved a significant decrease in length of stay for laparoscopic adjustable gastric banding, from 0.5 to 0.42 days.

The rate of readmission within 24 hours post discharge in laparoscopic sleeve gastrectomy patients decreased significantly by 19% after introduction of the DROP program. The trend was favorable, albeit not statistically significant, for the other two bariatric procedures studied.

Of note, hospitals in the two quartiles with the lowest preintervention 30-day all-cause readmission rates post bariatric surgery, with rates of 1.34% and 3.15%, respectively, didn’t derive any further reduction by participating in the DROP program. They already were performing many of the elements included in the intervention. But hospitals in the third quartile significantly improved their 30-day readmission rate from 4.84% to 4.13%, and those in the fourth quartile improved from 7.31% preintervention to 4.47% under the DROP program.

The program had no impact on postoperative leak rates or other surgical complications. However, patient satisfaction scores improved after introduction of the DROP intervention.

The preoperative components of the DROP readmission prevention bundle included a standardized 5-minute educational video featuring a surgeon, nutritionist, pharmacist, and psychologist or psychiatrist, with advice on key issues related to the upcoming operation. That’s also when the visits with the surgeon and a nutritionist were to be scheduled for within 30 days post surgery, and when the patient received phone numbers for the clinic and on-call surgeon in case questions arose later.

The in-hospital elements of the DROP intervention included provision of a clinical roadmap to guide patient expectations, as well as a nutritional consultation. The postoperative components included a day-after-discharge phone call from a nurse or physician assistant, a letter sent to the referring physician containing a discharge summary and recommendations, and a system to make sure that the scheduled follow-up appointments with the surgeon and nutritionist actually take place.

Since adherence to the various components of the DROP bundle varied from hospital to hospital, it was possible for Dr. Morton and his coinvestigators to determine which elements made the most difference in improving 30-day readmission rates. They found that the key difference makers were the nurse’s phone call on the day following discharge and the postoperative visits with the surgeon and nutritionist within the first several weeks.

Asked whether the study findings mean that hospitals that already have a 30-day all-cause readmission rate in the lower half of the national average don’t need to adopt the DROP program, Dr. Morton replied: “One size does not fit all. Maybe some centers don’t need to do all this.”

Thirty-day all-cause readmissions were selected for the first quality improvement project by the MBSAQIP in part because the Centers for Medicare & Medicaid Services has identified it as a priority area for surgery in general. Also, Dr. Morton was a coinvestigator in a study that found many readmissions after bariatric surgery are tied to preventable causes, including dietary indiscretions resulting in nausea and vomiting or dehydration, medication side effects, and inappropriate patient expectations (J Gastrointest Surg. 2016 Nov;20[11]:1797-1801).

“I think readmissions are a good outcome to study, because they incorporate many different elements of the patient experience, including patient safety and satisfaction. No surgeon wants to have a patient come back to the ER and be readmitted. And finally, there’s the cost,” Dr. Morton observed.

He noted that members of the MBSAQIP developed the DROP project in a highly efficient and cost-effective manner through a series of webinars and conference calls without the need for face-to-face meetings. The group plans to follow the same approach to its future quality improvement programs.

The DROP study was funded without industry support. Dr. Morton reported serving on advisory boards for Allurion and Novo Nordisk.

[email protected]

NEW ORLEANS – A significant reduction in 30-day all-cause hospital readmissions after sleeve gastrectomy was accomplished through the first-ever joint national quality improvement collaboration between the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery, John M. Morton, MD, reported at Obesity Week 2016.

The quality improvement program, known as DROP, for Decreasing Readmissions through Opportunities Provided, was developed by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP). It was put to the test in a year-long study conducted in 128 nationally representative U.S. hospitals. The study involved a comparison of the participating hospitals’ 30-day all-cause readmission rates following bariatric surgery in the year prior to vs. the year after launch of the DROP project.

Bruce Jancin/Frontline Medical News

Of particular interest was the finding that the readmission rate following laparoscopic sleeve gastrectomy decreased from 4.02% to 3.54%, a 12% reduction. That’s an important finding, because sleeve gastrectomy is now by far the most frequently performed type of bariatric surgery in the United States. Indeed, it accounted for 54% of the estimated 196,000 bariatric surgery procedures performed in the country in 2015. Roux-en-Y gastric bypass was a distant second at 23%, followed by surgical revisions at 13.6%.

Moreover, the impact of the DROP initiative appeared to accelerate over time. The initiative as tested consisted of a comprehensive bundle of numerous components addressing preoperative, in-hospital, and postoperative care, and it took a while for hospitals to implement. The 30-day readmission rate following laparoscopic sleeve gastrectomy actually increased by 9.2% in the first 3 months following launch of the DROP initiative. But the readmission rate then took a U-turn, declining by 13.2% in the second quarter compared to the year-before rate, by 16.9% in the third quarter, and falling by 27.1% in the final 3 months of the study.

Mean length of stay for patients undergoing laparoscopic sleeve gastrectomy fell significantly, from 1.9 days pre-DROP to 1.79 days. The DROP intervention also achieved a significant decrease in length of stay for laparoscopic adjustable gastric banding, from 0.5 to 0.42 days.

The rate of readmission within 24 hours post discharge in laparoscopic sleeve gastrectomy patients decreased significantly by 19% after introduction of the DROP program. The trend was favorable, albeit not statistically significant, for the other two bariatric procedures studied.

Of note, hospitals in the two quartiles with the lowest preintervention 30-day all-cause readmission rates post bariatric surgery, with rates of 1.34% and 3.15%, respectively, didn’t derive any further reduction by participating in the DROP program. They already were performing many of the elements included in the intervention. But hospitals in the third quartile significantly improved their 30-day readmission rate from 4.84% to 4.13%, and those in the fourth quartile improved from 7.31% preintervention to 4.47% under the DROP program.

The program had no impact on postoperative leak rates or other surgical complications. However, patient satisfaction scores improved after introduction of the DROP intervention.

The preoperative components of the DROP readmission prevention bundle included a standardized 5-minute educational video featuring a surgeon, nutritionist, pharmacist, and psychologist or psychiatrist, with advice on key issues related to the upcoming operation. That’s also when the visits with the surgeon and a nutritionist were to be scheduled for within 30 days post surgery, and when the patient received phone numbers for the clinic and on-call surgeon in case questions arose later.

The in-hospital elements of the DROP intervention included provision of a clinical roadmap to guide patient expectations, as well as a nutritional consultation. The postoperative components included a day-after-discharge phone call from a nurse or physician assistant, a letter sent to the referring physician containing a discharge summary and recommendations, and a system to make sure that the scheduled follow-up appointments with the surgeon and nutritionist actually take place.

Since adherence to the various components of the DROP bundle varied from hospital to hospital, it was possible for Dr. Morton and his coinvestigators to determine which elements made the most difference in improving 30-day readmission rates. They found that the key difference makers were the nurse’s phone call on the day following discharge and the postoperative visits with the surgeon and nutritionist within the first several weeks.

Asked whether the study findings mean that hospitals that already have a 30-day all-cause readmission rate in the lower half of the national average don’t need to adopt the DROP program, Dr. Morton replied: “One size does not fit all. Maybe some centers don’t need to do all this.”

Thirty-day all-cause readmissions were selected for the first quality improvement project by the MBSAQIP in part because the Centers for Medicare & Medicaid Services has identified it as a priority area for surgery in general. Also, Dr. Morton was a coinvestigator in a study that found many readmissions after bariatric surgery are tied to preventable causes, including dietary indiscretions resulting in nausea and vomiting or dehydration, medication side effects, and inappropriate patient expectations (J Gastrointest Surg. 2016 Nov;20[11]:1797-1801).

“I think readmissions are a good outcome to study, because they incorporate many different elements of the patient experience, including patient safety and satisfaction. No surgeon wants to have a patient come back to the ER and be readmitted. And finally, there’s the cost,” Dr. Morton observed.

He noted that members of the MBSAQIP developed the DROP project in a highly efficient and cost-effective manner through a series of webinars and conference calls without the need for face-to-face meetings. The group plans to follow the same approach to its future quality improvement programs.

The DROP study was funded without industry support. Dr. Morton reported serving on advisory boards for Allurion and Novo Nordisk.

[email protected]

NEW ORLEANS – A significant reduction in 30-day all-cause hospital readmissions after sleeve gastrectomy was accomplished through the first-ever joint national quality improvement collaboration between the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery, John M. Morton, MD, reported at Obesity Week 2016.

The quality improvement program, known as DROP, for Decreasing Readmissions through Opportunities Provided, was developed by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP). It was put to the test in a year-long study conducted in 128 nationally representative U.S. hospitals. The study involved a comparison of the participating hospitals’ 30-day all-cause readmission rates following bariatric surgery in the year prior to vs. the year after launch of the DROP project.

Bruce Jancin/Frontline Medical News

Of particular interest was the finding that the readmission rate following laparoscopic sleeve gastrectomy decreased from 4.02% to 3.54%, a 12% reduction. That’s an important finding, because sleeve gastrectomy is now by far the most frequently performed type of bariatric surgery in the United States. Indeed, it accounted for 54% of the estimated 196,000 bariatric surgery procedures performed in the country in 2015. Roux-en-Y gastric bypass was a distant second at 23%, followed by surgical revisions at 13.6%.

Moreover, the impact of the DROP initiative appeared to accelerate over time. The initiative as tested consisted of a comprehensive bundle of numerous components addressing preoperative, in-hospital, and postoperative care, and it took a while for hospitals to implement. The 30-day readmission rate following laparoscopic sleeve gastrectomy actually increased by 9.2% in the first 3 months following launch of the DROP initiative. But the readmission rate then took a U-turn, declining by 13.2% in the second quarter compared to the year-before rate, by 16.9% in the third quarter, and falling by 27.1% in the final 3 months of the study.

Mean length of stay for patients undergoing laparoscopic sleeve gastrectomy fell significantly, from 1.9 days pre-DROP to 1.79 days. The DROP intervention also achieved a significant decrease in length of stay for laparoscopic adjustable gastric banding, from 0.5 to 0.42 days.

The rate of readmission within 24 hours post discharge in laparoscopic sleeve gastrectomy patients decreased significantly by 19% after introduction of the DROP program. The trend was favorable, albeit not statistically significant, for the other two bariatric procedures studied.

Of note, hospitals in the two quartiles with the lowest preintervention 30-day all-cause readmission rates post bariatric surgery, with rates of 1.34% and 3.15%, respectively, didn’t derive any further reduction by participating in the DROP program. They already were performing many of the elements included in the intervention. But hospitals in the third quartile significantly improved their 30-day readmission rate from 4.84% to 4.13%, and those in the fourth quartile improved from 7.31% preintervention to 4.47% under the DROP program.

The program had no impact on postoperative leak rates or other surgical complications. However, patient satisfaction scores improved after introduction of the DROP intervention.

The preoperative components of the DROP readmission prevention bundle included a standardized 5-minute educational video featuring a surgeon, nutritionist, pharmacist, and psychologist or psychiatrist, with advice on key issues related to the upcoming operation. That’s also when the visits with the surgeon and a nutritionist were to be scheduled for within 30 days post surgery, and when the patient received phone numbers for the clinic and on-call surgeon in case questions arose later.

The in-hospital elements of the DROP intervention included provision of a clinical roadmap to guide patient expectations, as well as a nutritional consultation. The postoperative components included a day-after-discharge phone call from a nurse or physician assistant, a letter sent to the referring physician containing a discharge summary and recommendations, and a system to make sure that the scheduled follow-up appointments with the surgeon and nutritionist actually take place.

Since adherence to the various components of the DROP bundle varied from hospital to hospital, it was possible for Dr. Morton and his coinvestigators to determine which elements made the most difference in improving 30-day readmission rates. They found that the key difference makers were the nurse’s phone call on the day following discharge and the postoperative visits with the surgeon and nutritionist within the first several weeks.

Asked whether the study findings mean that hospitals that already have a 30-day all-cause readmission rate in the lower half of the national average don’t need to adopt the DROP program, Dr. Morton replied: “One size does not fit all. Maybe some centers don’t need to do all this.”

Thirty-day all-cause readmissions were selected for the first quality improvement project by the MBSAQIP in part because the Centers for Medicare & Medicaid Services has identified it as a priority area for surgery in general. Also, Dr. Morton was a coinvestigator in a study that found many readmissions after bariatric surgery are tied to preventable causes, including dietary indiscretions resulting in nausea and vomiting or dehydration, medication side effects, and inappropriate patient expectations (J Gastrointest Surg. 2016 Nov;20[11]:1797-1801).

“I think readmissions are a good outcome to study, because they incorporate many different elements of the patient experience, including patient safety and satisfaction. No surgeon wants to have a patient come back to the ER and be readmitted. And finally, there’s the cost,” Dr. Morton observed.

He noted that members of the MBSAQIP developed the DROP project in a highly efficient and cost-effective manner through a series of webinars and conference calls without the need for face-to-face meetings. The group plans to follow the same approach to its future quality improvement programs.

The DROP study was funded without industry support. Dr. Morton reported serving on advisory boards for Allurion and Novo Nordisk.

[email protected]

NEW ORLEANS – The first-ever analysis of medical malpractice closed claims involving bariatric surgeons spotlights key opportunities for improvement for the surgical specialty, Eric J. DeMaria, MD, declared at Obesity Week 2016.

Four of the nation’s largest medical malpractice insurance companies agreed to allow members of an American Society for Metabolic and Bariatric Surgery task force to make site visits to their corporate offices, where the surgeons sat in closed rooms to read and take notes on a total of 175 cases closed during 2010-2015. Those case notes were later shared with the full task force, which sifted through the details in order to identify common causal themes and opportunities for improvement, explained Dr. DeMaria, a bariatric surgeon in Suffolk, Va.

Bruce Jancin/Frontline Medical News

• The defense prevailed in 63% of cases. The mean expense for defending a lawsuit was $91,836.

• In the 37% of cases involving monetary awards, the mean figure was $293,500, ranging from $20,000 to $8 million.

• Mortality was involved in 35% of cases. Other notable complications resulting in lawsuits included leak in 18% of cases, bowel obstruction in 10%, bleeding in 5.3%, retained foreign body in 5.3%, and vascular injury from access in 4.4%.

• Preoperative issues such as informed consent and disclosure of information were rare.

• The defendant surgeon was a foreign medical graduate in 27.5% of cases, board certified in 75.9%, and only 43% of the hospitals where the surgery took place were accredited. All those figures are at odds with national norms.

• The panel determined that the cause of the complication was provider-related in 50% of cases, system-related in 29%, and intrinsic to the patient’s disease in 21%.

• In the panel’s view, the complication was preventable by the surgeon in nearly 60% of cases and not preventable by the surgeon in 20%, with the remainder of cases deemed impossible to judge.

• Better preoperative care would have prevented the complication in 20% of cases, in the panel’s view. Better postoperative care would have prevented the complication in 45%.

• Just over 5% of the malpractice claims involved nonstandard malabsorptive operations. “Some of them I’d never heard of before,” according to Dr. DeMaria.

• Care was deemed by the panel to be appropriate in roughly 21% of the malpractice cases and grossly negligent or incompetent in 8%. Twenty-three percent of lawsuits involved preventable error of such magnitude that significant coaching and instruction would be required in order to prevent a recurrence.

Dr. DeMaria observed that this analysis of closed claims suggests that in order to reduce future malpractice claims against bariatric surgeons, it makes sense to focus on a few key areas of practice where most of the serious problems occur.

“We found the same themes repeated over and over; for example, delays in diagnosis and treatment of leaks,” he said.

A substantial number of the lawsuits could have been prevented through the use of preinsufflation and optical trocars, or access away from the midline, he added.

But the number one theme to emerge from the lawsuit analysis was poor communication with the health care team and/or family. The experts on the task force considered the communication performance to be appropriate in only 20% of cases.

“I would emphasize the strong contribution of communication issues, and the strong contribution of coverage and handoff issues,” Dr. DeMaria said. “One example of an intervention that might be introduced would be to standardize the language used in the operating room just before you start to staple the stomach, very similar to what airplane pilots do in their communication. We saw cases over and over again where the anesthesia person was asked to take out the [nasogastric] tube didn’t realize that meant the esophageal stethoscope, too.

“We need to do a better job of not just making sure a coverage person has been identified, but actually communicating with that person and doing a standardized handoff procedure,” Dr. DeMaria continued. “Management of postoperative phone calls is another important area: Who answers the phone? What are they supposed to do with that information? How do you get patients to appropriate care?”

Discussant Ramsey M. Dallal, MD, congratulated Dr. DeMaria and his fellow ASMBS task force members on “the massive amount of work” entailed in this project. And he urged his colleagues to take to heart the lessons learned.

“People hear the word ‘malpractice’ and they get fearful. They think of lawyers and of being attacked. The reality is this is not a malpractice study; this is a patient safety study. A study like this is an excellent way to improve patient safety. The problem with registry data is we don’t get the details – and it’s the case details that point out problems and potential solutions,” said Dr. Dallal, director of bariatrics and vice chair of the department of surgery at the Einstein Healthcare Network in the Philadelphia area.

The closed claims analysis was conducted free of commercial support. Dr. DeMaria reported serving as a consultant to Covidien and Ethicon.

[email protected]
 

NEW ORLEANS – The first-ever analysis of medical malpractice closed claims involving bariatric surgeons spotlights key opportunities for improvement for the surgical specialty, Eric J. DeMaria, MD, declared at Obesity Week 2016.

Four of the nation’s largest medical malpractice insurance companies agreed to allow members of an American Society for Metabolic and Bariatric Surgery task force to make site visits to their corporate offices, where the surgeons sat in closed rooms to read and take notes on a total of 175 cases closed during 2010-2015. Those case notes were later shared with the full task force, which sifted through the details in order to identify common causal themes and opportunities for improvement, explained Dr. DeMaria, a bariatric surgeon in Suffolk, Va.

Bruce Jancin/Frontline Medical News

• The defense prevailed in 63% of cases. The mean expense for defending a lawsuit was $91,836.

• In the 37% of cases involving monetary awards, the mean figure was $293,500, ranging from $20,000 to $8 million.

• Mortality was involved in 35% of cases. Other notable complications resulting in lawsuits included leak in 18% of cases, bowel obstruction in 10%, bleeding in 5.3%, retained foreign body in 5.3%, and vascular injury from access in 4.4%.

• Preoperative issues such as informed consent and disclosure of information were rare.

• The defendant surgeon was a foreign medical graduate in 27.5% of cases, board certified in 75.9%, and only 43% of the hospitals where the surgery took place were accredited. All those figures are at odds with national norms.

• The panel determined that the cause of the complication was provider-related in 50% of cases, system-related in 29%, and intrinsic to the patient’s disease in 21%.

• In the panel’s view, the complication was preventable by the surgeon in nearly 60% of cases and not preventable by the surgeon in 20%, with the remainder of cases deemed impossible to judge.

• Better preoperative care would have prevented the complication in 20% of cases, in the panel’s view. Better postoperative care would have prevented the complication in 45%.

• Just over 5% of the malpractice claims involved nonstandard malabsorptive operations. “Some of them I’d never heard of before,” according to Dr. DeMaria.

• Care was deemed by the panel to be appropriate in roughly 21% of the malpractice cases and grossly negligent or incompetent in 8%. Twenty-three percent of lawsuits involved preventable error of such magnitude that significant coaching and instruction would be required in order to prevent a recurrence.

Dr. DeMaria observed that this analysis of closed claims suggests that in order to reduce future malpractice claims against bariatric surgeons, it makes sense to focus on a few key areas of practice where most of the serious problems occur.

“We found the same themes repeated over and over; for example, delays in diagnosis and treatment of leaks,” he said.

A substantial number of the lawsuits could have been prevented through the use of preinsufflation and optical trocars, or access away from the midline, he added.

But the number one theme to emerge from the lawsuit analysis was poor communication with the health care team and/or family. The experts on the task force considered the communication performance to be appropriate in only 20% of cases.

“I would emphasize the strong contribution of communication issues, and the strong contribution of coverage and handoff issues,” Dr. DeMaria said. “One example of an intervention that might be introduced would be to standardize the language used in the operating room just before you start to staple the stomach, very similar to what airplane pilots do in their communication. We saw cases over and over again where the anesthesia person was asked to take out the [nasogastric] tube didn’t realize that meant the esophageal stethoscope, too.

“We need to do a better job of not just making sure a coverage person has been identified, but actually communicating with that person and doing a standardized handoff procedure,” Dr. DeMaria continued. “Management of postoperative phone calls is another important area: Who answers the phone? What are they supposed to do with that information? How do you get patients to appropriate care?”

Discussant Ramsey M. Dallal, MD, congratulated Dr. DeMaria and his fellow ASMBS task force members on “the massive amount of work” entailed in this project. And he urged his colleagues to take to heart the lessons learned.

“People hear the word ‘malpractice’ and they get fearful. They think of lawyers and of being attacked. The reality is this is not a malpractice study; this is a patient safety study. A study like this is an excellent way to improve patient safety. The problem with registry data is we don’t get the details – and it’s the case details that point out problems and potential solutions,” said Dr. Dallal, director of bariatrics and vice chair of the department of surgery at the Einstein Healthcare Network in the Philadelphia area.

The closed claims analysis was conducted free of commercial support. Dr. DeMaria reported serving as a consultant to Covidien and Ethicon.

[email protected]
 

NEW ORLEANS – The first-ever analysis of medical malpractice closed claims involving bariatric surgeons spotlights key opportunities for improvement for the surgical specialty, Eric J. DeMaria, MD, declared at Obesity Week 2016.

Four of the nation’s largest medical malpractice insurance companies agreed to allow members of an American Society for Metabolic and Bariatric Surgery task force to make site visits to their corporate offices, where the surgeons sat in closed rooms to read and take notes on a total of 175 cases closed during 2010-2015. Those case notes were later shared with the full task force, which sifted through the details in order to identify common causal themes and opportunities for improvement, explained Dr. DeMaria, a bariatric surgeon in Suffolk, Va.

Bruce Jancin/Frontline Medical News

• The defense prevailed in 63% of cases. The mean expense for defending a lawsuit was $91,836.

• In the 37% of cases involving monetary awards, the mean figure was $293,500, ranging from $20,000 to $8 million.

• Mortality was involved in 35% of cases. Other notable complications resulting in lawsuits included leak in 18% of cases, bowel obstruction in 10%, bleeding in 5.3%, retained foreign body in 5.3%, and vascular injury from access in 4.4%.

• Preoperative issues such as informed consent and disclosure of information were rare.

• The defendant surgeon was a foreign medical graduate in 27.5% of cases, board certified in 75.9%, and only 43% of the hospitals where the surgery took place were accredited. All those figures are at odds with national norms.

• The panel determined that the cause of the complication was provider-related in 50% of cases, system-related in 29%, and intrinsic to the patient’s disease in 21%.

• In the panel’s view, the complication was preventable by the surgeon in nearly 60% of cases and not preventable by the surgeon in 20%, with the remainder of cases deemed impossible to judge.

• Better preoperative care would have prevented the complication in 20% of cases, in the panel’s view. Better postoperative care would have prevented the complication in 45%.

• Just over 5% of the malpractice claims involved nonstandard malabsorptive operations. “Some of them I’d never heard of before,” according to Dr. DeMaria.

• Care was deemed by the panel to be appropriate in roughly 21% of the malpractice cases and grossly negligent or incompetent in 8%. Twenty-three percent of lawsuits involved preventable error of such magnitude that significant coaching and instruction would be required in order to prevent a recurrence.

Dr. DeMaria observed that this analysis of closed claims suggests that in order to reduce future malpractice claims against bariatric surgeons, it makes sense to focus on a few key areas of practice where most of the serious problems occur.

“We found the same themes repeated over and over; for example, delays in diagnosis and treatment of leaks,” he said.

A substantial number of the lawsuits could have been prevented through the use of preinsufflation and optical trocars, or access away from the midline, he added.

But the number one theme to emerge from the lawsuit analysis was poor communication with the health care team and/or family. The experts on the task force considered the communication performance to be appropriate in only 20% of cases.

“I would emphasize the strong contribution of communication issues, and the strong contribution of coverage and handoff issues,” Dr. DeMaria said. “One example of an intervention that might be introduced would be to standardize the language used in the operating room just before you start to staple the stomach, very similar to what airplane pilots do in their communication. We saw cases over and over again where the anesthesia person was asked to take out the [nasogastric] tube didn’t realize that meant the esophageal stethoscope, too.

“We need to do a better job of not just making sure a coverage person has been identified, but actually communicating with that person and doing a standardized handoff procedure,” Dr. DeMaria continued. “Management of postoperative phone calls is another important area: Who answers the phone? What are they supposed to do with that information? How do you get patients to appropriate care?”

Discussant Ramsey M. Dallal, MD, congratulated Dr. DeMaria and his fellow ASMBS task force members on “the massive amount of work” entailed in this project. And he urged his colleagues to take to heart the lessons learned.

“People hear the word ‘malpractice’ and they get fearful. They think of lawyers and of being attacked. The reality is this is not a malpractice study; this is a patient safety study. A study like this is an excellent way to improve patient safety. The problem with registry data is we don’t get the details – and it’s the case details that point out problems and potential solutions,” said Dr. Dallal, director of bariatrics and vice chair of the department of surgery at the Einstein Healthcare Network in the Philadelphia area.

The closed claims analysis was conducted free of commercial support. Dr. DeMaria reported serving as a consultant to Covidien and Ethicon.

[email protected]