Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.

Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.

In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.

Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).

Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).

Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.

Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.

Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.

In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.

Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).

Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).

Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.

Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.

Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.

In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.

Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).

Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).

Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.

SAN DIEGO – Rough materials used for orthopedic implants, such as cobalt chromium and titanium, increased bacterial adherence, while smoother materials such as stainless steel did not, results from an image analysis demonstrated.

“In light of these results, it is important to question why we utilize the types of materials we use for various orthopedic procedures,” Dioscaris R. Garcia, Ph.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “There was no one-size-fits-all material to minimize adherence per the findings of this study, but the findings may suggest that having a smoother surface may minimize the ability of bacterial pathogens to adhere to the surface.”

He characterized the topic of bacterial adherence to orthopedic implants as “an issue of great interest due to how little is known about the biological implications of the materials utilized. The most researched of these materials is titanium, which is touted for its biocompatibility. This study aims to provide a base and a glimpse into how the most commonly utilized orthopedic-relevant materials interact with some of the most commonly encountered pathogens.”

For the study, Dr. Garcia, a molecular pharmacologist at Rhode Island Hospital in Providence, Dr. Alan H. Daniels, an orthopedic surgeon at the hospital, and their associates used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens (methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative Staphylococcus epidermidis, multidrug-resistant Acinetobacter baumannii, Propionibacterium acnes, and vancomycin-resistant Enterococcus faecalis) on five commonly used spinal implant materials (titanium, titanium alloy, stainless steel, cobalt chromium, and polyetherether ketone). The samples were fixed and dehydrated via ethanol dehydration gradient and critical point drying.

The researchers found that some pathogens, such as vancomycin-resistant E. faecalis and multidrug-resistant A. baumannii, were more likely to adhere to more textured materials such as cobalt chromium and titanium, compared with smoother materials such as stainless steel. “Additionally, the findings suggest that the microtopography of these materials may be the driving force behind the adherence of pathogens on the materials themselves,” Dr. Garcia said. Compared with smoother, polished materials, he explained, the rougher materials were more likely to harbor dense proliferation of bacterial pathogens, which could be characterized as biofilms.

“This study has been successful in providing a platform for future studies to build upon and expand to study additional parameters and statistical tools to give further insight into additional driving forces behind adherence and means for improvement of material design,” Dr. Garcia concluded.

Dr. Christopher T. Born, head of the Diane N. Weiss Center for Orthopedic Trauma Research at Rhode Island Hospital, was the study’s principal investigator. The study was supported by Stryker Corp.*

*Correction, 9/19/2015: Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.

[email protected]

SAN DIEGO – Rough materials used for orthopedic implants, such as cobalt chromium and titanium, increased bacterial adherence, while smoother materials such as stainless steel did not, results from an image analysis demonstrated.

“In light of these results, it is important to question why we utilize the types of materials we use for various orthopedic procedures,” Dioscaris R. Garcia, Ph.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “There was no one-size-fits-all material to minimize adherence per the findings of this study, but the findings may suggest that having a smoother surface may minimize the ability of bacterial pathogens to adhere to the surface.”

He characterized the topic of bacterial adherence to orthopedic implants as “an issue of great interest due to how little is known about the biological implications of the materials utilized. The most researched of these materials is titanium, which is touted for its biocompatibility. This study aims to provide a base and a glimpse into how the most commonly utilized orthopedic-relevant materials interact with some of the most commonly encountered pathogens.”

For the study, Dr. Garcia, a molecular pharmacologist at Rhode Island Hospital in Providence, Dr. Alan H. Daniels, an orthopedic surgeon at the hospital, and their associates used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens (methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative Staphylococcus epidermidis, multidrug-resistant Acinetobacter baumannii, Propionibacterium acnes, and vancomycin-resistant Enterococcus faecalis) on five commonly used spinal implant materials (titanium, titanium alloy, stainless steel, cobalt chromium, and polyetherether ketone). The samples were fixed and dehydrated via ethanol dehydration gradient and critical point drying.

The researchers found that some pathogens, such as vancomycin-resistant E. faecalis and multidrug-resistant A. baumannii, were more likely to adhere to more textured materials such as cobalt chromium and titanium, compared with smoother materials such as stainless steel. “Additionally, the findings suggest that the microtopography of these materials may be the driving force behind the adherence of pathogens on the materials themselves,” Dr. Garcia said. Compared with smoother, polished materials, he explained, the rougher materials were more likely to harbor dense proliferation of bacterial pathogens, which could be characterized as biofilms.

“This study has been successful in providing a platform for future studies to build upon and expand to study additional parameters and statistical tools to give further insight into additional driving forces behind adherence and means for improvement of material design,” Dr. Garcia concluded.

Dr. Christopher T. Born, head of the Diane N. Weiss Center for Orthopedic Trauma Research at Rhode Island Hospital, was the study’s principal investigator. The study was supported by Stryker Corp.*

*Correction, 9/19/2015: Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.

[email protected]

SAN DIEGO – Rough materials used for orthopedic implants, such as cobalt chromium and titanium, increased bacterial adherence, while smoother materials such as stainless steel did not, results from an image analysis demonstrated.

“In light of these results, it is important to question why we utilize the types of materials we use for various orthopedic procedures,” Dioscaris R. Garcia, Ph.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “There was no one-size-fits-all material to minimize adherence per the findings of this study, but the findings may suggest that having a smoother surface may minimize the ability of bacterial pathogens to adhere to the surface.”

He characterized the topic of bacterial adherence to orthopedic implants as “an issue of great interest due to how little is known about the biological implications of the materials utilized. The most researched of these materials is titanium, which is touted for its biocompatibility. This study aims to provide a base and a glimpse into how the most commonly utilized orthopedic-relevant materials interact with some of the most commonly encountered pathogens.”

For the study, Dr. Garcia, a molecular pharmacologist at Rhode Island Hospital in Providence, Dr. Alan H. Daniels, an orthopedic surgeon at the hospital, and their associates used scanning electron microscopy and confocal laser scanning microscopy to evaluate the adherence pattern, density, and propagation of six commonly encountered bacterial pathogens (methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, coagulase-negative Staphylococcus epidermidis, multidrug-resistant Acinetobacter baumannii, Propionibacterium acnes, and vancomycin-resistant Enterococcus faecalis) on five commonly used spinal implant materials (titanium, titanium alloy, stainless steel, cobalt chromium, and polyetherether ketone). The samples were fixed and dehydrated via ethanol dehydration gradient and critical point drying.

The researchers found that some pathogens, such as vancomycin-resistant E. faecalis and multidrug-resistant A. baumannii, were more likely to adhere to more textured materials such as cobalt chromium and titanium, compared with smoother materials such as stainless steel. “Additionally, the findings suggest that the microtopography of these materials may be the driving force behind the adherence of pathogens on the materials themselves,” Dr. Garcia said. Compared with smoother, polished materials, he explained, the rougher materials were more likely to harbor dense proliferation of bacterial pathogens, which could be characterized as biofilms.

“This study has been successful in providing a platform for future studies to build upon and expand to study additional parameters and statistical tools to give further insight into additional driving forces behind adherence and means for improvement of material design,” Dr. Garcia concluded.

Dr. Christopher T. Born, head of the Diane N. Weiss Center for Orthopedic Trauma Research at Rhode Island Hospital, was the study’s principal investigator. The study was supported by Stryker Corp.*

*Correction, 9/19/2015: Dr. Born is a consultant for Stryker. He also has stock ownership in Biointraface, does consulting for the company, and is a member of its board.

[email protected]

STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.

This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).

The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).

Sara Freeman/Frontline Medical News

Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.

“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”

Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.

So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.

Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”

Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”

EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.

Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).

Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.

The key secondary outcome of the trial was a composite of the primary outcome plus hospitalization for unstable angina. However, no significant difference for superiority was seen between the groups (P = .008, P less than .001 for noninferiority).

“I am here because of the importance of this,” said Dr. Andrew Boulton outgoing president of the EASD and professor of medicine at the University of Manchester, England, who introduced the EASD-sponsored symposium where the results were revealed.

In an interview, Dr. Boulton said it “looks promising.”

The results were presented by the senior authors of the study and independently commented upon afterward by the EASD-invited discussant Dr. Hertzel Gerstein of McMaster University and Hamilton (Ont.) Health Sciences. “Without question, the EMPA-REG investigators have designed a good protocol, and they have answered a very important question,” he said. “This was a well done and very important study,” he noted.

Dr. Gerstein observed that empagliflozin “clearly reduces CV death and heart failure hospitalization,” an effect that starts to appear after just 3 months. This early effect is unlikely to be down to just glucose-lowering, antihypertensive effects of the background medications used, or weight loss because of this speed of onset. It could be due to the diuretic properties of the SLGT2 inhibitor or, maybe more likely, a combination of beneficial effects. “It is probably a class effect,” he said, “but you can never be certain.”

Sara Freeman/Frontline Medical News

Based on the findings, he suggested that empagliflozin “may become first-line treatment for middle aged people with type 2 diabetes at risk for CV outcomes” and that the trial had “identified a treatment that could save many lives and reduce much suffering.” The results were unexpected and will open up new avenues for research.

Dr. Bernard Zinman of Mount Sinai Hospital, Toronto, lead author for the trial, said during the session that the number of patients needed to be treated with empagliflozin for 3 years to prevent one cardiovascular death was 39. By comparison, he said, the numbers needed to treat with simvastatin or ramipril for 5 years were 30 and 59, respectively.

Good safety was observed in the trial, reported Dr. David Fitchett, fellow author. Dr. Fitchett, a cardiologist at St Michael’s Hospital and associate professor at the University of Toronto, noted that overall rates of both any adverse events and serious adverse events were similar between the groups, with the exception of genital infections that were mainly mycoses and mostly in women.

Rates of confirmed hypoglycemic events were similar, he said, and there was no increase in diabetic ketoacidosis or bone fracture, which have been the focus of recent warnings issued by the Food and Drug Administration with regard to SLGT2 inhibitors.

Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.

STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.

This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).

The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).

Sara Freeman/Frontline Medical News

Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.

“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”

Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.

So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.

Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”

Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”

EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.

Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).

Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.

The key secondary outcome of the trial was a composite of the primary outcome plus hospitalization for unstable angina. However, no significant difference for superiority was seen between the groups (P = .008, P less than .001 for noninferiority).

“I am here because of the importance of this,” said Dr. Andrew Boulton outgoing president of the EASD and professor of medicine at the University of Manchester, England, who introduced the EASD-sponsored symposium where the results were revealed.

In an interview, Dr. Boulton said it “looks promising.”

The results were presented by the senior authors of the study and independently commented upon afterward by the EASD-invited discussant Dr. Hertzel Gerstein of McMaster University and Hamilton (Ont.) Health Sciences. “Without question, the EMPA-REG investigators have designed a good protocol, and they have answered a very important question,” he said. “This was a well done and very important study,” he noted.

Dr. Gerstein observed that empagliflozin “clearly reduces CV death and heart failure hospitalization,” an effect that starts to appear after just 3 months. This early effect is unlikely to be down to just glucose-lowering, antihypertensive effects of the background medications used, or weight loss because of this speed of onset. It could be due to the diuretic properties of the SLGT2 inhibitor or, maybe more likely, a combination of beneficial effects. “It is probably a class effect,” he said, “but you can never be certain.”

Sara Freeman/Frontline Medical News

Based on the findings, he suggested that empagliflozin “may become first-line treatment for middle aged people with type 2 diabetes at risk for CV outcomes” and that the trial had “identified a treatment that could save many lives and reduce much suffering.” The results were unexpected and will open up new avenues for research.

Dr. Bernard Zinman of Mount Sinai Hospital, Toronto, lead author for the trial, said during the session that the number of patients needed to be treated with empagliflozin for 3 years to prevent one cardiovascular death was 39. By comparison, he said, the numbers needed to treat with simvastatin or ramipril for 5 years were 30 and 59, respectively.

Good safety was observed in the trial, reported Dr. David Fitchett, fellow author. Dr. Fitchett, a cardiologist at St Michael’s Hospital and associate professor at the University of Toronto, noted that overall rates of both any adverse events and serious adverse events were similar between the groups, with the exception of genital infections that were mainly mycoses and mostly in women.

Rates of confirmed hypoglycemic events were similar, he said, and there was no increase in diabetic ketoacidosis or bone fracture, which have been the focus of recent warnings issued by the Food and Drug Administration with regard to SLGT2 inhibitors.

Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.

STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.

This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).

The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).

Sara Freeman/Frontline Medical News

Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.

“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”

Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.

So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.

Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”

Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”

EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.

Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).

Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.

The key secondary outcome of the trial was a composite of the primary outcome plus hospitalization for unstable angina. However, no significant difference for superiority was seen between the groups (P = .008, P less than .001 for noninferiority).

“I am here because of the importance of this,” said Dr. Andrew Boulton outgoing president of the EASD and professor of medicine at the University of Manchester, England, who introduced the EASD-sponsored symposium where the results were revealed.

In an interview, Dr. Boulton said it “looks promising.”

The results were presented by the senior authors of the study and independently commented upon afterward by the EASD-invited discussant Dr. Hertzel Gerstein of McMaster University and Hamilton (Ont.) Health Sciences. “Without question, the EMPA-REG investigators have designed a good protocol, and they have answered a very important question,” he said. “This was a well done and very important study,” he noted.

Dr. Gerstein observed that empagliflozin “clearly reduces CV death and heart failure hospitalization,” an effect that starts to appear after just 3 months. This early effect is unlikely to be down to just glucose-lowering, antihypertensive effects of the background medications used, or weight loss because of this speed of onset. It could be due to the diuretic properties of the SLGT2 inhibitor or, maybe more likely, a combination of beneficial effects. “It is probably a class effect,” he said, “but you can never be certain.”

Sara Freeman/Frontline Medical News

Based on the findings, he suggested that empagliflozin “may become first-line treatment for middle aged people with type 2 diabetes at risk for CV outcomes” and that the trial had “identified a treatment that could save many lives and reduce much suffering.” The results were unexpected and will open up new avenues for research.

Dr. Bernard Zinman of Mount Sinai Hospital, Toronto, lead author for the trial, said during the session that the number of patients needed to be treated with empagliflozin for 3 years to prevent one cardiovascular death was 39. By comparison, he said, the numbers needed to treat with simvastatin or ramipril for 5 years were 30 and 59, respectively.

Good safety was observed in the trial, reported Dr. David Fitchett, fellow author. Dr. Fitchett, a cardiologist at St Michael’s Hospital and associate professor at the University of Toronto, noted that overall rates of both any adverse events and serious adverse events were similar between the groups, with the exception of genital infections that were mainly mycoses and mostly in women.

Rates of confirmed hypoglycemic events were similar, he said, and there was no increase in diabetic ketoacidosis or bone fracture, which have been the focus of recent warnings issued by the Food and Drug Administration with regard to SLGT2 inhibitors.

Boehringer Ingelheim and Eli Lilly funded the study. Dr. Sattar disclosed ties with Amgen, Sanofi, and Merck Sharp & Dohme. Dr. Sattar and Dr. Rydén were on the panel of experts invited to talk about the study in a satellite symposium sponsored by Boehringer Ingelheim and Eli Lilly. Dr. Boulton did not report having disclosures. Dr. Gerstein reported ties with Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Abbot, Bayer, Berlin Chemie, Roche, GSK, Amgen, and Kaneq Bioscience. Dr. Zinman disclosed ties with Boehringer Ingelheim. Dr. Fitchett disclosed consulting for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Merck Sharp & Dohme. Dr. Inzucchi disclosed ties with Boehringer Ingelheim, Merck, Janssen, Novo Nordisk, Sanofi/Regeron, Intarcia, Lexicon, Paxel, Takeda, and Eli Lilly. He acknowledged CME-funding to Yale University from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbot, Merck Sharp & Dohme, and Sanofi.

Registered letters are a pain in the butt.

In the grand scheme of things, they’re a minor nuisance, albeit necessary. Documentation is everything is this job.

So here and there, I stop by the post office on the way home. It’s almost $7 a letter now, so maybe $28 a month, $336 a year. Not a huge sum.

But it’s annoying. It’s money that could be used for other expenses, and 80% of the time, the reason I have to do it is someone isn’t returning a call.

I suspect the scenario is similar in your practice. Patients are due for a follow-up MRI, MR angiography, labs, or whatever. So your staff calls them a few times. If they don’t return the call, you mail them letters. If they don’t respond, you send them registered letters. That way, even if they never respond, you can document that someone at that address got the letter.

Patients have several chances to answer the phone or call my office to schedule or refuse the test before I resort to the letter. But, for whatever reasons, sometimes they ignore them, leaving me with a trip to the post office and $7 down.

About one-third of the time we still never hear back, which is fine if that’s what they want. As long as I get the signed card, I don’t mind. Another third of the time they call to schedule, often wondering why I had to resort to a registered letter. “I got your call and other letter, so why did you send that?” And the others? They call us, usually to say they don’t want the test, or just angry that we sent them a registered letter, or (my favorite) to accuse us of harassing them. Because, you know, I enjoy making the extra trip and cost just to do that.

Unfortunately, the consequences of not doing this are (potentially) worse. In most cases, nothing would happen. But, sooner or later you risk having a medical disaster possibly occur because of whatever you were following. And then, correctly or not, they may blame you and call a lawyer. While it’s not guaranteed protection, it’s helpful to be able to prove, with a signed card, that they got your letter and chose to ignore it.

Is that worth the $7 and extra stop? Absolutely. But still, I wish people would be kind enough to just answer the phone or return a call. If they don’t want to do the study, I’m not offended. I just don’t like wasting time and money because someone won’t pick up a phone.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Registered letters are a pain in the butt.

In the grand scheme of things, they’re a minor nuisance, albeit necessary. Documentation is everything is this job.

So here and there, I stop by the post office on the way home. It’s almost $7 a letter now, so maybe $28 a month, $336 a year. Not a huge sum.

But it’s annoying. It’s money that could be used for other expenses, and 80% of the time, the reason I have to do it is someone isn’t returning a call.

I suspect the scenario is similar in your practice. Patients are due for a follow-up MRI, MR angiography, labs, or whatever. So your staff calls them a few times. If they don’t return the call, you mail them letters. If they don’t respond, you send them registered letters. That way, even if they never respond, you can document that someone at that address got the letter.

Patients have several chances to answer the phone or call my office to schedule or refuse the test before I resort to the letter. But, for whatever reasons, sometimes they ignore them, leaving me with a trip to the post office and $7 down.

About one-third of the time we still never hear back, which is fine if that’s what they want. As long as I get the signed card, I don’t mind. Another third of the time they call to schedule, often wondering why I had to resort to a registered letter. “I got your call and other letter, so why did you send that?” And the others? They call us, usually to say they don’t want the test, or just angry that we sent them a registered letter, or (my favorite) to accuse us of harassing them. Because, you know, I enjoy making the extra trip and cost just to do that.

Unfortunately, the consequences of not doing this are (potentially) worse. In most cases, nothing would happen. But, sooner or later you risk having a medical disaster possibly occur because of whatever you were following. And then, correctly or not, they may blame you and call a lawyer. While it’s not guaranteed protection, it’s helpful to be able to prove, with a signed card, that they got your letter and chose to ignore it.

Is that worth the $7 and extra stop? Absolutely. But still, I wish people would be kind enough to just answer the phone or return a call. If they don’t want to do the study, I’m not offended. I just don’t like wasting time and money because someone won’t pick up a phone.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Registered letters are a pain in the butt.

In the grand scheme of things, they’re a minor nuisance, albeit necessary. Documentation is everything is this job.

So here and there, I stop by the post office on the way home. It’s almost $7 a letter now, so maybe $28 a month, $336 a year. Not a huge sum.

But it’s annoying. It’s money that could be used for other expenses, and 80% of the time, the reason I have to do it is someone isn’t returning a call.

I suspect the scenario is similar in your practice. Patients are due for a follow-up MRI, MR angiography, labs, or whatever. So your staff calls them a few times. If they don’t return the call, you mail them letters. If they don’t respond, you send them registered letters. That way, even if they never respond, you can document that someone at that address got the letter.

Patients have several chances to answer the phone or call my office to schedule or refuse the test before I resort to the letter. But, for whatever reasons, sometimes they ignore them, leaving me with a trip to the post office and $7 down.

About one-third of the time we still never hear back, which is fine if that’s what they want. As long as I get the signed card, I don’t mind. Another third of the time they call to schedule, often wondering why I had to resort to a registered letter. “I got your call and other letter, so why did you send that?” And the others? They call us, usually to say they don’t want the test, or just angry that we sent them a registered letter, or (my favorite) to accuse us of harassing them. Because, you know, I enjoy making the extra trip and cost just to do that.

Unfortunately, the consequences of not doing this are (potentially) worse. In most cases, nothing would happen. But, sooner or later you risk having a medical disaster possibly occur because of whatever you were following. And then, correctly or not, they may blame you and call a lawyer. While it’s not guaranteed protection, it’s helpful to be able to prove, with a signed card, that they got your letter and chose to ignore it.

Is that worth the $7 and extra stop? Absolutely. But still, I wish people would be kind enough to just answer the phone or return a call. If they don’t want to do the study, I’m not offended. I just don’t like wasting time and money because someone won’t pick up a phone.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

LAS VEGAS – Choice of damage control resuscitation – plasma-platelet-red blood cell ratio of either 1:1:1 or 1:1:2 – did not affect whether severely injured patients required an emergency laparotomy, nor did it affect time to laparotomy or survival following laparotomy, according to findings from the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial.

“We were unable to detect significant effects of damage control resuscitation on the frequency and time to emergency laparotomy, outcomes, disposition at 30 days, or main endpoint survival,” said Dr. Vicente J. Undurraga Perl of the Oregon Health and Science University, Portland. The lack of a difference between the treatment groups with respect to emergency laparotomy and 30-day survival may be a result of the low overall mortality of 23% and to the study being underpowered to detect a difference between the groups.

The PROPPR trial demonstrated that damage control resuscitation, defined as “a massive transfusion strategy targeting a balanced delivery of plasma-platelet-RBC in a ratio of 1:1:1,” allows earlier achievement of hemostasis in a greater number of severely injured patients than does a 1:1:2 ratio. A corresponding reduction in deaths because of exsanguination was observed in the study subjects, who were enrolled from 12 level-1 trauma centers in North America, where they presented with severe injuries.

Of 680 patients who had severe injuries and were predicted to require massive transfusions, 613 underwent a surgical procedure and 397 underwent a laparotomy. Of the latter, 346 were emergency laparotomies. Of those who received damage control resuscitation using the 1:1:1 ratio, 52% underwent emergency laparotomy (defined as laparotomy within 90 minutes of arrival at a trauma center). Of those who received the 1:1:2 ratio, 50% underwent emergency laparotomy. The difference between the groups was not statistically significant, Dr. Perl reported at the annual meeting of the American Association for the Surgery of Trauma.

The median time to laparotomy was 28 minutes in both groups, and the proportions of patients who survived to 3 hours, 6 hours, 24 hours, and 30 days also were similar in the two groups. For example, 88% and 85% of those in the 1:1:1 and 1:1:2 groups, respectively, survived to 24 hours; 82% and 77%, respectively, survived to 30 days, he said.

There was no overall difference in mortality between the groups (hazard ratio, 0.78), nor was there a difference in survival by study site, he noted.

Dr. Perl reported having no disclosures.

[email protected]

LAS VEGAS – Choice of damage control resuscitation – plasma-platelet-red blood cell ratio of either 1:1:1 or 1:1:2 – did not affect whether severely injured patients required an emergency laparotomy, nor did it affect time to laparotomy or survival following laparotomy, according to findings from the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial.

“We were unable to detect significant effects of damage control resuscitation on the frequency and time to emergency laparotomy, outcomes, disposition at 30 days, or main endpoint survival,” said Dr. Vicente J. Undurraga Perl of the Oregon Health and Science University, Portland. The lack of a difference between the treatment groups with respect to emergency laparotomy and 30-day survival may be a result of the low overall mortality of 23% and to the study being underpowered to detect a difference between the groups.

The PROPPR trial demonstrated that damage control resuscitation, defined as “a massive transfusion strategy targeting a balanced delivery of plasma-platelet-RBC in a ratio of 1:1:1,” allows earlier achievement of hemostasis in a greater number of severely injured patients than does a 1:1:2 ratio. A corresponding reduction in deaths because of exsanguination was observed in the study subjects, who were enrolled from 12 level-1 trauma centers in North America, where they presented with severe injuries.

Of 680 patients who had severe injuries and were predicted to require massive transfusions, 613 underwent a surgical procedure and 397 underwent a laparotomy. Of the latter, 346 were emergency laparotomies. Of those who received damage control resuscitation using the 1:1:1 ratio, 52% underwent emergency laparotomy (defined as laparotomy within 90 minutes of arrival at a trauma center). Of those who received the 1:1:2 ratio, 50% underwent emergency laparotomy. The difference between the groups was not statistically significant, Dr. Perl reported at the annual meeting of the American Association for the Surgery of Trauma.

The median time to laparotomy was 28 minutes in both groups, and the proportions of patients who survived to 3 hours, 6 hours, 24 hours, and 30 days also were similar in the two groups. For example, 88% and 85% of those in the 1:1:1 and 1:1:2 groups, respectively, survived to 24 hours; 82% and 77%, respectively, survived to 30 days, he said.

There was no overall difference in mortality between the groups (hazard ratio, 0.78), nor was there a difference in survival by study site, he noted.

Dr. Perl reported having no disclosures.

[email protected]

LAS VEGAS – Choice of damage control resuscitation – plasma-platelet-red blood cell ratio of either 1:1:1 or 1:1:2 – did not affect whether severely injured patients required an emergency laparotomy, nor did it affect time to laparotomy or survival following laparotomy, according to findings from the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial.

“We were unable to detect significant effects of damage control resuscitation on the frequency and time to emergency laparotomy, outcomes, disposition at 30 days, or main endpoint survival,” said Dr. Vicente J. Undurraga Perl of the Oregon Health and Science University, Portland. The lack of a difference between the treatment groups with respect to emergency laparotomy and 30-day survival may be a result of the low overall mortality of 23% and to the study being underpowered to detect a difference between the groups.

The PROPPR trial demonstrated that damage control resuscitation, defined as “a massive transfusion strategy targeting a balanced delivery of plasma-platelet-RBC in a ratio of 1:1:1,” allows earlier achievement of hemostasis in a greater number of severely injured patients than does a 1:1:2 ratio. A corresponding reduction in deaths because of exsanguination was observed in the study subjects, who were enrolled from 12 level-1 trauma centers in North America, where they presented with severe injuries.

Of 680 patients who had severe injuries and were predicted to require massive transfusions, 613 underwent a surgical procedure and 397 underwent a laparotomy. Of the latter, 346 were emergency laparotomies. Of those who received damage control resuscitation using the 1:1:1 ratio, 52% underwent emergency laparotomy (defined as laparotomy within 90 minutes of arrival at a trauma center). Of those who received the 1:1:2 ratio, 50% underwent emergency laparotomy. The difference between the groups was not statistically significant, Dr. Perl reported at the annual meeting of the American Association for the Surgery of Trauma.

The median time to laparotomy was 28 minutes in both groups, and the proportions of patients who survived to 3 hours, 6 hours, 24 hours, and 30 days also were similar in the two groups. For example, 88% and 85% of those in the 1:1:1 and 1:1:2 groups, respectively, survived to 24 hours; 82% and 77%, respectively, survived to 30 days, he said.

There was no overall difference in mortality between the groups (hazard ratio, 0.78), nor was there a difference in survival by study site, he noted.

Dr. Perl reported having no disclosures.

[email protected]

“Have a nice time!”

I looked around, trying to tell where the piping, childish voice was coming from. I’d just swiped the barcode of my pass to the local lake I swim in every summer. There it was – the voice of one of the high school kids who works at the lake. She wore a wan smile.

I’ve been swimming at this lake for 35 years. No kid ever said a word to me before. “Have a good swim!” said a young man standing at the desk where, “All Children Under 12 Must Check In!”

Goodness me, I thought. The management consultants have made it to the lake.

You know who I mean. The ones who see to it that front-desk personnel always flash a bright smile and recite the corporate script. At the hardware store, the fast-food chain, the airline counter. Even the people in the auto dealer’s service department smile and murmur sweet nothings. They used to glare and growl, and make you feel like an idiot. “Whatsamattter, Bud? Dontcha know anything about cars?” Now it’s all politeness and smiles and “How may we help you, kind sir?”

And of course there’s the pharmacy. When I fill my prescription, the tech flashes a bright grin of welcome. Either that, or she has tetanus.

“Welcome to DrugTown!” she says. “May I have your name?”

I tell her. She retrieves the prescription. “Verify your address?” I do.

“Do you have a DrugTown Rewards Card?” she asks. I enter in my cellphone number, swipe my card, turn to leave.

“Be sound!” she says, still grinning. The DrugTown motto is: “Where Safe Meets Sound!”

It is easy to mock this sort of thing as formulaic and false. Insincere or not, smiling makes a difference. Some say you can actually get happier by making yourself smile. Whether that’s true or not, watching other people smile and make eye contact makes you feel good. Seeing them scowl and look away does the reverse.

This is true in doctors’ offices too. I learned this recently by being a patient.

I approached the front desk at my first visit. The lone receptionist was looking at some papers. I tried to get her attention. “Hello,” I said, “My name is ... ”

Still looking down, she shoved a clipboard across the counter. “Sign in,” she said. “And fill this out.” She handed me a sheaf of forms. “Leave it here when you’re done.” She was still looking away.

I sat in one of the waiting room chairs to work on the forms. I felt bad. As I watched the clerk ignore a succession of other patients, I asked myself why I felt so bad. First of all, it wasn’t personal; she was churlish to everyone. Second, what did this have to do with my visit? I was there to see the doctor, not his receptionist. Weren’t his skill and expertise what mattered?

True enough, but I still felt lousy. At later visits I took on the personal challenge of trying to force the clerk to make eye contact. I failed. In truth, her behavior colored my impression of the medical experience – mixed anyway – more than the medical outcome.

Sometimes I force myself to look at my own online reviews. The bad ones often focus on the alleged rudeness of my staff. It can be hard to tell from cranky patients whether their complaints are justified. But sometimes they are.

Management consultants know this. They teach employers that the customer experience has to do with more than the quality of the good or service provided. Even if the quarter-pounder is delicious, it may not taste that way if the burger-flipper is having a bad day and doesn’t know how to hide it.

So my office manager now trains our front-desk staff to be insistently cheery. This can be hard when patients are stacked three-deep, each with a form to scan, a credit card to swipe, a follow-up to book. But smile we have them do.

We don’t, however, have them recite a script when smiling. (“Make the scene! Wear sunscreen!”) We’re not up to that chapter in the customer-service handbook.

Who do you think we are? The town lake?

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. Write to him at [email protected].

“Have a nice time!”

I looked around, trying to tell where the piping, childish voice was coming from. I’d just swiped the barcode of my pass to the local lake I swim in every summer. There it was – the voice of one of the high school kids who works at the lake. She wore a wan smile.

I’ve been swimming at this lake for 35 years. No kid ever said a word to me before. “Have a good swim!” said a young man standing at the desk where, “All Children Under 12 Must Check In!”

Goodness me, I thought. The management consultants have made it to the lake.

You know who I mean. The ones who see to it that front-desk personnel always flash a bright smile and recite the corporate script. At the hardware store, the fast-food chain, the airline counter. Even the people in the auto dealer’s service department smile and murmur sweet nothings. They used to glare and growl, and make you feel like an idiot. “Whatsamattter, Bud? Dontcha know anything about cars?” Now it’s all politeness and smiles and “How may we help you, kind sir?”

And of course there’s the pharmacy. When I fill my prescription, the tech flashes a bright grin of welcome. Either that, or she has tetanus.

“Welcome to DrugTown!” she says. “May I have your name?”

I tell her. She retrieves the prescription. “Verify your address?” I do.

“Do you have a DrugTown Rewards Card?” she asks. I enter in my cellphone number, swipe my card, turn to leave.

“Be sound!” she says, still grinning. The DrugTown motto is: “Where Safe Meets Sound!”

It is easy to mock this sort of thing as formulaic and false. Insincere or not, smiling makes a difference. Some say you can actually get happier by making yourself smile. Whether that’s true or not, watching other people smile and make eye contact makes you feel good. Seeing them scowl and look away does the reverse.

This is true in doctors’ offices too. I learned this recently by being a patient.

I approached the front desk at my first visit. The lone receptionist was looking at some papers. I tried to get her attention. “Hello,” I said, “My name is ... ”

Still looking down, she shoved a clipboard across the counter. “Sign in,” she said. “And fill this out.” She handed me a sheaf of forms. “Leave it here when you’re done.” She was still looking away.

I sat in one of the waiting room chairs to work on the forms. I felt bad. As I watched the clerk ignore a succession of other patients, I asked myself why I felt so bad. First of all, it wasn’t personal; she was churlish to everyone. Second, what did this have to do with my visit? I was there to see the doctor, not his receptionist. Weren’t his skill and expertise what mattered?

True enough, but I still felt lousy. At later visits I took on the personal challenge of trying to force the clerk to make eye contact. I failed. In truth, her behavior colored my impression of the medical experience – mixed anyway – more than the medical outcome.

Sometimes I force myself to look at my own online reviews. The bad ones often focus on the alleged rudeness of my staff. It can be hard to tell from cranky patients whether their complaints are justified. But sometimes they are.

Management consultants know this. They teach employers that the customer experience has to do with more than the quality of the good or service provided. Even if the quarter-pounder is delicious, it may not taste that way if the burger-flipper is having a bad day and doesn’t know how to hide it.

So my office manager now trains our front-desk staff to be insistently cheery. This can be hard when patients are stacked three-deep, each with a form to scan, a credit card to swipe, a follow-up to book. But smile we have them do.

We don’t, however, have them recite a script when smiling. (“Make the scene! Wear sunscreen!”) We’re not up to that chapter in the customer-service handbook.

Who do you think we are? The town lake?

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. Write to him at [email protected].

“Have a nice time!”

I looked around, trying to tell where the piping, childish voice was coming from. I’d just swiped the barcode of my pass to the local lake I swim in every summer. There it was – the voice of one of the high school kids who works at the lake. She wore a wan smile.

I’ve been swimming at this lake for 35 years. No kid ever said a word to me before. “Have a good swim!” said a young man standing at the desk where, “All Children Under 12 Must Check In!”

Goodness me, I thought. The management consultants have made it to the lake.

You know who I mean. The ones who see to it that front-desk personnel always flash a bright smile and recite the corporate script. At the hardware store, the fast-food chain, the airline counter. Even the people in the auto dealer’s service department smile and murmur sweet nothings. They used to glare and growl, and make you feel like an idiot. “Whatsamattter, Bud? Dontcha know anything about cars?” Now it’s all politeness and smiles and “How may we help you, kind sir?”

And of course there’s the pharmacy. When I fill my prescription, the tech flashes a bright grin of welcome. Either that, or she has tetanus.

“Welcome to DrugTown!” she says. “May I have your name?”

I tell her. She retrieves the prescription. “Verify your address?” I do.

“Do you have a DrugTown Rewards Card?” she asks. I enter in my cellphone number, swipe my card, turn to leave.

“Be sound!” she says, still grinning. The DrugTown motto is: “Where Safe Meets Sound!”

It is easy to mock this sort of thing as formulaic and false. Insincere or not, smiling makes a difference. Some say you can actually get happier by making yourself smile. Whether that’s true or not, watching other people smile and make eye contact makes you feel good. Seeing them scowl and look away does the reverse.

This is true in doctors’ offices too. I learned this recently by being a patient.

I approached the front desk at my first visit. The lone receptionist was looking at some papers. I tried to get her attention. “Hello,” I said, “My name is ... ”

Still looking down, she shoved a clipboard across the counter. “Sign in,” she said. “And fill this out.” She handed me a sheaf of forms. “Leave it here when you’re done.” She was still looking away.

I sat in one of the waiting room chairs to work on the forms. I felt bad. As I watched the clerk ignore a succession of other patients, I asked myself why I felt so bad. First of all, it wasn’t personal; she was churlish to everyone. Second, what did this have to do with my visit? I was there to see the doctor, not his receptionist. Weren’t his skill and expertise what mattered?

True enough, but I still felt lousy. At later visits I took on the personal challenge of trying to force the clerk to make eye contact. I failed. In truth, her behavior colored my impression of the medical experience – mixed anyway – more than the medical outcome.

Sometimes I force myself to look at my own online reviews. The bad ones often focus on the alleged rudeness of my staff. It can be hard to tell from cranky patients whether their complaints are justified. But sometimes they are.

Management consultants know this. They teach employers that the customer experience has to do with more than the quality of the good or service provided. Even if the quarter-pounder is delicious, it may not taste that way if the burger-flipper is having a bad day and doesn’t know how to hide it.

So my office manager now trains our front-desk staff to be insistently cheery. This can be hard when patients are stacked three-deep, each with a form to scan, a credit card to swipe, a follow-up to book. But smile we have them do.

We don’t, however, have them recite a script when smiling. (“Make the scene! Wear sunscreen!”) We’re not up to that chapter in the customer-service handbook.

Who do you think we are? The town lake?

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. Write to him at [email protected].

Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.

Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi:10.1182/blood-2014-12-618025).

Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.

Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.

The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.

Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.

Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi:10.1182/blood-2014-12-618025).

Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.

Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.

The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.

Exosomes released by chronic lymphocytic leukemia (CLL) cells induce stromal cells to adopt a cancer-associated fibroblast phenotype, thereby creating a microenvironment conducive to CLL cell adhesion, survival, and growth.

Although the role of exosomes in other cancers has been well studied, their role in hematologic malignancies has not been well characterized. Also, this study confirmed that exosomes are present in CLL lymph nodes and promote tumor growth in vivo.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

“Our in vitro and in vivo data show that CLL exosomes harbor an oncogenic potential by stimulating stromal cells to induce an inflammatory and protumorigenic milieu, including increased angiogenesis, thus supporting the survival and outgrowth of CLL cells,” wrote Jerome Paggetti, Ph.D., of the laboratory of experimental hemato-oncology, Luxembourg Institute of Health (Blood 2015 Aug 27. doi:10.1182/blood-2014-12-618025).

Cells were obtained from 21 CLL patients; all patients had an absolute lymphocyte count of more than 30,000/mcL and were untreated for 3 months. The researchers established 30-day cocultures of bone marrow mesenchymal stem cells with primary CLL cells in culture inserts or they treated bone marrow mesenchymal stem cells weekly with exosomes. Similar experiments were performed with the Burkitt lymphoma cell line Namalwa to investigate whether the impact on stromal cells is CLL specific.

Based on gene expression analysis, CLL exosomes and CLL cells cocultured in inserts induced similar gene expression changes in bone marrow mesenchymal stem cells, highlighting the relevance of exosomes for microenvironment changes. “Importantly, lymphoma cells induced a distinct gene expression pattern in bone marrow mesenchymal stem cells, suggesting a specific response to CLL exosomes,” wrote Dr. Paggetti and coauthors.

The impact of CLL exosomes on tumor growth was studied in vivo by subcutaneously injecting cells with and without CLL exosomes into immunocompromised mice. Cells supplemented with exosomes resulted in an increased tumor size compared with tumor cells injected without additional exosomes. Also, the cells supplemented with exosomes accumulated in mice kidneys, confirming the renal involvement observed in CLL patients. “Our data demonstrate a protumorigenic effect of CLL-derived exosomes in vivo and their importance in the early onset of the disease when tumor cells impact the microenvironment to proliferate and promote angiogenesis,” the researchers concluded.

Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.

Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.

Wikimedia Commons

“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.

Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.

Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.

Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.

The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.

Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.

Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.

Wikimedia Commons

“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.

Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.

Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.

Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.

The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.

Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.

Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.

Wikimedia Commons

“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.

Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.

Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.

Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.

The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.

 

 

Hannah Karlsson, PhD

 

NEW YORK—For the first time, according to researchers, chimeric antigen receptor (CAR) T-cell therapy has been tested in a clinical trial in Sweden.

Early results have shown the treatment can produce complete responses (CRs) in leukemia and lymphoma, although most patients ultimately progressed.

Hannah Karlsson, PhD, of Uppsala University in Sweden, presented data from the phase 1/2a trial of the third-generation CD19 CAR T-cell therapy (abstract A041*) at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The trial is a collaboration between Uppsala University and Baylor College of Medicine and was funded by AFA Insurances AB and the Swedish Cancer Society.

“Third-generation CAR T cells are being tested in clinical trials for leukemia patients in the United States with success,” said senior study author Angelica Loskog, PhD, also of Uppsala University.

“[T]he main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukemia patients in Sweden and to also test if patients with lymphoma will also respond to this treatment.”

So the investigators enrolled 13 patients, 11 of whom were evaluable for efficacy at 3 months after CAR T-cell infusion. All patients had relapsed or refractory, CD19-positive, B-cell disease.

Two patients had acute lymphoblastic leukemia (ALL), 2 had chronic lymphocytic leukemia (CLL), and 7 had lymphoma—3 with diffuse large B-cell lymphoma (DLBCL), 2 with mantle cell lymphoma (MCL), 1 with follicular lymphoma (FL)/DLBCL, and 1 with Burkitt lymphoma.

All of the lymphoma patients received chemotherapy before CAR T-cell infusion to shrink their tumors. Seven patients—3 with leukemia and 4 with lymphoma—received pre-conditioning with cyclophosphamide plus fludarabine to reduce their immunosuppressive cell counts.

The investigators used CAR T cells containing signaling domains from both CD28 and 4-1BB and manufactured using a gamma retrovirus.

Patients received a single infusion of the CAR T cells, 2 patients at a dose of 2 x 10⁷ cells/m², 4 at a dose of 1 x 10⁸ cells/m², and 5 at 2 x 10⁸ cells/m².

Response and toxicity

Six patients had achieved a CR at the time of evaluation.

One patient with DLBCL experienced mild cytokine release syndrome (CRS) before achieving CR. However, the patient relapsed after a second CRS occurred (after 3 months).

Another DLBCL patient achieved a CR prior to T-cell infusion and remained in CR for 6 months before progressing.

One CLL patient and another DLBCL patient responded prior to T-cell infusion and remained in CR for more than 3 months. The CLL patient was still in CR at the time of the meeting.

One of the ALL patients achieved a CR after transient central nervous system toxicity but relapsed at 3 months with CD19-negative ALL. The other ALL patient was in CR for more than a month after experiencing CRS but ultimately progressed.

One CLL patient and 2 MCL patients had all progressed by 3 months.

The FL/DLBCL patient progressed after 1 month, with mild CRS. And the patient with Burkitt lymphoma had major CRS and progressive disease.

The investigators noted that 5 of the 6 patients who received pre-conditioning treatment had initial CRs.

The team is now analyzing whether there is any correlation between the level of immunosuppressive cells and patient response.

*Information presented at the meeting differs from the abstract.

 

 

Hannah Karlsson, PhD

 

NEW YORK—For the first time, according to researchers, chimeric antigen receptor (CAR) T-cell therapy has been tested in a clinical trial in Sweden.

Early results have shown the treatment can produce complete responses (CRs) in leukemia and lymphoma, although most patients ultimately progressed.

Hannah Karlsson, PhD, of Uppsala University in Sweden, presented data from the phase 1/2a trial of the third-generation CD19 CAR T-cell therapy (abstract A041*) at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The trial is a collaboration between Uppsala University and Baylor College of Medicine and was funded by AFA Insurances AB and the Swedish Cancer Society.

“Third-generation CAR T cells are being tested in clinical trials for leukemia patients in the United States with success,” said senior study author Angelica Loskog, PhD, also of Uppsala University.

“[T]he main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukemia patients in Sweden and to also test if patients with lymphoma will also respond to this treatment.”

So the investigators enrolled 13 patients, 11 of whom were evaluable for efficacy at 3 months after CAR T-cell infusion. All patients had relapsed or refractory, CD19-positive, B-cell disease.

Two patients had acute lymphoblastic leukemia (ALL), 2 had chronic lymphocytic leukemia (CLL), and 7 had lymphoma—3 with diffuse large B-cell lymphoma (DLBCL), 2 with mantle cell lymphoma (MCL), 1 with follicular lymphoma (FL)/DLBCL, and 1 with Burkitt lymphoma.

All of the lymphoma patients received chemotherapy before CAR T-cell infusion to shrink their tumors. Seven patients—3 with leukemia and 4 with lymphoma—received pre-conditioning with cyclophosphamide plus fludarabine to reduce their immunosuppressive cell counts.

The investigators used CAR T cells containing signaling domains from both CD28 and 4-1BB and manufactured using a gamma retrovirus.

Patients received a single infusion of the CAR T cells, 2 patients at a dose of 2 x 10⁷ cells/m², 4 at a dose of 1 x 10⁸ cells/m², and 5 at 2 x 10⁸ cells/m².

Response and toxicity

Six patients had achieved a CR at the time of evaluation.

One patient with DLBCL experienced mild cytokine release syndrome (CRS) before achieving CR. However, the patient relapsed after a second CRS occurred (after 3 months).

Another DLBCL patient achieved a CR prior to T-cell infusion and remained in CR for 6 months before progressing.

One CLL patient and another DLBCL patient responded prior to T-cell infusion and remained in CR for more than 3 months. The CLL patient was still in CR at the time of the meeting.

One of the ALL patients achieved a CR after transient central nervous system toxicity but relapsed at 3 months with CD19-negative ALL. The other ALL patient was in CR for more than a month after experiencing CRS but ultimately progressed.

One CLL patient and 2 MCL patients had all progressed by 3 months.

The FL/DLBCL patient progressed after 1 month, with mild CRS. And the patient with Burkitt lymphoma had major CRS and progressive disease.

The investigators noted that 5 of the 6 patients who received pre-conditioning treatment had initial CRs.

The team is now analyzing whether there is any correlation between the level of immunosuppressive cells and patient response.

*Information presented at the meeting differs from the abstract.

 

 

Hannah Karlsson, PhD

 

NEW YORK—For the first time, according to researchers, chimeric antigen receptor (CAR) T-cell therapy has been tested in a clinical trial in Sweden.

Early results have shown the treatment can produce complete responses (CRs) in leukemia and lymphoma, although most patients ultimately progressed.

Hannah Karlsson, PhD, of Uppsala University in Sweden, presented data from the phase 1/2a trial of the third-generation CD19 CAR T-cell therapy (abstract A041*) at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The trial is a collaboration between Uppsala University and Baylor College of Medicine and was funded by AFA Insurances AB and the Swedish Cancer Society.

“Third-generation CAR T cells are being tested in clinical trials for leukemia patients in the United States with success,” said senior study author Angelica Loskog, PhD, also of Uppsala University.

“[T]he main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukemia patients in Sweden and to also test if patients with lymphoma will also respond to this treatment.”

So the investigators enrolled 13 patients, 11 of whom were evaluable for efficacy at 3 months after CAR T-cell infusion. All patients had relapsed or refractory, CD19-positive, B-cell disease.

Two patients had acute lymphoblastic leukemia (ALL), 2 had chronic lymphocytic leukemia (CLL), and 7 had lymphoma—3 with diffuse large B-cell lymphoma (DLBCL), 2 with mantle cell lymphoma (MCL), 1 with follicular lymphoma (FL)/DLBCL, and 1 with Burkitt lymphoma.

All of the lymphoma patients received chemotherapy before CAR T-cell infusion to shrink their tumors. Seven patients—3 with leukemia and 4 with lymphoma—received pre-conditioning with cyclophosphamide plus fludarabine to reduce their immunosuppressive cell counts.

The investigators used CAR T cells containing signaling domains from both CD28 and 4-1BB and manufactured using a gamma retrovirus.

Patients received a single infusion of the CAR T cells, 2 patients at a dose of 2 x 10⁷ cells/m², 4 at a dose of 1 x 10⁸ cells/m², and 5 at 2 x 10⁸ cells/m².

Response and toxicity

Six patients had achieved a CR at the time of evaluation.

One patient with DLBCL experienced mild cytokine release syndrome (CRS) before achieving CR. However, the patient relapsed after a second CRS occurred (after 3 months).

Another DLBCL patient achieved a CR prior to T-cell infusion and remained in CR for 6 months before progressing.

One CLL patient and another DLBCL patient responded prior to T-cell infusion and remained in CR for more than 3 months. The CLL patient was still in CR at the time of the meeting.

One of the ALL patients achieved a CR after transient central nervous system toxicity but relapsed at 3 months with CD19-negative ALL. The other ALL patient was in CR for more than a month after experiencing CRS but ultimately progressed.

One CLL patient and 2 MCL patients had all progressed by 3 months.

The FL/DLBCL patient progressed after 1 month, with mild CRS. And the patient with Burkitt lymphoma had major CRS and progressive disease.

The investigators noted that 5 of the 6 patients who received pre-conditioning treatment had initial CRs.

The team is now analyzing whether there is any correlation between the level of immunosuppressive cells and patient response.

*Information presented at the meeting differs from the abstract.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.

Transplant preparation

Photo by Chad McNeeley

Chemotherapy-free allogeneic transplant can cure sickle cell disease (SCD) in adults, according to researchers.

In a phase 1/2 trial, the treatment normalized hemoglobin concentrations, reduced SCD-related complications, and improved cardiopulmonary function in 12 of 13 patients.

The single graft failure was due to noncompliance with post-transplant treatment.

There were no deaths and no cases of graft-vs-host disease. However, most patients did experience some form of transplant-related toxicity.

These transplants were performed at the University of Illinois Hospital & Health Sciences System in Chicago. But the chemotherapy-free transplant regimen was developed—and initially tested—at the National Institutes of Health in Bethesda, Maryland.

Physicians there have treated 30 patients with the regimen. An account of that work was published in JAMA last year.

The current study has been published in Biology of Blood & Marrow Transplantation.

“Adults with sickle cell disease can be cured without chemotherapy—the main barrier that has stood in the way for them for so long,” said study author Damiano Rondelli, MD, of the University of Illinois Hospital & Health Sciences System.

“Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

Treatment and outcome

The study included 13 patients, ages 17 to 40, who were transplanted between November 2011 and June 2014. Prior to transplant, patients received alemtuzumab and total-body irradiation (300 cGy).

They then received peripheral blood stem cells from matched related donors. All donors were a 10/10 human leukocyte antigen match, but 2 donors had different blood types than the recipients. After transplant, the patients received sirolimus.

All 13 patients initially engrafted, but 1 patient experienced secondary graft failure due to noncompliance with sirolimus.

At a median follow-up of 22 months (range, 12-44), all 13 patients are alive, and 12 have maintained a stable mixed donor/recipient chimerism.

At 1 year after transplant, the 12 patients with stable donor chimerism had significant improvements from baseline in hemoglobin, reticulocyte percentage, lactate dehydrogenase concentration, and cardiopulmonary function.

One of these patients required readmission to the hospital for vaso-occlusive crisis. Before transplant, this patient experienced about 12 crises a year.

No other SCD-related complications have occurred. And 4 patients have been able to stop taking sirolimus without transplant rejection or other complications.

Nine of the engrafted patients completed quality of life assessments before transplant and at 1 year after the procedure. They reported improvements in pain, general health, vitality, and social functioning.

“[W]ith this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just 1 month of the transplant,” Dr Rondelli said. “They are able to go back to school, go back to work, and can experience life without pain.”

Toxicity

Four patients did not experience any transplant-related toxicity. And there were no cases of acute or chronic graft-vs-host disease.

One patient developed gram-negative rods in her hip prosthesis after transplant, 1 patient experienced delayed hemolytic transfusion reaction after exchange transfusion, 1 patient developed viral pharyngitis, and 1 patient developed Coxsackie B.

One patient developed a urinary tract infection due to extended spectrum beta-lactamase, Clostridium difficile colitis, and Mycoplasma pneumoniae.

Two patients had grade 2 mucositis, one of whom also developed line-associated deep vein thrombosis and cytomegalovirus (CMV) reactivation. Two other patients had CMV reactivation as well, one of whom also had methicillin-resistant Staphylococcus aureus pneumonia.

All 3 patients with CMV reactivation were successfully treated with valgancyclovir and did not develop CMV disease.

Six patients had arthralgias attributed to sirolimus, and 2 of them required dose reductions.

One patient developed chest pain and a decline in carbon monoxide diffusion capacity by 30% that was attributed to sirolimus. The patient was switched to cyclosporine but developed posterior reversible encephalopathy syndrome and was then put on mycophenolate mofetil.

The patient has since maintained stable donor chimerism, and the carbon monoxide diffusing capacity has increased to near-baseline value.