Diana Mahoney

Early results from a small clinical trial suggest the new oral skin cancer drug vismodegib may be therapeutic in patients receiving chemotherapy for metastatic pancreatic cancer.

Half of 20 patients treated with vismodegib (Erivedge, GDC-0449) and gemcitabine (Gemzar) were progression free at 3 months, investigators reported during a pancreatic cancer conference sponsored by the American Association for Cancer Research. Five patients had partial responses, and five had stable disease.

The study found pretreatment sonic hedgehog expression level was the biological correlate most predictive of therapeutic benefit. Vismodegib, a small molecule drug from Genentech, blocks the Smoothened (SMO) protein in the hedgehog signaling pathway

If validated in additional studies, the combination of vismodegib and gemcitabine "has the potential to change the way we treat pancreatic cancer" lead author Dr. Edward Kim of the University of Michigan Comprehensive Cancer Center in Ann Arbor, said in a press briefing at the meeting in Lake Tahoe, Nev.

In previous research, the investigators determined that specific pancreatic cancer stem cells express significantly elevated levels of sonic hedgehog (Cancer Res. 2007;67:1030-7), which led to successful phase I studies, Dr. Kim said in an interview. Building on that foundation, for the current clinical trial, the researchers incorporated pair core tumor biopsies to prospectively compare the inhibition of the hedgehog pathway in pancreatic cancer before and after vismodegib treatment.

To date, 21 of the study’s planned 25 patients with advanced pancreatic cancer have been enrolled. Data from 20 of the patients with paired biopsies who had completed three treatment cycles were reported at the meeting.

All of the patients had previously untreated metastatic pancreatic cancer, for which the protocol initiated daily monotherapy with vismodegib for 4 weeks, followed by combination treatment with vismodegib and gemcitabine on days 1, 8, and 15 of each month in a 3-month cycle, Dr. Kim reported. Each patient underwent two sets of three core biopsies – one set prior to treatment and another set 3 weeks after treatment initiation.

To evaluate the effects of the experimental drug on pancreatic cancer stem cells, the investigators used immunohistochemistry to evaluate expression of sonic hedgehog and Ki-67, a static marker of tumor proliferation.

"After three cycles of therapy, five patients showed evidence of partial disease response [defined as a minimum 30% decrease in the sum of the longest-diameter target lesions relative to baseline, based on RECIST criteria] and five patients had stable disease, yielding 3-month progression-free survival rate of 50%," Dr. Kim stated. Additionally, half of the evaluable patients demonstrated an average 60% reduction in pancreatic cancer stem cells and a 54% decrease in the proliferation index.

Importantly, Dr. Kim noted, "sonic hedgehog expression was more highly expressed in patients who had a partial response or stable disease compared with patients whose disease progressed." Specifically, the mean pretreatment hedgehog expression H-score (intensity times the percentage of positive cells) was 285 in patients with partial response or stable disease compared with 168 in those with progression.

"We are currently conducting further correlative studies to determine the best predictors of which patients stand to benefit from this treatment regimen," he said. The researchers also are continuing to investigate the effect that vismodegib has on hedgehog pathway target genes.

The response rate observed in this study exceeded expectations, according to session moderator Dr. Daniel Von Hoff, chief scientific officer for the Scottsdale Healthcare Research Institute and physician-in-chief at TGen (Translational Genomics Research Institute) in Phoenix. "We usually see about a 5%-9% change of response to gemcitabine by itself, but here it was 25%. The good news is that this drug doesn’t add any toxicities."

The Food and Drug Administration approved vismodegib Jan. 30 for locally advanced or metastatic basal cell carcinoma that cannot be treated with surgery or radiation. It has not been considered for an indication in pancreatic cancer.

Dr. Kim and Dr. Von Hoff disclosed having no relevant financial conflicts of interest.

Early results from a small clinical trial suggest the new oral skin cancer drug vismodegib may be therapeutic in patients receiving chemotherapy for metastatic pancreatic cancer.

Half of 20 patients treated with vismodegib (Erivedge, GDC-0449) and gemcitabine (Gemzar) were progression free at 3 months, investigators reported during a pancreatic cancer conference sponsored by the American Association for Cancer Research. Five patients had partial responses, and five had stable disease.

The study found pretreatment sonic hedgehog expression level was the biological correlate most predictive of therapeutic benefit. Vismodegib, a small molecule drug from Genentech, blocks the Smoothened (SMO) protein in the hedgehog signaling pathway

If validated in additional studies, the combination of vismodegib and gemcitabine "has the potential to change the way we treat pancreatic cancer" lead author Dr. Edward Kim of the University of Michigan Comprehensive Cancer Center in Ann Arbor, said in a press briefing at the meeting in Lake Tahoe, Nev.

In previous research, the investigators determined that specific pancreatic cancer stem cells express significantly elevated levels of sonic hedgehog (Cancer Res. 2007;67:1030-7), which led to successful phase I studies, Dr. Kim said in an interview. Building on that foundation, for the current clinical trial, the researchers incorporated pair core tumor biopsies to prospectively compare the inhibition of the hedgehog pathway in pancreatic cancer before and after vismodegib treatment.

To date, 21 of the study’s planned 25 patients with advanced pancreatic cancer have been enrolled. Data from 20 of the patients with paired biopsies who had completed three treatment cycles were reported at the meeting.

All of the patients had previously untreated metastatic pancreatic cancer, for which the protocol initiated daily monotherapy with vismodegib for 4 weeks, followed by combination treatment with vismodegib and gemcitabine on days 1, 8, and 15 of each month in a 3-month cycle, Dr. Kim reported. Each patient underwent two sets of three core biopsies – one set prior to treatment and another set 3 weeks after treatment initiation.

To evaluate the effects of the experimental drug on pancreatic cancer stem cells, the investigators used immunohistochemistry to evaluate expression of sonic hedgehog and Ki-67, a static marker of tumor proliferation.

"After three cycles of therapy, five patients showed evidence of partial disease response [defined as a minimum 30% decrease in the sum of the longest-diameter target lesions relative to baseline, based on RECIST criteria] and five patients had stable disease, yielding 3-month progression-free survival rate of 50%," Dr. Kim stated. Additionally, half of the evaluable patients demonstrated an average 60% reduction in pancreatic cancer stem cells and a 54% decrease in the proliferation index.

Importantly, Dr. Kim noted, "sonic hedgehog expression was more highly expressed in patients who had a partial response or stable disease compared with patients whose disease progressed." Specifically, the mean pretreatment hedgehog expression H-score (intensity times the percentage of positive cells) was 285 in patients with partial response or stable disease compared with 168 in those with progression.

"We are currently conducting further correlative studies to determine the best predictors of which patients stand to benefit from this treatment regimen," he said. The researchers also are continuing to investigate the effect that vismodegib has on hedgehog pathway target genes.

The response rate observed in this study exceeded expectations, according to session moderator Dr. Daniel Von Hoff, chief scientific officer for the Scottsdale Healthcare Research Institute and physician-in-chief at TGen (Translational Genomics Research Institute) in Phoenix. "We usually see about a 5%-9% change of response to gemcitabine by itself, but here it was 25%. The good news is that this drug doesn’t add any toxicities."

The Food and Drug Administration approved vismodegib Jan. 30 for locally advanced or metastatic basal cell carcinoma that cannot be treated with surgery or radiation. It has not been considered for an indication in pancreatic cancer.

Dr. Kim and Dr. Von Hoff disclosed having no relevant financial conflicts of interest.

Early results from a small clinical trial suggest the new oral skin cancer drug vismodegib may be therapeutic in patients receiving chemotherapy for metastatic pancreatic cancer.

Half of 20 patients treated with vismodegib (Erivedge, GDC-0449) and gemcitabine (Gemzar) were progression free at 3 months, investigators reported during a pancreatic cancer conference sponsored by the American Association for Cancer Research. Five patients had partial responses, and five had stable disease.

The study found pretreatment sonic hedgehog expression level was the biological correlate most predictive of therapeutic benefit. Vismodegib, a small molecule drug from Genentech, blocks the Smoothened (SMO) protein in the hedgehog signaling pathway

If validated in additional studies, the combination of vismodegib and gemcitabine "has the potential to change the way we treat pancreatic cancer" lead author Dr. Edward Kim of the University of Michigan Comprehensive Cancer Center in Ann Arbor, said in a press briefing at the meeting in Lake Tahoe, Nev.

In previous research, the investigators determined that specific pancreatic cancer stem cells express significantly elevated levels of sonic hedgehog (Cancer Res. 2007;67:1030-7), which led to successful phase I studies, Dr. Kim said in an interview. Building on that foundation, for the current clinical trial, the researchers incorporated pair core tumor biopsies to prospectively compare the inhibition of the hedgehog pathway in pancreatic cancer before and after vismodegib treatment.

To date, 21 of the study’s planned 25 patients with advanced pancreatic cancer have been enrolled. Data from 20 of the patients with paired biopsies who had completed three treatment cycles were reported at the meeting.

All of the patients had previously untreated metastatic pancreatic cancer, for which the protocol initiated daily monotherapy with vismodegib for 4 weeks, followed by combination treatment with vismodegib and gemcitabine on days 1, 8, and 15 of each month in a 3-month cycle, Dr. Kim reported. Each patient underwent two sets of three core biopsies – one set prior to treatment and another set 3 weeks after treatment initiation.

To evaluate the effects of the experimental drug on pancreatic cancer stem cells, the investigators used immunohistochemistry to evaluate expression of sonic hedgehog and Ki-67, a static marker of tumor proliferation.

"After three cycles of therapy, five patients showed evidence of partial disease response [defined as a minimum 30% decrease in the sum of the longest-diameter target lesions relative to baseline, based on RECIST criteria] and five patients had stable disease, yielding 3-month progression-free survival rate of 50%," Dr. Kim stated. Additionally, half of the evaluable patients demonstrated an average 60% reduction in pancreatic cancer stem cells and a 54% decrease in the proliferation index.

Importantly, Dr. Kim noted, "sonic hedgehog expression was more highly expressed in patients who had a partial response or stable disease compared with patients whose disease progressed." Specifically, the mean pretreatment hedgehog expression H-score (intensity times the percentage of positive cells) was 285 in patients with partial response or stable disease compared with 168 in those with progression.

"We are currently conducting further correlative studies to determine the best predictors of which patients stand to benefit from this treatment regimen," he said. The researchers also are continuing to investigate the effect that vismodegib has on hedgehog pathway target genes.

The response rate observed in this study exceeded expectations, according to session moderator Dr. Daniel Von Hoff, chief scientific officer for the Scottsdale Healthcare Research Institute and physician-in-chief at TGen (Translational Genomics Research Institute) in Phoenix. "We usually see about a 5%-9% change of response to gemcitabine by itself, but here it was 25%. The good news is that this drug doesn’t add any toxicities."

The Food and Drug Administration approved vismodegib Jan. 30 for locally advanced or metastatic basal cell carcinoma that cannot be treated with surgery or radiation. It has not been considered for an indication in pancreatic cancer.

Dr. Kim and Dr. Von Hoff disclosed having no relevant financial conflicts of interest.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

SAN DIEGO – A proposed quality measure for pancreatic surgery has the potential to assess performance more thoroughly than current volume and mortality measures, judging by surgeons’ responses to a recent survey.

The 12-item "Quality Scorecard," developed by Dr. Brian T. Kalish of Beth Israel Deaconess Medical Center, Boston, and a team of pancreatic surgeons from multiple academic medical centers, consists of actionable and meaningful measures. The scorecard is aligned with the Institute of Medicine’s health care quality domains: safety, timeliness, effectiveness, patient centeredness, efficiency, and equitability.

"Traditional quality metrics in high-acuity surgery on their own cannot measure or satisfy the [IOM] domains," Dr. Kalish explained in a plenary presentation at the annual Digestive Disease Week. "Our goal was to evaluate the need for broader quality metrics and whether such broader metrics would align to contemporary IOM domains."

"We expect the scorecard to reveal quality to an extent that volume and mortality alone cannot."

Toward this end, the development team worked with a professional market research firm to create a web-based survey and distribute it to expert pancreatic surgeons identified through specialty societies and verified by survey demographics, Dr. Kalish explained. "The survey asked respondents to rank [62] proposed quality metrics on level of importance, from essential to not important, and to align the metric to one or more of the [IOM] quality domains." Points were awarded for level of importance and multidomain alignment, and the two scores for a given quality metric were averaged to render a total quality score that was then normalized to a 100-point scale, he said.

The 21% survey response rate represented 106 surgeons primarily from academic medical centers in North America who perform an average of 43 pancreatic operations per year, said Dr. Kalish. The need for improved quality metrics was indicated by 90% of the respondents, while 81% believed that a "quality scorecard" in pancreatic surgery would probably or definitely be of value, he reported. More than one-third of the proposed metrics aligned to more than one IOM domain, and at least half of the respondents rated these as essential or very important, he said.

Of the 62 metrics, 12 emerged with the highest total quality score. In rank order, they are: multidisciplinary services for pancreatic diseases, major complication rate, perioperative mortality, overall complication rate, incidence of postoperative hemorrhage, venous thromboembolism prophylaxis, patients with malignancy who undergo adjuvant therapy, readmission rates (30 day, 90 day, total), incidence of postoperative pancreatic fistula, timely and appropriate perioperative antibiotics, survival rates (1 year and 5 year), and timing from diagnosis to surgical consultation.

"The metrics related to mortality, the rate and severity of complications, and access to multidisciplinary services for pancreatic disease had the highest total quality scores; technical and perioperative metrics had intermediate scores; and metrics related to patient satisfaction with care, costs of care, and patient demographics had the lowest total quality scores," Dr. Kalish observed. With respect to the IOM domains, "the least represented domains were equitability, efficiency, and patient-centeredness," he said.

Although the actual performance thresholds for each of the metrics require further definition and validation, "we expect the scorecard to reveal quality to an extent that volume and mortality alone cannot," Dr. Kalish stated, noting that the development process is ongoing.

Future efforts include the organization of patient focus groups and a formal survey of patients and family members to attain insight into which quality metrics are important to those receiving care, as well as a multicenter prospective validation.

Dr. Kalish reported having no relevant financial conflicts of interest.

SAN DIEGO – A proposed quality measure for pancreatic surgery has the potential to assess performance more thoroughly than current volume and mortality measures, judging by surgeons’ responses to a recent survey.

The 12-item "Quality Scorecard," developed by Dr. Brian T. Kalish of Beth Israel Deaconess Medical Center, Boston, and a team of pancreatic surgeons from multiple academic medical centers, consists of actionable and meaningful measures. The scorecard is aligned with the Institute of Medicine’s health care quality domains: safety, timeliness, effectiveness, patient centeredness, efficiency, and equitability.

"Traditional quality metrics in high-acuity surgery on their own cannot measure or satisfy the [IOM] domains," Dr. Kalish explained in a plenary presentation at the annual Digestive Disease Week. "Our goal was to evaluate the need for broader quality metrics and whether such broader metrics would align to contemporary IOM domains."

"We expect the scorecard to reveal quality to an extent that volume and mortality alone cannot."

Toward this end, the development team worked with a professional market research firm to create a web-based survey and distribute it to expert pancreatic surgeons identified through specialty societies and verified by survey demographics, Dr. Kalish explained. "The survey asked respondents to rank [62] proposed quality metrics on level of importance, from essential to not important, and to align the metric to one or more of the [IOM] quality domains." Points were awarded for level of importance and multidomain alignment, and the two scores for a given quality metric were averaged to render a total quality score that was then normalized to a 100-point scale, he said.

The 21% survey response rate represented 106 surgeons primarily from academic medical centers in North America who perform an average of 43 pancreatic operations per year, said Dr. Kalish. The need for improved quality metrics was indicated by 90% of the respondents, while 81% believed that a "quality scorecard" in pancreatic surgery would probably or definitely be of value, he reported. More than one-third of the proposed metrics aligned to more than one IOM domain, and at least half of the respondents rated these as essential or very important, he said.

Of the 62 metrics, 12 emerged with the highest total quality score. In rank order, they are: multidisciplinary services for pancreatic diseases, major complication rate, perioperative mortality, overall complication rate, incidence of postoperative hemorrhage, venous thromboembolism prophylaxis, patients with malignancy who undergo adjuvant therapy, readmission rates (30 day, 90 day, total), incidence of postoperative pancreatic fistula, timely and appropriate perioperative antibiotics, survival rates (1 year and 5 year), and timing from diagnosis to surgical consultation.

"The metrics related to mortality, the rate and severity of complications, and access to multidisciplinary services for pancreatic disease had the highest total quality scores; technical and perioperative metrics had intermediate scores; and metrics related to patient satisfaction with care, costs of care, and patient demographics had the lowest total quality scores," Dr. Kalish observed. With respect to the IOM domains, "the least represented domains were equitability, efficiency, and patient-centeredness," he said.

Although the actual performance thresholds for each of the metrics require further definition and validation, "we expect the scorecard to reveal quality to an extent that volume and mortality alone cannot," Dr. Kalish stated, noting that the development process is ongoing.

Future efforts include the organization of patient focus groups and a formal survey of patients and family members to attain insight into which quality metrics are important to those receiving care, as well as a multicenter prospective validation.

Dr. Kalish reported having no relevant financial conflicts of interest.

SAN DIEGO – A proposed quality measure for pancreatic surgery has the potential to assess performance more thoroughly than current volume and mortality measures, judging by surgeons’ responses to a recent survey.

The 12-item "Quality Scorecard," developed by Dr. Brian T. Kalish of Beth Israel Deaconess Medical Center, Boston, and a team of pancreatic surgeons from multiple academic medical centers, consists of actionable and meaningful measures. The scorecard is aligned with the Institute of Medicine’s health care quality domains: safety, timeliness, effectiveness, patient centeredness, efficiency, and equitability.

"Traditional quality metrics in high-acuity surgery on their own cannot measure or satisfy the [IOM] domains," Dr. Kalish explained in a plenary presentation at the annual Digestive Disease Week. "Our goal was to evaluate the need for broader quality metrics and whether such broader metrics would align to contemporary IOM domains."

"We expect the scorecard to reveal quality to an extent that volume and mortality alone cannot."

Toward this end, the development team worked with a professional market research firm to create a web-based survey and distribute it to expert pancreatic surgeons identified through specialty societies and verified by survey demographics, Dr. Kalish explained. "The survey asked respondents to rank [62] proposed quality metrics on level of importance, from essential to not important, and to align the metric to one or more of the [IOM] quality domains." Points were awarded for level of importance and multidomain alignment, and the two scores for a given quality metric were averaged to render a total quality score that was then normalized to a 100-point scale, he said.

The 21% survey response rate represented 106 surgeons primarily from academic medical centers in North America who perform an average of 43 pancreatic operations per year, said Dr. Kalish. The need for improved quality metrics was indicated by 90% of the respondents, while 81% believed that a "quality scorecard" in pancreatic surgery would probably or definitely be of value, he reported. More than one-third of the proposed metrics aligned to more than one IOM domain, and at least half of the respondents rated these as essential or very important, he said.

Of the 62 metrics, 12 emerged with the highest total quality score. In rank order, they are: multidisciplinary services for pancreatic diseases, major complication rate, perioperative mortality, overall complication rate, incidence of postoperative hemorrhage, venous thromboembolism prophylaxis, patients with malignancy who undergo adjuvant therapy, readmission rates (30 day, 90 day, total), incidence of postoperative pancreatic fistula, timely and appropriate perioperative antibiotics, survival rates (1 year and 5 year), and timing from diagnosis to surgical consultation.

"The metrics related to mortality, the rate and severity of complications, and access to multidisciplinary services for pancreatic disease had the highest total quality scores; technical and perioperative metrics had intermediate scores; and metrics related to patient satisfaction with care, costs of care, and patient demographics had the lowest total quality scores," Dr. Kalish observed. With respect to the IOM domains, "the least represented domains were equitability, efficiency, and patient-centeredness," he said.

Although the actual performance thresholds for each of the metrics require further definition and validation, "we expect the scorecard to reveal quality to an extent that volume and mortality alone cannot," Dr. Kalish stated, noting that the development process is ongoing.

Future efforts include the organization of patient focus groups and a formal survey of patients and family members to attain insight into which quality metrics are important to those receiving care, as well as a multicenter prospective validation.

Dr. Kalish reported having no relevant financial conflicts of interest.

BOSTON – Consistently short sleep duration not only leaves otherwise healthy individuals tired, it also increases their risk of developing stroke, a study has shown.

Previous studies have linked self-reported sleep duration to incident stroke, but none have considered whether sleep-disordered breathing, which itself is associated with adverse cardiovascular outcomes, mediates that risk, said Megan Ruiter, Ph.D., of the University of Alabama at Birmingham. Dr. Ruiter and her colleagues used data from the national, population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to determine whether sleep duration predicts stroke risk among individuals at low risk for sleep apnea or hypopnea.

Funded by the National Institute of Neurological Disorders and Stroke, the ongoing REGARDS study enrolled more than 30,000 black and white volunteers, aged 45 years and older, to track stroke risk and cognitive health.

Based on self-reported stroke symptoms collected at 6-month intervals, Dr. Ruiter and her colleagues identified 5,666 participants who had been followed for up to 3 years without history of stroke, transient ischemic attack, stroke symptoms, or high risk for sleep-disordered breathing according to the Berlin Sleep Questionnaire. The researchers then conducted interval-censored, parametric survival models with exponential distributions to estimate the hazard ratios predicting time from measurement of sleep duration (less than 6 hours, 6-6.9 hours, 7-7.9 hours, 8-8.9 hours, and 9 or more hours) to first stroke symptoms. Data were adjusted for demographic information, cholesterol levels, hypertension, body mass index (BMI), sleep-disordered breathing, depressive symptoms, and anxiety.

"In people with a low risk for obstructive sleep apnea and a BMI in the optimal range of 18.5-24.99 kg/m², the risk of stroke symptoms was four times higher in those who had fewer than 6 hours of sleep per night, compared with participants in the same BMI range who reported 7-8 hours of sleep per night," Dr. Ruiter reported at the annual meeting of the Associated Professional Sleep Societies. Specifically, the hazard ratio for stroke symptoms among individuals within the normal BMI range who reported fewer than 6 hours of sleep nightly was 2.93, relative to the reference group. "We didn’t find any similar association between short sleep duration and stroke symptoms among overweight and obese individuals," she noted.

The association between shorter periods of sleep and stroke symptoms, including sudden body weakness, numbness, or vision deficits, remained significant after controlling for other known stroke risk factors, Dr. Ruiter said, acknowledging the possibility that "these participants may be late in the development of stroke."

The findings suggest that habitually short sleep duration may independently predispose middle-age adults to develop major stroke risk factors. "We speculate short sleep is precursor to other traditional risk factors and, once these traditional risk factors are present, they may become stronger risk factors than sleep duration alone," Dr. Ruiter hypothesized.

In a separate analysis, the investigators also evaluated the association between stroke symptoms and sleep duration by racial group and found a differential risk, according to Dr. Ruiter. "It is possible that sleep duration might partially explain the relationship between ethnic differences in stroke symptoms. For example, African Americans had a greater prevalence of short sleep and were more likely to have stroke symptoms," she said.

The study is limited by the reliance on self-reporting of stroke symptoms and the potential for recall inaccuracy, Dr. Ruiter said. Further studies are warranted to tease out the specific characteristics of sleep duration that are related to stroke symptoms, she said. For example, "Is it actually sleep fragmentation or one’s perception of sleep and factors that contribute to its quality rather than sleep duration itself?" she proposed. Additionally, "we need to see if sleep duration is related to actual stroke events." Many of these factors, she noted, are modifiable through behavioral treatment.

Dr. Ruiter had no relevant financial conflicts of interest to disclose.

BOSTON – Consistently short sleep duration not only leaves otherwise healthy individuals tired, it also increases their risk of developing stroke, a study has shown.

Previous studies have linked self-reported sleep duration to incident stroke, but none have considered whether sleep-disordered breathing, which itself is associated with adverse cardiovascular outcomes, mediates that risk, said Megan Ruiter, Ph.D., of the University of Alabama at Birmingham. Dr. Ruiter and her colleagues used data from the national, population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to determine whether sleep duration predicts stroke risk among individuals at low risk for sleep apnea or hypopnea.

Funded by the National Institute of Neurological Disorders and Stroke, the ongoing REGARDS study enrolled more than 30,000 black and white volunteers, aged 45 years and older, to track stroke risk and cognitive health.

Based on self-reported stroke symptoms collected at 6-month intervals, Dr. Ruiter and her colleagues identified 5,666 participants who had been followed for up to 3 years without history of stroke, transient ischemic attack, stroke symptoms, or high risk for sleep-disordered breathing according to the Berlin Sleep Questionnaire. The researchers then conducted interval-censored, parametric survival models with exponential distributions to estimate the hazard ratios predicting time from measurement of sleep duration (less than 6 hours, 6-6.9 hours, 7-7.9 hours, 8-8.9 hours, and 9 or more hours) to first stroke symptoms. Data were adjusted for demographic information, cholesterol levels, hypertension, body mass index (BMI), sleep-disordered breathing, depressive symptoms, and anxiety.

"In people with a low risk for obstructive sleep apnea and a BMI in the optimal range of 18.5-24.99 kg/m², the risk of stroke symptoms was four times higher in those who had fewer than 6 hours of sleep per night, compared with participants in the same BMI range who reported 7-8 hours of sleep per night," Dr. Ruiter reported at the annual meeting of the Associated Professional Sleep Societies. Specifically, the hazard ratio for stroke symptoms among individuals within the normal BMI range who reported fewer than 6 hours of sleep nightly was 2.93, relative to the reference group. "We didn’t find any similar association between short sleep duration and stroke symptoms among overweight and obese individuals," she noted.

The association between shorter periods of sleep and stroke symptoms, including sudden body weakness, numbness, or vision deficits, remained significant after controlling for other known stroke risk factors, Dr. Ruiter said, acknowledging the possibility that "these participants may be late in the development of stroke."

The findings suggest that habitually short sleep duration may independently predispose middle-age adults to develop major stroke risk factors. "We speculate short sleep is precursor to other traditional risk factors and, once these traditional risk factors are present, they may become stronger risk factors than sleep duration alone," Dr. Ruiter hypothesized.

In a separate analysis, the investigators also evaluated the association between stroke symptoms and sleep duration by racial group and found a differential risk, according to Dr. Ruiter. "It is possible that sleep duration might partially explain the relationship between ethnic differences in stroke symptoms. For example, African Americans had a greater prevalence of short sleep and were more likely to have stroke symptoms," she said.

The study is limited by the reliance on self-reporting of stroke symptoms and the potential for recall inaccuracy, Dr. Ruiter said. Further studies are warranted to tease out the specific characteristics of sleep duration that are related to stroke symptoms, she said. For example, "Is it actually sleep fragmentation or one’s perception of sleep and factors that contribute to its quality rather than sleep duration itself?" she proposed. Additionally, "we need to see if sleep duration is related to actual stroke events." Many of these factors, she noted, are modifiable through behavioral treatment.

Dr. Ruiter had no relevant financial conflicts of interest to disclose.

BOSTON – Consistently short sleep duration not only leaves otherwise healthy individuals tired, it also increases their risk of developing stroke, a study has shown.

Previous studies have linked self-reported sleep duration to incident stroke, but none have considered whether sleep-disordered breathing, which itself is associated with adverse cardiovascular outcomes, mediates that risk, said Megan Ruiter, Ph.D., of the University of Alabama at Birmingham. Dr. Ruiter and her colleagues used data from the national, population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to determine whether sleep duration predicts stroke risk among individuals at low risk for sleep apnea or hypopnea.

Funded by the National Institute of Neurological Disorders and Stroke, the ongoing REGARDS study enrolled more than 30,000 black and white volunteers, aged 45 years and older, to track stroke risk and cognitive health.

Based on self-reported stroke symptoms collected at 6-month intervals, Dr. Ruiter and her colleagues identified 5,666 participants who had been followed for up to 3 years without history of stroke, transient ischemic attack, stroke symptoms, or high risk for sleep-disordered breathing according to the Berlin Sleep Questionnaire. The researchers then conducted interval-censored, parametric survival models with exponential distributions to estimate the hazard ratios predicting time from measurement of sleep duration (less than 6 hours, 6-6.9 hours, 7-7.9 hours, 8-8.9 hours, and 9 or more hours) to first stroke symptoms. Data were adjusted for demographic information, cholesterol levels, hypertension, body mass index (BMI), sleep-disordered breathing, depressive symptoms, and anxiety.

"In people with a low risk for obstructive sleep apnea and a BMI in the optimal range of 18.5-24.99 kg/m², the risk of stroke symptoms was four times higher in those who had fewer than 6 hours of sleep per night, compared with participants in the same BMI range who reported 7-8 hours of sleep per night," Dr. Ruiter reported at the annual meeting of the Associated Professional Sleep Societies. Specifically, the hazard ratio for stroke symptoms among individuals within the normal BMI range who reported fewer than 6 hours of sleep nightly was 2.93, relative to the reference group. "We didn’t find any similar association between short sleep duration and stroke symptoms among overweight and obese individuals," she noted.

The association between shorter periods of sleep and stroke symptoms, including sudden body weakness, numbness, or vision deficits, remained significant after controlling for other known stroke risk factors, Dr. Ruiter said, acknowledging the possibility that "these participants may be late in the development of stroke."

The findings suggest that habitually short sleep duration may independently predispose middle-age adults to develop major stroke risk factors. "We speculate short sleep is precursor to other traditional risk factors and, once these traditional risk factors are present, they may become stronger risk factors than sleep duration alone," Dr. Ruiter hypothesized.

In a separate analysis, the investigators also evaluated the association between stroke symptoms and sleep duration by racial group and found a differential risk, according to Dr. Ruiter. "It is possible that sleep duration might partially explain the relationship between ethnic differences in stroke symptoms. For example, African Americans had a greater prevalence of short sleep and were more likely to have stroke symptoms," she said.

The study is limited by the reliance on self-reporting of stroke symptoms and the potential for recall inaccuracy, Dr. Ruiter said. Further studies are warranted to tease out the specific characteristics of sleep duration that are related to stroke symptoms, she said. For example, "Is it actually sleep fragmentation or one’s perception of sleep and factors that contribute to its quality rather than sleep duration itself?" she proposed. Additionally, "we need to see if sleep duration is related to actual stroke events." Many of these factors, she noted, are modifiable through behavioral treatment.

Dr. Ruiter had no relevant financial conflicts of interest to disclose.

SAN DIEGO – Nasal colonization of methicillin-resistant Staphylococcus aureus was linked to an increase in surgical site infections and longer hospital stays in patients undergoing major gastrointestinal surgery in a large retrospective study, a finding that surprised investigators who had hypothesized that nasal colonization of the organism, which is not routinely found or colonized in the GI tract, would have little impact on outcome measures.

"Gastrointestinal operations are different from other surgeries in that infectious pathogens are typically organisms found in the gut, not bacteria that colonize in the skin, which is why we didn’t expect to find a correlation," lead investigator Dr. Harry T. Papaconstantinou said during a teleconference reporting the results, which he presented on Sunday, May 20, at the annual Digestive Disease Week conference.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

While it’s unlikely that nasal colonization of MRSA necessarily increases the risk of developing a surgical site infection following GI surgery, "it is possible that it might be an indicator of the type of organism that is involved in the infection." For example, in the current analysis, wound culture data were available for 92 patients. In patients who tested positive for MRSA, 70% of the wound infections stemmed from MRSA, compared with only 8.5% in of those who tested negative, he said.

To evaluate the relationship between MRSA nasal colonization and surgical site infection, wound cultures, hospital length of stay, and mortality, Dr. Papaconstantinou, chief of colorectal surgery at Scott and White Memorial Hospital in Temple, Tex., and his colleagues examined the records of patients who underwent major GI surgery at the hospital between December 2007 and August 2009. The patients, who also had nasal swab tests within 24-48 hours after admission, were divided into one of three categories: MRSA-swab positive, methicillin-sensitive Staphylococcus aureus (MSSA)–swab positive, or negative for both.

Of the 1,137 patients, mean age 59.5 years, 73 (6.4%) were MRSA-swab positive, 167 (14.7%) were MSSA-swab positive, and 897 (78.9%) were negative, Dr. Papaconstantinou reported. Surgical site infection was identified in 101 patients (8.9%), and the rate of infection was highest, at 14%, in the MRSA-swab positive patients, compared with 4% and 9%, respectively, in the MSSA-swab positive and negative patients, he said. "When we controlled for other confounding factors, we didn’t find nasal swab to be an independent predictor of surgical site infection, but what we did find was a strong relationship between MRSA-positive nasal colonization and type of organism involved [in the surgical site infection]."

Regarding mean hospital length of stay, the respective durations for the MRSA-swab positive, MSSA-swab positive, and the negative groups overall were 12.5 days, 7.6 days, and 8.8 days, representing a significant increase, said Dr. Papaconstantinou. "By multiregression analysis, we found a MRSA-positive swab to be an independent risk factor for extended length of stay." However, when looking specifically at patients with surgical site infections, the presence of which increased hospital length of stay significantly from 6.2 days to 15.7 days, "there was no between group differences based on nasal swab," he said. Similarly, the 45 deaths in the study population wee distributed evenly across the nasal swab groups.

Based on the findings, Dr. Papaconstantinou said in an interview, "we can conclude that a positive MRSA nasal swab test for colonization is a strong predictor that MRSA-associated surgical site infections will occur in patients undergoing major GI surgery." As such, "we propose the possibility that it might be beneficial to preoperatively screen and decolonize these patients in an effort to reduce the incidence of these infections and improve patient outcomes following surgery." Toward this end, he and his colleagues are anticipating performing such a study and plan on including a cost-benefit analysis to determine whether screening is economically beneficial, he said.

Dr. Papaconstantinou disclosed a financial relationship with Covidien.

SAN DIEGO – Nasal colonization of methicillin-resistant Staphylococcus aureus was linked to an increase in surgical site infections and longer hospital stays in patients undergoing major gastrointestinal surgery in a large retrospective study, a finding that surprised investigators who had hypothesized that nasal colonization of the organism, which is not routinely found or colonized in the GI tract, would have little impact on outcome measures.

"Gastrointestinal operations are different from other surgeries in that infectious pathogens are typically organisms found in the gut, not bacteria that colonize in the skin, which is why we didn’t expect to find a correlation," lead investigator Dr. Harry T. Papaconstantinou said during a teleconference reporting the results, which he presented on Sunday, May 20, at the annual Digestive Disease Week conference.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

While it’s unlikely that nasal colonization of MRSA necessarily increases the risk of developing a surgical site infection following GI surgery, "it is possible that it might be an indicator of the type of organism that is involved in the infection." For example, in the current analysis, wound culture data were available for 92 patients. In patients who tested positive for MRSA, 70% of the wound infections stemmed from MRSA, compared with only 8.5% in of those who tested negative, he said.

To evaluate the relationship between MRSA nasal colonization and surgical site infection, wound cultures, hospital length of stay, and mortality, Dr. Papaconstantinou, chief of colorectal surgery at Scott and White Memorial Hospital in Temple, Tex., and his colleagues examined the records of patients who underwent major GI surgery at the hospital between December 2007 and August 2009. The patients, who also had nasal swab tests within 24-48 hours after admission, were divided into one of three categories: MRSA-swab positive, methicillin-sensitive Staphylococcus aureus (MSSA)–swab positive, or negative for both.

Of the 1,137 patients, mean age 59.5 years, 73 (6.4%) were MRSA-swab positive, 167 (14.7%) were MSSA-swab positive, and 897 (78.9%) were negative, Dr. Papaconstantinou reported. Surgical site infection was identified in 101 patients (8.9%), and the rate of infection was highest, at 14%, in the MRSA-swab positive patients, compared with 4% and 9%, respectively, in the MSSA-swab positive and negative patients, he said. "When we controlled for other confounding factors, we didn’t find nasal swab to be an independent predictor of surgical site infection, but what we did find was a strong relationship between MRSA-positive nasal colonization and type of organism involved [in the surgical site infection]."

Regarding mean hospital length of stay, the respective durations for the MRSA-swab positive, MSSA-swab positive, and the negative groups overall were 12.5 days, 7.6 days, and 8.8 days, representing a significant increase, said Dr. Papaconstantinou. "By multiregression analysis, we found a MRSA-positive swab to be an independent risk factor for extended length of stay." However, when looking specifically at patients with surgical site infections, the presence of which increased hospital length of stay significantly from 6.2 days to 15.7 days, "there was no between group differences based on nasal swab," he said. Similarly, the 45 deaths in the study population wee distributed evenly across the nasal swab groups.

Based on the findings, Dr. Papaconstantinou said in an interview, "we can conclude that a positive MRSA nasal swab test for colonization is a strong predictor that MRSA-associated surgical site infections will occur in patients undergoing major GI surgery." As such, "we propose the possibility that it might be beneficial to preoperatively screen and decolonize these patients in an effort to reduce the incidence of these infections and improve patient outcomes following surgery." Toward this end, he and his colleagues are anticipating performing such a study and plan on including a cost-benefit analysis to determine whether screening is economically beneficial, he said.

Dr. Papaconstantinou disclosed a financial relationship with Covidien.

SAN DIEGO – Nasal colonization of methicillin-resistant Staphylococcus aureus was linked to an increase in surgical site infections and longer hospital stays in patients undergoing major gastrointestinal surgery in a large retrospective study, a finding that surprised investigators who had hypothesized that nasal colonization of the organism, which is not routinely found or colonized in the GI tract, would have little impact on outcome measures.

"Gastrointestinal operations are different from other surgeries in that infectious pathogens are typically organisms found in the gut, not bacteria that colonize in the skin, which is why we didn’t expect to find a correlation," lead investigator Dr. Harry T. Papaconstantinou said during a teleconference reporting the results, which he presented on Sunday, May 20, at the annual Digestive Disease Week conference.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

While it’s unlikely that nasal colonization of MRSA necessarily increases the risk of developing a surgical site infection following GI surgery, "it is possible that it might be an indicator of the type of organism that is involved in the infection." For example, in the current analysis, wound culture data were available for 92 patients. In patients who tested positive for MRSA, 70% of the wound infections stemmed from MRSA, compared with only 8.5% in of those who tested negative, he said.

To evaluate the relationship between MRSA nasal colonization and surgical site infection, wound cultures, hospital length of stay, and mortality, Dr. Papaconstantinou, chief of colorectal surgery at Scott and White Memorial Hospital in Temple, Tex., and his colleagues examined the records of patients who underwent major GI surgery at the hospital between December 2007 and August 2009. The patients, who also had nasal swab tests within 24-48 hours after admission, were divided into one of three categories: MRSA-swab positive, methicillin-sensitive Staphylococcus aureus (MSSA)–swab positive, or negative for both.

Of the 1,137 patients, mean age 59.5 years, 73 (6.4%) were MRSA-swab positive, 167 (14.7%) were MSSA-swab positive, and 897 (78.9%) were negative, Dr. Papaconstantinou reported. Surgical site infection was identified in 101 patients (8.9%), and the rate of infection was highest, at 14%, in the MRSA-swab positive patients, compared with 4% and 9%, respectively, in the MSSA-swab positive and negative patients, he said. "When we controlled for other confounding factors, we didn’t find nasal swab to be an independent predictor of surgical site infection, but what we did find was a strong relationship between MRSA-positive nasal colonization and type of organism involved [in the surgical site infection]."

Regarding mean hospital length of stay, the respective durations for the MRSA-swab positive, MSSA-swab positive, and the negative groups overall were 12.5 days, 7.6 days, and 8.8 days, representing a significant increase, said Dr. Papaconstantinou. "By multiregression analysis, we found a MRSA-positive swab to be an independent risk factor for extended length of stay." However, when looking specifically at patients with surgical site infections, the presence of which increased hospital length of stay significantly from 6.2 days to 15.7 days, "there was no between group differences based on nasal swab," he said. Similarly, the 45 deaths in the study population wee distributed evenly across the nasal swab groups.

Based on the findings, Dr. Papaconstantinou said in an interview, "we can conclude that a positive MRSA nasal swab test for colonization is a strong predictor that MRSA-associated surgical site infections will occur in patients undergoing major GI surgery." As such, "we propose the possibility that it might be beneficial to preoperatively screen and decolonize these patients in an effort to reduce the incidence of these infections and improve patient outcomes following surgery." Toward this end, he and his colleagues are anticipating performing such a study and plan on including a cost-benefit analysis to determine whether screening is economically beneficial, he said.

Dr. Papaconstantinou disclosed a financial relationship with Covidien.

Digital ulcers are a frequent manifestation of systemic sclerosis, affecting approximately half of all patients with the multisystem connective tissue disorder. Often persistent and recurring, these ischemic wounds tend to be slow-healing and difficult to manage. In addition to pain and disability, severe complications such as tissue loss, infection, gangrene, autoamputation, and septicemia can exacerbate the clinical burden by an order of magnitude, according to Christopher Denton, Ph.D., director of the Center for Rheumatology at University College London.

In an effort to better understand the clinical and antibody characteristics, disease course, and outcomes associated with digital ulcers, Dr. Denton and his colleagues established the Digital Ulcers Outcome Registry, a European, multicenter, observational registry of systemic sclerosis (SSc) patients with ongoing digital ulcer disease. To date, the registry includes demographic, clinical, and treatment information for more than 2,500 patients, providing investigators with valuable insight into the nature and progression of digital ulcer disease in this at-risk population.

In this month’s column, Dr. Denton discusses the progress of the registry as well as the information that investigators have gleaned from it.

Question: What are the objectives for the Digital Ulcers Outcome (DUO) Registry?

Dr. Denton: The DUO registry is a prospective observational program for SSc patients with digital ulcers. In 2008, physicians at participating centers began enrolling consenting consecutive patients with ongoing digital ulcers associated with SSc. The objectives of the registry include tracking key information on the clinical course and outcome of digital ulcers, regardless of their treatment regimen, although an express goal is to collect safety information on the use of the dual endothelin receptor antagonist bosentan, which is approved in Europe for reducing the number of new digital ulcers in SSc.

The DUO registry is a noninterventional registry. Patients receive standard medical care and follow-up as determined by their physician. The data collected include patient demographics, SSc disease duration, classification of underlying disease, internal organ manifestations, autoantibodies, history of interventions and complications related to digital ulcers, ongoing complications related to digital ulcers, ongoing medications, and functional assessment based on a disease-specific questionnaire. Additionally, the presence of antinuclear antibodies, anti-scleroderma-70 antibodies, anticentromere antibodies, anti-RNA polymerase 3, anti-U1-ribonucleoprotein, and anti-U3-ribonucleoprotein is recorded, as well as all serology tests and other tests that have been performed.

Question: Based on the registry data collected to date, which SSc patients are most likely to develop digital ulcers?

Dr. Denton: Digital ulcers appear to develop earliest and most frequently in patients with diffuse cutaneous SSc, anti-scleroderma-70 antibodies, or both. In our recent review, we reported that among 2,439 patients enrolled through November 2010, most of whom had limited or diffuse cutaneous SSc, digital ulcers developed earlier in patients with the diffuse cutaneous subtype (Ann. Rheum. Dis. 2012;71:718-21). Patients who tested positive for anti-scleroderma-70 antibodies, in particular, developed first digital ulcers at a significantly younger mean age (44.7 years) than those who tested positive for anticentromere antibodies (ACAs) (50.1 years). Similarly, patients positive for anti-scleroderma-70 antibodies were younger than ACA-positive patients at the onset of the first symptoms of Raynaud’s phenomenon, and had less time between the onset of Raynaud’s and development of their first digital ulcer.

Question: What are some of the most common digital ulcer–associated complications that have been reported, and which patients are most vulnerable?

Dr. Denton: Infections requiring antibiotics, gangrene, and amputation were frequent complications across all of the major disease subsets. Patients positive for anti-scleroderma-70 were twice as likely to develop lung fibrosis compared with ACA-positive patients, and they were also more likely to have heart manifestations. Both lung fibrosis and heart disease are consistent with studies indicating more severe disease in patients positive for anti-scleroderma-70.

Question: Can the risk of the development of digital ulcers be minimized or prevented in SSc?

Dr. Denton: Treatment with the oral endothelin receptor antagonist bosentan appears to be effective in preventing new digital ulcers. Last year we reported results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial (Ann. Rheum. Dis. 2011;70:32-8) showing that treatment with bosentan reduced the occurrence of new digital ulcers by 30% over 24 weeks compared with placebo in patients with at least one active digital ulcer at the time of enrollment. The effect was greater in patients who entered the trial with more digital ulcers.

Question: What is the optimal treatment of digital ulcers in this population?

Dr. Denton: There is still a great clinical need for a tolerable, effective therapeutic option for improving tissue integrity and viability and promoting ulcer healing, in addition to reducing the formation of new ulcers. Although bosentan has been approved [in Europe] for the prevention of new digital ulcers in patients with SSc and ongoing digital ulcer disease, our findings [from the RAPIDS-2 trial] suggest that the treatment has no effect on digital ulcer healing. Vasodilators may improve digital circulation, and small studies suggest that the prostanoids epoprostenol and iloprost may improve healing, but controlled data supporting their use is lacking. The DUO registry may provide data that informs clinical trials of targeted therapies.

Dr. Denton reported that he has financial relationships with
Actelion Pharmaceuticals, Aspreva, Biovitrum, Digna,
Encysive Pharmaceuticals, Genzyme, and Pfizer.

Digital ulcers are a frequent manifestation of systemic sclerosis, affecting approximately half of all patients with the multisystem connective tissue disorder. Often persistent and recurring, these ischemic wounds tend to be slow-healing and difficult to manage. In addition to pain and disability, severe complications such as tissue loss, infection, gangrene, autoamputation, and septicemia can exacerbate the clinical burden by an order of magnitude, according to Christopher Denton, Ph.D., director of the Center for Rheumatology at University College London.

In an effort to better understand the clinical and antibody characteristics, disease course, and outcomes associated with digital ulcers, Dr. Denton and his colleagues established the Digital Ulcers Outcome Registry, a European, multicenter, observational registry of systemic sclerosis (SSc) patients with ongoing digital ulcer disease. To date, the registry includes demographic, clinical, and treatment information for more than 2,500 patients, providing investigators with valuable insight into the nature and progression of digital ulcer disease in this at-risk population.

In this month’s column, Dr. Denton discusses the progress of the registry as well as the information that investigators have gleaned from it.

Question: What are the objectives for the Digital Ulcers Outcome (DUO) Registry?

Dr. Denton: The DUO registry is a prospective observational program for SSc patients with digital ulcers. In 2008, physicians at participating centers began enrolling consenting consecutive patients with ongoing digital ulcers associated with SSc. The objectives of the registry include tracking key information on the clinical course and outcome of digital ulcers, regardless of their treatment regimen, although an express goal is to collect safety information on the use of the dual endothelin receptor antagonist bosentan, which is approved in Europe for reducing the number of new digital ulcers in SSc.

The DUO registry is a noninterventional registry. Patients receive standard medical care and follow-up as determined by their physician. The data collected include patient demographics, SSc disease duration, classification of underlying disease, internal organ manifestations, autoantibodies, history of interventions and complications related to digital ulcers, ongoing complications related to digital ulcers, ongoing medications, and functional assessment based on a disease-specific questionnaire. Additionally, the presence of antinuclear antibodies, anti-scleroderma-70 antibodies, anticentromere antibodies, anti-RNA polymerase 3, anti-U1-ribonucleoprotein, and anti-U3-ribonucleoprotein is recorded, as well as all serology tests and other tests that have been performed.

Question: Based on the registry data collected to date, which SSc patients are most likely to develop digital ulcers?

Dr. Denton: Digital ulcers appear to develop earliest and most frequently in patients with diffuse cutaneous SSc, anti-scleroderma-70 antibodies, or both. In our recent review, we reported that among 2,439 patients enrolled through November 2010, most of whom had limited or diffuse cutaneous SSc, digital ulcers developed earlier in patients with the diffuse cutaneous subtype (Ann. Rheum. Dis. 2012;71:718-21). Patients who tested positive for anti-scleroderma-70 antibodies, in particular, developed first digital ulcers at a significantly younger mean age (44.7 years) than those who tested positive for anticentromere antibodies (ACAs) (50.1 years). Similarly, patients positive for anti-scleroderma-70 antibodies were younger than ACA-positive patients at the onset of the first symptoms of Raynaud’s phenomenon, and had less time between the onset of Raynaud’s and development of their first digital ulcer.

Question: What are some of the most common digital ulcer–associated complications that have been reported, and which patients are most vulnerable?

Dr. Denton: Infections requiring antibiotics, gangrene, and amputation were frequent complications across all of the major disease subsets. Patients positive for anti-scleroderma-70 were twice as likely to develop lung fibrosis compared with ACA-positive patients, and they were also more likely to have heart manifestations. Both lung fibrosis and heart disease are consistent with studies indicating more severe disease in patients positive for anti-scleroderma-70.

Question: Can the risk of the development of digital ulcers be minimized or prevented in SSc?

Dr. Denton: Treatment with the oral endothelin receptor antagonist bosentan appears to be effective in preventing new digital ulcers. Last year we reported results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial (Ann. Rheum. Dis. 2011;70:32-8) showing that treatment with bosentan reduced the occurrence of new digital ulcers by 30% over 24 weeks compared with placebo in patients with at least one active digital ulcer at the time of enrollment. The effect was greater in patients who entered the trial with more digital ulcers.

Question: What is the optimal treatment of digital ulcers in this population?

Dr. Denton: There is still a great clinical need for a tolerable, effective therapeutic option for improving tissue integrity and viability and promoting ulcer healing, in addition to reducing the formation of new ulcers. Although bosentan has been approved [in Europe] for the prevention of new digital ulcers in patients with SSc and ongoing digital ulcer disease, our findings [from the RAPIDS-2 trial] suggest that the treatment has no effect on digital ulcer healing. Vasodilators may improve digital circulation, and small studies suggest that the prostanoids epoprostenol and iloprost may improve healing, but controlled data supporting their use is lacking. The DUO registry may provide data that informs clinical trials of targeted therapies.

Dr. Denton reported that he has financial relationships with
Actelion Pharmaceuticals, Aspreva, Biovitrum, Digna,
Encysive Pharmaceuticals, Genzyme, and Pfizer.

Digital ulcers are a frequent manifestation of systemic sclerosis, affecting approximately half of all patients with the multisystem connective tissue disorder. Often persistent and recurring, these ischemic wounds tend to be slow-healing and difficult to manage. In addition to pain and disability, severe complications such as tissue loss, infection, gangrene, autoamputation, and septicemia can exacerbate the clinical burden by an order of magnitude, according to Christopher Denton, Ph.D., director of the Center for Rheumatology at University College London.

In an effort to better understand the clinical and antibody characteristics, disease course, and outcomes associated with digital ulcers, Dr. Denton and his colleagues established the Digital Ulcers Outcome Registry, a European, multicenter, observational registry of systemic sclerosis (SSc) patients with ongoing digital ulcer disease. To date, the registry includes demographic, clinical, and treatment information for more than 2,500 patients, providing investigators with valuable insight into the nature and progression of digital ulcer disease in this at-risk population.

In this month’s column, Dr. Denton discusses the progress of the registry as well as the information that investigators have gleaned from it.

Question: What are the objectives for the Digital Ulcers Outcome (DUO) Registry?

Dr. Denton: The DUO registry is a prospective observational program for SSc patients with digital ulcers. In 2008, physicians at participating centers began enrolling consenting consecutive patients with ongoing digital ulcers associated with SSc. The objectives of the registry include tracking key information on the clinical course and outcome of digital ulcers, regardless of their treatment regimen, although an express goal is to collect safety information on the use of the dual endothelin receptor antagonist bosentan, which is approved in Europe for reducing the number of new digital ulcers in SSc.

The DUO registry is a noninterventional registry. Patients receive standard medical care and follow-up as determined by their physician. The data collected include patient demographics, SSc disease duration, classification of underlying disease, internal organ manifestations, autoantibodies, history of interventions and complications related to digital ulcers, ongoing complications related to digital ulcers, ongoing medications, and functional assessment based on a disease-specific questionnaire. Additionally, the presence of antinuclear antibodies, anti-scleroderma-70 antibodies, anticentromere antibodies, anti-RNA polymerase 3, anti-U1-ribonucleoprotein, and anti-U3-ribonucleoprotein is recorded, as well as all serology tests and other tests that have been performed.

Question: Based on the registry data collected to date, which SSc patients are most likely to develop digital ulcers?

Dr. Denton: Digital ulcers appear to develop earliest and most frequently in patients with diffuse cutaneous SSc, anti-scleroderma-70 antibodies, or both. In our recent review, we reported that among 2,439 patients enrolled through November 2010, most of whom had limited or diffuse cutaneous SSc, digital ulcers developed earlier in patients with the diffuse cutaneous subtype (Ann. Rheum. Dis. 2012;71:718-21). Patients who tested positive for anti-scleroderma-70 antibodies, in particular, developed first digital ulcers at a significantly younger mean age (44.7 years) than those who tested positive for anticentromere antibodies (ACAs) (50.1 years). Similarly, patients positive for anti-scleroderma-70 antibodies were younger than ACA-positive patients at the onset of the first symptoms of Raynaud’s phenomenon, and had less time between the onset of Raynaud’s and development of their first digital ulcer.

Question: What are some of the most common digital ulcer–associated complications that have been reported, and which patients are most vulnerable?

Dr. Denton: Infections requiring antibiotics, gangrene, and amputation were frequent complications across all of the major disease subsets. Patients positive for anti-scleroderma-70 were twice as likely to develop lung fibrosis compared with ACA-positive patients, and they were also more likely to have heart manifestations. Both lung fibrosis and heart disease are consistent with studies indicating more severe disease in patients positive for anti-scleroderma-70.

Question: Can the risk of the development of digital ulcers be minimized or prevented in SSc?

Dr. Denton: Treatment with the oral endothelin receptor antagonist bosentan appears to be effective in preventing new digital ulcers. Last year we reported results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial (Ann. Rheum. Dis. 2011;70:32-8) showing that treatment with bosentan reduced the occurrence of new digital ulcers by 30% over 24 weeks compared with placebo in patients with at least one active digital ulcer at the time of enrollment. The effect was greater in patients who entered the trial with more digital ulcers.

Question: What is the optimal treatment of digital ulcers in this population?

Dr. Denton: There is still a great clinical need for a tolerable, effective therapeutic option for improving tissue integrity and viability and promoting ulcer healing, in addition to reducing the formation of new ulcers. Although bosentan has been approved [in Europe] for the prevention of new digital ulcers in patients with SSc and ongoing digital ulcer disease, our findings [from the RAPIDS-2 trial] suggest that the treatment has no effect on digital ulcer healing. Vasodilators may improve digital circulation, and small studies suggest that the prostanoids epoprostenol and iloprost may improve healing, but controlled data supporting their use is lacking. The DUO registry may provide data that informs clinical trials of targeted therapies.

Dr. Denton reported that he has financial relationships with
Actelion Pharmaceuticals, Aspreva, Biovitrum, Digna,
Encysive Pharmaceuticals, Genzyme, and Pfizer.