Michele G. Sullivan

DENVER – The investigational drug REGN668, a monoclonal antibody that modulates interleukins 4 and 13, significantly improved overall quality of life and pruritus in patients with severe, longstanding atopic dermatitis.

Improvements for patients in the REGN668 (dupilumab) group were obvious in the first week of treatment and achieved statistical significance by week 2 of the placebo-controlled trial, Dr. Thomas Luger said at the annual meeting of the American Academy of Dermatology.

The drug probably works in two ways, said Dr. Luger of the University of Munster, Germany.

"It can be explained by its down-regulation of the immune mediators IL 4 and IL 13, but another issue is also important. IL4 has been shown to impair barrier function by down-modulating filaggrin expression," he noted.

The 12-week, multicenter trial randomized 109 patients to weekly injections of 300 mg dupilumab or placebo. The primary endpoint was the percent change in the Eczema Area and Severity Index (EASI) scale. Secondary endpoints were change from baseline in measures of pruritus and the proportion of patients who reached the EASI 50-75 level.

On the primary endpoint of change in EASI, dupilumab was associated with significantly greater improvement than placebo. By the end of week 1, the EASI had already dropped 10%, Dr. Luger said. By week 2, it had decreased 40% from baseline compared with placebo, and the improvement continued each week, then plateaued at about 7 weeks, with a mean decrease of 74%.

Changes in pruritus and overall quality of life were secondary endpoints for 65 patients who completed the quality of life portion. The validated survey was only available in French and German, and some of the study participants did not speak those languages.

The secondary exploratory endpoint was the change in baseline on the Quality of Life Index for Atopic Dermatitis, a 25-question survey, and its association with clinical outcomes. A higher score indicates worse quality of life; a two- to three-point change is considered clinically significant.

All of the patients were white; mean age was about 40 years and the mean disease duration was 28 years. The mean baseline EASI score was 27, indicating moderate severity. Scores on measures of pruritus indicated severe itching. The mean QoLIAD score was 12, with 25 being the worst.

The quality of life score followed the same pattern as the primary endpoint, Dr. Luger said. The average quality of life score had improved by approximately 25% after 1 week and by approximately 45% after 2 weeks. The score continued to drop, plateauing at an 80% decrease by week 7 and maintaining that level through the end of the treatment period. Almost all treated patients (91%) achieved at least at 50% reduction in symptoms, with 69% achieving at least a 75% reduction.

Pruritus was measured in two QoLIAD subscales: the numeric rating scale (NRS) and the 5-D itch scale. Itching began to improve early and continued to do so until it reached a maximum reduction of 65% in week 8 on the NRS. By week 12, the mean reduction in itching was 60%.

The 5-D scale followed a similar pattern, with early improvement that reached a maximum 50% reduction by week 8. By week 12, the mean reduction from baseline was 45%.

The overall QoLIAD score reflected these changes, improving by a mean of 6.5 points by week 12. In the placebo group, this score remained virtually unchanged. QoLIAD improvements strongly correlated with clinical improvements, Dr. Luger added.

Dupilumab was well tolerated overall. The most frequent adverse events were nasopharyngitis, headache, and conjunctivitis. Skin infections occurred in significantly fewer patients taking the drug, compared with placebo (5.5% vs. 24%). There were no infection-related serious adverse events or eczema herpeticum occurrences in the dupilumab group.

Sanofi and Regeneron, which are jointly developing dupilumab, sponsored the study. Dr. Luger is a consultant for numerous pharmaceutical companies but not for Sanofi or Regeneron.

[email protected]

On Twitter @alz_gal

DENVER – The investigational drug REGN668, a monoclonal antibody that modulates interleukins 4 and 13, significantly improved overall quality of life and pruritus in patients with severe, longstanding atopic dermatitis.

Improvements for patients in the REGN668 (dupilumab) group were obvious in the first week of treatment and achieved statistical significance by week 2 of the placebo-controlled trial, Dr. Thomas Luger said at the annual meeting of the American Academy of Dermatology.

The drug probably works in two ways, said Dr. Luger of the University of Munster, Germany.

"It can be explained by its down-regulation of the immune mediators IL 4 and IL 13, but another issue is also important. IL4 has been shown to impair barrier function by down-modulating filaggrin expression," he noted.

The 12-week, multicenter trial randomized 109 patients to weekly injections of 300 mg dupilumab or placebo. The primary endpoint was the percent change in the Eczema Area and Severity Index (EASI) scale. Secondary endpoints were change from baseline in measures of pruritus and the proportion of patients who reached the EASI 50-75 level.

On the primary endpoint of change in EASI, dupilumab was associated with significantly greater improvement than placebo. By the end of week 1, the EASI had already dropped 10%, Dr. Luger said. By week 2, it had decreased 40% from baseline compared with placebo, and the improvement continued each week, then plateaued at about 7 weeks, with a mean decrease of 74%.

Changes in pruritus and overall quality of life were secondary endpoints for 65 patients who completed the quality of life portion. The validated survey was only available in French and German, and some of the study participants did not speak those languages.

The secondary exploratory endpoint was the change in baseline on the Quality of Life Index for Atopic Dermatitis, a 25-question survey, and its association with clinical outcomes. A higher score indicates worse quality of life; a two- to three-point change is considered clinically significant.

All of the patients were white; mean age was about 40 years and the mean disease duration was 28 years. The mean baseline EASI score was 27, indicating moderate severity. Scores on measures of pruritus indicated severe itching. The mean QoLIAD score was 12, with 25 being the worst.

The quality of life score followed the same pattern as the primary endpoint, Dr. Luger said. The average quality of life score had improved by approximately 25% after 1 week and by approximately 45% after 2 weeks. The score continued to drop, plateauing at an 80% decrease by week 7 and maintaining that level through the end of the treatment period. Almost all treated patients (91%) achieved at least at 50% reduction in symptoms, with 69% achieving at least a 75% reduction.

Pruritus was measured in two QoLIAD subscales: the numeric rating scale (NRS) and the 5-D itch scale. Itching began to improve early and continued to do so until it reached a maximum reduction of 65% in week 8 on the NRS. By week 12, the mean reduction in itching was 60%.

The 5-D scale followed a similar pattern, with early improvement that reached a maximum 50% reduction by week 8. By week 12, the mean reduction from baseline was 45%.

The overall QoLIAD score reflected these changes, improving by a mean of 6.5 points by week 12. In the placebo group, this score remained virtually unchanged. QoLIAD improvements strongly correlated with clinical improvements, Dr. Luger added.

Dupilumab was well tolerated overall. The most frequent adverse events were nasopharyngitis, headache, and conjunctivitis. Skin infections occurred in significantly fewer patients taking the drug, compared with placebo (5.5% vs. 24%). There were no infection-related serious adverse events or eczema herpeticum occurrences in the dupilumab group.

Sanofi and Regeneron, which are jointly developing dupilumab, sponsored the study. Dr. Luger is a consultant for numerous pharmaceutical companies but not for Sanofi or Regeneron.

[email protected]

On Twitter @alz_gal

DENVER – The investigational drug REGN668, a monoclonal antibody that modulates interleukins 4 and 13, significantly improved overall quality of life and pruritus in patients with severe, longstanding atopic dermatitis.

Improvements for patients in the REGN668 (dupilumab) group were obvious in the first week of treatment and achieved statistical significance by week 2 of the placebo-controlled trial, Dr. Thomas Luger said at the annual meeting of the American Academy of Dermatology.

The drug probably works in two ways, said Dr. Luger of the University of Munster, Germany.

"It can be explained by its down-regulation of the immune mediators IL 4 and IL 13, but another issue is also important. IL4 has been shown to impair barrier function by down-modulating filaggrin expression," he noted.

The 12-week, multicenter trial randomized 109 patients to weekly injections of 300 mg dupilumab or placebo. The primary endpoint was the percent change in the Eczema Area and Severity Index (EASI) scale. Secondary endpoints were change from baseline in measures of pruritus and the proportion of patients who reached the EASI 50-75 level.

On the primary endpoint of change in EASI, dupilumab was associated with significantly greater improvement than placebo. By the end of week 1, the EASI had already dropped 10%, Dr. Luger said. By week 2, it had decreased 40% from baseline compared with placebo, and the improvement continued each week, then plateaued at about 7 weeks, with a mean decrease of 74%.

Changes in pruritus and overall quality of life were secondary endpoints for 65 patients who completed the quality of life portion. The validated survey was only available in French and German, and some of the study participants did not speak those languages.

The secondary exploratory endpoint was the change in baseline on the Quality of Life Index for Atopic Dermatitis, a 25-question survey, and its association with clinical outcomes. A higher score indicates worse quality of life; a two- to three-point change is considered clinically significant.

All of the patients were white; mean age was about 40 years and the mean disease duration was 28 years. The mean baseline EASI score was 27, indicating moderate severity. Scores on measures of pruritus indicated severe itching. The mean QoLIAD score was 12, with 25 being the worst.

The quality of life score followed the same pattern as the primary endpoint, Dr. Luger said. The average quality of life score had improved by approximately 25% after 1 week and by approximately 45% after 2 weeks. The score continued to drop, plateauing at an 80% decrease by week 7 and maintaining that level through the end of the treatment period. Almost all treated patients (91%) achieved at least at 50% reduction in symptoms, with 69% achieving at least a 75% reduction.

Pruritus was measured in two QoLIAD subscales: the numeric rating scale (NRS) and the 5-D itch scale. Itching began to improve early and continued to do so until it reached a maximum reduction of 65% in week 8 on the NRS. By week 12, the mean reduction in itching was 60%.

The 5-D scale followed a similar pattern, with early improvement that reached a maximum 50% reduction by week 8. By week 12, the mean reduction from baseline was 45%.

The overall QoLIAD score reflected these changes, improving by a mean of 6.5 points by week 12. In the placebo group, this score remained virtually unchanged. QoLIAD improvements strongly correlated with clinical improvements, Dr. Luger added.

Dupilumab was well tolerated overall. The most frequent adverse events were nasopharyngitis, headache, and conjunctivitis. Skin infections occurred in significantly fewer patients taking the drug, compared with placebo (5.5% vs. 24%). There were no infection-related serious adverse events or eczema herpeticum occurrences in the dupilumab group.

Sanofi and Regeneron, which are jointly developing dupilumab, sponsored the study. Dr. Luger is a consultant for numerous pharmaceutical companies but not for Sanofi or Regeneron.

[email protected]

On Twitter @alz_gal

Rheumatoid arthritis patients taking an anti–tumor necrosis factor agent who had a prior hospitalization because of an infection significantly reduced their risk of a subsequent infection-related hospitalization by switching to etanercept or abatacept in a retrospective study of Medicare data.

The risk of a second hospitalization declined by 20% with abatacept (Orencia) and by 17% with etanercept (Enbrel), Huifeng Yun, Ph.D., and her colleagues reported (Ann. Rheum. Dis. 2014 March 7 [doi:10.1136/annrheumdis-2013-204011]).

"These findings provide new evidence for clinical management of high-risk RA patients and suggest that drug-specific guidance may be more appropriate when making safety-based recommendations, rather than simply lumping drugs together based on" mechanism of action, wrote Dr. Yun, an epidemiologist at the University of Birmingham, Ala., and her coauthors.

For the retrospective study, investigators examined Medicare data from 2006 to 2010 on nearly 13,000 patients with rheumatoid arthritis (RA). All of them had been hospitalized for an infection that occurred while taking a tumor necrosis factor (TNF) inhibitor and then either continued on the same medication or switched to another.

Of these, most (54.0%) were on infliximab (Remicade). Other drugs were etanercept (25.1%), adalimumab (Humira, 19.8%), certolizumab pegol (Cimzia, 0.6%), and golimumab (Simponi, 0.5%). The most common infection was pneumonia or other respiratory tract infection (30%); others included urinary tract (23%), skin/soft tissue (17%), and septicemia/bacteremia (11%).

After discharge, most started the same anti-TNF drug (79%), but 2% switched to another anti-TNF biologic, 3% switched to a non–anti-TNF biologic, and 16% didn’t get any biologic over the next 18 months. Only 10% of those who initially restarted the same anti-TNF inhibitor later switched to another biologic during follow-up.

From this primary cohort, the authors had data on 10,183 patients who received any biologic during 18 months of follow-up. During that period, 2,666 subsequent hospitalized infections occurred, with crude incidence rates ranging from of 27.1 to 34.6 per 100 person-years.

When considering the different drugs taken after hospitalization, the risk of infection was significantly lower with abatacept and etanercept, compared with infliximab (hazard ratios of 0.80 and 0.83, respectively). There were no significant associations between the types of subsequent infections and any of the drugs taken after the first infection, Dr. Yun and her colleagues said.

Another analysis seemed to indicate that the risk of a subsequent infection peaked early for etanercept, infliximab, and adalimumab and dropped off after the first 3 months. In contrast, the risk curve with abatacept and rituximab stayed fairly flat throughout follow-up, they noted.

"These findings are compatible with studies suggesting an early increased risk for anti-TNF agents that declines over time," the authors wrote. "Perhaps further accentuating these differences, the substantial majority of anti-TNF users in the analysis were restarting therapy with a medication that they had been on, whereas most abatacept and rituximab users were new users."

The findings are somewhat at odds with national recommendations, Dr. Yun and her associates pointed out. The American College of Rheumatology recommends that RA patients on anti-TNF therapy switch to a non–anti-TNF biologic after a serious adverse event, including a hospitalized infection.

"Our results suggest that the ACR recommendation may be appropriate, especially if switching to abatacept, but considering the grouped safety profile of medications defined by an anti-TNF or non–anti-TNF common [mechanism of action] may not be appropriate."

The Agency for Healthcare Research and Quality funded the study. Dr. Yun did not report any financial disclosures, but several coauthors reported numerous financial relationships with a number of pharmaceutical companies marketing drugs for RA.

[email protected]

On Twitter @alz_gal

Rheumatoid arthritis patients taking an anti–tumor necrosis factor agent who had a prior hospitalization because of an infection significantly reduced their risk of a subsequent infection-related hospitalization by switching to etanercept or abatacept in a retrospective study of Medicare data.

The risk of a second hospitalization declined by 20% with abatacept (Orencia) and by 17% with etanercept (Enbrel), Huifeng Yun, Ph.D., and her colleagues reported (Ann. Rheum. Dis. 2014 March 7 [doi:10.1136/annrheumdis-2013-204011]).

"These findings provide new evidence for clinical management of high-risk RA patients and suggest that drug-specific guidance may be more appropriate when making safety-based recommendations, rather than simply lumping drugs together based on" mechanism of action, wrote Dr. Yun, an epidemiologist at the University of Birmingham, Ala., and her coauthors.

For the retrospective study, investigators examined Medicare data from 2006 to 2010 on nearly 13,000 patients with rheumatoid arthritis (RA). All of them had been hospitalized for an infection that occurred while taking a tumor necrosis factor (TNF) inhibitor and then either continued on the same medication or switched to another.

Of these, most (54.0%) were on infliximab (Remicade). Other drugs were etanercept (25.1%), adalimumab (Humira, 19.8%), certolizumab pegol (Cimzia, 0.6%), and golimumab (Simponi, 0.5%). The most common infection was pneumonia or other respiratory tract infection (30%); others included urinary tract (23%), skin/soft tissue (17%), and septicemia/bacteremia (11%).

After discharge, most started the same anti-TNF drug (79%), but 2% switched to another anti-TNF biologic, 3% switched to a non–anti-TNF biologic, and 16% didn’t get any biologic over the next 18 months. Only 10% of those who initially restarted the same anti-TNF inhibitor later switched to another biologic during follow-up.

From this primary cohort, the authors had data on 10,183 patients who received any biologic during 18 months of follow-up. During that period, 2,666 subsequent hospitalized infections occurred, with crude incidence rates ranging from of 27.1 to 34.6 per 100 person-years.

When considering the different drugs taken after hospitalization, the risk of infection was significantly lower with abatacept and etanercept, compared with infliximab (hazard ratios of 0.80 and 0.83, respectively). There were no significant associations between the types of subsequent infections and any of the drugs taken after the first infection, Dr. Yun and her colleagues said.

Another analysis seemed to indicate that the risk of a subsequent infection peaked early for etanercept, infliximab, and adalimumab and dropped off after the first 3 months. In contrast, the risk curve with abatacept and rituximab stayed fairly flat throughout follow-up, they noted.

"These findings are compatible with studies suggesting an early increased risk for anti-TNF agents that declines over time," the authors wrote. "Perhaps further accentuating these differences, the substantial majority of anti-TNF users in the analysis were restarting therapy with a medication that they had been on, whereas most abatacept and rituximab users were new users."

The findings are somewhat at odds with national recommendations, Dr. Yun and her associates pointed out. The American College of Rheumatology recommends that RA patients on anti-TNF therapy switch to a non–anti-TNF biologic after a serious adverse event, including a hospitalized infection.

"Our results suggest that the ACR recommendation may be appropriate, especially if switching to abatacept, but considering the grouped safety profile of medications defined by an anti-TNF or non–anti-TNF common [mechanism of action] may not be appropriate."

The Agency for Healthcare Research and Quality funded the study. Dr. Yun did not report any financial disclosures, but several coauthors reported numerous financial relationships with a number of pharmaceutical companies marketing drugs for RA.

[email protected]

On Twitter @alz_gal

Rheumatoid arthritis patients taking an anti–tumor necrosis factor agent who had a prior hospitalization because of an infection significantly reduced their risk of a subsequent infection-related hospitalization by switching to etanercept or abatacept in a retrospective study of Medicare data.

The risk of a second hospitalization declined by 20% with abatacept (Orencia) and by 17% with etanercept (Enbrel), Huifeng Yun, Ph.D., and her colleagues reported (Ann. Rheum. Dis. 2014 March 7 [doi:10.1136/annrheumdis-2013-204011]).

"These findings provide new evidence for clinical management of high-risk RA patients and suggest that drug-specific guidance may be more appropriate when making safety-based recommendations, rather than simply lumping drugs together based on" mechanism of action, wrote Dr. Yun, an epidemiologist at the University of Birmingham, Ala., and her coauthors.

For the retrospective study, investigators examined Medicare data from 2006 to 2010 on nearly 13,000 patients with rheumatoid arthritis (RA). All of them had been hospitalized for an infection that occurred while taking a tumor necrosis factor (TNF) inhibitor and then either continued on the same medication or switched to another.

Of these, most (54.0%) were on infliximab (Remicade). Other drugs were etanercept (25.1%), adalimumab (Humira, 19.8%), certolizumab pegol (Cimzia, 0.6%), and golimumab (Simponi, 0.5%). The most common infection was pneumonia or other respiratory tract infection (30%); others included urinary tract (23%), skin/soft tissue (17%), and septicemia/bacteremia (11%).

After discharge, most started the same anti-TNF drug (79%), but 2% switched to another anti-TNF biologic, 3% switched to a non–anti-TNF biologic, and 16% didn’t get any biologic over the next 18 months. Only 10% of those who initially restarted the same anti-TNF inhibitor later switched to another biologic during follow-up.

From this primary cohort, the authors had data on 10,183 patients who received any biologic during 18 months of follow-up. During that period, 2,666 subsequent hospitalized infections occurred, with crude incidence rates ranging from of 27.1 to 34.6 per 100 person-years.

When considering the different drugs taken after hospitalization, the risk of infection was significantly lower with abatacept and etanercept, compared with infliximab (hazard ratios of 0.80 and 0.83, respectively). There were no significant associations between the types of subsequent infections and any of the drugs taken after the first infection, Dr. Yun and her colleagues said.

Another analysis seemed to indicate that the risk of a subsequent infection peaked early for etanercept, infliximab, and adalimumab and dropped off after the first 3 months. In contrast, the risk curve with abatacept and rituximab stayed fairly flat throughout follow-up, they noted.

"These findings are compatible with studies suggesting an early increased risk for anti-TNF agents that declines over time," the authors wrote. "Perhaps further accentuating these differences, the substantial majority of anti-TNF users in the analysis were restarting therapy with a medication that they had been on, whereas most abatacept and rituximab users were new users."

The findings are somewhat at odds with national recommendations, Dr. Yun and her associates pointed out. The American College of Rheumatology recommends that RA patients on anti-TNF therapy switch to a non–anti-TNF biologic after a serious adverse event, including a hospitalized infection.

"Our results suggest that the ACR recommendation may be appropriate, especially if switching to abatacept, but considering the grouped safety profile of medications defined by an anti-TNF or non–anti-TNF common [mechanism of action] may not be appropriate."

The Agency for Healthcare Research and Quality funded the study. Dr. Yun did not report any financial disclosures, but several coauthors reported numerous financial relationships with a number of pharmaceutical companies marketing drugs for RA.

[email protected]

On Twitter @alz_gal

A high dose of simvastatin decreased whole-brain atrophy by 43% per year over 24 months, compared with placebo, in a phase II, randomized, controlled trial in patients with secondary progressive multiple sclerosis.

The drug had no apparent effect on relapses or new lesions. But patients who took it showed significantly better scores on the Multiple Sclerosis Impact Scale–29 (MSIS-29) and the Expanded Disability Status Scale (EDSS), suggesting that slowing brain atrophy may have a beneficial effect on function, reported Jeremy Chataway, Ph.D., of the University College London (Lancet 2014 March 19 [doi:10.1016/S0140-6736(13)62242-4]).

However, those results should be interpreted cautiously because functional status wasn’t the primary endpoint of the trial, wrote Dr. Chataway and his coauthors.

The study randomized 140 patients with secondary progressive multiple sclerosis to placebo or 80 mg/day simvastatin for 24 months. Brain volume and functional and psychological status were assessed at baseline and 1, 6, 12, and 24 months. The mean age of the patients was 52 years, and average disease duration was 21 years. The mean whole-brain volume was 1,100 mL. The mean EDSS score was 5.8, and the mean MSIS-29 score was 70.

Nine patients did not complete the full trial. Treatment compliance was 90% or greater for 77%-78% of the remaining patients.

At 24 months, whole-brain volume had declined in both groups. But the annual decline was significantly less in those taking simvastatin (–0.288% vs. –0.584%). The adjusted difference in annual atrophy was 0.254% per year, resulting in 43% less volume loss per year in the simvastatin group than in the placebo group. This effect was seen in MRI scans at both 12 and 24 months, and occurred in three-fourths of the treated population.

The rate of new or enlarging lesions was not significantly different, although there was a trend toward benefit in the treated group (1.50 vs. 2.19 per person per year). The relapse rates were similar (0.20 vs. 0.16 events per person/year).

At 24 months, the mean EDSS score in the simvastatin group was significantly lower than in the placebo group (a mean difference of –0.254 after adjustment for baseline measurements). The total mean MSIS-29 also showed a significant between-group difference in favor of simvastatin (–4.78 after adjustment). The difference was most pronounced in the physical subscale of the MSIS-29 (–3.73), but the psychological subscale was not significantly different. Overall, changes in these secondary measures by 24 months reflected worsening in both groups, but more so in the placebo group.

Cholesterol also decreased significantly in the simvastatin group (from 5.5 mmol/L to 4.1 mmol/L); it did not change in the placebo group. However, there were no differences in inflammatory markers.

Drug-related adverse events occurred in 23% of patients on simvastatin, compared with 19% of those on placebo. Simvastatin was generally well tolerated, with no safety issues.

It’s not entirely clear how a statin would slow disease progression, the researchers said. "gAccumulating evidence shows that statins have cell protective properties. For example, inhibition of inducible nitric oxide synthase, thus reducing release of free radicals from activated microglia and astrocytes or exerting a neuroprotective effect by prevention of glutamate-mediated excitotoxic effects."h

Simvastatin might also improve cerebral vasomotor reactivity, which could protect against hypoxic damage, they added. The general benefit of statins on vascular health could also be a contributor.

The study was partially supported by a grant from the U.K. National Institute for Health Research, the Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, and a personal contribution.

None of the authors had any financial disclosures.

[email protected]

On Twitter @alz_gal

A high dose of simvastatin decreased whole-brain atrophy by 43% per year over 24 months, compared with placebo, in a phase II, randomized, controlled trial in patients with secondary progressive multiple sclerosis.

The drug had no apparent effect on relapses or new lesions. But patients who took it showed significantly better scores on the Multiple Sclerosis Impact Scale–29 (MSIS-29) and the Expanded Disability Status Scale (EDSS), suggesting that slowing brain atrophy may have a beneficial effect on function, reported Jeremy Chataway, Ph.D., of the University College London (Lancet 2014 March 19 [doi:10.1016/S0140-6736(13)62242-4]).

However, those results should be interpreted cautiously because functional status wasn’t the primary endpoint of the trial, wrote Dr. Chataway and his coauthors.

The study randomized 140 patients with secondary progressive multiple sclerosis to placebo or 80 mg/day simvastatin for 24 months. Brain volume and functional and psychological status were assessed at baseline and 1, 6, 12, and 24 months. The mean age of the patients was 52 years, and average disease duration was 21 years. The mean whole-brain volume was 1,100 mL. The mean EDSS score was 5.8, and the mean MSIS-29 score was 70.

Nine patients did not complete the full trial. Treatment compliance was 90% or greater for 77%-78% of the remaining patients.

At 24 months, whole-brain volume had declined in both groups. But the annual decline was significantly less in those taking simvastatin (–0.288% vs. –0.584%). The adjusted difference in annual atrophy was 0.254% per year, resulting in 43% less volume loss per year in the simvastatin group than in the placebo group. This effect was seen in MRI scans at both 12 and 24 months, and occurred in three-fourths of the treated population.

The rate of new or enlarging lesions was not significantly different, although there was a trend toward benefit in the treated group (1.50 vs. 2.19 per person per year). The relapse rates were similar (0.20 vs. 0.16 events per person/year).

At 24 months, the mean EDSS score in the simvastatin group was significantly lower than in the placebo group (a mean difference of –0.254 after adjustment for baseline measurements). The total mean MSIS-29 also showed a significant between-group difference in favor of simvastatin (–4.78 after adjustment). The difference was most pronounced in the physical subscale of the MSIS-29 (–3.73), but the psychological subscale was not significantly different. Overall, changes in these secondary measures by 24 months reflected worsening in both groups, but more so in the placebo group.

Cholesterol also decreased significantly in the simvastatin group (from 5.5 mmol/L to 4.1 mmol/L); it did not change in the placebo group. However, there were no differences in inflammatory markers.

Drug-related adverse events occurred in 23% of patients on simvastatin, compared with 19% of those on placebo. Simvastatin was generally well tolerated, with no safety issues.

It’s not entirely clear how a statin would slow disease progression, the researchers said. "gAccumulating evidence shows that statins have cell protective properties. For example, inhibition of inducible nitric oxide synthase, thus reducing release of free radicals from activated microglia and astrocytes or exerting a neuroprotective effect by prevention of glutamate-mediated excitotoxic effects."h

Simvastatin might also improve cerebral vasomotor reactivity, which could protect against hypoxic damage, they added. The general benefit of statins on vascular health could also be a contributor.

The study was partially supported by a grant from the U.K. National Institute for Health Research, the Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, and a personal contribution.

None of the authors had any financial disclosures.

[email protected]

On Twitter @alz_gal

A high dose of simvastatin decreased whole-brain atrophy by 43% per year over 24 months, compared with placebo, in a phase II, randomized, controlled trial in patients with secondary progressive multiple sclerosis.

The drug had no apparent effect on relapses or new lesions. But patients who took it showed significantly better scores on the Multiple Sclerosis Impact Scale–29 (MSIS-29) and the Expanded Disability Status Scale (EDSS), suggesting that slowing brain atrophy may have a beneficial effect on function, reported Jeremy Chataway, Ph.D., of the University College London (Lancet 2014 March 19 [doi:10.1016/S0140-6736(13)62242-4]).

However, those results should be interpreted cautiously because functional status wasn’t the primary endpoint of the trial, wrote Dr. Chataway and his coauthors.

The study randomized 140 patients with secondary progressive multiple sclerosis to placebo or 80 mg/day simvastatin for 24 months. Brain volume and functional and psychological status were assessed at baseline and 1, 6, 12, and 24 months. The mean age of the patients was 52 years, and average disease duration was 21 years. The mean whole-brain volume was 1,100 mL. The mean EDSS score was 5.8, and the mean MSIS-29 score was 70.

Nine patients did not complete the full trial. Treatment compliance was 90% or greater for 77%-78% of the remaining patients.

At 24 months, whole-brain volume had declined in both groups. But the annual decline was significantly less in those taking simvastatin (–0.288% vs. –0.584%). The adjusted difference in annual atrophy was 0.254% per year, resulting in 43% less volume loss per year in the simvastatin group than in the placebo group. This effect was seen in MRI scans at both 12 and 24 months, and occurred in three-fourths of the treated population.

The rate of new or enlarging lesions was not significantly different, although there was a trend toward benefit in the treated group (1.50 vs. 2.19 per person per year). The relapse rates were similar (0.20 vs. 0.16 events per person/year).

At 24 months, the mean EDSS score in the simvastatin group was significantly lower than in the placebo group (a mean difference of –0.254 after adjustment for baseline measurements). The total mean MSIS-29 also showed a significant between-group difference in favor of simvastatin (–4.78 after adjustment). The difference was most pronounced in the physical subscale of the MSIS-29 (–3.73), but the psychological subscale was not significantly different. Overall, changes in these secondary measures by 24 months reflected worsening in both groups, but more so in the placebo group.

Cholesterol also decreased significantly in the simvastatin group (from 5.5 mmol/L to 4.1 mmol/L); it did not change in the placebo group. However, there were no differences in inflammatory markers.

Drug-related adverse events occurred in 23% of patients on simvastatin, compared with 19% of those on placebo. Simvastatin was generally well tolerated, with no safety issues.

It’s not entirely clear how a statin would slow disease progression, the researchers said. "gAccumulating evidence shows that statins have cell protective properties. For example, inhibition of inducible nitric oxide synthase, thus reducing release of free radicals from activated microglia and astrocytes or exerting a neuroprotective effect by prevention of glutamate-mediated excitotoxic effects."h

Simvastatin might also improve cerebral vasomotor reactivity, which could protect against hypoxic damage, they added. The general benefit of statins on vascular health could also be a contributor.

The study was partially supported by a grant from the U.K. National Institute for Health Research, the Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, and a personal contribution.

None of the authors had any financial disclosures.

[email protected]

On Twitter @alz_gal

Atacicept, a drug designed to interfere with B-cell differentiation and maturation, was associated with up to twice as many relapses as placebo among patients with multiple sclerosis in the 36-week, phase II ATAMS (Atacicept in Multiple Sclerosis Extension Study).

Interim findings were enough to halt the drug’s placebo-controlled dose-ranging study, Dr. Ludwig Kappos of the University Hospital Basel, Switzerland, and his colleagues reported (Lancet Neurol. 2014 [doi: 10.1016/S1474-4422(14)70028-6]). The trial results were originally reported at the 2011 joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The increase in disease activity was surprising, wrote Dr. Kappos and his coauthors, especially because atacicept did not cause such problems in other studies.

"Studies of atacicept in other autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, had not suggested that such B-cell-targeted interventions might enhance, rather than suppress, inflammatory activity," they said.

"Our finding of an early and robust increase in relapse activity with atacicept treatment in a typical population with relapsing-remitting multiple sclerosis was therefore unexpected. This increase in clinical disease activity occurred in parallel with reductions in serum immunoglobulin concentrations and mature B-cell counts of the same dynamics and degree as reported in previous atacicept studies."

Fortunately, the authors noted, the relapses didn’t translate into any increase in disease severity, and measurements of all the affected immune factors returned to normal shortly after treatment ceased.

In an editorial accompanying the published paper, Dr. Fred Lühder and Dr. Ralf Gold wrote that there’s little doubt that B cells are a valid therapeutic target in multiple sclerosis. But they seem to exist in a fine-tune balance that, if disrupted, can harm, rather than help (Lancet Neurol. 2014 March 6 [doi: 10.1016/S1474-4422(14)70050-X]).

Atacicept binds to B-lymphocyte stimulator (BLyS), a cytokine that helps control B-cell differentiation, maturation, and survival. But unlike other B-cell modulators, it doesn’t kill all of them immediately. In ATAMS, the maximum reduction was 60%-70%.

"A probably more important issue is the types of B cell that are preferentially depleted," Dr. Lühder and Dr. Gold wrote. "Experimental evidence in animal models suggests that B cells potentially have a dual role in the pathogenesis of neuroinflammation. ... Spontaneous demyelinating disease occurs when both receptors are brought together, suggesting that antigen-specific B-cells could provide the essential stimulus for antigen-specific T-cells."

The second type of B cells, which produce interleukin-10, exert a regulatory effect, controlling the action of activated T cells, and thus reduce disease severity.

"Since BLyS is believed to be involved in the differentiation of these regulatory B-cells, the targeting of BLyS might disturb the fine-tuned balance of conventional and regulatory B-cells in favor of the conventional cells, eventually resulting in increased disease activity, as seen in ATAMS," they wrote.

Researchers will learn as much from this failed trial as they would from any successful trial, Dr. Lühder and Dr. Gold said. "Many other candidates have gone the same way. B-cells should still be regarded as a valid target, but there are good and bad B-cells in multiple sclerosis, and the net effect of a particular treatment on this complex scenario can be unpredictable."

Dr. Lühder is with the neuroimmunology department at the Institute for Multiple Sclerosis Research and the Max Planck Institute for Experimental Medicine at the University of Göttingen, Germany. Dr. Gold is with the department of neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.

The study was sponsored by Merck Serono. Dr. Kappos’s institution has received Merck grant money. Most of the coauthors reported numerous financial disclosures, including financial relationships with Merck Serono.

[email protected]

Atacicept, a drug designed to interfere with B-cell differentiation and maturation, was associated with up to twice as many relapses as placebo among patients with multiple sclerosis in the 36-week, phase II ATAMS (Atacicept in Multiple Sclerosis Extension Study).

Interim findings were enough to halt the drug’s placebo-controlled dose-ranging study, Dr. Ludwig Kappos of the University Hospital Basel, Switzerland, and his colleagues reported (Lancet Neurol. 2014 [doi: 10.1016/S1474-4422(14)70028-6]). The trial results were originally reported at the 2011 joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The increase in disease activity was surprising, wrote Dr. Kappos and his coauthors, especially because atacicept did not cause such problems in other studies.

"Studies of atacicept in other autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, had not suggested that such B-cell-targeted interventions might enhance, rather than suppress, inflammatory activity," they said.

"Our finding of an early and robust increase in relapse activity with atacicept treatment in a typical population with relapsing-remitting multiple sclerosis was therefore unexpected. This increase in clinical disease activity occurred in parallel with reductions in serum immunoglobulin concentrations and mature B-cell counts of the same dynamics and degree as reported in previous atacicept studies."

Fortunately, the authors noted, the relapses didn’t translate into any increase in disease severity, and measurements of all the affected immune factors returned to normal shortly after treatment ceased.

In an editorial accompanying the published paper, Dr. Fred Lühder and Dr. Ralf Gold wrote that there’s little doubt that B cells are a valid therapeutic target in multiple sclerosis. But they seem to exist in a fine-tune balance that, if disrupted, can harm, rather than help (Lancet Neurol. 2014 March 6 [doi: 10.1016/S1474-4422(14)70050-X]).

Atacicept binds to B-lymphocyte stimulator (BLyS), a cytokine that helps control B-cell differentiation, maturation, and survival. But unlike other B-cell modulators, it doesn’t kill all of them immediately. In ATAMS, the maximum reduction was 60%-70%.

"A probably more important issue is the types of B cell that are preferentially depleted," Dr. Lühder and Dr. Gold wrote. "Experimental evidence in animal models suggests that B cells potentially have a dual role in the pathogenesis of neuroinflammation. ... Spontaneous demyelinating disease occurs when both receptors are brought together, suggesting that antigen-specific B-cells could provide the essential stimulus for antigen-specific T-cells."

The second type of B cells, which produce interleukin-10, exert a regulatory effect, controlling the action of activated T cells, and thus reduce disease severity.

"Since BLyS is believed to be involved in the differentiation of these regulatory B-cells, the targeting of BLyS might disturb the fine-tuned balance of conventional and regulatory B-cells in favor of the conventional cells, eventually resulting in increased disease activity, as seen in ATAMS," they wrote.

Researchers will learn as much from this failed trial as they would from any successful trial, Dr. Lühder and Dr. Gold said. "Many other candidates have gone the same way. B-cells should still be regarded as a valid target, but there are good and bad B-cells in multiple sclerosis, and the net effect of a particular treatment on this complex scenario can be unpredictable."

Dr. Lühder is with the neuroimmunology department at the Institute for Multiple Sclerosis Research and the Max Planck Institute for Experimental Medicine at the University of Göttingen, Germany. Dr. Gold is with the department of neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.

The study was sponsored by Merck Serono. Dr. Kappos’s institution has received Merck grant money. Most of the coauthors reported numerous financial disclosures, including financial relationships with Merck Serono.

[email protected]

Atacicept, a drug designed to interfere with B-cell differentiation and maturation, was associated with up to twice as many relapses as placebo among patients with multiple sclerosis in the 36-week, phase II ATAMS (Atacicept in Multiple Sclerosis Extension Study).

Interim findings were enough to halt the drug’s placebo-controlled dose-ranging study, Dr. Ludwig Kappos of the University Hospital Basel, Switzerland, and his colleagues reported (Lancet Neurol. 2014 [doi: 10.1016/S1474-4422(14)70028-6]). The trial results were originally reported at the 2011 joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The increase in disease activity was surprising, wrote Dr. Kappos and his coauthors, especially because atacicept did not cause such problems in other studies.

"Studies of atacicept in other autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, had not suggested that such B-cell-targeted interventions might enhance, rather than suppress, inflammatory activity," they said.

"Our finding of an early and robust increase in relapse activity with atacicept treatment in a typical population with relapsing-remitting multiple sclerosis was therefore unexpected. This increase in clinical disease activity occurred in parallel with reductions in serum immunoglobulin concentrations and mature B-cell counts of the same dynamics and degree as reported in previous atacicept studies."

Fortunately, the authors noted, the relapses didn’t translate into any increase in disease severity, and measurements of all the affected immune factors returned to normal shortly after treatment ceased.

In an editorial accompanying the published paper, Dr. Fred Lühder and Dr. Ralf Gold wrote that there’s little doubt that B cells are a valid therapeutic target in multiple sclerosis. But they seem to exist in a fine-tune balance that, if disrupted, can harm, rather than help (Lancet Neurol. 2014 March 6 [doi: 10.1016/S1474-4422(14)70050-X]).

Atacicept binds to B-lymphocyte stimulator (BLyS), a cytokine that helps control B-cell differentiation, maturation, and survival. But unlike other B-cell modulators, it doesn’t kill all of them immediately. In ATAMS, the maximum reduction was 60%-70%.

"A probably more important issue is the types of B cell that are preferentially depleted," Dr. Lühder and Dr. Gold wrote. "Experimental evidence in animal models suggests that B cells potentially have a dual role in the pathogenesis of neuroinflammation. ... Spontaneous demyelinating disease occurs when both receptors are brought together, suggesting that antigen-specific B-cells could provide the essential stimulus for antigen-specific T-cells."

The second type of B cells, which produce interleukin-10, exert a regulatory effect, controlling the action of activated T cells, and thus reduce disease severity.

"Since BLyS is believed to be involved in the differentiation of these regulatory B-cells, the targeting of BLyS might disturb the fine-tuned balance of conventional and regulatory B-cells in favor of the conventional cells, eventually resulting in increased disease activity, as seen in ATAMS," they wrote.

Researchers will learn as much from this failed trial as they would from any successful trial, Dr. Lühder and Dr. Gold said. "Many other candidates have gone the same way. B-cells should still be regarded as a valid target, but there are good and bad B-cells in multiple sclerosis, and the net effect of a particular treatment on this complex scenario can be unpredictable."

Dr. Lühder is with the neuroimmunology department at the Institute for Multiple Sclerosis Research and the Max Planck Institute for Experimental Medicine at the University of Göttingen, Germany. Dr. Gold is with the department of neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.

The study was sponsored by Merck Serono. Dr. Kappos’s institution has received Merck grant money. Most of the coauthors reported numerous financial disclosures, including financial relationships with Merck Serono.

[email protected]

MIAMI BEACH – A failure to develop hypophosphatemia during the first few days after major hepatectomy was associated with up to a threefold increase in the risk of major complications, hepatic insufficiency, and 30-day mortality.

Contrary to a widely held belief, hypophosphatemia may not be a problem requiring treatment, but rather a normal physiologic response to liver resection – a sign that hepatocytes are working hard to regenerate and recover their function, Dr. Malcolm Squires said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

"The process of liver regeneration is metabolically demanding," said Dr. Squires of Emory University, Atlanta. "Immediately after hepatectomy, the [adenosine triphosphate] content decreases by 35%. The level starts to recover by day 6, to about preoperative levels by day 14. But during that process, the hepatocytes are rapidly consuming ATP; there is a significant concurrent phosphate uptake by the liver remnant, and we see that decrease in serum phosphorus."

These are all signs of normal liver remnant recovery, Dr. Squires said. Consequently, the failure to follow this pathway suggests that the remnant is not on a good recovery trajectory, but instead, a path that could lead to big problems.

To examine this idea, he and his colleagues looked at 719 patients who had undergone major hepatectomy from 2000 to 2012 and who had serum phosphorus evaluated after surgery.

Measures included daily phosphorus levels for the first week after surgery, as well as the day of the phosphorus nadir. Mean age of the patients was 57 years. The most common type of resection was a right hepatectomy (39%), followed by a left (23%), extended right (20%), and extended left (6%). Ten percent of patients had a nonanatomic resection, and 20% a concurrent bile duct resection.

The most common pathology was metastatic colorectal cancer (32%), followed by cholangiocarcinoma (12%), hepatocellular carcinoma (9%), and metastatic neuroendocrine tumor (5%). Other pathologies made up the remainder.

Most patients (69%) got phosphorus repletion in the first 72 hours after surgery, although this intervention was not protocol driven, Dr. Squires noted.

Postoperative hepatic insufficiency developed in 63 patients (9%). About a fourth (169) had major complications. Mortality was 4% within 30 days and 5% within 90 days.

The median preoperative serum phosphorus level was 3.7 mg/dL. This fell precipitously to a median nadir of 2.4 mg/dL (the lower limit of normal), which occurred on postoperative day 2 or 3 for the majority of patients. Recovery was linear, with a near-complete postoperative recovery by day 14. Patients followed the same trajectory regardless of the type of hepatectomy.

The researchers dichotomized the patients into those with a postoperative day 2 phosphorus of 2.4 mg/dL or higher (72%), or below 2.4 mg/dL (28%).

Patients with the higher levels were significantly more likely to develop hepatic insufficiency (12% vs. 7%) and major complications (27% vs. 20%), and to die within 30 days (4% vs. 2%) and 90 days (8% vs. 4%).

A multivariate analysis found that phosphorus of more than 2.4 mg/dL increased the risk of hepatic insufficiency by 78% and major complications by 60%. It nearly tripled the risk of 30-day mortality (HR 2.7) and more than doubled the risk of 90-day mortality (HR 2.5).

The team also looked at the timing of phosphorus nadir. Most patients (80%) achieved this by postoperative day 3, so the researchers divided the group into those who had that level within 3 days and those who had it later. Patients with the delayed nadir were twice as likely to have hepatic insufficiency and major complications, and to die within 30 days. The trend was to increased death within 90 days as well, but Dr. Squires said the difference was not statistically significant.

Early postoperative phosphorus administration did not affect these findings, he added.

Dr. Squires reported having no financial disclosures.

[email protected]

MIAMI BEACH – A failure to develop hypophosphatemia during the first few days after major hepatectomy was associated with up to a threefold increase in the risk of major complications, hepatic insufficiency, and 30-day mortality.

Contrary to a widely held belief, hypophosphatemia may not be a problem requiring treatment, but rather a normal physiologic response to liver resection – a sign that hepatocytes are working hard to regenerate and recover their function, Dr. Malcolm Squires said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

"The process of liver regeneration is metabolically demanding," said Dr. Squires of Emory University, Atlanta. "Immediately after hepatectomy, the [adenosine triphosphate] content decreases by 35%. The level starts to recover by day 6, to about preoperative levels by day 14. But during that process, the hepatocytes are rapidly consuming ATP; there is a significant concurrent phosphate uptake by the liver remnant, and we see that decrease in serum phosphorus."

These are all signs of normal liver remnant recovery, Dr. Squires said. Consequently, the failure to follow this pathway suggests that the remnant is not on a good recovery trajectory, but instead, a path that could lead to big problems.

To examine this idea, he and his colleagues looked at 719 patients who had undergone major hepatectomy from 2000 to 2012 and who had serum phosphorus evaluated after surgery.

Measures included daily phosphorus levels for the first week after surgery, as well as the day of the phosphorus nadir. Mean age of the patients was 57 years. The most common type of resection was a right hepatectomy (39%), followed by a left (23%), extended right (20%), and extended left (6%). Ten percent of patients had a nonanatomic resection, and 20% a concurrent bile duct resection.

The most common pathology was metastatic colorectal cancer (32%), followed by cholangiocarcinoma (12%), hepatocellular carcinoma (9%), and metastatic neuroendocrine tumor (5%). Other pathologies made up the remainder.

Most patients (69%) got phosphorus repletion in the first 72 hours after surgery, although this intervention was not protocol driven, Dr. Squires noted.

Postoperative hepatic insufficiency developed in 63 patients (9%). About a fourth (169) had major complications. Mortality was 4% within 30 days and 5% within 90 days.

The median preoperative serum phosphorus level was 3.7 mg/dL. This fell precipitously to a median nadir of 2.4 mg/dL (the lower limit of normal), which occurred on postoperative day 2 or 3 for the majority of patients. Recovery was linear, with a near-complete postoperative recovery by day 14. Patients followed the same trajectory regardless of the type of hepatectomy.

The researchers dichotomized the patients into those with a postoperative day 2 phosphorus of 2.4 mg/dL or higher (72%), or below 2.4 mg/dL (28%).

Patients with the higher levels were significantly more likely to develop hepatic insufficiency (12% vs. 7%) and major complications (27% vs. 20%), and to die within 30 days (4% vs. 2%) and 90 days (8% vs. 4%).

A multivariate analysis found that phosphorus of more than 2.4 mg/dL increased the risk of hepatic insufficiency by 78% and major complications by 60%. It nearly tripled the risk of 30-day mortality (HR 2.7) and more than doubled the risk of 90-day mortality (HR 2.5).

The team also looked at the timing of phosphorus nadir. Most patients (80%) achieved this by postoperative day 3, so the researchers divided the group into those who had that level within 3 days and those who had it later. Patients with the delayed nadir were twice as likely to have hepatic insufficiency and major complications, and to die within 30 days. The trend was to increased death within 90 days as well, but Dr. Squires said the difference was not statistically significant.

Early postoperative phosphorus administration did not affect these findings, he added.

Dr. Squires reported having no financial disclosures.

[email protected]

MIAMI BEACH – A failure to develop hypophosphatemia during the first few days after major hepatectomy was associated with up to a threefold increase in the risk of major complications, hepatic insufficiency, and 30-day mortality.

Contrary to a widely held belief, hypophosphatemia may not be a problem requiring treatment, but rather a normal physiologic response to liver resection – a sign that hepatocytes are working hard to regenerate and recover their function, Dr. Malcolm Squires said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

"The process of liver regeneration is metabolically demanding," said Dr. Squires of Emory University, Atlanta. "Immediately after hepatectomy, the [adenosine triphosphate] content decreases by 35%. The level starts to recover by day 6, to about preoperative levels by day 14. But during that process, the hepatocytes are rapidly consuming ATP; there is a significant concurrent phosphate uptake by the liver remnant, and we see that decrease in serum phosphorus."

These are all signs of normal liver remnant recovery, Dr. Squires said. Consequently, the failure to follow this pathway suggests that the remnant is not on a good recovery trajectory, but instead, a path that could lead to big problems.

To examine this idea, he and his colleagues looked at 719 patients who had undergone major hepatectomy from 2000 to 2012 and who had serum phosphorus evaluated after surgery.

Measures included daily phosphorus levels for the first week after surgery, as well as the day of the phosphorus nadir. Mean age of the patients was 57 years. The most common type of resection was a right hepatectomy (39%), followed by a left (23%), extended right (20%), and extended left (6%). Ten percent of patients had a nonanatomic resection, and 20% a concurrent bile duct resection.

The most common pathology was metastatic colorectal cancer (32%), followed by cholangiocarcinoma (12%), hepatocellular carcinoma (9%), and metastatic neuroendocrine tumor (5%). Other pathologies made up the remainder.

Most patients (69%) got phosphorus repletion in the first 72 hours after surgery, although this intervention was not protocol driven, Dr. Squires noted.

Postoperative hepatic insufficiency developed in 63 patients (9%). About a fourth (169) had major complications. Mortality was 4% within 30 days and 5% within 90 days.

The median preoperative serum phosphorus level was 3.7 mg/dL. This fell precipitously to a median nadir of 2.4 mg/dL (the lower limit of normal), which occurred on postoperative day 2 or 3 for the majority of patients. Recovery was linear, with a near-complete postoperative recovery by day 14. Patients followed the same trajectory regardless of the type of hepatectomy.

The researchers dichotomized the patients into those with a postoperative day 2 phosphorus of 2.4 mg/dL or higher (72%), or below 2.4 mg/dL (28%).

Patients with the higher levels were significantly more likely to develop hepatic insufficiency (12% vs. 7%) and major complications (27% vs. 20%), and to die within 30 days (4% vs. 2%) and 90 days (8% vs. 4%).

A multivariate analysis found that phosphorus of more than 2.4 mg/dL increased the risk of hepatic insufficiency by 78% and major complications by 60%. It nearly tripled the risk of 30-day mortality (HR 2.7) and more than doubled the risk of 90-day mortality (HR 2.5).

The team also looked at the timing of phosphorus nadir. Most patients (80%) achieved this by postoperative day 3, so the researchers divided the group into those who had that level within 3 days and those who had it later. Patients with the delayed nadir were twice as likely to have hepatic insufficiency and major complications, and to die within 30 days. The trend was to increased death within 90 days as well, but Dr. Squires said the difference was not statistically significant.

Early postoperative phosphorus administration did not affect these findings, he added.

Dr. Squires reported having no financial disclosures.

[email protected]

Female-to-female transmission probably caused an HIV infection in a Texas woman, according to a report from the Centers for Disease Control and Prevention.

The 46-year-old woman was in a monogamous relationship with an HIV-positive 43-year-old woman. The patient reported no sexual contact with a man for 10 years prior to infection. She regularly sold plasma to supplement her income, and learned of her HIV status in April 2012*, when routine lab work required before every donation came back positive. The labs from her last donation 6 months earlier were clean, Shirley K. Chan and her colleagues wrote in the March 14 issue of the Morbidity and Mortality Weekly Report (2014; 63:209-12).

The patient* did not have any of the classic HIV risk factors, including intravenous drug use, tattoos, acupuncture, transfusions, or transplants. The strains in both women were nearly 98% genetically identical. Therefore, wrote Ms. Chan of the Houston Department of Health and Human Services and her coauthors, fluid exchange with the partner was the most likely source of transmission. The women reported sharing sex toys, engaging in sex during menstruation, and having sex rough enough to cause bleeding in either.

The HIV-positive partner had been diagnosed in 2008. At that time, her HIV-1 viral load was 82,000 copies/mL, and her CD4+ T-lymphocyte count was 372 cells/mm³ (25%). She began antiretroviral treatment in early 2009, but stopped in November 2010. When she was lost to follow-up in January 2011, her HIV-1 viral load had dropped to 178 copies/mL, and her CD4+ T-lymphocyte count had increased to 554 cells/mm³ (44%).

At the time of diagnosis, the patient’s HIV-1 viral load was 23,600 copies/mL. When the partner was tested at that point, her HIV-1 viral load was much lower than the last measurement (69,000 copies/mL).

Woman-to-woman HIV transmission is considered very rare, but the true rate is difficult to determine because confounding risk factors – most often intravenous drug use and sex with men – are usually present, the authors wrote in an editorial note. This finding underscores the need for preemptive counseling for all HIV patients, regardless of their sexual orientation and relationship status, the investigators noted.

"All persons at risk for HIV, including all discordant couples, should receive information regarding the prevention of HIV and sexually transmitted infections to prevent the HIV-negative partner from acquiring the infection. Furthermore, all persons identified as infected with HIV should be linked to and retained in medical care. Control of HIV infection with suppression of viral load can result in better health outcomes and a reduced chance of transmitting HIV to partners," Dr. Chan and her associates said.

As public health care workers, none of the authors had any financial disclosures.

[email protected]

On Twitter @alz_gal

*Correction, 3/13/2014: An earlier version of this article misstated the time of the patient's diagnosis. In addition, only that the patient did not have any of the classic HIV risk factors.

Female-to-female transmission probably caused an HIV infection in a Texas woman, according to a report from the Centers for Disease Control and Prevention.

The 46-year-old woman was in a monogamous relationship with an HIV-positive 43-year-old woman. The patient reported no sexual contact with a man for 10 years prior to infection. She regularly sold plasma to supplement her income, and learned of her HIV status in April 2012*, when routine lab work required before every donation came back positive. The labs from her last donation 6 months earlier were clean, Shirley K. Chan and her colleagues wrote in the March 14 issue of the Morbidity and Mortality Weekly Report (2014; 63:209-12).

The patient* did not have any of the classic HIV risk factors, including intravenous drug use, tattoos, acupuncture, transfusions, or transplants. The strains in both women were nearly 98% genetically identical. Therefore, wrote Ms. Chan of the Houston Department of Health and Human Services and her coauthors, fluid exchange with the partner was the most likely source of transmission. The women reported sharing sex toys, engaging in sex during menstruation, and having sex rough enough to cause bleeding in either.

The HIV-positive partner had been diagnosed in 2008. At that time, her HIV-1 viral load was 82,000 copies/mL, and her CD4+ T-lymphocyte count was 372 cells/mm³ (25%). She began antiretroviral treatment in early 2009, but stopped in November 2010. When she was lost to follow-up in January 2011, her HIV-1 viral load had dropped to 178 copies/mL, and her CD4+ T-lymphocyte count had increased to 554 cells/mm³ (44%).

At the time of diagnosis, the patient’s HIV-1 viral load was 23,600 copies/mL. When the partner was tested at that point, her HIV-1 viral load was much lower than the last measurement (69,000 copies/mL).

Woman-to-woman HIV transmission is considered very rare, but the true rate is difficult to determine because confounding risk factors – most often intravenous drug use and sex with men – are usually present, the authors wrote in an editorial note. This finding underscores the need for preemptive counseling for all HIV patients, regardless of their sexual orientation and relationship status, the investigators noted.

"All persons at risk for HIV, including all discordant couples, should receive information regarding the prevention of HIV and sexually transmitted infections to prevent the HIV-negative partner from acquiring the infection. Furthermore, all persons identified as infected with HIV should be linked to and retained in medical care. Control of HIV infection with suppression of viral load can result in better health outcomes and a reduced chance of transmitting HIV to partners," Dr. Chan and her associates said.

As public health care workers, none of the authors had any financial disclosures.

[email protected]

On Twitter @alz_gal

*Correction, 3/13/2014: An earlier version of this article misstated the time of the patient's diagnosis. In addition, only that the patient did not have any of the classic HIV risk factors.

Female-to-female transmission probably caused an HIV infection in a Texas woman, according to a report from the Centers for Disease Control and Prevention.

The 46-year-old woman was in a monogamous relationship with an HIV-positive 43-year-old woman. The patient reported no sexual contact with a man for 10 years prior to infection. She regularly sold plasma to supplement her income, and learned of her HIV status in April 2012*, when routine lab work required before every donation came back positive. The labs from her last donation 6 months earlier were clean, Shirley K. Chan and her colleagues wrote in the March 14 issue of the Morbidity and Mortality Weekly Report (2014; 63:209-12).

The patient* did not have any of the classic HIV risk factors, including intravenous drug use, tattoos, acupuncture, transfusions, or transplants. The strains in both women were nearly 98% genetically identical. Therefore, wrote Ms. Chan of the Houston Department of Health and Human Services and her coauthors, fluid exchange with the partner was the most likely source of transmission. The women reported sharing sex toys, engaging in sex during menstruation, and having sex rough enough to cause bleeding in either.

The HIV-positive partner had been diagnosed in 2008. At that time, her HIV-1 viral load was 82,000 copies/mL, and her CD4+ T-lymphocyte count was 372 cells/mm³ (25%). She began antiretroviral treatment in early 2009, but stopped in November 2010. When she was lost to follow-up in January 2011, her HIV-1 viral load had dropped to 178 copies/mL, and her CD4+ T-lymphocyte count had increased to 554 cells/mm³ (44%).

At the time of diagnosis, the patient’s HIV-1 viral load was 23,600 copies/mL. When the partner was tested at that point, her HIV-1 viral load was much lower than the last measurement (69,000 copies/mL).

Woman-to-woman HIV transmission is considered very rare, but the true rate is difficult to determine because confounding risk factors – most often intravenous drug use and sex with men – are usually present, the authors wrote in an editorial note. This finding underscores the need for preemptive counseling for all HIV patients, regardless of their sexual orientation and relationship status, the investigators noted.

"All persons at risk for HIV, including all discordant couples, should receive information regarding the prevention of HIV and sexually transmitted infections to prevent the HIV-negative partner from acquiring the infection. Furthermore, all persons identified as infected with HIV should be linked to and retained in medical care. Control of HIV infection with suppression of viral load can result in better health outcomes and a reduced chance of transmitting HIV to partners," Dr. Chan and her associates said.

As public health care workers, none of the authors had any financial disclosures.

[email protected]

On Twitter @alz_gal

*Correction, 3/13/2014: An earlier version of this article misstated the time of the patient's diagnosis. In addition, only that the patient did not have any of the classic HIV risk factors.

MIAMI BEACH – For patients with colorectal cancer and liver metastasis, one-stage surgery cuts hospital time and expense.

Compared to a staged approach, resecting both the primary and metastatic cancers shaved almost $28,000 off total hospital charges. Most of the savings came from the shortened hospital stay – an average of 6 fewer days than for patients with staged procedures, Dr. Aslam Ejaz said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

"The main driving factor [of costs] was the increasing length of stay," said Dr. Ejaz, a research fellow in surgical oncology at Johns Hopkins Hospital, Baltimore. "Each additional day resulted in a mean increase of $3,600."

Most studies have found similar clinical outcomes for such patients, regardless of whether their surgical treatment is staged or simultaneous. But there are few data comparing the techniques’ economic impact.

For the study, Dr. Ejaz used a Johns Hopkins database to examine the staged vs. the one-stage approach. His cohort included 224 patients who, from 1990 to 2012, underwent a liver resection with curative intent for synchronous colorectal liver metastasis. They had a simultaneous procedure (111) or a staged procedure (113).

Most of the patients were in their 50s. Preoperative chemotherapy was significantly more common among those who had staged surgery with liver resection first. Primary rectal cancers were significantly more common among patients who had staged surgery.

The overall hepatectomy-related morbidity rate was similar: 25% in the simultaneous surgery group and 27% in the staged surgery group. Major complications after hepatectomy occurred in 18% of the simultaneous and 13% of the staged group – not significantly different.

Clear margins were obtained in 85% of the simultaneous surgery group and 88% of the staged surgery group. Mortality was similar (1% vs. 2%). The total length of stay was significantly longer in the staged surgery group (13 vs. 7 days.).

When categorized into minor and major hepatectomies, the overall complication rate was similar. For minor hepatectomies, it was 25% in the simultaneous surgery group and 29% in the staged group. For major hepatectomies, the rates were 27% and 28%, respectively.

There were no deaths in the minor hepatectomy group. Among those who had major hepatectomy, 4% of each surgical group died.

The median overall survival was 33 months. In both groups, 5-year survival was about 28%. The median recurrence-free survival was 26 months. The median 5-year recurrence-free survival was 20% in both groups.

A multivariate analysis examined factors associated with complications. There were no significant associations with simultaneous resection, major hepatectomy, rectal tumor, bilateral hepatic disease, or extrahepatic metastasis. However, concurrent resection and ablation doubled the risk of a complication (odds ratio, 2.02).

Patients who had a simultaneous procedure had significantly shorter hospital stays than did those who underwent a staged procedure. Most who had simultaneous surgery went home in 6 days or less (48) or in 6-9 days (38). Just 12 stayed 9-11 days; 13 stayed for 11 or more days.

Among those who had staged procedures, none went home in 6 or fewer days, and only 7 went home in 6-9 days. All other staged surgery patients stayed longer: 26 stayed 9-11 days, 39 stayed 11-13 days, and 41 stayed more than 13 days.

This extra time translated into extra money, Dr. Ejaz said, with each hospital day costing a mean of $3,581. To tease out cost associations, he stratified patients by operative factors and disease-related characteristics.

Charges for patents with unilateral or bilateral disease were significantly different ($48,000 vs. $53,000). There also were significantly different charges for those who had resection only compared to resection plus ablation ($45,500 vs. $57,000), and minor hepatic surgery compared to major hepatic surgery ($44,300 vs. $54,500).

Surgery timing also significantly affected price. The mean total cost for those who had simultaneous surgery was $34,000, while it was $62,000 for those who had staged surgery – a 55% difference amounting to $28,000.

Since clinical outcomes were so similar, the study shows that patients with resectable synchronous colorectal liver metastasis can be safely managed with either simultaneous or staged approach, Dr. Ejaz said. "But a simultaneous approach results in fewer hospital days and overall lower hospital charges, and should be the preferred approach when it’s clinically appropriate and technically feasible."

Dr. Timothy Pawlik – Dr. Ejaz’s preceptor – said that the findings are useful to both patients and systems.

"This study can be used to explain to patients how a simultaneous operation is generally safe," he said in an interview. "It may, in fact, be more beneficial to surgeons and hospitals or health care systems, as it shows that a simultaneous operation can be performed safely and save on health care costs."

Neither Dr. Ejaz nor Dr. Pawlik had any financial disclosures.

[email protected]

MIAMI BEACH – For patients with colorectal cancer and liver metastasis, one-stage surgery cuts hospital time and expense.

Compared to a staged approach, resecting both the primary and metastatic cancers shaved almost $28,000 off total hospital charges. Most of the savings came from the shortened hospital stay – an average of 6 fewer days than for patients with staged procedures, Dr. Aslam Ejaz said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

"The main driving factor [of costs] was the increasing length of stay," said Dr. Ejaz, a research fellow in surgical oncology at Johns Hopkins Hospital, Baltimore. "Each additional day resulted in a mean increase of $3,600."

Most studies have found similar clinical outcomes for such patients, regardless of whether their surgical treatment is staged or simultaneous. But there are few data comparing the techniques’ economic impact.

For the study, Dr. Ejaz used a Johns Hopkins database to examine the staged vs. the one-stage approach. His cohort included 224 patients who, from 1990 to 2012, underwent a liver resection with curative intent for synchronous colorectal liver metastasis. They had a simultaneous procedure (111) or a staged procedure (113).

Most of the patients were in their 50s. Preoperative chemotherapy was significantly more common among those who had staged surgery with liver resection first. Primary rectal cancers were significantly more common among patients who had staged surgery.

The overall hepatectomy-related morbidity rate was similar: 25% in the simultaneous surgery group and 27% in the staged surgery group. Major complications after hepatectomy occurred in 18% of the simultaneous and 13% of the staged group – not significantly different.

Clear margins were obtained in 85% of the simultaneous surgery group and 88% of the staged surgery group. Mortality was similar (1% vs. 2%). The total length of stay was significantly longer in the staged surgery group (13 vs. 7 days.).

When categorized into minor and major hepatectomies, the overall complication rate was similar. For minor hepatectomies, it was 25% in the simultaneous surgery group and 29% in the staged group. For major hepatectomies, the rates were 27% and 28%, respectively.

There were no deaths in the minor hepatectomy group. Among those who had major hepatectomy, 4% of each surgical group died.

The median overall survival was 33 months. In both groups, 5-year survival was about 28%. The median recurrence-free survival was 26 months. The median 5-year recurrence-free survival was 20% in both groups.

A multivariate analysis examined factors associated with complications. There were no significant associations with simultaneous resection, major hepatectomy, rectal tumor, bilateral hepatic disease, or extrahepatic metastasis. However, concurrent resection and ablation doubled the risk of a complication (odds ratio, 2.02).

Patients who had a simultaneous procedure had significantly shorter hospital stays than did those who underwent a staged procedure. Most who had simultaneous surgery went home in 6 days or less (48) or in 6-9 days (38). Just 12 stayed 9-11 days; 13 stayed for 11 or more days.

Among those who had staged procedures, none went home in 6 or fewer days, and only 7 went home in 6-9 days. All other staged surgery patients stayed longer: 26 stayed 9-11 days, 39 stayed 11-13 days, and 41 stayed more than 13 days.

This extra time translated into extra money, Dr. Ejaz said, with each hospital day costing a mean of $3,581. To tease out cost associations, he stratified patients by operative factors and disease-related characteristics.

Charges for patents with unilateral or bilateral disease were significantly different ($48,000 vs. $53,000). There also were significantly different charges for those who had resection only compared to resection plus ablation ($45,500 vs. $57,000), and minor hepatic surgery compared to major hepatic surgery ($44,300 vs. $54,500).

Surgery timing also significantly affected price. The mean total cost for those who had simultaneous surgery was $34,000, while it was $62,000 for those who had staged surgery – a 55% difference amounting to $28,000.

Since clinical outcomes were so similar, the study shows that patients with resectable synchronous colorectal liver metastasis can be safely managed with either simultaneous or staged approach, Dr. Ejaz said. "But a simultaneous approach results in fewer hospital days and overall lower hospital charges, and should be the preferred approach when it’s clinically appropriate and technically feasible."

Dr. Timothy Pawlik – Dr. Ejaz’s preceptor – said that the findings are useful to both patients and systems.

"This study can be used to explain to patients how a simultaneous operation is generally safe," he said in an interview. "It may, in fact, be more beneficial to surgeons and hospitals or health care systems, as it shows that a simultaneous operation can be performed safely and save on health care costs."

Neither Dr. Ejaz nor Dr. Pawlik had any financial disclosures.

[email protected]

MIAMI BEACH – For patients with colorectal cancer and liver metastasis, one-stage surgery cuts hospital time and expense.

Compared to a staged approach, resecting both the primary and metastatic cancers shaved almost $28,000 off total hospital charges. Most of the savings came from the shortened hospital stay – an average of 6 fewer days than for patients with staged procedures, Dr. Aslam Ejaz said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

"The main driving factor [of costs] was the increasing length of stay," said Dr. Ejaz, a research fellow in surgical oncology at Johns Hopkins Hospital, Baltimore. "Each additional day resulted in a mean increase of $3,600."

Most studies have found similar clinical outcomes for such patients, regardless of whether their surgical treatment is staged or simultaneous. But there are few data comparing the techniques’ economic impact.

For the study, Dr. Ejaz used a Johns Hopkins database to examine the staged vs. the one-stage approach. His cohort included 224 patients who, from 1990 to 2012, underwent a liver resection with curative intent for synchronous colorectal liver metastasis. They had a simultaneous procedure (111) or a staged procedure (113).

Most of the patients were in their 50s. Preoperative chemotherapy was significantly more common among those who had staged surgery with liver resection first. Primary rectal cancers were significantly more common among patients who had staged surgery.

The overall hepatectomy-related morbidity rate was similar: 25% in the simultaneous surgery group and 27% in the staged surgery group. Major complications after hepatectomy occurred in 18% of the simultaneous and 13% of the staged group – not significantly different.

Clear margins were obtained in 85% of the simultaneous surgery group and 88% of the staged surgery group. Mortality was similar (1% vs. 2%). The total length of stay was significantly longer in the staged surgery group (13 vs. 7 days.).

When categorized into minor and major hepatectomies, the overall complication rate was similar. For minor hepatectomies, it was 25% in the simultaneous surgery group and 29% in the staged group. For major hepatectomies, the rates were 27% and 28%, respectively.

There were no deaths in the minor hepatectomy group. Among those who had major hepatectomy, 4% of each surgical group died.

The median overall survival was 33 months. In both groups, 5-year survival was about 28%. The median recurrence-free survival was 26 months. The median 5-year recurrence-free survival was 20% in both groups.

A multivariate analysis examined factors associated with complications. There were no significant associations with simultaneous resection, major hepatectomy, rectal tumor, bilateral hepatic disease, or extrahepatic metastasis. However, concurrent resection and ablation doubled the risk of a complication (odds ratio, 2.02).

Patients who had a simultaneous procedure had significantly shorter hospital stays than did those who underwent a staged procedure. Most who had simultaneous surgery went home in 6 days or less (48) or in 6-9 days (38). Just 12 stayed 9-11 days; 13 stayed for 11 or more days.

Among those who had staged procedures, none went home in 6 or fewer days, and only 7 went home in 6-9 days. All other staged surgery patients stayed longer: 26 stayed 9-11 days, 39 stayed 11-13 days, and 41 stayed more than 13 days.

This extra time translated into extra money, Dr. Ejaz said, with each hospital day costing a mean of $3,581. To tease out cost associations, he stratified patients by operative factors and disease-related characteristics.

Charges for patents with unilateral or bilateral disease were significantly different ($48,000 vs. $53,000). There also were significantly different charges for those who had resection only compared to resection plus ablation ($45,500 vs. $57,000), and minor hepatic surgery compared to major hepatic surgery ($44,300 vs. $54,500).

Surgery timing also significantly affected price. The mean total cost for those who had simultaneous surgery was $34,000, while it was $62,000 for those who had staged surgery – a 55% difference amounting to $28,000.

Since clinical outcomes were so similar, the study shows that patients with resectable synchronous colorectal liver metastasis can be safely managed with either simultaneous or staged approach, Dr. Ejaz said. "But a simultaneous approach results in fewer hospital days and overall lower hospital charges, and should be the preferred approach when it’s clinically appropriate and technically feasible."

Dr. Timothy Pawlik – Dr. Ejaz’s preceptor – said that the findings are useful to both patients and systems.

"This study can be used to explain to patients how a simultaneous operation is generally safe," he said in an interview. "It may, in fact, be more beneficial to surgeons and hospitals or health care systems, as it shows that a simultaneous operation can be performed safely and save on health care costs."

Neither Dr. Ejaz nor Dr. Pawlik had any financial disclosures.

[email protected]

An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.

Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.

But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.

The report appeared in the March 3 issue of the Journal of Clinical Oncology.

"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.

The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).

PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.

The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.

The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.

Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.

About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.

Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.

Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.

An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.

Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.

Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.

"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.

Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.

[email protected]

An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.

Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.

But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.

The report appeared in the March 3 issue of the Journal of Clinical Oncology.

"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.

The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).

PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.

The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.

The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.

Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.

About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.

Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.

Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.

An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.

Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.

Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.

"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.

Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.

[email protected]

An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.

Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.

But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.

The report appeared in the March 3 issue of the Journal of Clinical Oncology.

"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.

The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).

PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.

The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.

The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.

Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.

About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.

Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.

Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.

An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.

Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.

Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.

"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.

Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.

[email protected]

MIAMI BEACH – Intraoperative fluorescent cholangiography is just as effective as traditional cholangiography but costs hundreds of dollars less and is significantly faster to perform.

It’s also a great teaching tool, Dr. Fernando Dip said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association. In just one session, all of the third- and fourth-year surgical residents were able to correctly identify 100% of the biliary structures.

"It appears to be an additional tool for the laparoscopic surgeon," said Dr. Dip, chief of surgical research at the Cleveland Clinic in Weston, Fla. "It’s quick, inexpensive, real-time, there are no adverse events, and it’s an inciscionless procedure."

Common bile duct injury is the most frequent injury seen in laparoscopic cholecystectomy, he said, and although the overall incidence is low, the number of injuries each year is not inconsiderable, since more than 750,000 laparoscopic cholecystectomies are performed in the United States annually.

"Only 3% of these injuries are due to problems with technical skill," Dr. Dip said. "The other 97% are problems of visual perception – illusions of where the ducts are."

Intraoperative cholangiography helps surgeons visualize this anatomy, but its true usefulness is somewhat controversial. Dr. Dip cited a recent study of almost 93,000 patients – 40% of whom underwent the procedure. It showed that intraoperative cholangiography is not effective as a preventive strategy against common duct injury during cholecystectomy.

Intraoperative fluorescent cholangiography is sometimes used to identify biliary anatomy in extrahepatic surgery. Dr. Dip and his colleagues examined its usefulness in 45 patients undergoing laparoscopic cholecystectomy. Senior residents performed all of the procedures under the supervision of experienced laparoscopic surgeons. All patients underwent the investigational procedure, followed by standard cholangiography.

The patients had a mean age of 49 years and were evenly split between men and women. The mean body mass index was 28 kg/m². Surgical indications were cholelithiasis (22), acute cholecystitis (17), chronic cholecystitis (5), and polyp (1). About 1 hour before surgery, patients received an infusion of indocyanine green 0.5 mg/kg. During the laparoscopic exploration, surgeons used near-infrared light to make the marker fluoresce as it was excreted by the liver.

In a picture review before surgery, all residents correctly identified 100% of the anatomic structures visualized by the fluorescent procedure. They were able to complete the fluorescent procedure in all of the patients. The completion rate for cholangiography was 93% (42 patients). In three patients, cholangiography failed because the cystic duct could not be cannulated.

The residents identified the cystic duct in 44 of the patients (98%), the common bile duct in 36 (80%), and the common hepatic ducts in 27 (60%). Neither technique identified any aberrant or accessory ducts.

Because fluorescent cholangiography is a real-time surgical procedure, it allowed checking of the transection and resection of the gallbladder pedicle before smooth dissection in all of the patients.

The procedure was significantly quicker than standard cholangiography (0.71 minutes vs. 7.15 minutes). It was also significantly cheaper, costing a mean of $14 vs. $778. There were no adverse surgical events, and no adverse reactions to the dye or at the infusion site, Dr. Dip said. Additionally, he noted, fluorescent cholangiography does not rely on x-rays, and so spared the patients any radiation exposure.

He added that the Cleveland Clinic, in conjunction with the University of Tokyo, will soon launch a randomized clinical trial comparing the two methods. An ongoing trial from another institution is evaluating fluorescent cholangiography compared with critical view technique in visualizing anatomy during laparoscopic cholecystectomy. It was set to wrap up in January, but according to the trial record on clinicaltrials.gov, is still recruiting patients.

Dr. Dip had no financial disclosures.

[email protected]

On Twitter @alz_gal

MIAMI BEACH – Intraoperative fluorescent cholangiography is just as effective as traditional cholangiography but costs hundreds of dollars less and is significantly faster to perform.

It’s also a great teaching tool, Dr. Fernando Dip said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association. In just one session, all of the third- and fourth-year surgical residents were able to correctly identify 100% of the biliary structures.

"It appears to be an additional tool for the laparoscopic surgeon," said Dr. Dip, chief of surgical research at the Cleveland Clinic in Weston, Fla. "It’s quick, inexpensive, real-time, there are no adverse events, and it’s an inciscionless procedure."

Common bile duct injury is the most frequent injury seen in laparoscopic cholecystectomy, he said, and although the overall incidence is low, the number of injuries each year is not inconsiderable, since more than 750,000 laparoscopic cholecystectomies are performed in the United States annually.

"Only 3% of these injuries are due to problems with technical skill," Dr. Dip said. "The other 97% are problems of visual perception – illusions of where the ducts are."

Intraoperative cholangiography helps surgeons visualize this anatomy, but its true usefulness is somewhat controversial. Dr. Dip cited a recent study of almost 93,000 patients – 40% of whom underwent the procedure. It showed that intraoperative cholangiography is not effective as a preventive strategy against common duct injury during cholecystectomy.

Intraoperative fluorescent cholangiography is sometimes used to identify biliary anatomy in extrahepatic surgery. Dr. Dip and his colleagues examined its usefulness in 45 patients undergoing laparoscopic cholecystectomy. Senior residents performed all of the procedures under the supervision of experienced laparoscopic surgeons. All patients underwent the investigational procedure, followed by standard cholangiography.

The patients had a mean age of 49 years and were evenly split between men and women. The mean body mass index was 28 kg/m². Surgical indications were cholelithiasis (22), acute cholecystitis (17), chronic cholecystitis (5), and polyp (1). About 1 hour before surgery, patients received an infusion of indocyanine green 0.5 mg/kg. During the laparoscopic exploration, surgeons used near-infrared light to make the marker fluoresce as it was excreted by the liver.

In a picture review before surgery, all residents correctly identified 100% of the anatomic structures visualized by the fluorescent procedure. They were able to complete the fluorescent procedure in all of the patients. The completion rate for cholangiography was 93% (42 patients). In three patients, cholangiography failed because the cystic duct could not be cannulated.

The residents identified the cystic duct in 44 of the patients (98%), the common bile duct in 36 (80%), and the common hepatic ducts in 27 (60%). Neither technique identified any aberrant or accessory ducts.

Because fluorescent cholangiography is a real-time surgical procedure, it allowed checking of the transection and resection of the gallbladder pedicle before smooth dissection in all of the patients.

The procedure was significantly quicker than standard cholangiography (0.71 minutes vs. 7.15 minutes). It was also significantly cheaper, costing a mean of $14 vs. $778. There were no adverse surgical events, and no adverse reactions to the dye or at the infusion site, Dr. Dip said. Additionally, he noted, fluorescent cholangiography does not rely on x-rays, and so spared the patients any radiation exposure.

He added that the Cleveland Clinic, in conjunction with the University of Tokyo, will soon launch a randomized clinical trial comparing the two methods. An ongoing trial from another institution is evaluating fluorescent cholangiography compared with critical view technique in visualizing anatomy during laparoscopic cholecystectomy. It was set to wrap up in January, but according to the trial record on clinicaltrials.gov, is still recruiting patients.

Dr. Dip had no financial disclosures.

[email protected]

On Twitter @alz_gal

MIAMI BEACH – Intraoperative fluorescent cholangiography is just as effective as traditional cholangiography but costs hundreds of dollars less and is significantly faster to perform.

It’s also a great teaching tool, Dr. Fernando Dip said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association. In just one session, all of the third- and fourth-year surgical residents were able to correctly identify 100% of the biliary structures.

"It appears to be an additional tool for the laparoscopic surgeon," said Dr. Dip, chief of surgical research at the Cleveland Clinic in Weston, Fla. "It’s quick, inexpensive, real-time, there are no adverse events, and it’s an inciscionless procedure."

Common bile duct injury is the most frequent injury seen in laparoscopic cholecystectomy, he said, and although the overall incidence is low, the number of injuries each year is not inconsiderable, since more than 750,000 laparoscopic cholecystectomies are performed in the United States annually.

"Only 3% of these injuries are due to problems with technical skill," Dr. Dip said. "The other 97% are problems of visual perception – illusions of where the ducts are."

Intraoperative cholangiography helps surgeons visualize this anatomy, but its true usefulness is somewhat controversial. Dr. Dip cited a recent study of almost 93,000 patients – 40% of whom underwent the procedure. It showed that intraoperative cholangiography is not effective as a preventive strategy against common duct injury during cholecystectomy.

Intraoperative fluorescent cholangiography is sometimes used to identify biliary anatomy in extrahepatic surgery. Dr. Dip and his colleagues examined its usefulness in 45 patients undergoing laparoscopic cholecystectomy. Senior residents performed all of the procedures under the supervision of experienced laparoscopic surgeons. All patients underwent the investigational procedure, followed by standard cholangiography.

The patients had a mean age of 49 years and were evenly split between men and women. The mean body mass index was 28 kg/m². Surgical indications were cholelithiasis (22), acute cholecystitis (17), chronic cholecystitis (5), and polyp (1). About 1 hour before surgery, patients received an infusion of indocyanine green 0.5 mg/kg. During the laparoscopic exploration, surgeons used near-infrared light to make the marker fluoresce as it was excreted by the liver.

In a picture review before surgery, all residents correctly identified 100% of the anatomic structures visualized by the fluorescent procedure. They were able to complete the fluorescent procedure in all of the patients. The completion rate for cholangiography was 93% (42 patients). In three patients, cholangiography failed because the cystic duct could not be cannulated.

The residents identified the cystic duct in 44 of the patients (98%), the common bile duct in 36 (80%), and the common hepatic ducts in 27 (60%). Neither technique identified any aberrant or accessory ducts.

Because fluorescent cholangiography is a real-time surgical procedure, it allowed checking of the transection and resection of the gallbladder pedicle before smooth dissection in all of the patients.

The procedure was significantly quicker than standard cholangiography (0.71 minutes vs. 7.15 minutes). It was also significantly cheaper, costing a mean of $14 vs. $778. There were no adverse surgical events, and no adverse reactions to the dye or at the infusion site, Dr. Dip said. Additionally, he noted, fluorescent cholangiography does not rely on x-rays, and so spared the patients any radiation exposure.

He added that the Cleveland Clinic, in conjunction with the University of Tokyo, will soon launch a randomized clinical trial comparing the two methods. An ongoing trial from another institution is evaluating fluorescent cholangiography compared with critical view technique in visualizing anatomy during laparoscopic cholecystectomy. It was set to wrap up in January, but according to the trial record on clinicaltrials.gov, is still recruiting patients.

Dr. Dip had no financial disclosures.

[email protected]

On Twitter @alz_gal

MIAMI BEACH – An elevated bilirubin level on postoperative day 3 after major hepatectomy may be a harbinger of hepatic insufficiency that leads to poor outcomes – including an increased risk of death.

Compared with patients who had lower bilirubin levels, a level of 3 mg/dL or higher was associated with an eightfold increase in the risk of both a major complication and of dying within 90 days of surgery, Dr. Joanna W. Etra said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

Unfortunately, said Dr. Etra of the Winship Cancer Institute of Emory University, Atlanta, there seems to be no way to predict before surgery who will develop the elevated levels, and no preemptive treatment. Still, she said, the finding could be a good way to be alert to the possibility of a problem.

She presented a retrospective study of 535 patients who underwent a major hepatectomy at the center from 2000 to 2012. Their mean age was 55 years. Most (73%) had cancer; 39% had undergone preoperative chemotherapy. About a third (38%) had colorectal metastases in the liver. The average preoperative bilirubin level was 0.7 mg/dL. Most of the procedures (83%) were open, with a right hepatectomy most common (44%)

Postoperatively, 10% of the group developed hepatic insufficiency. Postoperative complications developed in 58%; of these, of which 22% were major. Death within 90 days occurred in 4.5% of the entire group.

Dr. Etra and her colleagues divided the group by postoperative day 3 bilirubin levels: lower than 3 mg/dL and 3 mg/dL or higher. They examined outcomes among the two groups.

Postoperative complications were significantly more common among those with the higher bilirubin levels (76% vs. 54%), as were major complications (46% vs. 18%), and 90-day mortality (16% vs. 2%).

A multivariate analysis found that the higher level doubled the risk of any complication, and tripled the risk of both a major complication and 90-day mortality,

"Having identified this association with outcomes, we refocused on the dichotomized bilirubin groups to see if we could also identify any pre- or intraoperative factors that might predict this elevated bilirubin," she said. "But in a multifactorial analysis, we found that no single factor – age, gender, cancer, preoperative platelets, MELD [model for end-stage liver disease] score, blood loss or transfusion – was a significant predictor."

Dr. Etra had no financial disclosures.

[email protected]

MIAMI BEACH – An elevated bilirubin level on postoperative day 3 after major hepatectomy may be a harbinger of hepatic insufficiency that leads to poor outcomes – including an increased risk of death.

Compared with patients who had lower bilirubin levels, a level of 3 mg/dL or higher was associated with an eightfold increase in the risk of both a major complication and of dying within 90 days of surgery, Dr. Joanna W. Etra said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

Unfortunately, said Dr. Etra of the Winship Cancer Institute of Emory University, Atlanta, there seems to be no way to predict before surgery who will develop the elevated levels, and no preemptive treatment. Still, she said, the finding could be a good way to be alert to the possibility of a problem.

She presented a retrospective study of 535 patients who underwent a major hepatectomy at the center from 2000 to 2012. Their mean age was 55 years. Most (73%) had cancer; 39% had undergone preoperative chemotherapy. About a third (38%) had colorectal metastases in the liver. The average preoperative bilirubin level was 0.7 mg/dL. Most of the procedures (83%) were open, with a right hepatectomy most common (44%)

Postoperatively, 10% of the group developed hepatic insufficiency. Postoperative complications developed in 58%; of these, of which 22% were major. Death within 90 days occurred in 4.5% of the entire group.

Dr. Etra and her colleagues divided the group by postoperative day 3 bilirubin levels: lower than 3 mg/dL and 3 mg/dL or higher. They examined outcomes among the two groups.

Postoperative complications were significantly more common among those with the higher bilirubin levels (76% vs. 54%), as were major complications (46% vs. 18%), and 90-day mortality (16% vs. 2%).

A multivariate analysis found that the higher level doubled the risk of any complication, and tripled the risk of both a major complication and 90-day mortality,

"Having identified this association with outcomes, we refocused on the dichotomized bilirubin groups to see if we could also identify any pre- or intraoperative factors that might predict this elevated bilirubin," she said. "But in a multifactorial analysis, we found that no single factor – age, gender, cancer, preoperative platelets, MELD [model for end-stage liver disease] score, blood loss or transfusion – was a significant predictor."

Dr. Etra had no financial disclosures.

[email protected]

MIAMI BEACH – An elevated bilirubin level on postoperative day 3 after major hepatectomy may be a harbinger of hepatic insufficiency that leads to poor outcomes – including an increased risk of death.

Compared with patients who had lower bilirubin levels, a level of 3 mg/dL or higher was associated with an eightfold increase in the risk of both a major complication and of dying within 90 days of surgery, Dr. Joanna W. Etra said at the annual meeting of the Americas Hepato-Pancreato-Biliary Association.

Unfortunately, said Dr. Etra of the Winship Cancer Institute of Emory University, Atlanta, there seems to be no way to predict before surgery who will develop the elevated levels, and no preemptive treatment. Still, she said, the finding could be a good way to be alert to the possibility of a problem.

She presented a retrospective study of 535 patients who underwent a major hepatectomy at the center from 2000 to 2012. Their mean age was 55 years. Most (73%) had cancer; 39% had undergone preoperative chemotherapy. About a third (38%) had colorectal metastases in the liver. The average preoperative bilirubin level was 0.7 mg/dL. Most of the procedures (83%) were open, with a right hepatectomy most common (44%)

Postoperatively, 10% of the group developed hepatic insufficiency. Postoperative complications developed in 58%; of these, of which 22% were major. Death within 90 days occurred in 4.5% of the entire group.

Dr. Etra and her colleagues divided the group by postoperative day 3 bilirubin levels: lower than 3 mg/dL and 3 mg/dL or higher. They examined outcomes among the two groups.

Postoperative complications were significantly more common among those with the higher bilirubin levels (76% vs. 54%), as were major complications (46% vs. 18%), and 90-day mortality (16% vs. 2%).

A multivariate analysis found that the higher level doubled the risk of any complication, and tripled the risk of both a major complication and 90-day mortality,

"Having identified this association with outcomes, we refocused on the dichotomized bilirubin groups to see if we could also identify any pre- or intraoperative factors that might predict this elevated bilirubin," she said. "But in a multifactorial analysis, we found that no single factor – age, gender, cancer, preoperative platelets, MELD [model for end-stage liver disease] score, blood loss or transfusion – was a significant predictor."

Dr. Etra had no financial disclosures.

[email protected]