Patrice Wendling

CHICAGO – Roughly a fourth of ED patients are ready to hit the delete button on standard written discharge instructions.

When asked 30 days post discharge how they preferred to receive their antibiotic discharge instructions, 26% of patients said they prefer text messages or voice mail to written instructions alone.

"It’s an interesting finding, and it’s not really been discussed in the literature that I could find," lead author Dr. Travis Olives said at the annual meeting of the Society for Academic Emergency Medicine.

He pointed out that ED discharge information is commonly written at 8th- to 13th-grade reading levels and that as many as 45% of ED patients are unable to comprehend this level of written complexity yet are unaware of their low level of comprehension.

"I can’t understand them myself when I read them, frankly," he quipped.

It was in this context that the investigators sought to determine whether patient preference for discharge instruction modality varies by health literacy levels.

The secondary analysis included 660 patients enrolled in a prospective randomized trial who were discharged with outpatient antibiotics from an urban county ED with an annual census of 100,000. Patients were randomly assigned to typed and verbal medication and case-specific instructions (standard of care) or standard of care plus text messages sent to the patient’s cell phone or standard of care plus voice-mailed instructions sent to the patient’s cell phone.

Health literacy assessment using the Newest Vital Sign test classified 23% as likely having limited literacy (NVS score 0-1), 31% as possibly having limited literacy (score 2-3), and 46% as having adequate literacy (score 4-6). Their median age was 30 years, and 55% were female.

Among the 51% of participants reached by telephone at 30 days, more than 50% across all health literacy levels preferred either a modality other than written or a combination of modalities, said Dr. Olives, a resident with the Hennepin County Medical Center in Minneapolis.

Text messages were preferred by 18.75% of participants with limited health literacy, 10.4% with possibly limited literacy, and 12.5% with adequate literacy. Voice-mailed instructions were preferred by 7.5%, 3.25%, and 6%, respectively.

To protect the privacy of participants, all text messages and voice mails were sent without identifiers or a diagnosis. For example, the script for a text simply said: "Take doxycycline 100 mg two times a day for 7 days."

Standard typewritten instructions were preferred by 40% of patients with limited literacy, 32% with possibly limited literacy, and 44% with adequate literacy, he said during the poster presentation.

© Hocus Focus Studio/iStockphoto.com

The proportion of patients who preferred discharge instructions in written form plus another modality varied significantly across health literacy levels (13.75% NVS score 0-1, 42% NVS score 2-3, and 20% NVS score 4-6; P = .017). With the exception of "written plus another modality," patient preference was similar across all NVS score groups.

Dr. Olives said the study is ongoing and that the goal is to access hard outcomes such as antibiotic compliance among 3,000 ED patients. So far 1,800 patients have been enrolled. The data show, not surprisingly, that 72-hour prescription pickup varies by health literacy level, with compliance increasing with increasing health literacy, he said.

An audience member asked whether the investigators had a hard time tracking patients down by telephone, remarking that when ED physicians ask a patient for a contact number, the number they’re given is usually different from the number the patient gave at registration.

Dr. Olives said they verified the phone number directly with the patient and then cross-referenced it with what was in the electronic medical record. If any discrepancy was found, health coordinators corrected the phone numbers in the record.

He said fewer than a dozen patients gave a bad cell phone number and pointed out that a recent unpublished study reported patient cell phone penetration of more than 99%.

"I know that’s not the case for all populations, but it’s a lot higher than I anticipated going in to this study," Dr. Olives added. "We did not have a lot of trouble with patients without a cell phone."

Dr. Olives reported no relevant conflicts of interest.

CHICAGO – Roughly a fourth of ED patients are ready to hit the delete button on standard written discharge instructions.

When asked 30 days post discharge how they preferred to receive their antibiotic discharge instructions, 26% of patients said they prefer text messages or voice mail to written instructions alone.

"It’s an interesting finding, and it’s not really been discussed in the literature that I could find," lead author Dr. Travis Olives said at the annual meeting of the Society for Academic Emergency Medicine.

He pointed out that ED discharge information is commonly written at 8th- to 13th-grade reading levels and that as many as 45% of ED patients are unable to comprehend this level of written complexity yet are unaware of their low level of comprehension.

"I can’t understand them myself when I read them, frankly," he quipped.

It was in this context that the investigators sought to determine whether patient preference for discharge instruction modality varies by health literacy levels.

The secondary analysis included 660 patients enrolled in a prospective randomized trial who were discharged with outpatient antibiotics from an urban county ED with an annual census of 100,000. Patients were randomly assigned to typed and verbal medication and case-specific instructions (standard of care) or standard of care plus text messages sent to the patient’s cell phone or standard of care plus voice-mailed instructions sent to the patient’s cell phone.

Health literacy assessment using the Newest Vital Sign test classified 23% as likely having limited literacy (NVS score 0-1), 31% as possibly having limited literacy (score 2-3), and 46% as having adequate literacy (score 4-6). Their median age was 30 years, and 55% were female.

Among the 51% of participants reached by telephone at 30 days, more than 50% across all health literacy levels preferred either a modality other than written or a combination of modalities, said Dr. Olives, a resident with the Hennepin County Medical Center in Minneapolis.

Text messages were preferred by 18.75% of participants with limited health literacy, 10.4% with possibly limited literacy, and 12.5% with adequate literacy. Voice-mailed instructions were preferred by 7.5%, 3.25%, and 6%, respectively.

To protect the privacy of participants, all text messages and voice mails were sent without identifiers or a diagnosis. For example, the script for a text simply said: "Take doxycycline 100 mg two times a day for 7 days."

Standard typewritten instructions were preferred by 40% of patients with limited literacy, 32% with possibly limited literacy, and 44% with adequate literacy, he said during the poster presentation.

© Hocus Focus Studio/iStockphoto.com

The proportion of patients who preferred discharge instructions in written form plus another modality varied significantly across health literacy levels (13.75% NVS score 0-1, 42% NVS score 2-3, and 20% NVS score 4-6; P = .017). With the exception of "written plus another modality," patient preference was similar across all NVS score groups.

Dr. Olives said the study is ongoing and that the goal is to access hard outcomes such as antibiotic compliance among 3,000 ED patients. So far 1,800 patients have been enrolled. The data show, not surprisingly, that 72-hour prescription pickup varies by health literacy level, with compliance increasing with increasing health literacy, he said.

An audience member asked whether the investigators had a hard time tracking patients down by telephone, remarking that when ED physicians ask a patient for a contact number, the number they’re given is usually different from the number the patient gave at registration.

Dr. Olives said they verified the phone number directly with the patient and then cross-referenced it with what was in the electronic medical record. If any discrepancy was found, health coordinators corrected the phone numbers in the record.

He said fewer than a dozen patients gave a bad cell phone number and pointed out that a recent unpublished study reported patient cell phone penetration of more than 99%.

"I know that’s not the case for all populations, but it’s a lot higher than I anticipated going in to this study," Dr. Olives added. "We did not have a lot of trouble with patients without a cell phone."

Dr. Olives reported no relevant conflicts of interest.

CHICAGO – Roughly a fourth of ED patients are ready to hit the delete button on standard written discharge instructions.

When asked 30 days post discharge how they preferred to receive their antibiotic discharge instructions, 26% of patients said they prefer text messages or voice mail to written instructions alone.

"It’s an interesting finding, and it’s not really been discussed in the literature that I could find," lead author Dr. Travis Olives said at the annual meeting of the Society for Academic Emergency Medicine.

He pointed out that ED discharge information is commonly written at 8th- to 13th-grade reading levels and that as many as 45% of ED patients are unable to comprehend this level of written complexity yet are unaware of their low level of comprehension.

"I can’t understand them myself when I read them, frankly," he quipped.

It was in this context that the investigators sought to determine whether patient preference for discharge instruction modality varies by health literacy levels.

The secondary analysis included 660 patients enrolled in a prospective randomized trial who were discharged with outpatient antibiotics from an urban county ED with an annual census of 100,000. Patients were randomly assigned to typed and verbal medication and case-specific instructions (standard of care) or standard of care plus text messages sent to the patient’s cell phone or standard of care plus voice-mailed instructions sent to the patient’s cell phone.

Health literacy assessment using the Newest Vital Sign test classified 23% as likely having limited literacy (NVS score 0-1), 31% as possibly having limited literacy (score 2-3), and 46% as having adequate literacy (score 4-6). Their median age was 30 years, and 55% were female.

Among the 51% of participants reached by telephone at 30 days, more than 50% across all health literacy levels preferred either a modality other than written or a combination of modalities, said Dr. Olives, a resident with the Hennepin County Medical Center in Minneapolis.

Text messages were preferred by 18.75% of participants with limited health literacy, 10.4% with possibly limited literacy, and 12.5% with adequate literacy. Voice-mailed instructions were preferred by 7.5%, 3.25%, and 6%, respectively.

To protect the privacy of participants, all text messages and voice mails were sent without identifiers or a diagnosis. For example, the script for a text simply said: "Take doxycycline 100 mg two times a day for 7 days."

Standard typewritten instructions were preferred by 40% of patients with limited literacy, 32% with possibly limited literacy, and 44% with adequate literacy, he said during the poster presentation.

© Hocus Focus Studio/iStockphoto.com

The proportion of patients who preferred discharge instructions in written form plus another modality varied significantly across health literacy levels (13.75% NVS score 0-1, 42% NVS score 2-3, and 20% NVS score 4-6; P = .017). With the exception of "written plus another modality," patient preference was similar across all NVS score groups.

Dr. Olives said the study is ongoing and that the goal is to access hard outcomes such as antibiotic compliance among 3,000 ED patients. So far 1,800 patients have been enrolled. The data show, not surprisingly, that 72-hour prescription pickup varies by health literacy level, with compliance increasing with increasing health literacy, he said.

An audience member asked whether the investigators had a hard time tracking patients down by telephone, remarking that when ED physicians ask a patient for a contact number, the number they’re given is usually different from the number the patient gave at registration.

Dr. Olives said they verified the phone number directly with the patient and then cross-referenced it with what was in the electronic medical record. If any discrepancy was found, health coordinators corrected the phone numbers in the record.

He said fewer than a dozen patients gave a bad cell phone number and pointed out that a recent unpublished study reported patient cell phone penetration of more than 99%.

"I know that’s not the case for all populations, but it’s a lot higher than I anticipated going in to this study," Dr. Olives added. "We did not have a lot of trouble with patients without a cell phone."

Dr. Olives reported no relevant conflicts of interest.

CHICAGO – The 2006 Massachusetts health care reform law that expanded insurance coverage to unprecedented levels resulted in modest increases in emergency department and hospital utilization among adults, according to preliminary results from a large observational study.

For adults under age 65, ED visits increased from 1,970,976 in 2005 to 2,279,492 in 2009, while hospitalizations increased from 457,298 to 490,458.

Adults older than 65 years had 450,933 ED visits before reform and 470,109 ED visits after reform, while hospitalizations in this group totaled 223,229 before and 300,596 after reform.

The rate of uninsured patients decreased over the same period, from 6.2% to 3.7% among ED patients and from 1.3% to 0.6% among hospitalized patients, Dr. Peter Smulowitz, an instructor in medicine at Harvard Medical School in Boston, said at the annual meeting of the Society for Academic Emergency Medicine.

In regression modeling that controlled for secular trends and other confounders, the increased insurance rates had a positive but nonsignificant effect on ED visits among those under age 65 (P = .09) and a significant, positive impact on those over 65 (P = .01).

Increasing insurance predicted increasing hospitalizations for the under-65 population (P = .03), while there was a negative effect for increasing insurance on hospitalizations for the over-65 population (P = .003).

The modest, nonsignificant uptick in ED use among younger adults may represent barriers in access to primary care, Dr. Smulowitz suggested. "The results are mostly consistent with our hypothesis that limitations and access to care will make it so that patients who are newly insured will not necessarily have another place to gain care, and so emergency department visits will remain constant, if not slightly increase, and hospitalizations might increase as well," he said.

The 2006 Massachusetts law has been used as a model for the Affordable Care Act and is being closely watched. Many physicians thought insurance would increase ED use because of continued barriers in access to care, while many policy makers thought reform efforts would result in a dramatic decrease in ED visits, Dr. Smulowitz observed.

Earlier research showed a null effect of the 2006 law on ED use in Massachusetts compared with neighboring Vermont and New Hampshire (N. Engl. J. Med. 2011;365:e25).

The current analysis compared geographic differences, at the zip code level, in the percentage of uninsured during a 1-year period before health care reform and an identical period after reform using administrative data from 2005 to 2009 in the Massachusetts Division of Health Care Finance and Policy Acute Hospital Case Mix database. Overall, there were 2,421,909 ED visits and 680,527 hospitalizations before reform and 2,580,088 ED visits and 791,054 hospitalizations after reform.

Session moderator Dr. Katherine Heilpern, chair of emergency medicine at Emory University in Atlanta, said the findings of a modest increase in ED and hospital utilization fly in the face of dire headlines about the Massachusetts experience, and asked whether the issue is just a matter of granularity.

Dr. Smulowitz responded that the ability to delve into the data over several years and to control for secular trends provides a very different take than just looking at raw numbers. He said additional models are warranted to further clarify the findings, particularly in terms of comparing differences in ED and hospitalization rates between the under- and over-65 populations.

He also stressed that the data are preliminary, and acknowledged that the study was limited by assumptions that the population within a zip code remains stable over time and that the changing insurance rate mirrors the overall population.

Dr. Smulowitz reported funding from the Charles A. King Trust Postdoctoral Research Fellow program and the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine.

CHICAGO – The 2006 Massachusetts health care reform law that expanded insurance coverage to unprecedented levels resulted in modest increases in emergency department and hospital utilization among adults, according to preliminary results from a large observational study.

For adults under age 65, ED visits increased from 1,970,976 in 2005 to 2,279,492 in 2009, while hospitalizations increased from 457,298 to 490,458.

Adults older than 65 years had 450,933 ED visits before reform and 470,109 ED visits after reform, while hospitalizations in this group totaled 223,229 before and 300,596 after reform.

The rate of uninsured patients decreased over the same period, from 6.2% to 3.7% among ED patients and from 1.3% to 0.6% among hospitalized patients, Dr. Peter Smulowitz, an instructor in medicine at Harvard Medical School in Boston, said at the annual meeting of the Society for Academic Emergency Medicine.

In regression modeling that controlled for secular trends and other confounders, the increased insurance rates had a positive but nonsignificant effect on ED visits among those under age 65 (P = .09) and a significant, positive impact on those over 65 (P = .01).

Increasing insurance predicted increasing hospitalizations for the under-65 population (P = .03), while there was a negative effect for increasing insurance on hospitalizations for the over-65 population (P = .003).

The modest, nonsignificant uptick in ED use among younger adults may represent barriers in access to primary care, Dr. Smulowitz suggested. "The results are mostly consistent with our hypothesis that limitations and access to care will make it so that patients who are newly insured will not necessarily have another place to gain care, and so emergency department visits will remain constant, if not slightly increase, and hospitalizations might increase as well," he said.

The 2006 Massachusetts law has been used as a model for the Affordable Care Act and is being closely watched. Many physicians thought insurance would increase ED use because of continued barriers in access to care, while many policy makers thought reform efforts would result in a dramatic decrease in ED visits, Dr. Smulowitz observed.

Earlier research showed a null effect of the 2006 law on ED use in Massachusetts compared with neighboring Vermont and New Hampshire (N. Engl. J. Med. 2011;365:e25).

The current analysis compared geographic differences, at the zip code level, in the percentage of uninsured during a 1-year period before health care reform and an identical period after reform using administrative data from 2005 to 2009 in the Massachusetts Division of Health Care Finance and Policy Acute Hospital Case Mix database. Overall, there were 2,421,909 ED visits and 680,527 hospitalizations before reform and 2,580,088 ED visits and 791,054 hospitalizations after reform.

Session moderator Dr. Katherine Heilpern, chair of emergency medicine at Emory University in Atlanta, said the findings of a modest increase in ED and hospital utilization fly in the face of dire headlines about the Massachusetts experience, and asked whether the issue is just a matter of granularity.

Dr. Smulowitz responded that the ability to delve into the data over several years and to control for secular trends provides a very different take than just looking at raw numbers. He said additional models are warranted to further clarify the findings, particularly in terms of comparing differences in ED and hospitalization rates between the under- and over-65 populations.

He also stressed that the data are preliminary, and acknowledged that the study was limited by assumptions that the population within a zip code remains stable over time and that the changing insurance rate mirrors the overall population.

Dr. Smulowitz reported funding from the Charles A. King Trust Postdoctoral Research Fellow program and the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine.

CHICAGO – The 2006 Massachusetts health care reform law that expanded insurance coverage to unprecedented levels resulted in modest increases in emergency department and hospital utilization among adults, according to preliminary results from a large observational study.

For adults under age 65, ED visits increased from 1,970,976 in 2005 to 2,279,492 in 2009, while hospitalizations increased from 457,298 to 490,458.

Adults older than 65 years had 450,933 ED visits before reform and 470,109 ED visits after reform, while hospitalizations in this group totaled 223,229 before and 300,596 after reform.

The rate of uninsured patients decreased over the same period, from 6.2% to 3.7% among ED patients and from 1.3% to 0.6% among hospitalized patients, Dr. Peter Smulowitz, an instructor in medicine at Harvard Medical School in Boston, said at the annual meeting of the Society for Academic Emergency Medicine.

In regression modeling that controlled for secular trends and other confounders, the increased insurance rates had a positive but nonsignificant effect on ED visits among those under age 65 (P = .09) and a significant, positive impact on those over 65 (P = .01).

Increasing insurance predicted increasing hospitalizations for the under-65 population (P = .03), while there was a negative effect for increasing insurance on hospitalizations for the over-65 population (P = .003).

The modest, nonsignificant uptick in ED use among younger adults may represent barriers in access to primary care, Dr. Smulowitz suggested. "The results are mostly consistent with our hypothesis that limitations and access to care will make it so that patients who are newly insured will not necessarily have another place to gain care, and so emergency department visits will remain constant, if not slightly increase, and hospitalizations might increase as well," he said.

The 2006 Massachusetts law has been used as a model for the Affordable Care Act and is being closely watched. Many physicians thought insurance would increase ED use because of continued barriers in access to care, while many policy makers thought reform efforts would result in a dramatic decrease in ED visits, Dr. Smulowitz observed.

Earlier research showed a null effect of the 2006 law on ED use in Massachusetts compared with neighboring Vermont and New Hampshire (N. Engl. J. Med. 2011;365:e25).

The current analysis compared geographic differences, at the zip code level, in the percentage of uninsured during a 1-year period before health care reform and an identical period after reform using administrative data from 2005 to 2009 in the Massachusetts Division of Health Care Finance and Policy Acute Hospital Case Mix database. Overall, there were 2,421,909 ED visits and 680,527 hospitalizations before reform and 2,580,088 ED visits and 791,054 hospitalizations after reform.

Session moderator Dr. Katherine Heilpern, chair of emergency medicine at Emory University in Atlanta, said the findings of a modest increase in ED and hospital utilization fly in the face of dire headlines about the Massachusetts experience, and asked whether the issue is just a matter of granularity.

Dr. Smulowitz responded that the ability to delve into the data over several years and to control for secular trends provides a very different take than just looking at raw numbers. He said additional models are warranted to further clarify the findings, particularly in terms of comparing differences in ED and hospitalization rates between the under- and over-65 populations.

He also stressed that the data are preliminary, and acknowledged that the study was limited by assumptions that the population within a zip code remains stable over time and that the changing insurance rate mirrors the overall population.

Dr. Smulowitz reported funding from the Charles A. King Trust Postdoctoral Research Fellow program and the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*

The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.

Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).

Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.

"This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors," Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A survival advantage with combination therapy was also seen in patients with MGMT (O⁶-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.

The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.

Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.

He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.

"The thing that’s important is that we now know that we get this huge increase in survival with PCV," he said. "The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions."

Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.

He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.

"If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?" he asked.

EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m² on day 1, procarbazine 60 mg/m² on day 8-21 and IV vincristine 1.4 mg/m² on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.

In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).

In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).

Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).

In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.

Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.

In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).

Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).

In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).

The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).

The same phenomenon was reported in the EORTC cohort.

"It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in," Dr. van den Bent speculated. "We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years."

Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.

Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.

Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.

RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.

* This story has been updated and revised on 6/8/2012.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Overweight children are 20% more likely to visit the emergency department than are normal-weight children, and they do so for reasons other than injuries and accidents, according to a nationally representative survey.

"I suspect that a big reason we’re seeing this increase in the overweight is that they have chronic conditions that are getting them to the ED," lead author James Dziura, Ph.D., an epidemiologist in the department of emergency medicine and deputy director of the Yale Center for Analytical Sciences in New Haven, Conn., said in an interview.

That supposition is supported by an alarming new report showing that the prevalence of prediabetes and diabetes among adolescents aged 12-19 years jumped from 9% in 1999 to 23% in 2008 (Pediatrics 2012 May 21 [doi: 10.1542/peds.2011-1082]).

The current analysis used parent-reported weight and height data for 46,707 children, aged 10-17 years, from the cross-sectional, telephone-administered National Survey of Children’s Health. Body mass index was calculated using sex-specific BMI for age growth charts from the Centers for Disease Control and Prevention. Children were categorized as underweight (BMI percentile of 5 or less), normal weight (more than 5 to less than 85), at risk for overweight (85 to less than 95), and overweight (95 or more).

Overall, 15.5% of children were reported to have used the ED in the past year, with the prevalence of at least one ED visit increasing significantly with BMI percentile, from 13% of underweight children to 15% of normal-weight or at-risk children to 19% of overweight children (P less than .001 for overweight vs. all groups or vs. normal weight). Additionally, overweight children were more likely to have more than one visit, Dr. Dziura reported at the annual meeting of the Society for Academic Emergency Medicine.

After adjustment for age, sex, race, ethnicity, insurance type, parent’s education, and parent’s primary language, the odds ratio for ED use was 1.24 in overweight children, compared with those at normal weight. The impact of BMI category was not significantly modified by sex, race, or Hispanic ethnicity.

In all, 49% of overweight children reported an injury, poisoning, or accident as the reason for their ED visit, compared with 61% of at-risk, 62% of normal-weight, and 63% of underweight children (P less than .05; odds ratio, 0.68 for overweight vs. normal weight). The survey asked only if the children came to the ED for one of those three reasons, so specific data on chronic conditions such as diabetes and asthma are not readily available, Dr. Dziura said.

Still, it’s likely that as rates of childhood obesity continue to skyrocket in the United States, there will be greater demands on the ED and an increased emphasis on the care of chronic conditions.

"Given the numbers that were reported in Pediatrics, ... the types of problems that these children are going into the ED with are totally different than what many people in the ED might have been trained for," he said. "So dealing with chronic conditions is going to be a big part of an ED doctor’s skill set."

The investigators hope to conduct a survey looking at the interaction between BMI and chronic conditions and the types of services given and problems encountered in the ED. Eventually, they hope to design a brief screening and intervention for obesity in the ambulatory setting.

"A lot of these children and parents of these children have never been told by a primary care physician they have a weight problem," he said.

A recent study suggests that despite some progress over the last decade, fewer than a quarter of parents of children with a BMI in the 85th percentile or higher report having been told by a physician or health care provider that their child was overweight (Arch. Pediatr. Adolesc. Med. 2012;166:317-22).

The authors reported having no disclosures.

CHICAGO – Overweight children are 20% more likely to visit the emergency department than are normal-weight children, and they do so for reasons other than injuries and accidents, according to a nationally representative survey.

"I suspect that a big reason we’re seeing this increase in the overweight is that they have chronic conditions that are getting them to the ED," lead author James Dziura, Ph.D., an epidemiologist in the department of emergency medicine and deputy director of the Yale Center for Analytical Sciences in New Haven, Conn., said in an interview.

That supposition is supported by an alarming new report showing that the prevalence of prediabetes and diabetes among adolescents aged 12-19 years jumped from 9% in 1999 to 23% in 2008 (Pediatrics 2012 May 21 [doi: 10.1542/peds.2011-1082]).

The current analysis used parent-reported weight and height data for 46,707 children, aged 10-17 years, from the cross-sectional, telephone-administered National Survey of Children’s Health. Body mass index was calculated using sex-specific BMI for age growth charts from the Centers for Disease Control and Prevention. Children were categorized as underweight (BMI percentile of 5 or less), normal weight (more than 5 to less than 85), at risk for overweight (85 to less than 95), and overweight (95 or more).

Overall, 15.5% of children were reported to have used the ED in the past year, with the prevalence of at least one ED visit increasing significantly with BMI percentile, from 13% of underweight children to 15% of normal-weight or at-risk children to 19% of overweight children (P less than .001 for overweight vs. all groups or vs. normal weight). Additionally, overweight children were more likely to have more than one visit, Dr. Dziura reported at the annual meeting of the Society for Academic Emergency Medicine.

After adjustment for age, sex, race, ethnicity, insurance type, parent’s education, and parent’s primary language, the odds ratio for ED use was 1.24 in overweight children, compared with those at normal weight. The impact of BMI category was not significantly modified by sex, race, or Hispanic ethnicity.

In all, 49% of overweight children reported an injury, poisoning, or accident as the reason for their ED visit, compared with 61% of at-risk, 62% of normal-weight, and 63% of underweight children (P less than .05; odds ratio, 0.68 for overweight vs. normal weight). The survey asked only if the children came to the ED for one of those three reasons, so specific data on chronic conditions such as diabetes and asthma are not readily available, Dr. Dziura said.

Still, it’s likely that as rates of childhood obesity continue to skyrocket in the United States, there will be greater demands on the ED and an increased emphasis on the care of chronic conditions.

"Given the numbers that were reported in Pediatrics, ... the types of problems that these children are going into the ED with are totally different than what many people in the ED might have been trained for," he said. "So dealing with chronic conditions is going to be a big part of an ED doctor’s skill set."

The investigators hope to conduct a survey looking at the interaction between BMI and chronic conditions and the types of services given and problems encountered in the ED. Eventually, they hope to design a brief screening and intervention for obesity in the ambulatory setting.

"A lot of these children and parents of these children have never been told by a primary care physician they have a weight problem," he said.

A recent study suggests that despite some progress over the last decade, fewer than a quarter of parents of children with a BMI in the 85th percentile or higher report having been told by a physician or health care provider that their child was overweight (Arch. Pediatr. Adolesc. Med. 2012;166:317-22).

The authors reported having no disclosures.

CHICAGO – Overweight children are 20% more likely to visit the emergency department than are normal-weight children, and they do so for reasons other than injuries and accidents, according to a nationally representative survey.

"I suspect that a big reason we’re seeing this increase in the overweight is that they have chronic conditions that are getting them to the ED," lead author James Dziura, Ph.D., an epidemiologist in the department of emergency medicine and deputy director of the Yale Center for Analytical Sciences in New Haven, Conn., said in an interview.

That supposition is supported by an alarming new report showing that the prevalence of prediabetes and diabetes among adolescents aged 12-19 years jumped from 9% in 1999 to 23% in 2008 (Pediatrics 2012 May 21 [doi: 10.1542/peds.2011-1082]).

The current analysis used parent-reported weight and height data for 46,707 children, aged 10-17 years, from the cross-sectional, telephone-administered National Survey of Children’s Health. Body mass index was calculated using sex-specific BMI for age growth charts from the Centers for Disease Control and Prevention. Children were categorized as underweight (BMI percentile of 5 or less), normal weight (more than 5 to less than 85), at risk for overweight (85 to less than 95), and overweight (95 or more).

Overall, 15.5% of children were reported to have used the ED in the past year, with the prevalence of at least one ED visit increasing significantly with BMI percentile, from 13% of underweight children to 15% of normal-weight or at-risk children to 19% of overweight children (P less than .001 for overweight vs. all groups or vs. normal weight). Additionally, overweight children were more likely to have more than one visit, Dr. Dziura reported at the annual meeting of the Society for Academic Emergency Medicine.

After adjustment for age, sex, race, ethnicity, insurance type, parent’s education, and parent’s primary language, the odds ratio for ED use was 1.24 in overweight children, compared with those at normal weight. The impact of BMI category was not significantly modified by sex, race, or Hispanic ethnicity.

In all, 49% of overweight children reported an injury, poisoning, or accident as the reason for their ED visit, compared with 61% of at-risk, 62% of normal-weight, and 63% of underweight children (P less than .05; odds ratio, 0.68 for overweight vs. normal weight). The survey asked only if the children came to the ED for one of those three reasons, so specific data on chronic conditions such as diabetes and asthma are not readily available, Dr. Dziura said.

Still, it’s likely that as rates of childhood obesity continue to skyrocket in the United States, there will be greater demands on the ED and an increased emphasis on the care of chronic conditions.

"Given the numbers that were reported in Pediatrics, ... the types of problems that these children are going into the ED with are totally different than what many people in the ED might have been trained for," he said. "So dealing with chronic conditions is going to be a big part of an ED doctor’s skill set."

The investigators hope to conduct a survey looking at the interaction between BMI and chronic conditions and the types of services given and problems encountered in the ED. Eventually, they hope to design a brief screening and intervention for obesity in the ambulatory setting.

"A lot of these children and parents of these children have never been told by a primary care physician they have a weight problem," he said.

A recent study suggests that despite some progress over the last decade, fewer than a quarter of parents of children with a BMI in the 85th percentile or higher report having been told by a physician or health care provider that their child was overweight (Arch. Pediatr. Adolesc. Med. 2012;166:317-22).

The authors reported having no disclosures.

CHICAGO – A move toward crystalloids for initial fluid therapy and away from dopamine as a first-line vasopressor are among the new recommendations in the Surviving Sepsis Campaign consensus guidelines for severe sepsis and septic shock due out later this year.

Efforts were extraordinarily vigorous to ensure the independence of the guideline revision, following controversy that unrestricted industry grant funding of previous guidelines may have influenced which treatments were included and how they were rated, Dr. Alan E. Jones said at the annual meeting of the Society for Academic Emergency Medicine (SAEM). No direct or indirect industry support was used for the 2012 revision, and committee members judged to have financial – or even academic – competing interests on a topic were recused from the closed discussion sessions and from voting on the topic.

The revised guidelines will also take into account the often-litigious issue of standard of care, said Dr. Jones, who represented the SAEM on the guideline-writing committee and is an emergency physician at Carolinas Medical Center in Charlotte, N.C. The authors note that resource limitations in some institutions and countries may prevent physicians from accomplishing particular recommendations, and clearly state that the recommendations are intended to be best practices and were not created with standard of care in mind.

"I can tell you that the use of the Surviving Sepsis Campaign guidelines in medical malpractice cases is unbelievable," he said. "Having this statement in there will really help [stress] the fact that these are guidelines and clinicians should not be held to these as a standard, but rather as best practice.

"I think that’s a huge step forward that the committee did truly recognize the power of the guidelines and how [they are] used by nonmedical personnel."

Dr. Stephen W. Trzeciak, who also served as a SAEM representative during the revision process, said the guidelines are important tools that decrease unnecessary heterogeneity in clinical practice, but they also represent a one-size-fits-all approach.

"We take in a lot of very important information at the bedside, and there are plenty of times that we need to deviate from guidelines because ... in taking care of an individual patient, our clinical judgment will be to do something else," he said. "That’s reasonable. In fact, it’s the right thing to do."

Diagnosis

The diagnostic tests that will allow clinicians to make a diagnosis in real time, including identification of the causative organism, are not yet ready for prime time, although this area of sepsis research is going to accelerate over the next 10 years, said Dr. Trzeciak, a critical care and emergency physician at Cooper University Hospital in Camden, N.J.

The guidance on diagnosis remains relatively unchanged, with at least two blood cultures to be obtained before antimicrobial therapy is administered, as long as doing so does not cause a significant delay. The revised guidelines, however, now define this delay as more than 45 minutes and specify that one of the cultures should be drawn percutaneously and the other drawn through a vascular access device.

Vasopressors

One of the big changes in the guidelines for emergency physicians is that norepinephrine is recommended as the first-choice vasopressor, rather than dopamine. This reflects accumulating evidence that dopamine use in patients with septic shock is associated with an increased risk of death and arrhythmias, compared with norepinephrine (Crit. Care Med. 2012;40:725-30), Dr. Trzeciak said. Phenylephrine was also removed from the guidelines and replaced with epinephrine as the treatment of choice when an additional agent is needed to maintain adequate blood pressure.

Initial Fluid Therapy

The new guidelines recommend that crystalloids be used in the initial fluid resuscitation of severe sepsis, and caution against the use of hydroxyethyl starches with a molecular weight greater than 200 kDa or a degree of substitution exceeding .04 because data show they may not be effective and may actually be detrimental, Dr. Jones said. The committee also suggests albumin in the initial fluid resuscitation, based in large part on a recent meta-analysis of 17 studies showing that use of albumin as a resuscitation fluid was associated with lower mortality (odds ratio 0.82; P = .047) in sepsis patients (Crit. Care Med. 2011;39:386-91).

Fluid Responsiveness

The 2012 guidelines also emphasize using dynamic measures such as delta pulse pressure or stroke volume variation to determine the adequacy of fluid resuscitation, rather than such static measures as central venous pressure. The newer dynamic measures of fluid responsiveness have really taken hold in the critical care community, particularly in Europe, and focus on what the left ventricle does in response to fluids rather than what the central venous pressure is, Dr. Jones said.

Initial Resuscitation

The guidelines now recommend a quantitative resuscitation protocol for patients with sepsis-induced shock, defined as tissue hypotension persisting after initial fluid challenge or blood lactate concentration of 4 mmol/L or more. The guidelines previously identified central venous pressure of 8-12 mm Hg, mean arterial pressure of at least 65 mm Hg, and urine output of at least 0.5 mL/kg per hour as treatment goals during the first 6 hours of resuscitation, and now add central venous (superior vena cava) or mixed venous oxygen saturation of at least 70% or at least 65%, respectively, as a fourth goal.

In patients with elevated lactate levels as a marker of tissue hypoperfusion, the guidelines for the first time suggest targeting resuscitation to normalize lactate as rapidly as possible. Several studies have recently looked at lactate clearance using a target of less than 10%, but in the absence of data on other lactate levels, the committee thought it made more sense to suggest lactate be normalized rather than to shoot for a specific level of clearance, Dr. Jones said.

The Surviving Sepsis Campaign guidelines for severe sepsis and septic shock were last updated in 2008 (Crit. Care Med. 2008;36:296-327). More than 25 international professional medical societies were represented in the review and revision process.

The Gordon and Betty Moore Foundation provides grant support for the Surviving Sepsis Campaign.

CHICAGO – A move toward crystalloids for initial fluid therapy and away from dopamine as a first-line vasopressor are among the new recommendations in the Surviving Sepsis Campaign consensus guidelines for severe sepsis and septic shock due out later this year.

Efforts were extraordinarily vigorous to ensure the independence of the guideline revision, following controversy that unrestricted industry grant funding of previous guidelines may have influenced which treatments were included and how they were rated, Dr. Alan E. Jones said at the annual meeting of the Society for Academic Emergency Medicine (SAEM). No direct or indirect industry support was used for the 2012 revision, and committee members judged to have financial – or even academic – competing interests on a topic were recused from the closed discussion sessions and from voting on the topic.

The revised guidelines will also take into account the often-litigious issue of standard of care, said Dr. Jones, who represented the SAEM on the guideline-writing committee and is an emergency physician at Carolinas Medical Center in Charlotte, N.C. The authors note that resource limitations in some institutions and countries may prevent physicians from accomplishing particular recommendations, and clearly state that the recommendations are intended to be best practices and were not created with standard of care in mind.

"I can tell you that the use of the Surviving Sepsis Campaign guidelines in medical malpractice cases is unbelievable," he said. "Having this statement in there will really help [stress] the fact that these are guidelines and clinicians should not be held to these as a standard, but rather as best practice.

"I think that’s a huge step forward that the committee did truly recognize the power of the guidelines and how [they are] used by nonmedical personnel."

Dr. Stephen W. Trzeciak, who also served as a SAEM representative during the revision process, said the guidelines are important tools that decrease unnecessary heterogeneity in clinical practice, but they also represent a one-size-fits-all approach.

"We take in a lot of very important information at the bedside, and there are plenty of times that we need to deviate from guidelines because ... in taking care of an individual patient, our clinical judgment will be to do something else," he said. "That’s reasonable. In fact, it’s the right thing to do."

Diagnosis

The diagnostic tests that will allow clinicians to make a diagnosis in real time, including identification of the causative organism, are not yet ready for prime time, although this area of sepsis research is going to accelerate over the next 10 years, said Dr. Trzeciak, a critical care and emergency physician at Cooper University Hospital in Camden, N.J.

The guidance on diagnosis remains relatively unchanged, with at least two blood cultures to be obtained before antimicrobial therapy is administered, as long as doing so does not cause a significant delay. The revised guidelines, however, now define this delay as more than 45 minutes and specify that one of the cultures should be drawn percutaneously and the other drawn through a vascular access device.

Vasopressors

One of the big changes in the guidelines for emergency physicians is that norepinephrine is recommended as the first-choice vasopressor, rather than dopamine. This reflects accumulating evidence that dopamine use in patients with septic shock is associated with an increased risk of death and arrhythmias, compared with norepinephrine (Crit. Care Med. 2012;40:725-30), Dr. Trzeciak said. Phenylephrine was also removed from the guidelines and replaced with epinephrine as the treatment of choice when an additional agent is needed to maintain adequate blood pressure.

Initial Fluid Therapy

The new guidelines recommend that crystalloids be used in the initial fluid resuscitation of severe sepsis, and caution against the use of hydroxyethyl starches with a molecular weight greater than 200 kDa or a degree of substitution exceeding .04 because data show they may not be effective and may actually be detrimental, Dr. Jones said. The committee also suggests albumin in the initial fluid resuscitation, based in large part on a recent meta-analysis of 17 studies showing that use of albumin as a resuscitation fluid was associated with lower mortality (odds ratio 0.82; P = .047) in sepsis patients (Crit. Care Med. 2011;39:386-91).

Fluid Responsiveness

The 2012 guidelines also emphasize using dynamic measures such as delta pulse pressure or stroke volume variation to determine the adequacy of fluid resuscitation, rather than such static measures as central venous pressure. The newer dynamic measures of fluid responsiveness have really taken hold in the critical care community, particularly in Europe, and focus on what the left ventricle does in response to fluids rather than what the central venous pressure is, Dr. Jones said.

Initial Resuscitation

The guidelines now recommend a quantitative resuscitation protocol for patients with sepsis-induced shock, defined as tissue hypotension persisting after initial fluid challenge or blood lactate concentration of 4 mmol/L or more. The guidelines previously identified central venous pressure of 8-12 mm Hg, mean arterial pressure of at least 65 mm Hg, and urine output of at least 0.5 mL/kg per hour as treatment goals during the first 6 hours of resuscitation, and now add central venous (superior vena cava) or mixed venous oxygen saturation of at least 70% or at least 65%, respectively, as a fourth goal.

In patients with elevated lactate levels as a marker of tissue hypoperfusion, the guidelines for the first time suggest targeting resuscitation to normalize lactate as rapidly as possible. Several studies have recently looked at lactate clearance using a target of less than 10%, but in the absence of data on other lactate levels, the committee thought it made more sense to suggest lactate be normalized rather than to shoot for a specific level of clearance, Dr. Jones said.

The Surviving Sepsis Campaign guidelines for severe sepsis and septic shock were last updated in 2008 (Crit. Care Med. 2008;36:296-327). More than 25 international professional medical societies were represented in the review and revision process.

The Gordon and Betty Moore Foundation provides grant support for the Surviving Sepsis Campaign.

CHICAGO – A move toward crystalloids for initial fluid therapy and away from dopamine as a first-line vasopressor are among the new recommendations in the Surviving Sepsis Campaign consensus guidelines for severe sepsis and septic shock due out later this year.

Efforts were extraordinarily vigorous to ensure the independence of the guideline revision, following controversy that unrestricted industry grant funding of previous guidelines may have influenced which treatments were included and how they were rated, Dr. Alan E. Jones said at the annual meeting of the Society for Academic Emergency Medicine (SAEM). No direct or indirect industry support was used for the 2012 revision, and committee members judged to have financial – or even academic – competing interests on a topic were recused from the closed discussion sessions and from voting on the topic.

The revised guidelines will also take into account the often-litigious issue of standard of care, said Dr. Jones, who represented the SAEM on the guideline-writing committee and is an emergency physician at Carolinas Medical Center in Charlotte, N.C. The authors note that resource limitations in some institutions and countries may prevent physicians from accomplishing particular recommendations, and clearly state that the recommendations are intended to be best practices and were not created with standard of care in mind.

"I can tell you that the use of the Surviving Sepsis Campaign guidelines in medical malpractice cases is unbelievable," he said. "Having this statement in there will really help [stress] the fact that these are guidelines and clinicians should not be held to these as a standard, but rather as best practice.

"I think that’s a huge step forward that the committee did truly recognize the power of the guidelines and how [they are] used by nonmedical personnel."

Dr. Stephen W. Trzeciak, who also served as a SAEM representative during the revision process, said the guidelines are important tools that decrease unnecessary heterogeneity in clinical practice, but they also represent a one-size-fits-all approach.

"We take in a lot of very important information at the bedside, and there are plenty of times that we need to deviate from guidelines because ... in taking care of an individual patient, our clinical judgment will be to do something else," he said. "That’s reasonable. In fact, it’s the right thing to do."

Diagnosis

The diagnostic tests that will allow clinicians to make a diagnosis in real time, including identification of the causative organism, are not yet ready for prime time, although this area of sepsis research is going to accelerate over the next 10 years, said Dr. Trzeciak, a critical care and emergency physician at Cooper University Hospital in Camden, N.J.

The guidance on diagnosis remains relatively unchanged, with at least two blood cultures to be obtained before antimicrobial therapy is administered, as long as doing so does not cause a significant delay. The revised guidelines, however, now define this delay as more than 45 minutes and specify that one of the cultures should be drawn percutaneously and the other drawn through a vascular access device.

Vasopressors

One of the big changes in the guidelines for emergency physicians is that norepinephrine is recommended as the first-choice vasopressor, rather than dopamine. This reflects accumulating evidence that dopamine use in patients with septic shock is associated with an increased risk of death and arrhythmias, compared with norepinephrine (Crit. Care Med. 2012;40:725-30), Dr. Trzeciak said. Phenylephrine was also removed from the guidelines and replaced with epinephrine as the treatment of choice when an additional agent is needed to maintain adequate blood pressure.

Initial Fluid Therapy

The new guidelines recommend that crystalloids be used in the initial fluid resuscitation of severe sepsis, and caution against the use of hydroxyethyl starches with a molecular weight greater than 200 kDa or a degree of substitution exceeding .04 because data show they may not be effective and may actually be detrimental, Dr. Jones said. The committee also suggests albumin in the initial fluid resuscitation, based in large part on a recent meta-analysis of 17 studies showing that use of albumin as a resuscitation fluid was associated with lower mortality (odds ratio 0.82; P = .047) in sepsis patients (Crit. Care Med. 2011;39:386-91).

Fluid Responsiveness

The 2012 guidelines also emphasize using dynamic measures such as delta pulse pressure or stroke volume variation to determine the adequacy of fluid resuscitation, rather than such static measures as central venous pressure. The newer dynamic measures of fluid responsiveness have really taken hold in the critical care community, particularly in Europe, and focus on what the left ventricle does in response to fluids rather than what the central venous pressure is, Dr. Jones said.

Initial Resuscitation

The guidelines now recommend a quantitative resuscitation protocol for patients with sepsis-induced shock, defined as tissue hypotension persisting after initial fluid challenge or blood lactate concentration of 4 mmol/L or more. The guidelines previously identified central venous pressure of 8-12 mm Hg, mean arterial pressure of at least 65 mm Hg, and urine output of at least 0.5 mL/kg per hour as treatment goals during the first 6 hours of resuscitation, and now add central venous (superior vena cava) or mixed venous oxygen saturation of at least 70% or at least 65%, respectively, as a fourth goal.

In patients with elevated lactate levels as a marker of tissue hypoperfusion, the guidelines for the first time suggest targeting resuscitation to normalize lactate as rapidly as possible. Several studies have recently looked at lactate clearance using a target of less than 10%, but in the absence of data on other lactate levels, the committee thought it made more sense to suggest lactate be normalized rather than to shoot for a specific level of clearance, Dr. Jones said.

The Surviving Sepsis Campaign guidelines for severe sepsis and septic shock were last updated in 2008 (Crit. Care Med. 2008;36:296-327). More than 25 international professional medical societies were represented in the review and revision process.

The Gordon and Betty Moore Foundation provides grant support for the Surviving Sepsis Campaign.

CHICAGO – Adding an additional physician shift in the ambulatory pod of a typical, high-volume academic center with severe emergency department overcrowding did not reduce overall length of stay in the randomized, controlled PICO-D trial.

"Despite the fact you could say this is a negative trial, the physician group almost unanimously voted to keep this intervention because they were seeing fewer patients, but their quality of life was improved," Dr. Brian H. Rowe said at the annual meeting of the Society for Academic Emergency Medicine. "There was more overlap, more discussion, and less staying 3, 4 hours after the end of their shift."

Patrice Wendling/IMNG Medical Media

The unblinded, parallel-group trial compared the traditional schedule of three emergency physician shifts per day (9 a.m. to 5 p.m., 2 p.m. to 10 p.m., and 7 p.m. to 3 a.m.) with four physician shifts per day (9 a.m. to 5 p.m., 1 p.m. to 9 p.m., 5 p.m. to 1 a.m., and 9 p.m. to 5 a.m.) in the ambulatory pod at the University of Alberta Hospital in Edmonton. The schedules were computer generated in 2-week blocks for a total of 12 weeks during mid-2011.

The tertiary care center ED has about 60,000 adult and 30,000 pediatric visits per year, static 8-hour shifts that are similar on weekdays and weekends, and no on-call system. It is the last fee-for-service ED in Canada and has serious overcrowding issues, said Dr. Rowe, a clinical emergency physician at the hospital and professor and research director of emergency medicine at the University of Alberta.

In the 3 months prior to and during the intervention, patient volumes were similar at 15,135 vs. 14,005, as was median patient age (both 46 years) and CTAS (Canadian Triage and Acuity Scale) status (23.8% vs. 22.5% levels 1, 2 [highest acuity]).

Physician initial assessment times decreased significantly from a median of 76 minutes on control days to 69 minutes on intervention days (P less than .001), Dr. Rowe said.

The median length of stay was not significantly decreased by the intervention for admitted patients (10.5 hours to 10.2 hours; P = .27) or for discharged patients (4.1 hours to 3.9 hours; P = .06).

In multiple linear regression modeling that adjusted for confounders such as age, sex, CTAS status, and consultations, the intervention did provide a statistically significant influence on overall length of stay (P = .003), he said.

In addition, the left-without-being-seen rate dropped significantly, from 5.1% on control days to 3.7% on intervention days (P less than .001). The proportion of patients leaving against medical advice was similar during both periods (0.7% vs. 0.5%; P = .08).

Although physicians saw five fewer patients per shift in the ambulatory pod on the intervention days (decreasing from 27 to 22 patients), the ED physicians rated their satisfaction higher, Dr. Rowe observed.

He said that this is the third randomized, controlled trial to be conducted in his institution’s ED, and that the physician group was particularly resistant to changes in the staffing model. Although there has been considerable research on throughput interventions to reduce ED overcrowding, volume-based staffing has been infrequently described in the literature.

Session moderator and emergency physician Dr. Robert A. Lowe of Oregon Health and Science University in Portland asked whether the lack of substantial change in length of stay is an argument that the problem of ED overcrowding is really due to a shortage of inpatient beds.

Dr. Rowe agreed, and said the physician group was able to demonstrate to the administration that despite their efforts, the problem remained.

"So it’s a good argument to administrations to stop blaming us," Dr. Lowe added.

Dr. Rowe reported no relevant conflicts of interest.

CHICAGO – Adding an additional physician shift in the ambulatory pod of a typical, high-volume academic center with severe emergency department overcrowding did not reduce overall length of stay in the randomized, controlled PICO-D trial.

"Despite the fact you could say this is a negative trial, the physician group almost unanimously voted to keep this intervention because they were seeing fewer patients, but their quality of life was improved," Dr. Brian H. Rowe said at the annual meeting of the Society for Academic Emergency Medicine. "There was more overlap, more discussion, and less staying 3, 4 hours after the end of their shift."

Patrice Wendling/IMNG Medical Media

The unblinded, parallel-group trial compared the traditional schedule of three emergency physician shifts per day (9 a.m. to 5 p.m., 2 p.m. to 10 p.m., and 7 p.m. to 3 a.m.) with four physician shifts per day (9 a.m. to 5 p.m., 1 p.m. to 9 p.m., 5 p.m. to 1 a.m., and 9 p.m. to 5 a.m.) in the ambulatory pod at the University of Alberta Hospital in Edmonton. The schedules were computer generated in 2-week blocks for a total of 12 weeks during mid-2011.

The tertiary care center ED has about 60,000 adult and 30,000 pediatric visits per year, static 8-hour shifts that are similar on weekdays and weekends, and no on-call system. It is the last fee-for-service ED in Canada and has serious overcrowding issues, said Dr. Rowe, a clinical emergency physician at the hospital and professor and research director of emergency medicine at the University of Alberta.

In the 3 months prior to and during the intervention, patient volumes were similar at 15,135 vs. 14,005, as was median patient age (both 46 years) and CTAS (Canadian Triage and Acuity Scale) status (23.8% vs. 22.5% levels 1, 2 [highest acuity]).

Physician initial assessment times decreased significantly from a median of 76 minutes on control days to 69 minutes on intervention days (P less than .001), Dr. Rowe said.

The median length of stay was not significantly decreased by the intervention for admitted patients (10.5 hours to 10.2 hours; P = .27) or for discharged patients (4.1 hours to 3.9 hours; P = .06).

In multiple linear regression modeling that adjusted for confounders such as age, sex, CTAS status, and consultations, the intervention did provide a statistically significant influence on overall length of stay (P = .003), he said.

In addition, the left-without-being-seen rate dropped significantly, from 5.1% on control days to 3.7% on intervention days (P less than .001). The proportion of patients leaving against medical advice was similar during both periods (0.7% vs. 0.5%; P = .08).

Although physicians saw five fewer patients per shift in the ambulatory pod on the intervention days (decreasing from 27 to 22 patients), the ED physicians rated their satisfaction higher, Dr. Rowe observed.

He said that this is the third randomized, controlled trial to be conducted in his institution’s ED, and that the physician group was particularly resistant to changes in the staffing model. Although there has been considerable research on throughput interventions to reduce ED overcrowding, volume-based staffing has been infrequently described in the literature.

Session moderator and emergency physician Dr. Robert A. Lowe of Oregon Health and Science University in Portland asked whether the lack of substantial change in length of stay is an argument that the problem of ED overcrowding is really due to a shortage of inpatient beds.

Dr. Rowe agreed, and said the physician group was able to demonstrate to the administration that despite their efforts, the problem remained.

"So it’s a good argument to administrations to stop blaming us," Dr. Lowe added.

Dr. Rowe reported no relevant conflicts of interest.

CHICAGO – Adding an additional physician shift in the ambulatory pod of a typical, high-volume academic center with severe emergency department overcrowding did not reduce overall length of stay in the randomized, controlled PICO-D trial.

"Despite the fact you could say this is a negative trial, the physician group almost unanimously voted to keep this intervention because they were seeing fewer patients, but their quality of life was improved," Dr. Brian H. Rowe said at the annual meeting of the Society for Academic Emergency Medicine. "There was more overlap, more discussion, and less staying 3, 4 hours after the end of their shift."

Patrice Wendling/IMNG Medical Media

The unblinded, parallel-group trial compared the traditional schedule of three emergency physician shifts per day (9 a.m. to 5 p.m., 2 p.m. to 10 p.m., and 7 p.m. to 3 a.m.) with four physician shifts per day (9 a.m. to 5 p.m., 1 p.m. to 9 p.m., 5 p.m. to 1 a.m., and 9 p.m. to 5 a.m.) in the ambulatory pod at the University of Alberta Hospital in Edmonton. The schedules were computer generated in 2-week blocks for a total of 12 weeks during mid-2011.

The tertiary care center ED has about 60,000 adult and 30,000 pediatric visits per year, static 8-hour shifts that are similar on weekdays and weekends, and no on-call system. It is the last fee-for-service ED in Canada and has serious overcrowding issues, said Dr. Rowe, a clinical emergency physician at the hospital and professor and research director of emergency medicine at the University of Alberta.

In the 3 months prior to and during the intervention, patient volumes were similar at 15,135 vs. 14,005, as was median patient age (both 46 years) and CTAS (Canadian Triage and Acuity Scale) status (23.8% vs. 22.5% levels 1, 2 [highest acuity]).

Physician initial assessment times decreased significantly from a median of 76 minutes on control days to 69 minutes on intervention days (P less than .001), Dr. Rowe said.

The median length of stay was not significantly decreased by the intervention for admitted patients (10.5 hours to 10.2 hours; P = .27) or for discharged patients (4.1 hours to 3.9 hours; P = .06).

In multiple linear regression modeling that adjusted for confounders such as age, sex, CTAS status, and consultations, the intervention did provide a statistically significant influence on overall length of stay (P = .003), he said.

In addition, the left-without-being-seen rate dropped significantly, from 5.1% on control days to 3.7% on intervention days (P less than .001). The proportion of patients leaving against medical advice was similar during both periods (0.7% vs. 0.5%; P = .08).

Although physicians saw five fewer patients per shift in the ambulatory pod on the intervention days (decreasing from 27 to 22 patients), the ED physicians rated their satisfaction higher, Dr. Rowe observed.

He said that this is the third randomized, controlled trial to be conducted in his institution’s ED, and that the physician group was particularly resistant to changes in the staffing model. Although there has been considerable research on throughput interventions to reduce ED overcrowding, volume-based staffing has been infrequently described in the literature.

Session moderator and emergency physician Dr. Robert A. Lowe of Oregon Health and Science University in Portland asked whether the lack of substantial change in length of stay is an argument that the problem of ED overcrowding is really due to a shortage of inpatient beds.

Dr. Rowe agreed, and said the physician group was able to demonstrate to the administration that despite their efforts, the problem remained.

"So it’s a good argument to administrations to stop blaming us," Dr. Lowe added.

Dr. Rowe reported no relevant conflicts of interest.

DALLAS – Deadly invasive fungal infections are increasingly being identified in soft-tissue and intra-abdominal wounds in troops deployed to Iraq and Afghanistan, prompting the creation of hospital-based clinical practice guidelines.

When the first case emerged in July 2009, the medical team initially suspected significant bacterial infection in a young, previously healthy Marine with extensive soft-tissue injuries. By the time appropriate antifungal therapies were initiated in week 3, it was too late. An autopsy revealed that the 22-year-old soldier’s death was from systemic angioinvasive Aspergillus terreus (Surg. Infect. [Larchmt.] 2011;12:397-400).

Patrice Wendling/IMNG Medical Media

"We were not expecting the degree of mold infestation early on," Col. Debra Malone, MC, USAF, trauma research director of the Walter Reed National Military Medical Center (NMMC) in Bethesda, Md., said in an interview. "It’s not necessarily that things were missed – it’s that the disease itself didn’t present early on.

"Sometimes it can take 2, 3, 6 weeks for certain molds to actually grow. Now we don’t wait for them to grow. If we have the clinical suspicion, we treat right away with very powerful antimold medications."

The NMMC has also developed a 24-hour invasive fungal infection (IFI) pathology protocol and hospital-based clinical practice guidelines to improve outcomes for trauma-related IFI, which has a reported mortality rate of 25% in previously immunocompetent patients.

From July 2009 to November 2011, IFI was suspected or identified on pathology in 75 of 2,755 trauma patients admitted to the NMMC, Dr. Malone reported at the annual meeting of the Surgical Infection Society.

Although the index case occurred in the heavily agricultural Helmand Province in Afghanistan, IFI cases are cropping up throughout Iraq and Afghanistan, particularly in troops with injuries caused by improvised explosive devices (IEDs).

"It’s not uncommon for the bomb to cause a big crater in the ground, and all that dirt or whatever has been displaced," she said. "We think it’s been driven up into the body, deep into the open wounds, and that the mold spores are sitting up there, just percolating."

The typical patient is an 18-year-old with devastating soft-tissue IED blast injuries who is resuscitated and has wounds debrided to normal tissue. However, 5-7 days later, there is evidence of infected tissue on successive washouts, and the patient is hypertensive and in shock.

Frozen-section histopathology was initially used for diagnosis because of its quick turnaround, but resulted in a 33% negative predictive value in their lab and is no longer used, Dr. Malone said. This led to the 24-hour IFI protocol utilizing permanent sections. Periodic acid-Schiff and Gomori methenamine silver staining have proved efficacious for Aspergillus species, but not as efficacious for identifying Mucorales species. Calcofluor white staining is also used and may allow morphology-based speciation.

In all, 42 (56%) of the 75 patients met histologic criteria for IFI. Notably, IFI was suspected clinically in the remaining patients but never proved by histologic criteria. More than a fourth (28%) of wounds infected with Mucor were coinfected with non-Mucor species. In addition, the vast majority of wounds will be coinfected with bacteria, according to the investigators, led by Dr. Carlos Rodriguez, an attending trauma and critical care surgeon at NMMC.

Therapy should include aggressive debridement, with minimization of blood loss. Surgery should be repeated every 24-48 hours until the wounds are clean, with compromised tissue sent from every surgery for histopathology and culture. Changes in surgical practice as related to the treatment of nonnecrotic tissue abnormalities may have led to improvement in tissue salvage.

Broad-spectrum antifungal medications should be tailored based on serial tissue specimen culture results. Focused antifungal therapies should be continued for 2-3 weeks after wound closure. Liposomal amphotericin B and the triazoles – voriconazole (Vfend) and posaconazole (Noxafil) – have been used as initial therapies. Vancomycin (Vancocin) and meropenem (Merrem IV) also should be considered because of the high risk of coinfection with bacteria.

Adjunctive therapies include minimization of immunosuppression, antimicrobial beads in open wounds, and negative-pressure wound therapy with a 0.025% Dakin’s solution (sodium hypochlorite). Intra-abdominal washings with amphotericin B, voriconazole, or bacitracin plus gentamicin can be utilized on a case-by-case basis.

Among the 75 patients, the time from injury to IFI diagnosis decreased from 10 days (range 7-12) in 2009 to 3 days (range 2-6 days) in 2011. The mortality rate was 4%; mean ICU length of stay, 13 days; and mean hospital stay, 48 days. All IFI patients were male; their mean age was 24 years, and their mean Injury Severity Score was 23.

Although the authors acknowledged that significant diagnostic challenges persist and that weaknesses still exist in their guidelines, progress has been made.

"We’re saving these guys now because the guideline that we developed is allowing us to do a better job," Dr. Malone said. "They’re losing less tissue with surgical debridements, and they’re surviving. So we’ve come a long way since we identified the problem."

"This observation is important not only for military patients but also for patients with contaminated civilian wounds," said Dr. Grace Rozycki, who was asked to comment on the findings. "As the authors point out, the diagnosis is difficult to make and cultures, although helpful, may take several weeks. A presumptive diagnosis is helpful so that antifungal and antibiotic therapy can be started early," said Dr. Rozycki, chief of the division of trauma/surgical critical care, department of surgery, Emory University, Atlanta.

The project was funded by the National Institute of Allergy and Infectious Diseases and the Department of the Navy under the Wounded, Ill, and Injured program.

DALLAS – Deadly invasive fungal infections are increasingly being identified in soft-tissue and intra-abdominal wounds in troops deployed to Iraq and Afghanistan, prompting the creation of hospital-based clinical practice guidelines.

When the first case emerged in July 2009, the medical team initially suspected significant bacterial infection in a young, previously healthy Marine with extensive soft-tissue injuries. By the time appropriate antifungal therapies were initiated in week 3, it was too late. An autopsy revealed that the 22-year-old soldier’s death was from systemic angioinvasive Aspergillus terreus (Surg. Infect. [Larchmt.] 2011;12:397-400).

Patrice Wendling/IMNG Medical Media

"We were not expecting the degree of mold infestation early on," Col. Debra Malone, MC, USAF, trauma research director of the Walter Reed National Military Medical Center (NMMC) in Bethesda, Md., said in an interview. "It’s not necessarily that things were missed – it’s that the disease itself didn’t present early on.

"Sometimes it can take 2, 3, 6 weeks for certain molds to actually grow. Now we don’t wait for them to grow. If we have the clinical suspicion, we treat right away with very powerful antimold medications."

The NMMC has also developed a 24-hour invasive fungal infection (IFI) pathology protocol and hospital-based clinical practice guidelines to improve outcomes for trauma-related IFI, which has a reported mortality rate of 25% in previously immunocompetent patients.

From July 2009 to November 2011, IFI was suspected or identified on pathology in 75 of 2,755 trauma patients admitted to the NMMC, Dr. Malone reported at the annual meeting of the Surgical Infection Society.

Although the index case occurred in the heavily agricultural Helmand Province in Afghanistan, IFI cases are cropping up throughout Iraq and Afghanistan, particularly in troops with injuries caused by improvised explosive devices (IEDs).

"It’s not uncommon for the bomb to cause a big crater in the ground, and all that dirt or whatever has been displaced," she said. "We think it’s been driven up into the body, deep into the open wounds, and that the mold spores are sitting up there, just percolating."

The typical patient is an 18-year-old with devastating soft-tissue IED blast injuries who is resuscitated and has wounds debrided to normal tissue. However, 5-7 days later, there is evidence of infected tissue on successive washouts, and the patient is hypertensive and in shock.

Frozen-section histopathology was initially used for diagnosis because of its quick turnaround, but resulted in a 33% negative predictive value in their lab and is no longer used, Dr. Malone said. This led to the 24-hour IFI protocol utilizing permanent sections. Periodic acid-Schiff and Gomori methenamine silver staining have proved efficacious for Aspergillus species, but not as efficacious for identifying Mucorales species. Calcofluor white staining is also used and may allow morphology-based speciation.

In all, 42 (56%) of the 75 patients met histologic criteria for IFI. Notably, IFI was suspected clinically in the remaining patients but never proved by histologic criteria. More than a fourth (28%) of wounds infected with Mucor were coinfected with non-Mucor species. In addition, the vast majority of wounds will be coinfected with bacteria, according to the investigators, led by Dr. Carlos Rodriguez, an attending trauma and critical care surgeon at NMMC.

Therapy should include aggressive debridement, with minimization of blood loss. Surgery should be repeated every 24-48 hours until the wounds are clean, with compromised tissue sent from every surgery for histopathology and culture. Changes in surgical practice as related to the treatment of nonnecrotic tissue abnormalities may have led to improvement in tissue salvage.

Broad-spectrum antifungal medications should be tailored based on serial tissue specimen culture results. Focused antifungal therapies should be continued for 2-3 weeks after wound closure. Liposomal amphotericin B and the triazoles – voriconazole (Vfend) and posaconazole (Noxafil) – have been used as initial therapies. Vancomycin (Vancocin) and meropenem (Merrem IV) also should be considered because of the high risk of coinfection with bacteria.

Adjunctive therapies include minimization of immunosuppression, antimicrobial beads in open wounds, and negative-pressure wound therapy with a 0.025% Dakin’s solution (sodium hypochlorite). Intra-abdominal washings with amphotericin B, voriconazole, or bacitracin plus gentamicin can be utilized on a case-by-case basis.

Among the 75 patients, the time from injury to IFI diagnosis decreased from 10 days (range 7-12) in 2009 to 3 days (range 2-6 days) in 2011. The mortality rate was 4%; mean ICU length of stay, 13 days; and mean hospital stay, 48 days. All IFI patients were male; their mean age was 24 years, and their mean Injury Severity Score was 23.

Although the authors acknowledged that significant diagnostic challenges persist and that weaknesses still exist in their guidelines, progress has been made.

"We’re saving these guys now because the guideline that we developed is allowing us to do a better job," Dr. Malone said. "They’re losing less tissue with surgical debridements, and they’re surviving. So we’ve come a long way since we identified the problem."

"This observation is important not only for military patients but also for patients with contaminated civilian wounds," said Dr. Grace Rozycki, who was asked to comment on the findings. "As the authors point out, the diagnosis is difficult to make and cultures, although helpful, may take several weeks. A presumptive diagnosis is helpful so that antifungal and antibiotic therapy can be started early," said Dr. Rozycki, chief of the division of trauma/surgical critical care, department of surgery, Emory University, Atlanta.

The project was funded by the National Institute of Allergy and Infectious Diseases and the Department of the Navy under the Wounded, Ill, and Injured program.

DALLAS – Deadly invasive fungal infections are increasingly being identified in soft-tissue and intra-abdominal wounds in troops deployed to Iraq and Afghanistan, prompting the creation of hospital-based clinical practice guidelines.

When the first case emerged in July 2009, the medical team initially suspected significant bacterial infection in a young, previously healthy Marine with extensive soft-tissue injuries. By the time appropriate antifungal therapies were initiated in week 3, it was too late. An autopsy revealed that the 22-year-old soldier’s death was from systemic angioinvasive Aspergillus terreus (Surg. Infect. [Larchmt.] 2011;12:397-400).

Patrice Wendling/IMNG Medical Media

"We were not expecting the degree of mold infestation early on," Col. Debra Malone, MC, USAF, trauma research director of the Walter Reed National Military Medical Center (NMMC) in Bethesda, Md., said in an interview. "It’s not necessarily that things were missed – it’s that the disease itself didn’t present early on.

"Sometimes it can take 2, 3, 6 weeks for certain molds to actually grow. Now we don’t wait for them to grow. If we have the clinical suspicion, we treat right away with very powerful antimold medications."

The NMMC has also developed a 24-hour invasive fungal infection (IFI) pathology protocol and hospital-based clinical practice guidelines to improve outcomes for trauma-related IFI, which has a reported mortality rate of 25% in previously immunocompetent patients.

From July 2009 to November 2011, IFI was suspected or identified on pathology in 75 of 2,755 trauma patients admitted to the NMMC, Dr. Malone reported at the annual meeting of the Surgical Infection Society.

Although the index case occurred in the heavily agricultural Helmand Province in Afghanistan, IFI cases are cropping up throughout Iraq and Afghanistan, particularly in troops with injuries caused by improvised explosive devices (IEDs).

"It’s not uncommon for the bomb to cause a big crater in the ground, and all that dirt or whatever has been displaced," she said. "We think it’s been driven up into the body, deep into the open wounds, and that the mold spores are sitting up there, just percolating."

The typical patient is an 18-year-old with devastating soft-tissue IED blast injuries who is resuscitated and has wounds debrided to normal tissue. However, 5-7 days later, there is evidence of infected tissue on successive washouts, and the patient is hypertensive and in shock.

Frozen-section histopathology was initially used for diagnosis because of its quick turnaround, but resulted in a 33% negative predictive value in their lab and is no longer used, Dr. Malone said. This led to the 24-hour IFI protocol utilizing permanent sections. Periodic acid-Schiff and Gomori methenamine silver staining have proved efficacious for Aspergillus species, but not as efficacious for identifying Mucorales species. Calcofluor white staining is also used and may allow morphology-based speciation.

In all, 42 (56%) of the 75 patients met histologic criteria for IFI. Notably, IFI was suspected clinically in the remaining patients but never proved by histologic criteria. More than a fourth (28%) of wounds infected with Mucor were coinfected with non-Mucor species. In addition, the vast majority of wounds will be coinfected with bacteria, according to the investigators, led by Dr. Carlos Rodriguez, an attending trauma and critical care surgeon at NMMC.

Therapy should include aggressive debridement, with minimization of blood loss. Surgery should be repeated every 24-48 hours until the wounds are clean, with compromised tissue sent from every surgery for histopathology and culture. Changes in surgical practice as related to the treatment of nonnecrotic tissue abnormalities may have led to improvement in tissue salvage.

Broad-spectrum antifungal medications should be tailored based on serial tissue specimen culture results. Focused antifungal therapies should be continued for 2-3 weeks after wound closure. Liposomal amphotericin B and the triazoles – voriconazole (Vfend) and posaconazole (Noxafil) – have been used as initial therapies. Vancomycin (Vancocin) and meropenem (Merrem IV) also should be considered because of the high risk of coinfection with bacteria.

Adjunctive therapies include minimization of immunosuppression, antimicrobial beads in open wounds, and negative-pressure wound therapy with a 0.025% Dakin’s solution (sodium hypochlorite). Intra-abdominal washings with amphotericin B, voriconazole, or bacitracin plus gentamicin can be utilized on a case-by-case basis.

Among the 75 patients, the time from injury to IFI diagnosis decreased from 10 days (range 7-12) in 2009 to 3 days (range 2-6 days) in 2011. The mortality rate was 4%; mean ICU length of stay, 13 days; and mean hospital stay, 48 days. All IFI patients were male; their mean age was 24 years, and their mean Injury Severity Score was 23.

Although the authors acknowledged that significant diagnostic challenges persist and that weaknesses still exist in their guidelines, progress has been made.

"We’re saving these guys now because the guideline that we developed is allowing us to do a better job," Dr. Malone said. "They’re losing less tissue with surgical debridements, and they’re surviving. So we’ve come a long way since we identified the problem."

"This observation is important not only for military patients but also for patients with contaminated civilian wounds," said Dr. Grace Rozycki, who was asked to comment on the findings. "As the authors point out, the diagnosis is difficult to make and cultures, although helpful, may take several weeks. A presumptive diagnosis is helpful so that antifungal and antibiotic therapy can be started early," said Dr. Rozycki, chief of the division of trauma/surgical critical care, department of surgery, Emory University, Atlanta.

The project was funded by the National Institute of Allergy and Infectious Diseases and the Department of the Navy under the Wounded, Ill, and Injured program.

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

"We know cancers are smart," said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. "They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research."

The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.

The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.

Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.

Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.

The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.

The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK.

* Updated: This paragraph was added on May 18, 2012.

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

"We know cancers are smart," said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. "They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research."

The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.

The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.

Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.

Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.

The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.

The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK.

* Updated: This paragraph was added on May 18, 2012.

Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.

Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.

Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.

"Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging," he said.

Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.

Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.

Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib (Zelboraf) in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.

(Data to be presented at ASCO will show that median overall survival reached 13.2 months with vemurafenib vs 9.6 months with dacarbazine chemotherapy, according to Emmy Wang, senior manager, corporate relations at Genentech. Overall, up to 24% of patients in clinical trials experienced squamous cell carcinoma, which was easily treated, she noted.)*

The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.

Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.

The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.

ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.

"We know cancers are smart," said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. "They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research."

The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.

The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.

Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.

Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.

The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.

The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK.

* Updated: This paragraph was added on May 18, 2012.