CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.

“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.

The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”

Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”

“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.

“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”

“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.

The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.

The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.

Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).

Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.

The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).

“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed

Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).

The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).

Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.

CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.

“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.

The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”

Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”

“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.

“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”

“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.

The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.

The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.

Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).

Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.

The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).

“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed

Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).

The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).

Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.

CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.

“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.

The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”

Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”

“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.

“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”

“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.

The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.

The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.

Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).

Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.

The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).

“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed

Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).

The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).

Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.

Attendees at ASCO 2015

© ASCO/Max Gersh

CHICAGO—Allogeneic and autologous transplants produce similar survival rates when used as first-line therapy in younger patients with peripheral

T-cell lymphoma (PTCL), according to interim results of the AATT trial.

The study also showed that deaths among patients who received autologous stem cell transplants (auto-SCTs) were a result of relapse and salvage treatment, while deaths among allogeneic SCT (allo-SCT) recipients were transplant-related.

Norbert Schmitz, MD, PhD, of Asklepios Hospital St. Georg in Hamburg, Germany, presented these findings at the 2015 ASCO Annual Meeting (abstract 8507*).

Dr Schmitz noted that only previous study comparing auto-SCT with allo-SCT as first-line therapy in PTCL was not designed or powered to evaluate the differences between the transplant types.

So he and his colleagues conducted the AATT trial to determine the differences. The team hypothesized that allo-SCT would improve 3-year event-free survival from 35% to 60%, given an α of 5% and a power of 80%. They needed 140 patients to prove or disprove this theory.

Ultimately, the investigators enrolled 104 patients and performed an interim analysis when 58 patients were evaluable for response.

Of the 58 patients, 30 were randomized to the auto-SCT arm and 28 to the allo-SCT arm. Baseline characteristics were similar between the arms, including patients’ median ages (49 and 50, respectively), the proportion of patients with stage III/IV disease (87% and 93%), and the proportion with ECOG status greater than 1 (23% and 18%).

Most patients in both arms had PTCL not otherwise specified (36% in the auto-SCT arm and 50% in the allo-SCT arm). Other subtypes included angioimmunoblastic T-cell lymphoma (23% and 32%, respectively), ALK-negative anaplastic large-cell lymphoma (20% and 4%), and “other” PTCLs (20% and 8%). The other PTCLs were NK/T-cell lymphoma, intestinal T/NK-cell lymphoma, hepatosplenic γδ lymphoma, and subcutaneous panniculitis-like PTCL.

Treatment characteristics

Before undergoing transplant, patients in both arms received treatment with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) on days 1, 15, 29, and 43. If they experienced a complete response (CR), partial response, or no change, patients received DHAP (dexamethasone, cytarabine, and cisplatin) on day 64.

Patients in the auto-SCT arm received BEAM (carmustine, etoposide, cytarabine, and melphalan) prior to transplant. And patients in the allo-SCT arm received FBC (fludarabine, busulfan, and cyclophosphamide).

Overall, 36 patients (62%) completed treatment per protocol, 19 in the auto-SCT arm and 17 in the allo-SCT arm. Thirty-eight percent of all patients could not proceed to transplant per protocol, mostly because of early lymphoma progression.

Response and survival

The researchers observed CRs/unconfirmed CRs (CRus) in 33% (n=10) of patients in the auto-SCT arm and 39% (n=11) in the allo-SCT arm. CR/CRus and progressive disease within 2 months occurred in 3% (n=1) and 4% (n=1) of patients, respectively.

Partial responses were seen in 17% (n=5) of patients in the auto-SCT arm and 7% (n=2) in the allo-SCT arm. There was no change in 7% (n=2) and 0% of patients, respectively. And responses were unknown in 7% (n=2) of patients in the auto-SCT arm.

Progressive disease occurred in 33% (n=10) of patients in the auto-SCT arm and 36% (n=10) in the allo-SCT arm. And treatment-related death occurred in 0% (n=0) and 14% (n=4), respectively.

At the interim analysis, there was no significant difference between the treatment arms with regard to event-free survival (P=0.963) or overall survival (P=0.174).

“At that time, the decision was made to stop the study,” Dr Schmitz said.

He explained that a conditional power analysis showed a low probability that the primary endpoint—a 25% improvement in event-free survival with allo-SCT—could still be met. So the data safety monitoring board decided to stop enrollment.

An updated analysis, performed at a median observation time of 26 months, showed there was still no significant difference in overall survival between the treatment arms (P=0.362).

Cause of death

In the intent-to-treat population—30 patients in the auto-SCT arm and 28 in the allo-SCT arm—there were 16 lymphoma-related deaths, 10 in the auto-SCT arm and 6 in the allo-SCT arm.

There were 6 deaths related to study treatment (4 early and 2 late), all in the allo-SCT arm. One patient in the allo-SCT arm died of post-transplant lymphoproliferative disorder, and 1 patient in the same arm died of hemorrhage after salvage. One patient in each arm died as a result of salvage treatment.

Dr Schmitz and his colleagues also looked at the cause of death among patients who received a transplant—19 in the auto-SCT arm and 17 in the allo-SCT arm.

After SCT, there were 7 deaths in each arm. In the auto-SCT arm, there were 6 lymphoma-related deaths and 1 death related to salvage treatment. In the allo-SCT arm, there were 7 cases of non-relapse-related mortality, including 1 patient with post-transplant lymphoproliferative disorder.

“There certainly seems to be a [graft-vs-lymphoma] effect of allo-transplant in T-cell lymphoma that is, unfortunately, in some way, counterbalanced by high transplant-related mortality,” Dr Schmitz said.

He added that results of a final analysis of the 104 patients enrolled on this study should be available in 2017.

*Information in the abstract differs from that presented at the meeting.

Attendees at ASCO 2015

© ASCO/Max Gersh

CHICAGO—Allogeneic and autologous transplants produce similar survival rates when used as first-line therapy in younger patients with peripheral

T-cell lymphoma (PTCL), according to interim results of the AATT trial.

The study also showed that deaths among patients who received autologous stem cell transplants (auto-SCTs) were a result of relapse and salvage treatment, while deaths among allogeneic SCT (allo-SCT) recipients were transplant-related.

Norbert Schmitz, MD, PhD, of Asklepios Hospital St. Georg in Hamburg, Germany, presented these findings at the 2015 ASCO Annual Meeting (abstract 8507*).

Dr Schmitz noted that only previous study comparing auto-SCT with allo-SCT as first-line therapy in PTCL was not designed or powered to evaluate the differences between the transplant types.

So he and his colleagues conducted the AATT trial to determine the differences. The team hypothesized that allo-SCT would improve 3-year event-free survival from 35% to 60%, given an α of 5% and a power of 80%. They needed 140 patients to prove or disprove this theory.

Ultimately, the investigators enrolled 104 patients and performed an interim analysis when 58 patients were evaluable for response.

Of the 58 patients, 30 were randomized to the auto-SCT arm and 28 to the allo-SCT arm. Baseline characteristics were similar between the arms, including patients’ median ages (49 and 50, respectively), the proportion of patients with stage III/IV disease (87% and 93%), and the proportion with ECOG status greater than 1 (23% and 18%).

Most patients in both arms had PTCL not otherwise specified (36% in the auto-SCT arm and 50% in the allo-SCT arm). Other subtypes included angioimmunoblastic T-cell lymphoma (23% and 32%, respectively), ALK-negative anaplastic large-cell lymphoma (20% and 4%), and “other” PTCLs (20% and 8%). The other PTCLs were NK/T-cell lymphoma, intestinal T/NK-cell lymphoma, hepatosplenic γδ lymphoma, and subcutaneous panniculitis-like PTCL.

Treatment characteristics

Before undergoing transplant, patients in both arms received treatment with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) on days 1, 15, 29, and 43. If they experienced a complete response (CR), partial response, or no change, patients received DHAP (dexamethasone, cytarabine, and cisplatin) on day 64.

Patients in the auto-SCT arm received BEAM (carmustine, etoposide, cytarabine, and melphalan) prior to transplant. And patients in the allo-SCT arm received FBC (fludarabine, busulfan, and cyclophosphamide).

Overall, 36 patients (62%) completed treatment per protocol, 19 in the auto-SCT arm and 17 in the allo-SCT arm. Thirty-eight percent of all patients could not proceed to transplant per protocol, mostly because of early lymphoma progression.

Response and survival

The researchers observed CRs/unconfirmed CRs (CRus) in 33% (n=10) of patients in the auto-SCT arm and 39% (n=11) in the allo-SCT arm. CR/CRus and progressive disease within 2 months occurred in 3% (n=1) and 4% (n=1) of patients, respectively.

Partial responses were seen in 17% (n=5) of patients in the auto-SCT arm and 7% (n=2) in the allo-SCT arm. There was no change in 7% (n=2) and 0% of patients, respectively. And responses were unknown in 7% (n=2) of patients in the auto-SCT arm.

Progressive disease occurred in 33% (n=10) of patients in the auto-SCT arm and 36% (n=10) in the allo-SCT arm. And treatment-related death occurred in 0% (n=0) and 14% (n=4), respectively.

At the interim analysis, there was no significant difference between the treatment arms with regard to event-free survival (P=0.963) or overall survival (P=0.174).

“At that time, the decision was made to stop the study,” Dr Schmitz said.

He explained that a conditional power analysis showed a low probability that the primary endpoint—a 25% improvement in event-free survival with allo-SCT—could still be met. So the data safety monitoring board decided to stop enrollment.

An updated analysis, performed at a median observation time of 26 months, showed there was still no significant difference in overall survival between the treatment arms (P=0.362).

Cause of death

In the intent-to-treat population—30 patients in the auto-SCT arm and 28 in the allo-SCT arm—there were 16 lymphoma-related deaths, 10 in the auto-SCT arm and 6 in the allo-SCT arm.

There were 6 deaths related to study treatment (4 early and 2 late), all in the allo-SCT arm. One patient in the allo-SCT arm died of post-transplant lymphoproliferative disorder, and 1 patient in the same arm died of hemorrhage after salvage. One patient in each arm died as a result of salvage treatment.

Dr Schmitz and his colleagues also looked at the cause of death among patients who received a transplant—19 in the auto-SCT arm and 17 in the allo-SCT arm.

After SCT, there were 7 deaths in each arm. In the auto-SCT arm, there were 6 lymphoma-related deaths and 1 death related to salvage treatment. In the allo-SCT arm, there were 7 cases of non-relapse-related mortality, including 1 patient with post-transplant lymphoproliferative disorder.

“There certainly seems to be a [graft-vs-lymphoma] effect of allo-transplant in T-cell lymphoma that is, unfortunately, in some way, counterbalanced by high transplant-related mortality,” Dr Schmitz said.

He added that results of a final analysis of the 104 patients enrolled on this study should be available in 2017.

*Information in the abstract differs from that presented at the meeting.

Attendees at ASCO 2015

© ASCO/Max Gersh

CHICAGO—Allogeneic and autologous transplants produce similar survival rates when used as first-line therapy in younger patients with peripheral

T-cell lymphoma (PTCL), according to interim results of the AATT trial.

The study also showed that deaths among patients who received autologous stem cell transplants (auto-SCTs) were a result of relapse and salvage treatment, while deaths among allogeneic SCT (allo-SCT) recipients were transplant-related.

Norbert Schmitz, MD, PhD, of Asklepios Hospital St. Georg in Hamburg, Germany, presented these findings at the 2015 ASCO Annual Meeting (abstract 8507*).

Dr Schmitz noted that only previous study comparing auto-SCT with allo-SCT as first-line therapy in PTCL was not designed or powered to evaluate the differences between the transplant types.

So he and his colleagues conducted the AATT trial to determine the differences. The team hypothesized that allo-SCT would improve 3-year event-free survival from 35% to 60%, given an α of 5% and a power of 80%. They needed 140 patients to prove or disprove this theory.

Ultimately, the investigators enrolled 104 patients and performed an interim analysis when 58 patients were evaluable for response.

Of the 58 patients, 30 were randomized to the auto-SCT arm and 28 to the allo-SCT arm. Baseline characteristics were similar between the arms, including patients’ median ages (49 and 50, respectively), the proportion of patients with stage III/IV disease (87% and 93%), and the proportion with ECOG status greater than 1 (23% and 18%).

Most patients in both arms had PTCL not otherwise specified (36% in the auto-SCT arm and 50% in the allo-SCT arm). Other subtypes included angioimmunoblastic T-cell lymphoma (23% and 32%, respectively), ALK-negative anaplastic large-cell lymphoma (20% and 4%), and “other” PTCLs (20% and 8%). The other PTCLs were NK/T-cell lymphoma, intestinal T/NK-cell lymphoma, hepatosplenic γδ lymphoma, and subcutaneous panniculitis-like PTCL.

Treatment characteristics

Before undergoing transplant, patients in both arms received treatment with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) on days 1, 15, 29, and 43. If they experienced a complete response (CR), partial response, or no change, patients received DHAP (dexamethasone, cytarabine, and cisplatin) on day 64.

Patients in the auto-SCT arm received BEAM (carmustine, etoposide, cytarabine, and melphalan) prior to transplant. And patients in the allo-SCT arm received FBC (fludarabine, busulfan, and cyclophosphamide).

Overall, 36 patients (62%) completed treatment per protocol, 19 in the auto-SCT arm and 17 in the allo-SCT arm. Thirty-eight percent of all patients could not proceed to transplant per protocol, mostly because of early lymphoma progression.

Response and survival

The researchers observed CRs/unconfirmed CRs (CRus) in 33% (n=10) of patients in the auto-SCT arm and 39% (n=11) in the allo-SCT arm. CR/CRus and progressive disease within 2 months occurred in 3% (n=1) and 4% (n=1) of patients, respectively.

Partial responses were seen in 17% (n=5) of patients in the auto-SCT arm and 7% (n=2) in the allo-SCT arm. There was no change in 7% (n=2) and 0% of patients, respectively. And responses were unknown in 7% (n=2) of patients in the auto-SCT arm.

Progressive disease occurred in 33% (n=10) of patients in the auto-SCT arm and 36% (n=10) in the allo-SCT arm. And treatment-related death occurred in 0% (n=0) and 14% (n=4), respectively.

At the interim analysis, there was no significant difference between the treatment arms with regard to event-free survival (P=0.963) or overall survival (P=0.174).

“At that time, the decision was made to stop the study,” Dr Schmitz said.

He explained that a conditional power analysis showed a low probability that the primary endpoint—a 25% improvement in event-free survival with allo-SCT—could still be met. So the data safety monitoring board decided to stop enrollment.

An updated analysis, performed at a median observation time of 26 months, showed there was still no significant difference in overall survival between the treatment arms (P=0.362).

Cause of death

In the intent-to-treat population—30 patients in the auto-SCT arm and 28 in the allo-SCT arm—there were 16 lymphoma-related deaths, 10 in the auto-SCT arm and 6 in the allo-SCT arm.

There were 6 deaths related to study treatment (4 early and 2 late), all in the allo-SCT arm. One patient in the allo-SCT arm died of post-transplant lymphoproliferative disorder, and 1 patient in the same arm died of hemorrhage after salvage. One patient in each arm died as a result of salvage treatment.

Dr Schmitz and his colleagues also looked at the cause of death among patients who received a transplant—19 in the auto-SCT arm and 17 in the allo-SCT arm.

After SCT, there were 7 deaths in each arm. In the auto-SCT arm, there were 6 lymphoma-related deaths and 1 death related to salvage treatment. In the allo-SCT arm, there were 7 cases of non-relapse-related mortality, including 1 patient with post-transplant lymphoproliferative disorder.

“There certainly seems to be a [graft-vs-lymphoma] effect of allo-transplant in T-cell lymphoma that is, unfortunately, in some way, counterbalanced by high transplant-related mortality,” Dr Schmitz said.

He added that results of a final analysis of the 104 patients enrolled on this study should be available in 2017.

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—A 3-drug combination is safe and highly active in certain patients with relapsed B-cell malignancies, according to a speaker at the 2015 ASCO Annual Meeting.

The combination consists of the anti-CD20 monoclonal antibody ublituximab, the PI3Kδ inhibitor TGR-1202, and the BTK inhibitor ibrutinib.

In a small, phase 1 study, the triplet produced an overall response rate of 62%. It was particularly active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and those with mantle cell lymphoma (MCL).

The most common adverse events were infusion reactions, gastrointestinal events, rash, and fatigue. Grade 3 neutropenia and leukopenia occurred in 1 patient each.

Nathan Fowler, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the meeting as abstract 8501.*

The trial enrolled 16 patients with CLL/SLL or non-Hodgkin lymphoma (NHL). Four had CLL, 1 had SLL, and 1 had Richter’s transformation. Four patients had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL), 2 had mantle cell lymphoma (MCL), and 1 had marginal zone lymphoma (MZL).

The patients’ median age was 63, and their median number of prior treatment regimens was 4 (range, 1-5). Fifty percent of patients (n=8) were refractory to prior therapy.

Treatment consisted of 900 mg of ublituximab, ibrutinib at either 420 mg (CLL/SLL) or 560 mg (NHL), and TGR-1202 at 3 different doses: 400 mg, 600 mg, or 800 mg. Ibrutinib and TGR-1202 were given once-daily beginning on day 1 of each cycle. Ublituximab was given on days 1, 8, and 15 of cycles 1 and 2, then on day 1 of cycles 4, 6, 9, and 12.

Safety and efficacy

Sixteen patients were evaluable for safety and 13 for efficacy. One of the patients was removed from the efficacy analysis at the discretion of the investigators, and it was too early to evaluate the other 2 patients.

The median time on study was 4 months (range, 1-9 months). The 5 CLL/SLL patients received TGR-1202 at 400 mg. One of these patients had a dose-limiting toxicity—reactivation of varicella zoster.

Of the NHL patients, 3 received TGR-1202 at 400 mg, 4 received 600 mg, and 4 received 800 mg. There were no dose-limiting toxicities in any of these patients.

Adverse events that were considered possibly related to treatment included infusion reactions (25%), diarrhea (19%), nausea (19%), fatigue (19%), rash (19%), anemia (13%), neutropenia (13%), leukopenia (13%), and insomnia (13%). Grade 3 events included neutropenia and leukopenia (6% each), and there were no grade 4 events.

“The majority of patients have demonstrated a response to the therapy,” Dr Fowler said. “All of the patients that have responded continue on treatment, and the longest [treatment duration] is about 10 months.”

The only complete response occurred in a patient with MCL. Partial responses occurred in all 3 CLL patients, 2 FL patients, the SLL patient, the MZL patient, and 1 MCL patient. One patient with FL, 2 with DLBCL, and 1 with Richter’s transformation did not respond to treatment.

In closing, Dr Fowler said this treatment was well-tolerated and showed significant early activity in this heavily pretreated patient population. Dose-escalation with TGR-1202 continues at 800 mg, and phase 2 studies of the triplet are planned.

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—A 3-drug combination is safe and highly active in certain patients with relapsed B-cell malignancies, according to a speaker at the 2015 ASCO Annual Meeting.

The combination consists of the anti-CD20 monoclonal antibody ublituximab, the PI3Kδ inhibitor TGR-1202, and the BTK inhibitor ibrutinib.

In a small, phase 1 study, the triplet produced an overall response rate of 62%. It was particularly active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and those with mantle cell lymphoma (MCL).

The most common adverse events were infusion reactions, gastrointestinal events, rash, and fatigue. Grade 3 neutropenia and leukopenia occurred in 1 patient each.

Nathan Fowler, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the meeting as abstract 8501.*

The trial enrolled 16 patients with CLL/SLL or non-Hodgkin lymphoma (NHL). Four had CLL, 1 had SLL, and 1 had Richter’s transformation. Four patients had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL), 2 had mantle cell lymphoma (MCL), and 1 had marginal zone lymphoma (MZL).

The patients’ median age was 63, and their median number of prior treatment regimens was 4 (range, 1-5). Fifty percent of patients (n=8) were refractory to prior therapy.

Treatment consisted of 900 mg of ublituximab, ibrutinib at either 420 mg (CLL/SLL) or 560 mg (NHL), and TGR-1202 at 3 different doses: 400 mg, 600 mg, or 800 mg. Ibrutinib and TGR-1202 were given once-daily beginning on day 1 of each cycle. Ublituximab was given on days 1, 8, and 15 of cycles 1 and 2, then on day 1 of cycles 4, 6, 9, and 12.

Safety and efficacy

Sixteen patients were evaluable for safety and 13 for efficacy. One of the patients was removed from the efficacy analysis at the discretion of the investigators, and it was too early to evaluate the other 2 patients.

The median time on study was 4 months (range, 1-9 months). The 5 CLL/SLL patients received TGR-1202 at 400 mg. One of these patients had a dose-limiting toxicity—reactivation of varicella zoster.

Of the NHL patients, 3 received TGR-1202 at 400 mg, 4 received 600 mg, and 4 received 800 mg. There were no dose-limiting toxicities in any of these patients.

Adverse events that were considered possibly related to treatment included infusion reactions (25%), diarrhea (19%), nausea (19%), fatigue (19%), rash (19%), anemia (13%), neutropenia (13%), leukopenia (13%), and insomnia (13%). Grade 3 events included neutropenia and leukopenia (6% each), and there were no grade 4 events.

“The majority of patients have demonstrated a response to the therapy,” Dr Fowler said. “All of the patients that have responded continue on treatment, and the longest [treatment duration] is about 10 months.”

The only complete response occurred in a patient with MCL. Partial responses occurred in all 3 CLL patients, 2 FL patients, the SLL patient, the MZL patient, and 1 MCL patient. One patient with FL, 2 with DLBCL, and 1 with Richter’s transformation did not respond to treatment.

In closing, Dr Fowler said this treatment was well-tolerated and showed significant early activity in this heavily pretreated patient population. Dose-escalation with TGR-1202 continues at 800 mg, and phase 2 studies of the triplet are planned.

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—A 3-drug combination is safe and highly active in certain patients with relapsed B-cell malignancies, according to a speaker at the 2015 ASCO Annual Meeting.

The combination consists of the anti-CD20 monoclonal antibody ublituximab, the PI3Kδ inhibitor TGR-1202, and the BTK inhibitor ibrutinib.

In a small, phase 1 study, the triplet produced an overall response rate of 62%. It was particularly active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and those with mantle cell lymphoma (MCL).

The most common adverse events were infusion reactions, gastrointestinal events, rash, and fatigue. Grade 3 neutropenia and leukopenia occurred in 1 patient each.

Nathan Fowler, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the meeting as abstract 8501.*

The trial enrolled 16 patients with CLL/SLL or non-Hodgkin lymphoma (NHL). Four had CLL, 1 had SLL, and 1 had Richter’s transformation. Four patients had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL), 2 had mantle cell lymphoma (MCL), and 1 had marginal zone lymphoma (MZL).

The patients’ median age was 63, and their median number of prior treatment regimens was 4 (range, 1-5). Fifty percent of patients (n=8) were refractory to prior therapy.

Treatment consisted of 900 mg of ublituximab, ibrutinib at either 420 mg (CLL/SLL) or 560 mg (NHL), and TGR-1202 at 3 different doses: 400 mg, 600 mg, or 800 mg. Ibrutinib and TGR-1202 were given once-daily beginning on day 1 of each cycle. Ublituximab was given on days 1, 8, and 15 of cycles 1 and 2, then on day 1 of cycles 4, 6, 9, and 12.

Safety and efficacy

Sixteen patients were evaluable for safety and 13 for efficacy. One of the patients was removed from the efficacy analysis at the discretion of the investigators, and it was too early to evaluate the other 2 patients.

The median time on study was 4 months (range, 1-9 months). The 5 CLL/SLL patients received TGR-1202 at 400 mg. One of these patients had a dose-limiting toxicity—reactivation of varicella zoster.

Of the NHL patients, 3 received TGR-1202 at 400 mg, 4 received 600 mg, and 4 received 800 mg. There were no dose-limiting toxicities in any of these patients.

Adverse events that were considered possibly related to treatment included infusion reactions (25%), diarrhea (19%), nausea (19%), fatigue (19%), rash (19%), anemia (13%), neutropenia (13%), leukopenia (13%), and insomnia (13%). Grade 3 events included neutropenia and leukopenia (6% each), and there were no grade 4 events.

“The majority of patients have demonstrated a response to the therapy,” Dr Fowler said. “All of the patients that have responded continue on treatment, and the longest [treatment duration] is about 10 months.”

The only complete response occurred in a patient with MCL. Partial responses occurred in all 3 CLL patients, 2 FL patients, the SLL patient, the MZL patient, and 1 MCL patient. One patient with FL, 2 with DLBCL, and 1 with Richter’s transformation did not respond to treatment.

In closing, Dr Fowler said this treatment was well-tolerated and showed significant early activity in this heavily pretreated patient population. Dose-escalation with TGR-1202 continues at 800 mg, and phase 2 studies of the triplet are planned.

*Information in the abstract differs from that presented at the meeting.

A sickled red blood cell

and a normal one

Image by Betty Pace

Two members of the US House of Representatives have introduced a resolution calling for expanded government efforts to increase sickle cell trait (SCT) research and improve access to SCT screening and education.

Barbara Lee (D-CA) and Michael C. Burgess (R-TX) introduced the resolution, which was assigned to a congressional committee that will consider it before possibly sending it on to the House or Senate as a whole.

The resolution, H.Res.296, encourages the medical community as well as state and federal governments to work to ensure that all individuals are made aware of their SCT status by developing a common strategy for disseminating screening results and providing education and counseling to parents and families in collaboration with all 50 states’ newborn screening programs.

The resolution calls on the US Department of Health and Human Services to develop a public awareness campaign stressing the importance of knowing your SCT status and to expand access for screening and appropriate counseling for SCT carriers.

The resolution also says the House commits to ensuring support for research that expands our understanding of SCT and sickle cell disease.

The American Society of Hematology (ASH) said it applauds this bipartisan effort to advance public understanding of SCT, which is estimated to affect more than 300,000 people in the US, many of whom are unaware of their status.

ASH also said it has identified several priorities for research in this area and has collaborated with the US Centers for Disease Control and Prevention and the Sickle Cell Disease Association of America to develop a Sickle Cell Trait Toolkit for SCT carriers and their families.

To follow the progress of the resolution, H.Res.296 – Calling for Sickle Cell Trait Research, visit Congress.gov.

A sickled red blood cell

and a normal one

Image by Betty Pace

Two members of the US House of Representatives have introduced a resolution calling for expanded government efforts to increase sickle cell trait (SCT) research and improve access to SCT screening and education.

Barbara Lee (D-CA) and Michael C. Burgess (R-TX) introduced the resolution, which was assigned to a congressional committee that will consider it before possibly sending it on to the House or Senate as a whole.

The resolution, H.Res.296, encourages the medical community as well as state and federal governments to work to ensure that all individuals are made aware of their SCT status by developing a common strategy for disseminating screening results and providing education and counseling to parents and families in collaboration with all 50 states’ newborn screening programs.

The resolution calls on the US Department of Health and Human Services to develop a public awareness campaign stressing the importance of knowing your SCT status and to expand access for screening and appropriate counseling for SCT carriers.

The resolution also says the House commits to ensuring support for research that expands our understanding of SCT and sickle cell disease.

The American Society of Hematology (ASH) said it applauds this bipartisan effort to advance public understanding of SCT, which is estimated to affect more than 300,000 people in the US, many of whom are unaware of their status.

ASH also said it has identified several priorities for research in this area and has collaborated with the US Centers for Disease Control and Prevention and the Sickle Cell Disease Association of America to develop a Sickle Cell Trait Toolkit for SCT carriers and their families.

To follow the progress of the resolution, H.Res.296 – Calling for Sickle Cell Trait Research, visit Congress.gov.

A sickled red blood cell

and a normal one

Image by Betty Pace

Two members of the US House of Representatives have introduced a resolution calling for expanded government efforts to increase sickle cell trait (SCT) research and improve access to SCT screening and education.

Barbara Lee (D-CA) and Michael C. Burgess (R-TX) introduced the resolution, which was assigned to a congressional committee that will consider it before possibly sending it on to the House or Senate as a whole.

The resolution, H.Res.296, encourages the medical community as well as state and federal governments to work to ensure that all individuals are made aware of their SCT status by developing a common strategy for disseminating screening results and providing education and counseling to parents and families in collaboration with all 50 states’ newborn screening programs.

The resolution calls on the US Department of Health and Human Services to develop a public awareness campaign stressing the importance of knowing your SCT status and to expand access for screening and appropriate counseling for SCT carriers.

The resolution also says the House commits to ensuring support for research that expands our understanding of SCT and sickle cell disease.

The American Society of Hematology (ASH) said it applauds this bipartisan effort to advance public understanding of SCT, which is estimated to affect more than 300,000 people in the US, many of whom are unaware of their status.

ASH also said it has identified several priorities for research in this area and has collaborated with the US Centers for Disease Control and Prevention and the Sickle Cell Disease Association of America to develop a Sickle Cell Trait Toolkit for SCT carriers and their families.

To follow the progress of the resolution, H.Res.296 – Calling for Sickle Cell Trait Research, visit Congress.gov.

Drop of blood

Photo by Максим Кукушкин

Scientists have reported that a new test can screen patients for current and past infection with more than 1000 viral strains, using a single drop of blood and for a cost of about $25 per blood sample.

The investigators used the test, known as VirScan, to screen more than 500 people from around the world and found that, on average, participants had been exposed to about 10 viral species over their lifetimes.

“Using this method, we can take a tiny drop of blood and determine what viruses a person has been infected with over the course of many years,” said Stephen Elledge, PhD, of Harvard Medical School in Boston, Massachusetts.

“What makes this so unique is the scale. Right now, a physician needs to guess what virus might be at play and individually test for it. With VirScan, we can look for virtually all viruses, even rare ones, with a single test.”

Dr Elledge and his colleagues described their work with VirScan in Science.

To develop VirScan, the group synthesized more than 93,000 short pieces of DNA encoding different segments of viral proteins. They introduced those pieces of DNA into bacteriophages.

Each bacteriophage manufactured a peptide and displayed it on the bacteriophage surface. As a group, the bacteriophages displayed all of the protein sequences found in the more than 1000 known strains of human viruses.

To perform the VirScan analysis, all of the peptide-displaying bacteriophages are allowed to mingle with a blood sample. Antiviral antibodies in the blood find and bind to their target epitopes within the displayed peptides.

The scientists then retrieve the antibodies and wash away everything except the few bacteriophages that cling to them. By sequencing the DNA of those bacteriophages, the team can identify which viral protein pieces are bound to antibodies in the blood sample.

That reveals which viruses a person’s immune system has previously encountered, either through infection or vaccination.

Dr Elledge estimated that it would take about 2 to 3 days to process 100 samples with VirScan, assuming sequencing is working optimally. He said he is optimistic the speed of the assay will increase with further development.

Putting VirScan to the test

To test VirScan, Dr Elledge and his colleagues used it to analyze blood samples from patients known to be infected with particular viruses, including HIV and hepatitis C.

“It turns out that it works really well,” Dr Elledge said. “We were in the sensitivity range of 95% to 100% for those, and the specificity was good. We didn’t falsely identify people who were negative. That gave us confidence that we could detect other viruses, and when we did see them, we would know they were real.”

So the investigators used VirScan to analyze the antibodies in 569 people from 4 countries (Peru, South Africa, Thailand, and the US), examining about 100 million potential antibody/epitope interactions.

The team found that, on average, each person had antibodies to 10 different species of viruses. As expected, antibodies against certain viruses were common among adults but not in children, suggesting that children had not yet been exposed to those viruses.

Individuals residing in South Africa, Peru, and Thailand tended to have antibodies against more viruses than people in the US. And people infected with HIV had antibodies against many more viruses than people without HIV.

Dr Elledge and his colleagues were surprised to find that antibody responses against specific viruses were similar between individuals, with different people’s antibodies recognizing identical amino acids in the viral peptides.

“In this paper alone, we identified more antibody/peptide interactions to viral proteins than had been identified in the previous history of all viral exploration,” Dr Elledge said.

The reproducibility of those interactions allowed the scientists to refine their analysis and improve the sensitivity of VirScan, Dr Elledge said, adding that the method will continue to improve as his team analyzes more samples.

The investigators also noted that their work is not limited to antiviral antibodies. They are now using it to look for antibodies that attack the body’s tissue in autoimmune diseases associated with cancers. A similar approach could be used to screen for antibodies against other types of pathogens as well.

Drop of blood

Photo by Максим Кукушкин

Scientists have reported that a new test can screen patients for current and past infection with more than 1000 viral strains, using a single drop of blood and for a cost of about $25 per blood sample.

The investigators used the test, known as VirScan, to screen more than 500 people from around the world and found that, on average, participants had been exposed to about 10 viral species over their lifetimes.

“Using this method, we can take a tiny drop of blood and determine what viruses a person has been infected with over the course of many years,” said Stephen Elledge, PhD, of Harvard Medical School in Boston, Massachusetts.

“What makes this so unique is the scale. Right now, a physician needs to guess what virus might be at play and individually test for it. With VirScan, we can look for virtually all viruses, even rare ones, with a single test.”

Dr Elledge and his colleagues described their work with VirScan in Science.

To develop VirScan, the group synthesized more than 93,000 short pieces of DNA encoding different segments of viral proteins. They introduced those pieces of DNA into bacteriophages.

Each bacteriophage manufactured a peptide and displayed it on the bacteriophage surface. As a group, the bacteriophages displayed all of the protein sequences found in the more than 1000 known strains of human viruses.

To perform the VirScan analysis, all of the peptide-displaying bacteriophages are allowed to mingle with a blood sample. Antiviral antibodies in the blood find and bind to their target epitopes within the displayed peptides.

The scientists then retrieve the antibodies and wash away everything except the few bacteriophages that cling to them. By sequencing the DNA of those bacteriophages, the team can identify which viral protein pieces are bound to antibodies in the blood sample.

That reveals which viruses a person’s immune system has previously encountered, either through infection or vaccination.

Dr Elledge estimated that it would take about 2 to 3 days to process 100 samples with VirScan, assuming sequencing is working optimally. He said he is optimistic the speed of the assay will increase with further development.

Putting VirScan to the test

To test VirScan, Dr Elledge and his colleagues used it to analyze blood samples from patients known to be infected with particular viruses, including HIV and hepatitis C.

“It turns out that it works really well,” Dr Elledge said. “We were in the sensitivity range of 95% to 100% for those, and the specificity was good. We didn’t falsely identify people who were negative. That gave us confidence that we could detect other viruses, and when we did see them, we would know they were real.”

So the investigators used VirScan to analyze the antibodies in 569 people from 4 countries (Peru, South Africa, Thailand, and the US), examining about 100 million potential antibody/epitope interactions.

The team found that, on average, each person had antibodies to 10 different species of viruses. As expected, antibodies against certain viruses were common among adults but not in children, suggesting that children had not yet been exposed to those viruses.

Individuals residing in South Africa, Peru, and Thailand tended to have antibodies against more viruses than people in the US. And people infected with HIV had antibodies against many more viruses than people without HIV.

Dr Elledge and his colleagues were surprised to find that antibody responses against specific viruses were similar between individuals, with different people’s antibodies recognizing identical amino acids in the viral peptides.

“In this paper alone, we identified more antibody/peptide interactions to viral proteins than had been identified in the previous history of all viral exploration,” Dr Elledge said.

The reproducibility of those interactions allowed the scientists to refine their analysis and improve the sensitivity of VirScan, Dr Elledge said, adding that the method will continue to improve as his team analyzes more samples.

The investigators also noted that their work is not limited to antiviral antibodies. They are now using it to look for antibodies that attack the body’s tissue in autoimmune diseases associated with cancers. A similar approach could be used to screen for antibodies against other types of pathogens as well.

Drop of blood

Photo by Максим Кукушкин

Scientists have reported that a new test can screen patients for current and past infection with more than 1000 viral strains, using a single drop of blood and for a cost of about $25 per blood sample.

The investigators used the test, known as VirScan, to screen more than 500 people from around the world and found that, on average, participants had been exposed to about 10 viral species over their lifetimes.

“Using this method, we can take a tiny drop of blood and determine what viruses a person has been infected with over the course of many years,” said Stephen Elledge, PhD, of Harvard Medical School in Boston, Massachusetts.

“What makes this so unique is the scale. Right now, a physician needs to guess what virus might be at play and individually test for it. With VirScan, we can look for virtually all viruses, even rare ones, with a single test.”

Dr Elledge and his colleagues described their work with VirScan in Science.

To develop VirScan, the group synthesized more than 93,000 short pieces of DNA encoding different segments of viral proteins. They introduced those pieces of DNA into bacteriophages.

Each bacteriophage manufactured a peptide and displayed it on the bacteriophage surface. As a group, the bacteriophages displayed all of the protein sequences found in the more than 1000 known strains of human viruses.

To perform the VirScan analysis, all of the peptide-displaying bacteriophages are allowed to mingle with a blood sample. Antiviral antibodies in the blood find and bind to their target epitopes within the displayed peptides.

The scientists then retrieve the antibodies and wash away everything except the few bacteriophages that cling to them. By sequencing the DNA of those bacteriophages, the team can identify which viral protein pieces are bound to antibodies in the blood sample.

That reveals which viruses a person’s immune system has previously encountered, either through infection or vaccination.

Dr Elledge estimated that it would take about 2 to 3 days to process 100 samples with VirScan, assuming sequencing is working optimally. He said he is optimistic the speed of the assay will increase with further development.

Putting VirScan to the test

To test VirScan, Dr Elledge and his colleagues used it to analyze blood samples from patients known to be infected with particular viruses, including HIV and hepatitis C.

“It turns out that it works really well,” Dr Elledge said. “We were in the sensitivity range of 95% to 100% for those, and the specificity was good. We didn’t falsely identify people who were negative. That gave us confidence that we could detect other viruses, and when we did see them, we would know they were real.”

So the investigators used VirScan to analyze the antibodies in 569 people from 4 countries (Peru, South Africa, Thailand, and the US), examining about 100 million potential antibody/epitope interactions.

The team found that, on average, each person had antibodies to 10 different species of viruses. As expected, antibodies against certain viruses were common among adults but not in children, suggesting that children had not yet been exposed to those viruses.

Individuals residing in South Africa, Peru, and Thailand tended to have antibodies against more viruses than people in the US. And people infected with HIV had antibodies against many more viruses than people without HIV.

Dr Elledge and his colleagues were surprised to find that antibody responses against specific viruses were similar between individuals, with different people’s antibodies recognizing identical amino acids in the viral peptides.

“In this paper alone, we identified more antibody/peptide interactions to viral proteins than had been identified in the previous history of all viral exploration,” Dr Elledge said.

The reproducibility of those interactions allowed the scientists to refine their analysis and improve the sensitivity of VirScan, Dr Elledge said, adding that the method will continue to improve as his team analyzes more samples.

The investigators also noted that their work is not limited to antiviral antibodies. They are now using it to look for antibodies that attack the body’s tissue in autoimmune diseases associated with cancers. A similar approach could be used to screen for antibodies against other types of pathogens as well.

Dr. Risley together with associate editor Dr. O. William Brown describe a case involving failure to document, a common complaint in malpractice litigation.

A 63-year-old white male, actively working, presented with a 5.3-cm infra-renal abdominal aortic aneurysm (AAA). His anatomy was deemed appropriate for endovascular AAA repair and was cleared by his cardiologist for that procedure. The patient underwent a thorough informed consent regarding endovascular and open options as well as the option for continued AAA surveillance. Of note, the patient never had his family with him at any time during the decision-making process, nor with him in the preoperative holding area.

He underwent an aorto- bi- iliac unibody endovascular graft placement. During delivery of the main body, the right common iliac artery ruptured. Initial attempts at endovascular control and subsequent right retroperitoneal exposure and repair of the iliac rupture were unsuccessful, ultimately requiring laparotomy, explant of the device, and aorto- bi-femoral bypass graft. The first time the surgeon met the large family was at the completion of the procedure to explain the complications that were encountered. The patient had a very “rocky” ICU course with complications of ARDS (acute respiratory distress syndrome), acute renal insufficiency, anemia, encephalopathy, and thrombocytopenia. He was initially started on Lovenox on POD # 2 in addition to SCDs (sequential compression devices) for DVT prophylaxis.

Lovenox was stopped because of thrombocytopenia, and mechanical SCD prophylaxis was maintained. As his platelet count recovered and his HIT (heparin-induced thrombocytopenia) screen came back negative, discussion was undertaken to resume his chemical thromboprophylaxis.

It was elected to leave him on only the SCDs because of potential bleeding complications. He continued to improve, but developed a swollen left lower extremity as a result of a DVT. He was placed on heparin drip and converted to Coumadin. Despite an INR of 2.7 on the day he was to be discharged to the rehabilitation center, and shortly after a walk with the therapists and his family, he suffered a fatal pulmonary embolism.

Ultimately, the hospital, the intensivist and the surgeon were sued for failure to adequately provide prophylaxis and treat the DVT. The case was settled. The criticisms were that the physicians failed to provide both mechanical and chemical thromboprophylaxis, particularly after the HIT panel was negative. No criticisms of the intra-operative complications were levied.

The plaintiff’s expert in this case was a physician who was board certified in internal medicine, anesthesiology, and critical care. He had no training in general surgery or vascular surgery. Accordingly, although he may have made suggestions regarding post operative surgical care he had no experience in being the responsible physician for making a postoperative surgical decision. In addition, assertions regarding the incidence of DVT in specific patient populations were exaggerated. Yet the case still settled.

This case emphasizes several important issues. First, communication is paramount in potentially avoiding medical malpractice litigation. The surgeon never met anyone from the patient’s large and involved family until he had to explain the reason his 2-hour planned procedure took 8 hours. The patient had clearly minimized to his family any of the risks discussed with him preoperatively. Prior to proceeding with any surgical intervention it is important that, if possible, a family member be informed of the risks and benefits of the planned procedure and that this conversation be documented in the chart.

Documentation remains very important not only during the informed consent process prior to surgery, but also in decision making regarding postoperative care. Although the physicians discussed the options of resuming the patient’s chemothromboprophylaxis, nothing was documented in the chart. If the discussion was documented, they may have been able to refute the allegation of failure to prevent the DVT.

Finally, in certain instances even when the facts support the judgments that were made regarding the care given, it may be the best “business decision” to settle a case. This is perhaps the most difficult concept for practicing surgeons to grasp. Whether physicians like it or not, medicine is a business and decisions made regarding defending or settling a law suit should not be based on emotion. We don’t do that in the operating room, and we should not do it in the courtroom.

Dr. Risley is the medical director of the Jacksonville Vein Center, Fla. 


The opinions expressed by the author neither imply nor establish a standard of care. Cases have been modified and may be fictional in order to maintain HIPPA and confidentiality regulations.

Dr. Risley together with associate editor Dr. O. William Brown describe a case involving failure to document, a common complaint in malpractice litigation.

A 63-year-old white male, actively working, presented with a 5.3-cm infra-renal abdominal aortic aneurysm (AAA). His anatomy was deemed appropriate for endovascular AAA repair and was cleared by his cardiologist for that procedure. The patient underwent a thorough informed consent regarding endovascular and open options as well as the option for continued AAA surveillance. Of note, the patient never had his family with him at any time during the decision-making process, nor with him in the preoperative holding area.

He underwent an aorto- bi- iliac unibody endovascular graft placement. During delivery of the main body, the right common iliac artery ruptured. Initial attempts at endovascular control and subsequent right retroperitoneal exposure and repair of the iliac rupture were unsuccessful, ultimately requiring laparotomy, explant of the device, and aorto- bi-femoral bypass graft. The first time the surgeon met the large family was at the completion of the procedure to explain the complications that were encountered. The patient had a very “rocky” ICU course with complications of ARDS (acute respiratory distress syndrome), acute renal insufficiency, anemia, encephalopathy, and thrombocytopenia. He was initially started on Lovenox on POD # 2 in addition to SCDs (sequential compression devices) for DVT prophylaxis.

Lovenox was stopped because of thrombocytopenia, and mechanical SCD prophylaxis was maintained. As his platelet count recovered and his HIT (heparin-induced thrombocytopenia) screen came back negative, discussion was undertaken to resume his chemical thromboprophylaxis.

It was elected to leave him on only the SCDs because of potential bleeding complications. He continued to improve, but developed a swollen left lower extremity as a result of a DVT. He was placed on heparin drip and converted to Coumadin. Despite an INR of 2.7 on the day he was to be discharged to the rehabilitation center, and shortly after a walk with the therapists and his family, he suffered a fatal pulmonary embolism.

Ultimately, the hospital, the intensivist and the surgeon were sued for failure to adequately provide prophylaxis and treat the DVT. The case was settled. The criticisms were that the physicians failed to provide both mechanical and chemical thromboprophylaxis, particularly after the HIT panel was negative. No criticisms of the intra-operative complications were levied.

The plaintiff’s expert in this case was a physician who was board certified in internal medicine, anesthesiology, and critical care. He had no training in general surgery or vascular surgery. Accordingly, although he may have made suggestions regarding post operative surgical care he had no experience in being the responsible physician for making a postoperative surgical decision. In addition, assertions regarding the incidence of DVT in specific patient populations were exaggerated. Yet the case still settled.

This case emphasizes several important issues. First, communication is paramount in potentially avoiding medical malpractice litigation. The surgeon never met anyone from the patient’s large and involved family until he had to explain the reason his 2-hour planned procedure took 8 hours. The patient had clearly minimized to his family any of the risks discussed with him preoperatively. Prior to proceeding with any surgical intervention it is important that, if possible, a family member be informed of the risks and benefits of the planned procedure and that this conversation be documented in the chart.

Documentation remains very important not only during the informed consent process prior to surgery, but also in decision making regarding postoperative care. Although the physicians discussed the options of resuming the patient’s chemothromboprophylaxis, nothing was documented in the chart. If the discussion was documented, they may have been able to refute the allegation of failure to prevent the DVT.

Finally, in certain instances even when the facts support the judgments that were made regarding the care given, it may be the best “business decision” to settle a case. This is perhaps the most difficult concept for practicing surgeons to grasp. Whether physicians like it or not, medicine is a business and decisions made regarding defending or settling a law suit should not be based on emotion. We don’t do that in the operating room, and we should not do it in the courtroom.

Dr. Risley is the medical director of the Jacksonville Vein Center, Fla. 


The opinions expressed by the author neither imply nor establish a standard of care. Cases have been modified and may be fictional in order to maintain HIPPA and confidentiality regulations.

Dr. Risley together with associate editor Dr. O. William Brown describe a case involving failure to document, a common complaint in malpractice litigation.

A 63-year-old white male, actively working, presented with a 5.3-cm infra-renal abdominal aortic aneurysm (AAA). His anatomy was deemed appropriate for endovascular AAA repair and was cleared by his cardiologist for that procedure. The patient underwent a thorough informed consent regarding endovascular and open options as well as the option for continued AAA surveillance. Of note, the patient never had his family with him at any time during the decision-making process, nor with him in the preoperative holding area.

He underwent an aorto- bi- iliac unibody endovascular graft placement. During delivery of the main body, the right common iliac artery ruptured. Initial attempts at endovascular control and subsequent right retroperitoneal exposure and repair of the iliac rupture were unsuccessful, ultimately requiring laparotomy, explant of the device, and aorto- bi-femoral bypass graft. The first time the surgeon met the large family was at the completion of the procedure to explain the complications that were encountered. The patient had a very “rocky” ICU course with complications of ARDS (acute respiratory distress syndrome), acute renal insufficiency, anemia, encephalopathy, and thrombocytopenia. He was initially started on Lovenox on POD # 2 in addition to SCDs (sequential compression devices) for DVT prophylaxis.

Lovenox was stopped because of thrombocytopenia, and mechanical SCD prophylaxis was maintained. As his platelet count recovered and his HIT (heparin-induced thrombocytopenia) screen came back negative, discussion was undertaken to resume his chemical thromboprophylaxis.

It was elected to leave him on only the SCDs because of potential bleeding complications. He continued to improve, but developed a swollen left lower extremity as a result of a DVT. He was placed on heparin drip and converted to Coumadin. Despite an INR of 2.7 on the day he was to be discharged to the rehabilitation center, and shortly after a walk with the therapists and his family, he suffered a fatal pulmonary embolism.

Ultimately, the hospital, the intensivist and the surgeon were sued for failure to adequately provide prophylaxis and treat the DVT. The case was settled. The criticisms were that the physicians failed to provide both mechanical and chemical thromboprophylaxis, particularly after the HIT panel was negative. No criticisms of the intra-operative complications were levied.

The plaintiff’s expert in this case was a physician who was board certified in internal medicine, anesthesiology, and critical care. He had no training in general surgery or vascular surgery. Accordingly, although he may have made suggestions regarding post operative surgical care he had no experience in being the responsible physician for making a postoperative surgical decision. In addition, assertions regarding the incidence of DVT in specific patient populations were exaggerated. Yet the case still settled.

This case emphasizes several important issues. First, communication is paramount in potentially avoiding medical malpractice litigation. The surgeon never met anyone from the patient’s large and involved family until he had to explain the reason his 2-hour planned procedure took 8 hours. The patient had clearly minimized to his family any of the risks discussed with him preoperatively. Prior to proceeding with any surgical intervention it is important that, if possible, a family member be informed of the risks and benefits of the planned procedure and that this conversation be documented in the chart.

Documentation remains very important not only during the informed consent process prior to surgery, but also in decision making regarding postoperative care. Although the physicians discussed the options of resuming the patient’s chemothromboprophylaxis, nothing was documented in the chart. If the discussion was documented, they may have been able to refute the allegation of failure to prevent the DVT.

Finally, in certain instances even when the facts support the judgments that were made regarding the care given, it may be the best “business decision” to settle a case. This is perhaps the most difficult concept for practicing surgeons to grasp. Whether physicians like it or not, medicine is a business and decisions made regarding defending or settling a law suit should not be based on emotion. We don’t do that in the operating room, and we should not do it in the courtroom.

Dr. Risley is the medical director of the Jacksonville Vein Center, Fla. 


The opinions expressed by the author neither imply nor establish a standard of care. Cases have been modified and may be fictional in order to maintain HIPPA and confidentiality regulations.

A substantial number of nursing home residents undergo lower-extremity revascularization each year, but very few of them gain any function and approximately half die within the year, according to an online report in JAMA Internal Medicine.

In a population-based analysis of Medicare claims and a database that tracks virtually all U.S. nursing homes, 82% of residents who underwent lower-extremity revascularization during a 3-year period had either died or were unable to walk a year afterward.

Most showed a clinically significant decline in function within 3 months of having the procedure, said Dr. Lawrence Oresanya of the department of surgery, University of California, San Francisco, and his associates. “Our findings can inform conversations between physicians, patients, and families about the risks and expected outcomes of surgery and whether the surgery is likely to be worthwhile. Our findings also highlight the importance of carefully considering a prognosis independent of vascular disease and assessing the goals of care. Ambulatory function … may be impossible to attain,” they wrote.

Lower-extremity revascularization is usually performed to maintain elderly patients’ functional independence by preserving their limbs. But a closer examination of these procedures is warranted in the nursing home population “because nursing home residents, in general, have high levels of functional dependence unrelated to peripheral arterial disease, and higher rates of mortality after most invasive procedures,” according to the investigators.

Dr. Oresanya and his colleagues identified 10,784 nursing home residents across the country who underwent lower-extremity revascularization.

The procedure was elective in 67% of cases and emergent or urgent in 33%. An endovascular approach was used in 56%, and an open approach in the remainder, with the endovacular approach being more associated with clinical success than open surgery.

The mean patient age was 82 years, and serious comorbidities were very common: 60% had cognitive impairment, 57% had heart failure, and 29% had renal failure. Three-fourths of the patients were nonambulatory at the time of surgery.

The investigators assumed that most patients in this setting had critical limb ischemia rather than claudication. They did not have information about the severity of the lower-extremity ischemia, or about the prevalence or duration of nonhealing wounds or gangrene.

One year after lower-extremity revascularization, mortality was 51% among ambulatory patients and 53% among nonambulatory patients.

Only 13% of the entire cohort were able to walk, and only 18% had maintained or improved their presurgical functional status.

“Revascularization rarely allowed a nonambulatory resident to become ambulatory,” Dr. Oresanya and his associates wrote (JAMA Intern. Med. 2015 April 6 [doi:10.1001/jamainternmed.2015.0486]).

The researchers were unable to determine whether these poor outcomes resulted from the surgery itself or were due to these patients’ “insufficient physiologic reserve.”

They also cautioned that they confined their study strictly to functional outcomes of lower-extremity revascularization, namely ambulation and mortality. Some patients may have derived other benefits from the procedure, such as relief of pain, healing of wounds, and avoidance of major amputation.

The authors reported having no relevant financial disclosures.

A substantial number of nursing home residents undergo lower-extremity revascularization each year, but very few of them gain any function and approximately half die within the year, according to an online report in JAMA Internal Medicine.

In a population-based analysis of Medicare claims and a database that tracks virtually all U.S. nursing homes, 82% of residents who underwent lower-extremity revascularization during a 3-year period had either died or were unable to walk a year afterward.

Most showed a clinically significant decline in function within 3 months of having the procedure, said Dr. Lawrence Oresanya of the department of surgery, University of California, San Francisco, and his associates. “Our findings can inform conversations between physicians, patients, and families about the risks and expected outcomes of surgery and whether the surgery is likely to be worthwhile. Our findings also highlight the importance of carefully considering a prognosis independent of vascular disease and assessing the goals of care. Ambulatory function … may be impossible to attain,” they wrote.

Lower-extremity revascularization is usually performed to maintain elderly patients’ functional independence by preserving their limbs. But a closer examination of these procedures is warranted in the nursing home population “because nursing home residents, in general, have high levels of functional dependence unrelated to peripheral arterial disease, and higher rates of mortality after most invasive procedures,” according to the investigators.

Dr. Oresanya and his colleagues identified 10,784 nursing home residents across the country who underwent lower-extremity revascularization.

The procedure was elective in 67% of cases and emergent or urgent in 33%. An endovascular approach was used in 56%, and an open approach in the remainder, with the endovacular approach being more associated with clinical success than open surgery.

The mean patient age was 82 years, and serious comorbidities were very common: 60% had cognitive impairment, 57% had heart failure, and 29% had renal failure. Three-fourths of the patients were nonambulatory at the time of surgery.

The investigators assumed that most patients in this setting had critical limb ischemia rather than claudication. They did not have information about the severity of the lower-extremity ischemia, or about the prevalence or duration of nonhealing wounds or gangrene.

One year after lower-extremity revascularization, mortality was 51% among ambulatory patients and 53% among nonambulatory patients.

Only 13% of the entire cohort were able to walk, and only 18% had maintained or improved their presurgical functional status.

“Revascularization rarely allowed a nonambulatory resident to become ambulatory,” Dr. Oresanya and his associates wrote (JAMA Intern. Med. 2015 April 6 [doi:10.1001/jamainternmed.2015.0486]).

The researchers were unable to determine whether these poor outcomes resulted from the surgery itself or were due to these patients’ “insufficient physiologic reserve.”

They also cautioned that they confined their study strictly to functional outcomes of lower-extremity revascularization, namely ambulation and mortality. Some patients may have derived other benefits from the procedure, such as relief of pain, healing of wounds, and avoidance of major amputation.

The authors reported having no relevant financial disclosures.

A substantial number of nursing home residents undergo lower-extremity revascularization each year, but very few of them gain any function and approximately half die within the year, according to an online report in JAMA Internal Medicine.

In a population-based analysis of Medicare claims and a database that tracks virtually all U.S. nursing homes, 82% of residents who underwent lower-extremity revascularization during a 3-year period had either died or were unable to walk a year afterward.

Most showed a clinically significant decline in function within 3 months of having the procedure, said Dr. Lawrence Oresanya of the department of surgery, University of California, San Francisco, and his associates. “Our findings can inform conversations between physicians, patients, and families about the risks and expected outcomes of surgery and whether the surgery is likely to be worthwhile. Our findings also highlight the importance of carefully considering a prognosis independent of vascular disease and assessing the goals of care. Ambulatory function … may be impossible to attain,” they wrote.

Lower-extremity revascularization is usually performed to maintain elderly patients’ functional independence by preserving their limbs. But a closer examination of these procedures is warranted in the nursing home population “because nursing home residents, in general, have high levels of functional dependence unrelated to peripheral arterial disease, and higher rates of mortality after most invasive procedures,” according to the investigators.

Dr. Oresanya and his colleagues identified 10,784 nursing home residents across the country who underwent lower-extremity revascularization.

The procedure was elective in 67% of cases and emergent or urgent in 33%. An endovascular approach was used in 56%, and an open approach in the remainder, with the endovacular approach being more associated with clinical success than open surgery.

The mean patient age was 82 years, and serious comorbidities were very common: 60% had cognitive impairment, 57% had heart failure, and 29% had renal failure. Three-fourths of the patients were nonambulatory at the time of surgery.

The investigators assumed that most patients in this setting had critical limb ischemia rather than claudication. They did not have information about the severity of the lower-extremity ischemia, or about the prevalence or duration of nonhealing wounds or gangrene.

One year after lower-extremity revascularization, mortality was 51% among ambulatory patients and 53% among nonambulatory patients.

Only 13% of the entire cohort were able to walk, and only 18% had maintained or improved their presurgical functional status.

“Revascularization rarely allowed a nonambulatory resident to become ambulatory,” Dr. Oresanya and his associates wrote (JAMA Intern. Med. 2015 April 6 [doi:10.1001/jamainternmed.2015.0486]).

The researchers were unable to determine whether these poor outcomes resulted from the surgery itself or were due to these patients’ “insufficient physiologic reserve.”

They also cautioned that they confined their study strictly to functional outcomes of lower-extremity revascularization, namely ambulation and mortality. Some patients may have derived other benefits from the procedure, such as relief of pain, healing of wounds, and avoidance of major amputation.

The authors reported having no relevant financial disclosures.

A 44-year-old man presents with what his primary care provider called “ringworm.” The condition has not responded to topical and oral antifungal medications (clotrimazole and oral terbinafine). Fortunately, the lesions are not particularly symptomatic.

The patient, who works in an oil field, claims to be in otherwise good health. He has no pets at home, and no one else in his household has been similarly affected. He is taking no medications at this time.

EXAMINATION
Multiple arcuate and annular scaly lesions are seen, most densely distributed across the patient’s upper back and posterior shoulders. They thin out inferiorly and are missing entirely below the waist.

Many of the lesions are larger than 10 cm (though on average half that size). They have well-defined, scaly margins and mostly clear centers. There is minimal erythema.

A KOH prep of the lesions does not show fungal elements. A 4-mm punch biopsy is performed, the results of which will be discussed in the next section.

What is the diagnosis?

DISCUSSION
This case nicely illustrates a common dilemma in dermatology: “ringworm” that is neither fungal nor any other kind of infection. Presented with this case, the vast majority of primary care providers would do what this man’s clinician did: treat it as fungal. This attempt would fail, for one basic reason: There is an extensive differential for round, scaly lesions, of which dermatophytosis (superficial fungal infection) is but one item.

In this case, there was no source from which our patient could have acquired a fungal infection (animal, child, soil) and no particular susceptibility by virtue of immune suppression. To these facts we add the negative KOH, forcing us to consider other items in the differential, including psoriasis, T-cell lymphoma, erythema annulare centrifugum, chronic cutaneous lupus, and nummular eczema, just to name a few.

One way to settle the issue is to obtain a skin biopsy, which in this case showed results most consistent with eczema and effectively ruled out items such as lupus or cutaneous T-cell lymphoma. This provides extremely useful treatment guidance, as well as reassurance to the patient. Stains for fungal organisms were requested and obtained as part of specimen processing—and, of course, results were negative.

In most derm clinics, skin biopsies are routinely done—but what really sets the specialty apart is the fact that a full differential is considered, not just the first (and often only) diagnostic idea that comes to mind. More often than not, a reasonable diagnosis can be found without biopsy, using corroborative history and physical data. 

This patient responded nicely to the application of a topical steroid lotion (fluocinonide 0.05%) and the use of emollients. In the process of history-taking, it was discovered that the patient had a habit of taking long, hot showers while standing with his back to the nozzle. Since this certainly can contribute to dry skin, he was advised to reduce the temperature to a more moderate level and limit his time spent in the shower.

TAKE-HOME LEARNING POINTS
• Just because a rash presents with round, scaly lesions doesn’t mean it’s fungal.

• The rather extensive differential for such rashes includes lupus, psoriasis, eczema, and a type of skin cancer called cutaneous T-cell lymphoma.

• Biopsy, performed under local anesthetic and with a 4-mm punch (closed with two sutures), can be extremely useful in sorting through the differential.

• A KOH prep is a helpful first step (one that would confirm or rule out fungal origin).

• In the absence of a source or indications of susceptibility, fungal infection is an unlikely diagnosis in these cases.

A 44-year-old man presents with what his primary care provider called “ringworm.” The condition has not responded to topical and oral antifungal medications (clotrimazole and oral terbinafine). Fortunately, the lesions are not particularly symptomatic.

The patient, who works in an oil field, claims to be in otherwise good health. He has no pets at home, and no one else in his household has been similarly affected. He is taking no medications at this time.

EXAMINATION
Multiple arcuate and annular scaly lesions are seen, most densely distributed across the patient’s upper back and posterior shoulders. They thin out inferiorly and are missing entirely below the waist.

Many of the lesions are larger than 10 cm (though on average half that size). They have well-defined, scaly margins and mostly clear centers. There is minimal erythema.

A KOH prep of the lesions does not show fungal elements. A 4-mm punch biopsy is performed, the results of which will be discussed in the next section.

What is the diagnosis?

DISCUSSION
This case nicely illustrates a common dilemma in dermatology: “ringworm” that is neither fungal nor any other kind of infection. Presented with this case, the vast majority of primary care providers would do what this man’s clinician did: treat it as fungal. This attempt would fail, for one basic reason: There is an extensive differential for round, scaly lesions, of which dermatophytosis (superficial fungal infection) is but one item.

In this case, there was no source from which our patient could have acquired a fungal infection (animal, child, soil) and no particular susceptibility by virtue of immune suppression. To these facts we add the negative KOH, forcing us to consider other items in the differential, including psoriasis, T-cell lymphoma, erythema annulare centrifugum, chronic cutaneous lupus, and nummular eczema, just to name a few.

One way to settle the issue is to obtain a skin biopsy, which in this case showed results most consistent with eczema and effectively ruled out items such as lupus or cutaneous T-cell lymphoma. This provides extremely useful treatment guidance, as well as reassurance to the patient. Stains for fungal organisms were requested and obtained as part of specimen processing—and, of course, results were negative.

In most derm clinics, skin biopsies are routinely done—but what really sets the specialty apart is the fact that a full differential is considered, not just the first (and often only) diagnostic idea that comes to mind. More often than not, a reasonable diagnosis can be found without biopsy, using corroborative history and physical data. 

This patient responded nicely to the application of a topical steroid lotion (fluocinonide 0.05%) and the use of emollients. In the process of history-taking, it was discovered that the patient had a habit of taking long, hot showers while standing with his back to the nozzle. Since this certainly can contribute to dry skin, he was advised to reduce the temperature to a more moderate level and limit his time spent in the shower.

TAKE-HOME LEARNING POINTS
• Just because a rash presents with round, scaly lesions doesn’t mean it’s fungal.

• The rather extensive differential for such rashes includes lupus, psoriasis, eczema, and a type of skin cancer called cutaneous T-cell lymphoma.

• Biopsy, performed under local anesthetic and with a 4-mm punch (closed with two sutures), can be extremely useful in sorting through the differential.

• A KOH prep is a helpful first step (one that would confirm or rule out fungal origin).

• In the absence of a source or indications of susceptibility, fungal infection is an unlikely diagnosis in these cases.

A 44-year-old man presents with what his primary care provider called “ringworm.” The condition has not responded to topical and oral antifungal medications (clotrimazole and oral terbinafine). Fortunately, the lesions are not particularly symptomatic.

The patient, who works in an oil field, claims to be in otherwise good health. He has no pets at home, and no one else in his household has been similarly affected. He is taking no medications at this time.

EXAMINATION
Multiple arcuate and annular scaly lesions are seen, most densely distributed across the patient’s upper back and posterior shoulders. They thin out inferiorly and are missing entirely below the waist.

Many of the lesions are larger than 10 cm (though on average half that size). They have well-defined, scaly margins and mostly clear centers. There is minimal erythema.

A KOH prep of the lesions does not show fungal elements. A 4-mm punch biopsy is performed, the results of which will be discussed in the next section.

What is the diagnosis?

DISCUSSION
This case nicely illustrates a common dilemma in dermatology: “ringworm” that is neither fungal nor any other kind of infection. Presented with this case, the vast majority of primary care providers would do what this man’s clinician did: treat it as fungal. This attempt would fail, for one basic reason: There is an extensive differential for round, scaly lesions, of which dermatophytosis (superficial fungal infection) is but one item.

In this case, there was no source from which our patient could have acquired a fungal infection (animal, child, soil) and no particular susceptibility by virtue of immune suppression. To these facts we add the negative KOH, forcing us to consider other items in the differential, including psoriasis, T-cell lymphoma, erythema annulare centrifugum, chronic cutaneous lupus, and nummular eczema, just to name a few.

One way to settle the issue is to obtain a skin biopsy, which in this case showed results most consistent with eczema and effectively ruled out items such as lupus or cutaneous T-cell lymphoma. This provides extremely useful treatment guidance, as well as reassurance to the patient. Stains for fungal organisms were requested and obtained as part of specimen processing—and, of course, results were negative.

In most derm clinics, skin biopsies are routinely done—but what really sets the specialty apart is the fact that a full differential is considered, not just the first (and often only) diagnostic idea that comes to mind. More often than not, a reasonable diagnosis can be found without biopsy, using corroborative history and physical data. 

This patient responded nicely to the application of a topical steroid lotion (fluocinonide 0.05%) and the use of emollients. In the process of history-taking, it was discovered that the patient had a habit of taking long, hot showers while standing with his back to the nozzle. Since this certainly can contribute to dry skin, he was advised to reduce the temperature to a more moderate level and limit his time spent in the shower.

TAKE-HOME LEARNING POINTS
• Just because a rash presents with round, scaly lesions doesn’t mean it’s fungal.

• The rather extensive differential for such rashes includes lupus, psoriasis, eczema, and a type of skin cancer called cutaneous T-cell lymphoma.

• Biopsy, performed under local anesthetic and with a 4-mm punch (closed with two sutures), can be extremely useful in sorting through the differential.

• A KOH prep is a helpful first step (one that would confirm or rule out fungal origin).

• In the absence of a source or indications of susceptibility, fungal infection is an unlikely diagnosis in these cases.

Crowd at ASCO 2015

© ASCO/Rodney White

CHICAGO—Researchers say they have identified 3 leukemia stem cell (LSC) phenotypes that are correlated with cytogenetic/molecular abnormalities and prognosis in acute myeloid leukemia (AML).

The investigators believe this knowledge could aid risk stratification of AML patients, particularly those without identifiable cytogenetic or molecular risk factors.

The findings may also pave the way for scientists to identify novel therapeutic targets on LSCs and monitor LSCs in response to therapy.

Jonathan Michael Gerber, MD, of Levine Cancer Institute in Charlotte, North Carolina, presented the findings at the 2015 ASCO Annual Meeting (abstract 7000*).

Via previous research, Dr Gerber and his colleagues identified 3 different LSC phenotypes in AML:

• LSCs that are CD34-negative
• LSCs that are CD34-positive, CD38-negative, and have intermediate levels of aldehyde dehydrogenase (ALDH^int)
• LSCs that are CD34-positive, CD38-negative, and have high levels of ALDH (ALDH^high).

With the current study, the researchers wanted to determine if these phenotypes correlate with cytogenetic/molecular features and treatment outcomes.

So they analyzed diagnostic samples from 98 patients with newly diagnosed AML who had normal or unfavorable cytogenetics. The patients were enrolled on a phase 2 trial comparing FLAM and 7+3 (Zeidner et al, haematologica 2015).

Dr Gerber and his colleagues identified 22 patients with CD34^- LSCs, 43 with ALDH^int LSCs, and 33 with ALDH^high LSCs.

Risk factors

“We found that leukemia stem cell phenotype indeed correlated quite strongly with cytogenetic and molecular risk factors,” Dr Gerber said.

NPM1 mutations were more common in patients with CD34^- LSCs (64%) than those with ALDH^int LSCs (14%) or ALDH^high LSCs (6%, P<0.001). NPM1 mutations were the sole abnormality in 50% of patients with CD34^- LSCs.

Poor-risk cytogenetics and/or FLT3-ITD mutations were more common in patients with ALDH^high LSCs (85%) than those with ALDH^int LCSs (35%) or CD34^- LSCs (18%, P<0.001).

Nine percent of patients in the CD34^- LSC group fell into the European Leukemia Network poor-risk category, compared to 73% of patients in the ALDH^high LSC group.

Only 2 patients had 11q23, and both had CD34^- LSCs. Fifty-five percent of patients with ALDH^high LSCs had prior myelodysplastic syndromes or myeloproliferative neoplasms.

Prognosis

“We found that leukemia stem cell phenotype correlated strongly with outcomes as well,” Dr Gerber said. “It turned out that CD34^- patients fared more favorably overall.”

Patients with CD34^- LSCs had the highest complete response rate (86%), followed by those with ALDH^int LSCs (67%) and ALDH^high LSCs (45%, P<0.01).

Patients in the CD34^- group also had a higher rate of event-free survival at 2 years (46%) than patients in the ALDH^int group (26%) or the ALDH^high group (0%). The median event-free survival was 13 months, 11.3 months, and 2.2 months, respectively (P<0.01).

The rate of overall survival at 2 years was best for the CD34^- group (76%), followed by the ALDH^int group (38%) and the ALDH^high group (34%). The median overall survival was not reached, 18.7 months, and 9.4 months, respectively (P=0.02).

Dr Gerber also noted that ALDH^high patients fared much better if they underwent hematopoietic stem cell transplant.

“There is 0% leukemia-free survival at the 2-year mark for the ALDH^high patients who were not transplanted,” he said. “Those that were transplanted fared about the same as everyone else in the series. So it was very striking that there were no chemotherapy survivors in that group.”

In closing, Dr Gerber said this research suggests the 3 LSC phenotypes are mutually exclusive and correlate with cytogenetic and molecular risk factors as well as outcomes in patients with AML.

“This [discovery] may allow for rapid risk stratification in this explosive disease, facilitate enrollment onto induction protocols . . . , and allow us to divert those ALDH^high, very high-risk patients earlier to novel therapies and/or transplant, given that they’re not really helped much by conventional chemotherapy.”

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

© ASCO/Rodney White

CHICAGO—Researchers say they have identified 3 leukemia stem cell (LSC) phenotypes that are correlated with cytogenetic/molecular abnormalities and prognosis in acute myeloid leukemia (AML).

The investigators believe this knowledge could aid risk stratification of AML patients, particularly those without identifiable cytogenetic or molecular risk factors.

The findings may also pave the way for scientists to identify novel therapeutic targets on LSCs and monitor LSCs in response to therapy.

Jonathan Michael Gerber, MD, of Levine Cancer Institute in Charlotte, North Carolina, presented the findings at the 2015 ASCO Annual Meeting (abstract 7000*).

Via previous research, Dr Gerber and his colleagues identified 3 different LSC phenotypes in AML:

• LSCs that are CD34-negative
• LSCs that are CD34-positive, CD38-negative, and have intermediate levels of aldehyde dehydrogenase (ALDH^int)
• LSCs that are CD34-positive, CD38-negative, and have high levels of ALDH (ALDH^high).

With the current study, the researchers wanted to determine if these phenotypes correlate with cytogenetic/molecular features and treatment outcomes.

So they analyzed diagnostic samples from 98 patients with newly diagnosed AML who had normal or unfavorable cytogenetics. The patients were enrolled on a phase 2 trial comparing FLAM and 7+3 (Zeidner et al, haematologica 2015).

Dr Gerber and his colleagues identified 22 patients with CD34^- LSCs, 43 with ALDH^int LSCs, and 33 with ALDH^high LSCs.

Risk factors

“We found that leukemia stem cell phenotype indeed correlated quite strongly with cytogenetic and molecular risk factors,” Dr Gerber said.

NPM1 mutations were more common in patients with CD34^- LSCs (64%) than those with ALDH^int LSCs (14%) or ALDH^high LSCs (6%, P<0.001). NPM1 mutations were the sole abnormality in 50% of patients with CD34^- LSCs.

Poor-risk cytogenetics and/or FLT3-ITD mutations were more common in patients with ALDH^high LSCs (85%) than those with ALDH^int LCSs (35%) or CD34^- LSCs (18%, P<0.001).

Nine percent of patients in the CD34^- LSC group fell into the European Leukemia Network poor-risk category, compared to 73% of patients in the ALDH^high LSC group.

Only 2 patients had 11q23, and both had CD34^- LSCs. Fifty-five percent of patients with ALDH^high LSCs had prior myelodysplastic syndromes or myeloproliferative neoplasms.

Prognosis

“We found that leukemia stem cell phenotype correlated strongly with outcomes as well,” Dr Gerber said. “It turned out that CD34^- patients fared more favorably overall.”

Patients with CD34^- LSCs had the highest complete response rate (86%), followed by those with ALDH^int LSCs (67%) and ALDH^high LSCs (45%, P<0.01).

Patients in the CD34^- group also had a higher rate of event-free survival at 2 years (46%) than patients in the ALDH^int group (26%) or the ALDH^high group (0%). The median event-free survival was 13 months, 11.3 months, and 2.2 months, respectively (P<0.01).

The rate of overall survival at 2 years was best for the CD34^- group (76%), followed by the ALDH^int group (38%) and the ALDH^high group (34%). The median overall survival was not reached, 18.7 months, and 9.4 months, respectively (P=0.02).

Dr Gerber also noted that ALDH^high patients fared much better if they underwent hematopoietic stem cell transplant.

“There is 0% leukemia-free survival at the 2-year mark for the ALDH^high patients who were not transplanted,” he said. “Those that were transplanted fared about the same as everyone else in the series. So it was very striking that there were no chemotherapy survivors in that group.”

In closing, Dr Gerber said this research suggests the 3 LSC phenotypes are mutually exclusive and correlate with cytogenetic and molecular risk factors as well as outcomes in patients with AML.

“This [discovery] may allow for rapid risk stratification in this explosive disease, facilitate enrollment onto induction protocols . . . , and allow us to divert those ALDH^high, very high-risk patients earlier to novel therapies and/or transplant, given that they’re not really helped much by conventional chemotherapy.”

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

© ASCO/Rodney White

CHICAGO—Researchers say they have identified 3 leukemia stem cell (LSC) phenotypes that are correlated with cytogenetic/molecular abnormalities and prognosis in acute myeloid leukemia (AML).

The investigators believe this knowledge could aid risk stratification of AML patients, particularly those without identifiable cytogenetic or molecular risk factors.

The findings may also pave the way for scientists to identify novel therapeutic targets on LSCs and monitor LSCs in response to therapy.

Jonathan Michael Gerber, MD, of Levine Cancer Institute in Charlotte, North Carolina, presented the findings at the 2015 ASCO Annual Meeting (abstract 7000*).

Via previous research, Dr Gerber and his colleagues identified 3 different LSC phenotypes in AML:

• LSCs that are CD34-negative
• LSCs that are CD34-positive, CD38-negative, and have intermediate levels of aldehyde dehydrogenase (ALDH^int)
• LSCs that are CD34-positive, CD38-negative, and have high levels of ALDH (ALDH^high).

With the current study, the researchers wanted to determine if these phenotypes correlate with cytogenetic/molecular features and treatment outcomes.

So they analyzed diagnostic samples from 98 patients with newly diagnosed AML who had normal or unfavorable cytogenetics. The patients were enrolled on a phase 2 trial comparing FLAM and 7+3 (Zeidner et al, haematologica 2015).

Dr Gerber and his colleagues identified 22 patients with CD34^- LSCs, 43 with ALDH^int LSCs, and 33 with ALDH^high LSCs.

Risk factors

“We found that leukemia stem cell phenotype indeed correlated quite strongly with cytogenetic and molecular risk factors,” Dr Gerber said.

NPM1 mutations were more common in patients with CD34^- LSCs (64%) than those with ALDH^int LSCs (14%) or ALDH^high LSCs (6%, P<0.001). NPM1 mutations were the sole abnormality in 50% of patients with CD34^- LSCs.

Poor-risk cytogenetics and/or FLT3-ITD mutations were more common in patients with ALDH^high LSCs (85%) than those with ALDH^int LCSs (35%) or CD34^- LSCs (18%, P<0.001).

Nine percent of patients in the CD34^- LSC group fell into the European Leukemia Network poor-risk category, compared to 73% of patients in the ALDH^high LSC group.

Only 2 patients had 11q23, and both had CD34^- LSCs. Fifty-five percent of patients with ALDH^high LSCs had prior myelodysplastic syndromes or myeloproliferative neoplasms.

Prognosis

“We found that leukemia stem cell phenotype correlated strongly with outcomes as well,” Dr Gerber said. “It turned out that CD34^- patients fared more favorably overall.”

Patients with CD34^- LSCs had the highest complete response rate (86%), followed by those with ALDH^int LSCs (67%) and ALDH^high LSCs (45%, P<0.01).

Patients in the CD34^- group also had a higher rate of event-free survival at 2 years (46%) than patients in the ALDH^int group (26%) or the ALDH^high group (0%). The median event-free survival was 13 months, 11.3 months, and 2.2 months, respectively (P<0.01).

The rate of overall survival at 2 years was best for the CD34^- group (76%), followed by the ALDH^int group (38%) and the ALDH^high group (34%). The median overall survival was not reached, 18.7 months, and 9.4 months, respectively (P=0.02).

Dr Gerber also noted that ALDH^high patients fared much better if they underwent hematopoietic stem cell transplant.

“There is 0% leukemia-free survival at the 2-year mark for the ALDH^high patients who were not transplanted,” he said. “Those that were transplanted fared about the same as everyone else in the series. So it was very striking that there were no chemotherapy survivors in that group.”

In closing, Dr Gerber said this research suggests the 3 LSC phenotypes are mutually exclusive and correlate with cytogenetic and molecular risk factors as well as outcomes in patients with AML.

“This [discovery] may allow for rapid risk stratification in this explosive disease, facilitate enrollment onto induction protocols . . . , and allow us to divert those ALDH^high, very high-risk patients earlier to novel therapies and/or transplant, given that they’re not really helped much by conventional chemotherapy.”

*Information in the abstract differs from that presented at the meeting.

Irwin “Ernie” Rose, PhD

Photo courtesy of UCI

Biochemist and Nobel laureate Irwin “Ernie” Rose, PhD, has passed away at the age of 88.

Dr Rose and colleagues from Israel won the Nobel Prize in Chemistry in 2004 for their discovery of ubiquitin-mediated protein degradation.

This research has wide-ranging implications for medicine and led to the development of anticancer drugs such as bortezomib, which is approved in the US to treat multiple myeloma and mantle cell lymphoma.

According to his friends and colleagues, Dr Rose was humble, generous, and endlessly curious.

“Ernie was not interested in personal fame and was oblivious to the politics of science,” said Ann Skalka, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“His total satisfaction came from solving intricate biochemical puzzles. Although Ernie was an intellectual leader on the project that ultimately won him the Nobel, he took no personal credit. He was rather surprised at being recognized, but all of us at Fox Chase knew that the Nobel Committee had gotten it right.”

Dr Rose was born in Brooklyn, New York, on July 16, 1926. His scientific ambitions began to take shape after he moved to Spokane, Washington, at 13. While in high school, he spent summers working at a local hospital. And this inspired him to pursue a career that involved “solving medical problems.”

Dr Rose attended Washington State College for his undergraduate work and went on to earn a doctoral degree at the University of Chicago, after a brief stint in the Navy. He spent the better part of his career as a research scientist at the Fox Chase Cancer Center.

There, during the late 1970s and early 1980s, Dr Rose helped reveal how ubiquitin molecules facilitate the breakdown of old and damaged proteins. The discovery of this process fostered a new understanding of the molecular activity present in cancers and other diseases.

For the work, Dr Rose shared the 2004 Nobel Prize in Chemistry with Avram Hershko, MD, PhD, and Aaron Ciechanover, MD, PhD, of the Israel Institute of Technology.

“Ernie had a genius for asking the right questions,” said Jonathan Chernoff, MD, PhD, of Fox Chase Cancer Center.

“In the mid-1950s, when many scientists were interested in how proteins are synthesized, Ernie became fascinated with the opposite issue—how are proteins degraded? With the collaboration of his Israeli colleagues, he cracked that problem with the discovery of the ubiquitin conjugating system.”

After retiring to Laguna Woods, California, in 1997, Dr Rose accepted a special research position with the University of California Irvine (UCI).

There, he studied the mechanisms of fumarase, an enzyme involved in the citric acid cycle, the cellular pathway by which higher organisms convert food into energy. And he quickly became a beloved colleague and mentor to students and faculty.

“[B]oth prior to and after winning the Nobel Prize, he would help any student or young postdoctoral researcher who was having a hard time with an experiment,” said Ralph Bradshaw, PhD, a former professor at UCI.

“It was a lot of fun working with him,” said James Nowick, PhD, of UCI. “He worked with his own hands, not relying on others, with old instrumentation, and was able to do literally superb science.”

“He was the quintessential scientist—perseverant, soft-spoken, and interested in science for science’s sake,” Dr Chernoff said. “We will miss him very much.”

Dr Rose died in his sleep on June 2 in Deerfield, Massachusetts. He is survived by his wife, Zelda; their sons, Howard, Frederic, and Robert; and 5 grandchildren. Dr Rose’s daughter, Sarah, died in 2005.

Irwin “Ernie” Rose, PhD

Photo courtesy of UCI

Biochemist and Nobel laureate Irwin “Ernie” Rose, PhD, has passed away at the age of 88.

Dr Rose and colleagues from Israel won the Nobel Prize in Chemistry in 2004 for their discovery of ubiquitin-mediated protein degradation.

This research has wide-ranging implications for medicine and led to the development of anticancer drugs such as bortezomib, which is approved in the US to treat multiple myeloma and mantle cell lymphoma.

According to his friends and colleagues, Dr Rose was humble, generous, and endlessly curious.

“Ernie was not interested in personal fame and was oblivious to the politics of science,” said Ann Skalka, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“His total satisfaction came from solving intricate biochemical puzzles. Although Ernie was an intellectual leader on the project that ultimately won him the Nobel, he took no personal credit. He was rather surprised at being recognized, but all of us at Fox Chase knew that the Nobel Committee had gotten it right.”

Dr Rose was born in Brooklyn, New York, on July 16, 1926. His scientific ambitions began to take shape after he moved to Spokane, Washington, at 13. While in high school, he spent summers working at a local hospital. And this inspired him to pursue a career that involved “solving medical problems.”

Dr Rose attended Washington State College for his undergraduate work and went on to earn a doctoral degree at the University of Chicago, after a brief stint in the Navy. He spent the better part of his career as a research scientist at the Fox Chase Cancer Center.

There, during the late 1970s and early 1980s, Dr Rose helped reveal how ubiquitin molecules facilitate the breakdown of old and damaged proteins. The discovery of this process fostered a new understanding of the molecular activity present in cancers and other diseases.

For the work, Dr Rose shared the 2004 Nobel Prize in Chemistry with Avram Hershko, MD, PhD, and Aaron Ciechanover, MD, PhD, of the Israel Institute of Technology.

“Ernie had a genius for asking the right questions,” said Jonathan Chernoff, MD, PhD, of Fox Chase Cancer Center.

“In the mid-1950s, when many scientists were interested in how proteins are synthesized, Ernie became fascinated with the opposite issue—how are proteins degraded? With the collaboration of his Israeli colleagues, he cracked that problem with the discovery of the ubiquitin conjugating system.”

After retiring to Laguna Woods, California, in 1997, Dr Rose accepted a special research position with the University of California Irvine (UCI).

There, he studied the mechanisms of fumarase, an enzyme involved in the citric acid cycle, the cellular pathway by which higher organisms convert food into energy. And he quickly became a beloved colleague and mentor to students and faculty.

“[B]oth prior to and after winning the Nobel Prize, he would help any student or young postdoctoral researcher who was having a hard time with an experiment,” said Ralph Bradshaw, PhD, a former professor at UCI.

“It was a lot of fun working with him,” said James Nowick, PhD, of UCI. “He worked with his own hands, not relying on others, with old instrumentation, and was able to do literally superb science.”

“He was the quintessential scientist—perseverant, soft-spoken, and interested in science for science’s sake,” Dr Chernoff said. “We will miss him very much.”

Dr Rose died in his sleep on June 2 in Deerfield, Massachusetts. He is survived by his wife, Zelda; their sons, Howard, Frederic, and Robert; and 5 grandchildren. Dr Rose’s daughter, Sarah, died in 2005.

Irwin “Ernie” Rose, PhD

Photo courtesy of UCI

Biochemist and Nobel laureate Irwin “Ernie” Rose, PhD, has passed away at the age of 88.

Dr Rose and colleagues from Israel won the Nobel Prize in Chemistry in 2004 for their discovery of ubiquitin-mediated protein degradation.

This research has wide-ranging implications for medicine and led to the development of anticancer drugs such as bortezomib, which is approved in the US to treat multiple myeloma and mantle cell lymphoma.

According to his friends and colleagues, Dr Rose was humble, generous, and endlessly curious.

“Ernie was not interested in personal fame and was oblivious to the politics of science,” said Ann Skalka, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“His total satisfaction came from solving intricate biochemical puzzles. Although Ernie was an intellectual leader on the project that ultimately won him the Nobel, he took no personal credit. He was rather surprised at being recognized, but all of us at Fox Chase knew that the Nobel Committee had gotten it right.”

Dr Rose was born in Brooklyn, New York, on July 16, 1926. His scientific ambitions began to take shape after he moved to Spokane, Washington, at 13. While in high school, he spent summers working at a local hospital. And this inspired him to pursue a career that involved “solving medical problems.”

Dr Rose attended Washington State College for his undergraduate work and went on to earn a doctoral degree at the University of Chicago, after a brief stint in the Navy. He spent the better part of his career as a research scientist at the Fox Chase Cancer Center.

There, during the late 1970s and early 1980s, Dr Rose helped reveal how ubiquitin molecules facilitate the breakdown of old and damaged proteins. The discovery of this process fostered a new understanding of the molecular activity present in cancers and other diseases.

For the work, Dr Rose shared the 2004 Nobel Prize in Chemistry with Avram Hershko, MD, PhD, and Aaron Ciechanover, MD, PhD, of the Israel Institute of Technology.

“Ernie had a genius for asking the right questions,” said Jonathan Chernoff, MD, PhD, of Fox Chase Cancer Center.

“In the mid-1950s, when many scientists were interested in how proteins are synthesized, Ernie became fascinated with the opposite issue—how are proteins degraded? With the collaboration of his Israeli colleagues, he cracked that problem with the discovery of the ubiquitin conjugating system.”

After retiring to Laguna Woods, California, in 1997, Dr Rose accepted a special research position with the University of California Irvine (UCI).

There, he studied the mechanisms of fumarase, an enzyme involved in the citric acid cycle, the cellular pathway by which higher organisms convert food into energy. And he quickly became a beloved colleague and mentor to students and faculty.

“[B]oth prior to and after winning the Nobel Prize, he would help any student or young postdoctoral researcher who was having a hard time with an experiment,” said Ralph Bradshaw, PhD, a former professor at UCI.

“It was a lot of fun working with him,” said James Nowick, PhD, of UCI. “He worked with his own hands, not relying on others, with old instrumentation, and was able to do literally superb science.”

“He was the quintessential scientist—perseverant, soft-spoken, and interested in science for science’s sake,” Dr Chernoff said. “We will miss him very much.”

Dr Rose died in his sleep on June 2 in Deerfield, Massachusetts. He is survived by his wife, Zelda; their sons, Howard, Frederic, and Robert; and 5 grandchildren. Dr Rose’s daughter, Sarah, died in 2005.