Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

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

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

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

Patient receives chemotherapy

Photo by Rhoda Baer

SAN DIGEO—A phase 3 study comparing conditioning regimens in multiple myeloma patients undergoing autologous transplant has yielded counterintuitive results.

Patients who received busulfan plus melphalan (bu-mel) had a lower complete response (CR) rate at 90 days and a higher rate of grade 3-4 non-hematologic

toxicity, compared to patients who received melphalan (mel) alone.

However, patients in the bu-mel arm enjoyed significantly longer progression-free survival (PFS).

These results suggest the rate of CR at 90 days is not a good endpoint for trials of autologous hematopoietic stem cell transplant (auto-HSCT), said Muzaffar H.

Qazilbash, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Qazilbash presented these and other findings at the 2015 BMT Tandem Meetings as abstract 83.*

“High-dose melphalan at 200 mg/m² is considered the standard of care for autologous stem cell transplantation for multiple myeloma,” he said. “However, most patients have disease recurrence or progression after an autologous transplant, even with the use of post-transplant maintenance.”

A recent retrospective study suggested that bu-mel might be associated with a longer PFS compared to mel alone. So Dr Qazilbash and his colleagues decided to

investigate that possibility in a randomized, phase 3 trial.

The trial included 92 patients with symptomatic multiple myeloma who had received at least 2 cycles of induction therapy. They were all within 12 months of the start of induction, and all had adequate cardiac, pulmonary, renal, and liver function.

Forty-nine patients received bu-mel—a 130 mg/m² daily infusion of busulfan for 4 days, followed by 2 daily doses of melphalan at 70 mg/m². All patients in this arm also received phenytoin for seizure prophylaxis. The 43 patients in the mel-only arm received a single dose of melphalan at 200 mg/m².

Baseline characteristics were similar between the 2 arms. The patients’ median ages were 58 in the bu-mel arm and 59 in the mel arm. At the time of transplant, 18% of patients in the bu-mel arm were in CR or near CR, as were 28% of patients in the mel arm.

Adverse events

At 100 days post-transplant, the transplant-related mortality was 0% in both arms.

“There was a significantly higher rate of grade 3-4 non-hematologic adverse events in the busulfan-plus-melphalan arm—78% vs 47% [P=0.002],” Dr Qazilbash noted. “And these adverse events were mostly infectious events.”

Grade 3 infection occurred in 71% of bu-mel-treated patients and 39% of mel-treated patients (P=0.003). Grade 2 gastrointestinal toxicities occurred in 69% and 48%, respectively (P=0.05).

There were no significant differences between the arms with regard to other adverse events. And there were no second primary malignancies in either arm.

Response

At 90 days, the CR rate was 16% in the bu-mel arm and 35% in the mel arm (P=0.05). The rates of CR plus very good partial response were 63% and 81%, respectively (P=0.06).

“The trial was stopped early, based on a prescribed rule in the trial design, because of a significantly higher CR rate in the control arm,” Dr Qazilbash said.

Still, he noted that, at 180 days, the CR rate was 26% in the bu-mel arm and 37% in the mel arm (P=0.36). And the 180-day rates of CR plus very good

partial response were 69% and 86%, respectively (P=0.65).

Maintenance

A majority of patients received maintenance therapy post-transplant—84% of patients in the bu-mel arm and 88% in the mel arm.

The median interval between auto-HSCT and maintenance was 4.6 months and 4.5 months, respectively. And the median duration of maintenance was 16 months and 14.2 months, respectively.

Maintenance largely consisted of lenalidomide. Sixty-five percent of patients in the bu-mel arm and 63% in the mel arm received the drug. Fewer patients received bortezomib—8% and 16%, respectively—or lenalidomide plus ixazomib—10% and 9%, respectively.

Survival

At a median follow-up of 19.5 months, bu-mel was associated with significantly longer PFS than mel alone (P=0.047). And a multivariate analysis showed that bu-mel was an independent predictor of PFS.

Dr Qazilbash noted that there was no significant difference in overall survival between the bu-mel and mel arms (P=0.97), but the follow-up is less than 2 years, so this is expected.

“Bu-mel was associated with a significantly lower day 90 CR rate, a significantly higher rate of grade 3-4 non-hematologic toxicity, no significant difference in transplant-related mortality . . . , and a significantly longer PFS,” Dr Qazilbash summarized.

He therefore concluded that, based on this study, day 90 CR is not an adequate endpoint for auto-HSCT trials. This trial was amended to change the primary

endpoint from day 90 CR to PFS, and accrual has been increased to 205 patients.

Dr Qazilbash and others involved in this study received research funding from Otsuka, makers of busulfan. Dr Qazilbash also reported relationships (advisory

board, honoraria) with Celgene, Millennium, and Onyx.

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

Diffuse large B-cell lymphoma

Researchers say they have developed a method that simulates Epstein-Barr virus (EBV) infection, and the immune cells that are activated as a result can kill non-Hodgkin lymphoma cells efficiently.

The team made use of antibodies that exhibit a piece of viral protein. The antibodies contain binding sites that target molecules on the surface of lymphoma cells.

The researchers used genetic engineering methods to fuse protein pieces of EBV to the “rear” end of the antibody protein.

As exposure to EBV is common, many people already have memory T cells that can mount a rapid immune response upon a new encounter with this pathogen.

The antibodies attach to the cancerous B cells and are subsequently engulfed into the cell interior. There, the antibody protein is degraded, and the individual fragments are presented by molecules on the surface of the cancer cells.

As a result, the viral protein is also exhibited on the cell surface, thus making it look like an EBV infection to the immune system.

The researchers found that T cells effectively killed the “infected” lymphoma cells in vitro. In blood cells from individuals who had been infected with EBV in the past, the antigen-armed antibodies successfully activated memory T cells.

“This is a clear indication that our antigen-armed antibodies can also induce an immune response against lymphoma cells in a living organism,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

To activate the immune system in as many people as possible, Dr Delecluse and his colleagues also inserted larger pieces of EBV proteins into their antibodies.

Depending on a person’s genetic makeup, the cells could then cut out various smaller protein segments and present them on their surface.

“A problem with antibody-based cancer therapies is that the tumor cells make the surface molecule targeted by the antibody disappear from their surface,” Dr Delecluse said. “To prevent this situation, we used a mixture of antibodies that target 4 different B-cell surface molecules.”

For more details, see the researchers’ article in Blood.

Diffuse large B-cell lymphoma

Researchers say they have developed a method that simulates Epstein-Barr virus (EBV) infection, and the immune cells that are activated as a result can kill non-Hodgkin lymphoma cells efficiently.

The team made use of antibodies that exhibit a piece of viral protein. The antibodies contain binding sites that target molecules on the surface of lymphoma cells.

The researchers used genetic engineering methods to fuse protein pieces of EBV to the “rear” end of the antibody protein.

As exposure to EBV is common, many people already have memory T cells that can mount a rapid immune response upon a new encounter with this pathogen.

The antibodies attach to the cancerous B cells and are subsequently engulfed into the cell interior. There, the antibody protein is degraded, and the individual fragments are presented by molecules on the surface of the cancer cells.

As a result, the viral protein is also exhibited on the cell surface, thus making it look like an EBV infection to the immune system.

The researchers found that T cells effectively killed the “infected” lymphoma cells in vitro. In blood cells from individuals who had been infected with EBV in the past, the antigen-armed antibodies successfully activated memory T cells.

“This is a clear indication that our antigen-armed antibodies can also induce an immune response against lymphoma cells in a living organism,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

To activate the immune system in as many people as possible, Dr Delecluse and his colleagues also inserted larger pieces of EBV proteins into their antibodies.

Depending on a person’s genetic makeup, the cells could then cut out various smaller protein segments and present them on their surface.

“A problem with antibody-based cancer therapies is that the tumor cells make the surface molecule targeted by the antibody disappear from their surface,” Dr Delecluse said. “To prevent this situation, we used a mixture of antibodies that target 4 different B-cell surface molecules.”

For more details, see the researchers’ article in Blood.

Diffuse large B-cell lymphoma

Researchers say they have developed a method that simulates Epstein-Barr virus (EBV) infection, and the immune cells that are activated as a result can kill non-Hodgkin lymphoma cells efficiently.

The team made use of antibodies that exhibit a piece of viral protein. The antibodies contain binding sites that target molecules on the surface of lymphoma cells.

The researchers used genetic engineering methods to fuse protein pieces of EBV to the “rear” end of the antibody protein.

As exposure to EBV is common, many people already have memory T cells that can mount a rapid immune response upon a new encounter with this pathogen.

The antibodies attach to the cancerous B cells and are subsequently engulfed into the cell interior. There, the antibody protein is degraded, and the individual fragments are presented by molecules on the surface of the cancer cells.

As a result, the viral protein is also exhibited on the cell surface, thus making it look like an EBV infection to the immune system.

The researchers found that T cells effectively killed the “infected” lymphoma cells in vitro. In blood cells from individuals who had been infected with EBV in the past, the antigen-armed antibodies successfully activated memory T cells.

“This is a clear indication that our antigen-armed antibodies can also induce an immune response against lymphoma cells in a living organism,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

To activate the immune system in as many people as possible, Dr Delecluse and his colleagues also inserted larger pieces of EBV proteins into their antibodies.

Depending on a person’s genetic makeup, the cells could then cut out various smaller protein segments and present them on their surface.

“A problem with antibody-based cancer therapies is that the tumor cells make the surface molecule targeted by the antibody disappear from their surface,” Dr Delecluse said. “To prevent this situation, we used a mixture of antibodies that target 4 different B-cell surface molecules.”

For more details, see the researchers’ article in Blood.

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Fitness class

Middle-aged women who are physically active a few times a week have a lower risk of vascular events than inactive women, according to research published in Circulation.

Women who engaged in physical activity 2 to 3 times per week were about 20% less likely to develop heart disease, stroke, or venous thromboembolism (VTE) than women who reported little or no activity.

However, more frequent activity was associated with an increased risk of vascular events.

“Inactive middle-aged women should try to do some activity regularly,” said study author Miranda Armstrong, PhD, of the University of Oxford in the UK.

“However, to prevent heart disease, stroke, and blood clots, women don’t need to do very frequent activity, as this seems to provide little additional benefit above that of moderately frequent activity.”

Dr Armstrong and her colleagues analyzed 1.1 million women in the UK with no history of cancer, heart disease, stroke, VTE, or diabetes who joined the Million Women Study from 1996 to 2001. Their average age at study entry was 56.

The women reported their level of physical activity—hours spent walking, cycling, gardening, and doing housework—at the beginning of the study and 3 years later. The researchers then examined hospital admissions and deaths in relation to participants’ responses.

During an average follow-up of 9 years, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first VTE.

Women who reportedly engaged in moderate physical activity had a significantly lower risk of each event compared to inactive women (P<0.001 for all).

On the other hand, the risk of cerebrovascular disease and VTE were significantly higher in women who engaged in physical activity daily, when compared to women who reported physical activity 2 to 3 times a week (P<0.001).

For coronary heart disease, women who reported daily activity had a significantly higher risk only if that activity was strenuous (P=0.002)—not for any physical activity (P=0.8).

Fitness class

Middle-aged women who are physically active a few times a week have a lower risk of vascular events than inactive women, according to research published in Circulation.

Women who engaged in physical activity 2 to 3 times per week were about 20% less likely to develop heart disease, stroke, or venous thromboembolism (VTE) than women who reported little or no activity.

However, more frequent activity was associated with an increased risk of vascular events.

“Inactive middle-aged women should try to do some activity regularly,” said study author Miranda Armstrong, PhD, of the University of Oxford in the UK.

“However, to prevent heart disease, stroke, and blood clots, women don’t need to do very frequent activity, as this seems to provide little additional benefit above that of moderately frequent activity.”

Dr Armstrong and her colleagues analyzed 1.1 million women in the UK with no history of cancer, heart disease, stroke, VTE, or diabetes who joined the Million Women Study from 1996 to 2001. Their average age at study entry was 56.

The women reported their level of physical activity—hours spent walking, cycling, gardening, and doing housework—at the beginning of the study and 3 years later. The researchers then examined hospital admissions and deaths in relation to participants’ responses.

During an average follow-up of 9 years, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first VTE.

Women who reportedly engaged in moderate physical activity had a significantly lower risk of each event compared to inactive women (P<0.001 for all).

On the other hand, the risk of cerebrovascular disease and VTE were significantly higher in women who engaged in physical activity daily, when compared to women who reported physical activity 2 to 3 times a week (P<0.001).

For coronary heart disease, women who reported daily activity had a significantly higher risk only if that activity was strenuous (P=0.002)—not for any physical activity (P=0.8).

Fitness class

Middle-aged women who are physically active a few times a week have a lower risk of vascular events than inactive women, according to research published in Circulation.

Women who engaged in physical activity 2 to 3 times per week were about 20% less likely to develop heart disease, stroke, or venous thromboembolism (VTE) than women who reported little or no activity.

However, more frequent activity was associated with an increased risk of vascular events.

“Inactive middle-aged women should try to do some activity regularly,” said study author Miranda Armstrong, PhD, of the University of Oxford in the UK.

“However, to prevent heart disease, stroke, and blood clots, women don’t need to do very frequent activity, as this seems to provide little additional benefit above that of moderately frequent activity.”

Dr Armstrong and her colleagues analyzed 1.1 million women in the UK with no history of cancer, heart disease, stroke, VTE, or diabetes who joined the Million Women Study from 1996 to 2001. Their average age at study entry was 56.

The women reported their level of physical activity—hours spent walking, cycling, gardening, and doing housework—at the beginning of the study and 3 years later. The researchers then examined hospital admissions and deaths in relation to participants’ responses.

During an average follow-up of 9 years, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first VTE.

Women who reportedly engaged in moderate physical activity had a significantly lower risk of each event compared to inactive women (P<0.001 for all).

On the other hand, the risk of cerebrovascular disease and VTE were significantly higher in women who engaged in physical activity daily, when compared to women who reported physical activity 2 to 3 times a week (P<0.001).

For coronary heart disease, women who reported daily activity had a significantly higher risk only if that activity was strenuous (P=0.002)—not for any physical activity (P=0.8).

Age is the most important risk factor for stroke in patients with atrial fibrillation, and not all stroke risk factors in the CHA2DS2-VASc score carry equal risk, a retrospective, population-based study showed.

Analysis of data from 186,570 Taiwanese patients with atrial fibrillation (AF) found that the risk of ischemic stroke ranged from 1.96% per year for men with vascular diseases to 3.5% per year for those aged 65-74 years. In women, the risk increased from 1.91% per year for women with hypertension to 3.34% per year for those aged 65-74 years, wrote Dr. Tze-Fan Chao of Taipei (Taiwan) Veterans General Hospital and coauthors (J. Am. Coll. Cardiol. 2015;65:635-42 [doi: 10.1016/j.jacc.2014.11.046]).

The study results showed that male AF patients with a CHA2DS2-VASc score of 1 had an annual stroke rate of 2.75%; women with a CHA2DS2-VASc score of 2 had a greater than two-fold increase in stroke risk, compared with women with a score of 1.

“Our study is the first population-based investigation analyzing the risk of ischemic stroke in nonanticoagulated AF male patients with a CHA2DS2-VASc score of 1 and female patients with a CHA2DS2-VASc score of 2, according to the specific covariates composing the CHA2DS2-VASc score,” Dr. Chao wrote.

The investigators cited several limitations. One is that they were unable to determine whether the cause of ischemic stroke was tied to AF-related thromboembolism or atherosclerosis and thrombosis of the cerebral artery. This limitation, however, was common among previous randomized trials, they noted.

The study was partly supported by grants from the National Science Council and Taipei (Taiwan) Veterans General Hospital. One author declared consultancies and speakers fees from private industry. No other conflicts of interest were declared.

Age is the most important risk factor for stroke in patients with atrial fibrillation, and not all stroke risk factors in the CHA2DS2-VASc score carry equal risk, a retrospective, population-based study showed.

Analysis of data from 186,570 Taiwanese patients with atrial fibrillation (AF) found that the risk of ischemic stroke ranged from 1.96% per year for men with vascular diseases to 3.5% per year for those aged 65-74 years. In women, the risk increased from 1.91% per year for women with hypertension to 3.34% per year for those aged 65-74 years, wrote Dr. Tze-Fan Chao of Taipei (Taiwan) Veterans General Hospital and coauthors (J. Am. Coll. Cardiol. 2015;65:635-42 [doi: 10.1016/j.jacc.2014.11.046]).

The study results showed that male AF patients with a CHA2DS2-VASc score of 1 had an annual stroke rate of 2.75%; women with a CHA2DS2-VASc score of 2 had a greater than two-fold increase in stroke risk, compared with women with a score of 1.

“Our study is the first population-based investigation analyzing the risk of ischemic stroke in nonanticoagulated AF male patients with a CHA2DS2-VASc score of 1 and female patients with a CHA2DS2-VASc score of 2, according to the specific covariates composing the CHA2DS2-VASc score,” Dr. Chao wrote.

The investigators cited several limitations. One is that they were unable to determine whether the cause of ischemic stroke was tied to AF-related thromboembolism or atherosclerosis and thrombosis of the cerebral artery. This limitation, however, was common among previous randomized trials, they noted.

The study was partly supported by grants from the National Science Council and Taipei (Taiwan) Veterans General Hospital. One author declared consultancies and speakers fees from private industry. No other conflicts of interest were declared.

Age is the most important risk factor for stroke in patients with atrial fibrillation, and not all stroke risk factors in the CHA2DS2-VASc score carry equal risk, a retrospective, population-based study showed.

Analysis of data from 186,570 Taiwanese patients with atrial fibrillation (AF) found that the risk of ischemic stroke ranged from 1.96% per year for men with vascular diseases to 3.5% per year for those aged 65-74 years. In women, the risk increased from 1.91% per year for women with hypertension to 3.34% per year for those aged 65-74 years, wrote Dr. Tze-Fan Chao of Taipei (Taiwan) Veterans General Hospital and coauthors (J. Am. Coll. Cardiol. 2015;65:635-42 [doi: 10.1016/j.jacc.2014.11.046]).

The study results showed that male AF patients with a CHA2DS2-VASc score of 1 had an annual stroke rate of 2.75%; women with a CHA2DS2-VASc score of 2 had a greater than two-fold increase in stroke risk, compared with women with a score of 1.

“Our study is the first population-based investigation analyzing the risk of ischemic stroke in nonanticoagulated AF male patients with a CHA2DS2-VASc score of 1 and female patients with a CHA2DS2-VASc score of 2, according to the specific covariates composing the CHA2DS2-VASc score,” Dr. Chao wrote.

The investigators cited several limitations. One is that they were unable to determine whether the cause of ischemic stroke was tied to AF-related thromboembolism or atherosclerosis and thrombosis of the cerebral artery. This limitation, however, was common among previous randomized trials, they noted.

The study was partly supported by grants from the National Science Council and Taipei (Taiwan) Veterans General Hospital. One author declared consultancies and speakers fees from private industry. No other conflicts of interest were declared.

Strenuous daily exercise actually increased the risk of coronary heart disease, venous thromboembolism, and cerebrovascular disease, compared with moderate physical activity, according to new data from the Million Women Study.

At baseline, the 1.1 million women who participated in the study were 55.9 years old on average, with a mean body mass index of 26 kg/m². Over the next 9 years, those reporting moderate activity had significantly lower risks of all three conditions than did inactive women, according to a study published online Feb. 16 in Circulation [doi:10.1161/CIRCULATIONAHA.114.010296].

©Monkey Business Images/thinkstockphotos.com

However, women who undertook daily strenuous activity had a 15% increase in their risk of coronary heart disease, a 25% increase in cerebrovascular disease risk, and a 29% increase in venous thromboembolism (VTE) risk, compared with those who exercised strenuously two to three times a week, judging from the findings of Cox regression models that controlled for BMI, smoking, and alcohol consumption.

“Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and even an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group,” wrote Dr. Miranda E. G. Armstrong of the University of Oxford, England, and colleagues.

The study was supported by the UK Medical Research Council, Cancer Research UK, and the BHF Centre of Research Excellence. There were no other conflicts of interest declared.

Strenuous daily exercise actually increased the risk of coronary heart disease, venous thromboembolism, and cerebrovascular disease, compared with moderate physical activity, according to new data from the Million Women Study.

At baseline, the 1.1 million women who participated in the study were 55.9 years old on average, with a mean body mass index of 26 kg/m². Over the next 9 years, those reporting moderate activity had significantly lower risks of all three conditions than did inactive women, according to a study published online Feb. 16 in Circulation [doi:10.1161/CIRCULATIONAHA.114.010296].

©Monkey Business Images/thinkstockphotos.com

However, women who undertook daily strenuous activity had a 15% increase in their risk of coronary heart disease, a 25% increase in cerebrovascular disease risk, and a 29% increase in venous thromboembolism (VTE) risk, compared with those who exercised strenuously two to three times a week, judging from the findings of Cox regression models that controlled for BMI, smoking, and alcohol consumption.

“Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and even an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group,” wrote Dr. Miranda E. G. Armstrong of the University of Oxford, England, and colleagues.

The study was supported by the UK Medical Research Council, Cancer Research UK, and the BHF Centre of Research Excellence. There were no other conflicts of interest declared.

Strenuous daily exercise actually increased the risk of coronary heart disease, venous thromboembolism, and cerebrovascular disease, compared with moderate physical activity, according to new data from the Million Women Study.

At baseline, the 1.1 million women who participated in the study were 55.9 years old on average, with a mean body mass index of 26 kg/m². Over the next 9 years, those reporting moderate activity had significantly lower risks of all three conditions than did inactive women, according to a study published online Feb. 16 in Circulation [doi:10.1161/CIRCULATIONAHA.114.010296].

©Monkey Business Images/thinkstockphotos.com

However, women who undertook daily strenuous activity had a 15% increase in their risk of coronary heart disease, a 25% increase in cerebrovascular disease risk, and a 29% increase in venous thromboembolism (VTE) risk, compared with those who exercised strenuously two to three times a week, judging from the findings of Cox regression models that controlled for BMI, smoking, and alcohol consumption.

“Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and even an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group,” wrote Dr. Miranda E. G. Armstrong of the University of Oxford, England, and colleagues.

The study was supported by the UK Medical Research Council, Cancer Research UK, and the BHF Centre of Research Excellence. There were no other conflicts of interest declared.

Hematopoietic stem cells

in the bone marrow

Scientists have reported a method for equipping mouse hematopoietic stem cells (HSCs) with a fluorescent marker that can be switched on from the outside.

Using this tool, they were able to observe how HSCs mature into blood cells under normal conditions, and they developed a mathematical model of the dynamics of hematopoiesis.

The research suggests the normal process of hematopoiesis differs from what scientists previously assumed when using data from stem cell transplants.

“[A] problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice,” said study author Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism.”

The researchers described this model in Nature.

The team genetically modified mice by introducing a protein into their HSCs that sends out a yellow fluorescent signal. This marker can be turned on by administering a reagent. All daughter cells that arise from a cell containing the marker also send out a light signal.

When they turned on the marker in adult mice, the researchers observed that at least a third of a mouse’s HSCs (approximately 5000 cells) produce differentiated progenitor cells.

“This was the first surprise,” said study author Katrin Busch, also of DKFZ. “Until now, scientists had believed that, in the normal state, very few stem cells—only about 10—are actively involved in blood formation.”

The researchers performed a mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. They were surprised to find that, under normal conditions, HSCs do not replenish blood cells.

Instead, blood cells are supplied by the first progenitor cells that develop during the differentiation step. These cells are able to regenerate themselves for a long time, though not quite as long as HSCs.

To ensure that the population of this cell type never runs out, HSCs must occasionally produce a couple of new first progenitors.

During murine embryonic development, however, the situation is different. To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from HSCs.

The researchers were also able to accelerate this process in adult mice by artificially depleting their white blood cells. Under these conditions, HSCs increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells.

During this process, several hundred times more myeloid cells (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells).

“When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost,” Dr Rodewald noted.

“Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism.”

The researchers now plan to use their model to investigate the impact of pathogenic challenges to blood formation; for example, in cancer, cachexia, or infection. This method would also allow them to follow potential aging processes in HSCs as they occur naturally in a living organism.

Hematopoietic stem cells

in the bone marrow

Scientists have reported a method for equipping mouse hematopoietic stem cells (HSCs) with a fluorescent marker that can be switched on from the outside.

Using this tool, they were able to observe how HSCs mature into blood cells under normal conditions, and they developed a mathematical model of the dynamics of hematopoiesis.

The research suggests the normal process of hematopoiesis differs from what scientists previously assumed when using data from stem cell transplants.

“[A] problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice,” said study author Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism.”

The researchers described this model in Nature.

The team genetically modified mice by introducing a protein into their HSCs that sends out a yellow fluorescent signal. This marker can be turned on by administering a reagent. All daughter cells that arise from a cell containing the marker also send out a light signal.

When they turned on the marker in adult mice, the researchers observed that at least a third of a mouse’s HSCs (approximately 5000 cells) produce differentiated progenitor cells.

“This was the first surprise,” said study author Katrin Busch, also of DKFZ. “Until now, scientists had believed that, in the normal state, very few stem cells—only about 10—are actively involved in blood formation.”

The researchers performed a mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. They were surprised to find that, under normal conditions, HSCs do not replenish blood cells.

Instead, blood cells are supplied by the first progenitor cells that develop during the differentiation step. These cells are able to regenerate themselves for a long time, though not quite as long as HSCs.

To ensure that the population of this cell type never runs out, HSCs must occasionally produce a couple of new first progenitors.

During murine embryonic development, however, the situation is different. To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from HSCs.

The researchers were also able to accelerate this process in adult mice by artificially depleting their white blood cells. Under these conditions, HSCs increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells.

During this process, several hundred times more myeloid cells (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells).

“When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost,” Dr Rodewald noted.

“Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism.”

The researchers now plan to use their model to investigate the impact of pathogenic challenges to blood formation; for example, in cancer, cachexia, or infection. This method would also allow them to follow potential aging processes in HSCs as they occur naturally in a living organism.

Hematopoietic stem cells

in the bone marrow

Scientists have reported a method for equipping mouse hematopoietic stem cells (HSCs) with a fluorescent marker that can be switched on from the outside.

Using this tool, they were able to observe how HSCs mature into blood cells under normal conditions, and they developed a mathematical model of the dynamics of hematopoiesis.

The research suggests the normal process of hematopoiesis differs from what scientists previously assumed when using data from stem cell transplants.

“[A] problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice,” said study author Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism.”

The researchers described this model in Nature.

The team genetically modified mice by introducing a protein into their HSCs that sends out a yellow fluorescent signal. This marker can be turned on by administering a reagent. All daughter cells that arise from a cell containing the marker also send out a light signal.

When they turned on the marker in adult mice, the researchers observed that at least a third of a mouse’s HSCs (approximately 5000 cells) produce differentiated progenitor cells.

“This was the first surprise,” said study author Katrin Busch, also of DKFZ. “Until now, scientists had believed that, in the normal state, very few stem cells—only about 10—are actively involved in blood formation.”

The researchers performed a mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. They were surprised to find that, under normal conditions, HSCs do not replenish blood cells.

Instead, blood cells are supplied by the first progenitor cells that develop during the differentiation step. These cells are able to regenerate themselves for a long time, though not quite as long as HSCs.

To ensure that the population of this cell type never runs out, HSCs must occasionally produce a couple of new first progenitors.

During murine embryonic development, however, the situation is different. To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from HSCs.

The researchers were also able to accelerate this process in adult mice by artificially depleting their white blood cells. Under these conditions, HSCs increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells.

During this process, several hundred times more myeloid cells (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells).

“When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost,” Dr Rodewald noted.

“Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism.”

The researchers now plan to use their model to investigate the impact of pathogenic challenges to blood formation; for example, in cancer, cachexia, or infection. This method would also allow them to follow potential aging processes in HSCs as they occur naturally in a living organism.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Micrograph showing MM

In a final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend pomalidomide (Imnovid) for the treatment of multiple myeloma (MM).

NICE recommends thalidomide for most MM patients as a first-line treatment and bortezomib for patients who are unable to receive thalidomide and those who fail first-line treatment.

For patients who have received 2 prior therapies, the agency recommends lenalidomide.

NICE considered pomalidomide for use in MM patients after their third or subsequent relapse.

The agency said it could not recommend pomalidomide, in combination with dexamethasone, within its marketing authorization, which is to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on their last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets pomalidomide, showed that the drug does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE’s final draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues its final guidance, National Health Service (NHS) bodies should make decisions locally on the funding of specific treatments.

This draft guidance does not mean that patients currently taking pomalidomide will stop receiving it. They have the option to continue treatment until they and their clinicians consider it appropriate to stop.

And pomalidomide is recommended for use within NHS Scotland.

Insufficient evidence

The committee advising NICE was not able to judge with any confidence how much more effective pomalidomide was compared with current treatment options based on the evidence provided by Celgene before and after consultation.

However, bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial, and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months, on average, when compared with standard NHS care.

Nevertheless, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years (QALYs) gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

Also, the committee concluded that the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on the QALYs gained.

All cost-per-QALY figures presented by Celgene were over £50,000 compared with bortezomib and over £70,000 compared with bendamustine plus thalidomide and dexamethasone. And the figures would further increase when a number of more realistic assumptions were included in the model, the committee said.

A pack of pomalidomide (21 tablets of 1 mg, 2 mg, 3 mg, or 4 mg) costs £8884. The recommended dosage of the drug is 4 mg once daily, taken on days 1 to 21 of repeated 28 day cycles. Treatment should continue until disease progression.

Micrograph showing MM

In a final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend pomalidomide (Imnovid) for the treatment of multiple myeloma (MM).

NICE recommends thalidomide for most MM patients as a first-line treatment and bortezomib for patients who are unable to receive thalidomide and those who fail first-line treatment.

For patients who have received 2 prior therapies, the agency recommends lenalidomide.

NICE considered pomalidomide for use in MM patients after their third or subsequent relapse.

The agency said it could not recommend pomalidomide, in combination with dexamethasone, within its marketing authorization, which is to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on their last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets pomalidomide, showed that the drug does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE’s final draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues its final guidance, National Health Service (NHS) bodies should make decisions locally on the funding of specific treatments.

This draft guidance does not mean that patients currently taking pomalidomide will stop receiving it. They have the option to continue treatment until they and their clinicians consider it appropriate to stop.

And pomalidomide is recommended for use within NHS Scotland.

Insufficient evidence

The committee advising NICE was not able to judge with any confidence how much more effective pomalidomide was compared with current treatment options based on the evidence provided by Celgene before and after consultation.

However, bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial, and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months, on average, when compared with standard NHS care.

Nevertheless, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years (QALYs) gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

Also, the committee concluded that the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on the QALYs gained.

All cost-per-QALY figures presented by Celgene were over £50,000 compared with bortezomib and over £70,000 compared with bendamustine plus thalidomide and dexamethasone. And the figures would further increase when a number of more realistic assumptions were included in the model, the committee said.

A pack of pomalidomide (21 tablets of 1 mg, 2 mg, 3 mg, or 4 mg) costs £8884. The recommended dosage of the drug is 4 mg once daily, taken on days 1 to 21 of repeated 28 day cycles. Treatment should continue until disease progression.

Micrograph showing MM

In a final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend pomalidomide (Imnovid) for the treatment of multiple myeloma (MM).

NICE recommends thalidomide for most MM patients as a first-line treatment and bortezomib for patients who are unable to receive thalidomide and those who fail first-line treatment.

For patients who have received 2 prior therapies, the agency recommends lenalidomide.

NICE considered pomalidomide for use in MM patients after their third or subsequent relapse.

The agency said it could not recommend pomalidomide, in combination with dexamethasone, within its marketing authorization, which is to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on their last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets pomalidomide, showed that the drug does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE’s final draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues its final guidance, National Health Service (NHS) bodies should make decisions locally on the funding of specific treatments.

This draft guidance does not mean that patients currently taking pomalidomide will stop receiving it. They have the option to continue treatment until they and their clinicians consider it appropriate to stop.

And pomalidomide is recommended for use within NHS Scotland.

Insufficient evidence

The committee advising NICE was not able to judge with any confidence how much more effective pomalidomide was compared with current treatment options based on the evidence provided by Celgene before and after consultation.

However, bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial, and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months, on average, when compared with standard NHS care.

Nevertheless, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years (QALYs) gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

Also, the committee concluded that the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on the QALYs gained.

All cost-per-QALY figures presented by Celgene were over £50,000 compared with bortezomib and over £70,000 compared with bendamustine plus thalidomide and dexamethasone. And the figures would further increase when a number of more realistic assumptions were included in the model, the committee said.

A pack of pomalidomide (21 tablets of 1 mg, 2 mg, 3 mg, or 4 mg) costs £8884. The recommended dosage of the drug is 4 mg once daily, taken on days 1 to 21 of repeated 28 day cycles. Treatment should continue until disease progression.

CT scan showing PE

Photo courtesy of Medical

College of Georgia

Pulmonary embolectomy, a procedure that was virtually abandoned in the 1950s because it resulted in high mortality rates, may actually prevent more deaths in severely ill patients with pulmonary embolism (PE) than current drug therapies alone, according to research published in the Texas Heart Institute Journal.

More than 2 dozen studies conducted between 1961 and 1984 suggest the death rate associated with pulmonary embolectomy is 32%.

But safer techniques have led to better outcomes, and surgeons continue to take their most seriously ill PE patients into the operating room.

Still, Alan R. Hartman, MD, of North Shore-LIJ Health System in Great Neck, New York, and his colleagues wanted to determine just how successful the surgery is and which patients are the best candidates for surgery.

To find out, the team went back into the surgical archives and identified 96 patients who underwent surgery during a 9-year period (from 2003 to 2011). The researchers assessed how many patients survived in the month following surgery and compared the results to historical mortality data from patients who did not undergo surgery.

All of the patients who had undergone surgery had acute, centrally located PE and severe global hyperkinetic right ventricular dysfunction.

All patients had either a large clot burden in the main pulmonary arteries or a saddle embolism. None of the patients had a history of chronic pulmonary thrombolytic disease or evidence of chronic disease on a computed-tomographic-angiography scan.

They all made it to surgery within an hour of the embolism. The surgery was performed through cardiopulmonary bypass, at normal body temperature, and without aortic cross-clamping, thus avoiding myocardial ischemia.

A pulmonary arteriotomy and clot extraction were performed under direct vision, according to Dr Hartman, which he believes is critical to the success of the procedure.

The mortality rate was 4.2%, which is lower than any other published reports. In addition, 68 patients (73.9%) were discharged home or to rehabilitation facilities.

Those patients with low blood pressure had a higher 30-day mortality rate—12.5% compared to 1.4% in those with normal blood pressure. Patients with low blood pressure also spent a longer time in the hospital—13.4 days compared to 9.1 days in patients with normal blood pressure.

Based on these results, the researchers concluded that acute pulmonary embolectomy can be a viable procedure for patients with severe, globally hypokinetic right ventricular dysfunction, with or without hemodynamic compromise.

However, they cautioned that rates of success are dependent upon experience, surgical ability, and careful patient selection.

CT scan showing PE

Photo courtesy of Medical

College of Georgia

Pulmonary embolectomy, a procedure that was virtually abandoned in the 1950s because it resulted in high mortality rates, may actually prevent more deaths in severely ill patients with pulmonary embolism (PE) than current drug therapies alone, according to research published in the Texas Heart Institute Journal.

More than 2 dozen studies conducted between 1961 and 1984 suggest the death rate associated with pulmonary embolectomy is 32%.

But safer techniques have led to better outcomes, and surgeons continue to take their most seriously ill PE patients into the operating room.

Still, Alan R. Hartman, MD, of North Shore-LIJ Health System in Great Neck, New York, and his colleagues wanted to determine just how successful the surgery is and which patients are the best candidates for surgery.

To find out, the team went back into the surgical archives and identified 96 patients who underwent surgery during a 9-year period (from 2003 to 2011). The researchers assessed how many patients survived in the month following surgery and compared the results to historical mortality data from patients who did not undergo surgery.

All of the patients who had undergone surgery had acute, centrally located PE and severe global hyperkinetic right ventricular dysfunction.

All patients had either a large clot burden in the main pulmonary arteries or a saddle embolism. None of the patients had a history of chronic pulmonary thrombolytic disease or evidence of chronic disease on a computed-tomographic-angiography scan.

They all made it to surgery within an hour of the embolism. The surgery was performed through cardiopulmonary bypass, at normal body temperature, and without aortic cross-clamping, thus avoiding myocardial ischemia.

A pulmonary arteriotomy and clot extraction were performed under direct vision, according to Dr Hartman, which he believes is critical to the success of the procedure.

The mortality rate was 4.2%, which is lower than any other published reports. In addition, 68 patients (73.9%) were discharged home or to rehabilitation facilities.

Those patients with low blood pressure had a higher 30-day mortality rate—12.5% compared to 1.4% in those with normal blood pressure. Patients with low blood pressure also spent a longer time in the hospital—13.4 days compared to 9.1 days in patients with normal blood pressure.

Based on these results, the researchers concluded that acute pulmonary embolectomy can be a viable procedure for patients with severe, globally hypokinetic right ventricular dysfunction, with or without hemodynamic compromise.

However, they cautioned that rates of success are dependent upon experience, surgical ability, and careful patient selection.

CT scan showing PE

Photo courtesy of Medical

College of Georgia

Pulmonary embolectomy, a procedure that was virtually abandoned in the 1950s because it resulted in high mortality rates, may actually prevent more deaths in severely ill patients with pulmonary embolism (PE) than current drug therapies alone, according to research published in the Texas Heart Institute Journal.

More than 2 dozen studies conducted between 1961 and 1984 suggest the death rate associated with pulmonary embolectomy is 32%.

But safer techniques have led to better outcomes, and surgeons continue to take their most seriously ill PE patients into the operating room.

Still, Alan R. Hartman, MD, of North Shore-LIJ Health System in Great Neck, New York, and his colleagues wanted to determine just how successful the surgery is and which patients are the best candidates for surgery.

To find out, the team went back into the surgical archives and identified 96 patients who underwent surgery during a 9-year period (from 2003 to 2011). The researchers assessed how many patients survived in the month following surgery and compared the results to historical mortality data from patients who did not undergo surgery.

All of the patients who had undergone surgery had acute, centrally located PE and severe global hyperkinetic right ventricular dysfunction.

All patients had either a large clot burden in the main pulmonary arteries or a saddle embolism. None of the patients had a history of chronic pulmonary thrombolytic disease or evidence of chronic disease on a computed-tomographic-angiography scan.

They all made it to surgery within an hour of the embolism. The surgery was performed through cardiopulmonary bypass, at normal body temperature, and without aortic cross-clamping, thus avoiding myocardial ischemia.

A pulmonary arteriotomy and clot extraction were performed under direct vision, according to Dr Hartman, which he believes is critical to the success of the procedure.

The mortality rate was 4.2%, which is lower than any other published reports. In addition, 68 patients (73.9%) were discharged home or to rehabilitation facilities.

Those patients with low blood pressure had a higher 30-day mortality rate—12.5% compared to 1.4% in those with normal blood pressure. Patients with low blood pressure also spent a longer time in the hospital—13.4 days compared to 9.1 days in patients with normal blood pressure.

Based on these results, the researchers concluded that acute pulmonary embolectomy can be a viable procedure for patients with severe, globally hypokinetic right ventricular dysfunction, with or without hemodynamic compromise.

However, they cautioned that rates of success are dependent upon experience, surgical ability, and careful patient selection.