More than 300 attendees heard Dr. Mickey Karram address urodynamics and cystoscopy at the annual Pelvic Anatomy and Gynecologic Surgery Symposium (PAGS) in Las Vegas, December 12-14, 2013. Here, a key topic from his presentation.

Dr. Karram is  Professor of OB/GYN and Urology, University of Cincinnati School of Medicine, and Director, Urogynecology, The Christ Hospital, Cincinnati, Ohio. He also is Course Director of the Pelvic Anatomy and Gynecologic Surgery Symposium (PAGS) and the Female Urology and Urogynecology Symposium (FUUS), both co-sponsored by OBG Management.

FUUS 2014: June 14-16, Aria, Las Vegas
Click here for more info.

More than 300 attendees heard Dr. Mickey Karram address urodynamics and cystoscopy at the annual Pelvic Anatomy and Gynecologic Surgery Symposium (PAGS) in Las Vegas, December 12-14, 2013. Here, a key topic from his presentation.

Dr. Karram is  Professor of OB/GYN and Urology, University of Cincinnati School of Medicine, and Director, Urogynecology, The Christ Hospital, Cincinnati, Ohio. He also is Course Director of the Pelvic Anatomy and Gynecologic Surgery Symposium (PAGS) and the Female Urology and Urogynecology Symposium (FUUS), both co-sponsored by OBG Management.

FUUS 2014: June 14-16, Aria, Las Vegas
Click here for more info.

More than 300 attendees heard Dr. Mickey Karram address urodynamics and cystoscopy at the annual Pelvic Anatomy and Gynecologic Surgery Symposium (PAGS) in Las Vegas, December 12-14, 2013. Here, a key topic from his presentation.

Dr. Karram is  Professor of OB/GYN and Urology, University of Cincinnati School of Medicine, and Director, Urogynecology, The Christ Hospital, Cincinnati, Ohio. He also is Course Director of the Pelvic Anatomy and Gynecologic Surgery Symposium (PAGS) and the Female Urology and Urogynecology Symposium (FUUS), both co-sponsored by OBG Management.

FUUS 2014: June 14-16, Aria, Las Vegas
Click here for more info.

Plasmodium parasite in a red

blood cell; Credit: St Jude

Children’s Research Hospital

A school-based, intermittent screening and treatment program for malaria did not confer any benefits for children living in an area of low-to-moderate malaria transmission.

The program, which was implemented at schools in Kenya, did not significantly reduce the incidence of malaria infection or the prevalence of anemia.

Katherine Halliday, of the London School of Hygiene & Tropical Medicine in the UK, and her colleagues reported these results in PLOS Medicine.

The study included 5233 children, ages 5 to 20, studying at 101 government schools located on the south coast of Kenya. Fifty-one of the schools were randomized to the intermittent screening and treatment program.

Over 24 months, children in these schools underwent screening for malaria parasites once each term (a total of 5 times). And those who tested positive for malaria parasitemia (whether symptomatic or asymptomatic) received 6 cycles of treatment with the anti-malarial drug artemether-lumefantrine.

Eighty-four percent of the children were screened at 4 or more rounds, and 66.8% were screened at all 5 rounds. By the fifth round, 20% of children had been lost due to death, withdrawal, or migration.

The percentage of children who were positive for malaria at each screening ranged from 14.8% to 19.2%, and there was no distinct trend over time. Overall, 99.1% of the positive results led to treatment, and 92.6% of these were recorded as receiving the fully supervised, 6-dose treatment regimen.

The investigators followed a majority of the children in each group for an additional 24 months after the intervention ended. And the team found that the intervention had no significant impact on the prevalence of Plasmodium falciparum infection at 12 months or 24 months.

At 12 months, the prevalence of P falciparum (adjusted for age, sex, and stratification effects) was 10.7% in the intervention group and 14.3% in the control group (P=0.131). At 24 months, the prevalence of P falciparum was 11.8% in the intervention group and 8.5% in the control group (P=0.124).

Similarly, there was no significant difference between the 2 groups with regard to anemia.

At 12 months, the prevalence of anemia was 38.5% among controls and 40.1% in the intervention group (P=0.621). At 24 months, the prevalence was 39.5% among controls and 41.5% in the intervention group (P=0.953).

The investigators also evaluated education-related outcomes at 9 months and 24 months of follow-up. They found no significant difference between the study groups with regard to classroom attention.

However, younger children in the intervention group did not score as well as controls in spelling or arithmetic tests.

The team said this may be a chance finding, or it may indicate that apprehension about the finger prick needed for the diagnostic test had a negative effect on the children’s performance during educational tests.

In closing, the investigators said there are a number of possible reasons why this screening and treatment intervention proved unsuccesful.

These include geographical heterogeneity in transmission, a rapid rate of reinfection following treatment, the variable reliability of the diagnostic tests used, and the relative contribution of malaria to the etiology of anemia in this setting.

In a related perspective article, Lorenz von Seidlein, MD, PhD, of the Menzies School of Health Research in Casuarina, Australia, discusses these possibilities in more detail, as well as the wider issues involved in failure of screening and treating as a malaria elimination strategy.

Plasmodium parasite in a red

blood cell; Credit: St Jude

Children’s Research Hospital

A school-based, intermittent screening and treatment program for malaria did not confer any benefits for children living in an area of low-to-moderate malaria transmission.

The program, which was implemented at schools in Kenya, did not significantly reduce the incidence of malaria infection or the prevalence of anemia.

Katherine Halliday, of the London School of Hygiene & Tropical Medicine in the UK, and her colleagues reported these results in PLOS Medicine.

The study included 5233 children, ages 5 to 20, studying at 101 government schools located on the south coast of Kenya. Fifty-one of the schools were randomized to the intermittent screening and treatment program.

Over 24 months, children in these schools underwent screening for malaria parasites once each term (a total of 5 times). And those who tested positive for malaria parasitemia (whether symptomatic or asymptomatic) received 6 cycles of treatment with the anti-malarial drug artemether-lumefantrine.

Eighty-four percent of the children were screened at 4 or more rounds, and 66.8% were screened at all 5 rounds. By the fifth round, 20% of children had been lost due to death, withdrawal, or migration.

The percentage of children who were positive for malaria at each screening ranged from 14.8% to 19.2%, and there was no distinct trend over time. Overall, 99.1% of the positive results led to treatment, and 92.6% of these were recorded as receiving the fully supervised, 6-dose treatment regimen.

The investigators followed a majority of the children in each group for an additional 24 months after the intervention ended. And the team found that the intervention had no significant impact on the prevalence of Plasmodium falciparum infection at 12 months or 24 months.

At 12 months, the prevalence of P falciparum (adjusted for age, sex, and stratification effects) was 10.7% in the intervention group and 14.3% in the control group (P=0.131). At 24 months, the prevalence of P falciparum was 11.8% in the intervention group and 8.5% in the control group (P=0.124).

Similarly, there was no significant difference between the 2 groups with regard to anemia.

At 12 months, the prevalence of anemia was 38.5% among controls and 40.1% in the intervention group (P=0.621). At 24 months, the prevalence was 39.5% among controls and 41.5% in the intervention group (P=0.953).

The investigators also evaluated education-related outcomes at 9 months and 24 months of follow-up. They found no significant difference between the study groups with regard to classroom attention.

However, younger children in the intervention group did not score as well as controls in spelling or arithmetic tests.

The team said this may be a chance finding, or it may indicate that apprehension about the finger prick needed for the diagnostic test had a negative effect on the children’s performance during educational tests.

In closing, the investigators said there are a number of possible reasons why this screening and treatment intervention proved unsuccesful.

These include geographical heterogeneity in transmission, a rapid rate of reinfection following treatment, the variable reliability of the diagnostic tests used, and the relative contribution of malaria to the etiology of anemia in this setting.

In a related perspective article, Lorenz von Seidlein, MD, PhD, of the Menzies School of Health Research in Casuarina, Australia, discusses these possibilities in more detail, as well as the wider issues involved in failure of screening and treating as a malaria elimination strategy.

Plasmodium parasite in a red

blood cell; Credit: St Jude

Children’s Research Hospital

A school-based, intermittent screening and treatment program for malaria did not confer any benefits for children living in an area of low-to-moderate malaria transmission.

The program, which was implemented at schools in Kenya, did not significantly reduce the incidence of malaria infection or the prevalence of anemia.

Katherine Halliday, of the London School of Hygiene & Tropical Medicine in the UK, and her colleagues reported these results in PLOS Medicine.

The study included 5233 children, ages 5 to 20, studying at 101 government schools located on the south coast of Kenya. Fifty-one of the schools were randomized to the intermittent screening and treatment program.

Over 24 months, children in these schools underwent screening for malaria parasites once each term (a total of 5 times). And those who tested positive for malaria parasitemia (whether symptomatic or asymptomatic) received 6 cycles of treatment with the anti-malarial drug artemether-lumefantrine.

Eighty-four percent of the children were screened at 4 or more rounds, and 66.8% were screened at all 5 rounds. By the fifth round, 20% of children had been lost due to death, withdrawal, or migration.

The percentage of children who were positive for malaria at each screening ranged from 14.8% to 19.2%, and there was no distinct trend over time. Overall, 99.1% of the positive results led to treatment, and 92.6% of these were recorded as receiving the fully supervised, 6-dose treatment regimen.

The investigators followed a majority of the children in each group for an additional 24 months after the intervention ended. And the team found that the intervention had no significant impact on the prevalence of Plasmodium falciparum infection at 12 months or 24 months.

At 12 months, the prevalence of P falciparum (adjusted for age, sex, and stratification effects) was 10.7% in the intervention group and 14.3% in the control group (P=0.131). At 24 months, the prevalence of P falciparum was 11.8% in the intervention group and 8.5% in the control group (P=0.124).

Similarly, there was no significant difference between the 2 groups with regard to anemia.

At 12 months, the prevalence of anemia was 38.5% among controls and 40.1% in the intervention group (P=0.621). At 24 months, the prevalence was 39.5% among controls and 41.5% in the intervention group (P=0.953).

The investigators also evaluated education-related outcomes at 9 months and 24 months of follow-up. They found no significant difference between the study groups with regard to classroom attention.

However, younger children in the intervention group did not score as well as controls in spelling or arithmetic tests.

The team said this may be a chance finding, or it may indicate that apprehension about the finger prick needed for the diagnostic test had a negative effect on the children’s performance during educational tests.

In closing, the investigators said there are a number of possible reasons why this screening and treatment intervention proved unsuccesful.

These include geographical heterogeneity in transmission, a rapid rate of reinfection following treatment, the variable reliability of the diagnostic tests used, and the relative contribution of malaria to the etiology of anemia in this setting.

In a related perspective article, Lorenz von Seidlein, MD, PhD, of the Menzies School of Health Research in Casuarina, Australia, discusses these possibilities in more detail, as well as the wider issues involved in failure of screening and treating as a malaria elimination strategy.

AML in the bone marrow

Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.

With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.

Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.

The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.

Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.

“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.

He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.

“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.

“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”

The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.

The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.

The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.

“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”

The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”

As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.

“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”

AML in the bone marrow

Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.

With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.

Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.

The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.

Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.

“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.

He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.

“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.

“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”

The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.

The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.

The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.

“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”

The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”

As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.

“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”

AML in the bone marrow

Studies have suggested that mutations in isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) are present in approximately 20% of all acute myeloid leukemias (AMLs), and this implies that mutant IDH proteins are attractive drug targets.

With this in mind, a group of scientists generated a transgenic mouse model of the most common IDH2 mutation in human AML.

Experiments conducted with this model revealed that mutant IDH2 contributes to leukemia initiation and is required for the maintenance of leukemic cells in a living organism.

The researchers said these findings, published in Cell Stem Cell, confirm a potent oncogenic role for IDH2 and support its relevance as a therapeutic target for AML.

Furthermore, the model can be used to evaluate the pharmacological efficacy of IDH2 inhibitors, either alone or in combination with other compounds.

“The real hope is that we would one day be able to treat IDH2-mutant leukemia patients with a drug that targets this genetic abnormality,” said senior study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center (BIDMC) in Boston.

He and his colleagues knew that IDH1 and IDH2 proteins are critical enzymes in the TCA cycle, which is centrally important to many biochemical pathways. Mutated forms of these proteins gain a novel ability to produce 2-hydroxyglutarate (2HG), a metabolite that has been shown to accumulate at high levels in cancer patients.

“Our goal was to generate an animal model of mutant IDH that was both inducible and reversible,” said Markus Reschke, PhD, also of BIDMC.

“This enabled us to address an important unanswered question: Does inhibition of mutant IDH proteins in active disease have an effect on tumor maintenance or progression in a living organism?”

The researchers studied 2 different models: a retroviral transduction model and a genetically engineered model in which IDH mice were crossed with mice harboring other leukemia-relevant mutations.

In the first model, the IDH mutation was combined with the oncogenes HoxA9 and Meis1a, 2 downstream targets of numerous pathways that are deregulated in AML.

The results showed evidence of differentiation within 2 weeks of genetic deinduction of mutant IDH. And 2 weeks later, 6 of 8 animals showed complete remission with elimination of any detectable leukemic cells.

The researchers said these results were both surprising and encouraging, demonstrating a situation in which IDH mutation occurs as an early event, and leukemic transformation occurs as a result of subsequent genetic hits.

“The retroviral model enabled us to observe that mutant IDH2 is essential for the maintenance of HoxA9/Meis1a-induced AML,” said Lev Kats, PhD, of BIDMC. “But this was still a surrogate model. This isn’t what happens in human patients, per se.”

The researchers therefore went on to develop a transgenic model that more closely recapitulates the genetics of human AML.

“By crossing the mutant IDH2 animals with other leukemia-relevant mutations, including mutations in the FMS-like tyrosine kinase 3 [FLT3], we observed that compound-mutant animals developed acute leukemias,” Dr Reschke said. “This exciting finding told us that mutant IDH2 contributes to leukemia initiation in vivo.”

As with the retroviral transduction model, genetic deinduction of mutant IDH2 in the context of a cooperating FLT3 mutation resulted in reduced proliferation and/or differentiation of leukemic cells, further demonstrating that mutant IDH2 expression is required for leukemia maintenance.

“This model has validated mutant IDH proteins as very strong candidates for continued development of targeted anticancer therapeutics,” Dr Pandolfi said. “The model will also be of paramount importance to study mechanisms of resistance to treatment that may occur.”

Lab mouse

A new analysis indicates that animal studies not funded by industry produce favorable results more often than animal studies that are industry-funded.

In other words, published reports of non-industry-sponsored studies were more likely to contain data suggesting a drug was effective.

However, reports of industry-funded studies were more likely to contain favorable conclusions, even though data were less favorable.

Investigators recounted these findings in PLOS Biology.

They analyzed 63 studies in which statins were tested in animal models. Forty-two of the studies had quantitative results and disclosed sponsorship.

Among these studies, industry-sponsored research was less likely to measure a benefit for the statins in slowing or preventing arterial disease. Favorable results were reported in 47% (9/19) of the industry-sponsored studies and 72% (18/25) of the studies not sponsored by industry.

“The interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials and overestimating efficacy in clinical trials,” said study author Lisa Bero, PhD, of the University of California, San Francisco.

“By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products. Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, Dr Bero and her colleagues also found that favorable conclusions were more likely in industry-sponsored studies, even when data were less favorable. Study authors drew favorable conclusions in 94.7% (18/19) of industry-sponsored studies and 75% (21/28) of studies not funded by industry.

Other key findings of this analysis were that methodological problems were common in both types of studies, and harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Dr Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

The investigators also noted that about half of the studies analyzed were randomized, and about half were blinded. Inclusion and exclusion criteria were often not included in the published reports, and many studies failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the studies in this analysis were conducted in rabbits and mice. To gauge atherosclerosis, targeted by statins, investigators quantified qualities such as the number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

Lab mouse

A new analysis indicates that animal studies not funded by industry produce favorable results more often than animal studies that are industry-funded.

In other words, published reports of non-industry-sponsored studies were more likely to contain data suggesting a drug was effective.

However, reports of industry-funded studies were more likely to contain favorable conclusions, even though data were less favorable.

Investigators recounted these findings in PLOS Biology.

They analyzed 63 studies in which statins were tested in animal models. Forty-two of the studies had quantitative results and disclosed sponsorship.

Among these studies, industry-sponsored research was less likely to measure a benefit for the statins in slowing or preventing arterial disease. Favorable results were reported in 47% (9/19) of the industry-sponsored studies and 72% (18/25) of the studies not sponsored by industry.

“The interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials and overestimating efficacy in clinical trials,” said study author Lisa Bero, PhD, of the University of California, San Francisco.

“By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products. Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, Dr Bero and her colleagues also found that favorable conclusions were more likely in industry-sponsored studies, even when data were less favorable. Study authors drew favorable conclusions in 94.7% (18/19) of industry-sponsored studies and 75% (21/28) of studies not funded by industry.

Other key findings of this analysis were that methodological problems were common in both types of studies, and harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Dr Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

The investigators also noted that about half of the studies analyzed were randomized, and about half were blinded. Inclusion and exclusion criteria were often not included in the published reports, and many studies failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the studies in this analysis were conducted in rabbits and mice. To gauge atherosclerosis, targeted by statins, investigators quantified qualities such as the number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

Lab mouse

A new analysis indicates that animal studies not funded by industry produce favorable results more often than animal studies that are industry-funded.

In other words, published reports of non-industry-sponsored studies were more likely to contain data suggesting a drug was effective.

However, reports of industry-funded studies were more likely to contain favorable conclusions, even though data were less favorable.

Investigators recounted these findings in PLOS Biology.

They analyzed 63 studies in which statins were tested in animal models. Forty-two of the studies had quantitative results and disclosed sponsorship.

Among these studies, industry-sponsored research was less likely to measure a benefit for the statins in slowing or preventing arterial disease. Favorable results were reported in 47% (9/19) of the industry-sponsored studies and 72% (18/25) of the studies not sponsored by industry.

“The interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials and overestimating efficacy in clinical trials,” said study author Lisa Bero, PhD, of the University of California, San Francisco.

“By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products. Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, Dr Bero and her colleagues also found that favorable conclusions were more likely in industry-sponsored studies, even when data were less favorable. Study authors drew favorable conclusions in 94.7% (18/19) of industry-sponsored studies and 75% (21/28) of studies not funded by industry.

Other key findings of this analysis were that methodological problems were common in both types of studies, and harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Dr Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

The investigators also noted that about half of the studies analyzed were randomized, and about half were blinded. Inclusion and exclusion criteria were often not included in the published reports, and many studies failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the studies in this analysis were conducted in rabbits and mice. To gauge atherosclerosis, targeted by statins, investigators quantified qualities such as the number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

Platelets, 3rd Edition

Edited by Alan Michelson, MD

The textbook marketplace is crowded with many titles pertinent to the topic of hemostasis and thrombosis, and the field is becoming increasingly complex, with the addition of new antiplatelet medications and novel, target-specific therapeutic agents.

It has become incumbent for hematologists and oncologist-hematologists who care for or consult on patients with any disease process involving platelets to understand the pathophysiology and rationale of treatment of these disorders.

This third edition of Platelets is again an aggregation of the most prominent physicians, physician-scientists, and basic researchers in platelet biology and clinical hemostasis.

Very much an encyclopedia of platelet biology, Platelets is an informative tome that will serve as a comprehensive resource for the busy clinician, the academic hematologist preparing for lectures on platelet physiology and hemostasis, the basic scientist preparing a research grant, the house officer trying to understand treatment algorithms, the blood banker who runs a busy transfusion service, and the clinical pathologist who supervises a coagulation laboratory.

The foreword chapter by Dr Barry Coller sets the tone for the book, with a thoughtful, interesting, and easily readable overview of the platelet in health and disease.

Over the next 63 chapters and more than 1300 pages, the platelet is examined as an active organ that expresses mRNAs from one-quarter to one-third of the human genome; contains a highly adaptive proteome responsive to external signals of both healthy and pathological processes; and can then participate directly and indirectly as modulators of hemostasis, inflammation, immunology, atherogenesis, angiogenesis, carcinogenesis, etc.

The chapters on laboratory measurements of platelet function and interpretation thereof are very useful and provide practical information for the clinician and clinical laboratorian. The review of the new antiplatelet aggregating agents succinctly and comprehensively describes their pharmacology and their appropriate placement in therapeutic algorithms of many disease processes.

Similarly, the chapters on thrombopoietin and autoimmune thrombocytopenia provide critical insight on the appropriate use of and the potential complications associated with use of the new thrombopoietic agonists.

Finally, the chapters that concentrate on the blood banking aspects of platelet therapy and platelet disorders are particularly well-written and understandable. The chapters on the pathogenesis, diagnosis, and treatment of neonatal alloimmune thrombocytopenia and post-transfusion purpura are very helpful, and I found myself consulting them in my clinical practice, even as I was preparing this review on Platelets.

In summary, Platelets fills an important niche on the bookshelf of any academic hematologist. The user- friendly online access to the figures contained in the textbook will be especially useful for teaching purposes. Notwithstanding its considerable size and weight, this encyclopedia of the platelet contains critical information for physicians, educators, students, and research scientists.

Craig M. Kessler, MD, MACP

Lombardi Comprehensive Cancer Center

Georgetown University School of Medicine, Washington, DC

Platelets, 3rd Edition

Edited by Alan Michelson, MD

The textbook marketplace is crowded with many titles pertinent to the topic of hemostasis and thrombosis, and the field is becoming increasingly complex, with the addition of new antiplatelet medications and novel, target-specific therapeutic agents.

It has become incumbent for hematologists and oncologist-hematologists who care for or consult on patients with any disease process involving platelets to understand the pathophysiology and rationale of treatment of these disorders.

This third edition of Platelets is again an aggregation of the most prominent physicians, physician-scientists, and basic researchers in platelet biology and clinical hemostasis.

Very much an encyclopedia of platelet biology, Platelets is an informative tome that will serve as a comprehensive resource for the busy clinician, the academic hematologist preparing for lectures on platelet physiology and hemostasis, the basic scientist preparing a research grant, the house officer trying to understand treatment algorithms, the blood banker who runs a busy transfusion service, and the clinical pathologist who supervises a coagulation laboratory.

The foreword chapter by Dr Barry Coller sets the tone for the book, with a thoughtful, interesting, and easily readable overview of the platelet in health and disease.

Over the next 63 chapters and more than 1300 pages, the platelet is examined as an active organ that expresses mRNAs from one-quarter to one-third of the human genome; contains a highly adaptive proteome responsive to external signals of both healthy and pathological processes; and can then participate directly and indirectly as modulators of hemostasis, inflammation, immunology, atherogenesis, angiogenesis, carcinogenesis, etc.

The chapters on laboratory measurements of platelet function and interpretation thereof are very useful and provide practical information for the clinician and clinical laboratorian. The review of the new antiplatelet aggregating agents succinctly and comprehensively describes their pharmacology and their appropriate placement in therapeutic algorithms of many disease processes.

Similarly, the chapters on thrombopoietin and autoimmune thrombocytopenia provide critical insight on the appropriate use of and the potential complications associated with use of the new thrombopoietic agonists.

Finally, the chapters that concentrate on the blood banking aspects of platelet therapy and platelet disorders are particularly well-written and understandable. The chapters on the pathogenesis, diagnosis, and treatment of neonatal alloimmune thrombocytopenia and post-transfusion purpura are very helpful, and I found myself consulting them in my clinical practice, even as I was preparing this review on Platelets.

In summary, Platelets fills an important niche on the bookshelf of any academic hematologist. The user- friendly online access to the figures contained in the textbook will be especially useful for teaching purposes. Notwithstanding its considerable size and weight, this encyclopedia of the platelet contains critical information for physicians, educators, students, and research scientists.

Craig M. Kessler, MD, MACP

Lombardi Comprehensive Cancer Center

Georgetown University School of Medicine, Washington, DC

Platelets, 3rd Edition

Edited by Alan Michelson, MD

The textbook marketplace is crowded with many titles pertinent to the topic of hemostasis and thrombosis, and the field is becoming increasingly complex, with the addition of new antiplatelet medications and novel, target-specific therapeutic agents.

It has become incumbent for hematologists and oncologist-hematologists who care for or consult on patients with any disease process involving platelets to understand the pathophysiology and rationale of treatment of these disorders.

This third edition of Platelets is again an aggregation of the most prominent physicians, physician-scientists, and basic researchers in platelet biology and clinical hemostasis.

Very much an encyclopedia of platelet biology, Platelets is an informative tome that will serve as a comprehensive resource for the busy clinician, the academic hematologist preparing for lectures on platelet physiology and hemostasis, the basic scientist preparing a research grant, the house officer trying to understand treatment algorithms, the blood banker who runs a busy transfusion service, and the clinical pathologist who supervises a coagulation laboratory.

The foreword chapter by Dr Barry Coller sets the tone for the book, with a thoughtful, interesting, and easily readable overview of the platelet in health and disease.

Over the next 63 chapters and more than 1300 pages, the platelet is examined as an active organ that expresses mRNAs from one-quarter to one-third of the human genome; contains a highly adaptive proteome responsive to external signals of both healthy and pathological processes; and can then participate directly and indirectly as modulators of hemostasis, inflammation, immunology, atherogenesis, angiogenesis, carcinogenesis, etc.

The chapters on laboratory measurements of platelet function and interpretation thereof are very useful and provide practical information for the clinician and clinical laboratorian. The review of the new antiplatelet aggregating agents succinctly and comprehensively describes their pharmacology and their appropriate placement in therapeutic algorithms of many disease processes.

Similarly, the chapters on thrombopoietin and autoimmune thrombocytopenia provide critical insight on the appropriate use of and the potential complications associated with use of the new thrombopoietic agonists.

Finally, the chapters that concentrate on the blood banking aspects of platelet therapy and platelet disorders are particularly well-written and understandable. The chapters on the pathogenesis, diagnosis, and treatment of neonatal alloimmune thrombocytopenia and post-transfusion purpura are very helpful, and I found myself consulting them in my clinical practice, even as I was preparing this review on Platelets.

In summary, Platelets fills an important niche on the bookshelf of any academic hematologist. The user- friendly online access to the figures contained in the textbook will be especially useful for teaching purposes. Notwithstanding its considerable size and weight, this encyclopedia of the platelet contains critical information for physicians, educators, students, and research scientists.

Craig M. Kessler, MD, MACP

Lombardi Comprehensive Cancer Center

Georgetown University School of Medicine, Washington, DC

Vasovagal syncope, or something far worse?

A 48-YEAR-OLD WOMAN with a history of syncopal events was brought to the emergency department (ED) by her daughter, following an episode in which the mother lost consciousness and vomited while driving. (The daughter was able to get the car safely to the shoulder of the road.) The episode occurred after the woman had eaten, and followed a week in which she’d experienced several episodes in which her left arm and chin briefly went numb. In fact, she experienced another chin/arm numbing episode while in the ED. The ED physician gave her a diagnosis of vasovagal syncope, instructed her to follow up with her primary care physician, and included “rule out transient ischemic attack (TIA)” on the discharge note.

The primary care physician subsequently established a differential diagnosis of “vasovagal vs hypoglycemia vs both or neurocardiogenic syncope” and referred the patient to an electrophysiologist, who concluded that she’d had a vasovagal syncope episode triggered by a gastrointestinal cause.

The patient continued to have arm/chin numbness but was unconcerned because her physicians didn’t seem worried. Months later, she sought treatment for low back pain, for which her primary care physician prescribed celecoxib; her numbness was not discussed with her physician. The next day, she suffered a stroke from an occluded right carotid artery. She had hemiparesis with little to no movement of her left shoulder, elbow, hand, hip, and ankle.

PLAINTIFF’S CLAIM The numbness and fainting were TIAs and an ultrasound should have been performed, which would have revealed the carotid artery occlusion and helped avoid the stroke.

THE DEFENSE The events the plaintiff experienced were not TIAs and there was no way to show whether, or to what degree, the carotid artery was occluded before the stroke. The plaintiff should have reported the continuing symptoms. Given that the patient had a long history of syncopal events—and a history of smoking—the diagnosis was reasonable.

VERDICT $1.6 million Wisconsin verdict.

COMMENT I think the lesson here is that physicians need to take focal neurological findings seriously and continue the evaluation until one has a reasonably certain diagnosis. The cause of this patient’s recurrent arm and chin numbness should have been pursued.

Failure to take full sexual history has devastating consequences

A MAN WITH A HISTORY OF ABNORMAL BLOOD TEST RESULTS sought treatment in the emergency department for extreme leg pain. He was given a diagnosis of sepsis and renal failure. A positive human immunodeficiency virus (HIV) test led to a diagnosis of acquired immunodeficiency syndrome (AIDS). The patient had been seeing his primary care physician for 10 years, but the doctor never asked about his sexual history. The patient survived, but suffers from AIDS-related kidney disease and must undergo peritoneal dialysis for the rest of his life.

PLAINTIFF’S CLAIM The physician should have tested for HIV much sooner to prevent the loss of kidney function. The physician’s questions were not specific enough to obtain proper information on whether the patient was having unprotected sex, if he had multiple partners, and what gender his partners were.

THE DEFENSE No information about the defense is available.

VERDICT $5.2 million Illinois verdict.

COMMENT I’m not sure the jury got this one right. Nonetheless, the Centers for Disease Control and Prevention now recommends HIV screening for all adults so it is worthwhile to offer it to all patients and to document refusal if a patient doesn’t want to be tested.

Vasovagal syncope, or something far worse?

A 48-YEAR-OLD WOMAN with a history of syncopal events was brought to the emergency department (ED) by her daughter, following an episode in which the mother lost consciousness and vomited while driving. (The daughter was able to get the car safely to the shoulder of the road.) The episode occurred after the woman had eaten, and followed a week in which she’d experienced several episodes in which her left arm and chin briefly went numb. In fact, she experienced another chin/arm numbing episode while in the ED. The ED physician gave her a diagnosis of vasovagal syncope, instructed her to follow up with her primary care physician, and included “rule out transient ischemic attack (TIA)” on the discharge note.

The primary care physician subsequently established a differential diagnosis of “vasovagal vs hypoglycemia vs both or neurocardiogenic syncope” and referred the patient to an electrophysiologist, who concluded that she’d had a vasovagal syncope episode triggered by a gastrointestinal cause.

The patient continued to have arm/chin numbness but was unconcerned because her physicians didn’t seem worried. Months later, she sought treatment for low back pain, for which her primary care physician prescribed celecoxib; her numbness was not discussed with her physician. The next day, she suffered a stroke from an occluded right carotid artery. She had hemiparesis with little to no movement of her left shoulder, elbow, hand, hip, and ankle.

PLAINTIFF’S CLAIM The numbness and fainting were TIAs and an ultrasound should have been performed, which would have revealed the carotid artery occlusion and helped avoid the stroke.

THE DEFENSE The events the plaintiff experienced were not TIAs and there was no way to show whether, or to what degree, the carotid artery was occluded before the stroke. The plaintiff should have reported the continuing symptoms. Given that the patient had a long history of syncopal events—and a history of smoking—the diagnosis was reasonable.

VERDICT $1.6 million Wisconsin verdict.

COMMENT I think the lesson here is that physicians need to take focal neurological findings seriously and continue the evaluation until one has a reasonably certain diagnosis. The cause of this patient’s recurrent arm and chin numbness should have been pursued.

Failure to take full sexual history has devastating consequences

A MAN WITH A HISTORY OF ABNORMAL BLOOD TEST RESULTS sought treatment in the emergency department for extreme leg pain. He was given a diagnosis of sepsis and renal failure. A positive human immunodeficiency virus (HIV) test led to a diagnosis of acquired immunodeficiency syndrome (AIDS). The patient had been seeing his primary care physician for 10 years, but the doctor never asked about his sexual history. The patient survived, but suffers from AIDS-related kidney disease and must undergo peritoneal dialysis for the rest of his life.

PLAINTIFF’S CLAIM The physician should have tested for HIV much sooner to prevent the loss of kidney function. The physician’s questions were not specific enough to obtain proper information on whether the patient was having unprotected sex, if he had multiple partners, and what gender his partners were.

THE DEFENSE No information about the defense is available.

VERDICT $5.2 million Illinois verdict.

COMMENT I’m not sure the jury got this one right. Nonetheless, the Centers for Disease Control and Prevention now recommends HIV screening for all adults so it is worthwhile to offer it to all patients and to document refusal if a patient doesn’t want to be tested.

Vasovagal syncope, or something far worse?

A 48-YEAR-OLD WOMAN with a history of syncopal events was brought to the emergency department (ED) by her daughter, following an episode in which the mother lost consciousness and vomited while driving. (The daughter was able to get the car safely to the shoulder of the road.) The episode occurred after the woman had eaten, and followed a week in which she’d experienced several episodes in which her left arm and chin briefly went numb. In fact, she experienced another chin/arm numbing episode while in the ED. The ED physician gave her a diagnosis of vasovagal syncope, instructed her to follow up with her primary care physician, and included “rule out transient ischemic attack (TIA)” on the discharge note.

The primary care physician subsequently established a differential diagnosis of “vasovagal vs hypoglycemia vs both or neurocardiogenic syncope” and referred the patient to an electrophysiologist, who concluded that she’d had a vasovagal syncope episode triggered by a gastrointestinal cause.

The patient continued to have arm/chin numbness but was unconcerned because her physicians didn’t seem worried. Months later, she sought treatment for low back pain, for which her primary care physician prescribed celecoxib; her numbness was not discussed with her physician. The next day, she suffered a stroke from an occluded right carotid artery. She had hemiparesis with little to no movement of her left shoulder, elbow, hand, hip, and ankle.

PLAINTIFF’S CLAIM The numbness and fainting were TIAs and an ultrasound should have been performed, which would have revealed the carotid artery occlusion and helped avoid the stroke.

THE DEFENSE The events the plaintiff experienced were not TIAs and there was no way to show whether, or to what degree, the carotid artery was occluded before the stroke. The plaintiff should have reported the continuing symptoms. Given that the patient had a long history of syncopal events—and a history of smoking—the diagnosis was reasonable.

VERDICT $1.6 million Wisconsin verdict.

COMMENT I think the lesson here is that physicians need to take focal neurological findings seriously and continue the evaluation until one has a reasonably certain diagnosis. The cause of this patient’s recurrent arm and chin numbness should have been pursued.

Failure to take full sexual history has devastating consequences

A MAN WITH A HISTORY OF ABNORMAL BLOOD TEST RESULTS sought treatment in the emergency department for extreme leg pain. He was given a diagnosis of sepsis and renal failure. A positive human immunodeficiency virus (HIV) test led to a diagnosis of acquired immunodeficiency syndrome (AIDS). The patient had been seeing his primary care physician for 10 years, but the doctor never asked about his sexual history. The patient survived, but suffers from AIDS-related kidney disease and must undergo peritoneal dialysis for the rest of his life.

PLAINTIFF’S CLAIM The physician should have tested for HIV much sooner to prevent the loss of kidney function. The physician’s questions were not specific enough to obtain proper information on whether the patient was having unprotected sex, if he had multiple partners, and what gender his partners were.

THE DEFENSE No information about the defense is available.

VERDICT $5.2 million Illinois verdict.

COMMENT I’m not sure the jury got this one right. Nonetheless, the Centers for Disease Control and Prevention now recommends HIV screening for all adults so it is worthwhile to offer it to all patients and to document refusal if a patient doesn’t want to be tested.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

Man jumping rope

Credit: Jason E. Miller

Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.

In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.

This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.

The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.

In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.

In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.

Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)

This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.

When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.

The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.

Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.

The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.

Man jumping rope

Credit: Jason E. Miller

Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.

In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.

This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.

The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.

In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.

In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.

Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)

This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.

When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.

The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.

Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.

The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.

Man jumping rope

Credit: Jason E. Miller

Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.

In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.

This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.

The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.

In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.

In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.

Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)

This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.

When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.

The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.

Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.

The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.

The machine used to perform

the WB-DWI scans

Photo courtesy of the

Institute of Cancer Research

A novel imaging technique could improve care for patients with multiple myeloma (MM) and reduce physicians’ reliance on bone marrow biopsies, according to researchers.

The group found that whole-body, diffusion-weighted imaging (WB-DWI) scans accurately showed the spread of MM throughout patients’ bone marrow.

And, most of the time, doctors were able to accurately determine which patients were responding to treatment by consulting the scans.

The investigators reported these results in Radiology.

They first performed WB-DWI on 8 healthy volunteers and 7 patients with MM, to assess the repeatability of quantitative apparent diffusion coefficient (ADC) estimates. ADC records how restricted water movement is within tissues.

The researchers found that ADC measurement was highly repeatable. The mean coefficient of variation was 3.8% in healthy volunteers and 2.8% in MM patients.

The team also performed pre-treatment WB-DWI scans on an additional 34 MM patients. Twenty-six of these patients had a post-treatment scan as well.

Physicians trained in imaging could pinpoint the exact sites of MM with WB-DWI, as the scans could show MM in nearly all bones. The skull remained difficult to image, however, partly because of the frequency of metal dental implants and fillings.

“This is the first time we’ve been able to obtain information from all the bones in the entire body for myeloma in 1 scan without having to rely on individual bone X-rays,” said study author Nandita deSouza, MD, of The Royal Marsden NHS Foundation Trust in the UK. “It enables us to measure the involvement of individual bones and follow their response to treatment.”

In 86% of cases, doctors were able to correctly identify whether patients responded to treatment. The physicians identified non-responders 80% of the time.

The investigators also assessed the visible changes on these scans using ADC. Changes in ADC correctly identified treatment response for 24 of 25 MM patients.

The mean ADC increased in 95% of responding patients and decreased in all non-responders (P=0.002). A 3.3% increase in ADC allowed the researchers to identify responding patients with 90% sensitivity and 100% specificity. An 8% increase in ADC yielded 70% sensitivity and 100% specificity.

The investigators said WB-DWI was suitable for more patients than conventional tests. For example, 7 patients had bone marrow biopsies, but their samples were inadequate for analysis.

“The scan is better than blood tests, which don’t tell us in which bones the cancer is located,” Dr deSouza said. “It also reduces the need for uncomfortable biopsies, which don’t reveal the extent or severity of the disease.”

The researchers did note that this study was conducted in a small number of patients. So the team plans to test the technology in more patients and refine the technique.

The machine used to perform

the WB-DWI scans

Photo courtesy of the

Institute of Cancer Research

A novel imaging technique could improve care for patients with multiple myeloma (MM) and reduce physicians’ reliance on bone marrow biopsies, according to researchers.

The group found that whole-body, diffusion-weighted imaging (WB-DWI) scans accurately showed the spread of MM throughout patients’ bone marrow.

And, most of the time, doctors were able to accurately determine which patients were responding to treatment by consulting the scans.

The investigators reported these results in Radiology.

They first performed WB-DWI on 8 healthy volunteers and 7 patients with MM, to assess the repeatability of quantitative apparent diffusion coefficient (ADC) estimates. ADC records how restricted water movement is within tissues.

The researchers found that ADC measurement was highly repeatable. The mean coefficient of variation was 3.8% in healthy volunteers and 2.8% in MM patients.

The team also performed pre-treatment WB-DWI scans on an additional 34 MM patients. Twenty-six of these patients had a post-treatment scan as well.

Physicians trained in imaging could pinpoint the exact sites of MM with WB-DWI, as the scans could show MM in nearly all bones. The skull remained difficult to image, however, partly because of the frequency of metal dental implants and fillings.

“This is the first time we’ve been able to obtain information from all the bones in the entire body for myeloma in 1 scan without having to rely on individual bone X-rays,” said study author Nandita deSouza, MD, of The Royal Marsden NHS Foundation Trust in the UK. “It enables us to measure the involvement of individual bones and follow their response to treatment.”

In 86% of cases, doctors were able to correctly identify whether patients responded to treatment. The physicians identified non-responders 80% of the time.

The investigators also assessed the visible changes on these scans using ADC. Changes in ADC correctly identified treatment response for 24 of 25 MM patients.

The mean ADC increased in 95% of responding patients and decreased in all non-responders (P=0.002). A 3.3% increase in ADC allowed the researchers to identify responding patients with 90% sensitivity and 100% specificity. An 8% increase in ADC yielded 70% sensitivity and 100% specificity.

The investigators said WB-DWI was suitable for more patients than conventional tests. For example, 7 patients had bone marrow biopsies, but their samples were inadequate for analysis.

“The scan is better than blood tests, which don’t tell us in which bones the cancer is located,” Dr deSouza said. “It also reduces the need for uncomfortable biopsies, which don’t reveal the extent or severity of the disease.”

The researchers did note that this study was conducted in a small number of patients. So the team plans to test the technology in more patients and refine the technique.

The machine used to perform

the WB-DWI scans

Photo courtesy of the

Institute of Cancer Research

A novel imaging technique could improve care for patients with multiple myeloma (MM) and reduce physicians’ reliance on bone marrow biopsies, according to researchers.

The group found that whole-body, diffusion-weighted imaging (WB-DWI) scans accurately showed the spread of MM throughout patients’ bone marrow.

And, most of the time, doctors were able to accurately determine which patients were responding to treatment by consulting the scans.

The investigators reported these results in Radiology.

They first performed WB-DWI on 8 healthy volunteers and 7 patients with MM, to assess the repeatability of quantitative apparent diffusion coefficient (ADC) estimates. ADC records how restricted water movement is within tissues.

The researchers found that ADC measurement was highly repeatable. The mean coefficient of variation was 3.8% in healthy volunteers and 2.8% in MM patients.

The team also performed pre-treatment WB-DWI scans on an additional 34 MM patients. Twenty-six of these patients had a post-treatment scan as well.

Physicians trained in imaging could pinpoint the exact sites of MM with WB-DWI, as the scans could show MM in nearly all bones. The skull remained difficult to image, however, partly because of the frequency of metal dental implants and fillings.

“This is the first time we’ve been able to obtain information from all the bones in the entire body for myeloma in 1 scan without having to rely on individual bone X-rays,” said study author Nandita deSouza, MD, of The Royal Marsden NHS Foundation Trust in the UK. “It enables us to measure the involvement of individual bones and follow their response to treatment.”

In 86% of cases, doctors were able to correctly identify whether patients responded to treatment. The physicians identified non-responders 80% of the time.

The investigators also assessed the visible changes on these scans using ADC. Changes in ADC correctly identified treatment response for 24 of 25 MM patients.

The mean ADC increased in 95% of responding patients and decreased in all non-responders (P=0.002). A 3.3% increase in ADC allowed the researchers to identify responding patients with 90% sensitivity and 100% specificity. An 8% increase in ADC yielded 70% sensitivity and 100% specificity.

The investigators said WB-DWI was suitable for more patients than conventional tests. For example, 7 patients had bone marrow biopsies, but their samples were inadequate for analysis.

“The scan is better than blood tests, which don’t tell us in which bones the cancer is located,” Dr deSouza said. “It also reduces the need for uncomfortable biopsies, which don’t reveal the extent or severity of the disease.”

The researchers did note that this study was conducted in a small number of patients. So the team plans to test the technology in more patients and refine the technique.