Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.

Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.

The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).

Safety concerns prompt action

Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.

Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.

The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.

Now, ponatinib is indicated for the treatment of:

• Adults with T315I-positive CML (chronic, accelerated, or blast phase)
• Adults with T315I-positive Ph+ ALL
• Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
• Adults with Ph+ ALL who cannot receive another TKI.

The starting dose of ponatinib remains 45 mg daily.

IND program

On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.

The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.

Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.

Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.

Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.

Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.

The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).

Safety concerns prompt action

Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.

Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.

The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.

Now, ponatinib is indicated for the treatment of:

• Adults with T315I-positive CML (chronic, accelerated, or blast phase)
• Adults with T315I-positive Ph+ ALL
• Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
• Adults with Ph+ ALL who cannot receive another TKI.

The starting dose of ponatinib remains 45 mg daily.

IND program

On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.

The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.

Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.

Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.

Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.

Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.

The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).

Safety concerns prompt action

Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.

Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.

The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.

Now, ponatinib is indicated for the treatment of:

• Adults with T315I-positive CML (chronic, accelerated, or blast phase)
• Adults with T315I-positive Ph+ ALL
• Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
• Adults with Ph+ ALL who cannot receive another TKI.

The starting dose of ponatinib remains 45 mg daily.

IND program

On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.

The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.

Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.

Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.

Inside a coronary artery

Credit: Mass. General Hospital

A US Food and Drug Administration (FDA) advisory committee has voted against expanding the indication for the anticoagulant rivaroxaban (Xarelto).

The drug’s developers are seeking approval for rivaroxaban to be used in combination with standard antiplatelet therapy to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The proposed dose is 2.5 mg twice daily for 90 days.

But the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted—nearly unanimously (with 1 abstention)—against this approval.

And the FDA will take this recommendation into account when deciding whether or not to expand rivaroxaban’s indication. This will be the FDA’s third time reviewing the drug for the aforementioned indication.

Rivaroxaban is currently FDA-approved to reduce the risk of stroke and thrombosis in patients with non-valvular atrial fibrillation, treat patients with venous thromboembolism (VTE), reduce the risk of recurrent VTE, and reduce the risk of VTE in patients who have undergone knee replacement surgery or hip replacement surgery.

Headed for a third rejection?

The advisory committee’s recommendation was based on a review of data from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in January 2012.

The study showed that rivaroxaban, given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients. But it also increased the risk of major bleeding and intracranial hemorrhage.

Based on these results, rivaroxaban’s developers—Janssen Research & Development, LLC, and Bayer HealthCare—filed for FDA approval of rivaroxaban to treat patients with ACS.

In June 2012, the FDA rejected the application, a month after an advisory committee voted against the approval. The committee had expressed concerns about the risks of bleeding associated with rivaroxaban, as well as reservations about missing data from the ATLAS ACS 2 TIMI 51 trial.

Though Janssen and Bayer went on to submit the missing data, the FDA rejected the drug again in March 2013. However, the FDA suggested the companies apply for approval using rivaroxaban for a limited time after ACS development, as the drug might be safer and more effective when given this way.

So the companies submitted an application for rivaroxaban given within the first 90 days of ACS diagnosis.

The advisory committee voted against this use of the drug, however, saying it seems the benefits of this treatment still do not outweigh the risks for this patient population.

A representative from Janssen said the company still believes rivaroxaban can be useful for patients with ACS, and Janssen and Bayer will work with the FDA to address the issues the committee raised.

For more details and data on rivaroxaban, see the briefing information compiled for the advisory committee’s meeting.

Inside a coronary artery

Credit: Mass. General Hospital

A US Food and Drug Administration (FDA) advisory committee has voted against expanding the indication for the anticoagulant rivaroxaban (Xarelto).

The drug’s developers are seeking approval for rivaroxaban to be used in combination with standard antiplatelet therapy to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The proposed dose is 2.5 mg twice daily for 90 days.

But the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted—nearly unanimously (with 1 abstention)—against this approval.

And the FDA will take this recommendation into account when deciding whether or not to expand rivaroxaban’s indication. This will be the FDA’s third time reviewing the drug for the aforementioned indication.

Rivaroxaban is currently FDA-approved to reduce the risk of stroke and thrombosis in patients with non-valvular atrial fibrillation, treat patients with venous thromboembolism (VTE), reduce the risk of recurrent VTE, and reduce the risk of VTE in patients who have undergone knee replacement surgery or hip replacement surgery.

Headed for a third rejection?

The advisory committee’s recommendation was based on a review of data from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in January 2012.

The study showed that rivaroxaban, given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients. But it also increased the risk of major bleeding and intracranial hemorrhage.

Based on these results, rivaroxaban’s developers—Janssen Research & Development, LLC, and Bayer HealthCare—filed for FDA approval of rivaroxaban to treat patients with ACS.

In June 2012, the FDA rejected the application, a month after an advisory committee voted against the approval. The committee had expressed concerns about the risks of bleeding associated with rivaroxaban, as well as reservations about missing data from the ATLAS ACS 2 TIMI 51 trial.

Though Janssen and Bayer went on to submit the missing data, the FDA rejected the drug again in March 2013. However, the FDA suggested the companies apply for approval using rivaroxaban for a limited time after ACS development, as the drug might be safer and more effective when given this way.

So the companies submitted an application for rivaroxaban given within the first 90 days of ACS diagnosis.

The advisory committee voted against this use of the drug, however, saying it seems the benefits of this treatment still do not outweigh the risks for this patient population.

A representative from Janssen said the company still believes rivaroxaban can be useful for patients with ACS, and Janssen and Bayer will work with the FDA to address the issues the committee raised.

For more details and data on rivaroxaban, see the briefing information compiled for the advisory committee’s meeting.

Inside a coronary artery

Credit: Mass. General Hospital

A US Food and Drug Administration (FDA) advisory committee has voted against expanding the indication for the anticoagulant rivaroxaban (Xarelto).

The drug’s developers are seeking approval for rivaroxaban to be used in combination with standard antiplatelet therapy to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The proposed dose is 2.5 mg twice daily for 90 days.

But the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted—nearly unanimously (with 1 abstention)—against this approval.

And the FDA will take this recommendation into account when deciding whether or not to expand rivaroxaban’s indication. This will be the FDA’s third time reviewing the drug for the aforementioned indication.

Rivaroxaban is currently FDA-approved to reduce the risk of stroke and thrombosis in patients with non-valvular atrial fibrillation, treat patients with venous thromboembolism (VTE), reduce the risk of recurrent VTE, and reduce the risk of VTE in patients who have undergone knee replacement surgery or hip replacement surgery.

Headed for a third rejection?

The advisory committee’s recommendation was based on a review of data from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in January 2012.

The study showed that rivaroxaban, given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients. But it also increased the risk of major bleeding and intracranial hemorrhage.

Based on these results, rivaroxaban’s developers—Janssen Research & Development, LLC, and Bayer HealthCare—filed for FDA approval of rivaroxaban to treat patients with ACS.

In June 2012, the FDA rejected the application, a month after an advisory committee voted against the approval. The committee had expressed concerns about the risks of bleeding associated with rivaroxaban, as well as reservations about missing data from the ATLAS ACS 2 TIMI 51 trial.

Though Janssen and Bayer went on to submit the missing data, the FDA rejected the drug again in March 2013. However, the FDA suggested the companies apply for approval using rivaroxaban for a limited time after ACS development, as the drug might be safer and more effective when given this way.

So the companies submitted an application for rivaroxaban given within the first 90 days of ACS diagnosis.

The advisory committee voted against this use of the drug, however, saying it seems the benefits of this treatment still do not outweigh the risks for this patient population.

A representative from Janssen said the company still believes rivaroxaban can be useful for patients with ACS, and Janssen and Bayer will work with the FDA to address the issues the committee raised.

For more details and data on rivaroxaban, see the briefing information compiled for the advisory committee’s meeting.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

Blood sample collection

Credit: Juan D. Alfonso

The theory behind the “Blood-Type Diet”—which claims an individual’s nutritional needs vary by blood type—is not valid, according to a study published in PLOS ONE.

The study showed that 3 of the 4 blood-type-specific diets conferred positive effects. But these benefits occurred independently of a person’s ABO genotype.

“The way an individual responds to any one of these diets has absolutely nothing to do with their blood type and has everything to do with their ability to stick to a sensible vegetarian or low-carbohydrate diet,” said study author Ahmed El-Sohemy, PhD, of the University of Toronto in Ontario, Canada.

About the diet(s)

The Blood-Type Diet was popularized in the book Eat Right for Your Type, written by Peter D’Adamo, ND. His theory is that people with different blood types process food differently, and the ABO blood type should match the dietary habits of our ancestors.

According to the theory, individuals adhering to a blood-type-specific diet can improve their health and decrease the risk of chronic illness such as cardiovascular disease.

The Type-A diet recommends that subjects consume mostly grains, fruits, and vegetables. The Type-B diet promotes a high intake of dairy products and a moderate intake of other food groups.

The Type-AB diet is similar to the Type-B diet but has more restrictions on specific foods. And the Type-O diet recommends that subjects consume mostly meat and avoid grain products.

Study results

To test that Blood-Type Diet theory, Dr El-Sohemy and his colleagues analyzed a population of 1455 adults aged 20 to 29 years. Subjects provided detailed information about their usual diets, as well as fasting blood samples.

The researchers used the samples to determine subjects’ ABO blood type and their level of cardiometabolic risk factors, such as insulin, cholesterol, and triglycerides.

The team also calculated diet scores based on the food items listed in Eat Right for Your Type to determine subjects’ relative adherence to each of the 4 blood-type diets.

Subjects whose diets closely resembled the Type-A diet had a lower body mass index and waist circumference, as well as reduced blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR, and HOMA-Beta (P<0.05). But these effects were seen regardless of the individual’s blood type.

Subjects whose diets resembled the Type-AB diet had reduced blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR, and HOMA-Beta (P<0.05), regardless of their blood type.

Adhering to the recommendations of the Type-O diet was associated with lower triglyceride levels (P<0.0001), regardless of blood type.

And there were no significant associations for subjects whose eating habits corresponded to the Type-B diet.

“[W]e found no evidence to support the Blood-Type Diet theory,” Dr El-Sohemy said. “It was an intriguing hypothesis, so we felt we should put it to the test. We can now be confident in saying that the Blood-Type Diet hypothesis is false.”

Blood sample collection

Credit: Juan D. Alfonso

The theory behind the “Blood-Type Diet”—which claims an individual’s nutritional needs vary by blood type—is not valid, according to a study published in PLOS ONE.

The study showed that 3 of the 4 blood-type-specific diets conferred positive effects. But these benefits occurred independently of a person’s ABO genotype.

“The way an individual responds to any one of these diets has absolutely nothing to do with their blood type and has everything to do with their ability to stick to a sensible vegetarian or low-carbohydrate diet,” said study author Ahmed El-Sohemy, PhD, of the University of Toronto in Ontario, Canada.

About the diet(s)

The Blood-Type Diet was popularized in the book Eat Right for Your Type, written by Peter D’Adamo, ND. His theory is that people with different blood types process food differently, and the ABO blood type should match the dietary habits of our ancestors.

According to the theory, individuals adhering to a blood-type-specific diet can improve their health and decrease the risk of chronic illness such as cardiovascular disease.

The Type-A diet recommends that subjects consume mostly grains, fruits, and vegetables. The Type-B diet promotes a high intake of dairy products and a moderate intake of other food groups.

The Type-AB diet is similar to the Type-B diet but has more restrictions on specific foods. And the Type-O diet recommends that subjects consume mostly meat and avoid grain products.

Study results

To test that Blood-Type Diet theory, Dr El-Sohemy and his colleagues analyzed a population of 1455 adults aged 20 to 29 years. Subjects provided detailed information about their usual diets, as well as fasting blood samples.

The researchers used the samples to determine subjects’ ABO blood type and their level of cardiometabolic risk factors, such as insulin, cholesterol, and triglycerides.

The team also calculated diet scores based on the food items listed in Eat Right for Your Type to determine subjects’ relative adherence to each of the 4 blood-type diets.

Subjects whose diets closely resembled the Type-A diet had a lower body mass index and waist circumference, as well as reduced blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR, and HOMA-Beta (P<0.05). But these effects were seen regardless of the individual’s blood type.

Subjects whose diets resembled the Type-AB diet had reduced blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR, and HOMA-Beta (P<0.05), regardless of their blood type.

Adhering to the recommendations of the Type-O diet was associated with lower triglyceride levels (P<0.0001), regardless of blood type.

And there were no significant associations for subjects whose eating habits corresponded to the Type-B diet.

“[W]e found no evidence to support the Blood-Type Diet theory,” Dr El-Sohemy said. “It was an intriguing hypothesis, so we felt we should put it to the test. We can now be confident in saying that the Blood-Type Diet hypothesis is false.”

Blood sample collection

Credit: Juan D. Alfonso

The theory behind the “Blood-Type Diet”—which claims an individual’s nutritional needs vary by blood type—is not valid, according to a study published in PLOS ONE.

The study showed that 3 of the 4 blood-type-specific diets conferred positive effects. But these benefits occurred independently of a person’s ABO genotype.

“The way an individual responds to any one of these diets has absolutely nothing to do with their blood type and has everything to do with their ability to stick to a sensible vegetarian or low-carbohydrate diet,” said study author Ahmed El-Sohemy, PhD, of the University of Toronto in Ontario, Canada.

About the diet(s)

The Blood-Type Diet was popularized in the book Eat Right for Your Type, written by Peter D’Adamo, ND. His theory is that people with different blood types process food differently, and the ABO blood type should match the dietary habits of our ancestors.

According to the theory, individuals adhering to a blood-type-specific diet can improve their health and decrease the risk of chronic illness such as cardiovascular disease.

The Type-A diet recommends that subjects consume mostly grains, fruits, and vegetables. The Type-B diet promotes a high intake of dairy products and a moderate intake of other food groups.

The Type-AB diet is similar to the Type-B diet but has more restrictions on specific foods. And the Type-O diet recommends that subjects consume mostly meat and avoid grain products.

Study results

To test that Blood-Type Diet theory, Dr El-Sohemy and his colleagues analyzed a population of 1455 adults aged 20 to 29 years. Subjects provided detailed information about their usual diets, as well as fasting blood samples.

The researchers used the samples to determine subjects’ ABO blood type and their level of cardiometabolic risk factors, such as insulin, cholesterol, and triglycerides.

The team also calculated diet scores based on the food items listed in Eat Right for Your Type to determine subjects’ relative adherence to each of the 4 blood-type diets.

Subjects whose diets closely resembled the Type-A diet had a lower body mass index and waist circumference, as well as reduced blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR, and HOMA-Beta (P<0.05). But these effects were seen regardless of the individual’s blood type.

Subjects whose diets resembled the Type-AB diet had reduced blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR, and HOMA-Beta (P<0.05), regardless of their blood type.

Adhering to the recommendations of the Type-O diet was associated with lower triglyceride levels (P<0.0001), regardless of blood type.

And there were no significant associations for subjects whose eating habits corresponded to the Type-B diet.

“[W]e found no evidence to support the Blood-Type Diet theory,” Dr El-Sohemy said. “It was an intriguing hypothesis, so we felt we should put it to the test. We can now be confident in saying that the Blood-Type Diet hypothesis is false.”

DNA coiled around histones

Credit: Eric Smith

Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.

And this finding could have implications for the treatment of leukemias and lymphomas.

Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.

Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.

Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.

But how the methylase’s activity was directed toward the appropriate targets was unclear.

Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.

The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.

The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.

“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”

Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.

The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.

This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.

But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.

The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.

Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.

In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.

The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.

The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.

The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.

DNA coiled around histones

Credit: Eric Smith

Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.

And this finding could have implications for the treatment of leukemias and lymphomas.

Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.

Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.

Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.

But how the methylase’s activity was directed toward the appropriate targets was unclear.

Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.

The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.

The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.

“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”

Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.

The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.

This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.

But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.

The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.

Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.

In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.

The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.

The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.

The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.

DNA coiled around histones

Credit: Eric Smith

Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.

And this finding could have implications for the treatment of leukemias and lymphomas.

Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.

Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.

Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.

But how the methylase’s activity was directed toward the appropriate targets was unclear.

Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.

The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.

The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.

“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”

Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.

The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.

This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.

But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.

The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.

Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.

In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.

The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.

The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.

The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.

Thrombus

Credit: Andre E.X. Brown

An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.

The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.

The FDA will take this opinion into account when deciding whether or not to approve the drug.

The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.

In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.

The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).

The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).

However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.

And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.

These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.

The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.

The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.

Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.

For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.

Thrombus

Credit: Andre E.X. Brown

An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.

The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.

The FDA will take this opinion into account when deciding whether or not to approve the drug.

The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.

In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.

The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).

The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).

However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.

And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.

These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.

The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.

The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.

Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.

For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.

Thrombus

Credit: Andre E.X. Brown

An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.

The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.

The FDA will take this opinion into account when deciding whether or not to approve the drug.

The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.

In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.

The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).

The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).

However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.

And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.

These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.

The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.

The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.

Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.

For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.

Salvador Macip, MD, PhD

Credit: University of Leicester

Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.

The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.

Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).

But new results in a patient with HCL suggest otherwise.

Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.

The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.

They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.

But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.

“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.

A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.

“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.

Salvador Macip, MD, PhD

Credit: University of Leicester

Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.

The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.

Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).

But new results in a patient with HCL suggest otherwise.

Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.

The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.

They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.

But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.

“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.

A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.

“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.

Salvador Macip, MD, PhD

Credit: University of Leicester

Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.

The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.

Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).

But new results in a patient with HCL suggest otherwise.

Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.

The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.

They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.

But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.

“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.

A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.

“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.

Clinical question

As compared with crystalloid therapy, does the use of colloid solutions for fluid resuscitation in the intensive care unit improve mortality in critically ill patients with hypovolemic shock?

Bottom line

For critically ill patients with acute hypovolemic shock, the use of colloid solutions for fluid resuscitation does not significantly affect short-term mortality as compared with the use of crystalloid solutions. However, the data suggest that deaths over 90 days may be reduced with colloids. More research is needed to confirm these findings. (LOE = 1b-)

Reference

Annane D, Siami S, Jaber S, et al, for the CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 2013:310(17);1809-1817.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Critically ill patients with acute hypovolemia were randomized, using concealed allocation, to receive fluid resuscitation with crystalloids or colloids. Patients who had already received fluid resuscitation while in the intensive care unit (ICU) were excluded from the study. Randomization was stratified according to diagnosis: sepsis, trauma, or other causes of hypovolemic shock. In the crystalloid group, patients received isotonic or hypertonic saline or other buffered solutions; patients in the colloid group received hypo- or hyper-oncotic solutions such as gelatins, dextrans, hydroxyethyl starches, or albumin. The amount and duration of fluid resuscitation was left to the discretion of the clinicians. Clinicians were not masked as it was considered infeasible to stock the units with adequately masked fluid solutions, especially for the use in emergencies. Analysis was by intention to treat. Baseline characteristics in the 2 groups were similar. The median age was 63 years and the majority of patients had hypovolemia due to sepsis. The median volume of fluid administered (excluding maintenance therapy) during the first 7 days in the ICU was higher in the crystalloid group (3 L vs 2 L; P < .001). For the primary outcome of mortality at 28 days, there was no significant difference detected between the 2 groups. Although there were fewer deaths in the colloid group at 90 days, this was a secondary outcome and the confidence interval approached 1 (31% vs. 34%; relative risk = 0.92; 95% CI, 0.86-0.99; P = .03). At the 28-day mark, patients in the colloid group were more likely to be alive without the need for mechanical ventilation (14.6 days vs 13.5 days; P = .01) or vasopressor therapy (16.2 days vs 15.2 days; P = .03).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

As compared with crystalloid therapy, does the use of colloid solutions for fluid resuscitation in the intensive care unit improve mortality in critically ill patients with hypovolemic shock?

Bottom line

For critically ill patients with acute hypovolemic shock, the use of colloid solutions for fluid resuscitation does not significantly affect short-term mortality as compared with the use of crystalloid solutions. However, the data suggest that deaths over 90 days may be reduced with colloids. More research is needed to confirm these findings. (LOE = 1b-)

Reference

Annane D, Siami S, Jaber S, et al, for the CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 2013:310(17);1809-1817.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Critically ill patients with acute hypovolemia were randomized, using concealed allocation, to receive fluid resuscitation with crystalloids or colloids. Patients who had already received fluid resuscitation while in the intensive care unit (ICU) were excluded from the study. Randomization was stratified according to diagnosis: sepsis, trauma, or other causes of hypovolemic shock. In the crystalloid group, patients received isotonic or hypertonic saline or other buffered solutions; patients in the colloid group received hypo- or hyper-oncotic solutions such as gelatins, dextrans, hydroxyethyl starches, or albumin. The amount and duration of fluid resuscitation was left to the discretion of the clinicians. Clinicians were not masked as it was considered infeasible to stock the units with adequately masked fluid solutions, especially for the use in emergencies. Analysis was by intention to treat. Baseline characteristics in the 2 groups were similar. The median age was 63 years and the majority of patients had hypovolemia due to sepsis. The median volume of fluid administered (excluding maintenance therapy) during the first 7 days in the ICU was higher in the crystalloid group (3 L vs 2 L; P < .001). For the primary outcome of mortality at 28 days, there was no significant difference detected between the 2 groups. Although there were fewer deaths in the colloid group at 90 days, this was a secondary outcome and the confidence interval approached 1 (31% vs. 34%; relative risk = 0.92; 95% CI, 0.86-0.99; P = .03). At the 28-day mark, patients in the colloid group were more likely to be alive without the need for mechanical ventilation (14.6 days vs 13.5 days; P = .01) or vasopressor therapy (16.2 days vs 15.2 days; P = .03).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

As compared with crystalloid therapy, does the use of colloid solutions for fluid resuscitation in the intensive care unit improve mortality in critically ill patients with hypovolemic shock?

Bottom line

For critically ill patients with acute hypovolemic shock, the use of colloid solutions for fluid resuscitation does not significantly affect short-term mortality as compared with the use of crystalloid solutions. However, the data suggest that deaths over 90 days may be reduced with colloids. More research is needed to confirm these findings. (LOE = 1b-)

Reference

Annane D, Siami S, Jaber S, et al, for the CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 2013:310(17);1809-1817.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Critically ill patients with acute hypovolemia were randomized, using concealed allocation, to receive fluid resuscitation with crystalloids or colloids. Patients who had already received fluid resuscitation while in the intensive care unit (ICU) were excluded from the study. Randomization was stratified according to diagnosis: sepsis, trauma, or other causes of hypovolemic shock. In the crystalloid group, patients received isotonic or hypertonic saline or other buffered solutions; patients in the colloid group received hypo- or hyper-oncotic solutions such as gelatins, dextrans, hydroxyethyl starches, or albumin. The amount and duration of fluid resuscitation was left to the discretion of the clinicians. Clinicians were not masked as it was considered infeasible to stock the units with adequately masked fluid solutions, especially for the use in emergencies. Analysis was by intention to treat. Baseline characteristics in the 2 groups were similar. The median age was 63 years and the majority of patients had hypovolemia due to sepsis. The median volume of fluid administered (excluding maintenance therapy) during the first 7 days in the ICU was higher in the crystalloid group (3 L vs 2 L; P < .001). For the primary outcome of mortality at 28 days, there was no significant difference detected between the 2 groups. Although there were fewer deaths in the colloid group at 90 days, this was a secondary outcome and the confidence interval approached 1 (31% vs. 34%; relative risk = 0.92; 95% CI, 0.86-0.99; P = .03). At the 28-day mark, patients in the colloid group were more likely to be alive without the need for mechanical ventilation (14.6 days vs 13.5 days; P = .01) or vasopressor therapy (16.2 days vs 15.2 days; P = .03).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does the use of renal artery stenting combined with aggressive medical therapy improve outcomes in patients with severe atherosclerotic renal artery stenosis?

Bottom line

In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting does not provide an additional benefit when added to comprehensive medical therapy that includes blood pressure and diabetes management and antiplatelet and lipid therapies. (LOE = 1b)

Reference

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov 13 [Epub ahead of print].

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Outpatient (any)

Synopsis

These investigators enrolled 947 patients with severe atherosclerotic renal artery stenosis (60% stenosis or more). Eligible patients also had either systolic hypertension while taking 2 or more antihypertensive medications or chronic kidney disease. Using concealed allocation, patients were randomized to receive either stenting plus medical therapy or medical therapy alone. Medical management included antiplatelet agents, antihypertensives, and lipid-lowering therapies. Specifically, all patients received candesartan with or without hydrochorthiazide, as well as the combination pill amlodipine-atorvastatin. Diabetes was managed according to clinical practice guidelines. The 2 groups had similar comorbidities at baseline. Overall, 90% of patients in each group had hyperlipidemia and approximately 30% had diabetes. The primary outcome was a composite of death from cardiovascular or renal causes, stroke, myocardial infarction, hospitalization for acute heart failure, worsening renal insufficiency, or the need for permanent dialysis. At a median follow-up of 43 months, there was no significant difference detected between the 2 groups in either the composite outcome (hazard ratio [HR] = 0.95; 95% CI, 0.76-1.17) or its individual components. All-cause mortality was also similar (HR = 0.80; 0.58-1.12).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does the use of renal artery stenting combined with aggressive medical therapy improve outcomes in patients with severe atherosclerotic renal artery stenosis?

Bottom line

In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting does not provide an additional benefit when added to comprehensive medical therapy that includes blood pressure and diabetes management and antiplatelet and lipid therapies. (LOE = 1b)

Reference

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov 13 [Epub ahead of print].

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Outpatient (any)

Synopsis

These investigators enrolled 947 patients with severe atherosclerotic renal artery stenosis (60% stenosis or more). Eligible patients also had either systolic hypertension while taking 2 or more antihypertensive medications or chronic kidney disease. Using concealed allocation, patients were randomized to receive either stenting plus medical therapy or medical therapy alone. Medical management included antiplatelet agents, antihypertensives, and lipid-lowering therapies. Specifically, all patients received candesartan with or without hydrochorthiazide, as well as the combination pill amlodipine-atorvastatin. Diabetes was managed according to clinical practice guidelines. The 2 groups had similar comorbidities at baseline. Overall, 90% of patients in each group had hyperlipidemia and approximately 30% had diabetes. The primary outcome was a composite of death from cardiovascular or renal causes, stroke, myocardial infarction, hospitalization for acute heart failure, worsening renal insufficiency, or the need for permanent dialysis. At a median follow-up of 43 months, there was no significant difference detected between the 2 groups in either the composite outcome (hazard ratio [HR] = 0.95; 95% CI, 0.76-1.17) or its individual components. All-cause mortality was also similar (HR = 0.80; 0.58-1.12).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does the use of renal artery stenting combined with aggressive medical therapy improve outcomes in patients with severe atherosclerotic renal artery stenosis?

Bottom line

In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting does not provide an additional benefit when added to comprehensive medical therapy that includes blood pressure and diabetes management and antiplatelet and lipid therapies. (LOE = 1b)

Reference

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov 13 [Epub ahead of print].

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Outpatient (any)

Synopsis

These investigators enrolled 947 patients with severe atherosclerotic renal artery stenosis (60% stenosis or more). Eligible patients also had either systolic hypertension while taking 2 or more antihypertensive medications or chronic kidney disease. Using concealed allocation, patients were randomized to receive either stenting plus medical therapy or medical therapy alone. Medical management included antiplatelet agents, antihypertensives, and lipid-lowering therapies. Specifically, all patients received candesartan with or without hydrochorthiazide, as well as the combination pill amlodipine-atorvastatin. Diabetes was managed according to clinical practice guidelines. The 2 groups had similar comorbidities at baseline. Overall, 90% of patients in each group had hyperlipidemia and approximately 30% had diabetes. The primary outcome was a composite of death from cardiovascular or renal causes, stroke, myocardial infarction, hospitalization for acute heart failure, worsening renal insufficiency, or the need for permanent dialysis. At a median follow-up of 43 months, there was no significant difference detected between the 2 groups in either the composite outcome (hazard ratio [HR] = 0.95; 95% CI, 0.76-1.17) or its individual components. All-cause mortality was also similar (HR = 0.80; 0.58-1.12).

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

I’ve just come across a really interesting project that I think we can all get behind: tuberculosis-sniffing rats.

It started with land mines. In many war-torn regions in Africa, people cannot access their land for agriculture because it is riddled with mines left over from previous conflicts. Bart Weetjens, a Belgian product development engineer with some experience of the difficulties of living in rural Africa, came across American experiments from the 1970s using gerbils to sniff out explosives. This inspired him to look into using rats to sniff out land mines. In 1997, he founded a nonprofit called Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) and received funding from the Belgian government to pursue his research.

Weetjens settled on using African giant pouch rats to sniff out land mines. The rats were inexpensive, intelligent, plentiful, sociable, trainable, and, most importantly, light enough to not set the land mines off. In 2003, they first tested the rats on real fields with real land mines in Mozambique. Now, they’ve received the backing of international peace agencies and have, to date, rendered safe 2.5 million square-meters of land area in Mozambique, effectively returning 100,000 people to their lands.

Given the success of this project, and the prevalence of pulmonary tuberculosis (TB) in the same communities affected by land mines, Weetjens thought of expanding the project into detection of tuberculosis from sputum samples. The premise is that Mycobacterium tuberculosis emits volatile organic compounds that the rats, with more genetic material dedicated to olfaction than any other mammal, might be able to detect.

It’s a fascinating demonstration of the intersection between science fiction and reality. You have to watch the videos to believe it, but the organization has trained several dozen rats in Tanzania and Mozambique to sniff out TB. It takes the rats 20 msec to sniff out and correctly identify a sample. The rats are able to process in 7 minutes the number of samples that a lab technician (or a lab "rat," if you will) would take a day to process using conventional light microscopy methods. In Dar es Salaam, using samples from more than 10,500 people from five hospitals, they increased the case detection rate by 44% over that of conventional microscopy. This method has a sensitivity of about 85% and a specificity of 90% – about the same rates as a 10-mm positive tuberculin test (Am. J. Trop. Med. Hyg. 2010;83:1308-10). It is even able to distinguish between M. tuberculosis and other mycobacterial species.

According to the World Health Organization, people with active tuberculosis can spread the disease to 10-15 close contacts in a year. WHO also says that TB is the second biggest infectious killer (behind HIV) worldwide, with over 1.3 million deaths in 2012. If these rats can really detect patients with TB at a much higher rate and with a greater sensitivity than standard microscopy, imagine the impact they would have on reducing the number of deaths worldwide from TB, especially in African nations where TB and HIV often co-occur, and access to health care is difficult.

APOPO’s project is a wonderful example of how simple innovations in science can have such a large footprint on global health. If you’re interested in learning more about APOPO, visit their website. You’ll find interesting videos and links to publications, plus ways to donate.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I’ve just come across a really interesting project that I think we can all get behind: tuberculosis-sniffing rats.

It started with land mines. In many war-torn regions in Africa, people cannot access their land for agriculture because it is riddled with mines left over from previous conflicts. Bart Weetjens, a Belgian product development engineer with some experience of the difficulties of living in rural Africa, came across American experiments from the 1970s using gerbils to sniff out explosives. This inspired him to look into using rats to sniff out land mines. In 1997, he founded a nonprofit called Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) and received funding from the Belgian government to pursue his research.

Weetjens settled on using African giant pouch rats to sniff out land mines. The rats were inexpensive, intelligent, plentiful, sociable, trainable, and, most importantly, light enough to not set the land mines off. In 2003, they first tested the rats on real fields with real land mines in Mozambique. Now, they’ve received the backing of international peace agencies and have, to date, rendered safe 2.5 million square-meters of land area in Mozambique, effectively returning 100,000 people to their lands.

Given the success of this project, and the prevalence of pulmonary tuberculosis (TB) in the same communities affected by land mines, Weetjens thought of expanding the project into detection of tuberculosis from sputum samples. The premise is that Mycobacterium tuberculosis emits volatile organic compounds that the rats, with more genetic material dedicated to olfaction than any other mammal, might be able to detect.

It’s a fascinating demonstration of the intersection between science fiction and reality. You have to watch the videos to believe it, but the organization has trained several dozen rats in Tanzania and Mozambique to sniff out TB. It takes the rats 20 msec to sniff out and correctly identify a sample. The rats are able to process in 7 minutes the number of samples that a lab technician (or a lab "rat," if you will) would take a day to process using conventional light microscopy methods. In Dar es Salaam, using samples from more than 10,500 people from five hospitals, they increased the case detection rate by 44% over that of conventional microscopy. This method has a sensitivity of about 85% and a specificity of 90% – about the same rates as a 10-mm positive tuberculin test (Am. J. Trop. Med. Hyg. 2010;83:1308-10). It is even able to distinguish between M. tuberculosis and other mycobacterial species.

According to the World Health Organization, people with active tuberculosis can spread the disease to 10-15 close contacts in a year. WHO also says that TB is the second biggest infectious killer (behind HIV) worldwide, with over 1.3 million deaths in 2012. If these rats can really detect patients with TB at a much higher rate and with a greater sensitivity than standard microscopy, imagine the impact they would have on reducing the number of deaths worldwide from TB, especially in African nations where TB and HIV often co-occur, and access to health care is difficult.

APOPO’s project is a wonderful example of how simple innovations in science can have such a large footprint on global health. If you’re interested in learning more about APOPO, visit their website. You’ll find interesting videos and links to publications, plus ways to donate.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I’ve just come across a really interesting project that I think we can all get behind: tuberculosis-sniffing rats.

It started with land mines. In many war-torn regions in Africa, people cannot access their land for agriculture because it is riddled with mines left over from previous conflicts. Bart Weetjens, a Belgian product development engineer with some experience of the difficulties of living in rural Africa, came across American experiments from the 1970s using gerbils to sniff out explosives. This inspired him to look into using rats to sniff out land mines. In 1997, he founded a nonprofit called Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) and received funding from the Belgian government to pursue his research.

Weetjens settled on using African giant pouch rats to sniff out land mines. The rats were inexpensive, intelligent, plentiful, sociable, trainable, and, most importantly, light enough to not set the land mines off. In 2003, they first tested the rats on real fields with real land mines in Mozambique. Now, they’ve received the backing of international peace agencies and have, to date, rendered safe 2.5 million square-meters of land area in Mozambique, effectively returning 100,000 people to their lands.

Given the success of this project, and the prevalence of pulmonary tuberculosis (TB) in the same communities affected by land mines, Weetjens thought of expanding the project into detection of tuberculosis from sputum samples. The premise is that Mycobacterium tuberculosis emits volatile organic compounds that the rats, with more genetic material dedicated to olfaction than any other mammal, might be able to detect.

It’s a fascinating demonstration of the intersection between science fiction and reality. You have to watch the videos to believe it, but the organization has trained several dozen rats in Tanzania and Mozambique to sniff out TB. It takes the rats 20 msec to sniff out and correctly identify a sample. The rats are able to process in 7 minutes the number of samples that a lab technician (or a lab "rat," if you will) would take a day to process using conventional light microscopy methods. In Dar es Salaam, using samples from more than 10,500 people from five hospitals, they increased the case detection rate by 44% over that of conventional microscopy. This method has a sensitivity of about 85% and a specificity of 90% – about the same rates as a 10-mm positive tuberculin test (Am. J. Trop. Med. Hyg. 2010;83:1308-10). It is even able to distinguish between M. tuberculosis and other mycobacterial species.

According to the World Health Organization, people with active tuberculosis can spread the disease to 10-15 close contacts in a year. WHO also says that TB is the second biggest infectious killer (behind HIV) worldwide, with over 1.3 million deaths in 2012. If these rats can really detect patients with TB at a much higher rate and with a greater sensitivity than standard microscopy, imagine the impact they would have on reducing the number of deaths worldwide from TB, especially in African nations where TB and HIV often co-occur, and access to health care is difficult.

APOPO’s project is a wonderful example of how simple innovations in science can have such a large footprint on global health. If you’re interested in learning more about APOPO, visit their website. You’ll find interesting videos and links to publications, plus ways to donate.

Dr. Chan practices rheumatology in Pawtucket, R.I.