Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

With no consensus regarding the normal endometrial thickness in postmenopausal women without vaginal bleeding, there are no guidelines for clinicians to follow on when to biopsy, if at all, in an older patient presenting with pelvic pain but no bleeding.

To determine at what endometrial thickness biopsy would be optimal, Michelle Louie, MD, and colleagues from Magee Women’s Hospital in Pittsburgh, Pennsylvania, performed a retrospective cohort analysis of postmenopausal women aged 50 or older who underwent transvaginal ultrasound (TVUS) for indications other than vaginal bleeding. They presented their findings in an abstract at the 43rd AAGL Global Congress in Vancouver, Canada.

Details of the study

Patients were included if they had an endometrial lining of 4 mm or greater and excluded if they had a history of tamoxifen use, hormone replacement, endometrial ablation, hereditary cancer syndrome, or no available pathology results.

Of 462 biopsies, 435 (94.2%) had benign pathology, nine (2.0%) had carcinoma, and seven (1.5%) had atypical hyperplasia.

Endometrial thickness of 14 mm or greater was associated with atypical hyperplasia (odds ratio [OR], 4.29; P = .02), with a negative predictive value of 98.3%. A thickness of 15 mm or greater was associated with carcinoma (OR, 4.53; P = .03), with a negative predictive value of 98.5%.

Under 14 mm, the risk of hyperplasia was low, the authors found, at 0.08%. Below 15 mm, the risk of cancer was 0.06%.

They found no significant associations between endometrial lining TVUS appearance, age, parity, body mass index, diabetes, hypertension, hyperlipidemia, and carcinoma or atypical hyperplasia.

When biopsy might not be necessary

Therefore, regardless of conventional risk factors for endometrial cancer, if a postmenopausal woman reports pelvic pain without vaginal bleeding, and is found to have a thickened endometrial lining of less than 14 mm on TVUS, biopsy might not be warranted, conclude the study authors.  

With no consensus regarding the normal endometrial thickness in postmenopausal women without vaginal bleeding, there are no guidelines for clinicians to follow on when to biopsy, if at all, in an older patient presenting with pelvic pain but no bleeding.

To determine at what endometrial thickness biopsy would be optimal, Michelle Louie, MD, and colleagues from Magee Women’s Hospital in Pittsburgh, Pennsylvania, performed a retrospective cohort analysis of postmenopausal women aged 50 or older who underwent transvaginal ultrasound (TVUS) for indications other than vaginal bleeding. They presented their findings in an abstract at the 43rd AAGL Global Congress in Vancouver, Canada.

Details of the study

Patients were included if they had an endometrial lining of 4 mm or greater and excluded if they had a history of tamoxifen use, hormone replacement, endometrial ablation, hereditary cancer syndrome, or no available pathology results.

Of 462 biopsies, 435 (94.2%) had benign pathology, nine (2.0%) had carcinoma, and seven (1.5%) had atypical hyperplasia.

Endometrial thickness of 14 mm or greater was associated with atypical hyperplasia (odds ratio [OR], 4.29; P = .02), with a negative predictive value of 98.3%. A thickness of 15 mm or greater was associated with carcinoma (OR, 4.53; P = .03), with a negative predictive value of 98.5%.

Under 14 mm, the risk of hyperplasia was low, the authors found, at 0.08%. Below 15 mm, the risk of cancer was 0.06%.

They found no significant associations between endometrial lining TVUS appearance, age, parity, body mass index, diabetes, hypertension, hyperlipidemia, and carcinoma or atypical hyperplasia.

When biopsy might not be necessary

Therefore, regardless of conventional risk factors for endometrial cancer, if a postmenopausal woman reports pelvic pain without vaginal bleeding, and is found to have a thickened endometrial lining of less than 14 mm on TVUS, biopsy might not be warranted, conclude the study authors.  

With no consensus regarding the normal endometrial thickness in postmenopausal women without vaginal bleeding, there are no guidelines for clinicians to follow on when to biopsy, if at all, in an older patient presenting with pelvic pain but no bleeding.

To determine at what endometrial thickness biopsy would be optimal, Michelle Louie, MD, and colleagues from Magee Women’s Hospital in Pittsburgh, Pennsylvania, performed a retrospective cohort analysis of postmenopausal women aged 50 or older who underwent transvaginal ultrasound (TVUS) for indications other than vaginal bleeding. They presented their findings in an abstract at the 43rd AAGL Global Congress in Vancouver, Canada.

Details of the study

Patients were included if they had an endometrial lining of 4 mm or greater and excluded if they had a history of tamoxifen use, hormone replacement, endometrial ablation, hereditary cancer syndrome, or no available pathology results.

Of 462 biopsies, 435 (94.2%) had benign pathology, nine (2.0%) had carcinoma, and seven (1.5%) had atypical hyperplasia.

Endometrial thickness of 14 mm or greater was associated with atypical hyperplasia (odds ratio [OR], 4.29; P = .02), with a negative predictive value of 98.3%. A thickness of 15 mm or greater was associated with carcinoma (OR, 4.53; P = .03), with a negative predictive value of 98.5%.

Under 14 mm, the risk of hyperplasia was low, the authors found, at 0.08%. Below 15 mm, the risk of cancer was 0.06%.

They found no significant associations between endometrial lining TVUS appearance, age, parity, body mass index, diabetes, hypertension, hyperlipidemia, and carcinoma or atypical hyperplasia.

When biopsy might not be necessary

Therefore, regardless of conventional risk factors for endometrial cancer, if a postmenopausal woman reports pelvic pain without vaginal bleeding, and is found to have a thickened endometrial lining of less than 14 mm on TVUS, biopsy might not be warranted, conclude the study authors.  

Plasma for transfusion

Credit: Cristina Granados

The US Food and Drug Administration (FDA) has accepted a clinical protocol to make the INTERCEPT Blood System available to treat plasma collected from Ebola survivors.

Transfusion of blood or plasma from recovered Ebola patients can be of benefit in patients with acute Ebola infections, but recovered patients may carry undetected pathogens such as malaria, which is where the INTERCEPT Blood System for plasma comes in.

The system is used for the preparation and storage of whole blood-derived and apheresis plasma (fresh or recently thawed). It can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via transfusion.

“The INTERCEPT pathogen inactivation process can diminish the risk of other pathogens that may contaminate the plasma of valuable Ebola convalescent donors and will provide a new therapeutic resource for patients with Ebola,” said Laurence Corash, MD, senior vice president and chief medical officer of Cerus Corporation, the company developing the INTERCEPT system.

The INTERCEPT Blood System for plasma does not have FDA approval. The agency has approved use of the system via an investigational device exemption (IDE). This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.

Under this IDE, investigators at Emory University will collect Ebola convalescent plasma from recovered patients and use the INTERCEPT system for onsite pathogen inactivation.

Following testing for Ebola antibodies at the Centers for Disease Control and Prevention, the treated plasma will be stored at Emory for use with future patients. If needed, Emory will also supply the treated plasma for use at other Ebola treatment centers, such as the University of Nebraska Medical Center.

To further increase the availability of convalescent plasma, Cerus and the trial investigators are collaborating with the American Red Cross and America’s Blood Centers to create a national network of plasma collection sites to access recovered Ebola patients.

“Having a supply of convalescent plasma that has been through pathogen inactivation is critical to making this therapy readily available as new Ebola patients are diagnosed and urgently require treatment,” said Anne Winkler, MD, principal investigator for the study and an assistant professor at the Emory University School of Medicine in Atlanta, Georgia.

The World Health Organization recently identified convalescent plasma as a potentially promising experimental approach to treat Ebola, issuing interim guidance suggesting how the plasma should be sourced and supplied.

The Bill & Melinda Gates Foundation recently announced a $5.7 million commitment to support efforts in Guinea and other Ebola-affected countries to scale up the production and evaluation of potential therapies for people infected with the Ebola virus, including convalescent plasma treated with pathogen inactivation.

Funding is being provided to Clinical Research Management, Inc., and an array of private sector partners to study Ebola convalescent plasma that will be collected through mobile donation units fully equipped with apheresis plasma collection systems and the INTERCEPT Blood System for plasma.

The INTERCEPT platelet and plasma systems have been approved for use in Europe for 8 years and are used in 20 countries. License applications for the systems are under FDA review, with an approval decision expected in 2015.

The FDA recently accepted Cerus’s clinical protocol to make the INTERCEPT Blood System for platelets available under an IDE to regions in the US and its territories with outbreaks of Chikungunya and dengue virus.

Plasma for transfusion

Credit: Cristina Granados

The US Food and Drug Administration (FDA) has accepted a clinical protocol to make the INTERCEPT Blood System available to treat plasma collected from Ebola survivors.

Transfusion of blood or plasma from recovered Ebola patients can be of benefit in patients with acute Ebola infections, but recovered patients may carry undetected pathogens such as malaria, which is where the INTERCEPT Blood System for plasma comes in.

The system is used for the preparation and storage of whole blood-derived and apheresis plasma (fresh or recently thawed). It can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via transfusion.

“The INTERCEPT pathogen inactivation process can diminish the risk of other pathogens that may contaminate the plasma of valuable Ebola convalescent donors and will provide a new therapeutic resource for patients with Ebola,” said Laurence Corash, MD, senior vice president and chief medical officer of Cerus Corporation, the company developing the INTERCEPT system.

The INTERCEPT Blood System for plasma does not have FDA approval. The agency has approved use of the system via an investigational device exemption (IDE). This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.

Under this IDE, investigators at Emory University will collect Ebola convalescent plasma from recovered patients and use the INTERCEPT system for onsite pathogen inactivation.

Following testing for Ebola antibodies at the Centers for Disease Control and Prevention, the treated plasma will be stored at Emory for use with future patients. If needed, Emory will also supply the treated plasma for use at other Ebola treatment centers, such as the University of Nebraska Medical Center.

To further increase the availability of convalescent plasma, Cerus and the trial investigators are collaborating with the American Red Cross and America’s Blood Centers to create a national network of plasma collection sites to access recovered Ebola patients.

“Having a supply of convalescent plasma that has been through pathogen inactivation is critical to making this therapy readily available as new Ebola patients are diagnosed and urgently require treatment,” said Anne Winkler, MD, principal investigator for the study and an assistant professor at the Emory University School of Medicine in Atlanta, Georgia.

The World Health Organization recently identified convalescent plasma as a potentially promising experimental approach to treat Ebola, issuing interim guidance suggesting how the plasma should be sourced and supplied.

The Bill & Melinda Gates Foundation recently announced a $5.7 million commitment to support efforts in Guinea and other Ebola-affected countries to scale up the production and evaluation of potential therapies for people infected with the Ebola virus, including convalescent plasma treated with pathogen inactivation.

Funding is being provided to Clinical Research Management, Inc., and an array of private sector partners to study Ebola convalescent plasma that will be collected through mobile donation units fully equipped with apheresis plasma collection systems and the INTERCEPT Blood System for plasma.

The INTERCEPT platelet and plasma systems have been approved for use in Europe for 8 years and are used in 20 countries. License applications for the systems are under FDA review, with an approval decision expected in 2015.

The FDA recently accepted Cerus’s clinical protocol to make the INTERCEPT Blood System for platelets available under an IDE to regions in the US and its territories with outbreaks of Chikungunya and dengue virus.

Plasma for transfusion

Credit: Cristina Granados

The US Food and Drug Administration (FDA) has accepted a clinical protocol to make the INTERCEPT Blood System available to treat plasma collected from Ebola survivors.

Transfusion of blood or plasma from recovered Ebola patients can be of benefit in patients with acute Ebola infections, but recovered patients may carry undetected pathogens such as malaria, which is where the INTERCEPT Blood System for plasma comes in.

The system is used for the preparation and storage of whole blood-derived and apheresis plasma (fresh or recently thawed). It can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via transfusion.

“The INTERCEPT pathogen inactivation process can diminish the risk of other pathogens that may contaminate the plasma of valuable Ebola convalescent donors and will provide a new therapeutic resource for patients with Ebola,” said Laurence Corash, MD, senior vice president and chief medical officer of Cerus Corporation, the company developing the INTERCEPT system.

The INTERCEPT Blood System for plasma does not have FDA approval. The agency has approved use of the system via an investigational device exemption (IDE). This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.

Under this IDE, investigators at Emory University will collect Ebola convalescent plasma from recovered patients and use the INTERCEPT system for onsite pathogen inactivation.

Following testing for Ebola antibodies at the Centers for Disease Control and Prevention, the treated plasma will be stored at Emory for use with future patients. If needed, Emory will also supply the treated plasma for use at other Ebola treatment centers, such as the University of Nebraska Medical Center.

To further increase the availability of convalescent plasma, Cerus and the trial investigators are collaborating with the American Red Cross and America’s Blood Centers to create a national network of plasma collection sites to access recovered Ebola patients.

“Having a supply of convalescent plasma that has been through pathogen inactivation is critical to making this therapy readily available as new Ebola patients are diagnosed and urgently require treatment,” said Anne Winkler, MD, principal investigator for the study and an assistant professor at the Emory University School of Medicine in Atlanta, Georgia.

The World Health Organization recently identified convalescent plasma as a potentially promising experimental approach to treat Ebola, issuing interim guidance suggesting how the plasma should be sourced and supplied.

The Bill & Melinda Gates Foundation recently announced a $5.7 million commitment to support efforts in Guinea and other Ebola-affected countries to scale up the production and evaluation of potential therapies for people infected with the Ebola virus, including convalescent plasma treated with pathogen inactivation.

Funding is being provided to Clinical Research Management, Inc., and an array of private sector partners to study Ebola convalescent plasma that will be collected through mobile donation units fully equipped with apheresis plasma collection systems and the INTERCEPT Blood System for plasma.

The INTERCEPT platelet and plasma systems have been approved for use in Europe for 8 years and are used in 20 countries. License applications for the systems are under FDA review, with an approval decision expected in 2015.

The FDA recently accepted Cerus’s clinical protocol to make the INTERCEPT Blood System for platelets available under an IDE to regions in the US and its territories with outbreaks of Chikungunya and dengue virus.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

During the 43rd AAGL Global Congress, held November 17–21 in Vancouver, British Columbia, Sarah L. Cohen, MD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, stepped attendees through diagnosis and surgical management of adnexal masses in pregnancy, noting the approaches backed by the highest-quality data.

The incidence of adnexal masses in pregnancy is 1 in every 600 live births. A mass can be benign or malignant. Among benign masses found in pregnancy are functional cysts, teratomas, and the corpus luteum.

Work-up
Ultrasound imaging is a valuable component of the work-up, owing to its risk-free nature. Magnetic resonance imaging may be appropriate in selected cases, but gadolinium contrast should be avoided.

In pregnancy, the aim is to limit ionizing radiation to less than 5 to 10 rads to minimize the risk of childhood malignancy/leukemia, with no single imaging study exceeding 5 rads.

Tumor markers may be helpful, but careful interpretation is critical, taking into account the effects of pregnancy itself on CA-125 (which peaks in the first trimester), human chorionic gonadotropin, alpha fetoprotein, inhibin A, and lactate dehydrogenase.

When expectant management may be appropriate
Watchful waiting may be considered for simple cysts less than 6 cm in size, provided the patient is asymptomatic with no signs of malignancy.

Surgery is indicated when the patient is symptomatic, when there is a concern for malignancy, and when a persistent mass exceeds 10 cm in size.

As always, elective surgery is preferable, as emergent surgery in pregnancy is associated with a risk of preterm labor of 22% to 35%.

Optimal timing of surgery
Surgery can be performed safely in any trimester, provided the gynecologist is aware of special concerns. For example, in the first trimester, organogenesis is under way and the corpus luteum is still present. If the corpus luteum is removed, progesterone supplementation is necessary.

When surgery can be postponed to the second trimester, it allows time for possible resolution of the mass.

Mode of surgery
Laparoscopy allows for faster recovery, less pain (and, therefore, lower narcotic exposure to the fetus), and improved maternal ventilation.

Prophylaxis for venous thromboembolism is indicated through the use of pneumatic compression devices and, when appropriate, heparin.

Initial port placement can be performed using a Hassan technique, Veress needle, or optical trocar.

Insufflation pressures of 10 to 15 mm Hg are safe, with intraoperative monitoring of carbon dioxide. 

Availability of guidelines
Surgeons should make use of guidelines, when feasible, to guide surgery. For example, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) publishes guidelines on surgery during pregnancy. The American College of Obstetricians and Gynecologists also offers guidelines.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

During the 43rd AAGL Global Congress, held November 17–21 in Vancouver, British Columbia, Sarah L. Cohen, MD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, stepped attendees through diagnosis and surgical management of adnexal masses in pregnancy, noting the approaches backed by the highest-quality data.

The incidence of adnexal masses in pregnancy is 1 in every 600 live births. A mass can be benign or malignant. Among benign masses found in pregnancy are functional cysts, teratomas, and the corpus luteum.

Work-up
Ultrasound imaging is a valuable component of the work-up, owing to its risk-free nature. Magnetic resonance imaging may be appropriate in selected cases, but gadolinium contrast should be avoided.

In pregnancy, the aim is to limit ionizing radiation to less than 5 to 10 rads to minimize the risk of childhood malignancy/leukemia, with no single imaging study exceeding 5 rads.

Tumor markers may be helpful, but careful interpretation is critical, taking into account the effects of pregnancy itself on CA-125 (which peaks in the first trimester), human chorionic gonadotropin, alpha fetoprotein, inhibin A, and lactate dehydrogenase.

When expectant management may be appropriate
Watchful waiting may be considered for simple cysts less than 6 cm in size, provided the patient is asymptomatic with no signs of malignancy.

Surgery is indicated when the patient is symptomatic, when there is a concern for malignancy, and when a persistent mass exceeds 10 cm in size.

As always, elective surgery is preferable, as emergent surgery in pregnancy is associated with a risk of preterm labor of 22% to 35%.

Optimal timing of surgery
Surgery can be performed safely in any trimester, provided the gynecologist is aware of special concerns. For example, in the first trimester, organogenesis is under way and the corpus luteum is still present. If the corpus luteum is removed, progesterone supplementation is necessary.

When surgery can be postponed to the second trimester, it allows time for possible resolution of the mass.

Mode of surgery
Laparoscopy allows for faster recovery, less pain (and, therefore, lower narcotic exposure to the fetus), and improved maternal ventilation.

Prophylaxis for venous thromboembolism is indicated through the use of pneumatic compression devices and, when appropriate, heparin.

Initial port placement can be performed using a Hassan technique, Veress needle, or optical trocar.

Insufflation pressures of 10 to 15 mm Hg are safe, with intraoperative monitoring of carbon dioxide. 

Availability of guidelines
Surgeons should make use of guidelines, when feasible, to guide surgery. For example, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) publishes guidelines on surgery during pregnancy. The American College of Obstetricians and Gynecologists also offers guidelines.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

During the 43rd AAGL Global Congress, held November 17–21 in Vancouver, British Columbia, Sarah L. Cohen, MD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, stepped attendees through diagnosis and surgical management of adnexal masses in pregnancy, noting the approaches backed by the highest-quality data.

The incidence of adnexal masses in pregnancy is 1 in every 600 live births. A mass can be benign or malignant. Among benign masses found in pregnancy are functional cysts, teratomas, and the corpus luteum.

Work-up
Ultrasound imaging is a valuable component of the work-up, owing to its risk-free nature. Magnetic resonance imaging may be appropriate in selected cases, but gadolinium contrast should be avoided.

In pregnancy, the aim is to limit ionizing radiation to less than 5 to 10 rads to minimize the risk of childhood malignancy/leukemia, with no single imaging study exceeding 5 rads.

Tumor markers may be helpful, but careful interpretation is critical, taking into account the effects of pregnancy itself on CA-125 (which peaks in the first trimester), human chorionic gonadotropin, alpha fetoprotein, inhibin A, and lactate dehydrogenase.

When expectant management may be appropriate
Watchful waiting may be considered for simple cysts less than 6 cm in size, provided the patient is asymptomatic with no signs of malignancy.

Surgery is indicated when the patient is symptomatic, when there is a concern for malignancy, and when a persistent mass exceeds 10 cm in size.

As always, elective surgery is preferable, as emergent surgery in pregnancy is associated with a risk of preterm labor of 22% to 35%.

Optimal timing of surgery
Surgery can be performed safely in any trimester, provided the gynecologist is aware of special concerns. For example, in the first trimester, organogenesis is under way and the corpus luteum is still present. If the corpus luteum is removed, progesterone supplementation is necessary.

When surgery can be postponed to the second trimester, it allows time for possible resolution of the mass.

Mode of surgery
Laparoscopy allows for faster recovery, less pain (and, therefore, lower narcotic exposure to the fetus), and improved maternal ventilation.

Prophylaxis for venous thromboembolism is indicated through the use of pneumatic compression devices and, when appropriate, heparin.

Initial port placement can be performed using a Hassan technique, Veress needle, or optical trocar.

Insufflation pressures of 10 to 15 mm Hg are safe, with intraoperative monitoring of carbon dioxide. 

Availability of guidelines
Surgeons should make use of guidelines, when feasible, to guide surgery. For example, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) publishes guidelines on surgery during pregnancy. The American College of Obstetricians and Gynecologists also offers guidelines.

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The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

Two-year folic acid and vitamin B12 supplementation did not improve performance in four cognitive domains in elderly people with elevated homocysteine levels, according to a study published online ahead of print November 12 in Neurology. A total of 2,919 participants with an average age of 74 took either a tablet with 400 μg of folic acid and 500 μg of vitamin B12, or a placebo every day for two years. Tests of memory and thinking skills were performed at the beginning and end of the study. All participants had high blood levels of homocysteine. “While the homocysteine levels decreased by more in the group taking the B vitamins than in the group taking the placebo, unfortunately, there was no difference between the two groups in the scores on the thinking and memory tests,” the researchers stated.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury (TBI) was identified on CT scans in 7% of the patients, according to a study published November 13 in the New England Journal of Medicine. In children 12 and younger, falls were the most common cause of head injury—among those younger than 2, falls accounted for 77% of head injuries, and in those 2 to 12, falls accounted for 38% of injuries. In children ages 13 to 17, 24% of injuries were due to assault, 19% were sports-related, and 18% resulted from motor vehicle accidents. Among all cases, 98% had mild head trauma. During diagnosis and treatment, cranial CT scans were performed on 37% of the children, “many arguably unnecessarily,” according to the researchers.

Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke, according to a study published online ahead of print November 5 in Neurology. Researchers analyzed records of 100,243 patients hospitalized for a first stroke between 2004 and 2012 and deaths within one month after the stroke. The investigators examined whether participants were current, former, or nonusers of these drugs within two months of the stroke. Overall, people who were current users of COX-2 inhibitors were 19% more likely to die after stroke than were people who did not take the drugs. New users of the older COX-2 drugs were 42% more likely to die from stroke than were those who were not taking the drugs.

Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among patients age 60 or older with atherosclerotic risk factors, according to a study published online ahead of print November 17 in JAMA. This study included 14,464 Japanese patients with hypertension, dyslipidemia, or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The researchers found no statistically significant difference between the two groups in time to the primary end point. The cumulative primary event rate was similar in participants in the aspirin group (2.77%) and those in the no-aspirin group (2.96%) five years after randomization. Aspirin significantly reduced the incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

Overall symptom burden is the only independent predictor of prolonged symptoms after sport-related concussion, investigators reported online ahead of print November 7 in Neurology. The researchers conducted a prospective cohort study of 531 patients in a sports concussion clinic. Participants completed questionnaires that included the Post-Concussion Symptom Scale (PCSS). Patients ranged in age from 7 to 26 (mean age, 14.6). The mean PCSS score at the initial visit was 26, and mean time to presentation was 12 days. Only total score on symptom inventory was independently associated with symptoms lasting longer than 28 days. No other potential predictor variables were independently associated with symptom duration or were useful in developing the optimal regression decision tree. Most participants with an initial PCSS score of less than 13 had resolution of their symptoms within 28 days of injury.

The ketogenic diet and modified Atkins diet show modest efficacy, although in some patients the effect is “remarkable” in the treatment of refractory epilepsy in adults, according to a study published online ahead of print October 29 in Neurology. Researchers reviewed five studies on the ketogenic diet that included 47 people and five studies on the modified Atkins diet that included 85 people. The investigators found that across all studies, 32% of people treated with the ketogenic diet and 29% of those treated with the modified Atkins diet had a 50% or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5% in the modified Atkins group had a greater than 90% reduction in seizures. “These studies show the diets are moderately to very effective as another option for people with epilepsy,” stated the study authors.

The evaluation of serum micro-RNAs may help to identify the severity of brain injury and the risk of developing adverse effects after traumatic brain injury (TBI), according to a study published November 7 in PLoS One. Researchers identified a unique and specific group of microRNAs, which were detected in blood immediately after injury to the brain in mice. The results suggest that the microRNAs can be measured in the blood as proxies for mild TBI. The microRNA panel identified in this study is unique and does not overlap with blood microRNAs of post-traumatic stress disorder, as previously reported. “This important finding is a step forward in identifying objective biomarkers for mild TBI that may be further validated to accurately and cost effectively identify mild TBI in service members and civilians with brain injuries,” said the investigators.

The FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The approval comes nearly one year after the FDA declined to approve the drug, citing a lack of well-controlled data from clinical studies at the time indicating that the benefits had outweighed the risks. After an appeal by Genzyme (Cambridge, Massachusetts) and a new review by the FDA, the agency approved the drug based on two pivotal, randomized phase III, open-label, rater-blinded studies, comparing treatment with Lemtrada to interferon beta-1a, in patients with relapsing-remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). Lemtrada is recommended for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Angiotensin-converting enzyme inhibitors (ACEIs) exhibited a dose-dependent inverse association with amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print November 10 in JAMA Neurology. Researchers included 729 patients diagnosed with ALS between January 2002 and December 2008. The patients were compared with 14,580 controls. Fifteen percent of patients with ALS reported ACEI use between two and five years before their ALS diagnosis, and 18% of the control group without ALS reported ACEI use. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 for the group prescribed ACEIs lower than 449.5 of the cumulative defined daily dose (cDDD) and 0.43 cDDD for the group with a cumulative ACEI use of greater than 449.5 cDDD.

Patients treated at hospitals with higher volumes of subarachnoid hemorrhage (SAH) cases have lower in-hospital mortality, independent of patient and hospital characteristics, according to a study published in the November Neurosurgery. In a large nationwide registry, researchers identified nearly 32,000 patients with SAH treated at 685 United States hospitals between 2003 and 2012. The median annual case volume per hospital was 8.5 patients. Mean in-hospital mortality was 25.7% but was lower with increasing annual SAH volume. Hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio, 0.79 for quartile 4 vs quartile 1), independent of patient and other hospital characteristics. “Our results may have significant implications for regional stroke policies and procedures and affirm the recent recommendations that patients with SAH be treated at high-volume centers,” said study authors.

The use of a specialized ambulance—stroke emergency mobile unit (STEMO)—increases the percentage of patients receiving thrombolysis within 60 minutes, according to a study published online ahead of print November 17 in JAMA Neurology. A total of 3,213 emergency calls for suspected stroke occurred during weeks when STEMO was available, and 2,969 calls occurred during control weeks when STEMO was not available. Two hundred of 614 patients with stroke (32.6%) received thrombolysis when the STEMO was deployed, and 330 of 1,497 patients (22%) received thrombolysis in conventional care. Median onset to treatment was 24.5 minutes shorter after STEMO deployment, compared with conventional care. In all ischemic strokes, the rate of “golden hour” thrombolysis increased from 16 of the 1,497 patients (1.1%) during conventional care to 62 of 614 (10.1%) after STEMO deployment. Overall, golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes, according to the researchers.

Granger causality (GC) analysis of intracranial EEG (iEEG) has the potential to increase understanding of preictal network activity and help improve surgical outcomes in cases of otherwise ambiguous iEEG onset, according to a study published online ahead of print November 4 in Epilepsia. In 10 retrospective and two prospective patients with epilepsy, iEEG was recorded at 500 or 1,000 Hz, using as many as 128 surface and depth electrodes. In all patients, the researchers found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning two to 42 seconds before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources and contributed to planning of more limited surgical resections. Both groups of patients had a class 1 outcome at one year.

Tiny silent acute infarcts may be a cause of leukoaraiosis, a finding that points toward a potentially treatable form of dementia, investigators reported online ahead of print October 4 in Annals of Neurology. The study involved five patients with leukoaraiosis who underwent detailed MRI scanning of their brains every week for 16 consecutive weeks. The MRI scans revealed new tiny spots arising de novo in the cerebral white matter. The lesions were “clinically silent and had the signature features of acute ischemic stroke, according to the researchers. “With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis,” the study authors stated.

—Kimberly D. Williams

Two-year folic acid and vitamin B12 supplementation did not improve performance in four cognitive domains in elderly people with elevated homocysteine levels, according to a study published online ahead of print November 12 in Neurology. A total of 2,919 participants with an average age of 74 took either a tablet with 400 μg of folic acid and 500 μg of vitamin B12, or a placebo every day for two years. Tests of memory and thinking skills were performed at the beginning and end of the study. All participants had high blood levels of homocysteine. “While the homocysteine levels decreased by more in the group taking the B vitamins than in the group taking the placebo, unfortunately, there was no difference between the two groups in the scores on the thinking and memory tests,” the researchers stated.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury (TBI) was identified on CT scans in 7% of the patients, according to a study published November 13 in the New England Journal of Medicine. In children 12 and younger, falls were the most common cause of head injury—among those younger than 2, falls accounted for 77% of head injuries, and in those 2 to 12, falls accounted for 38% of injuries. In children ages 13 to 17, 24% of injuries were due to assault, 19% were sports-related, and 18% resulted from motor vehicle accidents. Among all cases, 98% had mild head trauma. During diagnosis and treatment, cranial CT scans were performed on 37% of the children, “many arguably unnecessarily,” according to the researchers.

Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke, according to a study published online ahead of print November 5 in Neurology. Researchers analyzed records of 100,243 patients hospitalized for a first stroke between 2004 and 2012 and deaths within one month after the stroke. The investigators examined whether participants were current, former, or nonusers of these drugs within two months of the stroke. Overall, people who were current users of COX-2 inhibitors were 19% more likely to die after stroke than were people who did not take the drugs. New users of the older COX-2 drugs were 42% more likely to die from stroke than were those who were not taking the drugs.

Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among patients age 60 or older with atherosclerotic risk factors, according to a study published online ahead of print November 17 in JAMA. This study included 14,464 Japanese patients with hypertension, dyslipidemia, or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The researchers found no statistically significant difference between the two groups in time to the primary end point. The cumulative primary event rate was similar in participants in the aspirin group (2.77%) and those in the no-aspirin group (2.96%) five years after randomization. Aspirin significantly reduced the incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

Overall symptom burden is the only independent predictor of prolonged symptoms after sport-related concussion, investigators reported online ahead of print November 7 in Neurology. The researchers conducted a prospective cohort study of 531 patients in a sports concussion clinic. Participants completed questionnaires that included the Post-Concussion Symptom Scale (PCSS). Patients ranged in age from 7 to 26 (mean age, 14.6). The mean PCSS score at the initial visit was 26, and mean time to presentation was 12 days. Only total score on symptom inventory was independently associated with symptoms lasting longer than 28 days. No other potential predictor variables were independently associated with symptom duration or were useful in developing the optimal regression decision tree. Most participants with an initial PCSS score of less than 13 had resolution of their symptoms within 28 days of injury.

The ketogenic diet and modified Atkins diet show modest efficacy, although in some patients the effect is “remarkable” in the treatment of refractory epilepsy in adults, according to a study published online ahead of print October 29 in Neurology. Researchers reviewed five studies on the ketogenic diet that included 47 people and five studies on the modified Atkins diet that included 85 people. The investigators found that across all studies, 32% of people treated with the ketogenic diet and 29% of those treated with the modified Atkins diet had a 50% or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5% in the modified Atkins group had a greater than 90% reduction in seizures. “These studies show the diets are moderately to very effective as another option for people with epilepsy,” stated the study authors.

The evaluation of serum micro-RNAs may help to identify the severity of brain injury and the risk of developing adverse effects after traumatic brain injury (TBI), according to a study published November 7 in PLoS One. Researchers identified a unique and specific group of microRNAs, which were detected in blood immediately after injury to the brain in mice. The results suggest that the microRNAs can be measured in the blood as proxies for mild TBI. The microRNA panel identified in this study is unique and does not overlap with blood microRNAs of post-traumatic stress disorder, as previously reported. “This important finding is a step forward in identifying objective biomarkers for mild TBI that may be further validated to accurately and cost effectively identify mild TBI in service members and civilians with brain injuries,” said the investigators.

The FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The approval comes nearly one year after the FDA declined to approve the drug, citing a lack of well-controlled data from clinical studies at the time indicating that the benefits had outweighed the risks. After an appeal by Genzyme (Cambridge, Massachusetts) and a new review by the FDA, the agency approved the drug based on two pivotal, randomized phase III, open-label, rater-blinded studies, comparing treatment with Lemtrada to interferon beta-1a, in patients with relapsing-remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). Lemtrada is recommended for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Angiotensin-converting enzyme inhibitors (ACEIs) exhibited a dose-dependent inverse association with amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print November 10 in JAMA Neurology. Researchers included 729 patients diagnosed with ALS between January 2002 and December 2008. The patients were compared with 14,580 controls. Fifteen percent of patients with ALS reported ACEI use between two and five years before their ALS diagnosis, and 18% of the control group without ALS reported ACEI use. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 for the group prescribed ACEIs lower than 449.5 of the cumulative defined daily dose (cDDD) and 0.43 cDDD for the group with a cumulative ACEI use of greater than 449.5 cDDD.

Patients treated at hospitals with higher volumes of subarachnoid hemorrhage (SAH) cases have lower in-hospital mortality, independent of patient and hospital characteristics, according to a study published in the November Neurosurgery. In a large nationwide registry, researchers identified nearly 32,000 patients with SAH treated at 685 United States hospitals between 2003 and 2012. The median annual case volume per hospital was 8.5 patients. Mean in-hospital mortality was 25.7% but was lower with increasing annual SAH volume. Hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio, 0.79 for quartile 4 vs quartile 1), independent of patient and other hospital characteristics. “Our results may have significant implications for regional stroke policies and procedures and affirm the recent recommendations that patients with SAH be treated at high-volume centers,” said study authors.

The use of a specialized ambulance—stroke emergency mobile unit (STEMO)—increases the percentage of patients receiving thrombolysis within 60 minutes, according to a study published online ahead of print November 17 in JAMA Neurology. A total of 3,213 emergency calls for suspected stroke occurred during weeks when STEMO was available, and 2,969 calls occurred during control weeks when STEMO was not available. Two hundred of 614 patients with stroke (32.6%) received thrombolysis when the STEMO was deployed, and 330 of 1,497 patients (22%) received thrombolysis in conventional care. Median onset to treatment was 24.5 minutes shorter after STEMO deployment, compared with conventional care. In all ischemic strokes, the rate of “golden hour” thrombolysis increased from 16 of the 1,497 patients (1.1%) during conventional care to 62 of 614 (10.1%) after STEMO deployment. Overall, golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes, according to the researchers.

Granger causality (GC) analysis of intracranial EEG (iEEG) has the potential to increase understanding of preictal network activity and help improve surgical outcomes in cases of otherwise ambiguous iEEG onset, according to a study published online ahead of print November 4 in Epilepsia. In 10 retrospective and two prospective patients with epilepsy, iEEG was recorded at 500 or 1,000 Hz, using as many as 128 surface and depth electrodes. In all patients, the researchers found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning two to 42 seconds before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources and contributed to planning of more limited surgical resections. Both groups of patients had a class 1 outcome at one year.

Tiny silent acute infarcts may be a cause of leukoaraiosis, a finding that points toward a potentially treatable form of dementia, investigators reported online ahead of print October 4 in Annals of Neurology. The study involved five patients with leukoaraiosis who underwent detailed MRI scanning of their brains every week for 16 consecutive weeks. The MRI scans revealed new tiny spots arising de novo in the cerebral white matter. The lesions were “clinically silent and had the signature features of acute ischemic stroke, according to the researchers. “With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis,” the study authors stated.

—Kimberly D. Williams

Two-year folic acid and vitamin B12 supplementation did not improve performance in four cognitive domains in elderly people with elevated homocysteine levels, according to a study published online ahead of print November 12 in Neurology. A total of 2,919 participants with an average age of 74 took either a tablet with 400 μg of folic acid and 500 μg of vitamin B12, or a placebo every day for two years. Tests of memory and thinking skills were performed at the beginning and end of the study. All participants had high blood levels of homocysteine. “While the homocysteine levels decreased by more in the group taking the B vitamins than in the group taking the placebo, unfortunately, there was no difference between the two groups in the scores on the thinking and memory tests,” the researchers stated.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury (TBI) was identified on CT scans in 7% of the patients, according to a study published November 13 in the New England Journal of Medicine. In children 12 and younger, falls were the most common cause of head injury—among those younger than 2, falls accounted for 77% of head injuries, and in those 2 to 12, falls accounted for 38% of injuries. In children ages 13 to 17, 24% of injuries were due to assault, 19% were sports-related, and 18% resulted from motor vehicle accidents. Among all cases, 98% had mild head trauma. During diagnosis and treatment, cranial CT scans were performed on 37% of the children, “many arguably unnecessarily,” according to the researchers.

Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke, according to a study published online ahead of print November 5 in Neurology. Researchers analyzed records of 100,243 patients hospitalized for a first stroke between 2004 and 2012 and deaths within one month after the stroke. The investigators examined whether participants were current, former, or nonusers of these drugs within two months of the stroke. Overall, people who were current users of COX-2 inhibitors were 19% more likely to die after stroke than were people who did not take the drugs. New users of the older COX-2 drugs were 42% more likely to die from stroke than were those who were not taking the drugs.

Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among patients age 60 or older with atherosclerotic risk factors, according to a study published online ahead of print November 17 in JAMA. This study included 14,464 Japanese patients with hypertension, dyslipidemia, or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The researchers found no statistically significant difference between the two groups in time to the primary end point. The cumulative primary event rate was similar in participants in the aspirin group (2.77%) and those in the no-aspirin group (2.96%) five years after randomization. Aspirin significantly reduced the incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

Overall symptom burden is the only independent predictor of prolonged symptoms after sport-related concussion, investigators reported online ahead of print November 7 in Neurology. The researchers conducted a prospective cohort study of 531 patients in a sports concussion clinic. Participants completed questionnaires that included the Post-Concussion Symptom Scale (PCSS). Patients ranged in age from 7 to 26 (mean age, 14.6). The mean PCSS score at the initial visit was 26, and mean time to presentation was 12 days. Only total score on symptom inventory was independently associated with symptoms lasting longer than 28 days. No other potential predictor variables were independently associated with symptom duration or were useful in developing the optimal regression decision tree. Most participants with an initial PCSS score of less than 13 had resolution of their symptoms within 28 days of injury.

The ketogenic diet and modified Atkins diet show modest efficacy, although in some patients the effect is “remarkable” in the treatment of refractory epilepsy in adults, according to a study published online ahead of print October 29 in Neurology. Researchers reviewed five studies on the ketogenic diet that included 47 people and five studies on the modified Atkins diet that included 85 people. The investigators found that across all studies, 32% of people treated with the ketogenic diet and 29% of those treated with the modified Atkins diet had a 50% or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5% in the modified Atkins group had a greater than 90% reduction in seizures. “These studies show the diets are moderately to very effective as another option for people with epilepsy,” stated the study authors.

The evaluation of serum micro-RNAs may help to identify the severity of brain injury and the risk of developing adverse effects after traumatic brain injury (TBI), according to a study published November 7 in PLoS One. Researchers identified a unique and specific group of microRNAs, which were detected in blood immediately after injury to the brain in mice. The results suggest that the microRNAs can be measured in the blood as proxies for mild TBI. The microRNA panel identified in this study is unique and does not overlap with blood microRNAs of post-traumatic stress disorder, as previously reported. “This important finding is a step forward in identifying objective biomarkers for mild TBI that may be further validated to accurately and cost effectively identify mild TBI in service members and civilians with brain injuries,” said the investigators.

The FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The approval comes nearly one year after the FDA declined to approve the drug, citing a lack of well-controlled data from clinical studies at the time indicating that the benefits had outweighed the risks. After an appeal by Genzyme (Cambridge, Massachusetts) and a new review by the FDA, the agency approved the drug based on two pivotal, randomized phase III, open-label, rater-blinded studies, comparing treatment with Lemtrada to interferon beta-1a, in patients with relapsing-remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). Lemtrada is recommended for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Angiotensin-converting enzyme inhibitors (ACEIs) exhibited a dose-dependent inverse association with amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print November 10 in JAMA Neurology. Researchers included 729 patients diagnosed with ALS between January 2002 and December 2008. The patients were compared with 14,580 controls. Fifteen percent of patients with ALS reported ACEI use between two and five years before their ALS diagnosis, and 18% of the control group without ALS reported ACEI use. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 for the group prescribed ACEIs lower than 449.5 of the cumulative defined daily dose (cDDD) and 0.43 cDDD for the group with a cumulative ACEI use of greater than 449.5 cDDD.

Patients treated at hospitals with higher volumes of subarachnoid hemorrhage (SAH) cases have lower in-hospital mortality, independent of patient and hospital characteristics, according to a study published in the November Neurosurgery. In a large nationwide registry, researchers identified nearly 32,000 patients with SAH treated at 685 United States hospitals between 2003 and 2012. The median annual case volume per hospital was 8.5 patients. Mean in-hospital mortality was 25.7% but was lower with increasing annual SAH volume. Hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio, 0.79 for quartile 4 vs quartile 1), independent of patient and other hospital characteristics. “Our results may have significant implications for regional stroke policies and procedures and affirm the recent recommendations that patients with SAH be treated at high-volume centers,” said study authors.

The use of a specialized ambulance—stroke emergency mobile unit (STEMO)—increases the percentage of patients receiving thrombolysis within 60 minutes, according to a study published online ahead of print November 17 in JAMA Neurology. A total of 3,213 emergency calls for suspected stroke occurred during weeks when STEMO was available, and 2,969 calls occurred during control weeks when STEMO was not available. Two hundred of 614 patients with stroke (32.6%) received thrombolysis when the STEMO was deployed, and 330 of 1,497 patients (22%) received thrombolysis in conventional care. Median onset to treatment was 24.5 minutes shorter after STEMO deployment, compared with conventional care. In all ischemic strokes, the rate of “golden hour” thrombolysis increased from 16 of the 1,497 patients (1.1%) during conventional care to 62 of 614 (10.1%) after STEMO deployment. Overall, golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes, according to the researchers.

Granger causality (GC) analysis of intracranial EEG (iEEG) has the potential to increase understanding of preictal network activity and help improve surgical outcomes in cases of otherwise ambiguous iEEG onset, according to a study published online ahead of print November 4 in Epilepsia. In 10 retrospective and two prospective patients with epilepsy, iEEG was recorded at 500 or 1,000 Hz, using as many as 128 surface and depth electrodes. In all patients, the researchers found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning two to 42 seconds before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources and contributed to planning of more limited surgical resections. Both groups of patients had a class 1 outcome at one year.

Tiny silent acute infarcts may be a cause of leukoaraiosis, a finding that points toward a potentially treatable form of dementia, investigators reported online ahead of print October 4 in Annals of Neurology. The study involved five patients with leukoaraiosis who underwent detailed MRI scanning of their brains every week for 16 consecutive weeks. The MRI scans revealed new tiny spots arising de novo in the cerebral white matter. The lesions were “clinically silent and had the signature features of acute ischemic stroke, according to the researchers. “With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis,” the study authors stated.

—Kimberly D. Williams