Doctor evaluating patient

Credit: CDC

Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).

The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.

The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”

Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.

The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.

Sponsor violations

Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).

The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.

Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.

Investigator infractions

Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.

Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.

Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).

IRB transgressions

Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.

Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.

The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).

Comparing past and present

The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.

And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.

In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.

Doctor evaluating patient

Credit: CDC

Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).

The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.

The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”

Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.

The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.

Sponsor violations

Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).

The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.

Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.

Investigator infractions

Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.

Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.

Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).

IRB transgressions

Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.

Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.

The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).

Comparing past and present

The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.

And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.

In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.

Doctor evaluating patient

Credit: CDC

Patient safety violations emerged as a common theme in a review of “first warning” letters issued to clinical trial sponsors, investigators, and internal review boards (IRBs).

The US Food and Drug Administration (FDA) issued the 84 warning letters in response to trial violations uncovered during site visits.

The review of these letters showed that 55% of investigators failed to protect subjects’ safety and report adverse events to the IRB, 24% of sponsors failed to submit adverse event data to the FDA, and 22% of IRBs failed to “address risk minimization and protect vulnerable study subjects.”

Yashashri C. Shetty and Aafreen A. Saiyed, both of King Edward Memorial Hospital in Mumbai, detailed these findings in the Journal of Medical Ethics.

The researchers reviewed the content of 84 first-warning letters issued by the FDA following site visits between 2005 and 2012.

Sponsor violations

Forty-six warning letters were issued to trial sponsors. Their most common violations were failure to follow the monitoring schedule (58.69%) and failure to obtain investigator agreement (34.78%).

The same proportion of sponsors (30.43%) failed to secure investigators’ compliance and failed to maintain records, both of study data and for shipping product to the investigator.

Other violations included failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA (28.26%) and failure to review, evaluate, and submit adverse drug event reports to the FDA (23.91%). Two sponsors did not allow FDA inspection, and 1 did not obtain IRB approval.

Investigator infractions

Twenty warning letters were issued to investigators. Ninety-five percent of the letters said investigators were guilty of deviating from the investigational plan. Fifty-five percent of letters said the researchers failed to protect subject safety and report adverse events to the IRB.

Violations regarding records—largely, the failure to maintain and produce them for inspection—were documented in 40% of the letters. And informed consent issues were highlighted in 35%.

Other violations included those related to the product under investigation (15%), failure to obtain IRB approval (10%), and failure to personally supervise the study (30%).

IRB transgressions

Eighteen warning letters were issued to IRBs. The most common violation (61.11%) was failure to follow written procedures for continuing review.

Other common violations (55.56%) were those related to membership and meetings—failure to maintain minutes, inappropriate membership, quorum issues, misuse of expedited review, and the lack of a layperson in meetings.

The remaining violations included failure to follow regulatory requirements (44.4%), failure to follow standard operating procedures and maintain documentation (44.44%), failure to address risk minimization and protect vulnerable subjects (22.22%), conflicts of interest and informed consent issues (27.78%), and failure to appoint a qualified investigator (5.55%).

Comparing past and present

The study authors compared their findings with previously published research in the same arena, dating back as far as 1997. They found that regulatory compliance generally improved over the years, but supervision worsened.

And 2 new serious violations cropped up in the interim: failure to get the green light from an IRB before pressing ahead and submitting false data to the FDA and/or sponsors.

In a bid to boost compliance with good clinical practice, the authors suggest that every regulatory agency charged with overseeing clinical trials should pay main participating centers a visit and regularly publish the details of their findings.

Although the incidence of lung cancer in the United States has been falling in recent years because of a decrease in cigarette smoking, the disease is still the third most common cancer, and the leading cause of cancer death. In March 2014, the US Preventive Services Task Force (USPSTF) updated its 2004 recommendations for lung cancer screening by commissioning a systematic evidence review of low-dose computed tomography (CT) by focusing on new evidence from randomized clinical trials published since 2004. In addition, a modeling study provided information about the optimum screening age, screening interval, and the risk-benefit ratio for screening.
 

Click on the PDF icon at the top of this introduction to read the full article.

Although the incidence of lung cancer in the United States has been falling in recent years because of a decrease in cigarette smoking, the disease is still the third most common cancer, and the leading cause of cancer death. In March 2014, the US Preventive Services Task Force (USPSTF) updated its 2004 recommendations for lung cancer screening by commissioning a systematic evidence review of low-dose computed tomography (CT) by focusing on new evidence from randomized clinical trials published since 2004. In addition, a modeling study provided information about the optimum screening age, screening interval, and the risk-benefit ratio for screening.
 

Click on the PDF icon at the top of this introduction to read the full article.

Although the incidence of lung cancer in the United States has been falling in recent years because of a decrease in cigarette smoking, the disease is still the third most common cancer, and the leading cause of cancer death. In March 2014, the US Preventive Services Task Force (USPSTF) updated its 2004 recommendations for lung cancer screening by commissioning a systematic evidence review of low-dose computed tomography (CT) by focusing on new evidence from randomized clinical trials published since 2004. In addition, a modeling study provided information about the optimum screening age, screening interval, and the risk-benefit ratio for screening.
 

Click on the PDF icon at the top of this introduction to read the full article.

Lab mouse

A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.

Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.

Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.

Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.

The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.

Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).

In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.

Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.

By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.

So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.

“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.

“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”

Lab mouse

A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.

Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.

Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.

Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.

The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.

Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).

In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.

Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.

By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.

So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.

“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.

“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”

Lab mouse

A bromodomain and extraterminal (BET) inhibitor known as RVX2135 has shown preclinical activity against Myc-driven lymphoma.

Both in vitro and in vivo, RVX2135 inhibited proliferation and prompted apoptosis in lymphoma cells.

Investigation revealed that RVX2135 induces effects similar to those of histone deacetylase (HDAC) inhibitors. Furthermore, RVX2135 and the HDAC inhibitor vorinostat demonstrated synergy in lymphoma-bearing mice.

Jonas Nilsson, PhD, of the University of Gothenburg in Sweden, and his colleagues reported these results in Proceedings of the National Academy of Sciences.

The researchers first evaluated the in vitro antiproliferative effects of RVX2135 and another BET inhibitor called JQ1. They tested the inhibitors on lymphoma cells from Myc-transgenic mice and found that both restricted proliferation and induced apoptosis in a dose-dependent manner.

Next, the team tested RVX2135 in 2 mouse models of lymphoma. The inhibitor was most effective in mice transplanted with dispersed lymphoma from a λ-Myc mouse (ID 2749).

In fact, RVX2135 doubled both the median and overall survival of mice carrying 2749 lymphoma, when compared to vehicle-treated controls.

Dr Nilsson and his colleagues then investigated the mechanism behind these effects. They found that RVX2135 induces a complex transcriptional program without specifically inactivating transgenic Myc transcription.

By examining the genes induced by BET inhibition, the researchers discovered that RVX2135 activates the same genes as those activated by HDAC inhibitors.

So the team tested the HDAC inhibitor vorinostat in combination with RVX2135. And the combination increased survival in mice with 2749 lymphoma, when compared to either inhibitor alone.

“It was also possible to reduce the dose of HDAC inhibitors when used in combination with RVX2135, and this reduced adverse effects,” Dr Nilsson said.

“We see this as a breakthrough in the clinical development of this type of treatment. [W]e believe that the prospects for success with combination treatments are good.”

Drug release in a cancer cell

Credit: PNAS

Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.

Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.

And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.

This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.

“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.

“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”

The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.

Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.

Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.

The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.

Drug release in a cancer cell

Credit: PNAS

Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.

Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.

And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.

This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.

“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.

“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”

The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.

Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.

Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.

The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.

Drug release in a cancer cell

Credit: PNAS

Laser technology can help ensure the delivery of drug and gene therapy at the cellular level without damaging surrounding tissue, according to research published in Nature Scientific Reports.

Investigators paired crystalline magnetic carbon nanoparticles and continuous wave near-infrared laser beams in what is called photothermal delivery.

And they used this delivery method to introduce impermeable dyes and small DNA molecules into human cancer cells.

This work grew out of a previous study in which the researchers used a 50 to 100 milliwatt laser and the same carbon nanoparticle, which absorbs the beam, to heat up and destroy cancer cells in the lab.

“In [the current study, we] used a lower-power, 20 to 30 milliwatt, continuous wave near-infrared laser and the nanoparticle to permeate the cell membrane without killing the cells,” said Ali Koymen, PhD, of the University of Texas at Arlington.

“This method stretches the desired cell membrane to allow for delivery and has the added bonus of creating a fluid flow that speeds the movement of what is being delivered.”

The investigators noted that, currently, the predominant practice is using viruses for delivery to cells. Unfortunately, the scope of what can be delivered with viruses is severely limited, and virus interaction can lead to inflammatory responses and other complications.

Researchers looking to create a path into the cell without employing a virus have experimented with using UV-visible light laser beams alone. But that method damages surrounding cells and has a relatively shallow level of effectiveness.

Dr Koymen and his colleagues said a significant advantage of their method is that the near-infrared light absorption of the nanoparticle can be used to selectively amplify the interaction of low-power laser with targeted tissue, and laser-induced damage to non-targeted cells can be avoided.

The magnetic properties of the nanoparticles also mean they can be localized with an external magnetic field. Therefore, a smaller concentration can be used effectively.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

The incidence of kidney cancer in the United States is rising because the increased use of cross-sectional imaging is resulting in more tumors being detected and because the population is aging. In addition, a stage migration in kidney cancer has been observed, again because of improved detection, with an increase in stage T1 tumors and a concomitant decrease in the number of stage T2 to T4 tumors. Recent studies have shown that up to 80% of small renal tumors (SRTs) either have an indolent course or are histologically benign. These findings raise the question of what the optimal management of SRTs should be. Radical nephrectomy, the traditional, most aggressive, and still most frequently used extirpative surgery, has been shown to increase the risk of chronic kidney disease. Therefore, during the past 2 decades there has been a shift toward nephron-sparing surgery in carefully selected patients as such procedures have demonstrated equivalent oncologic outcomes with a decrease in long-term renal-induced morbidities.

Click on the PDF icon at the top of this introduction to read the full article.

The incidence of kidney cancer in the United States is rising because the increased use of cross-sectional imaging is resulting in more tumors being detected and because the population is aging. In addition, a stage migration in kidney cancer has been observed, again because of improved detection, with an increase in stage T1 tumors and a concomitant decrease in the number of stage T2 to T4 tumors. Recent studies have shown that up to 80% of small renal tumors (SRTs) either have an indolent course or are histologically benign. These findings raise the question of what the optimal management of SRTs should be. Radical nephrectomy, the traditional, most aggressive, and still most frequently used extirpative surgery, has been shown to increase the risk of chronic kidney disease. Therefore, during the past 2 decades there has been a shift toward nephron-sparing surgery in carefully selected patients as such procedures have demonstrated equivalent oncologic outcomes with a decrease in long-term renal-induced morbidities.

Click on the PDF icon at the top of this introduction to read the full article.

The incidence of kidney cancer in the United States is rising because the increased use of cross-sectional imaging is resulting in more tumors being detected and because the population is aging. In addition, a stage migration in kidney cancer has been observed, again because of improved detection, with an increase in stage T1 tumors and a concomitant decrease in the number of stage T2 to T4 tumors. Recent studies have shown that up to 80% of small renal tumors (SRTs) either have an indolent course or are histologically benign. These findings raise the question of what the optimal management of SRTs should be. Radical nephrectomy, the traditional, most aggressive, and still most frequently used extirpative surgery, has been shown to increase the risk of chronic kidney disease. Therefore, during the past 2 decades there has been a shift toward nephron-sparing surgery in carefully selected patients as such procedures have demonstrated equivalent oncologic outcomes with a decrease in long-term renal-induced morbidities.

Click on the PDF icon at the top of this introduction to read the full article.

People with a higher education recover better from a moderate to severe traumatic brain injury (TBI), according to a study published May 6 in Neurology. Researchers found that patients with the equivalent of at least a college education were seven times more likely than those who did not finish high school to be disability-free one year after a TBI. The investigators examined 769 patients, 219 of whom were free of any detectable disability. The study authors theorized that TBI patients with increased cognitive reserve capabilities may heal in a different way that allows them to return to their pre-injury function. These patients also may be able to adapt and form new pathways in their brains to compensate for the injury.

The risk of stroke may be reduced by eating more fruits and vegetables, according to a study published online ahead of print May 8 in Stroke. Researchers conducted a meta-analysis of 20 studies published within the past 19 years to assess the effects of fruit and vegetable consumption on the risk of stroke; the combined studies included 760,629 men and 16,981 women who previously had strokes. The findings suggest that stroke risk decreased by 32% with every 200 grams of fruit consumed daily and 11% with every 200 grams of vegetables consumed daily. The investigators combined the results of six studies from the United States, six from Asia, and eight from Europe. “Improving diet and lifestyle is critical for heart and stroke risk reduction in the general population,” the researchers stated.

One-third of all unruptured intracranial aneurysms in people of working age ruptured during a lifelong follow-up, according to a study published online ahead of print May 22 in Stroke. Researchers monitored 118 patients (median age at diagnosis, 43.5) with aneurysms from 1956 until death or subarachnoid hemorrhage occurred. The risk of rupture was particularly high for female smokers with brain aneurysms 7 mm or more in diameter, and the size of an aneurysm had little impact on its risk for rupture, particularly for men. The risk of rupture among nonsmoking men was also exceptionally low. “Because even small unruptured intracranial aneurysms ruptured, treatment decisions of unruptured intracranial aneurysms should perhaps be based on the risk factor status,” the investigators concluded.

An international group of researchers in multiple sclerosis (MS) has proposed updated clinical course descriptions of the disease, according to a report published online ahead of print May 28 in Neurology. The International Advisory Committee on Clinical Trials of MS, which is jointly supported by the National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS), suggested that clinicians not only determine a person’s course of MS, but also further subcategorize that course as active or not active and progressing or not progressing, based on clinical evidence of changes in disability. Another recommended area for further research by the committee includes long-term studies to track people with MS over time. “These revisions should make communication with patients and among physicians clearer and should also enhance the design, recruitment, and conduct of future clinical trials,” the investigators stated.

A moderate level of dietary protein intake may lower the risk of stroke, according to a meta-analysis that was published online ahead of print June 11 in Neurology. The analysis consisted of seven studies with a total of 254,489 participants who were followed for an average of 14 years. Overall, participants with the highest amount of protein in their diets were 20% less likely to develop a stroke, compared with those who had the lowest amount of protein in their diets. For every extra 20 grams per day of protein eaten, the risk of stroke decreased by 26%. The results accounted for other factors that could affect the risk of stroke, such as high cholesterol and smoking. “These results indicate that stroke risk may be reduced by replacing red meat with other protein sources, such as fish,” stated the researchers.

The FDA will review Genzyme’s resubmission of its supplemental Biologics License Application seeking approval of Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The resubmission is based on data from the same clinical trials included in the original application. It also provides additional information and supplemental analyses to address issues previously outlined by the FDA in its December 27, 2013, Complete Response Letter. A six-month review period has been assigned, and Genzyme (Cambridge, Massachusetts) expects the FDA to begin that review in the fourth quarter.

The risk of developing cognitive impairment is significantly higher for individuals with poor cardiovascular health than for those with intermediate or ideal cardiovascular health, investigators reported June 11 in the Journal of the American Heart Association. The study included 17,761 people ages 45 and older who had normal cognitive function and no history of stroke (mental function was evaluated four years later). The researchers used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study to determine cardiovascular health status based on the American Heart Association Life’s Simple 7 score. Study findings showed that people with the lowest cardiovascular health scores were more likely to have impairment on learning, memory, and verbal fluency tests than were their counterparts with intermediate or better risk profiles.

Researchers have developed an MRI technique that aids in the early diagnosis of Parkinson’s disease with 85% accuracy, according to a study published online ahead of print June 11 in Neurology. The investigators compared 19 people with early-stage Parkinson’s disease while not on medication with 19 healthy people, matched for gender and age. Data suggest that patients with Parkinson’s disease had much lower connectivity in the basal ganglia. The researchers defined a threshold level of connectivity within the basal ganglia network. Connectivity below this level helped to predict who had Parkinson’s disease with 100% sensitivity and 89.5% specificity. The study authors also conducted their MRI test in a second group of 13 early-stage Parkinson’s patients as a validation of the approach; they correctly identified 11 of the 13 patients.

Blood pressure in later life may affect brain pathology and cognitive performance, depending on blood pressure at midlife, according to a study that was published online ahead of print June 4 in Neurology. Researchers examined data regarding 4,057 older participants (average age, 76) without dementia whose blood pressure had been measured during middle age. The patients’ blood pressure was measured again, and participants underwent MRI and tests of memory and cognition. Higher blood pressure in late life was associated with an increased risk of brain lesions, especially among patients without high blood pressure in middle age. Among participants with high blood pressure in middle age, lower diastolic blood pressure in late life was associated with smaller brain volumes and decreased memory and cognitive performance.

A copper compound could provide a therapy for patients with amyotrophic lateral sclerosis (ALS), according to a study that was published June 4 in the Journal of Neuroscience. Mutations in copper–zinc-superoxide dismutase (SOD1) are believed to cause ALS in humans and transgenic mice. Investigators found that most SOD1 in the spinal cord of mouse models of ALS was copper deficient. Treatment with copper (ATSM) decreased the pool of copper-deficient SOD1 and increased the pool of fully metallated SOD1 in the mice’s spinal cords. In addition, the compound significantly extended the mice’s survival and improved their locomotor function. When the researchers tracked isotopically enriched copper, they found that the increase in fully metallated SOD1 depended on the transfer of copper from copper (ATSM) to SOD1, suggesting that increased copper content of mutant SOD1 improved survival and locomotor function.

Quantitative susceptibility (QS) MRI may reflect disease progression accurately in patients with multiple sclerosis (MS), according to a study published online ahead of print May 4 in Radiology. Twenty-five patients with relapsing-remitting MS or clinically isolated syndrome and 15 age- and sex-matched controls underwent 7-T MRI. Researchers computed quantitative maps of MRI susceptibility parameters. The QS maps identified voxel-level increases in iron deposition in the subcortical gray matter of patients with MS, compared with controls. QS was strongly correlated with patients’ Expanded Disability Status Scale (EDSS) scores. The volume of total white matter damage on QS maps correlated significantly with EDSS. Voxelwise QS indicated that age contributed to demyelination in patients with MS, suggesting that age-adjusted clinical scores may provide robust measures of disease severity.

—Kimberly Williams

People with a higher education recover better from a moderate to severe traumatic brain injury (TBI), according to a study published May 6 in Neurology. Researchers found that patients with the equivalent of at least a college education were seven times more likely than those who did not finish high school to be disability-free one year after a TBI. The investigators examined 769 patients, 219 of whom were free of any detectable disability. The study authors theorized that TBI patients with increased cognitive reserve capabilities may heal in a different way that allows them to return to their pre-injury function. These patients also may be able to adapt and form new pathways in their brains to compensate for the injury.

The risk of stroke may be reduced by eating more fruits and vegetables, according to a study published online ahead of print May 8 in Stroke. Researchers conducted a meta-analysis of 20 studies published within the past 19 years to assess the effects of fruit and vegetable consumption on the risk of stroke; the combined studies included 760,629 men and 16,981 women who previously had strokes. The findings suggest that stroke risk decreased by 32% with every 200 grams of fruit consumed daily and 11% with every 200 grams of vegetables consumed daily. The investigators combined the results of six studies from the United States, six from Asia, and eight from Europe. “Improving diet and lifestyle is critical for heart and stroke risk reduction in the general population,” the researchers stated.

One-third of all unruptured intracranial aneurysms in people of working age ruptured during a lifelong follow-up, according to a study published online ahead of print May 22 in Stroke. Researchers monitored 118 patients (median age at diagnosis, 43.5) with aneurysms from 1956 until death or subarachnoid hemorrhage occurred. The risk of rupture was particularly high for female smokers with brain aneurysms 7 mm or more in diameter, and the size of an aneurysm had little impact on its risk for rupture, particularly for men. The risk of rupture among nonsmoking men was also exceptionally low. “Because even small unruptured intracranial aneurysms ruptured, treatment decisions of unruptured intracranial aneurysms should perhaps be based on the risk factor status,” the investigators concluded.

An international group of researchers in multiple sclerosis (MS) has proposed updated clinical course descriptions of the disease, according to a report published online ahead of print May 28 in Neurology. The International Advisory Committee on Clinical Trials of MS, which is jointly supported by the National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS), suggested that clinicians not only determine a person’s course of MS, but also further subcategorize that course as active or not active and progressing or not progressing, based on clinical evidence of changes in disability. Another recommended area for further research by the committee includes long-term studies to track people with MS over time. “These revisions should make communication with patients and among physicians clearer and should also enhance the design, recruitment, and conduct of future clinical trials,” the investigators stated.

A moderate level of dietary protein intake may lower the risk of stroke, according to a meta-analysis that was published online ahead of print June 11 in Neurology. The analysis consisted of seven studies with a total of 254,489 participants who were followed for an average of 14 years. Overall, participants with the highest amount of protein in their diets were 20% less likely to develop a stroke, compared with those who had the lowest amount of protein in their diets. For every extra 20 grams per day of protein eaten, the risk of stroke decreased by 26%. The results accounted for other factors that could affect the risk of stroke, such as high cholesterol and smoking. “These results indicate that stroke risk may be reduced by replacing red meat with other protein sources, such as fish,” stated the researchers.

The FDA will review Genzyme’s resubmission of its supplemental Biologics License Application seeking approval of Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The resubmission is based on data from the same clinical trials included in the original application. It also provides additional information and supplemental analyses to address issues previously outlined by the FDA in its December 27, 2013, Complete Response Letter. A six-month review period has been assigned, and Genzyme (Cambridge, Massachusetts) expects the FDA to begin that review in the fourth quarter.

The risk of developing cognitive impairment is significantly higher for individuals with poor cardiovascular health than for those with intermediate or ideal cardiovascular health, investigators reported June 11 in the Journal of the American Heart Association. The study included 17,761 people ages 45 and older who had normal cognitive function and no history of stroke (mental function was evaluated four years later). The researchers used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study to determine cardiovascular health status based on the American Heart Association Life’s Simple 7 score. Study findings showed that people with the lowest cardiovascular health scores were more likely to have impairment on learning, memory, and verbal fluency tests than were their counterparts with intermediate or better risk profiles.

Researchers have developed an MRI technique that aids in the early diagnosis of Parkinson’s disease with 85% accuracy, according to a study published online ahead of print June 11 in Neurology. The investigators compared 19 people with early-stage Parkinson’s disease while not on medication with 19 healthy people, matched for gender and age. Data suggest that patients with Parkinson’s disease had much lower connectivity in the basal ganglia. The researchers defined a threshold level of connectivity within the basal ganglia network. Connectivity below this level helped to predict who had Parkinson’s disease with 100% sensitivity and 89.5% specificity. The study authors also conducted their MRI test in a second group of 13 early-stage Parkinson’s patients as a validation of the approach; they correctly identified 11 of the 13 patients.

Blood pressure in later life may affect brain pathology and cognitive performance, depending on blood pressure at midlife, according to a study that was published online ahead of print June 4 in Neurology. Researchers examined data regarding 4,057 older participants (average age, 76) without dementia whose blood pressure had been measured during middle age. The patients’ blood pressure was measured again, and participants underwent MRI and tests of memory and cognition. Higher blood pressure in late life was associated with an increased risk of brain lesions, especially among patients without high blood pressure in middle age. Among participants with high blood pressure in middle age, lower diastolic blood pressure in late life was associated with smaller brain volumes and decreased memory and cognitive performance.

A copper compound could provide a therapy for patients with amyotrophic lateral sclerosis (ALS), according to a study that was published June 4 in the Journal of Neuroscience. Mutations in copper–zinc-superoxide dismutase (SOD1) are believed to cause ALS in humans and transgenic mice. Investigators found that most SOD1 in the spinal cord of mouse models of ALS was copper deficient. Treatment with copper (ATSM) decreased the pool of copper-deficient SOD1 and increased the pool of fully metallated SOD1 in the mice’s spinal cords. In addition, the compound significantly extended the mice’s survival and improved their locomotor function. When the researchers tracked isotopically enriched copper, they found that the increase in fully metallated SOD1 depended on the transfer of copper from copper (ATSM) to SOD1, suggesting that increased copper content of mutant SOD1 improved survival and locomotor function.

Quantitative susceptibility (QS) MRI may reflect disease progression accurately in patients with multiple sclerosis (MS), according to a study published online ahead of print May 4 in Radiology. Twenty-five patients with relapsing-remitting MS or clinically isolated syndrome and 15 age- and sex-matched controls underwent 7-T MRI. Researchers computed quantitative maps of MRI susceptibility parameters. The QS maps identified voxel-level increases in iron deposition in the subcortical gray matter of patients with MS, compared with controls. QS was strongly correlated with patients’ Expanded Disability Status Scale (EDSS) scores. The volume of total white matter damage on QS maps correlated significantly with EDSS. Voxelwise QS indicated that age contributed to demyelination in patients with MS, suggesting that age-adjusted clinical scores may provide robust measures of disease severity.

—Kimberly Williams

People with a higher education recover better from a moderate to severe traumatic brain injury (TBI), according to a study published May 6 in Neurology. Researchers found that patients with the equivalent of at least a college education were seven times more likely than those who did not finish high school to be disability-free one year after a TBI. The investigators examined 769 patients, 219 of whom were free of any detectable disability. The study authors theorized that TBI patients with increased cognitive reserve capabilities may heal in a different way that allows them to return to their pre-injury function. These patients also may be able to adapt and form new pathways in their brains to compensate for the injury.

The risk of stroke may be reduced by eating more fruits and vegetables, according to a study published online ahead of print May 8 in Stroke. Researchers conducted a meta-analysis of 20 studies published within the past 19 years to assess the effects of fruit and vegetable consumption on the risk of stroke; the combined studies included 760,629 men and 16,981 women who previously had strokes. The findings suggest that stroke risk decreased by 32% with every 200 grams of fruit consumed daily and 11% with every 200 grams of vegetables consumed daily. The investigators combined the results of six studies from the United States, six from Asia, and eight from Europe. “Improving diet and lifestyle is critical for heart and stroke risk reduction in the general population,” the researchers stated.

One-third of all unruptured intracranial aneurysms in people of working age ruptured during a lifelong follow-up, according to a study published online ahead of print May 22 in Stroke. Researchers monitored 118 patients (median age at diagnosis, 43.5) with aneurysms from 1956 until death or subarachnoid hemorrhage occurred. The risk of rupture was particularly high for female smokers with brain aneurysms 7 mm or more in diameter, and the size of an aneurysm had little impact on its risk for rupture, particularly for men. The risk of rupture among nonsmoking men was also exceptionally low. “Because even small unruptured intracranial aneurysms ruptured, treatment decisions of unruptured intracranial aneurysms should perhaps be based on the risk factor status,” the investigators concluded.

An international group of researchers in multiple sclerosis (MS) has proposed updated clinical course descriptions of the disease, according to a report published online ahead of print May 28 in Neurology. The International Advisory Committee on Clinical Trials of MS, which is jointly supported by the National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS), suggested that clinicians not only determine a person’s course of MS, but also further subcategorize that course as active or not active and progressing or not progressing, based on clinical evidence of changes in disability. Another recommended area for further research by the committee includes long-term studies to track people with MS over time. “These revisions should make communication with patients and among physicians clearer and should also enhance the design, recruitment, and conduct of future clinical trials,” the investigators stated.

A moderate level of dietary protein intake may lower the risk of stroke, according to a meta-analysis that was published online ahead of print June 11 in Neurology. The analysis consisted of seven studies with a total of 254,489 participants who were followed for an average of 14 years. Overall, participants with the highest amount of protein in their diets were 20% less likely to develop a stroke, compared with those who had the lowest amount of protein in their diets. For every extra 20 grams per day of protein eaten, the risk of stroke decreased by 26%. The results accounted for other factors that could affect the risk of stroke, such as high cholesterol and smoking. “These results indicate that stroke risk may be reduced by replacing red meat with other protein sources, such as fish,” stated the researchers.

The FDA will review Genzyme’s resubmission of its supplemental Biologics License Application seeking approval of Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The resubmission is based on data from the same clinical trials included in the original application. It also provides additional information and supplemental analyses to address issues previously outlined by the FDA in its December 27, 2013, Complete Response Letter. A six-month review period has been assigned, and Genzyme (Cambridge, Massachusetts) expects the FDA to begin that review in the fourth quarter.

The risk of developing cognitive impairment is significantly higher for individuals with poor cardiovascular health than for those with intermediate or ideal cardiovascular health, investigators reported June 11 in the Journal of the American Heart Association. The study included 17,761 people ages 45 and older who had normal cognitive function and no history of stroke (mental function was evaluated four years later). The researchers used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study to determine cardiovascular health status based on the American Heart Association Life’s Simple 7 score. Study findings showed that people with the lowest cardiovascular health scores were more likely to have impairment on learning, memory, and verbal fluency tests than were their counterparts with intermediate or better risk profiles.

Researchers have developed an MRI technique that aids in the early diagnosis of Parkinson’s disease with 85% accuracy, according to a study published online ahead of print June 11 in Neurology. The investigators compared 19 people with early-stage Parkinson’s disease while not on medication with 19 healthy people, matched for gender and age. Data suggest that patients with Parkinson’s disease had much lower connectivity in the basal ganglia. The researchers defined a threshold level of connectivity within the basal ganglia network. Connectivity below this level helped to predict who had Parkinson’s disease with 100% sensitivity and 89.5% specificity. The study authors also conducted their MRI test in a second group of 13 early-stage Parkinson’s patients as a validation of the approach; they correctly identified 11 of the 13 patients.

Blood pressure in later life may affect brain pathology and cognitive performance, depending on blood pressure at midlife, according to a study that was published online ahead of print June 4 in Neurology. Researchers examined data regarding 4,057 older participants (average age, 76) without dementia whose blood pressure had been measured during middle age. The patients’ blood pressure was measured again, and participants underwent MRI and tests of memory and cognition. Higher blood pressure in late life was associated with an increased risk of brain lesions, especially among patients without high blood pressure in middle age. Among participants with high blood pressure in middle age, lower diastolic blood pressure in late life was associated with smaller brain volumes and decreased memory and cognitive performance.

A copper compound could provide a therapy for patients with amyotrophic lateral sclerosis (ALS), according to a study that was published June 4 in the Journal of Neuroscience. Mutations in copper–zinc-superoxide dismutase (SOD1) are believed to cause ALS in humans and transgenic mice. Investigators found that most SOD1 in the spinal cord of mouse models of ALS was copper deficient. Treatment with copper (ATSM) decreased the pool of copper-deficient SOD1 and increased the pool of fully metallated SOD1 in the mice’s spinal cords. In addition, the compound significantly extended the mice’s survival and improved their locomotor function. When the researchers tracked isotopically enriched copper, they found that the increase in fully metallated SOD1 depended on the transfer of copper from copper (ATSM) to SOD1, suggesting that increased copper content of mutant SOD1 improved survival and locomotor function.

Quantitative susceptibility (QS) MRI may reflect disease progression accurately in patients with multiple sclerosis (MS), according to a study published online ahead of print May 4 in Radiology. Twenty-five patients with relapsing-remitting MS or clinically isolated syndrome and 15 age- and sex-matched controls underwent 7-T MRI. Researchers computed quantitative maps of MRI susceptibility parameters. The QS maps identified voxel-level increases in iron deposition in the subcortical gray matter of patients with MS, compared with controls. QS was strongly correlated with patients’ Expanded Disability Status Scale (EDSS) scores. The volume of total white matter damage on QS maps correlated significantly with EDSS. Voxelwise QS indicated that age contributed to demyelination in patients with MS, suggesting that age-adjusted clinical scores may provide robust measures of disease severity.

—Kimberly Williams