Neuro-oncology

NEW ORLEANS — For the treatment of pediatric brain cancer, more than 25% of radiation oncologists said they would not expect parents to partake in decision making for scenarios with a high risk for neurocognitive impairment, according to a study by Dr. Robert Olson, a resident in radiation oncology at the University of British Columbia in Vancouver.

“Cure rates for pediatric cancers have risen, but at the cost of increased late effects. Historically, physicians have decided on the trade-off between cure and late effects. More recently, patients' right to choose their own risk/benefit ratio has been accepted in adult oncology, but it is less accepted in pediatric oncology, and oncologists' views about joint decision making have not been well evaluated,” Dr. Olson said at the meeting.

The survey, developed by the British Columbia Cancer Agency, collected demographic information, practice patterns, and views on informed consent and joint decision making from 56 oncologists, 84% of whom were radiation oncologists. They primarily practiced in the United States (39%), Canada (30%), and Europe (25%), for a mean of 19 years.

Shared decision making was defined as a process in which the patient and the clinician share information with each other, take steps to participate in the process, and agree on a course of action. Patients can delegate the decision to the physician, but would share in the discussion first, Dr. Olson noted.

Several hypothetical cases were presented to illustrate the difficulty in quantifying the risk/benefit ratio and the complexity of discussions.

The first case involved a 5-year-old boy with metastatic medulloblastoma to the craniospinal axis for which radiation treatment would likely cause severe cognitive impairment. In this scenario, 100% of respondents said they would discuss cognitive side effects with the parents, and 84% said they would find these discussions stressful. The more complicated scenario was case number two, involving a 4-year-old boy with a completely excised medulloblastoma that was confined to the posterior fossa. The treatment choices were radiotherapy with minimally intense chemotherapy, which offered an 80%-90% chance of cure but a high risk of neurocognitive impairment, and high-dose chemotherapy with stem cell rescue, which offered a 40%-70% chance of cure but a low risk for neurocognitive impairment. For treatment, 84% of respondents chose radiotherapy, which could be partly explained by the fact that most responders were radiation oncologists.

For this scenario, 72% of respondents indicated that there was a role for joint decision making with parents, whereas 23% felt there was not. Their answers did not differ significantly according to age, sex, country, years in practice, time spent with patients, and number of new patients per year.

The oncologists' comments for this scenario included: “Parents must have a say and a choice of treatment”; “Clinicians should guide but not burden the parents to decide”; and “It is important not to make the parents the final deciders, as they may well carry significant guilt if there are adverse outcomes.”

“It is worrisome that only [three-quarters or less] of oncologists feel that parents should have a say in these treatment decisions,” Dr. Olson remarked, “but, still, there has been a shift toward shared decision making compared to a time when parents were not often given a say at all.”

NEW ORLEANS — For the treatment of pediatric brain cancer, more than 25% of radiation oncologists said they would not expect parents to partake in decision making for scenarios with a high risk for neurocognitive impairment, according to a study by Dr. Robert Olson, a resident in radiation oncology at the University of British Columbia in Vancouver.

“Cure rates for pediatric cancers have risen, but at the cost of increased late effects. Historically, physicians have decided on the trade-off between cure and late effects. More recently, patients' right to choose their own risk/benefit ratio has been accepted in adult oncology, but it is less accepted in pediatric oncology, and oncologists' views about joint decision making have not been well evaluated,” Dr. Olson said at the meeting.

The survey, developed by the British Columbia Cancer Agency, collected demographic information, practice patterns, and views on informed consent and joint decision making from 56 oncologists, 84% of whom were radiation oncologists. They primarily practiced in the United States (39%), Canada (30%), and Europe (25%), for a mean of 19 years.

Shared decision making was defined as a process in which the patient and the clinician share information with each other, take steps to participate in the process, and agree on a course of action. Patients can delegate the decision to the physician, but would share in the discussion first, Dr. Olson noted.

Several hypothetical cases were presented to illustrate the difficulty in quantifying the risk/benefit ratio and the complexity of discussions.

The first case involved a 5-year-old boy with metastatic medulloblastoma to the craniospinal axis for which radiation treatment would likely cause severe cognitive impairment. In this scenario, 100% of respondents said they would discuss cognitive side effects with the parents, and 84% said they would find these discussions stressful. The more complicated scenario was case number two, involving a 4-year-old boy with a completely excised medulloblastoma that was confined to the posterior fossa. The treatment choices were radiotherapy with minimally intense chemotherapy, which offered an 80%-90% chance of cure but a high risk of neurocognitive impairment, and high-dose chemotherapy with stem cell rescue, which offered a 40%-70% chance of cure but a low risk for neurocognitive impairment. For treatment, 84% of respondents chose radiotherapy, which could be partly explained by the fact that most responders were radiation oncologists.

For this scenario, 72% of respondents indicated that there was a role for joint decision making with parents, whereas 23% felt there was not. Their answers did not differ significantly according to age, sex, country, years in practice, time spent with patients, and number of new patients per year.

The oncologists' comments for this scenario included: “Parents must have a say and a choice of treatment”; “Clinicians should guide but not burden the parents to decide”; and “It is important not to make the parents the final deciders, as they may well carry significant guilt if there are adverse outcomes.”

“It is worrisome that only [three-quarters or less] of oncologists feel that parents should have a say in these treatment decisions,” Dr. Olson remarked, “but, still, there has been a shift toward shared decision making compared to a time when parents were not often given a say at all.”

NEW ORLEANS — For the treatment of pediatric brain cancer, more than 25% of radiation oncologists said they would not expect parents to partake in decision making for scenarios with a high risk for neurocognitive impairment, according to a study by Dr. Robert Olson, a resident in radiation oncology at the University of British Columbia in Vancouver.

“Cure rates for pediatric cancers have risen, but at the cost of increased late effects. Historically, physicians have decided on the trade-off between cure and late effects. More recently, patients' right to choose their own risk/benefit ratio has been accepted in adult oncology, but it is less accepted in pediatric oncology, and oncologists' views about joint decision making have not been well evaluated,” Dr. Olson said at the meeting.

The survey, developed by the British Columbia Cancer Agency, collected demographic information, practice patterns, and views on informed consent and joint decision making from 56 oncologists, 84% of whom were radiation oncologists. They primarily practiced in the United States (39%), Canada (30%), and Europe (25%), for a mean of 19 years.

Shared decision making was defined as a process in which the patient and the clinician share information with each other, take steps to participate in the process, and agree on a course of action. Patients can delegate the decision to the physician, but would share in the discussion first, Dr. Olson noted.

Several hypothetical cases were presented to illustrate the difficulty in quantifying the risk/benefit ratio and the complexity of discussions.

The first case involved a 5-year-old boy with metastatic medulloblastoma to the craniospinal axis for which radiation treatment would likely cause severe cognitive impairment. In this scenario, 100% of respondents said they would discuss cognitive side effects with the parents, and 84% said they would find these discussions stressful. The more complicated scenario was case number two, involving a 4-year-old boy with a completely excised medulloblastoma that was confined to the posterior fossa. The treatment choices were radiotherapy with minimally intense chemotherapy, which offered an 80%-90% chance of cure but a high risk of neurocognitive impairment, and high-dose chemotherapy with stem cell rescue, which offered a 40%-70% chance of cure but a low risk for neurocognitive impairment. For treatment, 84% of respondents chose radiotherapy, which could be partly explained by the fact that most responders were radiation oncologists.

For this scenario, 72% of respondents indicated that there was a role for joint decision making with parents, whereas 23% felt there was not. Their answers did not differ significantly according to age, sex, country, years in practice, time spent with patients, and number of new patients per year.

The oncologists' comments for this scenario included: “Parents must have a say and a choice of treatment”; “Clinicians should guide but not burden the parents to decide”; and “It is important not to make the parents the final deciders, as they may well carry significant guilt if there are adverse outcomes.”

“It is worrisome that only [three-quarters or less] of oncologists feel that parents should have a say in these treatment decisions,” Dr. Olson remarked, “but, still, there has been a shift toward shared decision making compared to a time when parents were not often given a say at all.”

Major Finding: Median overall survival in patients having recurrent glioblastoma was 6.6 months with NovoTTF vs. 6.0 months with best standard chemotherapy, and NovoTTF had minimal adverse effects.

Data Source: A randomized, open-label phase III trial (the EF11 trial) among 237 patients with recurrent glioblastoma.

Disclosures: Some of the investigators were employees of, owned stock in, or received research funding from NovoCure, the manufacturer of NovoTTF.

CHICAGO — Treatment with electric fields that disrupt tumor cell processes appears to be at least as effective as the best standard chemotherapy for recurrent glioblastoma and is safe and well tolerated, according to the results of a randomized, open-label, phase III trial.

In the study of 237 patients with recurrent glioblastoma, some of whom were heavily pretreated, median overall survival was 6.6 months among those assigned to treatment with NovoTTF-100A, an investigational device that delivers low-amplitude alternating electric fields through noninvasive, disposable electrodes applied to the shaved head. Among those treated with the standard chemotherapy selected by their physicians, median survival was 6.0 months.

The main adverse event associated with NovoTTF-100A use was mild to moderate skin irritation related to the electrodes in 17% of patients, whereas patients treated with chemotherapy had higher rates of grade 3/4 hematologic adverse events and gastrointestinal adverse events.

“We were afraid that we would… induce seizures with this device,” commented lead investigator Dr. Roger Stupp, an oncologist at the University of Lausanne (Switzerland) Hospitals. But “actually, there was no increase in seizure frequency in the patients who got the NovoTTF.”

Dr. Stupp explained that the device, which is powered through a portable battery pack, “should generate forces that will disrupt and interfere with cell division and assembly of organelles, either directly or by indirect mechanisms.”

Adult patients in the United States, Europe, and Israel were eligible for the trial, called EF-11, if they had recurrent glioblastoma and a good performance status. There was no limitation on the number of prior therapies, and previous surgery for the recurrence was also allowed.

In all, 120 patients were randomized to NovoTTF, with a target of at least 20 hours of use daily, while 117 patients were randomized to best standard chemotherapy at their physician's discretion. All underwent magnetic resonance imaging every 2 months.

The patients had a median age of 54 years, and 70% were men. The median time from initial glioblastoma diagnosis was 11 months.

On average, the patients had received two prior lines of chemotherapy (range, one to five), and 26% had had surgery for their recurrence. Overall, 53% were being treated for a second or third recurrence.

Fully 78% of patients in the NovoTTF group were treated per protocol, defined as having received a dose intensity of at least 70% of that planned during the first month, Dr. Stupp reported. The median daily duration of use was 20 hours.

Similarly, 79% of patients in the chemotherapy group were treated per protocol. The chemotherapies were most often nitrosoureas, PCV (procarbazine, lomustine, and vincristine), or procarbazine (33%); bevacizumab with or without other agents (13%); platinum-based therapy (11%); and temozolomide (11%).

In an intent-to-treat analysis, median overall survival—the trial's primary efficacy end point—was 6.6 months with NovoTTF and 6.0 months with chemotherapy. The 1-year rate of survival was 23.6% vs. 20.7%, respectively, a statistically nonsignificant difference.

However, in a per-protocol analysis, median overall survival was 7.8 months with NovoTTF and 6.1 months with chemotherapy. The 1-year rate of survival in this case was 29.5% vs.19.1%, respectively (hazard ratio, 0.64; P = .01).

Similarly, the 6-month rate of progression-free survival did not differ significantly between groups on an intent-to-treat basis (24% vs. 17%), but was twice as high in the NovoTTF group on a per-protocol basis (28% vs. 14%, P = .04), according to Dr. Stupp.

He cautioned that the effects of NovoTTF may not become apparent on scans for at least several months.

The effects of NovoTTF-100A may not become apparent on MR imaging scans for at least several months.

Source DR. STUPP

My Take

Option for Failed, Intolerable Chemo

This study is intriguing because it potentially offers our patients a novel therapy with improved tolerability compared to chemotherapy. Once patients with recurrent glioblastoma have had tumor progression in spite of bevacizumab, treatment options are limited. The per-protocol data analysis was most compelling with a statistically significant overall survival of 7.8 months and 1-year survival of 29.5% with the use of the NovoTTF-100A, compared with 6.1 months and 19.1% in the chemotherapy arm.

Imaging was performed in 2-month intervals, and Dr. Stupp alludes to the fact that tumor regression may not be seen on MRI for several months. Therefore, adequate treatment time must be allowed prior to abandoning therapy. One must assume from this statement that the imaging was revealing for tumor stability rather than progression followed by regression. I question whether or not the device has any adverse radiographic effects comparable to radiation necrosis that improves over time. NovoTTF-100A is a promising therapy for patients with recurrent glioblastoma and is an exciting option for patients in whom chemotherapy has failed and or has been intolerable.

ALYX B. PORTER, M.D., is a neuro-oncologist at the Mayo Clinic Arizona. She has no relevant disclosures and wrote her commentary upon request.

Major Finding: Median overall survival in patients having recurrent glioblastoma was 6.6 months with NovoTTF vs. 6.0 months with best standard chemotherapy, and NovoTTF had minimal adverse effects.

Data Source: A randomized, open-label phase III trial (the EF11 trial) among 237 patients with recurrent glioblastoma.

Disclosures: Some of the investigators were employees of, owned stock in, or received research funding from NovoCure, the manufacturer of NovoTTF.

CHICAGO — Treatment with electric fields that disrupt tumor cell processes appears to be at least as effective as the best standard chemotherapy for recurrent glioblastoma and is safe and well tolerated, according to the results of a randomized, open-label, phase III trial.

In the study of 237 patients with recurrent glioblastoma, some of whom were heavily pretreated, median overall survival was 6.6 months among those assigned to treatment with NovoTTF-100A, an investigational device that delivers low-amplitude alternating electric fields through noninvasive, disposable electrodes applied to the shaved head. Among those treated with the standard chemotherapy selected by their physicians, median survival was 6.0 months.

The main adverse event associated with NovoTTF-100A use was mild to moderate skin irritation related to the electrodes in 17% of patients, whereas patients treated with chemotherapy had higher rates of grade 3/4 hematologic adverse events and gastrointestinal adverse events.

“We were afraid that we would… induce seizures with this device,” commented lead investigator Dr. Roger Stupp, an oncologist at the University of Lausanne (Switzerland) Hospitals. But “actually, there was no increase in seizure frequency in the patients who got the NovoTTF.”

Dr. Stupp explained that the device, which is powered through a portable battery pack, “should generate forces that will disrupt and interfere with cell division and assembly of organelles, either directly or by indirect mechanisms.”

Adult patients in the United States, Europe, and Israel were eligible for the trial, called EF-11, if they had recurrent glioblastoma and a good performance status. There was no limitation on the number of prior therapies, and previous surgery for the recurrence was also allowed.

In all, 120 patients were randomized to NovoTTF, with a target of at least 20 hours of use daily, while 117 patients were randomized to best standard chemotherapy at their physician's discretion. All underwent magnetic resonance imaging every 2 months.

The patients had a median age of 54 years, and 70% were men. The median time from initial glioblastoma diagnosis was 11 months.

On average, the patients had received two prior lines of chemotherapy (range, one to five), and 26% had had surgery for their recurrence. Overall, 53% were being treated for a second or third recurrence.

Fully 78% of patients in the NovoTTF group were treated per protocol, defined as having received a dose intensity of at least 70% of that planned during the first month, Dr. Stupp reported. The median daily duration of use was 20 hours.

Similarly, 79% of patients in the chemotherapy group were treated per protocol. The chemotherapies were most often nitrosoureas, PCV (procarbazine, lomustine, and vincristine), or procarbazine (33%); bevacizumab with or without other agents (13%); platinum-based therapy (11%); and temozolomide (11%).

In an intent-to-treat analysis, median overall survival—the trial's primary efficacy end point—was 6.6 months with NovoTTF and 6.0 months with chemotherapy. The 1-year rate of survival was 23.6% vs. 20.7%, respectively, a statistically nonsignificant difference.

However, in a per-protocol analysis, median overall survival was 7.8 months with NovoTTF and 6.1 months with chemotherapy. The 1-year rate of survival in this case was 29.5% vs.19.1%, respectively (hazard ratio, 0.64; P = .01).

Similarly, the 6-month rate of progression-free survival did not differ significantly between groups on an intent-to-treat basis (24% vs. 17%), but was twice as high in the NovoTTF group on a per-protocol basis (28% vs. 14%, P = .04), according to Dr. Stupp.

He cautioned that the effects of NovoTTF may not become apparent on scans for at least several months.

The effects of NovoTTF-100A may not become apparent on MR imaging scans for at least several months.

Source DR. STUPP

My Take

Option for Failed, Intolerable Chemo

This study is intriguing because it potentially offers our patients a novel therapy with improved tolerability compared to chemotherapy. Once patients with recurrent glioblastoma have had tumor progression in spite of bevacizumab, treatment options are limited. The per-protocol data analysis was most compelling with a statistically significant overall survival of 7.8 months and 1-year survival of 29.5% with the use of the NovoTTF-100A, compared with 6.1 months and 19.1% in the chemotherapy arm.

Imaging was performed in 2-month intervals, and Dr. Stupp alludes to the fact that tumor regression may not be seen on MRI for several months. Therefore, adequate treatment time must be allowed prior to abandoning therapy. One must assume from this statement that the imaging was revealing for tumor stability rather than progression followed by regression. I question whether or not the device has any adverse radiographic effects comparable to radiation necrosis that improves over time. NovoTTF-100A is a promising therapy for patients with recurrent glioblastoma and is an exciting option for patients in whom chemotherapy has failed and or has been intolerable.

ALYX B. PORTER, M.D., is a neuro-oncologist at the Mayo Clinic Arizona. She has no relevant disclosures and wrote her commentary upon request.

Major Finding: Median overall survival in patients having recurrent glioblastoma was 6.6 months with NovoTTF vs. 6.0 months with best standard chemotherapy, and NovoTTF had minimal adverse effects.

Data Source: A randomized, open-label phase III trial (the EF11 trial) among 237 patients with recurrent glioblastoma.

Disclosures: Some of the investigators were employees of, owned stock in, or received research funding from NovoCure, the manufacturer of NovoTTF.

CHICAGO — Treatment with electric fields that disrupt tumor cell processes appears to be at least as effective as the best standard chemotherapy for recurrent glioblastoma and is safe and well tolerated, according to the results of a randomized, open-label, phase III trial.

In the study of 237 patients with recurrent glioblastoma, some of whom were heavily pretreated, median overall survival was 6.6 months among those assigned to treatment with NovoTTF-100A, an investigational device that delivers low-amplitude alternating electric fields through noninvasive, disposable electrodes applied to the shaved head. Among those treated with the standard chemotherapy selected by their physicians, median survival was 6.0 months.

The main adverse event associated with NovoTTF-100A use was mild to moderate skin irritation related to the electrodes in 17% of patients, whereas patients treated with chemotherapy had higher rates of grade 3/4 hematologic adverse events and gastrointestinal adverse events.

“We were afraid that we would… induce seizures with this device,” commented lead investigator Dr. Roger Stupp, an oncologist at the University of Lausanne (Switzerland) Hospitals. But “actually, there was no increase in seizure frequency in the patients who got the NovoTTF.”

Dr. Stupp explained that the device, which is powered through a portable battery pack, “should generate forces that will disrupt and interfere with cell division and assembly of organelles, either directly or by indirect mechanisms.”

Adult patients in the United States, Europe, and Israel were eligible for the trial, called EF-11, if they had recurrent glioblastoma and a good performance status. There was no limitation on the number of prior therapies, and previous surgery for the recurrence was also allowed.

In all, 120 patients were randomized to NovoTTF, with a target of at least 20 hours of use daily, while 117 patients were randomized to best standard chemotherapy at their physician's discretion. All underwent magnetic resonance imaging every 2 months.

The patients had a median age of 54 years, and 70% were men. The median time from initial glioblastoma diagnosis was 11 months.

On average, the patients had received two prior lines of chemotherapy (range, one to five), and 26% had had surgery for their recurrence. Overall, 53% were being treated for a second or third recurrence.

Fully 78% of patients in the NovoTTF group were treated per protocol, defined as having received a dose intensity of at least 70% of that planned during the first month, Dr. Stupp reported. The median daily duration of use was 20 hours.

Similarly, 79% of patients in the chemotherapy group were treated per protocol. The chemotherapies were most often nitrosoureas, PCV (procarbazine, lomustine, and vincristine), or procarbazine (33%); bevacizumab with or without other agents (13%); platinum-based therapy (11%); and temozolomide (11%).

In an intent-to-treat analysis, median overall survival—the trial's primary efficacy end point—was 6.6 months with NovoTTF and 6.0 months with chemotherapy. The 1-year rate of survival was 23.6% vs. 20.7%, respectively, a statistically nonsignificant difference.

However, in a per-protocol analysis, median overall survival was 7.8 months with NovoTTF and 6.1 months with chemotherapy. The 1-year rate of survival in this case was 29.5% vs.19.1%, respectively (hazard ratio, 0.64; P = .01).

Similarly, the 6-month rate of progression-free survival did not differ significantly between groups on an intent-to-treat basis (24% vs. 17%), but was twice as high in the NovoTTF group on a per-protocol basis (28% vs. 14%, P = .04), according to Dr. Stupp.

He cautioned that the effects of NovoTTF may not become apparent on scans for at least several months.

The effects of NovoTTF-100A may not become apparent on MR imaging scans for at least several months.

Source DR. STUPP

My Take

Option for Failed, Intolerable Chemo

This study is intriguing because it potentially offers our patients a novel therapy with improved tolerability compared to chemotherapy. Once patients with recurrent glioblastoma have had tumor progression in spite of bevacizumab, treatment options are limited. The per-protocol data analysis was most compelling with a statistically significant overall survival of 7.8 months and 1-year survival of 29.5% with the use of the NovoTTF-100A, compared with 6.1 months and 19.1% in the chemotherapy arm.

Imaging was performed in 2-month intervals, and Dr. Stupp alludes to the fact that tumor regression may not be seen on MRI for several months. Therefore, adequate treatment time must be allowed prior to abandoning therapy. One must assume from this statement that the imaging was revealing for tumor stability rather than progression followed by regression. I question whether or not the device has any adverse radiographic effects comparable to radiation necrosis that improves over time. NovoTTF-100A is a promising therapy for patients with recurrent glioblastoma and is an exciting option for patients in whom chemotherapy has failed and or has been intolerable.

ALYX B. PORTER, M.D., is a neuro-oncologist at the Mayo Clinic Arizona. She has no relevant disclosures and wrote her commentary upon request.

Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.

Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.

Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.

Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.

Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”

Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.

The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.

Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.

My Take

Astrocytoma Results Are 'Encouraging'

Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.

PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.

Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.

Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.

Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.

Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.

Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”

Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.

The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.

Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.

My Take

Astrocytoma Results Are 'Encouraging'

Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.

PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.

Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.

Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.

Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.

Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.

Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”

Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.

The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.

Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.

My Take

Astrocytoma Results Are 'Encouraging'

Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.

PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.

The woman previously had undergone coronary artery bypass graft surgery and resection for colon carcinoma. She also had atrial fibrillation, hypertension, and diverticulosis, according to Dr. M. Yasir Haroon and Dr. Victor Jaramillo of Conemaugh Memorial Medical Center in Johnstown, Pa.

At the time of the incident, she had no associated headache, visual changes, dysarthria or dysphagia, tonic-clonic movements, incontinence, chest pain, palpitations, or shortness of breath.

In the emergency department, the patient was hemodynamically stable, awake, alert, and oriented. An electrocardiogram showed T-wave inversion in the lateral and inferior leads.

The woman was admitted for further evaluation of the syncopal episode and her left jaw pain. A previously performed x-ray of the mandible showed no bony abnormality. A chest x-ray performed at admission showed no acute pulmonary process.

Dr. Haroon and Dr. Jaramillo were consulted for possible trigeminal neuralgia, which may be initially experienced in short, mild attacks that may progress to longer, more frequent bouts of searing pain through the face. It is known to affect women more often than men as well as patients older than 50 years.

The neurologic exam was nonfocal. A brain MRI was performed, which showed a large, multilobular mass suggestive of meningioma in the prepontine region. The mass measured 3.6 cm craniocaudal by 3.2 cm transverse by 2.3 cm anterior-posterior, causing moderate mass effect.

An old infarction also was noted in the right basal ganglia, along with chronic white matter microvascular ischemic changes. An EEG showed slight abnormality with bilateral temporoparietal sharp wave discharges with epileptogenic potential.

A cardiac evaluation also was performed, revealing moderate stenosis of the right internal carotid artery and mild stenosis of the left internal carotid. A stress test was negative and an echocardiogram showed a left ventricular ejection fraction of 58% with no gross valvular abnormalities.

Dr. Haroon and Dr. Jaramillo concluded that the woman had trigeminal neuralgia and that her syncope episode was due to the large prepontine meningioma. Although the patient was referred for neurosurgery, she refused surgical treatment.

Posterior fossa tumors or meningiomas are rarely associated with syncope and trigeminal neuralgia in the literature. There have been very few case reports of trigeminal neuralgia caused by meningiomas located in the cerebellopontine angle and posterior fossa, Dr. Haroon noted. In this patient, the prepontine meningioma ipsilaterally compressed the trigeminal nerve. The doctors suggested that a posterior fossa tumor should be considered a potential cause of trigeminal neuralgia and syncope.

MRI shows a large lobular mass in the left prepontine region in coronal (left), T2 axial (middle), and T1 axial (right) views. PHOTOS COURTESY DR. M. YASIR HAROON

The woman previously had undergone coronary artery bypass graft surgery and resection for colon carcinoma. She also had atrial fibrillation, hypertension, and diverticulosis, according to Dr. M. Yasir Haroon and Dr. Victor Jaramillo of Conemaugh Memorial Medical Center in Johnstown, Pa.

At the time of the incident, she had no associated headache, visual changes, dysarthria or dysphagia, tonic-clonic movements, incontinence, chest pain, palpitations, or shortness of breath.

In the emergency department, the patient was hemodynamically stable, awake, alert, and oriented. An electrocardiogram showed T-wave inversion in the lateral and inferior leads.

The woman was admitted for further evaluation of the syncopal episode and her left jaw pain. A previously performed x-ray of the mandible showed no bony abnormality. A chest x-ray performed at admission showed no acute pulmonary process.

Dr. Haroon and Dr. Jaramillo were consulted for possible trigeminal neuralgia, which may be initially experienced in short, mild attacks that may progress to longer, more frequent bouts of searing pain through the face. It is known to affect women more often than men as well as patients older than 50 years.

The neurologic exam was nonfocal. A brain MRI was performed, which showed a large, multilobular mass suggestive of meningioma in the prepontine region. The mass measured 3.6 cm craniocaudal by 3.2 cm transverse by 2.3 cm anterior-posterior, causing moderate mass effect.

An old infarction also was noted in the right basal ganglia, along with chronic white matter microvascular ischemic changes. An EEG showed slight abnormality with bilateral temporoparietal sharp wave discharges with epileptogenic potential.

A cardiac evaluation also was performed, revealing moderate stenosis of the right internal carotid artery and mild stenosis of the left internal carotid. A stress test was negative and an echocardiogram showed a left ventricular ejection fraction of 58% with no gross valvular abnormalities.

Dr. Haroon and Dr. Jaramillo concluded that the woman had trigeminal neuralgia and that her syncope episode was due to the large prepontine meningioma. Although the patient was referred for neurosurgery, she refused surgical treatment.

Posterior fossa tumors or meningiomas are rarely associated with syncope and trigeminal neuralgia in the literature. There have been very few case reports of trigeminal neuralgia caused by meningiomas located in the cerebellopontine angle and posterior fossa, Dr. Haroon noted. In this patient, the prepontine meningioma ipsilaterally compressed the trigeminal nerve. The doctors suggested that a posterior fossa tumor should be considered a potential cause of trigeminal neuralgia and syncope.

MRI shows a large lobular mass in the left prepontine region in coronal (left), T2 axial (middle), and T1 axial (right) views. PHOTOS COURTESY DR. M. YASIR HAROON

The woman previously had undergone coronary artery bypass graft surgery and resection for colon carcinoma. She also had atrial fibrillation, hypertension, and diverticulosis, according to Dr. M. Yasir Haroon and Dr. Victor Jaramillo of Conemaugh Memorial Medical Center in Johnstown, Pa.

At the time of the incident, she had no associated headache, visual changes, dysarthria or dysphagia, tonic-clonic movements, incontinence, chest pain, palpitations, or shortness of breath.

In the emergency department, the patient was hemodynamically stable, awake, alert, and oriented. An electrocardiogram showed T-wave inversion in the lateral and inferior leads.

The woman was admitted for further evaluation of the syncopal episode and her left jaw pain. A previously performed x-ray of the mandible showed no bony abnormality. A chest x-ray performed at admission showed no acute pulmonary process.

Dr. Haroon and Dr. Jaramillo were consulted for possible trigeminal neuralgia, which may be initially experienced in short, mild attacks that may progress to longer, more frequent bouts of searing pain through the face. It is known to affect women more often than men as well as patients older than 50 years.

The neurologic exam was nonfocal. A brain MRI was performed, which showed a large, multilobular mass suggestive of meningioma in the prepontine region. The mass measured 3.6 cm craniocaudal by 3.2 cm transverse by 2.3 cm anterior-posterior, causing moderate mass effect.

An old infarction also was noted in the right basal ganglia, along with chronic white matter microvascular ischemic changes. An EEG showed slight abnormality with bilateral temporoparietal sharp wave discharges with epileptogenic potential.

A cardiac evaluation also was performed, revealing moderate stenosis of the right internal carotid artery and mild stenosis of the left internal carotid. A stress test was negative and an echocardiogram showed a left ventricular ejection fraction of 58% with no gross valvular abnormalities.

Dr. Haroon and Dr. Jaramillo concluded that the woman had trigeminal neuralgia and that her syncope episode was due to the large prepontine meningioma. Although the patient was referred for neurosurgery, she refused surgical treatment.

Posterior fossa tumors or meningiomas are rarely associated with syncope and trigeminal neuralgia in the literature. There have been very few case reports of trigeminal neuralgia caused by meningiomas located in the cerebellopontine angle and posterior fossa, Dr. Haroon noted. In this patient, the prepontine meningioma ipsilaterally compressed the trigeminal nerve. The doctors suggested that a posterior fossa tumor should be considered a potential cause of trigeminal neuralgia and syncope.

MRI shows a large lobular mass in the left prepontine region in coronal (left), T2 axial (middle), and T1 axial (right) views. PHOTOS COURTESY DR. M. YASIR HAROON

SALT LAKE CITY—Micro­RNAs (miRNAs) represent a previously unsuspected layer of gene regulation that is probably as complex as transcription, according to Kenneth S. Kosik, MD, who addressed the 133rd Annual Meeting of the American Neurological Association. Whereas transcription works in a combinatorial manner to turn genes on and off, miRNAs function in a complex manner to turn messages on and off by controlling their translation. This class of genes, discovered within the last decade, is of increasing relevance to various disease states, including glioblastoma and synaptic plasticity, said Dr. Kosik, who is Harriman Professor of Neuroscience Research in the Department of Molecular, Cellular, and Developmental Biology and Codirector of the Neuroscience Research Institute at the University of California, Santa Barbara.

miRNA genes are organized in the genome like any other gene, even though their product is a mere 21-nucleotide sequence that does encode a protein. These so-called noncoding transcripts are considerably more common and more abundant than was previously believed. The importance of the miRNAs is underscored by their extraordinary conservation, noted Dr. Kosik. Even 600 million years following the evolutionary diversification of animals, some miRNAs retain the identical ancestral sequence, he said. Although genomes have undergone many changes during this time period, the absence of changes in some miRNAs suggests that they serve a critical and fundamental function for many organisms, which cannot tolerate mutations in these short sequences.

miRNA Biogenesis Pathway
Like a coded gene, miRNA undergoes transcription and splicing but is then diverted to a microprocessor pathway in which it gets cut into a 70-nucleotide stem-loop structure, explained Dr. Kosik. The 70-nucleotide stem-loop structure is then exported from the nucleus into the cytoplasm by Exportin-5 and delivers the double-stranded RNA to the RNA-induced silencing complex (RISC) in the cytoplasm. As prelude to entry into the RISC, the Dicer enzyme cuts the loop from the stem, and the remaining stem is guided toward a target messenger RNA (mRNA). Then, either the target mRNA is degraded or its translation is suppressed by a stable miRNA/mRNA duplex. In this way, miRNAs control the level of specific proteins. Although Watson-Crick binding between the miRNA and the target mRNA does occur, partial complementarity of the two sequences can result in some mismatches. Each of the 500 to 1,000 miRNAs in the human genome may have as many as 300 targets, but they are very challenging to predict because of these mismatches.

miRNAs also probe expression boundaries and are present in cells to maintain their identities. For this reason, the early findings in the area of miRNAs that pertain to medicine have been related to cancer and stem cells. Cells have to cross expression boundaries to acquire new identity states. The loss of “cell identity” that occurs when a cluster of genes in a transcriptome crosses an expression boundary is related to the process by which cancer cells begin to acquire new identity states, said Dr. Kosik. Dysregulation of certain key transcripts regulated by miRNAs causes uncontrollable cell division.

Because miRNAs can affect the levels of some mRNAs, it is possible to find a miRNA signature in a transcriptional profile. To look for this signature, Dr. Kosik and colleagues examined glioma samples for highly correlated fluctuations in the miRNA and mRNA levels of each sample. Specifically, the researchers were looking for “perfect correlations” in the miRNA/mRNA relationships and found a set of 35 outliers that were highly unlikely to occur by chance. Among the findings was a high degree of correlation between miRNA-181c and the tumor suppressor gene dcaf. Despite the lack of a target relationship between these two genes, they changed consistently through every sample, suggesting that a pathway could be built from this informatically inferred relationship.

In another study profiling miRNAs in various tumors, Dr. Kosik and colleagues observed that miR-21 “was massively overexpressed in glioblastomas.” He added, “This has turned out to be the most elevated miRNA in many cancers, including breast, ovarian, and colon. Many miRNAs decline in cancer, and a few go up. miR-21 goes up more than most.” The researchers found that when miR-21 was suppressed, cell numbers declined and the amount of apoptosis increased. In addition, cells that were responsive to doxorubicin became resistant to it. miR-21 was observed to affect apoptotic pathways, directly targeting Apaf-1 as well as several elements in the p53 and transforming growth factor β (TGF-β) pathways.

“We can conclude that miR-21 regulates a functionally related network of genes in the p53 and TGF-β mitochondrial pathways by direct targeting and indirect effects,” Dr. Kosik said. He also noted, “If miRNAs will ever be used therapeutically in gliomas, we face the same problems as the RNA interference field in developing delivery methodologies.”

miRNAs and Plasticity
miRNAs function not only in a constitutive manner, maintaining lifelong cellular identity, but also in a short-term manner at the level of the synapses. To affect long-term changes at the synapses, local translation at the synapses is needed. “Synapses have nearly all of the translational machinery of cells,” said Dr. Kosik. “That allows two synapses on the same neuron to be controlled quite differently.”

Using in situ hybridization, Dr. Kosik’s group confirmed the presence of miRNA in dendrites and determined their copy numbers. Neurons have about 103 to 104 miRNAs per cell. Dr. Kosik speculated that the numbers of miRNAs may approximate the numbers of synapses. This implies either that a single synapse contains very small numbers of miRNAs or they are very unevenly distributed.

“If the numbers of [miRNAs] and synapses are very small and therefore take on stochastic properties, whether or not a synapse will go on to exhibit the translational changes needed for short-term memory has a random facet to it,” concluded Dr. Kosik.

SALT LAKE CITY—Micro­RNAs (miRNAs) represent a previously unsuspected layer of gene regulation that is probably as complex as transcription, according to Kenneth S. Kosik, MD, who addressed the 133rd Annual Meeting of the American Neurological Association. Whereas transcription works in a combinatorial manner to turn genes on and off, miRNAs function in a complex manner to turn messages on and off by controlling their translation. This class of genes, discovered within the last decade, is of increasing relevance to various disease states, including glioblastoma and synaptic plasticity, said Dr. Kosik, who is Harriman Professor of Neuroscience Research in the Department of Molecular, Cellular, and Developmental Biology and Codirector of the Neuroscience Research Institute at the University of California, Santa Barbara.

miRNA genes are organized in the genome like any other gene, even though their product is a mere 21-nucleotide sequence that does encode a protein. These so-called noncoding transcripts are considerably more common and more abundant than was previously believed. The importance of the miRNAs is underscored by their extraordinary conservation, noted Dr. Kosik. Even 600 million years following the evolutionary diversification of animals, some miRNAs retain the identical ancestral sequence, he said. Although genomes have undergone many changes during this time period, the absence of changes in some miRNAs suggests that they serve a critical and fundamental function for many organisms, which cannot tolerate mutations in these short sequences.

miRNA Biogenesis Pathway
Like a coded gene, miRNA undergoes transcription and splicing but is then diverted to a microprocessor pathway in which it gets cut into a 70-nucleotide stem-loop structure, explained Dr. Kosik. The 70-nucleotide stem-loop structure is then exported from the nucleus into the cytoplasm by Exportin-5 and delivers the double-stranded RNA to the RNA-induced silencing complex (RISC) in the cytoplasm. As prelude to entry into the RISC, the Dicer enzyme cuts the loop from the stem, and the remaining stem is guided toward a target messenger RNA (mRNA). Then, either the target mRNA is degraded or its translation is suppressed by a stable miRNA/mRNA duplex. In this way, miRNAs control the level of specific proteins. Although Watson-Crick binding between the miRNA and the target mRNA does occur, partial complementarity of the two sequences can result in some mismatches. Each of the 500 to 1,000 miRNAs in the human genome may have as many as 300 targets, but they are very challenging to predict because of these mismatches.

miRNAs also probe expression boundaries and are present in cells to maintain their identities. For this reason, the early findings in the area of miRNAs that pertain to medicine have been related to cancer and stem cells. Cells have to cross expression boundaries to acquire new identity states. The loss of “cell identity” that occurs when a cluster of genes in a transcriptome crosses an expression boundary is related to the process by which cancer cells begin to acquire new identity states, said Dr. Kosik. Dysregulation of certain key transcripts regulated by miRNAs causes uncontrollable cell division.

Because miRNAs can affect the levels of some mRNAs, it is possible to find a miRNA signature in a transcriptional profile. To look for this signature, Dr. Kosik and colleagues examined glioma samples for highly correlated fluctuations in the miRNA and mRNA levels of each sample. Specifically, the researchers were looking for “perfect correlations” in the miRNA/mRNA relationships and found a set of 35 outliers that were highly unlikely to occur by chance. Among the findings was a high degree of correlation between miRNA-181c and the tumor suppressor gene dcaf. Despite the lack of a target relationship between these two genes, they changed consistently through every sample, suggesting that a pathway could be built from this informatically inferred relationship.

In another study profiling miRNAs in various tumors, Dr. Kosik and colleagues observed that miR-21 “was massively overexpressed in glioblastomas.” He added, “This has turned out to be the most elevated miRNA in many cancers, including breast, ovarian, and colon. Many miRNAs decline in cancer, and a few go up. miR-21 goes up more than most.” The researchers found that when miR-21 was suppressed, cell numbers declined and the amount of apoptosis increased. In addition, cells that were responsive to doxorubicin became resistant to it. miR-21 was observed to affect apoptotic pathways, directly targeting Apaf-1 as well as several elements in the p53 and transforming growth factor β (TGF-β) pathways.

“We can conclude that miR-21 regulates a functionally related network of genes in the p53 and TGF-β mitochondrial pathways by direct targeting and indirect effects,” Dr. Kosik said. He also noted, “If miRNAs will ever be used therapeutically in gliomas, we face the same problems as the RNA interference field in developing delivery methodologies.”

miRNAs and Plasticity
miRNAs function not only in a constitutive manner, maintaining lifelong cellular identity, but also in a short-term manner at the level of the synapses. To affect long-term changes at the synapses, local translation at the synapses is needed. “Synapses have nearly all of the translational machinery of cells,” said Dr. Kosik. “That allows two synapses on the same neuron to be controlled quite differently.”

Using in situ hybridization, Dr. Kosik’s group confirmed the presence of miRNA in dendrites and determined their copy numbers. Neurons have about 103 to 104 miRNAs per cell. Dr. Kosik speculated that the numbers of miRNAs may approximate the numbers of synapses. This implies either that a single synapse contains very small numbers of miRNAs or they are very unevenly distributed.

“If the numbers of [miRNAs] and synapses are very small and therefore take on stochastic properties, whether or not a synapse will go on to exhibit the translational changes needed for short-term memory has a random facet to it,” concluded Dr. Kosik.

SALT LAKE CITY—Micro­RNAs (miRNAs) represent a previously unsuspected layer of gene regulation that is probably as complex as transcription, according to Kenneth S. Kosik, MD, who addressed the 133rd Annual Meeting of the American Neurological Association. Whereas transcription works in a combinatorial manner to turn genes on and off, miRNAs function in a complex manner to turn messages on and off by controlling their translation. This class of genes, discovered within the last decade, is of increasing relevance to various disease states, including glioblastoma and synaptic plasticity, said Dr. Kosik, who is Harriman Professor of Neuroscience Research in the Department of Molecular, Cellular, and Developmental Biology and Codirector of the Neuroscience Research Institute at the University of California, Santa Barbara.

miRNA genes are organized in the genome like any other gene, even though their product is a mere 21-nucleotide sequence that does encode a protein. These so-called noncoding transcripts are considerably more common and more abundant than was previously believed. The importance of the miRNAs is underscored by their extraordinary conservation, noted Dr. Kosik. Even 600 million years following the evolutionary diversification of animals, some miRNAs retain the identical ancestral sequence, he said. Although genomes have undergone many changes during this time period, the absence of changes in some miRNAs suggests that they serve a critical and fundamental function for many organisms, which cannot tolerate mutations in these short sequences.

miRNA Biogenesis Pathway
Like a coded gene, miRNA undergoes transcription and splicing but is then diverted to a microprocessor pathway in which it gets cut into a 70-nucleotide stem-loop structure, explained Dr. Kosik. The 70-nucleotide stem-loop structure is then exported from the nucleus into the cytoplasm by Exportin-5 and delivers the double-stranded RNA to the RNA-induced silencing complex (RISC) in the cytoplasm. As prelude to entry into the RISC, the Dicer enzyme cuts the loop from the stem, and the remaining stem is guided toward a target messenger RNA (mRNA). Then, either the target mRNA is degraded or its translation is suppressed by a stable miRNA/mRNA duplex. In this way, miRNAs control the level of specific proteins. Although Watson-Crick binding between the miRNA and the target mRNA does occur, partial complementarity of the two sequences can result in some mismatches. Each of the 500 to 1,000 miRNAs in the human genome may have as many as 300 targets, but they are very challenging to predict because of these mismatches.

miRNAs also probe expression boundaries and are present in cells to maintain their identities. For this reason, the early findings in the area of miRNAs that pertain to medicine have been related to cancer and stem cells. Cells have to cross expression boundaries to acquire new identity states. The loss of “cell identity” that occurs when a cluster of genes in a transcriptome crosses an expression boundary is related to the process by which cancer cells begin to acquire new identity states, said Dr. Kosik. Dysregulation of certain key transcripts regulated by miRNAs causes uncontrollable cell division.

Because miRNAs can affect the levels of some mRNAs, it is possible to find a miRNA signature in a transcriptional profile. To look for this signature, Dr. Kosik and colleagues examined glioma samples for highly correlated fluctuations in the miRNA and mRNA levels of each sample. Specifically, the researchers were looking for “perfect correlations” in the miRNA/mRNA relationships and found a set of 35 outliers that were highly unlikely to occur by chance. Among the findings was a high degree of correlation between miRNA-181c and the tumor suppressor gene dcaf. Despite the lack of a target relationship between these two genes, they changed consistently through every sample, suggesting that a pathway could be built from this informatically inferred relationship.

In another study profiling miRNAs in various tumors, Dr. Kosik and colleagues observed that miR-21 “was massively overexpressed in glioblastomas.” He added, “This has turned out to be the most elevated miRNA in many cancers, including breast, ovarian, and colon. Many miRNAs decline in cancer, and a few go up. miR-21 goes up more than most.” The researchers found that when miR-21 was suppressed, cell numbers declined and the amount of apoptosis increased. In addition, cells that were responsive to doxorubicin became resistant to it. miR-21 was observed to affect apoptotic pathways, directly targeting Apaf-1 as well as several elements in the p53 and transforming growth factor β (TGF-β) pathways.

“We can conclude that miR-21 regulates a functionally related network of genes in the p53 and TGF-β mitochondrial pathways by direct targeting and indirect effects,” Dr. Kosik said. He also noted, “If miRNAs will ever be used therapeutically in gliomas, we face the same problems as the RNA interference field in developing delivery methodologies.”

miRNAs and Plasticity
miRNAs function not only in a constitutive manner, maintaining lifelong cellular identity, but also in a short-term manner at the level of the synapses. To affect long-term changes at the synapses, local translation at the synapses is needed. “Synapses have nearly all of the translational machinery of cells,” said Dr. Kosik. “That allows two synapses on the same neuron to be controlled quite differently.”

Using in situ hybridization, Dr. Kosik’s group confirmed the presence of miRNA in dendrites and determined their copy numbers. Neurons have about 103 to 104 miRNAs per cell. Dr. Kosik speculated that the numbers of miRNAs may approximate the numbers of synapses. This implies either that a single synapse contains very small numbers of miRNAs or they are very unevenly distributed.

“If the numbers of [miRNAs] and synapses are very small and therefore take on stochastic properties, whether or not a synapse will go on to exhibit the translational changes needed for short-term memory has a random facet to it,” concluded Dr. Kosik.

NEW ORLEANS — Functional MRI seems to be a reliable, safe, and effective technique to guide preoperative planning of brain tumor resection from eloquent cortex when used in conjunction with intraoperative stereotactic guidance, according to Kristin Houseknecht.

One benefit of using functional MRI (fMRI) preoperatively is that surgeons can avoid extensive intraoperative maneuvers such as awake craniotomy and cortical mapping.

“Awake craniotomy has the advantage of allowing real-time evaluation of function. However, there are unique intraoperative risks associated with awake craniotomy, and it also requires a willing and compliant patient,” noted Ms. Houseknecht, who is a fourth-year medical student at the University of South Florida, Tampa.

In this large series gathered as a retrospective chart review, 209 patients were identified who had undergone fMRI and then resective craniotomy under general anesthesia for either primary or secondary brain tumor in eloquent cortex between July 2002 and December 2005.

Postoperatively, 53% were neurologically stable, 30% showed neurologic improvement, and 17% experienced a decline in neurologic function.

Of those who had postoperative impairment, deficits were transient in about 30% and permanent in 13%.

Most patients in this group recovered rapidly and were discharged from the hospital within 2 days.

Tumors were located in the frontal (31%), parietal (20%), and temporal (11%) lobes, mostly within a single lobe.

Pathologically, 34% of tumors were glioblastoma, 12% grade 3 glioma, and 7% grade 2 glioma, and in a large number of patients, the brain tumors were secondary to cancer in other regions.

About half of the group had presented with motor deficits, 8% had speech deficits, and 11% had cognitive problems.

fMRI paradigms were chosen according to the function of the eloquent cortex in proximity to the brain tumor.

A test of foot flexion and extension or finger tapping was used to evaluate motor cortex and a number counting paradigm was employed to test the speech cortex.

“The majority of patients were able to satisfactorily complete the fMRI paradigms,” Ms. Houseknecht said.

Intraoperative somatosensory evoked potential monitoring was used to confirm sensory and motor cortex in some patients.

“Currently most tumors in eloquent cortex are referred to tertiary or quaternary referral centers because traditionally these cases are treated with an awake craniotomy to minimize postoperative neurologic deficits,” according to Dr. Nicolas Arredondo, a neurosurgery chief resident at the University of South Florida and one of the coinvestigators of the study.

“These preliminary data suggest that with preoperative fMRI and meticulous surgical technique, comparable outcomes may be possible in some cases without all of the resources that are required to successfully perform an awake craniotomy,” he commented.

Since the close of the enrollment date for this study, several hundred more patients with brain tumors have undergone fMRI, Ms. Houseknecht said at the American Society of Neuroradiology annual meeting.

“These results are just the tip of the iceberg,” he said.

Right motor strip (red shading) activated when the patient moved her left hand; at 1 month post resection of lesion, the patient was neurologically stable. Courtesy Dr. F. Reed Murtagh

NEW ORLEANS — Functional MRI seems to be a reliable, safe, and effective technique to guide preoperative planning of brain tumor resection from eloquent cortex when used in conjunction with intraoperative stereotactic guidance, according to Kristin Houseknecht.

One benefit of using functional MRI (fMRI) preoperatively is that surgeons can avoid extensive intraoperative maneuvers such as awake craniotomy and cortical mapping.

“Awake craniotomy has the advantage of allowing real-time evaluation of function. However, there are unique intraoperative risks associated with awake craniotomy, and it also requires a willing and compliant patient,” noted Ms. Houseknecht, who is a fourth-year medical student at the University of South Florida, Tampa.

In this large series gathered as a retrospective chart review, 209 patients were identified who had undergone fMRI and then resective craniotomy under general anesthesia for either primary or secondary brain tumor in eloquent cortex between July 2002 and December 2005.

Postoperatively, 53% were neurologically stable, 30% showed neurologic improvement, and 17% experienced a decline in neurologic function.

Of those who had postoperative impairment, deficits were transient in about 30% and permanent in 13%.

Most patients in this group recovered rapidly and were discharged from the hospital within 2 days.

Tumors were located in the frontal (31%), parietal (20%), and temporal (11%) lobes, mostly within a single lobe.

Pathologically, 34% of tumors were glioblastoma, 12% grade 3 glioma, and 7% grade 2 glioma, and in a large number of patients, the brain tumors were secondary to cancer in other regions.

About half of the group had presented with motor deficits, 8% had speech deficits, and 11% had cognitive problems.

fMRI paradigms were chosen according to the function of the eloquent cortex in proximity to the brain tumor.

A test of foot flexion and extension or finger tapping was used to evaluate motor cortex and a number counting paradigm was employed to test the speech cortex.

“The majority of patients were able to satisfactorily complete the fMRI paradigms,” Ms. Houseknecht said.

Intraoperative somatosensory evoked potential monitoring was used to confirm sensory and motor cortex in some patients.

“Currently most tumors in eloquent cortex are referred to tertiary or quaternary referral centers because traditionally these cases are treated with an awake craniotomy to minimize postoperative neurologic deficits,” according to Dr. Nicolas Arredondo, a neurosurgery chief resident at the University of South Florida and one of the coinvestigators of the study.

“These preliminary data suggest that with preoperative fMRI and meticulous surgical technique, comparable outcomes may be possible in some cases without all of the resources that are required to successfully perform an awake craniotomy,” he commented.

Since the close of the enrollment date for this study, several hundred more patients with brain tumors have undergone fMRI, Ms. Houseknecht said at the American Society of Neuroradiology annual meeting.

“These results are just the tip of the iceberg,” he said.

Right motor strip (red shading) activated when the patient moved her left hand; at 1 month post resection of lesion, the patient was neurologically stable. Courtesy Dr. F. Reed Murtagh

NEW ORLEANS — Functional MRI seems to be a reliable, safe, and effective technique to guide preoperative planning of brain tumor resection from eloquent cortex when used in conjunction with intraoperative stereotactic guidance, according to Kristin Houseknecht.

One benefit of using functional MRI (fMRI) preoperatively is that surgeons can avoid extensive intraoperative maneuvers such as awake craniotomy and cortical mapping.

“Awake craniotomy has the advantage of allowing real-time evaluation of function. However, there are unique intraoperative risks associated with awake craniotomy, and it also requires a willing and compliant patient,” noted Ms. Houseknecht, who is a fourth-year medical student at the University of South Florida, Tampa.

In this large series gathered as a retrospective chart review, 209 patients were identified who had undergone fMRI and then resective craniotomy under general anesthesia for either primary or secondary brain tumor in eloquent cortex between July 2002 and December 2005.

Postoperatively, 53% were neurologically stable, 30% showed neurologic improvement, and 17% experienced a decline in neurologic function.

Of those who had postoperative impairment, deficits were transient in about 30% and permanent in 13%.

Most patients in this group recovered rapidly and were discharged from the hospital within 2 days.

Tumors were located in the frontal (31%), parietal (20%), and temporal (11%) lobes, mostly within a single lobe.

Pathologically, 34% of tumors were glioblastoma, 12% grade 3 glioma, and 7% grade 2 glioma, and in a large number of patients, the brain tumors were secondary to cancer in other regions.

About half of the group had presented with motor deficits, 8% had speech deficits, and 11% had cognitive problems.

fMRI paradigms were chosen according to the function of the eloquent cortex in proximity to the brain tumor.

A test of foot flexion and extension or finger tapping was used to evaluate motor cortex and a number counting paradigm was employed to test the speech cortex.

“The majority of patients were able to satisfactorily complete the fMRI paradigms,” Ms. Houseknecht said.

Intraoperative somatosensory evoked potential monitoring was used to confirm sensory and motor cortex in some patients.

“Currently most tumors in eloquent cortex are referred to tertiary or quaternary referral centers because traditionally these cases are treated with an awake craniotomy to minimize postoperative neurologic deficits,” according to Dr. Nicolas Arredondo, a neurosurgery chief resident at the University of South Florida and one of the coinvestigators of the study.

“These preliminary data suggest that with preoperative fMRI and meticulous surgical technique, comparable outcomes may be possible in some cases without all of the resources that are required to successfully perform an awake craniotomy,” he commented.

Since the close of the enrollment date for this study, several hundred more patients with brain tumors have undergone fMRI, Ms. Houseknecht said at the American Society of Neuroradiology annual meeting.

“These results are just the tip of the iceberg,” he said.

Right motor strip (red shading) activated when the patient moved her left hand; at 1 month post resection of lesion, the patient was neurologically stable. Courtesy Dr. F. Reed Murtagh

CHICAGO — The wakefulness-promoting drug modafinil (marketed as Provigil) reduced self-reported severe fatigue, according to a recent study of more than 600 cancer patients who were undergoing chemotherapy.

Gary R. Morrow, Ph.D., of the University of Rochester (N.Y.) and his colleagues randomized 631 patients undergoing four cycles of chemotherapy to receive either 200 mg modafinil daily or placebo. Among those with severe fatigue at baseline, patients on modafinil had significantly greater reductions in fatigue, compared with those on placebo.

Dr. Morrow presented his study's findings at the annual meeting of the American Society of Clinical Oncology.

Study participants were asked to rate their level of fatigue at baseline (during the second cycle of chemotherapy) and during the final cycle.

They rated fatigue on a 10-point scale: mild (1–4), moderate (5–6), and severe (7–10).

A total of 67 patients reported mild fatigue at baseline; 106 and 458 reported moderate and severe fatigue, respectively.

Among patients with mild and moderate fatigue, modafinil also reduced fatigue, compared with placebo, but the differences were not significant.

This was not surprising, Dr. Morrow commented during a press briefing.

“With side effects, quite often the potency of the effect is somewhat dependent on where you began,” he said.

Modafinil—a nonamphetamine stimulant—is currently indicated for the treatment of excessive sleepiness resulting from obstructive sleep apnea, shift-work sleep disorder, and narcolepsy. Last year, researchers also at the University of Rochester reported success with modafinil in treating “chemobrain,” a reduction in cognitive function that has been associated with chemotherapy.

There may be some overlap between chemobrain and fatigue, Dr. Morrow said in an interview. Problems with executive function are commonly described in chemobrain.

Cancer-related fatigue appears to particularly affect tasks associated with executive function.

Cancer patients complain of not being able to “get around” to doing things they know they should do.

The pharmaceutical company Cephalon Inc. provided modafinil and placebo for the trial.

Dr. Morrow reported that he has no relevant financial relationships to disclose.

CHICAGO — The wakefulness-promoting drug modafinil (marketed as Provigil) reduced self-reported severe fatigue, according to a recent study of more than 600 cancer patients who were undergoing chemotherapy.

Gary R. Morrow, Ph.D., of the University of Rochester (N.Y.) and his colleagues randomized 631 patients undergoing four cycles of chemotherapy to receive either 200 mg modafinil daily or placebo. Among those with severe fatigue at baseline, patients on modafinil had significantly greater reductions in fatigue, compared with those on placebo.

Dr. Morrow presented his study's findings at the annual meeting of the American Society of Clinical Oncology.

Study participants were asked to rate their level of fatigue at baseline (during the second cycle of chemotherapy) and during the final cycle.

They rated fatigue on a 10-point scale: mild (1–4), moderate (5–6), and severe (7–10).

A total of 67 patients reported mild fatigue at baseline; 106 and 458 reported moderate and severe fatigue, respectively.

Among patients with mild and moderate fatigue, modafinil also reduced fatigue, compared with placebo, but the differences were not significant.

This was not surprising, Dr. Morrow commented during a press briefing.

“With side effects, quite often the potency of the effect is somewhat dependent on where you began,” he said.

Modafinil—a nonamphetamine stimulant—is currently indicated for the treatment of excessive sleepiness resulting from obstructive sleep apnea, shift-work sleep disorder, and narcolepsy. Last year, researchers also at the University of Rochester reported success with modafinil in treating “chemobrain,” a reduction in cognitive function that has been associated with chemotherapy.

There may be some overlap between chemobrain and fatigue, Dr. Morrow said in an interview. Problems with executive function are commonly described in chemobrain.

Cancer-related fatigue appears to particularly affect tasks associated with executive function.

Cancer patients complain of not being able to “get around” to doing things they know they should do.

The pharmaceutical company Cephalon Inc. provided modafinil and placebo for the trial.

Dr. Morrow reported that he has no relevant financial relationships to disclose.

CHICAGO — The wakefulness-promoting drug modafinil (marketed as Provigil) reduced self-reported severe fatigue, according to a recent study of more than 600 cancer patients who were undergoing chemotherapy.

Gary R. Morrow, Ph.D., of the University of Rochester (N.Y.) and his colleagues randomized 631 patients undergoing four cycles of chemotherapy to receive either 200 mg modafinil daily or placebo. Among those with severe fatigue at baseline, patients on modafinil had significantly greater reductions in fatigue, compared with those on placebo.

Dr. Morrow presented his study's findings at the annual meeting of the American Society of Clinical Oncology.

Study participants were asked to rate their level of fatigue at baseline (during the second cycle of chemotherapy) and during the final cycle.

They rated fatigue on a 10-point scale: mild (1–4), moderate (5–6), and severe (7–10).

A total of 67 patients reported mild fatigue at baseline; 106 and 458 reported moderate and severe fatigue, respectively.

Among patients with mild and moderate fatigue, modafinil also reduced fatigue, compared with placebo, but the differences were not significant.

This was not surprising, Dr. Morrow commented during a press briefing.

“With side effects, quite often the potency of the effect is somewhat dependent on where you began,” he said.

Modafinil—a nonamphetamine stimulant—is currently indicated for the treatment of excessive sleepiness resulting from obstructive sleep apnea, shift-work sleep disorder, and narcolepsy. Last year, researchers also at the University of Rochester reported success with modafinil in treating “chemobrain,” a reduction in cognitive function that has been associated with chemotherapy.

There may be some overlap between chemobrain and fatigue, Dr. Morrow said in an interview. Problems with executive function are commonly described in chemobrain.

Cancer-related fatigue appears to particularly affect tasks associated with executive function.

Cancer patients complain of not being able to “get around” to doing things they know they should do.

The pharmaceutical company Cephalon Inc. provided modafinil and placebo for the trial.

Dr. Morrow reported that he has no relevant financial relationships to disclose.

CHICAGO — Chemotherapy-related cognitive impairment was infrequent in a small study of 30 patients who underwent adjuvant chemotherapy for nonmetastatic breast cancer.

“People could be making decisions about whether or not to have chemotherapy based on stories they've heard about 'chemofog' or 'chemobrain,'” according to Dr. David G. Darby. “We hope this information will help people make informed decisions.”

Dr. Darby and his colleagues looked at a total of 30 women who had already undergone either lumpectomy or mastectomy and were scheduled to undergo either the chemotherapy regimen known as AC (n = 15) or CEF or CMF regimens (n = 15).

▸ The AC regimen involves doxorubicin 60 mg/m

▸ The CEF regimen involves cyclophosphamide administered orally in doses of 75 mg/m

▸ The CMF regimen involves cyclophosphamide 100 mg/m

The women were compared with 30 age-matched controls.

Women took several tests designed to measure cognition as well as mood a few days before initiating chemotherapy (but after the diagnosis had been given and treatment course was decided); again at the start of each new treatment cycle; and for the last time 28 days after the final treatment cycle had begun in each group. Patients were assessed on the National Institute of Mental Health's Center for Epidemiologic Studies Depression Scale (CES-D) depression, the state trait anxiety inventory (STAI) scale, and a test of Dr. Darby's own design, which measures detection speed, identification speed, working memory, and learning ability in a 10- to 12-minute battery.

Dr. Darby is the chief medical officer of a company he formed, called CogState, which produces and scores these tests. It is based in Australia and partly funded this study.

“The first finding of interest was that prior to the first cycle of chemo there was impairment in learning of moderate amplitude, and that was also associated with a mild reduction on mood scales or depressive scales,” said Dr. Darby in an interview. No women were clinically depressed (clinically depressed patients were excluded from the study) and none of the women was on antidepressants at baseline or throughout the study. However, “there may have been an impairment there initially, prior to chemo.”

Two other findings also emerged, both good and bad. “There was an improvement of some of the learning aspects of their performance and a mild improvement on scores on anxiety scales, but there was also a mild deterioration in aspects of concentration and psychomotor speed [as the study progressed].” There was also evidence that patients' mood was declining slightly throughout the treatment.

Individual patients showed “quite a lot of variation—in particular, some patients would have impairment on only one occasion and then improve, and others would have impairment on two or more occasions,” he said. Persistent impairment, that occurring on two consecutive occasions, was seen in only three patients, or 10% of the total, Dr. Darby reported at the annual meeting of the American Academy of Neurology.

Impairment in concentration was not severe, “equivalent to the sort of jet-lag that I'm feeling now, having traveled from Australia.” He also likened it to the sort of impairment one would feel after being awake for about 17 hours.

Dr. Darby found no significant differences in the risk for cognitive impairment based on the women's age, menopausal status (pre-, peri-, or post-), or time from surgery.

“When women are confronting breast cancer, coming to terms with the many different aspects of it, and trying to take advice and understand what's happening to them, the issues of quality of life are important. They should realize that these sorts of changes seem to be very mild. They are present in a minority of women, and they can be measured as well, if need be. In general, discussion with the patients about the mildness of these sorts of changes is probably the most appropriate [course for the treating physician],” said Dr. Darby.

CHICAGO — Chemotherapy-related cognitive impairment was infrequent in a small study of 30 patients who underwent adjuvant chemotherapy for nonmetastatic breast cancer.

“People could be making decisions about whether or not to have chemotherapy based on stories they've heard about 'chemofog' or 'chemobrain,'” according to Dr. David G. Darby. “We hope this information will help people make informed decisions.”

Dr. Darby and his colleagues looked at a total of 30 women who had already undergone either lumpectomy or mastectomy and were scheduled to undergo either the chemotherapy regimen known as AC (n = 15) or CEF or CMF regimens (n = 15).

▸ The AC regimen involves doxorubicin 60 mg/m

▸ The CEF regimen involves cyclophosphamide administered orally in doses of 75 mg/m

▸ The CMF regimen involves cyclophosphamide 100 mg/m

The women were compared with 30 age-matched controls.

Women took several tests designed to measure cognition as well as mood a few days before initiating chemotherapy (but after the diagnosis had been given and treatment course was decided); again at the start of each new treatment cycle; and for the last time 28 days after the final treatment cycle had begun in each group. Patients were assessed on the National Institute of Mental Health's Center for Epidemiologic Studies Depression Scale (CES-D) depression, the state trait anxiety inventory (STAI) scale, and a test of Dr. Darby's own design, which measures detection speed, identification speed, working memory, and learning ability in a 10- to 12-minute battery.

Dr. Darby is the chief medical officer of a company he formed, called CogState, which produces and scores these tests. It is based in Australia and partly funded this study.

“The first finding of interest was that prior to the first cycle of chemo there was impairment in learning of moderate amplitude, and that was also associated with a mild reduction on mood scales or depressive scales,” said Dr. Darby in an interview. No women were clinically depressed (clinically depressed patients were excluded from the study) and none of the women was on antidepressants at baseline or throughout the study. However, “there may have been an impairment there initially, prior to chemo.”

Two other findings also emerged, both good and bad. “There was an improvement of some of the learning aspects of their performance and a mild improvement on scores on anxiety scales, but there was also a mild deterioration in aspects of concentration and psychomotor speed [as the study progressed].” There was also evidence that patients' mood was declining slightly throughout the treatment.

Individual patients showed “quite a lot of variation—in particular, some patients would have impairment on only one occasion and then improve, and others would have impairment on two or more occasions,” he said. Persistent impairment, that occurring on two consecutive occasions, was seen in only three patients, or 10% of the total, Dr. Darby reported at the annual meeting of the American Academy of Neurology.

Impairment in concentration was not severe, “equivalent to the sort of jet-lag that I'm feeling now, having traveled from Australia.” He also likened it to the sort of impairment one would feel after being awake for about 17 hours.

Dr. Darby found no significant differences in the risk for cognitive impairment based on the women's age, menopausal status (pre-, peri-, or post-), or time from surgery.

“When women are confronting breast cancer, coming to terms with the many different aspects of it, and trying to take advice and understand what's happening to them, the issues of quality of life are important. They should realize that these sorts of changes seem to be very mild. They are present in a minority of women, and they can be measured as well, if need be. In general, discussion with the patients about the mildness of these sorts of changes is probably the most appropriate [course for the treating physician],” said Dr. Darby.

CHICAGO — Chemotherapy-related cognitive impairment was infrequent in a small study of 30 patients who underwent adjuvant chemotherapy for nonmetastatic breast cancer.

“People could be making decisions about whether or not to have chemotherapy based on stories they've heard about 'chemofog' or 'chemobrain,'” according to Dr. David G. Darby. “We hope this information will help people make informed decisions.”

Dr. Darby and his colleagues looked at a total of 30 women who had already undergone either lumpectomy or mastectomy and were scheduled to undergo either the chemotherapy regimen known as AC (n = 15) or CEF or CMF regimens (n = 15).

▸ The AC regimen involves doxorubicin 60 mg/m

▸ The CEF regimen involves cyclophosphamide administered orally in doses of 75 mg/m

▸ The CMF regimen involves cyclophosphamide 100 mg/m

The women were compared with 30 age-matched controls.

Women took several tests designed to measure cognition as well as mood a few days before initiating chemotherapy (but after the diagnosis had been given and treatment course was decided); again at the start of each new treatment cycle; and for the last time 28 days after the final treatment cycle had begun in each group. Patients were assessed on the National Institute of Mental Health's Center for Epidemiologic Studies Depression Scale (CES-D) depression, the state trait anxiety inventory (STAI) scale, and a test of Dr. Darby's own design, which measures detection speed, identification speed, working memory, and learning ability in a 10- to 12-minute battery.

Dr. Darby is the chief medical officer of a company he formed, called CogState, which produces and scores these tests. It is based in Australia and partly funded this study.

“The first finding of interest was that prior to the first cycle of chemo there was impairment in learning of moderate amplitude, and that was also associated with a mild reduction on mood scales or depressive scales,” said Dr. Darby in an interview. No women were clinically depressed (clinically depressed patients were excluded from the study) and none of the women was on antidepressants at baseline or throughout the study. However, “there may have been an impairment there initially, prior to chemo.”

Two other findings also emerged, both good and bad. “There was an improvement of some of the learning aspects of their performance and a mild improvement on scores on anxiety scales, but there was also a mild deterioration in aspects of concentration and psychomotor speed [as the study progressed].” There was also evidence that patients' mood was declining slightly throughout the treatment.

Individual patients showed “quite a lot of variation—in particular, some patients would have impairment on only one occasion and then improve, and others would have impairment on two or more occasions,” he said. Persistent impairment, that occurring on two consecutive occasions, was seen in only three patients, or 10% of the total, Dr. Darby reported at the annual meeting of the American Academy of Neurology.

Impairment in concentration was not severe, “equivalent to the sort of jet-lag that I'm feeling now, having traveled from Australia.” He also likened it to the sort of impairment one would feel after being awake for about 17 hours.

Dr. Darby found no significant differences in the risk for cognitive impairment based on the women's age, menopausal status (pre-, peri-, or post-), or time from surgery.

“When women are confronting breast cancer, coming to terms with the many different aspects of it, and trying to take advice and understand what's happening to them, the issues of quality of life are important. They should realize that these sorts of changes seem to be very mild. They are present in a minority of women, and they can be measured as well, if need be. In general, discussion with the patients about the mildness of these sorts of changes is probably the most appropriate [course for the treating physician],” said Dr. Darby.

CHICAGO — Patients suffering from depression at the time of malignant brain astrocytoma surgery had significantly reduced survival compared with nondepressed patients in a retrospective analysis of 1,052 patients.

Although no causative association can be inferred because of the study's retrospective design, recognizing and treating preoperative depression could maximize survival in patients with malignant brain tumors, Dr. Alfredo Quiñones-Hinojosa said at the annual meeting of the American Association of Neurological Surgeons.

Currently, patient age, tumor grade, and functional status are known preoperative prognostic indicators of survival. Identification of any reversible comorbidity would be important, as malignant astrocytoma, also known as glioma or glioblastoma multiforme, typically results in death in about 1 year, even with the latest, most effective therapies.

Researchers at Johns Hopkins University in Baltimore, led by Dr. Matthew J. McGirt, analyzed the outcomes of 1,052 patients with malignant astrocytoma who underwent surgery from 1995 to 2006.

Of these patients, 605 underwent primary resection, 410 underwent secondary resection, and 37 had a biopsy only. Excluding the biopsies, 213 tumors were World Health Organization grade III and 802 tumors were grade IV.

A total of 204 patients received subtotal resection, 274 received adjuvant therapy, and 136 required subsequent resection.

Only 49 patients (5%) who were found to be taking antidepressant medication for clinical depression at the time they underwent surgery met the study's definition of having depression. All demographic and clinical characteristics were similar between the two groups, said Dr. Quiñones-Hinojosa. Their mean age was 51 years and median preoperative Karnofsky Performance Scale (KPS) score was 80. Among survivors, the median follow-up was 12 months (range 3–18 months).

In a Kaplan Meier analysis, patients with depression had more than a 40% increase in the relative risk of mortality compared with nondepressed patients (relative risk 1.41), regardless of KPS, WHO tumor grade, patient age, or clinical presentation. This association was independent of extent of resection and postoperative treatment with either adjuvant temozolomide chemotherapy or Gliadel wafer use, Dr. Quiñones-Hinojosa said.

Median survival was 7 months among patients with depression, vs. 11 months in those without depression.

At 2 years post surgery, 5% of patients with depression were alive, compared with 23% of nondepressed patients. The difference was significant, he said.

Dr. Quiñones-Hinojosa acknowledged that the investigators could not be certain that the patients' depression was not a response to the recent diagnosis of a terminal disease. In addition, many patients with clinical depression may have been undiagnosed and unmedicated, lowering the sensitivity of the classification scheme.

Discussant Stephen B. Tatter, a neurosurgery professor at Wake Forest University, Winston-Salem, N.C., said treating depression in this patient population is important as it might influence a variety of patient decisions, particularly when to stop treatment. “We don't want just to prolong life but to provide quality that is acceptable to patients,” Dr. Tatter said.

CHICAGO — Patients suffering from depression at the time of malignant brain astrocytoma surgery had significantly reduced survival compared with nondepressed patients in a retrospective analysis of 1,052 patients.

Although no causative association can be inferred because of the study's retrospective design, recognizing and treating preoperative depression could maximize survival in patients with malignant brain tumors, Dr. Alfredo Quiñones-Hinojosa said at the annual meeting of the American Association of Neurological Surgeons.

Currently, patient age, tumor grade, and functional status are known preoperative prognostic indicators of survival. Identification of any reversible comorbidity would be important, as malignant astrocytoma, also known as glioma or glioblastoma multiforme, typically results in death in about 1 year, even with the latest, most effective therapies.

Researchers at Johns Hopkins University in Baltimore, led by Dr. Matthew J. McGirt, analyzed the outcomes of 1,052 patients with malignant astrocytoma who underwent surgery from 1995 to 2006.

Of these patients, 605 underwent primary resection, 410 underwent secondary resection, and 37 had a biopsy only. Excluding the biopsies, 213 tumors were World Health Organization grade III and 802 tumors were grade IV.

A total of 204 patients received subtotal resection, 274 received adjuvant therapy, and 136 required subsequent resection.

Only 49 patients (5%) who were found to be taking antidepressant medication for clinical depression at the time they underwent surgery met the study's definition of having depression. All demographic and clinical characteristics were similar between the two groups, said Dr. Quiñones-Hinojosa. Their mean age was 51 years and median preoperative Karnofsky Performance Scale (KPS) score was 80. Among survivors, the median follow-up was 12 months (range 3–18 months).

In a Kaplan Meier analysis, patients with depression had more than a 40% increase in the relative risk of mortality compared with nondepressed patients (relative risk 1.41), regardless of KPS, WHO tumor grade, patient age, or clinical presentation. This association was independent of extent of resection and postoperative treatment with either adjuvant temozolomide chemotherapy or Gliadel wafer use, Dr. Quiñones-Hinojosa said.

Median survival was 7 months among patients with depression, vs. 11 months in those without depression.

At 2 years post surgery, 5% of patients with depression were alive, compared with 23% of nondepressed patients. The difference was significant, he said.

Dr. Quiñones-Hinojosa acknowledged that the investigators could not be certain that the patients' depression was not a response to the recent diagnosis of a terminal disease. In addition, many patients with clinical depression may have been undiagnosed and unmedicated, lowering the sensitivity of the classification scheme.

Discussant Stephen B. Tatter, a neurosurgery professor at Wake Forest University, Winston-Salem, N.C., said treating depression in this patient population is important as it might influence a variety of patient decisions, particularly when to stop treatment. “We don't want just to prolong life but to provide quality that is acceptable to patients,” Dr. Tatter said.

CHICAGO — Patients suffering from depression at the time of malignant brain astrocytoma surgery had significantly reduced survival compared with nondepressed patients in a retrospective analysis of 1,052 patients.

Although no causative association can be inferred because of the study's retrospective design, recognizing and treating preoperative depression could maximize survival in patients with malignant brain tumors, Dr. Alfredo Quiñones-Hinojosa said at the annual meeting of the American Association of Neurological Surgeons.

Currently, patient age, tumor grade, and functional status are known preoperative prognostic indicators of survival. Identification of any reversible comorbidity would be important, as malignant astrocytoma, also known as glioma or glioblastoma multiforme, typically results in death in about 1 year, even with the latest, most effective therapies.

Researchers at Johns Hopkins University in Baltimore, led by Dr. Matthew J. McGirt, analyzed the outcomes of 1,052 patients with malignant astrocytoma who underwent surgery from 1995 to 2006.

Of these patients, 605 underwent primary resection, 410 underwent secondary resection, and 37 had a biopsy only. Excluding the biopsies, 213 tumors were World Health Organization grade III and 802 tumors were grade IV.

A total of 204 patients received subtotal resection, 274 received adjuvant therapy, and 136 required subsequent resection.

Only 49 patients (5%) who were found to be taking antidepressant medication for clinical depression at the time they underwent surgery met the study's definition of having depression. All demographic and clinical characteristics were similar between the two groups, said Dr. Quiñones-Hinojosa. Their mean age was 51 years and median preoperative Karnofsky Performance Scale (KPS) score was 80. Among survivors, the median follow-up was 12 months (range 3–18 months).

In a Kaplan Meier analysis, patients with depression had more than a 40% increase in the relative risk of mortality compared with nondepressed patients (relative risk 1.41), regardless of KPS, WHO tumor grade, patient age, or clinical presentation. This association was independent of extent of resection and postoperative treatment with either adjuvant temozolomide chemotherapy or Gliadel wafer use, Dr. Quiñones-Hinojosa said.

Median survival was 7 months among patients with depression, vs. 11 months in those without depression.

At 2 years post surgery, 5% of patients with depression were alive, compared with 23% of nondepressed patients. The difference was significant, he said.

Dr. Quiñones-Hinojosa acknowledged that the investigators could not be certain that the patients' depression was not a response to the recent diagnosis of a terminal disease. In addition, many patients with clinical depression may have been undiagnosed and unmedicated, lowering the sensitivity of the classification scheme.

Discussant Stephen B. Tatter, a neurosurgery professor at Wake Forest University, Winston-Salem, N.C., said treating depression in this patient population is important as it might influence a variety of patient decisions, particularly when to stop treatment. “We don't want just to prolong life but to provide quality that is acceptable to patients,” Dr. Tatter said.

CHICAGO — Surgical resection remains the treatment of choice for carotid body tumors, as presented in a review of 88 patients at one center.

Radiation therapy and chemotherapy are unsuitable alternatives because these rare tumors are too slow growing, and radiation exposes the carotid arteries to radiation arteritis, accelerated atherosclerosis, and even necrosis, Dr. Thomas A. Whitehill said at a vascular surgery symposium sponsored by Northwestern University.

Preoperative percutaneous tumor embolization has been tried with mixed results, but can be an important adjunct when treating select patients with large tumors (greater than 6 cm). There has been one report of a successful use of covered stents to facilitate resection (J. Vasc. Surg. 2003;38:389–91).

The malignancy rate for carotid body tumors is hard to define because there are no reliable histologic markers, but is thought to range from 2% to 5%, he said. Even if benign on histologic exam, all tumors, once discovered, should be surgically removed because they will ultimately wrap around the internal and external carotid arteries, erode into the base of the skull, and entrap neighboring cranial nerves. Increasing size also can interfere with speech, swallowing, and respiration, said Dr. Whitehill of the vascular surgery division of University of Colorado Health Science Center, Denver.

From 1993 to 2007, Dr. Whitehill and colleagues surgically resected 88 Shamblin classification II or III carotid body tumors, with an average diameter of 10.4 cm (range 5–16 cm). The patients ranged in age from 30 to 40 years.

Surgery time ranged from 4 to 14 hours, with an average blood loss of 375 mL (range 50–1800 mL). An internal carotid artery (ICA) resection bypass was performed in three patients, and ICA ligation in none.

Complications were relatively low, Dr. Whitehill said, and included cranial nerve IX neuropraxia (4%) or injury (1%), cranial nerve XII neuropraxia (30%), and superior laryngeal nerve injury (10%). There were no strokes or deaths.

Surgical advances and the widespread use of CT and MRI have decreased the overall risk of postoperative stroke over the past 25 years from about 30% to less than 2%, although the incidence of cranial nerve injury remains high at 15%–35%, he said.

Skip Angiography, and Other Surgical Pearls

Dr. Thomas A. Whitehill offered tips for carotid body tumors.

▸ Skip the angiography suite when making the diagnosis, and focus on CT imaging, preferably axial cuts rather than reconstructions. MRI may be slightly better at evaluating distant, metastatic deposits at the skull base.

▸ A nerve stimulator may be useful for preoperative identification of the cranial nerve.

▸ Do preoperative vocal cord and speech evaluations.

▸ Consider serial embolization in patients who are too old or have too many comorbidities to tolerate surgery.

▸ On a side CT view, draw a line between the mastoid tip and the angle of the mandible to get an idea of how high an exposure is needed and to help with preoperative planning.

▸ Utilize nasotracheal intubation in most patients, as it provides greater mobility with the mandible when resecting large tumors.

▸ In high access cases, mobilize the parotid gland anteriorly, up to the level of the facial nerve.

▸ Gain vascular control, if possible, and mobilize the tumor circumferentially to assess the extent of disease.

▸ Resect the tumor from proximal to distal.

▸ Fine mosquito clamp dissection and 3–0 or 4–0 silk ligation can give the best hemostasis.

▸ Send all suspicious lymph nodes for frozen permanent sections.

▸ Rather than using maxillomandibular arch bar fixation to obtain mandibular subluxation, consider interdental cross-wiring between the maxilla and mandible using bicuspids in dentate patients and Steinmann pins in patients with no teeth.

▸ For very distal tumors, cutting the digastric muscle will get you within 2 cm of the skull base.

▸ For large tumors, ligating the external carotid artery near its takeoff provides greater mobility.

▸ Avoid ligation of the internal carotid artery.

▸ If a tumor is 6 cm or more in diameter, consider preoperative embolization.

▸ Pushing the tumor completely through the bifurcation or pulling it anteriorly through the bifurcation may improve exposure angles and ease dissection.

▸ Take your time after the tumor is cleared of the two carotid arteries. The posterior surface and medial side of the tumor still must be separated from the deeper parapharyngeal tissues. Haste at this stage can result in the superior or inferior laryngeal nerves being transected or medial pharyngeal injuries, causing substantial swelling and neck pain in patients.

CHICAGO — Surgical resection remains the treatment of choice for carotid body tumors, as presented in a review of 88 patients at one center.

Radiation therapy and chemotherapy are unsuitable alternatives because these rare tumors are too slow growing, and radiation exposes the carotid arteries to radiation arteritis, accelerated atherosclerosis, and even necrosis, Dr. Thomas A. Whitehill said at a vascular surgery symposium sponsored by Northwestern University.

Preoperative percutaneous tumor embolization has been tried with mixed results, but can be an important adjunct when treating select patients with large tumors (greater than 6 cm). There has been one report of a successful use of covered stents to facilitate resection (J. Vasc. Surg. 2003;38:389–91).

The malignancy rate for carotid body tumors is hard to define because there are no reliable histologic markers, but is thought to range from 2% to 5%, he said. Even if benign on histologic exam, all tumors, once discovered, should be surgically removed because they will ultimately wrap around the internal and external carotid arteries, erode into the base of the skull, and entrap neighboring cranial nerves. Increasing size also can interfere with speech, swallowing, and respiration, said Dr. Whitehill of the vascular surgery division of University of Colorado Health Science Center, Denver.

From 1993 to 2007, Dr. Whitehill and colleagues surgically resected 88 Shamblin classification II or III carotid body tumors, with an average diameter of 10.4 cm (range 5–16 cm). The patients ranged in age from 30 to 40 years.

Surgery time ranged from 4 to 14 hours, with an average blood loss of 375 mL (range 50–1800 mL). An internal carotid artery (ICA) resection bypass was performed in three patients, and ICA ligation in none.

Complications were relatively low, Dr. Whitehill said, and included cranial nerve IX neuropraxia (4%) or injury (1%), cranial nerve XII neuropraxia (30%), and superior laryngeal nerve injury (10%). There were no strokes or deaths.

Surgical advances and the widespread use of CT and MRI have decreased the overall risk of postoperative stroke over the past 25 years from about 30% to less than 2%, although the incidence of cranial nerve injury remains high at 15%–35%, he said.

Skip Angiography, and Other Surgical Pearls

Dr. Thomas A. Whitehill offered tips for carotid body tumors.

▸ Skip the angiography suite when making the diagnosis, and focus on CT imaging, preferably axial cuts rather than reconstructions. MRI may be slightly better at evaluating distant, metastatic deposits at the skull base.

▸ A nerve stimulator may be useful for preoperative identification of the cranial nerve.

▸ Do preoperative vocal cord and speech evaluations.

▸ Consider serial embolization in patients who are too old or have too many comorbidities to tolerate surgery.

▸ On a side CT view, draw a line between the mastoid tip and the angle of the mandible to get an idea of how high an exposure is needed and to help with preoperative planning.

▸ Utilize nasotracheal intubation in most patients, as it provides greater mobility with the mandible when resecting large tumors.

▸ In high access cases, mobilize the parotid gland anteriorly, up to the level of the facial nerve.

▸ Gain vascular control, if possible, and mobilize the tumor circumferentially to assess the extent of disease.

▸ Resect the tumor from proximal to distal.

▸ Fine mosquito clamp dissection and 3–0 or 4–0 silk ligation can give the best hemostasis.

▸ Send all suspicious lymph nodes for frozen permanent sections.

▸ Rather than using maxillomandibular arch bar fixation to obtain mandibular subluxation, consider interdental cross-wiring between the maxilla and mandible using bicuspids in dentate patients and Steinmann pins in patients with no teeth.

▸ For very distal tumors, cutting the digastric muscle will get you within 2 cm of the skull base.

▸ For large tumors, ligating the external carotid artery near its takeoff provides greater mobility.

▸ Avoid ligation of the internal carotid artery.

▸ If a tumor is 6 cm or more in diameter, consider preoperative embolization.

▸ Pushing the tumor completely through the bifurcation or pulling it anteriorly through the bifurcation may improve exposure angles and ease dissection.

▸ Take your time after the tumor is cleared of the two carotid arteries. The posterior surface and medial side of the tumor still must be separated from the deeper parapharyngeal tissues. Haste at this stage can result in the superior or inferior laryngeal nerves being transected or medial pharyngeal injuries, causing substantial swelling and neck pain in patients.

CHICAGO — Surgical resection remains the treatment of choice for carotid body tumors, as presented in a review of 88 patients at one center.

Radiation therapy and chemotherapy are unsuitable alternatives because these rare tumors are too slow growing, and radiation exposes the carotid arteries to radiation arteritis, accelerated atherosclerosis, and even necrosis, Dr. Thomas A. Whitehill said at a vascular surgery symposium sponsored by Northwestern University.

Preoperative percutaneous tumor embolization has been tried with mixed results, but can be an important adjunct when treating select patients with large tumors (greater than 6 cm). There has been one report of a successful use of covered stents to facilitate resection (J. Vasc. Surg. 2003;38:389–91).

The malignancy rate for carotid body tumors is hard to define because there are no reliable histologic markers, but is thought to range from 2% to 5%, he said. Even if benign on histologic exam, all tumors, once discovered, should be surgically removed because they will ultimately wrap around the internal and external carotid arteries, erode into the base of the skull, and entrap neighboring cranial nerves. Increasing size also can interfere with speech, swallowing, and respiration, said Dr. Whitehill of the vascular surgery division of University of Colorado Health Science Center, Denver.

From 1993 to 2007, Dr. Whitehill and colleagues surgically resected 88 Shamblin classification II or III carotid body tumors, with an average diameter of 10.4 cm (range 5–16 cm). The patients ranged in age from 30 to 40 years.

Surgery time ranged from 4 to 14 hours, with an average blood loss of 375 mL (range 50–1800 mL). An internal carotid artery (ICA) resection bypass was performed in three patients, and ICA ligation in none.

Complications were relatively low, Dr. Whitehill said, and included cranial nerve IX neuropraxia (4%) or injury (1%), cranial nerve XII neuropraxia (30%), and superior laryngeal nerve injury (10%). There were no strokes or deaths.

Surgical advances and the widespread use of CT and MRI have decreased the overall risk of postoperative stroke over the past 25 years from about 30% to less than 2%, although the incidence of cranial nerve injury remains high at 15%–35%, he said.

Skip Angiography, and Other Surgical Pearls

Dr. Thomas A. Whitehill offered tips for carotid body tumors.

▸ Skip the angiography suite when making the diagnosis, and focus on CT imaging, preferably axial cuts rather than reconstructions. MRI may be slightly better at evaluating distant, metastatic deposits at the skull base.

▸ A nerve stimulator may be useful for preoperative identification of the cranial nerve.

▸ Do preoperative vocal cord and speech evaluations.

▸ Consider serial embolization in patients who are too old or have too many comorbidities to tolerate surgery.

▸ On a side CT view, draw a line between the mastoid tip and the angle of the mandible to get an idea of how high an exposure is needed and to help with preoperative planning.

▸ Utilize nasotracheal intubation in most patients, as it provides greater mobility with the mandible when resecting large tumors.

▸ In high access cases, mobilize the parotid gland anteriorly, up to the level of the facial nerve.

▸ Gain vascular control, if possible, and mobilize the tumor circumferentially to assess the extent of disease.

▸ Resect the tumor from proximal to distal.

▸ Fine mosquito clamp dissection and 3–0 or 4–0 silk ligation can give the best hemostasis.

▸ Send all suspicious lymph nodes for frozen permanent sections.

▸ Rather than using maxillomandibular arch bar fixation to obtain mandibular subluxation, consider interdental cross-wiring between the maxilla and mandible using bicuspids in dentate patients and Steinmann pins in patients with no teeth.

▸ For very distal tumors, cutting the digastric muscle will get you within 2 cm of the skull base.

▸ For large tumors, ligating the external carotid artery near its takeoff provides greater mobility.

▸ Avoid ligation of the internal carotid artery.

▸ If a tumor is 6 cm or more in diameter, consider preoperative embolization.

▸ Pushing the tumor completely through the bifurcation or pulling it anteriorly through the bifurcation may improve exposure angles and ease dissection.

▸ Take your time after the tumor is cleared of the two carotid arteries. The posterior surface and medial side of the tumor still must be separated from the deeper parapharyngeal tissues. Haste at this stage can result in the superior or inferior laryngeal nerves being transected or medial pharyngeal injuries, causing substantial swelling and neck pain in patients.