Mary Ann Moon

Zolpidem, a frequently prescribed sleep aid, suppresses nocturnal awakenings that are an important CNS response to acid reflux events.

By enabling users to sleep through reflux events, the drug has the unintended effect of increasing esophageal exposure to stomach acid. This in turn opens the door to gastroesophageal reflux disease (GERD) complications such as erosive esophagitis, stricture formation, Barrett's esophagus, and esophageal adenocarcinoma, said Dr. Gregg Gagliardi of Thomas Jefferson University, Philadelphia, and his associates.

This finding is especially concerning because epidemiologic studies suggest that sleep disturbances occur in as many as 75% of patients who have frequent heartburn. If they take the sleep aid to manage their sleep disturbances, they may unwittingly worsen their heartburn.

In addition, almost 30% of patients with sleep disturbances are thought to have undiagnosed GERD, and those who use zolpidem to manage their sleep disturbances may exacerbate reflux events and induce esophageal complications, the investigators noted (Clin. Gastroenterol. Hepatol. 2009;7:948-52).

Normally, these nocturnal events trigger awakening or arousal from sleep, which leads to a swallow reflex. This initiates peristalsis and exposure of the esophageal mucosa to saliva rich in bicarbonate. The saliva neutralizes the acid content in the esophagus and the peristalsis clears the acid through to the stomach. Suppressing this protective mechanism may lead to prolonged acid exposure and mucosal injury over time.

The researchers performed a double-blind, placebo-controlled trial to examine the issue in 15 GERD patients and 8 normal control subjects. The study was supported in part by AstraZeneca Pharmaceuticals LP.

Each study subject underwent separate sleep studies at a 2-week interval after taking zolpidem (Ambien, Sanofi-Aventis) or a matching placebo. A transnasal esophageal pH catheter with a sensor placed 5 cm above the lower esophageal sphincter recorded reflux events and the acid clearance time for each event, while polysomnography recorded reflux-associated arousals and awakenings.

In both the subjects with GERD and the healthy control subjects who had taken placebo, a nocturnal acid reflux event caused arousal or awakening 89% of the time. In contrast, after they had taken zolpidem, reflux events caused arousal or awakening only 40% of the time.

Among the control subjects, the mean time until acid was cleared from the esophagus during reflux episodes was 1.15 seconds after they had taken placebo, compared with 15.67 seconds after they had taken zolpidem.

Exposure time also was dramatically increased among the GERD subjects. The mean time until acid was cleared from the esophagus was 37.8 seconds after they had taken placebo, compared with 363.3 seconds after they had taken zolpidem.

When this exposure time is multiplied by the number of reflux events over the course of the entire sleep period, it has significant ramifications for the development of erosive esophagitis, strictures, Barrett's esophagus, and esophageal cancer, the researchers noted.

Suppression of the arousal reflex was most marked early in the evening for both GERD subjects and controls, perhaps because zolpidem has a relatively short duration of action. However, reflux events are most common early in the evening.

It is possible that other CNS depressants or psychotropic medications may exert similar effects on nighttime arousals as zolpidem did in this study. The use of such sleep aids is increasing in the United States, Dr. Gagliardi and his colleagues noted. “If this effect of blunted arousals or awakenings by hypnotics is substantiated, this would suggest caution in the use of sleep aids without first considering GERD as an etiologic factor in patients with complaints of disturbed sleep,” they added.

This study was limited by its small sample size, with just 23 subjects. However, the researchers attempted to counterbalance this drawback by analyzing each reflux event rather than each subject.

Dr. Gagliardi's associate, Dr. Karl Doghramji, also of Thomas Jefferson University, is a consultant for Sanofi-Aventis. No other conflicts of interest were reported.

Zolpidem, a frequently prescribed sleep aid, suppresses nocturnal awakenings that are an important CNS response to acid reflux events.

By enabling users to sleep through reflux events, the drug has the unintended effect of increasing esophageal exposure to stomach acid. This in turn opens the door to gastroesophageal reflux disease (GERD) complications such as erosive esophagitis, stricture formation, Barrett's esophagus, and esophageal adenocarcinoma, said Dr. Gregg Gagliardi of Thomas Jefferson University, Philadelphia, and his associates.

This finding is especially concerning because epidemiologic studies suggest that sleep disturbances occur in as many as 75% of patients who have frequent heartburn. If they take the sleep aid to manage their sleep disturbances, they may unwittingly worsen their heartburn.

In addition, almost 30% of patients with sleep disturbances are thought to have undiagnosed GERD, and those who use zolpidem to manage their sleep disturbances may exacerbate reflux events and induce esophageal complications, the investigators noted (Clin. Gastroenterol. Hepatol. 2009;7:948-52).

Normally, these nocturnal events trigger awakening or arousal from sleep, which leads to a swallow reflex. This initiates peristalsis and exposure of the esophageal mucosa to saliva rich in bicarbonate. The saliva neutralizes the acid content in the esophagus and the peristalsis clears the acid through to the stomach. Suppressing this protective mechanism may lead to prolonged acid exposure and mucosal injury over time.

The researchers performed a double-blind, placebo-controlled trial to examine the issue in 15 GERD patients and 8 normal control subjects. The study was supported in part by AstraZeneca Pharmaceuticals LP.

Each study subject underwent separate sleep studies at a 2-week interval after taking zolpidem (Ambien, Sanofi-Aventis) or a matching placebo. A transnasal esophageal pH catheter with a sensor placed 5 cm above the lower esophageal sphincter recorded reflux events and the acid clearance time for each event, while polysomnography recorded reflux-associated arousals and awakenings.

In both the subjects with GERD and the healthy control subjects who had taken placebo, a nocturnal acid reflux event caused arousal or awakening 89% of the time. In contrast, after they had taken zolpidem, reflux events caused arousal or awakening only 40% of the time.

Among the control subjects, the mean time until acid was cleared from the esophagus during reflux episodes was 1.15 seconds after they had taken placebo, compared with 15.67 seconds after they had taken zolpidem.

Exposure time also was dramatically increased among the GERD subjects. The mean time until acid was cleared from the esophagus was 37.8 seconds after they had taken placebo, compared with 363.3 seconds after they had taken zolpidem.

When this exposure time is multiplied by the number of reflux events over the course of the entire sleep period, it has significant ramifications for the development of erosive esophagitis, strictures, Barrett's esophagus, and esophageal cancer, the researchers noted.

Suppression of the arousal reflex was most marked early in the evening for both GERD subjects and controls, perhaps because zolpidem has a relatively short duration of action. However, reflux events are most common early in the evening.

It is possible that other CNS depressants or psychotropic medications may exert similar effects on nighttime arousals as zolpidem did in this study. The use of such sleep aids is increasing in the United States, Dr. Gagliardi and his colleagues noted. “If this effect of blunted arousals or awakenings by hypnotics is substantiated, this would suggest caution in the use of sleep aids without first considering GERD as an etiologic factor in patients with complaints of disturbed sleep,” they added.

This study was limited by its small sample size, with just 23 subjects. However, the researchers attempted to counterbalance this drawback by analyzing each reflux event rather than each subject.

Dr. Gagliardi's associate, Dr. Karl Doghramji, also of Thomas Jefferson University, is a consultant for Sanofi-Aventis. No other conflicts of interest were reported.

Zolpidem, a frequently prescribed sleep aid, suppresses nocturnal awakenings that are an important CNS response to acid reflux events.

By enabling users to sleep through reflux events, the drug has the unintended effect of increasing esophageal exposure to stomach acid. This in turn opens the door to gastroesophageal reflux disease (GERD) complications such as erosive esophagitis, stricture formation, Barrett's esophagus, and esophageal adenocarcinoma, said Dr. Gregg Gagliardi of Thomas Jefferson University, Philadelphia, and his associates.

This finding is especially concerning because epidemiologic studies suggest that sleep disturbances occur in as many as 75% of patients who have frequent heartburn. If they take the sleep aid to manage their sleep disturbances, they may unwittingly worsen their heartburn.

In addition, almost 30% of patients with sleep disturbances are thought to have undiagnosed GERD, and those who use zolpidem to manage their sleep disturbances may exacerbate reflux events and induce esophageal complications, the investigators noted (Clin. Gastroenterol. Hepatol. 2009;7:948-52).

Normally, these nocturnal events trigger awakening or arousal from sleep, which leads to a swallow reflex. This initiates peristalsis and exposure of the esophageal mucosa to saliva rich in bicarbonate. The saliva neutralizes the acid content in the esophagus and the peristalsis clears the acid through to the stomach. Suppressing this protective mechanism may lead to prolonged acid exposure and mucosal injury over time.

The researchers performed a double-blind, placebo-controlled trial to examine the issue in 15 GERD patients and 8 normal control subjects. The study was supported in part by AstraZeneca Pharmaceuticals LP.

Each study subject underwent separate sleep studies at a 2-week interval after taking zolpidem (Ambien, Sanofi-Aventis) or a matching placebo. A transnasal esophageal pH catheter with a sensor placed 5 cm above the lower esophageal sphincter recorded reflux events and the acid clearance time for each event, while polysomnography recorded reflux-associated arousals and awakenings.

In both the subjects with GERD and the healthy control subjects who had taken placebo, a nocturnal acid reflux event caused arousal or awakening 89% of the time. In contrast, after they had taken zolpidem, reflux events caused arousal or awakening only 40% of the time.

Among the control subjects, the mean time until acid was cleared from the esophagus during reflux episodes was 1.15 seconds after they had taken placebo, compared with 15.67 seconds after they had taken zolpidem.

Exposure time also was dramatically increased among the GERD subjects. The mean time until acid was cleared from the esophagus was 37.8 seconds after they had taken placebo, compared with 363.3 seconds after they had taken zolpidem.

When this exposure time is multiplied by the number of reflux events over the course of the entire sleep period, it has significant ramifications for the development of erosive esophagitis, strictures, Barrett's esophagus, and esophageal cancer, the researchers noted.

Suppression of the arousal reflex was most marked early in the evening for both GERD subjects and controls, perhaps because zolpidem has a relatively short duration of action. However, reflux events are most common early in the evening.

It is possible that other CNS depressants or psychotropic medications may exert similar effects on nighttime arousals as zolpidem did in this study. The use of such sleep aids is increasing in the United States, Dr. Gagliardi and his colleagues noted. “If this effect of blunted arousals or awakenings by hypnotics is substantiated, this would suggest caution in the use of sleep aids without first considering GERD as an etiologic factor in patients with complaints of disturbed sleep,” they added.

This study was limited by its small sample size, with just 23 subjects. However, the researchers attempted to counterbalance this drawback by analyzing each reflux event rather than each subject.

Dr. Gagliardi's associate, Dr. Karl Doghramji, also of Thomas Jefferson University, is a consultant for Sanofi-Aventis. No other conflicts of interest were reported.

Rasagiline appears to slow the progression of Parkinson's disease, not just ameliorate its symptoms in the short term, according to a report in the New England Journal of Medicine.

A complex study design that incorporates several complicated statistical methods–the delayed-start study design–was used to differentiate the drug's short-term symptom effects from true disease-modifying effects, and the results were mixed. A 1-mg dose of rasagiline seemed to slow PD progression over the course of 18 months, but a 2-mg dose did not (N. Engl. J. Med. 2009;361:1268-78).

“From a practical point of view, the study findings suggest a possible benefit of the early use of rasagiline at a dose of 1 mg per day; however, given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects,” said Dr. C. Warren Olanow of the department of neurology, Mount Sinai School of Medicine, New York, and his associates.

“It will be important to determine whether these results can be confirmed and whether benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive dysfunction,” they noted.

The investigators conducted the study in 1,176 PD patients aged 30-80 who had not received any treatment for the disease and were recruited from 129 medical centers in 14 countries. The mean duration of PD at baseline was 4.5 months.

In the first 36-week phase of the trial, subjects were randomly assigned to receive the 1-mg dose of rasagiline, the 2-mg dose, or matching placebos. In the second 36-week phase, subjects in the placebo groups switched to one of the active treatments, while those taking rasagiline continued their assigned treatment.

Theoretically, improvements seen in the first phase of a delayed-start study reflect the drug's symptom effects, and the difference between improvements in the early-start and delayed-start groups reflects the drug's disease-modifying effects.

In this study, subjects' mental function, activities of daily living, and motor function were assessed frequently using the Unified Parkinson's Disease Rating Scale. The mean total UPDRS score was 20.4 at baseline.

Teva Pharmaceutical Industries, manufacturer of rasagiline, funded the study and was responsible for data collection, monitoring, and statistical analysis.

The 1-mg dose of rasagiline met the three primary end points for results to be considered positive: There was less worsening in UPDRS scores during phase 1 with the drug than with placebo (0.09 points per week vs. 0.04 ppw), less worsening during phase 2 among subjects in the early-start group (2.82 ppw vs. 4.50 ppw) than in the delayed-start group, and noninferiority in the rate of worsening among the delayed-start patients during phase 2 (0.085 ppw in both).

The 2-mg dose did not meet these end points, though it did improve symptoms. “It is difficult to explain why the two doses did not provide similar results [and] to imagine that protective effects could be lost with a mere doubling of the dose,” Dr. Olanow and his colleagues said.

Dr. Olanow reported receiving consulting and lecture fees from Teva and Lundbeck; receiving consulting fees from Boehringer Ingelheim, Novartis/Orion, Solvay, Ceregene, and Merck Serona; and owning equity in Ceregene.

His colleagues also reported receiving consulting and lecture fees from Teva and other pharmaceutical companies.

Rasagiline appears to slow the progression of Parkinson's disease, not just ameliorate its symptoms in the short term, according to a report in the New England Journal of Medicine.

A complex study design that incorporates several complicated statistical methods–the delayed-start study design–was used to differentiate the drug's short-term symptom effects from true disease-modifying effects, and the results were mixed. A 1-mg dose of rasagiline seemed to slow PD progression over the course of 18 months, but a 2-mg dose did not (N. Engl. J. Med. 2009;361:1268-78).

“From a practical point of view, the study findings suggest a possible benefit of the early use of rasagiline at a dose of 1 mg per day; however, given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects,” said Dr. C. Warren Olanow of the department of neurology, Mount Sinai School of Medicine, New York, and his associates.

“It will be important to determine whether these results can be confirmed and whether benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive dysfunction,” they noted.

The investigators conducted the study in 1,176 PD patients aged 30-80 who had not received any treatment for the disease and were recruited from 129 medical centers in 14 countries. The mean duration of PD at baseline was 4.5 months.

In the first 36-week phase of the trial, subjects were randomly assigned to receive the 1-mg dose of rasagiline, the 2-mg dose, or matching placebos. In the second 36-week phase, subjects in the placebo groups switched to one of the active treatments, while those taking rasagiline continued their assigned treatment.

Theoretically, improvements seen in the first phase of a delayed-start study reflect the drug's symptom effects, and the difference between improvements in the early-start and delayed-start groups reflects the drug's disease-modifying effects.

In this study, subjects' mental function, activities of daily living, and motor function were assessed frequently using the Unified Parkinson's Disease Rating Scale. The mean total UPDRS score was 20.4 at baseline.

Teva Pharmaceutical Industries, manufacturer of rasagiline, funded the study and was responsible for data collection, monitoring, and statistical analysis.

The 1-mg dose of rasagiline met the three primary end points for results to be considered positive: There was less worsening in UPDRS scores during phase 1 with the drug than with placebo (0.09 points per week vs. 0.04 ppw), less worsening during phase 2 among subjects in the early-start group (2.82 ppw vs. 4.50 ppw) than in the delayed-start group, and noninferiority in the rate of worsening among the delayed-start patients during phase 2 (0.085 ppw in both).

The 2-mg dose did not meet these end points, though it did improve symptoms. “It is difficult to explain why the two doses did not provide similar results [and] to imagine that protective effects could be lost with a mere doubling of the dose,” Dr. Olanow and his colleagues said.

Dr. Olanow reported receiving consulting and lecture fees from Teva and Lundbeck; receiving consulting fees from Boehringer Ingelheim, Novartis/Orion, Solvay, Ceregene, and Merck Serona; and owning equity in Ceregene.

His colleagues also reported receiving consulting and lecture fees from Teva and other pharmaceutical companies.

Rasagiline appears to slow the progression of Parkinson's disease, not just ameliorate its symptoms in the short term, according to a report in the New England Journal of Medicine.

A complex study design that incorporates several complicated statistical methods–the delayed-start study design–was used to differentiate the drug's short-term symptom effects from true disease-modifying effects, and the results were mixed. A 1-mg dose of rasagiline seemed to slow PD progression over the course of 18 months, but a 2-mg dose did not (N. Engl. J. Med. 2009;361:1268-78).

“From a practical point of view, the study findings suggest a possible benefit of the early use of rasagiline at a dose of 1 mg per day; however, given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects,” said Dr. C. Warren Olanow of the department of neurology, Mount Sinai School of Medicine, New York, and his associates.

“It will be important to determine whether these results can be confirmed and whether benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive dysfunction,” they noted.

The investigators conducted the study in 1,176 PD patients aged 30-80 who had not received any treatment for the disease and were recruited from 129 medical centers in 14 countries. The mean duration of PD at baseline was 4.5 months.

In the first 36-week phase of the trial, subjects were randomly assigned to receive the 1-mg dose of rasagiline, the 2-mg dose, or matching placebos. In the second 36-week phase, subjects in the placebo groups switched to one of the active treatments, while those taking rasagiline continued their assigned treatment.

Theoretically, improvements seen in the first phase of a delayed-start study reflect the drug's symptom effects, and the difference between improvements in the early-start and delayed-start groups reflects the drug's disease-modifying effects.

In this study, subjects' mental function, activities of daily living, and motor function were assessed frequently using the Unified Parkinson's Disease Rating Scale. The mean total UPDRS score was 20.4 at baseline.

Teva Pharmaceutical Industries, manufacturer of rasagiline, funded the study and was responsible for data collection, monitoring, and statistical analysis.

The 1-mg dose of rasagiline met the three primary end points for results to be considered positive: There was less worsening in UPDRS scores during phase 1 with the drug than with placebo (0.09 points per week vs. 0.04 ppw), less worsening during phase 2 among subjects in the early-start group (2.82 ppw vs. 4.50 ppw) than in the delayed-start group, and noninferiority in the rate of worsening among the delayed-start patients during phase 2 (0.085 ppw in both).

The 2-mg dose did not meet these end points, though it did improve symptoms. “It is difficult to explain why the two doses did not provide similar results [and] to imagine that protective effects could be lost with a mere doubling of the dose,” Dr. Olanow and his colleagues said.

Dr. Olanow reported receiving consulting and lecture fees from Teva and Lundbeck; receiving consulting fees from Boehringer Ingelheim, Novartis/Orion, Solvay, Ceregene, and Merck Serona; and owning equity in Ceregene.

His colleagues also reported receiving consulting and lecture fees from Teva and other pharmaceutical companies.

A new drug that inhibits the hedgehog signaling pathway has shown "remarkable" antitumor activity against basal cell carcinoma and medulloblastoma, according to two reports.

The hedgehog signaling pathway regulates cell growth and differentiation during early development but is inactive in healthy adults. However, it appears that mutations in components of the pathway can cause malignant growth in some cases of medulloblastoma, the most common brain cancer in children, and in several cancers in adults, notably basal cell carcinoma.

The hedgehog pathway derived its name from its signaling molecule, a polypeptide ligand called Hedgehog [Hh] because the mutation it caused when it was first discovered in fruit flies produced stubby, hairy-looking larvae resembling hedgehogs.

The new oral agent, GDC-0449, was developed to selectively and potently inhibit hedgehog signaling without producing the adverse effects common with conventional chemotherapy. It appears to have done so in a phase I clinical trial of patients with advanced or metastatic basal cell carcinoma and in a single case study testing it against medulloblastoma refractory to all other treatments. Both studies were supported by Genentech Inc., developer of GDC-0449.

These results indicate that targeting the hedgehog signaling pathway may be a promising avenue for a whole new class of cancer therapies, Dr. Andrzej A. Dlugosz and Dr. Moshe Talpaz of the University of Michigan, Ann Arbor, said in an editorial comment accompanying the two reports.

"Although the total number of patients with advanced or metastatic basal cell carcinoma is small, these studies should ignite renewed interest in testing hedgehog pathway inhibitors in patients with typical basal cell carcinoma" as well as other cancers, they said.

"For patients at especially high risk for multiple basal cell tumors, an effective medical treatment would be a welcome alternative to repeated surgical procedures, which can be especially disfiguring when the tumors occur on the face," Dr. Dlugosz and Dr. Talpaz said (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMe0906092

Alternatively, tumor debulking with the use of hedgehog inhibitors, followed by surgical excision, might prove beneficial in many patients, they added.

In the clinical trial, Dr. Daniel D. Von Hoff of the Translational Genomics Research Institute in Scottsdale, Ariz., and his associates assessed GDC-0449 in 18 patients with metastatic and 15 patients with locally advanced basal cell carcinoma that had been refractory to surgery, radiotherapy, and chemotherapy.

A total of 18 patients showed a clinical response, 11 showed stable disease for up to 10 months, and 4 had disease progression, Dr. Von Hoff and his colleagues reported (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMoa0905360

The overall response rate was 55%. Dr. Dlugosz and Dr. Talpaz termed the 50% response rate among patients with metastatic disease "remarkable."

There were no dose-limiting toxic effects or grade-5 adverse events during the study. One grade-4 event occurred (asymptomatic hyponatremia) and several patients reported a variety of problems that may or may not have been related to treatment, such as fatigue and weight loss. Only one patient discontinued treatment after 8 months, citing abdominal pain, fatigue, weight loss, anorexia, and dysgeusia.

In the case study, Dr. Charles M. Rudin of Johns Hopkins University, Baltimore, and his associates assessed GDC-0449 in a 26-year-old man with a 4-year history of medulloblastoma. The patient had undergone gross total resection of the tumor, craniospinal irradiation, extensive chemotherapy, autologous stem-cell transplantation, and additional systemic treatment with temozolomide and bevacizumab, but nevertheless had widespread skeletal and soft tissue metastases. With no alternative therapies left, he was offered CDC-0449.

Within 1 month, supraclavicular lymphadenopathy resolved, sternal masses regressed, and the patient reported that his intractable pain had resolved. After a few more weeks, more nodules regressed and the patient had returned to a normal level of activity. After a few more weeks, further metastases were markedly diminished or, in the case of a disabling epidural mass at C7, no longer detectable.

After 3 months of treatment, however, there was renewed tumor activity, including new lesions as well as regrowth of old lesions. The patient progressed rapidly, despite a series of subsequent therapies, and died.

"The tumor had a remarkable, although incomplete, and rapid, although transient, response to inhibition of the hedgehog pathway with GDC-0449," Dr. Rudin and his colleagues noted (N. Engl. J. Med. 2009 [doi:10.1056/NEJMoa0902903

"The regression is notable because of the tumor burden and the extent of metastasis in this patient, with substantial soft tissue and bony tissue involvement and clinically significant bone marrow compromise, and underscores the primary role that the hedgehog pathway played in maintaining and driving the growth of this patient's tumor," they added.

Examining the possibility of acquired resistance to hedgehog pathway inhibitors will be key in future studies, they noted. The potential adverse effects of hedgehog pathway blockade in children must also be delineated, as they are the largest population of patients with medulloblastoma.

Dr. Dlugosz reported receiving consulting fees from Merck & Co. and grant support from Pfizer Inc. Dr. Von Hoff reported receiving clinical research funding from Genentech Inc. Dr. Rudin reported receiving research funding and a BioOncology Grant Program Award from Genentech, as well as a clinical scientist award in translational research from Burroughs Wellcome Fund. Dr. Talpaz had no conflicts to report.

A new drug that inhibits the hedgehog signaling pathway has shown "remarkable" antitumor activity against basal cell carcinoma and medulloblastoma, according to two reports.

The hedgehog signaling pathway regulates cell growth and differentiation during early development but is inactive in healthy adults. However, it appears that mutations in components of the pathway can cause malignant growth in some cases of medulloblastoma, the most common brain cancer in children, and in several cancers in adults, notably basal cell carcinoma.

The hedgehog pathway derived its name from its signaling molecule, a polypeptide ligand called Hedgehog [Hh] because the mutation it caused when it was first discovered in fruit flies produced stubby, hairy-looking larvae resembling hedgehogs.

The new oral agent, GDC-0449, was developed to selectively and potently inhibit hedgehog signaling without producing the adverse effects common with conventional chemotherapy. It appears to have done so in a phase I clinical trial of patients with advanced or metastatic basal cell carcinoma and in a single case study testing it against medulloblastoma refractory to all other treatments. Both studies were supported by Genentech Inc., developer of GDC-0449.

These results indicate that targeting the hedgehog signaling pathway may be a promising avenue for a whole new class of cancer therapies, Dr. Andrzej A. Dlugosz and Dr. Moshe Talpaz of the University of Michigan, Ann Arbor, said in an editorial comment accompanying the two reports.

"Although the total number of patients with advanced or metastatic basal cell carcinoma is small, these studies should ignite renewed interest in testing hedgehog pathway inhibitors in patients with typical basal cell carcinoma" as well as other cancers, they said.

"For patients at especially high risk for multiple basal cell tumors, an effective medical treatment would be a welcome alternative to repeated surgical procedures, which can be especially disfiguring when the tumors occur on the face," Dr. Dlugosz and Dr. Talpaz said (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMe0906092

Alternatively, tumor debulking with the use of hedgehog inhibitors, followed by surgical excision, might prove beneficial in many patients, they added.

In the clinical trial, Dr. Daniel D. Von Hoff of the Translational Genomics Research Institute in Scottsdale, Ariz., and his associates assessed GDC-0449 in 18 patients with metastatic and 15 patients with locally advanced basal cell carcinoma that had been refractory to surgery, radiotherapy, and chemotherapy.

A total of 18 patients showed a clinical response, 11 showed stable disease for up to 10 months, and 4 had disease progression, Dr. Von Hoff and his colleagues reported (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMoa0905360

The overall response rate was 55%. Dr. Dlugosz and Dr. Talpaz termed the 50% response rate among patients with metastatic disease "remarkable."

There were no dose-limiting toxic effects or grade-5 adverse events during the study. One grade-4 event occurred (asymptomatic hyponatremia) and several patients reported a variety of problems that may or may not have been related to treatment, such as fatigue and weight loss. Only one patient discontinued treatment after 8 months, citing abdominal pain, fatigue, weight loss, anorexia, and dysgeusia.

In the case study, Dr. Charles M. Rudin of Johns Hopkins University, Baltimore, and his associates assessed GDC-0449 in a 26-year-old man with a 4-year history of medulloblastoma. The patient had undergone gross total resection of the tumor, craniospinal irradiation, extensive chemotherapy, autologous stem-cell transplantation, and additional systemic treatment with temozolomide and bevacizumab, but nevertheless had widespread skeletal and soft tissue metastases. With no alternative therapies left, he was offered CDC-0449.

Within 1 month, supraclavicular lymphadenopathy resolved, sternal masses regressed, and the patient reported that his intractable pain had resolved. After a few more weeks, more nodules regressed and the patient had returned to a normal level of activity. After a few more weeks, further metastases were markedly diminished or, in the case of a disabling epidural mass at C7, no longer detectable.

After 3 months of treatment, however, there was renewed tumor activity, including new lesions as well as regrowth of old lesions. The patient progressed rapidly, despite a series of subsequent therapies, and died.

"The tumor had a remarkable, although incomplete, and rapid, although transient, response to inhibition of the hedgehog pathway with GDC-0449," Dr. Rudin and his colleagues noted (N. Engl. J. Med. 2009 [doi:10.1056/NEJMoa0902903

"The regression is notable because of the tumor burden and the extent of metastasis in this patient, with substantial soft tissue and bony tissue involvement and clinically significant bone marrow compromise, and underscores the primary role that the hedgehog pathway played in maintaining and driving the growth of this patient's tumor," they added.

Examining the possibility of acquired resistance to hedgehog pathway inhibitors will be key in future studies, they noted. The potential adverse effects of hedgehog pathway blockade in children must also be delineated, as they are the largest population of patients with medulloblastoma.

Dr. Dlugosz reported receiving consulting fees from Merck & Co. and grant support from Pfizer Inc. Dr. Von Hoff reported receiving clinical research funding from Genentech Inc. Dr. Rudin reported receiving research funding and a BioOncology Grant Program Award from Genentech, as well as a clinical scientist award in translational research from Burroughs Wellcome Fund. Dr. Talpaz had no conflicts to report.

A new drug that inhibits the hedgehog signaling pathway has shown "remarkable" antitumor activity against basal cell carcinoma and medulloblastoma, according to two reports.

The hedgehog signaling pathway regulates cell growth and differentiation during early development but is inactive in healthy adults. However, it appears that mutations in components of the pathway can cause malignant growth in some cases of medulloblastoma, the most common brain cancer in children, and in several cancers in adults, notably basal cell carcinoma.

The hedgehog pathway derived its name from its signaling molecule, a polypeptide ligand called Hedgehog [Hh] because the mutation it caused when it was first discovered in fruit flies produced stubby, hairy-looking larvae resembling hedgehogs.

The new oral agent, GDC-0449, was developed to selectively and potently inhibit hedgehog signaling without producing the adverse effects common with conventional chemotherapy. It appears to have done so in a phase I clinical trial of patients with advanced or metastatic basal cell carcinoma and in a single case study testing it against medulloblastoma refractory to all other treatments. Both studies were supported by Genentech Inc., developer of GDC-0449.

These results indicate that targeting the hedgehog signaling pathway may be a promising avenue for a whole new class of cancer therapies, Dr. Andrzej A. Dlugosz and Dr. Moshe Talpaz of the University of Michigan, Ann Arbor, said in an editorial comment accompanying the two reports.

"Although the total number of patients with advanced or metastatic basal cell carcinoma is small, these studies should ignite renewed interest in testing hedgehog pathway inhibitors in patients with typical basal cell carcinoma" as well as other cancers, they said.

"For patients at especially high risk for multiple basal cell tumors, an effective medical treatment would be a welcome alternative to repeated surgical procedures, which can be especially disfiguring when the tumors occur on the face," Dr. Dlugosz and Dr. Talpaz said (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMe0906092

Alternatively, tumor debulking with the use of hedgehog inhibitors, followed by surgical excision, might prove beneficial in many patients, they added.

In the clinical trial, Dr. Daniel D. Von Hoff of the Translational Genomics Research Institute in Scottsdale, Ariz., and his associates assessed GDC-0449 in 18 patients with metastatic and 15 patients with locally advanced basal cell carcinoma that had been refractory to surgery, radiotherapy, and chemotherapy.

A total of 18 patients showed a clinical response, 11 showed stable disease for up to 10 months, and 4 had disease progression, Dr. Von Hoff and his colleagues reported (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMoa0905360

The overall response rate was 55%. Dr. Dlugosz and Dr. Talpaz termed the 50% response rate among patients with metastatic disease "remarkable."

There were no dose-limiting toxic effects or grade-5 adverse events during the study. One grade-4 event occurred (asymptomatic hyponatremia) and several patients reported a variety of problems that may or may not have been related to treatment, such as fatigue and weight loss. Only one patient discontinued treatment after 8 months, citing abdominal pain, fatigue, weight loss, anorexia, and dysgeusia.

In the case study, Dr. Charles M. Rudin of Johns Hopkins University, Baltimore, and his associates assessed GDC-0449 in a 26-year-old man with a 4-year history of medulloblastoma. The patient had undergone gross total resection of the tumor, craniospinal irradiation, extensive chemotherapy, autologous stem-cell transplantation, and additional systemic treatment with temozolomide and bevacizumab, but nevertheless had widespread skeletal and soft tissue metastases. With no alternative therapies left, he was offered CDC-0449.

Within 1 month, supraclavicular lymphadenopathy resolved, sternal masses regressed, and the patient reported that his intractable pain had resolved. After a few more weeks, more nodules regressed and the patient had returned to a normal level of activity. After a few more weeks, further metastases were markedly diminished or, in the case of a disabling epidural mass at C7, no longer detectable.

After 3 months of treatment, however, there was renewed tumor activity, including new lesions as well as regrowth of old lesions. The patient progressed rapidly, despite a series of subsequent therapies, and died.

"The tumor had a remarkable, although incomplete, and rapid, although transient, response to inhibition of the hedgehog pathway with GDC-0449," Dr. Rudin and his colleagues noted (N. Engl. J. Med. 2009 [doi:10.1056/NEJMoa0902903

"The regression is notable because of the tumor burden and the extent of metastasis in this patient, with substantial soft tissue and bony tissue involvement and clinically significant bone marrow compromise, and underscores the primary role that the hedgehog pathway played in maintaining and driving the growth of this patient's tumor," they added.

Examining the possibility of acquired resistance to hedgehog pathway inhibitors will be key in future studies, they noted. The potential adverse effects of hedgehog pathway blockade in children must also be delineated, as they are the largest population of patients with medulloblastoma.

Dr. Dlugosz reported receiving consulting fees from Merck & Co. and grant support from Pfizer Inc. Dr. Von Hoff reported receiving clinical research funding from Genentech Inc. Dr. Rudin reported receiving research funding and a BioOncology Grant Program Award from Genentech, as well as a clinical scientist award in translational research from Burroughs Wellcome Fund. Dr. Talpaz had no conflicts to report.

Uterosacral nerve ablation via laparoscopy failed to improve chronic pelvic pain, dysmenorrhea, dyspareunia, and quality of life in a clinical trial four times larger than any previously published study of the issue.

Laparoscopic uterosacral nerve ablation (LUNA) using either lasers or electrodiathermy has become increasingly popular for chronic pelvic pain, even though systematic reviews have been “inconclusive” as to its benefit. “Clinicians' beliefs about LUNA's effectiveness vary widely, and LUNA remains a controversial procedure,” said Jane Daniels of Birmingham (U.K.) Women's Hospital and her associates.

The investigators performed a randomized study of 487 women with chronic pelvic pain undergoing laparoscopy for a differential diagnosis at 18 British hospitals. Intraoperatively, the women were assigned to undergo immediate LUNA or no nerve ablation.

“The ablation was performed as close to the posterior aspect of the cervix as possible and continued for a minimum of 1 cm posterolaterally on either side with the intended aim of destroying the sensory nerve fibers and the secondary ganglia as they left the uterus and lie within the uterosacral ligaments,” Ms. Daniels and her colleagues noted. “Full or partial transaction of the ligaments was achieved bilaterally with laser or electrodiathermy, according to the surgeon's preference.”

Median follow-up was 69 months. The patients assessed their pain and health-related quality of life at 3 and 6 months, and 1, 2, 3, and 5 years post procedure.

There were no differences between women who had LUNA and those who did not in terms of severity of chronic pelvic pain, dysmenorrhea, or dyspareunia at any time point, Ms. Daniels and her colleagues said (JAMA 2009;302:955–61).

There also was no difference in health-related quality of life. One year after the procedure, the two groups reported a similar number of visits to their general practitioners and a similar number of days off from work. There were eight cases of minor hemorrhaging during LUNA and one case that required conversion to an open surgery.

“LUNA was adopted by many practitioners because afferent nerves from pelvic organs pass through the uterosacral ligament, and it was thought that disruption of these would reduce the perceived pain. Lack of efficacy in our study and in prior studies provides evidence that the anatomical and physiological picture of chronic pelvic pain is more complicated.”

No financial conflicts of interest were reported by the study investigators.

Uterosacral nerve ablation via laparoscopy failed to improve chronic pelvic pain, dysmenorrhea, dyspareunia, and quality of life in a clinical trial four times larger than any previously published study of the issue.

Laparoscopic uterosacral nerve ablation (LUNA) using either lasers or electrodiathermy has become increasingly popular for chronic pelvic pain, even though systematic reviews have been “inconclusive” as to its benefit. “Clinicians' beliefs about LUNA's effectiveness vary widely, and LUNA remains a controversial procedure,” said Jane Daniels of Birmingham (U.K.) Women's Hospital and her associates.

The investigators performed a randomized study of 487 women with chronic pelvic pain undergoing laparoscopy for a differential diagnosis at 18 British hospitals. Intraoperatively, the women were assigned to undergo immediate LUNA or no nerve ablation.

“The ablation was performed as close to the posterior aspect of the cervix as possible and continued for a minimum of 1 cm posterolaterally on either side with the intended aim of destroying the sensory nerve fibers and the secondary ganglia as they left the uterus and lie within the uterosacral ligaments,” Ms. Daniels and her colleagues noted. “Full or partial transaction of the ligaments was achieved bilaterally with laser or electrodiathermy, according to the surgeon's preference.”

Median follow-up was 69 months. The patients assessed their pain and health-related quality of life at 3 and 6 months, and 1, 2, 3, and 5 years post procedure.

There were no differences between women who had LUNA and those who did not in terms of severity of chronic pelvic pain, dysmenorrhea, or dyspareunia at any time point, Ms. Daniels and her colleagues said (JAMA 2009;302:955–61).

There also was no difference in health-related quality of life. One year after the procedure, the two groups reported a similar number of visits to their general practitioners and a similar number of days off from work. There were eight cases of minor hemorrhaging during LUNA and one case that required conversion to an open surgery.

“LUNA was adopted by many practitioners because afferent nerves from pelvic organs pass through the uterosacral ligament, and it was thought that disruption of these would reduce the perceived pain. Lack of efficacy in our study and in prior studies provides evidence that the anatomical and physiological picture of chronic pelvic pain is more complicated.”

No financial conflicts of interest were reported by the study investigators.

Uterosacral nerve ablation via laparoscopy failed to improve chronic pelvic pain, dysmenorrhea, dyspareunia, and quality of life in a clinical trial four times larger than any previously published study of the issue.

Laparoscopic uterosacral nerve ablation (LUNA) using either lasers or electrodiathermy has become increasingly popular for chronic pelvic pain, even though systematic reviews have been “inconclusive” as to its benefit. “Clinicians' beliefs about LUNA's effectiveness vary widely, and LUNA remains a controversial procedure,” said Jane Daniels of Birmingham (U.K.) Women's Hospital and her associates.

The investigators performed a randomized study of 487 women with chronic pelvic pain undergoing laparoscopy for a differential diagnosis at 18 British hospitals. Intraoperatively, the women were assigned to undergo immediate LUNA or no nerve ablation.

“The ablation was performed as close to the posterior aspect of the cervix as possible and continued for a minimum of 1 cm posterolaterally on either side with the intended aim of destroying the sensory nerve fibers and the secondary ganglia as they left the uterus and lie within the uterosacral ligaments,” Ms. Daniels and her colleagues noted. “Full or partial transaction of the ligaments was achieved bilaterally with laser or electrodiathermy, according to the surgeon's preference.”

Median follow-up was 69 months. The patients assessed their pain and health-related quality of life at 3 and 6 months, and 1, 2, 3, and 5 years post procedure.

There were no differences between women who had LUNA and those who did not in terms of severity of chronic pelvic pain, dysmenorrhea, or dyspareunia at any time point, Ms. Daniels and her colleagues said (JAMA 2009;302:955–61).

There also was no difference in health-related quality of life. One year after the procedure, the two groups reported a similar number of visits to their general practitioners and a similar number of days off from work. There were eight cases of minor hemorrhaging during LUNA and one case that required conversion to an open surgery.

“LUNA was adopted by many practitioners because afferent nerves from pelvic organs pass through the uterosacral ligament, and it was thought that disruption of these would reduce the perceived pain. Lack of efficacy in our study and in prior studies provides evidence that the anatomical and physiological picture of chronic pelvic pain is more complicated.”

No financial conflicts of interest were reported by the study investigators.

In patients attending a general dermatology practice, most melanomas diagnosed during a 3-year period were not the presenting complaint, but were only discovered because a dermatologist performed a full-body skin examination.

Such melanomas, discovered incidentally during an unrelated office visit, were more likely to be thinner or in-situ lesions than those that were inquired about by the patient or someone who observed them on the patient, said Dr. Jonathan Kantor and Deborah E. Kantor, CRNP, of North Florida Dermatology Associates, Jacksonville.

The U.S. Preventive Service Task Force has stated that current evidence is insufficient to recommend either for or against routine full-body melanoma screening, and previous studies of patients in tertiary referral centers have reported that physicians detect only 14–34% of melanomas.

“Our aim was to determine the proportion of patients in a private dermatology practice in whom melanoma was detected but was not the presenting complaint. If a substantial proportion of melanomas are detected only after a dermatologist's examination, this may suggest that FBSE (full-body skin examination), and not simply a problem-focused approach, should at least be considered for selected patients,” the researchers said.

The investigators performed a retrospective case series of all patients diagnosed as having melanoma (51 cases) or melanoma in situ (75 cases) during a 3-year period. Patients were aged 15–92 years (mean age, 60 years).

A total of 56% of the melanomas were discovered by a dermatologist and had not been noted by the patient, a spouse, a friend, or another physician. Similarly, 60% of the melanomas-in-situ were discovered by a dermatologist, they said (Arch. Dermatol. 2009;145:873–6).

“Moreover, we found that dermatologist detection was associated with thinner melanomas and an increasing likelihood of the melanoma being in-situ,” they said.

“Thus, full-body skin examinations confer both an absolute benefit (detecting most melanomas) as well as a clinically significant marginal benefit (detecting melanomas with less tumor thickness). We hope that these findings will help spur large population-based studies in high-risk populations to develop an evidence-based approach to determining appropriate screening practices and intervals,” the investigators added.

The researchers reported no financial disclosures.

In patients attending a general dermatology practice, most melanomas diagnosed during a 3-year period were not the presenting complaint, but were only discovered because a dermatologist performed a full-body skin examination.

Such melanomas, discovered incidentally during an unrelated office visit, were more likely to be thinner or in-situ lesions than those that were inquired about by the patient or someone who observed them on the patient, said Dr. Jonathan Kantor and Deborah E. Kantor, CRNP, of North Florida Dermatology Associates, Jacksonville.

The U.S. Preventive Service Task Force has stated that current evidence is insufficient to recommend either for or against routine full-body melanoma screening, and previous studies of patients in tertiary referral centers have reported that physicians detect only 14–34% of melanomas.

“Our aim was to determine the proportion of patients in a private dermatology practice in whom melanoma was detected but was not the presenting complaint. If a substantial proportion of melanomas are detected only after a dermatologist's examination, this may suggest that FBSE (full-body skin examination), and not simply a problem-focused approach, should at least be considered for selected patients,” the researchers said.

The investigators performed a retrospective case series of all patients diagnosed as having melanoma (51 cases) or melanoma in situ (75 cases) during a 3-year period. Patients were aged 15–92 years (mean age, 60 years).

A total of 56% of the melanomas were discovered by a dermatologist and had not been noted by the patient, a spouse, a friend, or another physician. Similarly, 60% of the melanomas-in-situ were discovered by a dermatologist, they said (Arch. Dermatol. 2009;145:873–6).

“Moreover, we found that dermatologist detection was associated with thinner melanomas and an increasing likelihood of the melanoma being in-situ,” they said.

“Thus, full-body skin examinations confer both an absolute benefit (detecting most melanomas) as well as a clinically significant marginal benefit (detecting melanomas with less tumor thickness). We hope that these findings will help spur large population-based studies in high-risk populations to develop an evidence-based approach to determining appropriate screening practices and intervals,” the investigators added.

The researchers reported no financial disclosures.

In patients attending a general dermatology practice, most melanomas diagnosed during a 3-year period were not the presenting complaint, but were only discovered because a dermatologist performed a full-body skin examination.

Such melanomas, discovered incidentally during an unrelated office visit, were more likely to be thinner or in-situ lesions than those that were inquired about by the patient or someone who observed them on the patient, said Dr. Jonathan Kantor and Deborah E. Kantor, CRNP, of North Florida Dermatology Associates, Jacksonville.

The U.S. Preventive Service Task Force has stated that current evidence is insufficient to recommend either for or against routine full-body melanoma screening, and previous studies of patients in tertiary referral centers have reported that physicians detect only 14–34% of melanomas.

“Our aim was to determine the proportion of patients in a private dermatology practice in whom melanoma was detected but was not the presenting complaint. If a substantial proportion of melanomas are detected only after a dermatologist's examination, this may suggest that FBSE (full-body skin examination), and not simply a problem-focused approach, should at least be considered for selected patients,” the researchers said.

The investigators performed a retrospective case series of all patients diagnosed as having melanoma (51 cases) or melanoma in situ (75 cases) during a 3-year period. Patients were aged 15–92 years (mean age, 60 years).

A total of 56% of the melanomas were discovered by a dermatologist and had not been noted by the patient, a spouse, a friend, or another physician. Similarly, 60% of the melanomas-in-situ were discovered by a dermatologist, they said (Arch. Dermatol. 2009;145:873–6).

“Moreover, we found that dermatologist detection was associated with thinner melanomas and an increasing likelihood of the melanoma being in-situ,” they said.

“Thus, full-body skin examinations confer both an absolute benefit (detecting most melanomas) as well as a clinically significant marginal benefit (detecting melanomas with less tumor thickness). We hope that these findings will help spur large population-based studies in high-risk populations to develop an evidence-based approach to determining appropriate screening practices and intervals,” the investigators added.

The researchers reported no financial disclosures.

Vertebroplasty was no more beneficial than a sham procedure for painful osteoporotic vertebral fractures in the first two blinded, randomized, controlled trials ever to assess the technique, according to two separate reports.

These findings are likely to transform percutaneous vertebroplasty—a widely accepted method of pain relief that has become routine therapy—from “a procedure that is virtually always considered to be successful” into one “considered no better than placebo,” James N. Weinstein, D.O., of Dartmouth-Hitchcock Medical Center, Hanover, N.H., said in an editorial.

Public institutions such as the Centers for Medicare and Medicaid Services, as well as radiologic and neurologic surgery societies, have recommended reimbursement of vertebroplasty—endorsements that have boosted a dramatic rise in its popularity. The number of vertebroplasties performed in the United States has more than doubled in the past 6 years, Dr. Weinstein noted (N. Engl. J. Med. 2009;361:619-21).

The procedure involves injecting medical cement directly into a vertebral fracture to stabilize it and immediately relieve pain. Many case series and small, unblinded, nonrandomized, noncontrolled studies have suggested that it is effective, though the precise mechanism of action has never been delineated.

In one of the reports, Rachelle Buchbinder, Ph.D., of Monash University, Malvern, Australia, and her associates randomly assigned 38 patients with one or two recent vertebral fractures to vertebroplasty and 40 to a sham procedure.

The primary outcome measure, overall pain score, was no different between the two groups at 1-week, 1-month, 3-month, or 6-month assessments. Pain at rest, pain during the night, physical functioning, and quality of life measures also did not differ significantly, nor did the use of opioid analgesics, the researchers said (N. Engl. J. Med. 2009;361:557-68).

These results were consistent regardless of patients' duration of symptoms and history of previous fractures.

One subject who underwent vertebroplasty and could not receive prophylactic cephalothin because of drug allergies developed an adjacent new fracture and osteomyelitis requiring surgery. Some studies have suggested that vertebroplasty raises the risk of subsequent fractures, particularly in vertebrae adjacent to treated areas, sometimes after the medical cement has leaked into those areas, they added.

“Our results show … the hazards of relying on the results of uncontrolled or poorly controlled studies to assess treatment efficacy,” Dr. Buchbinder and her colleagues noted.

Earlier studies may have overestimated the benefit of vertebroplasty “by failing to take into account the favorable natural history of the condition, the tendency of regression to the mean, and the placebo response to treatment, which may be amplified when the treatment is invasive,” they added.

In the other study, Dr. David F. Kallmes of the Mayo Clinic, Rochester, Minn., and his associates enrolled patients at 11 medical centers in the United States, the United Kingdon, and Australia. A total of 68 were randomly assigned to vertebroplasty and 63 to a sham procedure.

At 1 month, the two groups did not differ significantly on the two primary outcomes, which were separate measures of pain and disability. Secondary outcomes of pain intensity, disability, and quality of life also were not significantly different, Dr. Kallmes and colleagues said (N. Engl. J. Med. 2009;361:569-79).

One patient who underwent vertebroplasty sustained an injury to the thecal sac during the procedure and required hospitalization, they added.

Dr. Buchbinder reports receiving grant support for the trial from Cook Australia, a manufacturer of medical products and devices. Dr. Kallmes reports receiving consulting fees from Zelos Therapeutics and grant support from ArthroCare, Stryker, Cardinal, and Cook and serving as an unpaid consultant to Bone Support. Dr. Weinstein reported no disclosures.

Vertebroplasty was no more beneficial than a sham procedure for painful osteoporotic vertebral fractures in the first two blinded, randomized, controlled trials ever to assess the technique, according to two separate reports.

These findings are likely to transform percutaneous vertebroplasty—a widely accepted method of pain relief that has become routine therapy—from “a procedure that is virtually always considered to be successful” into one “considered no better than placebo,” James N. Weinstein, D.O., of Dartmouth-Hitchcock Medical Center, Hanover, N.H., said in an editorial.

Public institutions such as the Centers for Medicare and Medicaid Services, as well as radiologic and neurologic surgery societies, have recommended reimbursement of vertebroplasty—endorsements that have boosted a dramatic rise in its popularity. The number of vertebroplasties performed in the United States has more than doubled in the past 6 years, Dr. Weinstein noted (N. Engl. J. Med. 2009;361:619-21).

The procedure involves injecting medical cement directly into a vertebral fracture to stabilize it and immediately relieve pain. Many case series and small, unblinded, nonrandomized, noncontrolled studies have suggested that it is effective, though the precise mechanism of action has never been delineated.

In one of the reports, Rachelle Buchbinder, Ph.D., of Monash University, Malvern, Australia, and her associates randomly assigned 38 patients with one or two recent vertebral fractures to vertebroplasty and 40 to a sham procedure.

The primary outcome measure, overall pain score, was no different between the two groups at 1-week, 1-month, 3-month, or 6-month assessments. Pain at rest, pain during the night, physical functioning, and quality of life measures also did not differ significantly, nor did the use of opioid analgesics, the researchers said (N. Engl. J. Med. 2009;361:557-68).

These results were consistent regardless of patients' duration of symptoms and history of previous fractures.

One subject who underwent vertebroplasty and could not receive prophylactic cephalothin because of drug allergies developed an adjacent new fracture and osteomyelitis requiring surgery. Some studies have suggested that vertebroplasty raises the risk of subsequent fractures, particularly in vertebrae adjacent to treated areas, sometimes after the medical cement has leaked into those areas, they added.

“Our results show … the hazards of relying on the results of uncontrolled or poorly controlled studies to assess treatment efficacy,” Dr. Buchbinder and her colleagues noted.

Earlier studies may have overestimated the benefit of vertebroplasty “by failing to take into account the favorable natural history of the condition, the tendency of regression to the mean, and the placebo response to treatment, which may be amplified when the treatment is invasive,” they added.

In the other study, Dr. David F. Kallmes of the Mayo Clinic, Rochester, Minn., and his associates enrolled patients at 11 medical centers in the United States, the United Kingdon, and Australia. A total of 68 were randomly assigned to vertebroplasty and 63 to a sham procedure.

At 1 month, the two groups did not differ significantly on the two primary outcomes, which were separate measures of pain and disability. Secondary outcomes of pain intensity, disability, and quality of life also were not significantly different, Dr. Kallmes and colleagues said (N. Engl. J. Med. 2009;361:569-79).

One patient who underwent vertebroplasty sustained an injury to the thecal sac during the procedure and required hospitalization, they added.

Dr. Buchbinder reports receiving grant support for the trial from Cook Australia, a manufacturer of medical products and devices. Dr. Kallmes reports receiving consulting fees from Zelos Therapeutics and grant support from ArthroCare, Stryker, Cardinal, and Cook and serving as an unpaid consultant to Bone Support. Dr. Weinstein reported no disclosures.

Vertebroplasty was no more beneficial than a sham procedure for painful osteoporotic vertebral fractures in the first two blinded, randomized, controlled trials ever to assess the technique, according to two separate reports.

These findings are likely to transform percutaneous vertebroplasty—a widely accepted method of pain relief that has become routine therapy—from “a procedure that is virtually always considered to be successful” into one “considered no better than placebo,” James N. Weinstein, D.O., of Dartmouth-Hitchcock Medical Center, Hanover, N.H., said in an editorial.

Public institutions such as the Centers for Medicare and Medicaid Services, as well as radiologic and neurologic surgery societies, have recommended reimbursement of vertebroplasty—endorsements that have boosted a dramatic rise in its popularity. The number of vertebroplasties performed in the United States has more than doubled in the past 6 years, Dr. Weinstein noted (N. Engl. J. Med. 2009;361:619-21).

The procedure involves injecting medical cement directly into a vertebral fracture to stabilize it and immediately relieve pain. Many case series and small, unblinded, nonrandomized, noncontrolled studies have suggested that it is effective, though the precise mechanism of action has never been delineated.

In one of the reports, Rachelle Buchbinder, Ph.D., of Monash University, Malvern, Australia, and her associates randomly assigned 38 patients with one or two recent vertebral fractures to vertebroplasty and 40 to a sham procedure.

The primary outcome measure, overall pain score, was no different between the two groups at 1-week, 1-month, 3-month, or 6-month assessments. Pain at rest, pain during the night, physical functioning, and quality of life measures also did not differ significantly, nor did the use of opioid analgesics, the researchers said (N. Engl. J. Med. 2009;361:557-68).

These results were consistent regardless of patients' duration of symptoms and history of previous fractures.

One subject who underwent vertebroplasty and could not receive prophylactic cephalothin because of drug allergies developed an adjacent new fracture and osteomyelitis requiring surgery. Some studies have suggested that vertebroplasty raises the risk of subsequent fractures, particularly in vertebrae adjacent to treated areas, sometimes after the medical cement has leaked into those areas, they added.

“Our results show … the hazards of relying on the results of uncontrolled or poorly controlled studies to assess treatment efficacy,” Dr. Buchbinder and her colleagues noted.

Earlier studies may have overestimated the benefit of vertebroplasty “by failing to take into account the favorable natural history of the condition, the tendency of regression to the mean, and the placebo response to treatment, which may be amplified when the treatment is invasive,” they added.

In the other study, Dr. David F. Kallmes of the Mayo Clinic, Rochester, Minn., and his associates enrolled patients at 11 medical centers in the United States, the United Kingdon, and Australia. A total of 68 were randomly assigned to vertebroplasty and 63 to a sham procedure.

At 1 month, the two groups did not differ significantly on the two primary outcomes, which were separate measures of pain and disability. Secondary outcomes of pain intensity, disability, and quality of life also were not significantly different, Dr. Kallmes and colleagues said (N. Engl. J. Med. 2009;361:569-79).

One patient who underwent vertebroplasty sustained an injury to the thecal sac during the procedure and required hospitalization, they added.

Dr. Buchbinder reports receiving grant support for the trial from Cook Australia, a manufacturer of medical products and devices. Dr. Kallmes reports receiving consulting fees from Zelos Therapeutics and grant support from ArthroCare, Stryker, Cardinal, and Cook and serving as an unpaid consultant to Bone Support. Dr. Weinstein reported no disclosures.

A low plasma level of sex hormone–binding globulin strongly predicts increased risk for type 2 diabetes in both men and women, while a high level predicts decreased risk, according to an analysis of two longitudinal studies.

Sex hormone–binding globulin (SHBG) appears to have a predictive ability beyond that of traditional risk factors, including glycosylated hemoglobin and C-reactive protein (CRP), said Eric L. Ding, Sc.D., of Harvard School of Public Health, Boston, and his associates.

The findings were obtained in several different analyses of data from the Women's Health Study, then replicated in several further analyses of data from the Physicians' Health Study II. “These strong and consistent findings, obtained with the use of multiple analytic approaches and subgroup analyses in two independent cohorts, support the notion that sex hormone–binding globulin may play an important role in the development of type 2 diabetes at both the genomic and phenotypic levels and that [SHBG] could be an important target in stratification for the risk of type 2 diabetes and early intervention,” the researchers noted.

The primary function of SHBG was thought to be to bind circulating hormones, and to sequester circulating androgens and estrogens in particular. More recently, SHBG has been implicated in the maintenance of glucose homeostasis, and several variations in the SHBG gene have been associated with insulin resistance.

Dr. Ding and his colleagues studied plasma SHBG levels in a prospective cohort of 12,304 postmenopausal women participating in the Women's Health Study. A subset of 359 of these subjects who had developed type 2 diabetes during 10-year follow-up were matched for age and race with 359 control subjects who had not.

High plasma levels of SHBG at baseline were robustly associated with low risk for developing diabetes, as well as with low body mass index, low likelihood of having hypertension, and favorable lipid profiles and CRP levels.

The results were identical in a replication study involving 170 men participating in the Physicians' Health Study II who had developed type 2 diabetes during 8-year follow-up and 170 matched controls who had not. Study subjects who had SHBG levels in the lowest quartile at baseline were at 10 times the risk for diabetes of those who had SHBG levels in the highest quartile, the investigators wrote (N. Engl. J. Med. 2009 Aug. 5 [doi:10.1056/NEJMoa0804381]).

Moreover, two variants in the SHBG gene, the rs6257 and the rs6259 polymorphisms, were consistently associated with SHBG levels and diabetes risk, they added.

“Our results may provide a potential explanation of the intriguing divergent effects on the risk of diabetes, observed in two randomized trials, of transdermal estradiol (which elevates plasma glucose levels) and oral estrogen (which lowers glucose levels). In direct comparisons, transdermal estradiol does not affect [SHBG] levels, whereas oral-estrogen therapy favorably increases levels of [SHBG],” Dr. Ding and his associates noted.

Dr. Ding is listed on a provisional patent application filed by the University of California at Los Angeles for the use of SHBG for determining risk of type 2 diabetes.

A low plasma level of sex hormone–binding globulin strongly predicts increased risk for type 2 diabetes in both men and women, while a high level predicts decreased risk, according to an analysis of two longitudinal studies.

Sex hormone–binding globulin (SHBG) appears to have a predictive ability beyond that of traditional risk factors, including glycosylated hemoglobin and C-reactive protein (CRP), said Eric L. Ding, Sc.D., of Harvard School of Public Health, Boston, and his associates.

The findings were obtained in several different analyses of data from the Women's Health Study, then replicated in several further analyses of data from the Physicians' Health Study II. “These strong and consistent findings, obtained with the use of multiple analytic approaches and subgroup analyses in two independent cohorts, support the notion that sex hormone–binding globulin may play an important role in the development of type 2 diabetes at both the genomic and phenotypic levels and that [SHBG] could be an important target in stratification for the risk of type 2 diabetes and early intervention,” the researchers noted.

The primary function of SHBG was thought to be to bind circulating hormones, and to sequester circulating androgens and estrogens in particular. More recently, SHBG has been implicated in the maintenance of glucose homeostasis, and several variations in the SHBG gene have been associated with insulin resistance.

Dr. Ding and his colleagues studied plasma SHBG levels in a prospective cohort of 12,304 postmenopausal women participating in the Women's Health Study. A subset of 359 of these subjects who had developed type 2 diabetes during 10-year follow-up were matched for age and race with 359 control subjects who had not.

High plasma levels of SHBG at baseline were robustly associated with low risk for developing diabetes, as well as with low body mass index, low likelihood of having hypertension, and favorable lipid profiles and CRP levels.

The results were identical in a replication study involving 170 men participating in the Physicians' Health Study II who had developed type 2 diabetes during 8-year follow-up and 170 matched controls who had not. Study subjects who had SHBG levels in the lowest quartile at baseline were at 10 times the risk for diabetes of those who had SHBG levels in the highest quartile, the investigators wrote (N. Engl. J. Med. 2009 Aug. 5 [doi:10.1056/NEJMoa0804381]).

Moreover, two variants in the SHBG gene, the rs6257 and the rs6259 polymorphisms, were consistently associated with SHBG levels and diabetes risk, they added.

“Our results may provide a potential explanation of the intriguing divergent effects on the risk of diabetes, observed in two randomized trials, of transdermal estradiol (which elevates plasma glucose levels) and oral estrogen (which lowers glucose levels). In direct comparisons, transdermal estradiol does not affect [SHBG] levels, whereas oral-estrogen therapy favorably increases levels of [SHBG],” Dr. Ding and his associates noted.

Dr. Ding is listed on a provisional patent application filed by the University of California at Los Angeles for the use of SHBG for determining risk of type 2 diabetes.

A low plasma level of sex hormone–binding globulin strongly predicts increased risk for type 2 diabetes in both men and women, while a high level predicts decreased risk, according to an analysis of two longitudinal studies.

Sex hormone–binding globulin (SHBG) appears to have a predictive ability beyond that of traditional risk factors, including glycosylated hemoglobin and C-reactive protein (CRP), said Eric L. Ding, Sc.D., of Harvard School of Public Health, Boston, and his associates.

The findings were obtained in several different analyses of data from the Women's Health Study, then replicated in several further analyses of data from the Physicians' Health Study II. “These strong and consistent findings, obtained with the use of multiple analytic approaches and subgroup analyses in two independent cohorts, support the notion that sex hormone–binding globulin may play an important role in the development of type 2 diabetes at both the genomic and phenotypic levels and that [SHBG] could be an important target in stratification for the risk of type 2 diabetes and early intervention,” the researchers noted.

The primary function of SHBG was thought to be to bind circulating hormones, and to sequester circulating androgens and estrogens in particular. More recently, SHBG has been implicated in the maintenance of glucose homeostasis, and several variations in the SHBG gene have been associated with insulin resistance.

Dr. Ding and his colleagues studied plasma SHBG levels in a prospective cohort of 12,304 postmenopausal women participating in the Women's Health Study. A subset of 359 of these subjects who had developed type 2 diabetes during 10-year follow-up were matched for age and race with 359 control subjects who had not.

High plasma levels of SHBG at baseline were robustly associated with low risk for developing diabetes, as well as with low body mass index, low likelihood of having hypertension, and favorable lipid profiles and CRP levels.

The results were identical in a replication study involving 170 men participating in the Physicians' Health Study II who had developed type 2 diabetes during 8-year follow-up and 170 matched controls who had not. Study subjects who had SHBG levels in the lowest quartile at baseline were at 10 times the risk for diabetes of those who had SHBG levels in the highest quartile, the investigators wrote (N. Engl. J. Med. 2009 Aug. 5 [doi:10.1056/NEJMoa0804381]).

Moreover, two variants in the SHBG gene, the rs6257 and the rs6259 polymorphisms, were consistently associated with SHBG levels and diabetes risk, they added.

“Our results may provide a potential explanation of the intriguing divergent effects on the risk of diabetes, observed in two randomized trials, of transdermal estradiol (which elevates plasma glucose levels) and oral estrogen (which lowers glucose levels). In direct comparisons, transdermal estradiol does not affect [SHBG] levels, whereas oral-estrogen therapy favorably increases levels of [SHBG],” Dr. Ding and his associates noted.

Dr. Ding is listed on a provisional patent application filed by the University of California at Los Angeles for the use of SHBG for determining risk of type 2 diabetes.

Screening all women at primary care visits for intimate partner violence does not appear to be beneficial, according to one study.

Such screening did not appear to cause any harm, but neither did it prompt affected women to access services or otherwise deter intimate partner violence (IPV), said Dr. Harriet L. MacMillan of McMaster University, Hamilton, Ont., and her associates.

Some medical organizations, including the American Medical Association and the American College of Obstetricians and Gynecologists, recommend such screening of all women, “despite the lack of evidence that it is effective.” Others—including the U.S. Preventive Services Task Force and the Canadian Task Force on Preventive Health Care—say that there isn't sufficient evidence either for or against such screening.

Dr. MacMillan and her colleagues conducted a study to assess whether IPV screening reduced subsequent violence or improved womens' quality of life. They randomly assigned 6,743 women to be screened or not screened at primary care visits, then followed them for 18 months to determine whether intimate violence decreased (JAMA 2009;302:493–501).

The study subjects were aged 18–64 years and were recruited when they attended 12 primary care sites, 11 emergency departments, and 3 ob.gyn. clinics in Ontario in 2005–2006. They completed the Woman Abuse Screening Tool, an eight-item self-report instrument that measures physical, sexual, and emotional abuse in the preceding year, before consulting the clinician.

Any discussion of positive findings on the screen and referral for further treatment was left to the discretion of the treating clinician. Overall, 44% of the women who were screened for IPV reported discussing violence with the clinician, compared with 8% of those who were not screened.

The women also were assessed for depressive symptoms, posttraumatic stress disorder, alcohol abuse/dependency, and global mental and physical well-being. All were given an information card listing available resources for women exposed to violence.

A subset of 347 screened women and 360 unscreened were included in the data analysis for this study. The proportion of these subjects who were lost to follow-up was high: 43% of those who were screened for IPV and 41% of those who were not screened.

No significant differences were foundbetween the two groups in IPV recurrence, and only a weak, nonsignificant benefit in depression and quality of life scores with screening, Dr. MacMillan and her colleagues said.

“If there were an effective intervention to which women could have been referred once identified as exposed to IPV, it is possible that the results of this trial would have been more positive,” Dr. MacMillan and her associates noted.

Some experts have raised concerns about possible harmful effects of routine IPV screening, “including reprisal violence, psychological distress, family disruption, and risk of a child being removed from a mother's care following child protective services involvement,” the investigators added. Their study showed no evidence of a harmful effect on either abused or nonabused women.

In an accompanying editorial, Kathryn E. Moracco, Ph.D., of the University of North Carolina, Chapel Hill, and Dr. Thomas B. Cole, contributing editor of the JAMA, noted that universal screening for IPV must be distinguished from specifically assessing abuse in women who are at increased risk. In the latter case, screening “may not only detect violence but may also lead to more accurate diagnosis and treatment of co-occurring health problems,” they said (JAMA 2009;302:568–9). “The results of the study by MacMillan et al. should dispel any illusions that universal screening with passive referrals to community services is an adequate response to violence in intimate relationships,” they wrote

Neither the investigators nor the editorial writers reported financial disclosures. The study was funded by the former Ontario Women's Health Council.

Screening all women at primary care visits for intimate partner violence does not appear to be beneficial, according to one study.

Such screening did not appear to cause any harm, but neither did it prompt affected women to access services or otherwise deter intimate partner violence (IPV), said Dr. Harriet L. MacMillan of McMaster University, Hamilton, Ont., and her associates.

Some medical organizations, including the American Medical Association and the American College of Obstetricians and Gynecologists, recommend such screening of all women, “despite the lack of evidence that it is effective.” Others—including the U.S. Preventive Services Task Force and the Canadian Task Force on Preventive Health Care—say that there isn't sufficient evidence either for or against such screening.

Dr. MacMillan and her colleagues conducted a study to assess whether IPV screening reduced subsequent violence or improved womens' quality of life. They randomly assigned 6,743 women to be screened or not screened at primary care visits, then followed them for 18 months to determine whether intimate violence decreased (JAMA 2009;302:493–501).

The study subjects were aged 18–64 years and were recruited when they attended 12 primary care sites, 11 emergency departments, and 3 ob.gyn. clinics in Ontario in 2005–2006. They completed the Woman Abuse Screening Tool, an eight-item self-report instrument that measures physical, sexual, and emotional abuse in the preceding year, before consulting the clinician.

Any discussion of positive findings on the screen and referral for further treatment was left to the discretion of the treating clinician. Overall, 44% of the women who were screened for IPV reported discussing violence with the clinician, compared with 8% of those who were not screened.

The women also were assessed for depressive symptoms, posttraumatic stress disorder, alcohol abuse/dependency, and global mental and physical well-being. All were given an information card listing available resources for women exposed to violence.

A subset of 347 screened women and 360 unscreened were included in the data analysis for this study. The proportion of these subjects who were lost to follow-up was high: 43% of those who were screened for IPV and 41% of those who were not screened.

No significant differences were foundbetween the two groups in IPV recurrence, and only a weak, nonsignificant benefit in depression and quality of life scores with screening, Dr. MacMillan and her colleagues said.

“If there were an effective intervention to which women could have been referred once identified as exposed to IPV, it is possible that the results of this trial would have been more positive,” Dr. MacMillan and her associates noted.

Some experts have raised concerns about possible harmful effects of routine IPV screening, “including reprisal violence, psychological distress, family disruption, and risk of a child being removed from a mother's care following child protective services involvement,” the investigators added. Their study showed no evidence of a harmful effect on either abused or nonabused women.

In an accompanying editorial, Kathryn E. Moracco, Ph.D., of the University of North Carolina, Chapel Hill, and Dr. Thomas B. Cole, contributing editor of the JAMA, noted that universal screening for IPV must be distinguished from specifically assessing abuse in women who are at increased risk. In the latter case, screening “may not only detect violence but may also lead to more accurate diagnosis and treatment of co-occurring health problems,” they said (JAMA 2009;302:568–9). “The results of the study by MacMillan et al. should dispel any illusions that universal screening with passive referrals to community services is an adequate response to violence in intimate relationships,” they wrote

Neither the investigators nor the editorial writers reported financial disclosures. The study was funded by the former Ontario Women's Health Council.

Screening all women at primary care visits for intimate partner violence does not appear to be beneficial, according to one study.

Such screening did not appear to cause any harm, but neither did it prompt affected women to access services or otherwise deter intimate partner violence (IPV), said Dr. Harriet L. MacMillan of McMaster University, Hamilton, Ont., and her associates.

Some medical organizations, including the American Medical Association and the American College of Obstetricians and Gynecologists, recommend such screening of all women, “despite the lack of evidence that it is effective.” Others—including the U.S. Preventive Services Task Force and the Canadian Task Force on Preventive Health Care—say that there isn't sufficient evidence either for or against such screening.

Dr. MacMillan and her colleagues conducted a study to assess whether IPV screening reduced subsequent violence or improved womens' quality of life. They randomly assigned 6,743 women to be screened or not screened at primary care visits, then followed them for 18 months to determine whether intimate violence decreased (JAMA 2009;302:493–501).

The study subjects were aged 18–64 years and were recruited when they attended 12 primary care sites, 11 emergency departments, and 3 ob.gyn. clinics in Ontario in 2005–2006. They completed the Woman Abuse Screening Tool, an eight-item self-report instrument that measures physical, sexual, and emotional abuse in the preceding year, before consulting the clinician.

Any discussion of positive findings on the screen and referral for further treatment was left to the discretion of the treating clinician. Overall, 44% of the women who were screened for IPV reported discussing violence with the clinician, compared with 8% of those who were not screened.

The women also were assessed for depressive symptoms, posttraumatic stress disorder, alcohol abuse/dependency, and global mental and physical well-being. All were given an information card listing available resources for women exposed to violence.

A subset of 347 screened women and 360 unscreened were included in the data analysis for this study. The proportion of these subjects who were lost to follow-up was high: 43% of those who were screened for IPV and 41% of those who were not screened.

No significant differences were foundbetween the two groups in IPV recurrence, and only a weak, nonsignificant benefit in depression and quality of life scores with screening, Dr. MacMillan and her colleagues said.

“If there were an effective intervention to which women could have been referred once identified as exposed to IPV, it is possible that the results of this trial would have been more positive,” Dr. MacMillan and her associates noted.

Some experts have raised concerns about possible harmful effects of routine IPV screening, “including reprisal violence, psychological distress, family disruption, and risk of a child being removed from a mother's care following child protective services involvement,” the investigators added. Their study showed no evidence of a harmful effect on either abused or nonabused women.

In an accompanying editorial, Kathryn E. Moracco, Ph.D., of the University of North Carolina, Chapel Hill, and Dr. Thomas B. Cole, contributing editor of the JAMA, noted that universal screening for IPV must be distinguished from specifically assessing abuse in women who are at increased risk. In the latter case, screening “may not only detect violence but may also lead to more accurate diagnosis and treatment of co-occurring health problems,” they said (JAMA 2009;302:568–9). “The results of the study by MacMillan et al. should dispel any illusions that universal screening with passive referrals to community services is an adequate response to violence in intimate relationships,” they wrote

Neither the investigators nor the editorial writers reported financial disclosures. The study was funded by the former Ontario Women's Health Council.

The use of metoclopramide to control nausea and vomiting in the first trimester does not increase the risk for congenital malformations, low birth weight, or perinatal death, according to a report in the New England Journal of Medicine.

These findings from a large retrospective cohort study “provide reassurance about the safety of metoclopramide,” which has not been convincingly established until now, wrote Ilan Matok of Ben-Gurion University of the Negev, Beer-Sheva, Israel, and associates.

“Despite its extensive use, only a few studies have assessed the safety to the fetus of maternal exposure to metoclopramide during the first trimester, and the relatively small sizes of these studies limited their power to detect adverse effects of the drug,” they noted.

The researchers assessed singleton deliveries between 1998 and 2007 at the largest HMO in Israel, where metoclopramide is the antiemetic drug of choice during pregnancy. Approximately half of the 81,703 infants in the study were born to Jewish parents and half to Bedouin Muslim parents.

A total of 3,458 (4%) of these infants were exposed to metoclopramide during the first trimester. The mean duration of exposure was 1 week.

The rate of major congenital malformations was 5.3% among exposed infants, compared with 4.9% among unexposed infants, a nonsignificant difference. This difference remained nonsignificant when data from pregnancies that were terminated were included in the analysis.

The rates of minor congenital malformations (3.8% vs. 3.5%) and of multiple malformations (2.5% vs. 2.3%) also were similar between exposed and nonexposed infants. There also were no significant associations between subclasses of congenital malformations and metoclopramide exposure, nor was there any clustering of anomalies among exposed infants.

When the data were analyzed according to subjects' ethnic backgrounds, the drug did not raise risks to infants of either Jewish or Bedouin Muslim parents (N. Engl. J. Med. 2009;360:2528–35).

Metoclopramide also was not associated with an increased risk of preterm birth, low Apgar scores, perinatal death, or low birth weight.

A subgroup of 758 mothers who took metoclopramide refilled their prescriptions at least once. No dose-response effect of exposure to the drug was found.

The researchers reported having no relevant conflicts of interest.

The use of metoclopramide to control nausea and vomiting in the first trimester does not increase the risk for congenital malformations, low birth weight, or perinatal death, according to a report in the New England Journal of Medicine.

These findings from a large retrospective cohort study “provide reassurance about the safety of metoclopramide,” which has not been convincingly established until now, wrote Ilan Matok of Ben-Gurion University of the Negev, Beer-Sheva, Israel, and associates.

“Despite its extensive use, only a few studies have assessed the safety to the fetus of maternal exposure to metoclopramide during the first trimester, and the relatively small sizes of these studies limited their power to detect adverse effects of the drug,” they noted.

The researchers assessed singleton deliveries between 1998 and 2007 at the largest HMO in Israel, where metoclopramide is the antiemetic drug of choice during pregnancy. Approximately half of the 81,703 infants in the study were born to Jewish parents and half to Bedouin Muslim parents.

A total of 3,458 (4%) of these infants were exposed to metoclopramide during the first trimester. The mean duration of exposure was 1 week.

The rate of major congenital malformations was 5.3% among exposed infants, compared with 4.9% among unexposed infants, a nonsignificant difference. This difference remained nonsignificant when data from pregnancies that were terminated were included in the analysis.

The rates of minor congenital malformations (3.8% vs. 3.5%) and of multiple malformations (2.5% vs. 2.3%) also were similar between exposed and nonexposed infants. There also were no significant associations between subclasses of congenital malformations and metoclopramide exposure, nor was there any clustering of anomalies among exposed infants.

When the data were analyzed according to subjects' ethnic backgrounds, the drug did not raise risks to infants of either Jewish or Bedouin Muslim parents (N. Engl. J. Med. 2009;360:2528–35).

Metoclopramide also was not associated with an increased risk of preterm birth, low Apgar scores, perinatal death, or low birth weight.

A subgroup of 758 mothers who took metoclopramide refilled their prescriptions at least once. No dose-response effect of exposure to the drug was found.

The researchers reported having no relevant conflicts of interest.

The use of metoclopramide to control nausea and vomiting in the first trimester does not increase the risk for congenital malformations, low birth weight, or perinatal death, according to a report in the New England Journal of Medicine.

These findings from a large retrospective cohort study “provide reassurance about the safety of metoclopramide,” which has not been convincingly established until now, wrote Ilan Matok of Ben-Gurion University of the Negev, Beer-Sheva, Israel, and associates.

“Despite its extensive use, only a few studies have assessed the safety to the fetus of maternal exposure to metoclopramide during the first trimester, and the relatively small sizes of these studies limited their power to detect adverse effects of the drug,” they noted.

The researchers assessed singleton deliveries between 1998 and 2007 at the largest HMO in Israel, where metoclopramide is the antiemetic drug of choice during pregnancy. Approximately half of the 81,703 infants in the study were born to Jewish parents and half to Bedouin Muslim parents.

A total of 3,458 (4%) of these infants were exposed to metoclopramide during the first trimester. The mean duration of exposure was 1 week.

The rate of major congenital malformations was 5.3% among exposed infants, compared with 4.9% among unexposed infants, a nonsignificant difference. This difference remained nonsignificant when data from pregnancies that were terminated were included in the analysis.

The rates of minor congenital malformations (3.8% vs. 3.5%) and of multiple malformations (2.5% vs. 2.3%) also were similar between exposed and nonexposed infants. There also were no significant associations between subclasses of congenital malformations and metoclopramide exposure, nor was there any clustering of anomalies among exposed infants.

When the data were analyzed according to subjects' ethnic backgrounds, the drug did not raise risks to infants of either Jewish or Bedouin Muslim parents (N. Engl. J. Med. 2009;360:2528–35).

Metoclopramide also was not associated with an increased risk of preterm birth, low Apgar scores, perinatal death, or low birth weight.

A subgroup of 758 mothers who took metoclopramide refilled their prescriptions at least once. No dose-response effect of exposure to the drug was found.

The researchers reported having no relevant conflicts of interest.

In women with a first-degree family history of breast cancer, breastfeeding may protect against the development of premenopausal breast cancer, according to results from a prospective cohort study of more than 60,000 women.

Analysis of data from the Nurses' Health Study II revealed that ever having breastfed appeared to reduce the risk of breast cancer by 59% in women with a family history of breast cancer, study investigators reported.

This reduction is comparable to that seen with hormonal treatments such as tamoxifen for these high-risk women, wrote Dr. Alison M. Stuebe of Brigham and Women's Hospital, Boston, and her associates. Only women who had a first-degree relative with breast cancer showed the benefit of breastfeeding.

“These data suggest that women with a family history of breast cancer should be strongly encouraged to breastfeed,” they noted.

The investigators assessed the relationship between breastfeeding intensity and later development of breast cancer in a subset of 60,075 subjects from the Nurses' Health Study II. These women had completed a detailed questionnaire on lactation in a 1997 assessment of the longitudinal study, and then continued to be followed every 2 years through 2007. A total of 68 cases of premenopausal breast cancer were diagnosed, with a mean age at diagnosis of 46 years.

Women who had ever breastfed for at least 1 month showed a lower risk of developing breast cancer than those who had never breastfed, but this benefit was restricted to those who had a first-degree relative with the disease.

“We found a 59% reduction in incidence of premenopausal breast cancer” in this subgroup of study subjects.

“No other prospective study to our knowledge has examined whether family history modifies the association between breastfeeding and breast cancer risk,” the researchers said.

“As in any observational study, we cannot exclude the possibility that unmeasured confounding explains the observed difference in incident disease, but such a confounder would have to be strongly associated with both breastfeeding and breast cancer risk to produce an association of this magnitude,” Dr. Stuebe and her colleagues wrote (Arch. Intern. Med. 2009;169:1364–71).

There was no association between incident breast cancer and duration of lactation, use of supplemental feedings, number of children who were breastfed, or maternal age at first birth.

The use of medication to suppress lactation modified the association between breastfeeding and incident cancer.

“We found a lower incidence of breast cancer among women who had never breastfed but had suppressed lactation than among those who had neither breastfed nor suppressed lactation,” the researchers said.

They attributed this finding to disordered involution in women who neither breastfed nor suppressed lactation. “During involution, a highly coordinated process of apoptosis, remodeling, and inflammation returns mammary tissue to its prepregnant state. In physiologic weaning, this process occurs over weeks or months.

“By contrast, if a woman does not breastfeed, she experiences abrupt engorgement, and mammary tissue may become progressively inflamed. We hypothesize that both breastfeeding and use of suppressive medications prevent this inflammation, thereby preventing disordered involution,” they explained.

No financial conflicts of interest were reported for this study.

In women with a first-degree family history of breast cancer, breastfeeding may protect against the development of premenopausal breast cancer, according to results from a prospective cohort study of more than 60,000 women.

Analysis of data from the Nurses' Health Study II revealed that ever having breastfed appeared to reduce the risk of breast cancer by 59% in women with a family history of breast cancer, study investigators reported.

This reduction is comparable to that seen with hormonal treatments such as tamoxifen for these high-risk women, wrote Dr. Alison M. Stuebe of Brigham and Women's Hospital, Boston, and her associates. Only women who had a first-degree relative with breast cancer showed the benefit of breastfeeding.

“These data suggest that women with a family history of breast cancer should be strongly encouraged to breastfeed,” they noted.

The investigators assessed the relationship between breastfeeding intensity and later development of breast cancer in a subset of 60,075 subjects from the Nurses' Health Study II. These women had completed a detailed questionnaire on lactation in a 1997 assessment of the longitudinal study, and then continued to be followed every 2 years through 2007. A total of 68 cases of premenopausal breast cancer were diagnosed, with a mean age at diagnosis of 46 years.

Women who had ever breastfed for at least 1 month showed a lower risk of developing breast cancer than those who had never breastfed, but this benefit was restricted to those who had a first-degree relative with the disease.

“We found a 59% reduction in incidence of premenopausal breast cancer” in this subgroup of study subjects.

“No other prospective study to our knowledge has examined whether family history modifies the association between breastfeeding and breast cancer risk,” the researchers said.

“As in any observational study, we cannot exclude the possibility that unmeasured confounding explains the observed difference in incident disease, but such a confounder would have to be strongly associated with both breastfeeding and breast cancer risk to produce an association of this magnitude,” Dr. Stuebe and her colleagues wrote (Arch. Intern. Med. 2009;169:1364–71).

There was no association between incident breast cancer and duration of lactation, use of supplemental feedings, number of children who were breastfed, or maternal age at first birth.

The use of medication to suppress lactation modified the association between breastfeeding and incident cancer.

“We found a lower incidence of breast cancer among women who had never breastfed but had suppressed lactation than among those who had neither breastfed nor suppressed lactation,” the researchers said.

They attributed this finding to disordered involution in women who neither breastfed nor suppressed lactation. “During involution, a highly coordinated process of apoptosis, remodeling, and inflammation returns mammary tissue to its prepregnant state. In physiologic weaning, this process occurs over weeks or months.

“By contrast, if a woman does not breastfeed, she experiences abrupt engorgement, and mammary tissue may become progressively inflamed. We hypothesize that both breastfeeding and use of suppressive medications prevent this inflammation, thereby preventing disordered involution,” they explained.

No financial conflicts of interest were reported for this study.

In women with a first-degree family history of breast cancer, breastfeeding may protect against the development of premenopausal breast cancer, according to results from a prospective cohort study of more than 60,000 women.

Analysis of data from the Nurses' Health Study II revealed that ever having breastfed appeared to reduce the risk of breast cancer by 59% in women with a family history of breast cancer, study investigators reported.

This reduction is comparable to that seen with hormonal treatments such as tamoxifen for these high-risk women, wrote Dr. Alison M. Stuebe of Brigham and Women's Hospital, Boston, and her associates. Only women who had a first-degree relative with breast cancer showed the benefit of breastfeeding.

“These data suggest that women with a family history of breast cancer should be strongly encouraged to breastfeed,” they noted.

The investigators assessed the relationship between breastfeeding intensity and later development of breast cancer in a subset of 60,075 subjects from the Nurses' Health Study II. These women had completed a detailed questionnaire on lactation in a 1997 assessment of the longitudinal study, and then continued to be followed every 2 years through 2007. A total of 68 cases of premenopausal breast cancer were diagnosed, with a mean age at diagnosis of 46 years.

Women who had ever breastfed for at least 1 month showed a lower risk of developing breast cancer than those who had never breastfed, but this benefit was restricted to those who had a first-degree relative with the disease.

“We found a 59% reduction in incidence of premenopausal breast cancer” in this subgroup of study subjects.

“No other prospective study to our knowledge has examined whether family history modifies the association between breastfeeding and breast cancer risk,” the researchers said.

“As in any observational study, we cannot exclude the possibility that unmeasured confounding explains the observed difference in incident disease, but such a confounder would have to be strongly associated with both breastfeeding and breast cancer risk to produce an association of this magnitude,” Dr. Stuebe and her colleagues wrote (Arch. Intern. Med. 2009;169:1364–71).

There was no association between incident breast cancer and duration of lactation, use of supplemental feedings, number of children who were breastfed, or maternal age at first birth.

The use of medication to suppress lactation modified the association between breastfeeding and incident cancer.

“We found a lower incidence of breast cancer among women who had never breastfed but had suppressed lactation than among those who had neither breastfed nor suppressed lactation,” the researchers said.

They attributed this finding to disordered involution in women who neither breastfed nor suppressed lactation. “During involution, a highly coordinated process of apoptosis, remodeling, and inflammation returns mammary tissue to its prepregnant state. In physiologic weaning, this process occurs over weeks or months.

“By contrast, if a woman does not breastfeed, she experiences abrupt engorgement, and mammary tissue may become progressively inflamed. We hypothesize that both breastfeeding and use of suppressive medications prevent this inflammation, thereby preventing disordered involution,” they explained.

No financial conflicts of interest were reported for this study.