Mary Ann Moon

Endoscopic ultrasound–guided transmural gallbladder drainage was as safe and effective as was percutaneous transhepatic gallbladder drainage in patients with acute cholecystitis who did not respond to medical therapy and were unsuitable for emergency cholecystectomy, according to a report by Dr. Ji-Woong Jang and colleagues in the April issue of Gastroenterology.

In a noninferiority trial that directly compared the two approaches among 59 consecutive patients, the rates of technical success and clinical success were comparable. There also were no differences in complication rates or in conversion to open cholecystectomy.

Therefore, endoscopic ultrasound–guided transmural gallbladder drainage (EUS-GBD) may be a safe alternative treatment for high-risk patients with acute cholecystitis who are not candidates for emergency cholecystectomy, they said.

Dr. Jang and associates performed what they described as the first prospective, randomized controlled trial to compare the two procedures. Until now, the literature has included only case reports or pilot studies of EUS-GBD, while percutaneous transhepatic gallbladder drainage (PTGBD) has been used for decades in high-risk patients and is considered the preferred method of treatment.

Despite its usefulness, PTGBD has been associated with adverse events such as bleeding, pneumothorax, and bile peritonitis. It is contraindicated in patients with massive ascites or coagulopathy. And the drainage catheters cause pain, restrict patients’ movements, and are subject to inadvertent removal or migration.

In contrast, EUS-GBD can be used when there are large amounts of perihepatic ascites and when patients have coagulopathy or have been taking antiplatelet or antithrombotic medications. The procedure minimizes bleeding because the puncture site is less vascularized than the primary puncture site for PTGBD, the liver. There is less pain with EUS-GBD because the puncture site is less sensitive to pain, and the nasobiliary tube is less likely to be dislodged, said Dr. Jang of the department of gastroenterology, Asan Medical Center, Seoul, South Korea, and colleagues.

In this study, 30 of the 59 adults were randomly assigned to undergo EUS-GBD, and 29 to undergo PTGBD. The two groups were similar in terms of age, gender, underlying conditions, and causes of cholecystitis. The patients presented to a single medical center during a 6-month period.

For EUS-GBD, patients were sedated and the initial puncture was made at the prepyloric antrum of the stomach or the bulb of the duodenum, so that the gallbladder body or neck could be accessed while blood vessels were visualized and avoided. A 19-gauge needle was inserted into the stomach or duodenal wall and into the gallbladder, and a guidewire was passed and coiled in the gallbladder.

A bougie was then used to dilate this tract. A 5F nasobiliary drainage tube was then coiled into the gallbladder. Using a tube this size obviates the need for a larger tract, which is the main cause of bile leakage in PTGBD, they noted.

For PTGBD, local anesthesia was used and an 8.5 F pigtail drainage catheter was passed transhepatically and placed between the seventh or eighth intercostal space under sonographic and fluoroscopic guidance.

All the study subjects were followed for a minimum of 3 months. The primary end point was the technical success rate, defined as the ability to access and drain the gallbladder by placement of a drainage tube, or maintenance of good drainage tube function.

This end point was achieved in 29 of 30 EUS-GBD patients (97%) and 28 of 29 PTGBD patients (97%), qualifying the new procedure as noninferior to the standard method.

A secondary end point was the clinical success rate, defined as improvement of typical symptoms and laboratory tests, with or without improved radiologic findings, 3 days after the procedure. This was achieved in all 29 of the EUS-GBD patients and 27 of 28 (96%) of the PTGBD patients.

The average procedure time was 23 minutes for EUS-GBD and 24 minutes for PTGBD. Postoperative pain level was significantly lower with EUS-GBD.

Two patients (7%) in the EUS-GBD group and 1 (3%) in the PTGBD group developed complications. The EUS-GBD patients both developed pneumoperitoneum, which was managed conservatively, and the PTGBD patient developed hemobilia, which responded to transfusion of packed red blood cells.

No EUS-GBD patients had nasobiliary tube dislodgement, while 1 PTGBD patient had catheter dislodgement. EUS-GBD also did not cause severe inflammation or adhesions in the tissue surrounding the gallbladder, nor did it cause bile leakage or bile peritonitis, which is the chief risk associated with the procedure, Dr. Jang and associates said.

The study was supported by a grant from the Asan Institute for Life Sciences. The authors declared no conflicts of interest.

Endoscopic ultrasound–guided transmural gallbladder drainage was as safe and effective as was percutaneous transhepatic gallbladder drainage in patients with acute cholecystitis who did not respond to medical therapy and were unsuitable for emergency cholecystectomy, according to a report by Dr. Ji-Woong Jang and colleagues in the April issue of Gastroenterology.

In a noninferiority trial that directly compared the two approaches among 59 consecutive patients, the rates of technical success and clinical success were comparable. There also were no differences in complication rates or in conversion to open cholecystectomy.

Therefore, endoscopic ultrasound–guided transmural gallbladder drainage (EUS-GBD) may be a safe alternative treatment for high-risk patients with acute cholecystitis who are not candidates for emergency cholecystectomy, they said.

Dr. Jang and associates performed what they described as the first prospective, randomized controlled trial to compare the two procedures. Until now, the literature has included only case reports or pilot studies of EUS-GBD, while percutaneous transhepatic gallbladder drainage (PTGBD) has been used for decades in high-risk patients and is considered the preferred method of treatment.

Despite its usefulness, PTGBD has been associated with adverse events such as bleeding, pneumothorax, and bile peritonitis. It is contraindicated in patients with massive ascites or coagulopathy. And the drainage catheters cause pain, restrict patients’ movements, and are subject to inadvertent removal or migration.

In contrast, EUS-GBD can be used when there are large amounts of perihepatic ascites and when patients have coagulopathy or have been taking antiplatelet or antithrombotic medications. The procedure minimizes bleeding because the puncture site is less vascularized than the primary puncture site for PTGBD, the liver. There is less pain with EUS-GBD because the puncture site is less sensitive to pain, and the nasobiliary tube is less likely to be dislodged, said Dr. Jang of the department of gastroenterology, Asan Medical Center, Seoul, South Korea, and colleagues.

In this study, 30 of the 59 adults were randomly assigned to undergo EUS-GBD, and 29 to undergo PTGBD. The two groups were similar in terms of age, gender, underlying conditions, and causes of cholecystitis. The patients presented to a single medical center during a 6-month period.

For EUS-GBD, patients were sedated and the initial puncture was made at the prepyloric antrum of the stomach or the bulb of the duodenum, so that the gallbladder body or neck could be accessed while blood vessels were visualized and avoided. A 19-gauge needle was inserted into the stomach or duodenal wall and into the gallbladder, and a guidewire was passed and coiled in the gallbladder.

A bougie was then used to dilate this tract. A 5F nasobiliary drainage tube was then coiled into the gallbladder. Using a tube this size obviates the need for a larger tract, which is the main cause of bile leakage in PTGBD, they noted.

For PTGBD, local anesthesia was used and an 8.5 F pigtail drainage catheter was passed transhepatically and placed between the seventh or eighth intercostal space under sonographic and fluoroscopic guidance.

All the study subjects were followed for a minimum of 3 months. The primary end point was the technical success rate, defined as the ability to access and drain the gallbladder by placement of a drainage tube, or maintenance of good drainage tube function.

This end point was achieved in 29 of 30 EUS-GBD patients (97%) and 28 of 29 PTGBD patients (97%), qualifying the new procedure as noninferior to the standard method.

A secondary end point was the clinical success rate, defined as improvement of typical symptoms and laboratory tests, with or without improved radiologic findings, 3 days after the procedure. This was achieved in all 29 of the EUS-GBD patients and 27 of 28 (96%) of the PTGBD patients.

The average procedure time was 23 minutes for EUS-GBD and 24 minutes for PTGBD. Postoperative pain level was significantly lower with EUS-GBD.

Two patients (7%) in the EUS-GBD group and 1 (3%) in the PTGBD group developed complications. The EUS-GBD patients both developed pneumoperitoneum, which was managed conservatively, and the PTGBD patient developed hemobilia, which responded to transfusion of packed red blood cells.

No EUS-GBD patients had nasobiliary tube dislodgement, while 1 PTGBD patient had catheter dislodgement. EUS-GBD also did not cause severe inflammation or adhesions in the tissue surrounding the gallbladder, nor did it cause bile leakage or bile peritonitis, which is the chief risk associated with the procedure, Dr. Jang and associates said.

The study was supported by a grant from the Asan Institute for Life Sciences. The authors declared no conflicts of interest.

Endoscopic ultrasound–guided transmural gallbladder drainage was as safe and effective as was percutaneous transhepatic gallbladder drainage in patients with acute cholecystitis who did not respond to medical therapy and were unsuitable for emergency cholecystectomy, according to a report by Dr. Ji-Woong Jang and colleagues in the April issue of Gastroenterology.

In a noninferiority trial that directly compared the two approaches among 59 consecutive patients, the rates of technical success and clinical success were comparable. There also were no differences in complication rates or in conversion to open cholecystectomy.

Therefore, endoscopic ultrasound–guided transmural gallbladder drainage (EUS-GBD) may be a safe alternative treatment for high-risk patients with acute cholecystitis who are not candidates for emergency cholecystectomy, they said.

Dr. Jang and associates performed what they described as the first prospective, randomized controlled trial to compare the two procedures. Until now, the literature has included only case reports or pilot studies of EUS-GBD, while percutaneous transhepatic gallbladder drainage (PTGBD) has been used for decades in high-risk patients and is considered the preferred method of treatment.

Despite its usefulness, PTGBD has been associated with adverse events such as bleeding, pneumothorax, and bile peritonitis. It is contraindicated in patients with massive ascites or coagulopathy. And the drainage catheters cause pain, restrict patients’ movements, and are subject to inadvertent removal or migration.

In contrast, EUS-GBD can be used when there are large amounts of perihepatic ascites and when patients have coagulopathy or have been taking antiplatelet or antithrombotic medications. The procedure minimizes bleeding because the puncture site is less vascularized than the primary puncture site for PTGBD, the liver. There is less pain with EUS-GBD because the puncture site is less sensitive to pain, and the nasobiliary tube is less likely to be dislodged, said Dr. Jang of the department of gastroenterology, Asan Medical Center, Seoul, South Korea, and colleagues.

In this study, 30 of the 59 adults were randomly assigned to undergo EUS-GBD, and 29 to undergo PTGBD. The two groups were similar in terms of age, gender, underlying conditions, and causes of cholecystitis. The patients presented to a single medical center during a 6-month period.

For EUS-GBD, patients were sedated and the initial puncture was made at the prepyloric antrum of the stomach or the bulb of the duodenum, so that the gallbladder body or neck could be accessed while blood vessels were visualized and avoided. A 19-gauge needle was inserted into the stomach or duodenal wall and into the gallbladder, and a guidewire was passed and coiled in the gallbladder.

A bougie was then used to dilate this tract. A 5F nasobiliary drainage tube was then coiled into the gallbladder. Using a tube this size obviates the need for a larger tract, which is the main cause of bile leakage in PTGBD, they noted.

For PTGBD, local anesthesia was used and an 8.5 F pigtail drainage catheter was passed transhepatically and placed between the seventh or eighth intercostal space under sonographic and fluoroscopic guidance.

All the study subjects were followed for a minimum of 3 months. The primary end point was the technical success rate, defined as the ability to access and drain the gallbladder by placement of a drainage tube, or maintenance of good drainage tube function.

This end point was achieved in 29 of 30 EUS-GBD patients (97%) and 28 of 29 PTGBD patients (97%), qualifying the new procedure as noninferior to the standard method.

A secondary end point was the clinical success rate, defined as improvement of typical symptoms and laboratory tests, with or without improved radiologic findings, 3 days after the procedure. This was achieved in all 29 of the EUS-GBD patients and 27 of 28 (96%) of the PTGBD patients.

The average procedure time was 23 minutes for EUS-GBD and 24 minutes for PTGBD. Postoperative pain level was significantly lower with EUS-GBD.

Two patients (7%) in the EUS-GBD group and 1 (3%) in the PTGBD group developed complications. The EUS-GBD patients both developed pneumoperitoneum, which was managed conservatively, and the PTGBD patient developed hemobilia, which responded to transfusion of packed red blood cells.

No EUS-GBD patients had nasobiliary tube dislodgement, while 1 PTGBD patient had catheter dislodgement. EUS-GBD also did not cause severe inflammation or adhesions in the tissue surrounding the gallbladder, nor did it cause bile leakage or bile peritonitis, which is the chief risk associated with the procedure, Dr. Jang and associates said.

The study was supported by a grant from the Asan Institute for Life Sciences. The authors declared no conflicts of interest.

Regular users of statins had a "marginally significant" lower risk of developing Parkinson’s disease than did nonusers in a prospective, observational analysis of two large, ongoing study cohorts.

The protective effect was stronger at ages younger than 60 years than at older ages, Dr. Xiang Gao and his associates reported March 12 in Archives of Neurology. Dr. Gao is in the department of nutrition at Harvard University School of Public Health and the department of epidemiology at Brigham and Women’s Hospital, both in Boston.

The study builds on several previous studies that examined the association between statin use and Parkinson’s disease (PD), but did not control for important confounders such as smoking status and caffeine intake. Given the mixed results of those studies, Dr. Gao and his colleagues advised that the marginal significance of current study’s results should be interpreted with caution and noted that further study is needed.

Statins have potent anti-inflammatory and immunomodulating effects that could be neuroprotective, but they also may lower levels of coenzyme Q, which is itself neuroprotective and is being investigated as a possible treatment for PD, the researchers said.

They assessed 90,874 women in the Nurses Health Study who were aged 30-55 years at baseline in 1976 and 38,192 men in the Health Professionals Follow-Up Study who were aged 40-75 years at baseline in 1986. In both studies, subjects updated their health information by way of questionnaires every 2 years.

During an average of 12 years of follow-up, 644 incident cases of PD developed in 338 women and 306 men. The incidence of PD was lower in statin users than in nonusers, with a pooled relative risk of PD of 0.74, the investigators reported (Arch. Neurol. 2012;69:380-4).

This association did not change when the data were adjusted to account for potential confounders such as subject age, smoking status, caffeine consumption, lactose intake, use of ibuprofen, duration of hypercholesterolemia, and comorbidities. It also remained robust when the analysis was restricted only to subjects whose PD had been confirmed by a neurologist, as well as in a sensitivity analysis that took into account the duration of statin use.

There was a significant interaction between statin use and subject age with regard to PD risk. The association between statin use and the risk of PD was significant only in those who were aged 60 years or younger at the beginning of follow-up, according to Dr. Gao and his colleagues.

These findings are consistent with the results of animal and in-vitro studies "which suggest that statins could reduce alpha-synuclein accumulation and oxidative stress, suppress cyclooxygenase 2 expression, reduce release of TNF-alpha and nuclear factor kappaB activation, activate peroxisome proliferator-activated receptor-gamma, and up-regulate dopamine D₁ and D₂ receptors in the brain," they added.

This study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Gao reported that he has been a consultant for Teva Pharmaceuticals.

Regular users of statins had a "marginally significant" lower risk of developing Parkinson’s disease than did nonusers in a prospective, observational analysis of two large, ongoing study cohorts.

The protective effect was stronger at ages younger than 60 years than at older ages, Dr. Xiang Gao and his associates reported March 12 in Archives of Neurology. Dr. Gao is in the department of nutrition at Harvard University School of Public Health and the department of epidemiology at Brigham and Women’s Hospital, both in Boston.

The study builds on several previous studies that examined the association between statin use and Parkinson’s disease (PD), but did not control for important confounders such as smoking status and caffeine intake. Given the mixed results of those studies, Dr. Gao and his colleagues advised that the marginal significance of current study’s results should be interpreted with caution and noted that further study is needed.

Statins have potent anti-inflammatory and immunomodulating effects that could be neuroprotective, but they also may lower levels of coenzyme Q, which is itself neuroprotective and is being investigated as a possible treatment for PD, the researchers said.

They assessed 90,874 women in the Nurses Health Study who were aged 30-55 years at baseline in 1976 and 38,192 men in the Health Professionals Follow-Up Study who were aged 40-75 years at baseline in 1986. In both studies, subjects updated their health information by way of questionnaires every 2 years.

During an average of 12 years of follow-up, 644 incident cases of PD developed in 338 women and 306 men. The incidence of PD was lower in statin users than in nonusers, with a pooled relative risk of PD of 0.74, the investigators reported (Arch. Neurol. 2012;69:380-4).

This association did not change when the data were adjusted to account for potential confounders such as subject age, smoking status, caffeine consumption, lactose intake, use of ibuprofen, duration of hypercholesterolemia, and comorbidities. It also remained robust when the analysis was restricted only to subjects whose PD had been confirmed by a neurologist, as well as in a sensitivity analysis that took into account the duration of statin use.

There was a significant interaction between statin use and subject age with regard to PD risk. The association between statin use and the risk of PD was significant only in those who were aged 60 years or younger at the beginning of follow-up, according to Dr. Gao and his colleagues.

These findings are consistent with the results of animal and in-vitro studies "which suggest that statins could reduce alpha-synuclein accumulation and oxidative stress, suppress cyclooxygenase 2 expression, reduce release of TNF-alpha and nuclear factor kappaB activation, activate peroxisome proliferator-activated receptor-gamma, and up-regulate dopamine D₁ and D₂ receptors in the brain," they added.

This study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Gao reported that he has been a consultant for Teva Pharmaceuticals.

Regular users of statins had a "marginally significant" lower risk of developing Parkinson’s disease than did nonusers in a prospective, observational analysis of two large, ongoing study cohorts.

The protective effect was stronger at ages younger than 60 years than at older ages, Dr. Xiang Gao and his associates reported March 12 in Archives of Neurology. Dr. Gao is in the department of nutrition at Harvard University School of Public Health and the department of epidemiology at Brigham and Women’s Hospital, both in Boston.

The study builds on several previous studies that examined the association between statin use and Parkinson’s disease (PD), but did not control for important confounders such as smoking status and caffeine intake. Given the mixed results of those studies, Dr. Gao and his colleagues advised that the marginal significance of current study’s results should be interpreted with caution and noted that further study is needed.

Statins have potent anti-inflammatory and immunomodulating effects that could be neuroprotective, but they also may lower levels of coenzyme Q, which is itself neuroprotective and is being investigated as a possible treatment for PD, the researchers said.

They assessed 90,874 women in the Nurses Health Study who were aged 30-55 years at baseline in 1976 and 38,192 men in the Health Professionals Follow-Up Study who were aged 40-75 years at baseline in 1986. In both studies, subjects updated their health information by way of questionnaires every 2 years.

During an average of 12 years of follow-up, 644 incident cases of PD developed in 338 women and 306 men. The incidence of PD was lower in statin users than in nonusers, with a pooled relative risk of PD of 0.74, the investigators reported (Arch. Neurol. 2012;69:380-4).

This association did not change when the data were adjusted to account for potential confounders such as subject age, smoking status, caffeine consumption, lactose intake, use of ibuprofen, duration of hypercholesterolemia, and comorbidities. It also remained robust when the analysis was restricted only to subjects whose PD had been confirmed by a neurologist, as well as in a sensitivity analysis that took into account the duration of statin use.

There was a significant interaction between statin use and subject age with regard to PD risk. The association between statin use and the risk of PD was significant only in those who were aged 60 years or younger at the beginning of follow-up, according to Dr. Gao and his colleagues.

These findings are consistent with the results of animal and in-vitro studies "which suggest that statins could reduce alpha-synuclein accumulation and oxidative stress, suppress cyclooxygenase 2 expression, reduce release of TNF-alpha and nuclear factor kappaB activation, activate peroxisome proliferator-activated receptor-gamma, and up-regulate dopamine D₁ and D₂ receptors in the brain," they added.

This study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Gao reported that he has been a consultant for Teva Pharmaceuticals.

Patients with chronic pancreatitis show decreased cortical thickness in five areas of the brain known to be involved in the processing of visceral pain, Dr. Jens Brondum Frøkjær and his colleagues reported in the April issue of Clinical Gastroenterology and Hepatology.

Moreover, these reductions in cortical thickness correlated with scores in the patients’ pain diaries, so that patients with the most pain showed the greatest cortical thinning on MRI.

The findings indicate that the chronic pain caused "structural reorganization of the neuromatrix expressed as regional differences in cortical thickness," wrote Dr. Frøkjær of the department of gastroenterology and hepatology and the department of radiology at Aalborg (Denmark) Hospital and Aarhus University Hospital, and his associates (Clin. Gastroenterol. Hepatol. 2011 [10.1016/j.cgh.2011.11.024]).

Their study results further suggest that MRI measurements of cortical thickness, which they characterized as quick and relatively easy to obtain, may serve as a valid indicator of "the overall damage and dysfunction of the pain system."

Dr. Frøkjær and his colleagues assessed cortical thickness in patients with chronic pancreatitis using the same high-resolution three-dimensional MRI technique that other investigators have used when assessing brain changes in patients with the chronic pain of irritable bowel syndrome or trigeminal neuropathy. The recently improved methods now permit "accurate, robust, and rapid analysis of cortical thickness," they said.

The investigators assessed 19 adults with chronic pancreatitis and 15 healthy volunteers matched for age and gender who served as control subjects. All the study subjects completed pain diaries for 1 week before undergoing brain MRI.

Compared with controls, the pancreatitis patients showed cortical thinning in the secondary somatosensory cortex (the Rolandic operculum), the dorsolateral prefrontal cortex (the middle frontal gyrus), the laterofrontal cortex (the orbital parts of the superior and inferior frontal gyrus), the midsection of the cingulate cortex, and the insula.

In previous studies, activation of the secondary somatosensory cortex has been linked to patients’ efforts to attend to and to rate the strength and quality of pain. The prefrontal cortex is central to the processing of visceral pain and "the cognitive aspects of the pain experience," and the frontal cortex receives sensory inputs and is involved in pain processing. The middle cingulate cortex is thought to connect with the hypothalamus and the periaqueductal grey matter "as part of the descending pain modulation system," and the insula is involved in integrating visceral sensory and motor function as well as transmitting pain input to the frontal cortex.

In contrast, no differences between patients and controls were seen in cortical thickness in a control area of the brain – the occipital middle sulcus – that is not involved in central nervous system processing of pain.

Cortical thinning in the five areas of interest were found to correlate with patients’ clinical pain scores.

There were no correlations between cortical thickness and several factors that may have contributed to pancreatic pain, such as excessive alcohol use, the presence of diabetes, and the use of opioid treatments. Cortical thickness also was no different between patients who reported a continuous pattern of pancreatic pain and those who instead suffered discrete attacks of pancreatic pain.

These findings all suggest that the ongoing pain input to the brain results in structural reorganization of the neuromatrix, which has also been proposed to occur in other diseases characterized by chronic pain. The cortical thinning "could be a result of neuroplasticity induced by sustained chronic pain and of increased synaptic activity in the brain’s pain matrix related to the greater inhibitory activity generated to counterbalance the nociceptive input," the researchers said.

However, it is also possible that other factors related to pancreatitis may have contributed to these structural brain alterations. This study could not address that question because there was no matching control group of patients with pancreatitis who did not have abdominal pain. "Such patients are very difficult to find," Dr. Frøkjær and his colleagues noted.

This study was supported by the Karen Elise Jensen Foundation, SparNord Foundation, the Obelske Family foundation, and Heinrich Kopp. No relevant financial conflicts of interest were reported.

Patients with chronic pancreatitis show decreased cortical thickness in five areas of the brain known to be involved in the processing of visceral pain, Dr. Jens Brondum Frøkjær and his colleagues reported in the April issue of Clinical Gastroenterology and Hepatology.

Moreover, these reductions in cortical thickness correlated with scores in the patients’ pain diaries, so that patients with the most pain showed the greatest cortical thinning on MRI.

The findings indicate that the chronic pain caused "structural reorganization of the neuromatrix expressed as regional differences in cortical thickness," wrote Dr. Frøkjær of the department of gastroenterology and hepatology and the department of radiology at Aalborg (Denmark) Hospital and Aarhus University Hospital, and his associates (Clin. Gastroenterol. Hepatol. 2011 [10.1016/j.cgh.2011.11.024]).

Their study results further suggest that MRI measurements of cortical thickness, which they characterized as quick and relatively easy to obtain, may serve as a valid indicator of "the overall damage and dysfunction of the pain system."

Dr. Frøkjær and his colleagues assessed cortical thickness in patients with chronic pancreatitis using the same high-resolution three-dimensional MRI technique that other investigators have used when assessing brain changes in patients with the chronic pain of irritable bowel syndrome or trigeminal neuropathy. The recently improved methods now permit "accurate, robust, and rapid analysis of cortical thickness," they said.

The investigators assessed 19 adults with chronic pancreatitis and 15 healthy volunteers matched for age and gender who served as control subjects. All the study subjects completed pain diaries for 1 week before undergoing brain MRI.

Compared with controls, the pancreatitis patients showed cortical thinning in the secondary somatosensory cortex (the Rolandic operculum), the dorsolateral prefrontal cortex (the middle frontal gyrus), the laterofrontal cortex (the orbital parts of the superior and inferior frontal gyrus), the midsection of the cingulate cortex, and the insula.

In previous studies, activation of the secondary somatosensory cortex has been linked to patients’ efforts to attend to and to rate the strength and quality of pain. The prefrontal cortex is central to the processing of visceral pain and "the cognitive aspects of the pain experience," and the frontal cortex receives sensory inputs and is involved in pain processing. The middle cingulate cortex is thought to connect with the hypothalamus and the periaqueductal grey matter "as part of the descending pain modulation system," and the insula is involved in integrating visceral sensory and motor function as well as transmitting pain input to the frontal cortex.

In contrast, no differences between patients and controls were seen in cortical thickness in a control area of the brain – the occipital middle sulcus – that is not involved in central nervous system processing of pain.

Cortical thinning in the five areas of interest were found to correlate with patients’ clinical pain scores.

There were no correlations between cortical thickness and several factors that may have contributed to pancreatic pain, such as excessive alcohol use, the presence of diabetes, and the use of opioid treatments. Cortical thickness also was no different between patients who reported a continuous pattern of pancreatic pain and those who instead suffered discrete attacks of pancreatic pain.

These findings all suggest that the ongoing pain input to the brain results in structural reorganization of the neuromatrix, which has also been proposed to occur in other diseases characterized by chronic pain. The cortical thinning "could be a result of neuroplasticity induced by sustained chronic pain and of increased synaptic activity in the brain’s pain matrix related to the greater inhibitory activity generated to counterbalance the nociceptive input," the researchers said.

However, it is also possible that other factors related to pancreatitis may have contributed to these structural brain alterations. This study could not address that question because there was no matching control group of patients with pancreatitis who did not have abdominal pain. "Such patients are very difficult to find," Dr. Frøkjær and his colleagues noted.

This study was supported by the Karen Elise Jensen Foundation, SparNord Foundation, the Obelske Family foundation, and Heinrich Kopp. No relevant financial conflicts of interest were reported.

Patients with chronic pancreatitis show decreased cortical thickness in five areas of the brain known to be involved in the processing of visceral pain, Dr. Jens Brondum Frøkjær and his colleagues reported in the April issue of Clinical Gastroenterology and Hepatology.

Moreover, these reductions in cortical thickness correlated with scores in the patients’ pain diaries, so that patients with the most pain showed the greatest cortical thinning on MRI.

The findings indicate that the chronic pain caused "structural reorganization of the neuromatrix expressed as regional differences in cortical thickness," wrote Dr. Frøkjær of the department of gastroenterology and hepatology and the department of radiology at Aalborg (Denmark) Hospital and Aarhus University Hospital, and his associates (Clin. Gastroenterol. Hepatol. 2011 [10.1016/j.cgh.2011.11.024]).

Their study results further suggest that MRI measurements of cortical thickness, which they characterized as quick and relatively easy to obtain, may serve as a valid indicator of "the overall damage and dysfunction of the pain system."

Dr. Frøkjær and his colleagues assessed cortical thickness in patients with chronic pancreatitis using the same high-resolution three-dimensional MRI technique that other investigators have used when assessing brain changes in patients with the chronic pain of irritable bowel syndrome or trigeminal neuropathy. The recently improved methods now permit "accurate, robust, and rapid analysis of cortical thickness," they said.

The investigators assessed 19 adults with chronic pancreatitis and 15 healthy volunteers matched for age and gender who served as control subjects. All the study subjects completed pain diaries for 1 week before undergoing brain MRI.

Compared with controls, the pancreatitis patients showed cortical thinning in the secondary somatosensory cortex (the Rolandic operculum), the dorsolateral prefrontal cortex (the middle frontal gyrus), the laterofrontal cortex (the orbital parts of the superior and inferior frontal gyrus), the midsection of the cingulate cortex, and the insula.

In previous studies, activation of the secondary somatosensory cortex has been linked to patients’ efforts to attend to and to rate the strength and quality of pain. The prefrontal cortex is central to the processing of visceral pain and "the cognitive aspects of the pain experience," and the frontal cortex receives sensory inputs and is involved in pain processing. The middle cingulate cortex is thought to connect with the hypothalamus and the periaqueductal grey matter "as part of the descending pain modulation system," and the insula is involved in integrating visceral sensory and motor function as well as transmitting pain input to the frontal cortex.

In contrast, no differences between patients and controls were seen in cortical thickness in a control area of the brain – the occipital middle sulcus – that is not involved in central nervous system processing of pain.

Cortical thinning in the five areas of interest were found to correlate with patients’ clinical pain scores.

There were no correlations between cortical thickness and several factors that may have contributed to pancreatic pain, such as excessive alcohol use, the presence of diabetes, and the use of opioid treatments. Cortical thickness also was no different between patients who reported a continuous pattern of pancreatic pain and those who instead suffered discrete attacks of pancreatic pain.

These findings all suggest that the ongoing pain input to the brain results in structural reorganization of the neuromatrix, which has also been proposed to occur in other diseases characterized by chronic pain. The cortical thinning "could be a result of neuroplasticity induced by sustained chronic pain and of increased synaptic activity in the brain’s pain matrix related to the greater inhibitory activity generated to counterbalance the nociceptive input," the researchers said.

However, it is also possible that other factors related to pancreatitis may have contributed to these structural brain alterations. This study could not address that question because there was no matching control group of patients with pancreatitis who did not have abdominal pain. "Such patients are very difficult to find," Dr. Frøkjær and his colleagues noted.

This study was supported by the Karen Elise Jensen Foundation, SparNord Foundation, the Obelske Family foundation, and Heinrich Kopp. No relevant financial conflicts of interest were reported.

For patients with Crohn’s disease who have intra-abdominal abscesses, percutaneous drainage plus anti–tumor necrosis factor therapy can be as effective as surgery, Dr. Douglas L. Nguyen and his colleagues reported in the April issue of Clinical Gastroenterology and Hepatology.

"It is clear that there are lower-risk patients who can be effectively and safely managed with medical therapy. In fact, we identified a subset of patients who had percutaneous drainage as an outpatient procedure and received oral antibiotics without the need for inpatient observation," said Dr. Nguyen of the Mayo Clinic, Rochester, Minn., and his associates (Clin. Gastroenterol. Hepatol. 2012 April [doi: 10.1016/j.cgh.2011.11.023]).

The researchers examined this issue because until now there have been very little data on the short- or long-term outcomes of medical treatment in this setting, particularly when it involves anti-TNF agents.

"In theory, percutaneous drainage converts an intra-abdominal abscess (which is a contraindication to anti-TNF therapy) into an enterocutaneous fistula (which is an indication for anti-TNF therapy). The procedure allows an abscess cavity to safely drain, while the anti-TNF drug reduces inflammation and promotes fistula healing.

"The desired outcome would be abscess resolution and tract closure without surgical intervention," they explained.

Dr. Nguyen and his colleagues retrospectively identified 95 adults with Crohn’s disease who were treated at the Mayo Clinic for abdominal or pelvic abscesses in 1999-2006. Forty of these study subjects underwent initial laparotomy, with or without concomitant bowel resection.

The other 55 subjects instead had radiographically guided percutaneous drainage or aspiration, with or without drain placement, followed by a course of anti-TNF therapy, with or without additional immunosuppressive drug treatment.

After a median follow-up of more than 40 months, the researchers found no difference in short- and long-term recurrence between the surgical and medical management groups.

The rates of early recurrence (within 30 days) were the same between the two study groups. And the estimated 5-year cumulative rate of recurrence was 20.3% for the surgical group and 31.2% for the medical group, a nonsignificant difference.

Compared with patients who did not receive anti-TNF therapy after drainage, those who did were much less likely to develop a recurrence of abscess. Anti-TNF therapy in combination with another immunosuppressant – typically methotrexate, 6-mercaptopurine, or azathioprine – was even more protective against recurrence.

"In our cohort, there was no documentation of systemic sepsis or opportunistic infections among patients who received either anti-TNF or immunosuppressive therapy after abscess drainage," the researchers said.

Hospital stay was significantly shorter for the medical-therapy group (5 days) than the surgery group (15 days). However, the researchers postulated that perhaps patients with more severe illness, including those with multiple abscesses, were more likely to be selected for surgery. This study was not randomized; instead, the treating physicians chose whether or not to operate on each patient.

Even with such selection bias, this study provides clear evidence that at least some patients can be safely and effectively managed without surgery. Twelve of the 55 patients in the medical group (22%) were managed as outpatients, the investigators noted.

The mean size of the abscess was similar between the two study groups, "indicating that size alone does not preclude successful percutaneous drainage as an initial treatment plan," they added.

In addition to abscess size, several other factors thought to raise the risk of recurrence – including patient age, length of hospitalization, medical therapy prior to drainage, history of penetrating disease, and drainage modality – were found to have no effect on risk.

A history of perianal disease and active ileal disease at the time of abscess diagnosis were the only two factors were found to be significantly associated with recurrence.

Dr. Nguyen and his associates concluded that medical therapy can provide durable resolution of abscesses in Crohn’s disease. However, they said, "We do believe that there is clearly a subset of patients, including those with hemodynamic instability or long-standing fibrostenotic disease, who are better served with a surgical intervention."

Dr. Nguyen’s associates reported ties to Centocor Ortho Biotech.

For patients with Crohn’s disease who have intra-abdominal abscesses, percutaneous drainage plus anti–tumor necrosis factor therapy can be as effective as surgery, Dr. Douglas L. Nguyen and his colleagues reported in the April issue of Clinical Gastroenterology and Hepatology.

"It is clear that there are lower-risk patients who can be effectively and safely managed with medical therapy. In fact, we identified a subset of patients who had percutaneous drainage as an outpatient procedure and received oral antibiotics without the need for inpatient observation," said Dr. Nguyen of the Mayo Clinic, Rochester, Minn., and his associates (Clin. Gastroenterol. Hepatol. 2012 April [doi: 10.1016/j.cgh.2011.11.023]).

The researchers examined this issue because until now there have been very little data on the short- or long-term outcomes of medical treatment in this setting, particularly when it involves anti-TNF agents.

"In theory, percutaneous drainage converts an intra-abdominal abscess (which is a contraindication to anti-TNF therapy) into an enterocutaneous fistula (which is an indication for anti-TNF therapy). The procedure allows an abscess cavity to safely drain, while the anti-TNF drug reduces inflammation and promotes fistula healing.

"The desired outcome would be abscess resolution and tract closure without surgical intervention," they explained.

Dr. Nguyen and his colleagues retrospectively identified 95 adults with Crohn’s disease who were treated at the Mayo Clinic for abdominal or pelvic abscesses in 1999-2006. Forty of these study subjects underwent initial laparotomy, with or without concomitant bowel resection.

The other 55 subjects instead had radiographically guided percutaneous drainage or aspiration, with or without drain placement, followed by a course of anti-TNF therapy, with or without additional immunosuppressive drug treatment.

After a median follow-up of more than 40 months, the researchers found no difference in short- and long-term recurrence between the surgical and medical management groups.

The rates of early recurrence (within 30 days) were the same between the two study groups. And the estimated 5-year cumulative rate of recurrence was 20.3% for the surgical group and 31.2% for the medical group, a nonsignificant difference.

Compared with patients who did not receive anti-TNF therapy after drainage, those who did were much less likely to develop a recurrence of abscess. Anti-TNF therapy in combination with another immunosuppressant – typically methotrexate, 6-mercaptopurine, or azathioprine – was even more protective against recurrence.

"In our cohort, there was no documentation of systemic sepsis or opportunistic infections among patients who received either anti-TNF or immunosuppressive therapy after abscess drainage," the researchers said.

Hospital stay was significantly shorter for the medical-therapy group (5 days) than the surgery group (15 days). However, the researchers postulated that perhaps patients with more severe illness, including those with multiple abscesses, were more likely to be selected for surgery. This study was not randomized; instead, the treating physicians chose whether or not to operate on each patient.

Even with such selection bias, this study provides clear evidence that at least some patients can be safely and effectively managed without surgery. Twelve of the 55 patients in the medical group (22%) were managed as outpatients, the investigators noted.

The mean size of the abscess was similar between the two study groups, "indicating that size alone does not preclude successful percutaneous drainage as an initial treatment plan," they added.

In addition to abscess size, several other factors thought to raise the risk of recurrence – including patient age, length of hospitalization, medical therapy prior to drainage, history of penetrating disease, and drainage modality – were found to have no effect on risk.

A history of perianal disease and active ileal disease at the time of abscess diagnosis were the only two factors were found to be significantly associated with recurrence.

Dr. Nguyen and his associates concluded that medical therapy can provide durable resolution of abscesses in Crohn’s disease. However, they said, "We do believe that there is clearly a subset of patients, including those with hemodynamic instability or long-standing fibrostenotic disease, who are better served with a surgical intervention."

Dr. Nguyen’s associates reported ties to Centocor Ortho Biotech.

For patients with Crohn’s disease who have intra-abdominal abscesses, percutaneous drainage plus anti–tumor necrosis factor therapy can be as effective as surgery, Dr. Douglas L. Nguyen and his colleagues reported in the April issue of Clinical Gastroenterology and Hepatology.

"It is clear that there are lower-risk patients who can be effectively and safely managed with medical therapy. In fact, we identified a subset of patients who had percutaneous drainage as an outpatient procedure and received oral antibiotics without the need for inpatient observation," said Dr. Nguyen of the Mayo Clinic, Rochester, Minn., and his associates (Clin. Gastroenterol. Hepatol. 2012 April [doi: 10.1016/j.cgh.2011.11.023]).

The researchers examined this issue because until now there have been very little data on the short- or long-term outcomes of medical treatment in this setting, particularly when it involves anti-TNF agents.

"In theory, percutaneous drainage converts an intra-abdominal abscess (which is a contraindication to anti-TNF therapy) into an enterocutaneous fistula (which is an indication for anti-TNF therapy). The procedure allows an abscess cavity to safely drain, while the anti-TNF drug reduces inflammation and promotes fistula healing.

"The desired outcome would be abscess resolution and tract closure without surgical intervention," they explained.

Dr. Nguyen and his colleagues retrospectively identified 95 adults with Crohn’s disease who were treated at the Mayo Clinic for abdominal or pelvic abscesses in 1999-2006. Forty of these study subjects underwent initial laparotomy, with or without concomitant bowel resection.

The other 55 subjects instead had radiographically guided percutaneous drainage or aspiration, with or without drain placement, followed by a course of anti-TNF therapy, with or without additional immunosuppressive drug treatment.

After a median follow-up of more than 40 months, the researchers found no difference in short- and long-term recurrence between the surgical and medical management groups.

The rates of early recurrence (within 30 days) were the same between the two study groups. And the estimated 5-year cumulative rate of recurrence was 20.3% for the surgical group and 31.2% for the medical group, a nonsignificant difference.

Compared with patients who did not receive anti-TNF therapy after drainage, those who did were much less likely to develop a recurrence of abscess. Anti-TNF therapy in combination with another immunosuppressant – typically methotrexate, 6-mercaptopurine, or azathioprine – was even more protective against recurrence.

"In our cohort, there was no documentation of systemic sepsis or opportunistic infections among patients who received either anti-TNF or immunosuppressive therapy after abscess drainage," the researchers said.

Hospital stay was significantly shorter for the medical-therapy group (5 days) than the surgery group (15 days). However, the researchers postulated that perhaps patients with more severe illness, including those with multiple abscesses, were more likely to be selected for surgery. This study was not randomized; instead, the treating physicians chose whether or not to operate on each patient.

Even with such selection bias, this study provides clear evidence that at least some patients can be safely and effectively managed without surgery. Twelve of the 55 patients in the medical group (22%) were managed as outpatients, the investigators noted.

The mean size of the abscess was similar between the two study groups, "indicating that size alone does not preclude successful percutaneous drainage as an initial treatment plan," they added.

In addition to abscess size, several other factors thought to raise the risk of recurrence – including patient age, length of hospitalization, medical therapy prior to drainage, history of penetrating disease, and drainage modality – were found to have no effect on risk.

A history of perianal disease and active ileal disease at the time of abscess diagnosis were the only two factors were found to be significantly associated with recurrence.

Dr. Nguyen and his associates concluded that medical therapy can provide durable resolution of abscesses in Crohn’s disease. However, they said, "We do believe that there is clearly a subset of patients, including those with hemodynamic instability or long-standing fibrostenotic disease, who are better served with a surgical intervention."

Dr. Nguyen’s associates reported ties to Centocor Ortho Biotech.

Patients with moderate or severe Alzheimer’s disease who continued to worsen despite treatment with donepezil appeared to retain a small but significant benefit over those who added or switched to memantine or stopped taking medication for Alzheimer’s altogether in a randomized trial.

The patients in the 1-year study, DOMINO (Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease), who continued on donepezil (Aricept) showed improved cognitive and functional outcomes, compared with all other groups, Dr. Robert Howard of the Institute of Psychiatry, King’s College London, and his associates reported March 8 in the New England Journal of Medicine.

Patients who stopped donepezil and started memantine (Namenda) showed smaller but still significant benefits. Those who stopped donepezil and didn’t switch to memantine did not improve. And patients who continued donepezil and added memantine to their regimen did not improve further than those who simply continued donepezil.

However, "the improvements in cognition and function associated with donepezil and memantine were small relative to the overall size of the decline in cognitive and functional status that was seen in all patients," the investigators noted.

Noting that there is little evidence to guide the difficult decision regarding continuing or changing treatment when Alzheimer’s disease (AD) progresses, Dr. Howard and his colleagues studied 295 community-living patients with moderate or severe AD who had already taken donepezil for 2-3 years and whose clinicians were considering changing medication.

All the patients scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE), which ranges in score from 0 to 30; higher scores indicate better cognitive function. The investigators randomly assigned them to continue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking memantine (76 patients), or continue donepezil and start taking memantine (73 patients).

During a 1-year follow-up period, 137 (46%) withdrew from the trial, usually because of a perceived lack of benefit from continued treatment.

Compared with patients who discontinued donepezil, those who continued the drug scored better by 1.9 points on the SMMSE. They also scored better by 3 points on the 60-point, caregiver-rated Bristol Activities of Daily Living Scale (BADLS), indicating less functional impairment, the investigators said (N. Engl. J. Med. 2012;366:893-903).

Patients who began taking memantine scored a mean of 1.2 higher on the SMMSE and a mean of 1.5 points better on the BADLS, compared with patients who did not start the drug. However, combined treatment with the drugs did not provide any significant benefits beyond treatment with donepezil alone for any of the primary or secondary outcomes.

This study was funded by the U.K. Medical Research Council and the Alzheimer’s Society. Pfizer-Eisai and Lundbeck donated the drugs and placebos used in the study. Many of the authors reported financial ties to Pfizer and Eisai, which together market donepezil in the United States, as well as other companies that manufacture drugs for Alzheimer’s disease.

Patients with moderate or severe Alzheimer’s disease who continued to worsen despite treatment with donepezil appeared to retain a small but significant benefit over those who added or switched to memantine or stopped taking medication for Alzheimer’s altogether in a randomized trial.

The patients in the 1-year study, DOMINO (Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease), who continued on donepezil (Aricept) showed improved cognitive and functional outcomes, compared with all other groups, Dr. Robert Howard of the Institute of Psychiatry, King’s College London, and his associates reported March 8 in the New England Journal of Medicine.

Patients who stopped donepezil and started memantine (Namenda) showed smaller but still significant benefits. Those who stopped donepezil and didn’t switch to memantine did not improve. And patients who continued donepezil and added memantine to their regimen did not improve further than those who simply continued donepezil.

However, "the improvements in cognition and function associated with donepezil and memantine were small relative to the overall size of the decline in cognitive and functional status that was seen in all patients," the investigators noted.

Noting that there is little evidence to guide the difficult decision regarding continuing or changing treatment when Alzheimer’s disease (AD) progresses, Dr. Howard and his colleagues studied 295 community-living patients with moderate or severe AD who had already taken donepezil for 2-3 years and whose clinicians were considering changing medication.

All the patients scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE), which ranges in score from 0 to 30; higher scores indicate better cognitive function. The investigators randomly assigned them to continue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking memantine (76 patients), or continue donepezil and start taking memantine (73 patients).

During a 1-year follow-up period, 137 (46%) withdrew from the trial, usually because of a perceived lack of benefit from continued treatment.

Compared with patients who discontinued donepezil, those who continued the drug scored better by 1.9 points on the SMMSE. They also scored better by 3 points on the 60-point, caregiver-rated Bristol Activities of Daily Living Scale (BADLS), indicating less functional impairment, the investigators said (N. Engl. J. Med. 2012;366:893-903).

Patients who began taking memantine scored a mean of 1.2 higher on the SMMSE and a mean of 1.5 points better on the BADLS, compared with patients who did not start the drug. However, combined treatment with the drugs did not provide any significant benefits beyond treatment with donepezil alone for any of the primary or secondary outcomes.

This study was funded by the U.K. Medical Research Council and the Alzheimer’s Society. Pfizer-Eisai and Lundbeck donated the drugs and placebos used in the study. Many of the authors reported financial ties to Pfizer and Eisai, which together market donepezil in the United States, as well as other companies that manufacture drugs for Alzheimer’s disease.

Patients with moderate or severe Alzheimer’s disease who continued to worsen despite treatment with donepezil appeared to retain a small but significant benefit over those who added or switched to memantine or stopped taking medication for Alzheimer’s altogether in a randomized trial.

The patients in the 1-year study, DOMINO (Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease), who continued on donepezil (Aricept) showed improved cognitive and functional outcomes, compared with all other groups, Dr. Robert Howard of the Institute of Psychiatry, King’s College London, and his associates reported March 8 in the New England Journal of Medicine.

Patients who stopped donepezil and started memantine (Namenda) showed smaller but still significant benefits. Those who stopped donepezil and didn’t switch to memantine did not improve. And patients who continued donepezil and added memantine to their regimen did not improve further than those who simply continued donepezil.

However, "the improvements in cognition and function associated with donepezil and memantine were small relative to the overall size of the decline in cognitive and functional status that was seen in all patients," the investigators noted.

Noting that there is little evidence to guide the difficult decision regarding continuing or changing treatment when Alzheimer’s disease (AD) progresses, Dr. Howard and his colleagues studied 295 community-living patients with moderate or severe AD who had already taken donepezil for 2-3 years and whose clinicians were considering changing medication.

All the patients scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE), which ranges in score from 0 to 30; higher scores indicate better cognitive function. The investigators randomly assigned them to continue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking memantine (76 patients), or continue donepezil and start taking memantine (73 patients).

During a 1-year follow-up period, 137 (46%) withdrew from the trial, usually because of a perceived lack of benefit from continued treatment.

Compared with patients who discontinued donepezil, those who continued the drug scored better by 1.9 points on the SMMSE. They also scored better by 3 points on the 60-point, caregiver-rated Bristol Activities of Daily Living Scale (BADLS), indicating less functional impairment, the investigators said (N. Engl. J. Med. 2012;366:893-903).

Patients who began taking memantine scored a mean of 1.2 higher on the SMMSE and a mean of 1.5 points better on the BADLS, compared with patients who did not start the drug. However, combined treatment with the drugs did not provide any significant benefits beyond treatment with donepezil alone for any of the primary or secondary outcomes.

This study was funded by the U.K. Medical Research Council and the Alzheimer’s Society. Pfizer-Eisai and Lundbeck donated the drugs and placebos used in the study. Many of the authors reported financial ties to Pfizer and Eisai, which together market donepezil in the United States, as well as other companies that manufacture drugs for Alzheimer’s disease.

The somatostatin analogue pasireotide substantially reduced high cortisol levels in patients with Cushing’s disease, in a phase III clinical trial published in the March 8 issue of the New England Journal of Medicine.

This decline was accompanied by improvements in the signs and symptoms of Cushing’s disease and by increases in health-related quality of life scores, said Dr. Annamaria Colao of the department of molecular and clinical endocrinology and oncology, University of Naples (Italy) Federico II, and her associates.

However, hyperglycemia-related adverse events developed in 73% of patients, and glucose and glycated hemoglobin levels increased soon after the drug was initiated, requiring medical management. "Blood glucose should be monitored in pasireotide-treated patients, with special attention to patients with impaired glucose tolerance or diabetes mellitus," the researchers noted.

They assessed pasireotide in an industry-sponsored study of 162 adults who had moderate to very severe hypercortisolism. All the study subjects had persistent or recurrent Cushing’s disease, or they had newly diagnosed disease but were not candidates for surgery.

The study subjects were randomly assigned to receive subcutaneous pasireotide, beginning at a dose of 600 mcg (82 subjects) or 900 mcg (80 patients) twice daily for 3 months. Those who responded to the treatment continued with their randomly assigned injections in a double-blind fashion through another 3 months, while the others were unblinded and given dose increases of 300 mcg for that 3 months.

At 6 months, all the study subjects entered an open-label phase of the trial that lasted until month 12. During this time, dose escalations were permitted to improve treatment response.

The mean duration of treatment was 10.8 months, and 78 patients (48%) completed the full 12 months of therapy.

The primary end point of the study was normalization of the urinary free cortisol level at month 6 without any dose escalations. This was achieved in 12 of 82 (15%) of the patients receiving 600 mcg and in 21 of the 80 (26%) of those receiving 900 mcg, Dr. Colao and her colleagues said (N. Engl. J. Med. 2012;366:914-24).

The majority of the remaining patients had substantial (50% or greater) reductions in urinary free cortisol levels at month 6, even if they did not achieve normalization of those levels. Both these patients and the ones whose urinary cortisol levels normalized showed marked improvement in the signs and symptoms of Cushing’s syndrome, "suggesting that a reduction in the cortisol level may be associated with a long-term clinical benefit," the researchers said.

These changes included a mean decrease of 6.1 mm Hg in blood pressure, a mean decrease of 3.7 mm Hg in diastolic blood pressure, a mean decrease of 2 mg/dL in triglycerides, a mean decrease of 15 mg/dL in LDL cholesterol, and a mean decrease of 6.7 kg in weight. Facial rubor and supraclavicular and dorsal fat pads also diminished.

Pituitary tumor volume on MRI decreased by a mean of 9% in the lower-dose group and by 44% in the higher-dose group.

Concomitantly, scores for health-related quality of life on the Cushing quality of life questionnaire increased by 11 points, reflecting an 11% improvement.

The treatment effect occurred rapidly, with 50% reductions in urinary free cortisol noted within 2 months and remaining stable for the duration of treatment. And 90% of patients whose hypercortisolism was uncontrolled at 2 months still had hypercortisolism at 12 months. This indicates that clinicians should be able to identify patients who are unlikely to respond to pasireotide within the first few months of therapy, Dr. Colao and her associates said.

Hyperglycemia developed in 13% of patients, including 6% who discontinued pasireotide because of this adverse event. Diabetes mellitus developed in 7%. And 118 patients (73%) experienced a hyperglycemia-related adverse event.

Adverse events related to hypocortisolism occurred in 13 patients (8%). And of 137 patients who had undergone gallbladder ultrasonography at baseline, 9 developed "detectable sludge" and 27 developed gallstones at their most recent follow-up. Six of these patients have undergone cholecystectomy to date.

This study was funded by Novartis Pharma. Dr. Colao’s associates reported ties to Corcept Therapeutics, Ipsen, and Pfizer.

The somatostatin analogue pasireotide substantially reduced high cortisol levels in patients with Cushing’s disease, in a phase III clinical trial published in the March 8 issue of the New England Journal of Medicine.

This decline was accompanied by improvements in the signs and symptoms of Cushing’s disease and by increases in health-related quality of life scores, said Dr. Annamaria Colao of the department of molecular and clinical endocrinology and oncology, University of Naples (Italy) Federico II, and her associates.

However, hyperglycemia-related adverse events developed in 73% of patients, and glucose and glycated hemoglobin levels increased soon after the drug was initiated, requiring medical management. "Blood glucose should be monitored in pasireotide-treated patients, with special attention to patients with impaired glucose tolerance or diabetes mellitus," the researchers noted.

They assessed pasireotide in an industry-sponsored study of 162 adults who had moderate to very severe hypercortisolism. All the study subjects had persistent or recurrent Cushing’s disease, or they had newly diagnosed disease but were not candidates for surgery.

The study subjects were randomly assigned to receive subcutaneous pasireotide, beginning at a dose of 600 mcg (82 subjects) or 900 mcg (80 patients) twice daily for 3 months. Those who responded to the treatment continued with their randomly assigned injections in a double-blind fashion through another 3 months, while the others were unblinded and given dose increases of 300 mcg for that 3 months.

At 6 months, all the study subjects entered an open-label phase of the trial that lasted until month 12. During this time, dose escalations were permitted to improve treatment response.

The mean duration of treatment was 10.8 months, and 78 patients (48%) completed the full 12 months of therapy.

The primary end point of the study was normalization of the urinary free cortisol level at month 6 without any dose escalations. This was achieved in 12 of 82 (15%) of the patients receiving 600 mcg and in 21 of the 80 (26%) of those receiving 900 mcg, Dr. Colao and her colleagues said (N. Engl. J. Med. 2012;366:914-24).

The majority of the remaining patients had substantial (50% or greater) reductions in urinary free cortisol levels at month 6, even if they did not achieve normalization of those levels. Both these patients and the ones whose urinary cortisol levels normalized showed marked improvement in the signs and symptoms of Cushing’s syndrome, "suggesting that a reduction in the cortisol level may be associated with a long-term clinical benefit," the researchers said.

These changes included a mean decrease of 6.1 mm Hg in blood pressure, a mean decrease of 3.7 mm Hg in diastolic blood pressure, a mean decrease of 2 mg/dL in triglycerides, a mean decrease of 15 mg/dL in LDL cholesterol, and a mean decrease of 6.7 kg in weight. Facial rubor and supraclavicular and dorsal fat pads also diminished.

Pituitary tumor volume on MRI decreased by a mean of 9% in the lower-dose group and by 44% in the higher-dose group.

Concomitantly, scores for health-related quality of life on the Cushing quality of life questionnaire increased by 11 points, reflecting an 11% improvement.

The treatment effect occurred rapidly, with 50% reductions in urinary free cortisol noted within 2 months and remaining stable for the duration of treatment. And 90% of patients whose hypercortisolism was uncontrolled at 2 months still had hypercortisolism at 12 months. This indicates that clinicians should be able to identify patients who are unlikely to respond to pasireotide within the first few months of therapy, Dr. Colao and her associates said.

Hyperglycemia developed in 13% of patients, including 6% who discontinued pasireotide because of this adverse event. Diabetes mellitus developed in 7%. And 118 patients (73%) experienced a hyperglycemia-related adverse event.

Adverse events related to hypocortisolism occurred in 13 patients (8%). And of 137 patients who had undergone gallbladder ultrasonography at baseline, 9 developed "detectable sludge" and 27 developed gallstones at their most recent follow-up. Six of these patients have undergone cholecystectomy to date.

This study was funded by Novartis Pharma. Dr. Colao’s associates reported ties to Corcept Therapeutics, Ipsen, and Pfizer.

The somatostatin analogue pasireotide substantially reduced high cortisol levels in patients with Cushing’s disease, in a phase III clinical trial published in the March 8 issue of the New England Journal of Medicine.

This decline was accompanied by improvements in the signs and symptoms of Cushing’s disease and by increases in health-related quality of life scores, said Dr. Annamaria Colao of the department of molecular and clinical endocrinology and oncology, University of Naples (Italy) Federico II, and her associates.

However, hyperglycemia-related adverse events developed in 73% of patients, and glucose and glycated hemoglobin levels increased soon after the drug was initiated, requiring medical management. "Blood glucose should be monitored in pasireotide-treated patients, with special attention to patients with impaired glucose tolerance or diabetes mellitus," the researchers noted.

They assessed pasireotide in an industry-sponsored study of 162 adults who had moderate to very severe hypercortisolism. All the study subjects had persistent or recurrent Cushing’s disease, or they had newly diagnosed disease but were not candidates for surgery.

The study subjects were randomly assigned to receive subcutaneous pasireotide, beginning at a dose of 600 mcg (82 subjects) or 900 mcg (80 patients) twice daily for 3 months. Those who responded to the treatment continued with their randomly assigned injections in a double-blind fashion through another 3 months, while the others were unblinded and given dose increases of 300 mcg for that 3 months.

At 6 months, all the study subjects entered an open-label phase of the trial that lasted until month 12. During this time, dose escalations were permitted to improve treatment response.

The mean duration of treatment was 10.8 months, and 78 patients (48%) completed the full 12 months of therapy.

The primary end point of the study was normalization of the urinary free cortisol level at month 6 without any dose escalations. This was achieved in 12 of 82 (15%) of the patients receiving 600 mcg and in 21 of the 80 (26%) of those receiving 900 mcg, Dr. Colao and her colleagues said (N. Engl. J. Med. 2012;366:914-24).

The majority of the remaining patients had substantial (50% or greater) reductions in urinary free cortisol levels at month 6, even if they did not achieve normalization of those levels. Both these patients and the ones whose urinary cortisol levels normalized showed marked improvement in the signs and symptoms of Cushing’s syndrome, "suggesting that a reduction in the cortisol level may be associated with a long-term clinical benefit," the researchers said.

These changes included a mean decrease of 6.1 mm Hg in blood pressure, a mean decrease of 3.7 mm Hg in diastolic blood pressure, a mean decrease of 2 mg/dL in triglycerides, a mean decrease of 15 mg/dL in LDL cholesterol, and a mean decrease of 6.7 kg in weight. Facial rubor and supraclavicular and dorsal fat pads also diminished.

Pituitary tumor volume on MRI decreased by a mean of 9% in the lower-dose group and by 44% in the higher-dose group.

Concomitantly, scores for health-related quality of life on the Cushing quality of life questionnaire increased by 11 points, reflecting an 11% improvement.

The treatment effect occurred rapidly, with 50% reductions in urinary free cortisol noted within 2 months and remaining stable for the duration of treatment. And 90% of patients whose hypercortisolism was uncontrolled at 2 months still had hypercortisolism at 12 months. This indicates that clinicians should be able to identify patients who are unlikely to respond to pasireotide within the first few months of therapy, Dr. Colao and her associates said.

Hyperglycemia developed in 13% of patients, including 6% who discontinued pasireotide because of this adverse event. Diabetes mellitus developed in 7%. And 118 patients (73%) experienced a hyperglycemia-related adverse event.

Adverse events related to hypocortisolism occurred in 13 patients (8%). And of 137 patients who had undergone gallbladder ultrasonography at baseline, 9 developed "detectable sludge" and 27 developed gallstones at their most recent follow-up. Six of these patients have undergone cholecystectomy to date.

This study was funded by Novartis Pharma. Dr. Colao’s associates reported ties to Corcept Therapeutics, Ipsen, and Pfizer.

In a study of postmenopausal women who had undergone hysterectomy, the use of unopposed estrogen significantly reduced the incidence of invasive breast cancer for up to 5 years after they stopped taking the hormone, according to a report published online March 7 in the Lancet Oncology.

For study subjects who did develop breast cancer, estrogen use reduced breast-cancer mortality and all-cause mortality, Garnet L. Anderson, Ph.D., and her associates reported in an extended follow-up study of 7,645 participants in the Women’s Health Initiative (WHI).

"Our findings ... provide reassurance about breast cancer safety for postmenopausal women with [a] previous hysterectomy who receive unopposed estrogen to reduce climacteric symptoms," they noted.

The WHI, a multicenter, randomized clinical trial involving more than 10,000 women, compared outcomes between those who took conjugated equine estrogen and those who took a matching placebo.

The intervention phase of the WHI was terminated early in February 2004, after a mean follow-up of 7 years. Approximately 78% of the study subjects – 3,778 who had been randomly assigned to receive estrogen and 3,867 to receive placebo – agreed to extended follow-up until August 2009, for a total median follow-up of 11.8 years.

At this final assessment, women who had taken estrogen for a median of 6 years during the intervention phase had an overall incidence of invasive breast cancer of 0.27% per year (151 cases), which was significantly lower than the 0.35% per year rate (199 cases) among women who had taken placebo, said Dr. Anderson of the Fred Hutchinson Cancer Research Center, Seattle, and her colleagues.

"The continued, postintervention effect of estrogen on breast cancer incidence is akin to that reported for other hormone-targeted drugs shown to reduce breast cancer incidence," the investigators said (Lancet Oncol. 2012 March 7 [doi:10.1016/S1470-2045(12)70075-x]).

Estrogen was associated with a reduced risk of developing infiltrating ductal carcinoma but not infiltrating lobular cancers. It also decreased the risk of human epidermal growth factor receptor 2 (HER-2)–negative tumors but not HER-2–positive tumors, and appeared to reduce the risk of small and node-negative cancers but not large (2 cm or larger) or node-positive cancers. However, these differences among tumor subtypes did not reach statistical significance.

Among the study subjects who did develop breast cancer, those in the estrogen group were significantly less likely to die of any cause (30 deaths, for a mortality of 0.046% per year) than were those in the placebo group (50 deaths, for a mortality of 0.076% per year).

Breast-cancer-specific mortality also was significantly lower in the estrogen recipients (6 deaths, for a mortality of 0.009% per year) than in the placebo recipients (16 deaths, for a mortality of 0.024% per year).

However, the number of deaths was small, limiting the strength of these associations, Dr. Anderson and her associates noted.

These protective effects appeared to be restricted to women who had a lower risk for breast cancer. They did not apply to women with a history of benign breast disease or those with a first-degree family history of breast cancer.

In subgroup analyses, estrogen’s protective effects showed no interactions with patient age, body mass index, oophorectomy status, years since the onset of menopause, previous estrogen use, or the presence of vasomotor symptoms.

The WHI was limited in that it assessed "only one dose and schedule of oral conjugated equine estrogens; whether these findings apply to lower doses, other estrogen preparations, or longer durations of use is not known," the researchers noted.

They reported no relevant financial disclosures. The WHI was supported by the National Heart, Lung, and Blood Institute; the National Institutes of Health; the Department of Health and Human Services; and Wyeth. One of Dr. Anderson’s associates reported ties to AstraZeneca, Novartis, Amgen, and Pfizer. Dr. Anderson and the other investigators said they had no relevant financial disclosures.

In a study of postmenopausal women who had undergone hysterectomy, the use of unopposed estrogen significantly reduced the incidence of invasive breast cancer for up to 5 years after they stopped taking the hormone, according to a report published online March 7 in the Lancet Oncology.

For study subjects who did develop breast cancer, estrogen use reduced breast-cancer mortality and all-cause mortality, Garnet L. Anderson, Ph.D., and her associates reported in an extended follow-up study of 7,645 participants in the Women’s Health Initiative (WHI).

"Our findings ... provide reassurance about breast cancer safety for postmenopausal women with [a] previous hysterectomy who receive unopposed estrogen to reduce climacteric symptoms," they noted.

The WHI, a multicenter, randomized clinical trial involving more than 10,000 women, compared outcomes between those who took conjugated equine estrogen and those who took a matching placebo.

The intervention phase of the WHI was terminated early in February 2004, after a mean follow-up of 7 years. Approximately 78% of the study subjects – 3,778 who had been randomly assigned to receive estrogen and 3,867 to receive placebo – agreed to extended follow-up until August 2009, for a total median follow-up of 11.8 years.

At this final assessment, women who had taken estrogen for a median of 6 years during the intervention phase had an overall incidence of invasive breast cancer of 0.27% per year (151 cases), which was significantly lower than the 0.35% per year rate (199 cases) among women who had taken placebo, said Dr. Anderson of the Fred Hutchinson Cancer Research Center, Seattle, and her colleagues.

"The continued, postintervention effect of estrogen on breast cancer incidence is akin to that reported for other hormone-targeted drugs shown to reduce breast cancer incidence," the investigators said (Lancet Oncol. 2012 March 7 [doi:10.1016/S1470-2045(12)70075-x]).

Estrogen was associated with a reduced risk of developing infiltrating ductal carcinoma but not infiltrating lobular cancers. It also decreased the risk of human epidermal growth factor receptor 2 (HER-2)–negative tumors but not HER-2–positive tumors, and appeared to reduce the risk of small and node-negative cancers but not large (2 cm or larger) or node-positive cancers. However, these differences among tumor subtypes did not reach statistical significance.

Among the study subjects who did develop breast cancer, those in the estrogen group were significantly less likely to die of any cause (30 deaths, for a mortality of 0.046% per year) than were those in the placebo group (50 deaths, for a mortality of 0.076% per year).

Breast-cancer-specific mortality also was significantly lower in the estrogen recipients (6 deaths, for a mortality of 0.009% per year) than in the placebo recipients (16 deaths, for a mortality of 0.024% per year).

However, the number of deaths was small, limiting the strength of these associations, Dr. Anderson and her associates noted.

These protective effects appeared to be restricted to women who had a lower risk for breast cancer. They did not apply to women with a history of benign breast disease or those with a first-degree family history of breast cancer.

In subgroup analyses, estrogen’s protective effects showed no interactions with patient age, body mass index, oophorectomy status, years since the onset of menopause, previous estrogen use, or the presence of vasomotor symptoms.

The WHI was limited in that it assessed "only one dose and schedule of oral conjugated equine estrogens; whether these findings apply to lower doses, other estrogen preparations, or longer durations of use is not known," the researchers noted.

They reported no relevant financial disclosures. The WHI was supported by the National Heart, Lung, and Blood Institute; the National Institutes of Health; the Department of Health and Human Services; and Wyeth. One of Dr. Anderson’s associates reported ties to AstraZeneca, Novartis, Amgen, and Pfizer. Dr. Anderson and the other investigators said they had no relevant financial disclosures.

In a study of postmenopausal women who had undergone hysterectomy, the use of unopposed estrogen significantly reduced the incidence of invasive breast cancer for up to 5 years after they stopped taking the hormone, according to a report published online March 7 in the Lancet Oncology.

For study subjects who did develop breast cancer, estrogen use reduced breast-cancer mortality and all-cause mortality, Garnet L. Anderson, Ph.D., and her associates reported in an extended follow-up study of 7,645 participants in the Women’s Health Initiative (WHI).

"Our findings ... provide reassurance about breast cancer safety for postmenopausal women with [a] previous hysterectomy who receive unopposed estrogen to reduce climacteric symptoms," they noted.

The WHI, a multicenter, randomized clinical trial involving more than 10,000 women, compared outcomes between those who took conjugated equine estrogen and those who took a matching placebo.

The intervention phase of the WHI was terminated early in February 2004, after a mean follow-up of 7 years. Approximately 78% of the study subjects – 3,778 who had been randomly assigned to receive estrogen and 3,867 to receive placebo – agreed to extended follow-up until August 2009, for a total median follow-up of 11.8 years.

At this final assessment, women who had taken estrogen for a median of 6 years during the intervention phase had an overall incidence of invasive breast cancer of 0.27% per year (151 cases), which was significantly lower than the 0.35% per year rate (199 cases) among women who had taken placebo, said Dr. Anderson of the Fred Hutchinson Cancer Research Center, Seattle, and her colleagues.

"The continued, postintervention effect of estrogen on breast cancer incidence is akin to that reported for other hormone-targeted drugs shown to reduce breast cancer incidence," the investigators said (Lancet Oncol. 2012 March 7 [doi:10.1016/S1470-2045(12)70075-x]).

Estrogen was associated with a reduced risk of developing infiltrating ductal carcinoma but not infiltrating lobular cancers. It also decreased the risk of human epidermal growth factor receptor 2 (HER-2)–negative tumors but not HER-2–positive tumors, and appeared to reduce the risk of small and node-negative cancers but not large (2 cm or larger) or node-positive cancers. However, these differences among tumor subtypes did not reach statistical significance.

Among the study subjects who did develop breast cancer, those in the estrogen group were significantly less likely to die of any cause (30 deaths, for a mortality of 0.046% per year) than were those in the placebo group (50 deaths, for a mortality of 0.076% per year).

Breast-cancer-specific mortality also was significantly lower in the estrogen recipients (6 deaths, for a mortality of 0.009% per year) than in the placebo recipients (16 deaths, for a mortality of 0.024% per year).

However, the number of deaths was small, limiting the strength of these associations, Dr. Anderson and her associates noted.

These protective effects appeared to be restricted to women who had a lower risk for breast cancer. They did not apply to women with a history of benign breast disease or those with a first-degree family history of breast cancer.

In subgroup analyses, estrogen’s protective effects showed no interactions with patient age, body mass index, oophorectomy status, years since the onset of menopause, previous estrogen use, or the presence of vasomotor symptoms.

The WHI was limited in that it assessed "only one dose and schedule of oral conjugated equine estrogens; whether these findings apply to lower doses, other estrogen preparations, or longer durations of use is not known," the researchers noted.

They reported no relevant financial disclosures. The WHI was supported by the National Heart, Lung, and Blood Institute; the National Institutes of Health; the Department of Health and Human Services; and Wyeth. One of Dr. Anderson’s associates reported ties to AstraZeneca, Novartis, Amgen, and Pfizer. Dr. Anderson and the other investigators said they had no relevant financial disclosures.

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

"We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial)," and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. "There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients," Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered "a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs]," the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, "the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency," the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. "Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory," the investigators wrote.

Nevertheless, the sample size in this study "was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy," they added.

Overall, the ERSET results "reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability," Dr. Engel and his colleagues said.

The findings also remind clinicians that "all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed," they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

"We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial)," and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. "There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients," Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered "a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs]," the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, "the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency," the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. "Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory," the investigators wrote.

Nevertheless, the sample size in this study "was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy," they added.

Overall, the ERSET results "reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability," Dr. Engel and his colleagues said.

The findings also remind clinicians that "all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed," they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

"We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial)," and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. "There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients," Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered "a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs]," the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, "the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency," the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. "Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory," the investigators wrote.

Nevertheless, the sample size in this study "was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy," they added.

Overall, the ERSET results "reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability," Dr. Engel and his colleagues said.

The findings also remind clinicians that "all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed," they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

Surrogate decision makers for incapacitated, critically ill patients systematically interpreted prognostic information as being more optimistic than it actually was, in a study published in the March 6 issue of the Annals of Internal Medicine.

These surrogate decision makers accurately interpreted prognostic information that was positive, but not prognostic information expressing a high risk of death. Instead, they showed "a systematic bias," consistently interpreting "grim" prognostic statements in an overly optimistic way, said Dr. Lucas S. Zier of the University of California, San Francisco, and his associates.

"These findings challenge the prevailing assumption in the medical literature that discordance between physicians and surrogates about prognosis is due largely to unclear disclosure by physicians or simple misunderstandings by surrogates," the investigators noted.

The results also indicate that any efforts to improve this aspect of decision making must address not just the clarity of prognostic statements but also the "emotional and psychological factors that affect how individuals process such information," they added.

"Clinicians who communicate with surrogate decision makers in the care of incapacitated patients should be aware of the diverse causes for discordance about prognosis."

Dr. Zier and his colleagues examined how surrogate decision makers interpret physicians’ statements about their loved ones’ prognosis by administering a questionnaire to 80 such surrogates who were accompanying an incapacitated patient at medical-surgical ICUs in a Veterans Affairs hospital, a tertiary academic hospital, and a public county hospital.

The questionnaire presented 16 possible prognostic statements in the language used by physicians and made it clear that these represented hypothetical clinical situations unrelated to their loved one’s cases. Study subjects were asked what exactly each prognostic statement meant to them, and used a numerical scale to demarcate the patient’s chance of survival corresponding to each prognostic statement.

Examples of general and somewhat equivocal prognostic statements included "It is very likely that he will survive," "It is very unlikely that he will die," "I am concerned that he will not survive," "It is possible he will not survive," and "He probably will not survive." Unequivocal prognostic statements were "He will definitely survive" and "He will definitely not survive."

There also were three unequivocal numerical prognostic statements: "He has a 90% chance of surviving," "He has a 50% chance of surviving," and "He has a 5% chance of surviving."

Only twelve surrogate decision makers (15% of the entire group) interpreted the three numerical prognostic statements accurately. Almost as many – 13% –interpreted all three numerical prognostic statements more optimistically than they actually were.

Most surrogates interpreted the statement of a low risk of death ("90% chance of surviving") accurately, but severely misinterpreted the statements of a median or high risk of death. Forty percent thought that "a 50% chance of surviving" meant that the patient was likely to survive, and 65% thought that "a 5% chance of surviving" meant that the patient was likely to survive.

No surrogates interpreted any of the numerical prognostic statements more pessimistically than they actually were.

Some experts have advocated using straightforward, numerical language when communicating medical risk to surrogate decision makers, but these findings clearly show that numbers are not straightforward to everyone and are frequently misinterpreted, Dr. Zier and his associates said (Ann. Intern. Med. 2012;156:360-6).

In the second phase of this study, 15 subjects whose interpretations of prognostic statements had been particularly off-base were interviewed about why there was such a discrepancy between what the physician said and what the subject thought was meant.

Seven of the 15 said they were unaware that almost all their interpretations were overly optimistic. These subjects were surprised when it was pointed out to them and couldn’t offer of an explanation.

The other eight surrogate decision makers gave four reasons for their "optimism bias."

Some said they intentionally expressed optimism as long as there was any hope whatsoever. This may represent a coping strategy to help surrogates deal with having a critically ill loved one. Or it may represent "magical thinking" in which people believe their positive thoughts and expectations can actually improve the patient’s outcome, the researchers said.

Other surrogate decision makers said they believed their loved one was exceptional and wouldn’t die because of an unusual will to live and ability to survive. This "may represent a cognitive bias known as illusory superiority, unrealistic optimism, or the ‘Lake Wobegon effect,’ a cognitive bias that leads people to overestimate, in relation to others, their likelihood of experiencing positive outcomes and avoiding negative outcomes," the investigators said.

Some study subjects said they intentionally ignored numerical probabilities and precise language, preferring to judge "the overall feeling that the doctor is conveying."

And some said they didn’t believe physicians could ever accurately predict survival. However, such skepticism about physicians’ accuracy would result in a random distribution of interpretations rather than in the systematic optimism observed here, Dr. Zier and his colleagues noted.

The findings of this study show that "clinicians who communicate with surrogate decision makers in the care of incapacitated patients should be aware of the diverse causes for discordance about prognosis." Unrealistic optimism may not be benign; it can lead to treatment decisions that do not reflect the true values of the patient but that instead serve the surrogate decision maker’s impulse toward self-protection, they added.

This study was supported by the National Heart, Lung, and Blood Institute, the Greenwall Foundation, and the University of California, Berkeley–University of California, San Francisco, Joint Medical Program.

Surrogate decision makers for incapacitated, critically ill patients systematically interpreted prognostic information as being more optimistic than it actually was, in a study published in the March 6 issue of the Annals of Internal Medicine.

These surrogate decision makers accurately interpreted prognostic information that was positive, but not prognostic information expressing a high risk of death. Instead, they showed "a systematic bias," consistently interpreting "grim" prognostic statements in an overly optimistic way, said Dr. Lucas S. Zier of the University of California, San Francisco, and his associates.

"These findings challenge the prevailing assumption in the medical literature that discordance between physicians and surrogates about prognosis is due largely to unclear disclosure by physicians or simple misunderstandings by surrogates," the investigators noted.

The results also indicate that any efforts to improve this aspect of decision making must address not just the clarity of prognostic statements but also the "emotional and psychological factors that affect how individuals process such information," they added.

"Clinicians who communicate with surrogate decision makers in the care of incapacitated patients should be aware of the diverse causes for discordance about prognosis."

Dr. Zier and his colleagues examined how surrogate decision makers interpret physicians’ statements about their loved ones’ prognosis by administering a questionnaire to 80 such surrogates who were accompanying an incapacitated patient at medical-surgical ICUs in a Veterans Affairs hospital, a tertiary academic hospital, and a public county hospital.

The questionnaire presented 16 possible prognostic statements in the language used by physicians and made it clear that these represented hypothetical clinical situations unrelated to their loved one’s cases. Study subjects were asked what exactly each prognostic statement meant to them, and used a numerical scale to demarcate the patient’s chance of survival corresponding to each prognostic statement.

Examples of general and somewhat equivocal prognostic statements included "It is very likely that he will survive," "It is very unlikely that he will die," "I am concerned that he will not survive," "It is possible he will not survive," and "He probably will not survive." Unequivocal prognostic statements were "He will definitely survive" and "He will definitely not survive."

There also were three unequivocal numerical prognostic statements: "He has a 90% chance of surviving," "He has a 50% chance of surviving," and "He has a 5% chance of surviving."

Only twelve surrogate decision makers (15% of the entire group) interpreted the three numerical prognostic statements accurately. Almost as many – 13% –interpreted all three numerical prognostic statements more optimistically than they actually were.

Most surrogates interpreted the statement of a low risk of death ("90% chance of surviving") accurately, but severely misinterpreted the statements of a median or high risk of death. Forty percent thought that "a 50% chance of surviving" meant that the patient was likely to survive, and 65% thought that "a 5% chance of surviving" meant that the patient was likely to survive.

No surrogates interpreted any of the numerical prognostic statements more pessimistically than they actually were.

Some experts have advocated using straightforward, numerical language when communicating medical risk to surrogate decision makers, but these findings clearly show that numbers are not straightforward to everyone and are frequently misinterpreted, Dr. Zier and his associates said (Ann. Intern. Med. 2012;156:360-6).

In the second phase of this study, 15 subjects whose interpretations of prognostic statements had been particularly off-base were interviewed about why there was such a discrepancy between what the physician said and what the subject thought was meant.

Seven of the 15 said they were unaware that almost all their interpretations were overly optimistic. These subjects were surprised when it was pointed out to them and couldn’t offer of an explanation.

The other eight surrogate decision makers gave four reasons for their "optimism bias."

Some said they intentionally expressed optimism as long as there was any hope whatsoever. This may represent a coping strategy to help surrogates deal with having a critically ill loved one. Or it may represent "magical thinking" in which people believe their positive thoughts and expectations can actually improve the patient’s outcome, the researchers said.

Other surrogate decision makers said they believed their loved one was exceptional and wouldn’t die because of an unusual will to live and ability to survive. This "may represent a cognitive bias known as illusory superiority, unrealistic optimism, or the ‘Lake Wobegon effect,’ a cognitive bias that leads people to overestimate, in relation to others, their likelihood of experiencing positive outcomes and avoiding negative outcomes," the investigators said.

Some study subjects said they intentionally ignored numerical probabilities and precise language, preferring to judge "the overall feeling that the doctor is conveying."

And some said they didn’t believe physicians could ever accurately predict survival. However, such skepticism about physicians’ accuracy would result in a random distribution of interpretations rather than in the systematic optimism observed here, Dr. Zier and his colleagues noted.

The findings of this study show that "clinicians who communicate with surrogate decision makers in the care of incapacitated patients should be aware of the diverse causes for discordance about prognosis." Unrealistic optimism may not be benign; it can lead to treatment decisions that do not reflect the true values of the patient but that instead serve the surrogate decision maker’s impulse toward self-protection, they added.

This study was supported by the National Heart, Lung, and Blood Institute, the Greenwall Foundation, and the University of California, Berkeley–University of California, San Francisco, Joint Medical Program.

Surrogate decision makers for incapacitated, critically ill patients systematically interpreted prognostic information as being more optimistic than it actually was, in a study published in the March 6 issue of the Annals of Internal Medicine.

These surrogate decision makers accurately interpreted prognostic information that was positive, but not prognostic information expressing a high risk of death. Instead, they showed "a systematic bias," consistently interpreting "grim" prognostic statements in an overly optimistic way, said Dr. Lucas S. Zier of the University of California, San Francisco, and his associates.

"These findings challenge the prevailing assumption in the medical literature that discordance between physicians and surrogates about prognosis is due largely to unclear disclosure by physicians or simple misunderstandings by surrogates," the investigators noted.

The results also indicate that any efforts to improve this aspect of decision making must address not just the clarity of prognostic statements but also the "emotional and psychological factors that affect how individuals process such information," they added.

"Clinicians who communicate with surrogate decision makers in the care of incapacitated patients should be aware of the diverse causes for discordance about prognosis."

Dr. Zier and his colleagues examined how surrogate decision makers interpret physicians’ statements about their loved ones’ prognosis by administering a questionnaire to 80 such surrogates who were accompanying an incapacitated patient at medical-surgical ICUs in a Veterans Affairs hospital, a tertiary academic hospital, and a public county hospital.

The questionnaire presented 16 possible prognostic statements in the language used by physicians and made it clear that these represented hypothetical clinical situations unrelated to their loved one’s cases. Study subjects were asked what exactly each prognostic statement meant to them, and used a numerical scale to demarcate the patient’s chance of survival corresponding to each prognostic statement.

Examples of general and somewhat equivocal prognostic statements included "It is very likely that he will survive," "It is very unlikely that he will die," "I am concerned that he will not survive," "It is possible he will not survive," and "He probably will not survive." Unequivocal prognostic statements were "He will definitely survive" and "He will definitely not survive."

There also were three unequivocal numerical prognostic statements: "He has a 90% chance of surviving," "He has a 50% chance of surviving," and "He has a 5% chance of surviving."

Only twelve surrogate decision makers (15% of the entire group) interpreted the three numerical prognostic statements accurately. Almost as many – 13% –interpreted all three numerical prognostic statements more optimistically than they actually were.

Most surrogates interpreted the statement of a low risk of death ("90% chance of surviving") accurately, but severely misinterpreted the statements of a median or high risk of death. Forty percent thought that "a 50% chance of surviving" meant that the patient was likely to survive, and 65% thought that "a 5% chance of surviving" meant that the patient was likely to survive.

No surrogates interpreted any of the numerical prognostic statements more pessimistically than they actually were.

Some experts have advocated using straightforward, numerical language when communicating medical risk to surrogate decision makers, but these findings clearly show that numbers are not straightforward to everyone and are frequently misinterpreted, Dr. Zier and his associates said (Ann. Intern. Med. 2012;156:360-6).

In the second phase of this study, 15 subjects whose interpretations of prognostic statements had been particularly off-base were interviewed about why there was such a discrepancy between what the physician said and what the subject thought was meant.

Seven of the 15 said they were unaware that almost all their interpretations were overly optimistic. These subjects were surprised when it was pointed out to them and couldn’t offer of an explanation.

The other eight surrogate decision makers gave four reasons for their "optimism bias."

Some said they intentionally expressed optimism as long as there was any hope whatsoever. This may represent a coping strategy to help surrogates deal with having a critically ill loved one. Or it may represent "magical thinking" in which people believe their positive thoughts and expectations can actually improve the patient’s outcome, the researchers said.

Other surrogate decision makers said they believed their loved one was exceptional and wouldn’t die because of an unusual will to live and ability to survive. This "may represent a cognitive bias known as illusory superiority, unrealistic optimism, or the ‘Lake Wobegon effect,’ a cognitive bias that leads people to overestimate, in relation to others, their likelihood of experiencing positive outcomes and avoiding negative outcomes," the investigators said.

Some study subjects said they intentionally ignored numerical probabilities and precise language, preferring to judge "the overall feeling that the doctor is conveying."

And some said they didn’t believe physicians could ever accurately predict survival. However, such skepticism about physicians’ accuracy would result in a random distribution of interpretations rather than in the systematic optimism observed here, Dr. Zier and his colleagues noted.

The findings of this study show that "clinicians who communicate with surrogate decision makers in the care of incapacitated patients should be aware of the diverse causes for discordance about prognosis." Unrealistic optimism may not be benign; it can lead to treatment decisions that do not reflect the true values of the patient but that instead serve the surrogate decision maker’s impulse toward self-protection, they added.

This study was supported by the National Heart, Lung, and Blood Institute, the Greenwall Foundation, and the University of California, Berkeley–University of California, San Francisco, Joint Medical Program.