Mary Ann Moon

Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.

"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.

After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.

These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.

Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.

Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.

In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.

The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.

A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.

The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.

Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.

The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).

The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.

The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.

The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.

Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.

The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.

The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.

This study was funded by Amgen and UCB Pharma, makers of romosozumab. Dr. McClung reported receiving fees and honoraria from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott, and his associates reported ties to numerous industry sources.

Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.

"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.

After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.

These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.

Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.

Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.

In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.

The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.

A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.

The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.

Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.

The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).

The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.

The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.

The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.

Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.

The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.

The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.

This study was funded by Amgen and UCB Pharma, makers of romosozumab. Dr. McClung reported receiving fees and honoraria from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott, and his associates reported ties to numerous industry sources.

Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.

"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.

After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.

These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.

Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.

Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.

In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.

The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.

A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.

The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.

Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.

The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).

The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.

The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.

The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.

Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.

The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.

The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.

This study was funded by Amgen and UCB Pharma, makers of romosozumab. Dr. McClung reported receiving fees and honoraria from Amgen, Eli Lilly, Merck, Novartis, and Warner Chilcott, and his associates reported ties to numerous industry sources.

Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor and a rapid onset of severe, refractory seizures or status epilepticus in a series of six patients.

It appears that in affected patients these antibodies cause a selective reduction of clusters of gamma-aminobutyric acid-A receptor (GABA_AR) at the synapses. Unlike the GABA_B receptor, the GABA_AR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.

The investigators first noted the disorder in two patients seen at their medical center within 4 months of each other. Both presented with encephalitis and severe, refractory seizures, and both showed serum and cerebrospinal fluid (CSF) cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. "The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunological information from patients with similar symptoms," they wrote.

They collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin, and found 140 who had antibodies against the same unknown rat brain neuropil antigen. They also examined samples from 75 healthy blood donors (controls) and 416 patients with a range of neurological disorders.

Four of the 140 patients, in addition to the 2 index patients, showed high titers of antibodies to the GABA_AR, whereas none of the control patients did.

Among these six patients, three were children (aged 3 years, 4 years, and 16 years) and three were adults (aged 28 years, 51 years, and 63 years). All had a rapidly progressive encephalopathy either preceded by or associated with a change in behavior or level of cognition. All developed refractory seizures, and five had status epilepticus.

Five of the six had at least one CSF abnormality.

All six had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from those seen in other forms of autoimmune encephalitis, the researchers noted (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(13)70299-0]).

All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.

This new form of encephalitis was not associated with any underlying tumor. In contrast, up to 60% of patients with GABA_BR antibodies are found to have underlying small-cell lung cancer.

In addition to the GABA_AR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABA_BR antibodies. This indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation. Further supporting that connection, one of the six patients had a history of idiopathic thrombocytopenic purpura and another had a history of Hodgkin’s lymphoma, the investigators said.

Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed "substantial recovery," but 3 years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received both immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus.

In addition to these 6 patients who had high titers of GABA_AR antibodies, another 12 from the 140 global cases had low but still detectable levels of GABA_AR antibodies. Most of the 12 also had low titers of other antibodies, which "could explain the broader range of symptoms in this group."

Of these 12 patients, 6 presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.

These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin, with MRI and CSF abnormalities suggestive of an inflammatory process, should be tested for GABA_AR antibodies, Petit-Pedrol and associates said.

In addition, "future studies should establish, in a prospective manner, the incidence of serum and CSF GABA_AR antibodies in patients with seizures or status epilepticus, opsoclonus-myoclonus, and stiff-person syndrome," they said.

"Whether these antibodies might also have a role in milder syndromes, or perhaps in cryptogenic epilepsy, warrants further study," Dr. Lawrence J. Hirsch wrote in an editorial accompanying the report (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(14)70013-4]).

This preliminary study could not determine which, if any, antiepileptic drugs might be effective, nor which immunotherapies might be helpful. Future research should address those issues as well, said Dr. Hirsch of the department of neurology at Yale University, New Haven, Conn. He had no disclosures.

This study was supported by the Instituto Carlos III, the National Institutes of Health, a McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, the Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research, and the Dutch Epilepsy Foundation. Two authors reported holding patents or filing patents for various antibody diagnostic tests, including GABA_AR, and GABA_BR, and also reported receiving research grant support from Euroimmun. Another author received a travel grant for lecturing in India from Sun Pharma, India. The other authors reported having no disclosures.

Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor and a rapid onset of severe, refractory seizures or status epilepticus in a series of six patients.

It appears that in affected patients these antibodies cause a selective reduction of clusters of gamma-aminobutyric acid-A receptor (GABA_AR) at the synapses. Unlike the GABA_B receptor, the GABA_AR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.

The investigators first noted the disorder in two patients seen at their medical center within 4 months of each other. Both presented with encephalitis and severe, refractory seizures, and both showed serum and cerebrospinal fluid (CSF) cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. "The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunological information from patients with similar symptoms," they wrote.

They collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin, and found 140 who had antibodies against the same unknown rat brain neuropil antigen. They also examined samples from 75 healthy blood donors (controls) and 416 patients with a range of neurological disorders.

Four of the 140 patients, in addition to the 2 index patients, showed high titers of antibodies to the GABA_AR, whereas none of the control patients did.

Among these six patients, three were children (aged 3 years, 4 years, and 16 years) and three were adults (aged 28 years, 51 years, and 63 years). All had a rapidly progressive encephalopathy either preceded by or associated with a change in behavior or level of cognition. All developed refractory seizures, and five had status epilepticus.

Five of the six had at least one CSF abnormality.

All six had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from those seen in other forms of autoimmune encephalitis, the researchers noted (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(13)70299-0]).

All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.

This new form of encephalitis was not associated with any underlying tumor. In contrast, up to 60% of patients with GABA_BR antibodies are found to have underlying small-cell lung cancer.

In addition to the GABA_AR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABA_BR antibodies. This indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation. Further supporting that connection, one of the six patients had a history of idiopathic thrombocytopenic purpura and another had a history of Hodgkin’s lymphoma, the investigators said.

Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed "substantial recovery," but 3 years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received both immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus.

In addition to these 6 patients who had high titers of GABA_AR antibodies, another 12 from the 140 global cases had low but still detectable levels of GABA_AR antibodies. Most of the 12 also had low titers of other antibodies, which "could explain the broader range of symptoms in this group."

Of these 12 patients, 6 presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.

These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin, with MRI and CSF abnormalities suggestive of an inflammatory process, should be tested for GABA_AR antibodies, Petit-Pedrol and associates said.

In addition, "future studies should establish, in a prospective manner, the incidence of serum and CSF GABA_AR antibodies in patients with seizures or status epilepticus, opsoclonus-myoclonus, and stiff-person syndrome," they said.

"Whether these antibodies might also have a role in milder syndromes, or perhaps in cryptogenic epilepsy, warrants further study," Dr. Lawrence J. Hirsch wrote in an editorial accompanying the report (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(14)70013-4]).

This preliminary study could not determine which, if any, antiepileptic drugs might be effective, nor which immunotherapies might be helpful. Future research should address those issues as well, said Dr. Hirsch of the department of neurology at Yale University, New Haven, Conn. He had no disclosures.

This study was supported by the Instituto Carlos III, the National Institutes of Health, a McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, the Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research, and the Dutch Epilepsy Foundation. Two authors reported holding patents or filing patents for various antibody diagnostic tests, including GABA_AR, and GABA_BR, and also reported receiving research grant support from Euroimmun. Another author received a travel grant for lecturing in India from Sun Pharma, India. The other authors reported having no disclosures.

Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor and a rapid onset of severe, refractory seizures or status epilepticus in a series of six patients.

It appears that in affected patients these antibodies cause a selective reduction of clusters of gamma-aminobutyric acid-A receptor (GABA_AR) at the synapses. Unlike the GABA_B receptor, the GABA_AR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.

The investigators first noted the disorder in two patients seen at their medical center within 4 months of each other. Both presented with encephalitis and severe, refractory seizures, and both showed serum and cerebrospinal fluid (CSF) cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. "The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunological information from patients with similar symptoms," they wrote.

They collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin, and found 140 who had antibodies against the same unknown rat brain neuropil antigen. They also examined samples from 75 healthy blood donors (controls) and 416 patients with a range of neurological disorders.

Four of the 140 patients, in addition to the 2 index patients, showed high titers of antibodies to the GABA_AR, whereas none of the control patients did.

Among these six patients, three were children (aged 3 years, 4 years, and 16 years) and three were adults (aged 28 years, 51 years, and 63 years). All had a rapidly progressive encephalopathy either preceded by or associated with a change in behavior or level of cognition. All developed refractory seizures, and five had status epilepticus.

Five of the six had at least one CSF abnormality.

All six had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from those seen in other forms of autoimmune encephalitis, the researchers noted (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(13)70299-0]).

All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.

This new form of encephalitis was not associated with any underlying tumor. In contrast, up to 60% of patients with GABA_BR antibodies are found to have underlying small-cell lung cancer.

In addition to the GABA_AR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABA_BR antibodies. This indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation. Further supporting that connection, one of the six patients had a history of idiopathic thrombocytopenic purpura and another had a history of Hodgkin’s lymphoma, the investigators said.

Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed "substantial recovery," but 3 years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received both immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus.

In addition to these 6 patients who had high titers of GABA_AR antibodies, another 12 from the 140 global cases had low but still detectable levels of GABA_AR antibodies. Most of the 12 also had low titers of other antibodies, which "could explain the broader range of symptoms in this group."

Of these 12 patients, 6 presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.

These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin, with MRI and CSF abnormalities suggestive of an inflammatory process, should be tested for GABA_AR antibodies, Petit-Pedrol and associates said.

In addition, "future studies should establish, in a prospective manner, the incidence of serum and CSF GABA_AR antibodies in patients with seizures or status epilepticus, opsoclonus-myoclonus, and stiff-person syndrome," they said.

"Whether these antibodies might also have a role in milder syndromes, or perhaps in cryptogenic epilepsy, warrants further study," Dr. Lawrence J. Hirsch wrote in an editorial accompanying the report (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(14)70013-4]).

This preliminary study could not determine which, if any, antiepileptic drugs might be effective, nor which immunotherapies might be helpful. Future research should address those issues as well, said Dr. Hirsch of the department of neurology at Yale University, New Haven, Conn. He had no disclosures.

This study was supported by the Instituto Carlos III, the National Institutes of Health, a McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, the Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research, and the Dutch Epilepsy Foundation. Two authors reported holding patents or filing patents for various antibody diagnostic tests, including GABA_AR, and GABA_BR, and also reported receiving research grant support from Euroimmun. Another author received a travel grant for lecturing in India from Sun Pharma, India. The other authors reported having no disclosures.

Exam-room posters declaring a clinician’s commitment to make appropriate antibiotics prescriptions may be a simple, low-cost approach to reducing inappropriate use of antibiotics for acute respiratory infections, according to a report published online Jan. 27 in JAMA Internal Medicine.

Compared with standard practice, the intervention reduced inappropriate prescribing by 20% but had no effect on appropriate prescribing of antibiotics among 11 physicians and three nurse practitioners treating acute respiratory infection at five outpatient primary care clinics. The improvement is comparable to that reported previously for more intensive and expensive interventions, said Daniella Meeker, Ph.D., of RAND Corp., Santa Monica, Calif., and her associates (JAMA Intern. Med. 2014 [doi:10.1001/jamainternmed.2013.14191]).

© Fuse/Thinkstock

If these results were extrapolated to the entire United States, the intervention "could eliminate 2.6 million unnecessary antibiotic prescriptions and save $70.4 million annually on drug costs alone," the investigators noted.

"To encourage more judicious use of antibiotics, we designed an intervention that takes advantage of clinicians’ desire to be consistent with their pubic commitments," Dr. Meeker and her colleagues said. "We developed a ... behavioral ‘nudge’ in the form of a public commitment device: a poster-sized letter signed by clinicians and posted in their examination rooms indicating their commitment to reducing inappropriate antibiotic use for acute respiratory infections."

"Public commitment" is a psychological principle that holds that people are much more likely to follow a course of action if they and others have publicly stated that they will do so. It was hoped that an intervention that taps into existing internal motivations would be a more subtle and effective approach than external "reeducation" programs or heavy-handed penalties such as withholding reimbursement for writing too many prescriptions.

Other public commitment approaches have proved successful at increasing participation in recycling programs, getting hotel guests to reuse their towels, increasing donations to organizations serving the disabled, and raising voting rates in elections.

The intervention was a form letter written at the eighth-grade reading level in both English and Spanish and displayed on a poster hung in the exam room. The poster explained why antibiotics were not appropriate for many acute respiratory infections, and it emphasized the clinician’s commitment to follow guidelines for appropriate prescribing. The poster included a photo of the clinician and his or her signature on the letter.

For this study, the posters were used for 12-week periods by clinicians at five Los Angeles community clinics and were used in such a way that an entire 1-year flu cycle was covered. The medical records, including antibiotic prescriptions, were reviewed for all adults seen by the participating clinicians and diagnosed as having an acute respiratory infection for which antibiotics may or may not have been appropriate.

The 14 participating clinicians were randomly assigned to either the intervention (7 using the study condition) or to standard practice (7 control subjects). Eleven of these clinicians were women, and 3 were men. The mean age was 54 years, and the mean duration in practice was 18 years.

A total of 449 patients were included in the intervention group and 505 in the control group. Most (77%) were women, and their mean age was 48 years. Approximately 43% were uninsured.

Diagnoses included acute nasopharyngitis (12 visits), acute laryngitis without obstruction (4 visits), acute laryngopharyngitis (3 visits), acute bronchitis (125 visits), acute upper respiratory tract infections of other sites (10 visits) acute upper respiratory tract infections not otherwise specified (448 visits), bronchitis not specified as acute or chronic (181 visits), nonstreptococcal pharyngitis (161 visits), and influenza with other respiratory manifestations (10 visits).

At baseline, before the intervention was employed, the inappropriate-prescribing rate was 43.5% for clinicians in the intervention group and 42.8% for those in the control group, a nonsignificant difference. During the 12-week intervention period, the inappropriate-prescribing rate dropped to 33.7% for the intervention group but rose to 52.7% for the control group.

That represents a 19.7% reduction for the intervention group, compared with the control group, Dr. Meeker and her associates said.

There was no evidence that the participating clinicians may have undermined the intervention by shifting diagnosis codes away from those that don’t require antibiotics and toward those that might. Diagnostic codes did not change appreciably between baseline and intervention periods in either study group, the researchers said.

Moreover, the rate of appropriate antibiotic prescribing did not change during the intervention period, indicating that clinicians continued to prescribe antibiotics when they were indicated and only stopped prescribing them when they were truly unnecessary.

The intervention, based on a psychological principle, was more effective at curtailing inappropriate prescription of antibiotics than are many others currently in use. Those others typically are based on a model holding that clinicians will change their behavior simply because it makes rational sense to do so, and they use techniques such as education, awareness training, electronic alerts or reminders, and financial incentives, the researchers explained.

"[Our] findings support an alternative model suggesting that clinicians are influenced by interpersonal factors within the context of patient care – in particular, a desire to remain consistent with a prior public commitment," Dr. Meeker and her associates said.

They added that their study was limited because it covered a relatively small geographic area, involved a small number of clinicians, and was of short duration. Moreover, even though the intervention succeeded in reducing inappropriate prescribing significantly, the rate of inappropriate prescribing still remained high among the study participants.

The National Institutes of Health and the National Institute on Aging funded the study. Dr. Meeker and her associates reported no relevant financial conflicts of interest.

Exam-room posters declaring a clinician’s commitment to make appropriate antibiotics prescriptions may be a simple, low-cost approach to reducing inappropriate use of antibiotics for acute respiratory infections, according to a report published online Jan. 27 in JAMA Internal Medicine.

Compared with standard practice, the intervention reduced inappropriate prescribing by 20% but had no effect on appropriate prescribing of antibiotics among 11 physicians and three nurse practitioners treating acute respiratory infection at five outpatient primary care clinics. The improvement is comparable to that reported previously for more intensive and expensive interventions, said Daniella Meeker, Ph.D., of RAND Corp., Santa Monica, Calif., and her associates (JAMA Intern. Med. 2014 [doi:10.1001/jamainternmed.2013.14191]).

© Fuse/Thinkstock

If these results were extrapolated to the entire United States, the intervention "could eliminate 2.6 million unnecessary antibiotic prescriptions and save $70.4 million annually on drug costs alone," the investigators noted.

"To encourage more judicious use of antibiotics, we designed an intervention that takes advantage of clinicians’ desire to be consistent with their pubic commitments," Dr. Meeker and her colleagues said. "We developed a ... behavioral ‘nudge’ in the form of a public commitment device: a poster-sized letter signed by clinicians and posted in their examination rooms indicating their commitment to reducing inappropriate antibiotic use for acute respiratory infections."

"Public commitment" is a psychological principle that holds that people are much more likely to follow a course of action if they and others have publicly stated that they will do so. It was hoped that an intervention that taps into existing internal motivations would be a more subtle and effective approach than external "reeducation" programs or heavy-handed penalties such as withholding reimbursement for writing too many prescriptions.

Other public commitment approaches have proved successful at increasing participation in recycling programs, getting hotel guests to reuse their towels, increasing donations to organizations serving the disabled, and raising voting rates in elections.

The intervention was a form letter written at the eighth-grade reading level in both English and Spanish and displayed on a poster hung in the exam room. The poster explained why antibiotics were not appropriate for many acute respiratory infections, and it emphasized the clinician’s commitment to follow guidelines for appropriate prescribing. The poster included a photo of the clinician and his or her signature on the letter.

For this study, the posters were used for 12-week periods by clinicians at five Los Angeles community clinics and were used in such a way that an entire 1-year flu cycle was covered. The medical records, including antibiotic prescriptions, were reviewed for all adults seen by the participating clinicians and diagnosed as having an acute respiratory infection for which antibiotics may or may not have been appropriate.

The 14 participating clinicians were randomly assigned to either the intervention (7 using the study condition) or to standard practice (7 control subjects). Eleven of these clinicians were women, and 3 were men. The mean age was 54 years, and the mean duration in practice was 18 years.

A total of 449 patients were included in the intervention group and 505 in the control group. Most (77%) were women, and their mean age was 48 years. Approximately 43% were uninsured.

Diagnoses included acute nasopharyngitis (12 visits), acute laryngitis without obstruction (4 visits), acute laryngopharyngitis (3 visits), acute bronchitis (125 visits), acute upper respiratory tract infections of other sites (10 visits) acute upper respiratory tract infections not otherwise specified (448 visits), bronchitis not specified as acute or chronic (181 visits), nonstreptococcal pharyngitis (161 visits), and influenza with other respiratory manifestations (10 visits).

At baseline, before the intervention was employed, the inappropriate-prescribing rate was 43.5% for clinicians in the intervention group and 42.8% for those in the control group, a nonsignificant difference. During the 12-week intervention period, the inappropriate-prescribing rate dropped to 33.7% for the intervention group but rose to 52.7% for the control group.

That represents a 19.7% reduction for the intervention group, compared with the control group, Dr. Meeker and her associates said.

There was no evidence that the participating clinicians may have undermined the intervention by shifting diagnosis codes away from those that don’t require antibiotics and toward those that might. Diagnostic codes did not change appreciably between baseline and intervention periods in either study group, the researchers said.

Moreover, the rate of appropriate antibiotic prescribing did not change during the intervention period, indicating that clinicians continued to prescribe antibiotics when they were indicated and only stopped prescribing them when they were truly unnecessary.

The intervention, based on a psychological principle, was more effective at curtailing inappropriate prescription of antibiotics than are many others currently in use. Those others typically are based on a model holding that clinicians will change their behavior simply because it makes rational sense to do so, and they use techniques such as education, awareness training, electronic alerts or reminders, and financial incentives, the researchers explained.

"[Our] findings support an alternative model suggesting that clinicians are influenced by interpersonal factors within the context of patient care – in particular, a desire to remain consistent with a prior public commitment," Dr. Meeker and her associates said.

They added that their study was limited because it covered a relatively small geographic area, involved a small number of clinicians, and was of short duration. Moreover, even though the intervention succeeded in reducing inappropriate prescribing significantly, the rate of inappropriate prescribing still remained high among the study participants.

The National Institutes of Health and the National Institute on Aging funded the study. Dr. Meeker and her associates reported no relevant financial conflicts of interest.

Exam-room posters declaring a clinician’s commitment to make appropriate antibiotics prescriptions may be a simple, low-cost approach to reducing inappropriate use of antibiotics for acute respiratory infections, according to a report published online Jan. 27 in JAMA Internal Medicine.

Compared with standard practice, the intervention reduced inappropriate prescribing by 20% but had no effect on appropriate prescribing of antibiotics among 11 physicians and three nurse practitioners treating acute respiratory infection at five outpatient primary care clinics. The improvement is comparable to that reported previously for more intensive and expensive interventions, said Daniella Meeker, Ph.D., of RAND Corp., Santa Monica, Calif., and her associates (JAMA Intern. Med. 2014 [doi:10.1001/jamainternmed.2013.14191]).

© Fuse/Thinkstock

If these results were extrapolated to the entire United States, the intervention "could eliminate 2.6 million unnecessary antibiotic prescriptions and save $70.4 million annually on drug costs alone," the investigators noted.

"To encourage more judicious use of antibiotics, we designed an intervention that takes advantage of clinicians’ desire to be consistent with their pubic commitments," Dr. Meeker and her colleagues said. "We developed a ... behavioral ‘nudge’ in the form of a public commitment device: a poster-sized letter signed by clinicians and posted in their examination rooms indicating their commitment to reducing inappropriate antibiotic use for acute respiratory infections."

"Public commitment" is a psychological principle that holds that people are much more likely to follow a course of action if they and others have publicly stated that they will do so. It was hoped that an intervention that taps into existing internal motivations would be a more subtle and effective approach than external "reeducation" programs or heavy-handed penalties such as withholding reimbursement for writing too many prescriptions.

Other public commitment approaches have proved successful at increasing participation in recycling programs, getting hotel guests to reuse their towels, increasing donations to organizations serving the disabled, and raising voting rates in elections.

The intervention was a form letter written at the eighth-grade reading level in both English and Spanish and displayed on a poster hung in the exam room. The poster explained why antibiotics were not appropriate for many acute respiratory infections, and it emphasized the clinician’s commitment to follow guidelines for appropriate prescribing. The poster included a photo of the clinician and his or her signature on the letter.

For this study, the posters were used for 12-week periods by clinicians at five Los Angeles community clinics and were used in such a way that an entire 1-year flu cycle was covered. The medical records, including antibiotic prescriptions, were reviewed for all adults seen by the participating clinicians and diagnosed as having an acute respiratory infection for which antibiotics may or may not have been appropriate.

The 14 participating clinicians were randomly assigned to either the intervention (7 using the study condition) or to standard practice (7 control subjects). Eleven of these clinicians were women, and 3 were men. The mean age was 54 years, and the mean duration in practice was 18 years.

A total of 449 patients were included in the intervention group and 505 in the control group. Most (77%) were women, and their mean age was 48 years. Approximately 43% were uninsured.

Diagnoses included acute nasopharyngitis (12 visits), acute laryngitis without obstruction (4 visits), acute laryngopharyngitis (3 visits), acute bronchitis (125 visits), acute upper respiratory tract infections of other sites (10 visits) acute upper respiratory tract infections not otherwise specified (448 visits), bronchitis not specified as acute or chronic (181 visits), nonstreptococcal pharyngitis (161 visits), and influenza with other respiratory manifestations (10 visits).

At baseline, before the intervention was employed, the inappropriate-prescribing rate was 43.5% for clinicians in the intervention group and 42.8% for those in the control group, a nonsignificant difference. During the 12-week intervention period, the inappropriate-prescribing rate dropped to 33.7% for the intervention group but rose to 52.7% for the control group.

That represents a 19.7% reduction for the intervention group, compared with the control group, Dr. Meeker and her associates said.

There was no evidence that the participating clinicians may have undermined the intervention by shifting diagnosis codes away from those that don’t require antibiotics and toward those that might. Diagnostic codes did not change appreciably between baseline and intervention periods in either study group, the researchers said.

Moreover, the rate of appropriate antibiotic prescribing did not change during the intervention period, indicating that clinicians continued to prescribe antibiotics when they were indicated and only stopped prescribing them when they were truly unnecessary.

The intervention, based on a psychological principle, was more effective at curtailing inappropriate prescription of antibiotics than are many others currently in use. Those others typically are based on a model holding that clinicians will change their behavior simply because it makes rational sense to do so, and they use techniques such as education, awareness training, electronic alerts or reminders, and financial incentives, the researchers explained.

"[Our] findings support an alternative model suggesting that clinicians are influenced by interpersonal factors within the context of patient care – in particular, a desire to remain consistent with a prior public commitment," Dr. Meeker and her associates said.

They added that their study was limited because it covered a relatively small geographic area, involved a small number of clinicians, and was of short duration. Moreover, even though the intervention succeeded in reducing inappropriate prescribing significantly, the rate of inappropriate prescribing still remained high among the study participants.

The National Institutes of Health and the National Institute on Aging funded the study. Dr. Meeker and her associates reported no relevant financial conflicts of interest.

Researchers have identified two novel panels of microRNAs that eventually might be used to screen patients for pancreatic cancer, distinguishing affected patients from healthy individuals and from people who have other diseases of the pancreas, particularly pancreatitis, according to a report published online Jan. 21 in JAMA.

The two microRNA panels were better than standard serum cancer antigen 19-9 (CA19-9) testing at identifying pancreatic cancer within the initial study cohort used to assess hundreds of microRNA candidates. However, CA19-9 had better diagnostic accuracy in the validation cohort used to replicate those results. Combining the results of either microRNA panel with CA19-9 offered the best diagnostic accuracy of all, said Dr. Nicolai A. Schultz, of the department of oncology, Herlev Hospital and Copenhagen University Hospital, and his associates (JAMA 2013;311:392-404).

The discovery may lead to earlier diagnosis of pancreatic cancer at a stage when it is more treatable. At present, only 20% of patients can be operated on with curative intent, because most already have advanced disease by the time they are diagnosed, Dr. Schultz and his colleagues said.

However, the investigators emphasized that their findings are preliminary. "Further research is necessary to understand whether these microRNAs have clinical implications as a screening test for early detection of pancreatic cancer and how much this information adds to serum CA19-9," they noted.

The investigators began their search for relevant biomarkers by screening whole blood samples for the presence of any of 754 microRNAs suspected of being expressed in circulating blood by pancreatic cancers. MicroRNAs are small (17-25 nucleotides long), noncoding, single-stranded RNAs that promote oncogenesis by inhibiting the expression of tumor suppressor genes or by upregulating the expression of oncogenes. They are active in the pathogenesis, progression, and metastasis of pancreatic cancer.

The blood samples had been taken from 409 patients with histologically verified pancreatic cancer and 337 control patients, consisting of 25 patients with chronic pancreatitis and 312 healthy blood donors. Samples were drawn from the pancreatic cancer patients before they underwent any treatment; 44 had resectable tumors, and 365 had unresectable tumors.

The microRNA panels were identified and tested in a three-step process using discovery, training, and validation cohorts of patients.

In the discovery cohort, 38 microRNAs were found to have the potential to distinguish pancreatic cancer patients from other participants. Thirteen of those microRNAs were the strongest predictors and were used to develop the two diagnostic panels, which were then tested in the validation cohort.

The first diagnostic panel, termed index I, comprised 4 microRNAs, and the second panel, index II, comprised 10 microRNAs. Both panels correctly diagnosed pancreatic cancer in 85% of affected patients and correctly diagnosed chronic pancreatitis in 29% of affected patients.

Among control patients, index I correctly ruled out pancreatic disease in 48% and index II in 54%. When CA19-9 results were added to the panel results, index I correctly ruled out pancreatic disease in 98% of the control patients, and index II did so in 89%.

Thus, "the indices do achieve some separation of pancreatic cancer from healthy participants, but not a complete separation," Dr. Schultz and his associates said.

"When this microRNA biomarker study was designed in 2008, the aim was to identify microRNAs in whole blood that could identify pancreatic cancer (local, locally advanced, and metastatic) in individuals thought to be healthy," the investigators explained. "We first wanted to test the extremes (i.e., patients with known pancreatic cancer vs healthy blood donors), because if panels of microRNA could not differentiate patients with . . . high tumor burden from these healthy individuals, it would be difficult to develop a diagnostic microRNA test for patients with small tumors and low-stage cancer.

"In the future, we will assess the accuracy of indices I and II in combination with serum CA19-9 in large cohorts of patients either seen by a family physician or referred to hospitals on suspicion of cancer ... and assess whether it is possible to identify patients with pancreatic cancer at an early stage," Dr. Schultz and his associates said.

This study was supported by Herlev Hospital; the Danish Ministry of Science, Technology, and Innovation; the Danish Cancer Society; Region Hovedstadens forskinings fond til Sundhedsforskning; Aase og Ejnar Danielsens Fond; and Prosektor Axel Søeborg Ohlsen og Else Søeborg Ohlsen Mindelegat. Dr. Schultz and his associates reported holding a European patent application submitted by Copenhagen University Hospital.

Researchers have identified two novel panels of microRNAs that eventually might be used to screen patients for pancreatic cancer, distinguishing affected patients from healthy individuals and from people who have other diseases of the pancreas, particularly pancreatitis, according to a report published online Jan. 21 in JAMA.

The two microRNA panels were better than standard serum cancer antigen 19-9 (CA19-9) testing at identifying pancreatic cancer within the initial study cohort used to assess hundreds of microRNA candidates. However, CA19-9 had better diagnostic accuracy in the validation cohort used to replicate those results. Combining the results of either microRNA panel with CA19-9 offered the best diagnostic accuracy of all, said Dr. Nicolai A. Schultz, of the department of oncology, Herlev Hospital and Copenhagen University Hospital, and his associates (JAMA 2013;311:392-404).

The discovery may lead to earlier diagnosis of pancreatic cancer at a stage when it is more treatable. At present, only 20% of patients can be operated on with curative intent, because most already have advanced disease by the time they are diagnosed, Dr. Schultz and his colleagues said.

However, the investigators emphasized that their findings are preliminary. "Further research is necessary to understand whether these microRNAs have clinical implications as a screening test for early detection of pancreatic cancer and how much this information adds to serum CA19-9," they noted.

The investigators began their search for relevant biomarkers by screening whole blood samples for the presence of any of 754 microRNAs suspected of being expressed in circulating blood by pancreatic cancers. MicroRNAs are small (17-25 nucleotides long), noncoding, single-stranded RNAs that promote oncogenesis by inhibiting the expression of tumor suppressor genes or by upregulating the expression of oncogenes. They are active in the pathogenesis, progression, and metastasis of pancreatic cancer.

The blood samples had been taken from 409 patients with histologically verified pancreatic cancer and 337 control patients, consisting of 25 patients with chronic pancreatitis and 312 healthy blood donors. Samples were drawn from the pancreatic cancer patients before they underwent any treatment; 44 had resectable tumors, and 365 had unresectable tumors.

The microRNA panels were identified and tested in a three-step process using discovery, training, and validation cohorts of patients.

In the discovery cohort, 38 microRNAs were found to have the potential to distinguish pancreatic cancer patients from other participants. Thirteen of those microRNAs were the strongest predictors and were used to develop the two diagnostic panels, which were then tested in the validation cohort.

The first diagnostic panel, termed index I, comprised 4 microRNAs, and the second panel, index II, comprised 10 microRNAs. Both panels correctly diagnosed pancreatic cancer in 85% of affected patients and correctly diagnosed chronic pancreatitis in 29% of affected patients.

Among control patients, index I correctly ruled out pancreatic disease in 48% and index II in 54%. When CA19-9 results were added to the panel results, index I correctly ruled out pancreatic disease in 98% of the control patients, and index II did so in 89%.

Thus, "the indices do achieve some separation of pancreatic cancer from healthy participants, but not a complete separation," Dr. Schultz and his associates said.

"When this microRNA biomarker study was designed in 2008, the aim was to identify microRNAs in whole blood that could identify pancreatic cancer (local, locally advanced, and metastatic) in individuals thought to be healthy," the investigators explained. "We first wanted to test the extremes (i.e., patients with known pancreatic cancer vs healthy blood donors), because if panels of microRNA could not differentiate patients with . . . high tumor burden from these healthy individuals, it would be difficult to develop a diagnostic microRNA test for patients with small tumors and low-stage cancer.

"In the future, we will assess the accuracy of indices I and II in combination with serum CA19-9 in large cohorts of patients either seen by a family physician or referred to hospitals on suspicion of cancer ... and assess whether it is possible to identify patients with pancreatic cancer at an early stage," Dr. Schultz and his associates said.

This study was supported by Herlev Hospital; the Danish Ministry of Science, Technology, and Innovation; the Danish Cancer Society; Region Hovedstadens forskinings fond til Sundhedsforskning; Aase og Ejnar Danielsens Fond; and Prosektor Axel Søeborg Ohlsen og Else Søeborg Ohlsen Mindelegat. Dr. Schultz and his associates reported holding a European patent application submitted by Copenhagen University Hospital.

Researchers have identified two novel panels of microRNAs that eventually might be used to screen patients for pancreatic cancer, distinguishing affected patients from healthy individuals and from people who have other diseases of the pancreas, particularly pancreatitis, according to a report published online Jan. 21 in JAMA.

The two microRNA panels were better than standard serum cancer antigen 19-9 (CA19-9) testing at identifying pancreatic cancer within the initial study cohort used to assess hundreds of microRNA candidates. However, CA19-9 had better diagnostic accuracy in the validation cohort used to replicate those results. Combining the results of either microRNA panel with CA19-9 offered the best diagnostic accuracy of all, said Dr. Nicolai A. Schultz, of the department of oncology, Herlev Hospital and Copenhagen University Hospital, and his associates (JAMA 2013;311:392-404).

The discovery may lead to earlier diagnosis of pancreatic cancer at a stage when it is more treatable. At present, only 20% of patients can be operated on with curative intent, because most already have advanced disease by the time they are diagnosed, Dr. Schultz and his colleagues said.

However, the investigators emphasized that their findings are preliminary. "Further research is necessary to understand whether these microRNAs have clinical implications as a screening test for early detection of pancreatic cancer and how much this information adds to serum CA19-9," they noted.

The investigators began their search for relevant biomarkers by screening whole blood samples for the presence of any of 754 microRNAs suspected of being expressed in circulating blood by pancreatic cancers. MicroRNAs are small (17-25 nucleotides long), noncoding, single-stranded RNAs that promote oncogenesis by inhibiting the expression of tumor suppressor genes or by upregulating the expression of oncogenes. They are active in the pathogenesis, progression, and metastasis of pancreatic cancer.

The blood samples had been taken from 409 patients with histologically verified pancreatic cancer and 337 control patients, consisting of 25 patients with chronic pancreatitis and 312 healthy blood donors. Samples were drawn from the pancreatic cancer patients before they underwent any treatment; 44 had resectable tumors, and 365 had unresectable tumors.

The microRNA panels were identified and tested in a three-step process using discovery, training, and validation cohorts of patients.

In the discovery cohort, 38 microRNAs were found to have the potential to distinguish pancreatic cancer patients from other participants. Thirteen of those microRNAs were the strongest predictors and were used to develop the two diagnostic panels, which were then tested in the validation cohort.

The first diagnostic panel, termed index I, comprised 4 microRNAs, and the second panel, index II, comprised 10 microRNAs. Both panels correctly diagnosed pancreatic cancer in 85% of affected patients and correctly diagnosed chronic pancreatitis in 29% of affected patients.

Among control patients, index I correctly ruled out pancreatic disease in 48% and index II in 54%. When CA19-9 results were added to the panel results, index I correctly ruled out pancreatic disease in 98% of the control patients, and index II did so in 89%.

Thus, "the indices do achieve some separation of pancreatic cancer from healthy participants, but not a complete separation," Dr. Schultz and his associates said.

"When this microRNA biomarker study was designed in 2008, the aim was to identify microRNAs in whole blood that could identify pancreatic cancer (local, locally advanced, and metastatic) in individuals thought to be healthy," the investigators explained. "We first wanted to test the extremes (i.e., patients with known pancreatic cancer vs healthy blood donors), because if panels of microRNA could not differentiate patients with . . . high tumor burden from these healthy individuals, it would be difficult to develop a diagnostic microRNA test for patients with small tumors and low-stage cancer.

"In the future, we will assess the accuracy of indices I and II in combination with serum CA19-9 in large cohorts of patients either seen by a family physician or referred to hospitals on suspicion of cancer ... and assess whether it is possible to identify patients with pancreatic cancer at an early stage," Dr. Schultz and his associates said.

This study was supported by Herlev Hospital; the Danish Ministry of Science, Technology, and Innovation; the Danish Cancer Society; Region Hovedstadens forskinings fond til Sundhedsforskning; Aase og Ejnar Danielsens Fond; and Prosektor Axel Søeborg Ohlsen og Else Søeborg Ohlsen Mindelegat. Dr. Schultz and his associates reported holding a European patent application submitted by Copenhagen University Hospital.

Two variations of the Mediterranean diet were associated with a lower risk of peripheral artery disease, compared with a control diet, in a secondary analysis of the PREDIMED randomized clinical trial, as reported in a Research Letter to the editor in the January 22/29 issue of JAMA.

Among older adults at high cardiovascular risk, following a Mediterranean diet supplemented by extra virgin olive oil (EVOO) for a median of 5 years was associated with a reduced risk of PAD (hazard ratio, 0.34), compared with the control diet. Similarly, following a Mediterranean diet supplemented with extra nuts was associated with a reduced risk of PAD (HR, 0.50), said Miguel Ruiz-Canela, Ph.D., of the department of preventive medicine and public health, University of Navarra, Pamplona (Spain), and his associates in the PREDIMED (Prevencion con Dieta Mediterranea) trial.

©Alex Bramwell/thinkstockphotos

The number needed to treat to prevent one case of PAD was 336 for the Mediterranean diet plus EVOO and 448 for the Mediterranean diet plus extra nuts, they said (JAMA 2014;311:415-7).

The PREDIMED investigators enrolled men aged 55-80 years and women aged 60-80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least three cardiovascular risk factors. Those patients were randomly assigned to follow a Mediterranean diet supplemented with EVOO (1,154 patients), a Mediterranean diet supplemented with mixed walnuts, almonds, and hazelnuts (1,240 patients), or a diet advising reduced intake of all types of fat (1,147 control patients).

PREDIMED’s primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes: The hazard ratios were 0.70 and 0.72 for the Mediterranean diet with EVOO and the Mediterranean diet with nuts, respectively, compared with controls (N. Engl. J. Med. 2013;368:1279-90).

The investigators cautioned that this must be considered an exploratory analysis, because PAD wasn’t a prespecified endpoint of PREDIMED. "Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn," they noted.

"We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD," they added.

This study was supported by numerous government and university sources in Spain. Supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and LaMorella Nuts. Dr. Ruiz-Canela reported no financial conflicts of interest; one of his associates reported receiving funding from and serving as a consultant to the International Nut Council.

Two variations of the Mediterranean diet were associated with a lower risk of peripheral artery disease, compared with a control diet, in a secondary analysis of the PREDIMED randomized clinical trial, as reported in a Research Letter to the editor in the January 22/29 issue of JAMA.

Among older adults at high cardiovascular risk, following a Mediterranean diet supplemented by extra virgin olive oil (EVOO) for a median of 5 years was associated with a reduced risk of PAD (hazard ratio, 0.34), compared with the control diet. Similarly, following a Mediterranean diet supplemented with extra nuts was associated with a reduced risk of PAD (HR, 0.50), said Miguel Ruiz-Canela, Ph.D., of the department of preventive medicine and public health, University of Navarra, Pamplona (Spain), and his associates in the PREDIMED (Prevencion con Dieta Mediterranea) trial.

©Alex Bramwell/thinkstockphotos

The number needed to treat to prevent one case of PAD was 336 for the Mediterranean diet plus EVOO and 448 for the Mediterranean diet plus extra nuts, they said (JAMA 2014;311:415-7).

The PREDIMED investigators enrolled men aged 55-80 years and women aged 60-80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least three cardiovascular risk factors. Those patients were randomly assigned to follow a Mediterranean diet supplemented with EVOO (1,154 patients), a Mediterranean diet supplemented with mixed walnuts, almonds, and hazelnuts (1,240 patients), or a diet advising reduced intake of all types of fat (1,147 control patients).

PREDIMED’s primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes: The hazard ratios were 0.70 and 0.72 for the Mediterranean diet with EVOO and the Mediterranean diet with nuts, respectively, compared with controls (N. Engl. J. Med. 2013;368:1279-90).

The investigators cautioned that this must be considered an exploratory analysis, because PAD wasn’t a prespecified endpoint of PREDIMED. "Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn," they noted.

"We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD," they added.

This study was supported by numerous government and university sources in Spain. Supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and LaMorella Nuts. Dr. Ruiz-Canela reported no financial conflicts of interest; one of his associates reported receiving funding from and serving as a consultant to the International Nut Council.

Two variations of the Mediterranean diet were associated with a lower risk of peripheral artery disease, compared with a control diet, in a secondary analysis of the PREDIMED randomized clinical trial, as reported in a Research Letter to the editor in the January 22/29 issue of JAMA.

Among older adults at high cardiovascular risk, following a Mediterranean diet supplemented by extra virgin olive oil (EVOO) for a median of 5 years was associated with a reduced risk of PAD (hazard ratio, 0.34), compared with the control diet. Similarly, following a Mediterranean diet supplemented with extra nuts was associated with a reduced risk of PAD (HR, 0.50), said Miguel Ruiz-Canela, Ph.D., of the department of preventive medicine and public health, University of Navarra, Pamplona (Spain), and his associates in the PREDIMED (Prevencion con Dieta Mediterranea) trial.

©Alex Bramwell/thinkstockphotos

The number needed to treat to prevent one case of PAD was 336 for the Mediterranean diet plus EVOO and 448 for the Mediterranean diet plus extra nuts, they said (JAMA 2014;311:415-7).

The PREDIMED investigators enrolled men aged 55-80 years and women aged 60-80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least three cardiovascular risk factors. Those patients were randomly assigned to follow a Mediterranean diet supplemented with EVOO (1,154 patients), a Mediterranean diet supplemented with mixed walnuts, almonds, and hazelnuts (1,240 patients), or a diet advising reduced intake of all types of fat (1,147 control patients).

PREDIMED’s primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes: The hazard ratios were 0.70 and 0.72 for the Mediterranean diet with EVOO and the Mediterranean diet with nuts, respectively, compared with controls (N. Engl. J. Med. 2013;368:1279-90).

The investigators cautioned that this must be considered an exploratory analysis, because PAD wasn’t a prespecified endpoint of PREDIMED. "Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn," they noted.

"We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD," they added.

This study was supported by numerous government and university sources in Spain. Supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and LaMorella Nuts. Dr. Ruiz-Canela reported no financial conflicts of interest; one of his associates reported receiving funding from and serving as a consultant to the International Nut Council.

Mitral valve repair was no better than chordal-sparing mitral valve replacement in the first randomized clinical trial attempting to settle the controversy over which procedure is superior for treating functional ischemic mitral regurgitation, which was simultaneously reported at the annual scientific sessions of the American Heart Association and online in the New England Journal of Medicine.

In the past few years, the use of mitral valve repair has far exceeded that of mitral valve replacement for this indication, largely on the basis of reports that the repair procedure yields lower operative mortality, improved left ventricular function, and higher long-term survival rates. In particular, a 2011 meta-analysis found a 35% lower relative risk of death in the long term with mitral valve repair, compared with replacement, said Dr. Michael A. Acker and his associates in the Cardiothoracic Surgical Trials Network (CTSN).

But in their multicenter study directly comparing the two procedures in 251 patients with severe functional ischemic mitral regurgitation, there was no significant difference between the surgeries in left ventricular end-systolic volume index at 1 year, nor in mortality at either 1 month or 1 year.

Moreover, study participants who underwent mitral valve repair showed a disturbing excess in the rate of recurrence of mitral regurgitation at 1 year, with a rate that was 30 percentage points higher than that among patients who underwent mitral valve replacement. "This lack of durability in correction of mitral regurgitation is disconcerting, given its reported association with further progression and long-term negative outcomes," said Dr. Acker of the division of cardiovascular surgery, University of Pennsylvania, Philadelphia, and his associates.

Functional ischemic mitral regurgitation, a "high-prevalence" condition affecting an estimated 2-3 million Americans, differs from primary degenerative mitral regurgitation in that the valve leaflets themselves remain normal while the defect occurs in the myocardium. "Ischemic mitral regurgitation is a consequence of adverse left ventricular remodeling after myocardial injury, with enlargement of the left ventricular chamber and mitral annulus, apical and lateral migration of the papillary muscles, leaflet retethering, and reduced closing forces. These processes lead to malcoaptation of the leaflets and variable degrees of mitral regurgitation that can fluctuate dynamically as a function of volume status, afterload, heart rhythm, and residual ischemia," the researchers said.

Current guidelines recommend mitral valve repair or chordal-sparing mitral valve replacement for severe regurgitation unresponsive to medical therapy, but do not specify which procedure is preferred because there is no conclusive evidence demonstrating the superiority of one over the other. "Recently, the field has embraced mitral valve repair over replacement," even without such evidence, Dr. Acker and his colleagues said.

The CTSN performed this study at 22 medical centers to assess the relative benefits of the two surgeries, with 126 patients randomized to undergo mitral valve repair and 125 to undergo replacement that included complete preservation of the subvalvular apparatus.

The primary endpoint was the degree of LV reverse remodeling, as measured by the left ventricular end-systolic volume index (LVESVI) on transthoracic echocardiography, at 1 year. The mean LVESVI was not significantly different between the repair group (54.6 mL per square meter) and the replacement group (60.7 mL per square meter), reflecting decreases of 6.6 mL per square meter and 6.8 mL per square meter, respectively, the investigators said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1312808]).

The median between group difference in the change in LVESVI score after surgery also was not clinically significant. However, 32.6% of patients who underwent mitral valve repair had a recurrence of regurgitation within 1 year, compared with only 2.3% of those who had mitral valve replacement. Three patients in the repair group required reoperation, compared with none in the replacement group.

There were no significant differences in cumulative mortality, 30-day postoperative mortality, or 1-year mortality between the two groups, and no significant difference in a composite endpoint of major adverse cardiac or cerebrovascular events.

Rates of serious adverse events were similar, and the durations of hospitalization were similar between the two study groups, as were rates of readmission. All measures of quality of life and functional status on two assessment tools were similar.

"Our findings contradict much of the published literature on this topic, which reports several advantages to mitral valve repair over replacement, including lower operative mortality, improved left ventricular function, and higher rates of long-term survival," Dr. Acker and his associates noted.

The evolution of the valve replacement procedure, which now includes chordal sparing, "may account for the improved results we observed, as compared with previous studies, since the retention of the internal architectural support of the left ventricle may preserve contractile efficiency and reduce left ventricular dilatation and dysfunction," they said.

Dr. Acker reported no conflicts.

Mitral valve repair was no better than chordal-sparing mitral valve replacement in the first randomized clinical trial attempting to settle the controversy over which procedure is superior for treating functional ischemic mitral regurgitation, which was simultaneously reported at the annual scientific sessions of the American Heart Association and online in the New England Journal of Medicine.

In the past few years, the use of mitral valve repair has far exceeded that of mitral valve replacement for this indication, largely on the basis of reports that the repair procedure yields lower operative mortality, improved left ventricular function, and higher long-term survival rates. In particular, a 2011 meta-analysis found a 35% lower relative risk of death in the long term with mitral valve repair, compared with replacement, said Dr. Michael A. Acker and his associates in the Cardiothoracic Surgical Trials Network (CTSN).

But in their multicenter study directly comparing the two procedures in 251 patients with severe functional ischemic mitral regurgitation, there was no significant difference between the surgeries in left ventricular end-systolic volume index at 1 year, nor in mortality at either 1 month or 1 year.

Moreover, study participants who underwent mitral valve repair showed a disturbing excess in the rate of recurrence of mitral regurgitation at 1 year, with a rate that was 30 percentage points higher than that among patients who underwent mitral valve replacement. "This lack of durability in correction of mitral regurgitation is disconcerting, given its reported association with further progression and long-term negative outcomes," said Dr. Acker of the division of cardiovascular surgery, University of Pennsylvania, Philadelphia, and his associates.

Functional ischemic mitral regurgitation, a "high-prevalence" condition affecting an estimated 2-3 million Americans, differs from primary degenerative mitral regurgitation in that the valve leaflets themselves remain normal while the defect occurs in the myocardium. "Ischemic mitral regurgitation is a consequence of adverse left ventricular remodeling after myocardial injury, with enlargement of the left ventricular chamber and mitral annulus, apical and lateral migration of the papillary muscles, leaflet retethering, and reduced closing forces. These processes lead to malcoaptation of the leaflets and variable degrees of mitral regurgitation that can fluctuate dynamically as a function of volume status, afterload, heart rhythm, and residual ischemia," the researchers said.

Current guidelines recommend mitral valve repair or chordal-sparing mitral valve replacement for severe regurgitation unresponsive to medical therapy, but do not specify which procedure is preferred because there is no conclusive evidence demonstrating the superiority of one over the other. "Recently, the field has embraced mitral valve repair over replacement," even without such evidence, Dr. Acker and his colleagues said.

The CTSN performed this study at 22 medical centers to assess the relative benefits of the two surgeries, with 126 patients randomized to undergo mitral valve repair and 125 to undergo replacement that included complete preservation of the subvalvular apparatus.

The primary endpoint was the degree of LV reverse remodeling, as measured by the left ventricular end-systolic volume index (LVESVI) on transthoracic echocardiography, at 1 year. The mean LVESVI was not significantly different between the repair group (54.6 mL per square meter) and the replacement group (60.7 mL per square meter), reflecting decreases of 6.6 mL per square meter and 6.8 mL per square meter, respectively, the investigators said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1312808]).

The median between group difference in the change in LVESVI score after surgery also was not clinically significant. However, 32.6% of patients who underwent mitral valve repair had a recurrence of regurgitation within 1 year, compared with only 2.3% of those who had mitral valve replacement. Three patients in the repair group required reoperation, compared with none in the replacement group.

There were no significant differences in cumulative mortality, 30-day postoperative mortality, or 1-year mortality between the two groups, and no significant difference in a composite endpoint of major adverse cardiac or cerebrovascular events.

Rates of serious adverse events were similar, and the durations of hospitalization were similar between the two study groups, as were rates of readmission. All measures of quality of life and functional status on two assessment tools were similar.

"Our findings contradict much of the published literature on this topic, which reports several advantages to mitral valve repair over replacement, including lower operative mortality, improved left ventricular function, and higher rates of long-term survival," Dr. Acker and his associates noted.

The evolution of the valve replacement procedure, which now includes chordal sparing, "may account for the improved results we observed, as compared with previous studies, since the retention of the internal architectural support of the left ventricle may preserve contractile efficiency and reduce left ventricular dilatation and dysfunction," they said.

Dr. Acker reported no conflicts.

Mitral valve repair was no better than chordal-sparing mitral valve replacement in the first randomized clinical trial attempting to settle the controversy over which procedure is superior for treating functional ischemic mitral regurgitation, which was simultaneously reported at the annual scientific sessions of the American Heart Association and online in the New England Journal of Medicine.

In the past few years, the use of mitral valve repair has far exceeded that of mitral valve replacement for this indication, largely on the basis of reports that the repair procedure yields lower operative mortality, improved left ventricular function, and higher long-term survival rates. In particular, a 2011 meta-analysis found a 35% lower relative risk of death in the long term with mitral valve repair, compared with replacement, said Dr. Michael A. Acker and his associates in the Cardiothoracic Surgical Trials Network (CTSN).

But in their multicenter study directly comparing the two procedures in 251 patients with severe functional ischemic mitral regurgitation, there was no significant difference between the surgeries in left ventricular end-systolic volume index at 1 year, nor in mortality at either 1 month or 1 year.

Moreover, study participants who underwent mitral valve repair showed a disturbing excess in the rate of recurrence of mitral regurgitation at 1 year, with a rate that was 30 percentage points higher than that among patients who underwent mitral valve replacement. "This lack of durability in correction of mitral regurgitation is disconcerting, given its reported association with further progression and long-term negative outcomes," said Dr. Acker of the division of cardiovascular surgery, University of Pennsylvania, Philadelphia, and his associates.

Functional ischemic mitral regurgitation, a "high-prevalence" condition affecting an estimated 2-3 million Americans, differs from primary degenerative mitral regurgitation in that the valve leaflets themselves remain normal while the defect occurs in the myocardium. "Ischemic mitral regurgitation is a consequence of adverse left ventricular remodeling after myocardial injury, with enlargement of the left ventricular chamber and mitral annulus, apical and lateral migration of the papillary muscles, leaflet retethering, and reduced closing forces. These processes lead to malcoaptation of the leaflets and variable degrees of mitral regurgitation that can fluctuate dynamically as a function of volume status, afterload, heart rhythm, and residual ischemia," the researchers said.

Current guidelines recommend mitral valve repair or chordal-sparing mitral valve replacement for severe regurgitation unresponsive to medical therapy, but do not specify which procedure is preferred because there is no conclusive evidence demonstrating the superiority of one over the other. "Recently, the field has embraced mitral valve repair over replacement," even without such evidence, Dr. Acker and his colleagues said.

The CTSN performed this study at 22 medical centers to assess the relative benefits of the two surgeries, with 126 patients randomized to undergo mitral valve repair and 125 to undergo replacement that included complete preservation of the subvalvular apparatus.

The primary endpoint was the degree of LV reverse remodeling, as measured by the left ventricular end-systolic volume index (LVESVI) on transthoracic echocardiography, at 1 year. The mean LVESVI was not significantly different between the repair group (54.6 mL per square meter) and the replacement group (60.7 mL per square meter), reflecting decreases of 6.6 mL per square meter and 6.8 mL per square meter, respectively, the investigators said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1312808]).

The median between group difference in the change in LVESVI score after surgery also was not clinically significant. However, 32.6% of patients who underwent mitral valve repair had a recurrence of regurgitation within 1 year, compared with only 2.3% of those who had mitral valve replacement. Three patients in the repair group required reoperation, compared with none in the replacement group.

There were no significant differences in cumulative mortality, 30-day postoperative mortality, or 1-year mortality between the two groups, and no significant difference in a composite endpoint of major adverse cardiac or cerebrovascular events.

Rates of serious adverse events were similar, and the durations of hospitalization were similar between the two study groups, as were rates of readmission. All measures of quality of life and functional status on two assessment tools were similar.

"Our findings contradict much of the published literature on this topic, which reports several advantages to mitral valve repair over replacement, including lower operative mortality, improved left ventricular function, and higher rates of long-term survival," Dr. Acker and his associates noted.

The evolution of the valve replacement procedure, which now includes chordal sparing, "may account for the improved results we observed, as compared with previous studies, since the retention of the internal architectural support of the left ventricle may preserve contractile efficiency and reduce left ventricular dilatation and dysfunction," they said.

Dr. Acker reported no conflicts.

Excessive evaluations of well-appearing neonates declined markedly, as intended, when the most recent (2010) CDC guidelines for assessing early-onset group B streptococcal sepsis were implemented, according to a report from one hospital published online Jan. 20 in Pediatrics.

This decrease was accompanied by a marked drop in health care costs and was not associated with any apparent harmful effects, indicating that the evaluations that were avoided were indeed unnecessary, said Dr. Sagori Mukhopadhyay of Boston Children’s Hospital and Harvard Medical School and her associates.

The guidelines from the Centers for Disease Control and Prevention (CDC) were revised so that healthy-appearing infants born to mothers who had inadequate intrapartum antibiotic prophylaxis for group B streptococcus would only be evaluated for early-onset GBS sepsis if they had additional indications: gestational age of less than 37 weeks, rupture of membranes that preceded delivery by 18 hours or longer, maternal fever, or chorioamnionitis. Preliminary studies indicated that implementing these more restrictive guidelines would decrease excessive evaluations of healthy newborns by approximately 25%, "but the real-life impact of changes in medical policy is rarely straightforward," the investigators said.

© Janice Haney Carr/CDC

There was concern that some well-appearing infants who weren’t closely evaluated might go on to develop early-onset GBS sepsis that could have been prevented. So Dr. Mukhopadhyay and her colleagues performed a retrospective cohort study involving 14,286 live births to assess the effect of implementing the new guidelines.

They compared infants born at Brigham and Women’s Hospital, Boston, during two time periods: 7,282 born the year before the new guidelines were adopted (spring 2009–spring 2010), and 7,004 born the year afterward (spring 2011–spring 2012).

Typical evaluations for early-onset GBS sepsis involved immediate transfer to the neonatal intensive care unit, measurement of vital signs, blood sampling, peripheral IV catheter insertion, empiric antibiotic therapy, and close observation for several hours.

The number of such evaluations declined substantially after implementation of the new guidelines, from 920 to 476. This represents a rate decrease from 126 per 1,000 live births to 68 per 1,000 live births, the investigators reported (Pediatrics 2014;33:196-203).

The number of infants given empiric antibiotics also declined, from 527 to 365.

There was no increase in the number of infants who developed early-onset GBS sepsis between the two study periods. The overall rate of culture-confirmed infection was 0.25 per 1,000 live births in 2009-2010, which was not significantly different from the rate of 0.39 per 1,000 in 2011-2012.

Costs of care dramatically decreased along with the decline in "unnecessary" newborn evaluations. "The resources expended over the study periods among asymptomatic infants at risk for early-onset sepsis were considerable: more than 2,200 nursing hours were required to evaluate 1,396 infants, including 890 uninfected infants treated with antibiotics, at an estimated cost of nearly $400,000. These efforts detected only 2 early-onset sepsis cases," Dr. Mukhopadhyay and her associates said.

They added that the American Academy of Pediatrics’ Committee on the Fetus and Newborn recently published its own guidelines for early-onset sepsis evaluation and prevention. Because these AAP guidelines differ somewhat from the CDC guidelines, implementing them will likely have a somewhat different effect on the frequency and costs of such evaluations, the investigators said.

This study was supported by the National Institutes of Health, the Harvard Catalyst/Harvard Clinical and Translational Science Center, the National Center for Research Resources, the National Center for Advancing Translational Sciences, and Harvard University. No financial conflicts of interest were reported.

Excessive evaluations of well-appearing neonates declined markedly, as intended, when the most recent (2010) CDC guidelines for assessing early-onset group B streptococcal sepsis were implemented, according to a report from one hospital published online Jan. 20 in Pediatrics.

This decrease was accompanied by a marked drop in health care costs and was not associated with any apparent harmful effects, indicating that the evaluations that were avoided were indeed unnecessary, said Dr. Sagori Mukhopadhyay of Boston Children’s Hospital and Harvard Medical School and her associates.

The guidelines from the Centers for Disease Control and Prevention (CDC) were revised so that healthy-appearing infants born to mothers who had inadequate intrapartum antibiotic prophylaxis for group B streptococcus would only be evaluated for early-onset GBS sepsis if they had additional indications: gestational age of less than 37 weeks, rupture of membranes that preceded delivery by 18 hours or longer, maternal fever, or chorioamnionitis. Preliminary studies indicated that implementing these more restrictive guidelines would decrease excessive evaluations of healthy newborns by approximately 25%, "but the real-life impact of changes in medical policy is rarely straightforward," the investigators said.

© Janice Haney Carr/CDC

There was concern that some well-appearing infants who weren’t closely evaluated might go on to develop early-onset GBS sepsis that could have been prevented. So Dr. Mukhopadhyay and her colleagues performed a retrospective cohort study involving 14,286 live births to assess the effect of implementing the new guidelines.

They compared infants born at Brigham and Women’s Hospital, Boston, during two time periods: 7,282 born the year before the new guidelines were adopted (spring 2009–spring 2010), and 7,004 born the year afterward (spring 2011–spring 2012).

Typical evaluations for early-onset GBS sepsis involved immediate transfer to the neonatal intensive care unit, measurement of vital signs, blood sampling, peripheral IV catheter insertion, empiric antibiotic therapy, and close observation for several hours.

The number of such evaluations declined substantially after implementation of the new guidelines, from 920 to 476. This represents a rate decrease from 126 per 1,000 live births to 68 per 1,000 live births, the investigators reported (Pediatrics 2014;33:196-203).

The number of infants given empiric antibiotics also declined, from 527 to 365.

There was no increase in the number of infants who developed early-onset GBS sepsis between the two study periods. The overall rate of culture-confirmed infection was 0.25 per 1,000 live births in 2009-2010, which was not significantly different from the rate of 0.39 per 1,000 in 2011-2012.

Costs of care dramatically decreased along with the decline in "unnecessary" newborn evaluations. "The resources expended over the study periods among asymptomatic infants at risk for early-onset sepsis were considerable: more than 2,200 nursing hours were required to evaluate 1,396 infants, including 890 uninfected infants treated with antibiotics, at an estimated cost of nearly $400,000. These efforts detected only 2 early-onset sepsis cases," Dr. Mukhopadhyay and her associates said.

They added that the American Academy of Pediatrics’ Committee on the Fetus and Newborn recently published its own guidelines for early-onset sepsis evaluation and prevention. Because these AAP guidelines differ somewhat from the CDC guidelines, implementing them will likely have a somewhat different effect on the frequency and costs of such evaluations, the investigators said.

This study was supported by the National Institutes of Health, the Harvard Catalyst/Harvard Clinical and Translational Science Center, the National Center for Research Resources, the National Center for Advancing Translational Sciences, and Harvard University. No financial conflicts of interest were reported.

Excessive evaluations of well-appearing neonates declined markedly, as intended, when the most recent (2010) CDC guidelines for assessing early-onset group B streptococcal sepsis were implemented, according to a report from one hospital published online Jan. 20 in Pediatrics.

This decrease was accompanied by a marked drop in health care costs and was not associated with any apparent harmful effects, indicating that the evaluations that were avoided were indeed unnecessary, said Dr. Sagori Mukhopadhyay of Boston Children’s Hospital and Harvard Medical School and her associates.

The guidelines from the Centers for Disease Control and Prevention (CDC) were revised so that healthy-appearing infants born to mothers who had inadequate intrapartum antibiotic prophylaxis for group B streptococcus would only be evaluated for early-onset GBS sepsis if they had additional indications: gestational age of less than 37 weeks, rupture of membranes that preceded delivery by 18 hours or longer, maternal fever, or chorioamnionitis. Preliminary studies indicated that implementing these more restrictive guidelines would decrease excessive evaluations of healthy newborns by approximately 25%, "but the real-life impact of changes in medical policy is rarely straightforward," the investigators said.

© Janice Haney Carr/CDC

There was concern that some well-appearing infants who weren’t closely evaluated might go on to develop early-onset GBS sepsis that could have been prevented. So Dr. Mukhopadhyay and her colleagues performed a retrospective cohort study involving 14,286 live births to assess the effect of implementing the new guidelines.

They compared infants born at Brigham and Women’s Hospital, Boston, during two time periods: 7,282 born the year before the new guidelines were adopted (spring 2009–spring 2010), and 7,004 born the year afterward (spring 2011–spring 2012).

Typical evaluations for early-onset GBS sepsis involved immediate transfer to the neonatal intensive care unit, measurement of vital signs, blood sampling, peripheral IV catheter insertion, empiric antibiotic therapy, and close observation for several hours.

The number of such evaluations declined substantially after implementation of the new guidelines, from 920 to 476. This represents a rate decrease from 126 per 1,000 live births to 68 per 1,000 live births, the investigators reported (Pediatrics 2014;33:196-203).

The number of infants given empiric antibiotics also declined, from 527 to 365.

There was no increase in the number of infants who developed early-onset GBS sepsis between the two study periods. The overall rate of culture-confirmed infection was 0.25 per 1,000 live births in 2009-2010, which was not significantly different from the rate of 0.39 per 1,000 in 2011-2012.

Costs of care dramatically decreased along with the decline in "unnecessary" newborn evaluations. "The resources expended over the study periods among asymptomatic infants at risk for early-onset sepsis were considerable: more than 2,200 nursing hours were required to evaluate 1,396 infants, including 890 uninfected infants treated with antibiotics, at an estimated cost of nearly $400,000. These efforts detected only 2 early-onset sepsis cases," Dr. Mukhopadhyay and her associates said.

They added that the American Academy of Pediatrics’ Committee on the Fetus and Newborn recently published its own guidelines for early-onset sepsis evaluation and prevention. Because these AAP guidelines differ somewhat from the CDC guidelines, implementing them will likely have a somewhat different effect on the frequency and costs of such evaluations, the investigators said.

This study was supported by the National Institutes of Health, the Harvard Catalyst/Harvard Clinical and Translational Science Center, the National Center for Research Resources, the National Center for Advancing Translational Sciences, and Harvard University. No financial conflicts of interest were reported.

The incidence of invasive candidiasis declined substantially in recent years among more than 700,000 infants treated in 322 neonatal intensive care units of a national health care system, according to a report published online January 20 in Pediatrics.

The study sample included such a large proportion of all low-birth-weight (LBW) neonates that "our findings are likely representative of the actual burden of disease in this population," so the results provide "evidence for an overall downward trend of invasive candidiasis in the NICU population across the country," said Dr. Sofia Aliaga of the division of neonatal-perinatal medicine at the University of North Carolina, Chapel Hill, and her associates.

The decline in candidiasis cases was associated with a concomitant rise in the use of antifungal prophylaxis, an increase in empirical antifungal therapy, and a decrease in the use of broad-spectrum antibacterial antibiotics in this patient population. Although a retrospective cohort study such as this cannot determine causality, these changes in clinical practice probably contributed heavily to the decline in invasive neonatal candidiasis, they noted.

To track rates of neonatal candidiasis over time, Dr. Aliaga and her colleagues assessed 709,325 infants treated in NICUs across the country from 1997 through 2010. The researchers identified 2,063 neonates (0.3%) who developed invasive candidiasis.

During the study period, the annual incidence of invasive candidiasis declined from 3.6 to 1.4 cases per 1,000 infants. The greatest decrease occurred in the smallest infants: from 82.7 to 23.8 cases per 1,000 neonates weighing less than 750 g and from 24.2 to 11.6 per 1,000 neonates weighing 750-999 g, the investigators said (Pediatrics 2014;133:236-42).

At the same time, the use of fluconazole antifungal prophylaxis rose from 0.1 to 7.4 per 1,000 infants. The use of empirical antifungal therapy rose from 4.0 to 11.5 per 1,000 infants, and the use of broad-spectrum antibiotics decreased from 275.7 to 48.5 per 1,000 infants.

"Exposure to broad-spectrum antibacterial antibiotics was associated with an increased risk of invasive candidiasis (adjusted odds ratio: 1.88)," the researchers said.

Among the smallest infants, each 10% decrease in the use of broad-spectrum antibacterial antibiotics was associated with a 3%-7% decrease in the incidence of the disease. In addition, the results of a regression analysis "imply that, on average, sites that reduced broad-spectrum antibiotic use the most had the largest decrease in candidiasis," Dr. Aliaga and her associates said.

Other factors also may have contributed to the decline in the disease. For example, several NICU quality-improvement initiatives that were implemented in the past 15 years targeted the management of central catheters and were intended to decrease central line–associated bloodstream infections, so they may have helped reduce invasive candidiasis. Compliance with higher dosing recommendations for fluconazole therapy and the introduction of newer antifungal agents such as echinocandins during the study period also may have contributed.

Other contributing factors may have included greater attention to hand-washing protocols in recent years, decreased exposure to other risk factors such as the use of histamine-2 blocking agents and the use of mechanical ventilation, and changes in feeding practices in the NICU.

Even though this cohort study could not demonstrate the reason for the robust decline in invasive candidiasis among NICU patients, it is unlikely that prospective clinical trials to make that determination will be feasible because the current incidence is so low. "Given a cumulative incidence of 1.4 infections per 1,000 infants, a 250-infant study would require 10 years and 100 NICUs [just] to complete enrollment," Dr. Aliaga and her associates noted.

This study was supported by the National Institutes of Health, the U.S. Department of Health and Human Services, and the American Recovery and Reinvestment Act. Dr. Aliaga reported no potential financial conflicts of interest. Her associates reported industry funding for the development of neonatal and pediatric drugs, as well as ties to Astellas (maker of micafungin), Pfizer (maker of anidulafungin and fluconazole), Merck (maker of caspofungin), and Novartis and Gilead (makers of other antifungal agents used against neonatal candidiasis.

The incidence of invasive candidiasis declined substantially in recent years among more than 700,000 infants treated in 322 neonatal intensive care units of a national health care system, according to a report published online January 20 in Pediatrics.

The study sample included such a large proportion of all low-birth-weight (LBW) neonates that "our findings are likely representative of the actual burden of disease in this population," so the results provide "evidence for an overall downward trend of invasive candidiasis in the NICU population across the country," said Dr. Sofia Aliaga of the division of neonatal-perinatal medicine at the University of North Carolina, Chapel Hill, and her associates.

The decline in candidiasis cases was associated with a concomitant rise in the use of antifungal prophylaxis, an increase in empirical antifungal therapy, and a decrease in the use of broad-spectrum antibacterial antibiotics in this patient population. Although a retrospective cohort study such as this cannot determine causality, these changes in clinical practice probably contributed heavily to the decline in invasive neonatal candidiasis, they noted.

To track rates of neonatal candidiasis over time, Dr. Aliaga and her colleagues assessed 709,325 infants treated in NICUs across the country from 1997 through 2010. The researchers identified 2,063 neonates (0.3%) who developed invasive candidiasis.

During the study period, the annual incidence of invasive candidiasis declined from 3.6 to 1.4 cases per 1,000 infants. The greatest decrease occurred in the smallest infants: from 82.7 to 23.8 cases per 1,000 neonates weighing less than 750 g and from 24.2 to 11.6 per 1,000 neonates weighing 750-999 g, the investigators said (Pediatrics 2014;133:236-42).

At the same time, the use of fluconazole antifungal prophylaxis rose from 0.1 to 7.4 per 1,000 infants. The use of empirical antifungal therapy rose from 4.0 to 11.5 per 1,000 infants, and the use of broad-spectrum antibiotics decreased from 275.7 to 48.5 per 1,000 infants.

"Exposure to broad-spectrum antibacterial antibiotics was associated with an increased risk of invasive candidiasis (adjusted odds ratio: 1.88)," the researchers said.

Among the smallest infants, each 10% decrease in the use of broad-spectrum antibacterial antibiotics was associated with a 3%-7% decrease in the incidence of the disease. In addition, the results of a regression analysis "imply that, on average, sites that reduced broad-spectrum antibiotic use the most had the largest decrease in candidiasis," Dr. Aliaga and her associates said.

Other factors also may have contributed to the decline in the disease. For example, several NICU quality-improvement initiatives that were implemented in the past 15 years targeted the management of central catheters and were intended to decrease central line–associated bloodstream infections, so they may have helped reduce invasive candidiasis. Compliance with higher dosing recommendations for fluconazole therapy and the introduction of newer antifungal agents such as echinocandins during the study period also may have contributed.

Other contributing factors may have included greater attention to hand-washing protocols in recent years, decreased exposure to other risk factors such as the use of histamine-2 blocking agents and the use of mechanical ventilation, and changes in feeding practices in the NICU.

Even though this cohort study could not demonstrate the reason for the robust decline in invasive candidiasis among NICU patients, it is unlikely that prospective clinical trials to make that determination will be feasible because the current incidence is so low. "Given a cumulative incidence of 1.4 infections per 1,000 infants, a 250-infant study would require 10 years and 100 NICUs [just] to complete enrollment," Dr. Aliaga and her associates noted.

This study was supported by the National Institutes of Health, the U.S. Department of Health and Human Services, and the American Recovery and Reinvestment Act. Dr. Aliaga reported no potential financial conflicts of interest. Her associates reported industry funding for the development of neonatal and pediatric drugs, as well as ties to Astellas (maker of micafungin), Pfizer (maker of anidulafungin and fluconazole), Merck (maker of caspofungin), and Novartis and Gilead (makers of other antifungal agents used against neonatal candidiasis.

The incidence of invasive candidiasis declined substantially in recent years among more than 700,000 infants treated in 322 neonatal intensive care units of a national health care system, according to a report published online January 20 in Pediatrics.

The study sample included such a large proportion of all low-birth-weight (LBW) neonates that "our findings are likely representative of the actual burden of disease in this population," so the results provide "evidence for an overall downward trend of invasive candidiasis in the NICU population across the country," said Dr. Sofia Aliaga of the division of neonatal-perinatal medicine at the University of North Carolina, Chapel Hill, and her associates.

The decline in candidiasis cases was associated with a concomitant rise in the use of antifungal prophylaxis, an increase in empirical antifungal therapy, and a decrease in the use of broad-spectrum antibacterial antibiotics in this patient population. Although a retrospective cohort study such as this cannot determine causality, these changes in clinical practice probably contributed heavily to the decline in invasive neonatal candidiasis, they noted.

To track rates of neonatal candidiasis over time, Dr. Aliaga and her colleagues assessed 709,325 infants treated in NICUs across the country from 1997 through 2010. The researchers identified 2,063 neonates (0.3%) who developed invasive candidiasis.

During the study period, the annual incidence of invasive candidiasis declined from 3.6 to 1.4 cases per 1,000 infants. The greatest decrease occurred in the smallest infants: from 82.7 to 23.8 cases per 1,000 neonates weighing less than 750 g and from 24.2 to 11.6 per 1,000 neonates weighing 750-999 g, the investigators said (Pediatrics 2014;133:236-42).

At the same time, the use of fluconazole antifungal prophylaxis rose from 0.1 to 7.4 per 1,000 infants. The use of empirical antifungal therapy rose from 4.0 to 11.5 per 1,000 infants, and the use of broad-spectrum antibiotics decreased from 275.7 to 48.5 per 1,000 infants.

"Exposure to broad-spectrum antibacterial antibiotics was associated with an increased risk of invasive candidiasis (adjusted odds ratio: 1.88)," the researchers said.

Among the smallest infants, each 10% decrease in the use of broad-spectrum antibacterial antibiotics was associated with a 3%-7% decrease in the incidence of the disease. In addition, the results of a regression analysis "imply that, on average, sites that reduced broad-spectrum antibiotic use the most had the largest decrease in candidiasis," Dr. Aliaga and her associates said.

Other factors also may have contributed to the decline in the disease. For example, several NICU quality-improvement initiatives that were implemented in the past 15 years targeted the management of central catheters and were intended to decrease central line–associated bloodstream infections, so they may have helped reduce invasive candidiasis. Compliance with higher dosing recommendations for fluconazole therapy and the introduction of newer antifungal agents such as echinocandins during the study period also may have contributed.

Other contributing factors may have included greater attention to hand-washing protocols in recent years, decreased exposure to other risk factors such as the use of histamine-2 blocking agents and the use of mechanical ventilation, and changes in feeding practices in the NICU.

Even though this cohort study could not demonstrate the reason for the robust decline in invasive candidiasis among NICU patients, it is unlikely that prospective clinical trials to make that determination will be feasible because the current incidence is so low. "Given a cumulative incidence of 1.4 infections per 1,000 infants, a 250-infant study would require 10 years and 100 NICUs [just] to complete enrollment," Dr. Aliaga and her associates noted.

This study was supported by the National Institutes of Health, the U.S. Department of Health and Human Services, and the American Recovery and Reinvestment Act. Dr. Aliaga reported no potential financial conflicts of interest. Her associates reported industry funding for the development of neonatal and pediatric drugs, as well as ties to Astellas (maker of micafungin), Pfizer (maker of anidulafungin and fluconazole), Merck (maker of caspofungin), and Novartis and Gilead (makers of other antifungal agents used against neonatal candidiasis.

The diagnosis of renal cell cancer in a patient aged 46 or younger should prompt a referral for germline mutation testing and genetic counseling, according to a report published online in the Journal of Clinical Oncology.

"Early" onset is a known clinical factor for hereditary renal cell cancer (RCC), but this study establishes a proposed age threshold for genetic testing. Dr. Brian Shuch and his associates at the National Cancer Institute analyzed 106,224 cases of RCC from the general U.S. population in the SEER-17 (Surveillance, Epidemiology, and End Results–17) database, as well as 608 cases of hereditary RCC in an NCI database. This represents the largest cohort of patients with hereditary RCC studied to date, the researchers noted.

The age of presentation for hereditary forms of RCC was consistently much younger – typically 27 years younger – than that for sporadic RCC. The median age of onset was 37 years and the mean age of onset was 39 years for hereditary RCC, compared with 63 and 64 years, respectively, for sporadic RCC.

The researchers found that using the 10th percentile of the typical age of onset in the general population – age 46 years or younger – made a practical cutoff point that yielded the most sensitive and specific criterion for recommending genetic testing and counseling.

Once a syndrome is identified, specific recommendations can be given regarding nephron-sparing surgery, partial nephrectomy, the timing of interventions, and surveillance of the renal mass, as well as for the screening of relatives, Dr. Shuch and his associates said (J. Clin. Oncol. 2013 Dec. 30 [doi:10.1200/JCO.2013.50.8192]).

The authors reported having no relevant financial disclosures.

The diagnosis of renal cell cancer in a patient aged 46 or younger should prompt a referral for germline mutation testing and genetic counseling, according to a report published online in the Journal of Clinical Oncology.

"Early" onset is a known clinical factor for hereditary renal cell cancer (RCC), but this study establishes a proposed age threshold for genetic testing. Dr. Brian Shuch and his associates at the National Cancer Institute analyzed 106,224 cases of RCC from the general U.S. population in the SEER-17 (Surveillance, Epidemiology, and End Results–17) database, as well as 608 cases of hereditary RCC in an NCI database. This represents the largest cohort of patients with hereditary RCC studied to date, the researchers noted.

The age of presentation for hereditary forms of RCC was consistently much younger – typically 27 years younger – than that for sporadic RCC. The median age of onset was 37 years and the mean age of onset was 39 years for hereditary RCC, compared with 63 and 64 years, respectively, for sporadic RCC.

The researchers found that using the 10th percentile of the typical age of onset in the general population – age 46 years or younger – made a practical cutoff point that yielded the most sensitive and specific criterion for recommending genetic testing and counseling.

Once a syndrome is identified, specific recommendations can be given regarding nephron-sparing surgery, partial nephrectomy, the timing of interventions, and surveillance of the renal mass, as well as for the screening of relatives, Dr. Shuch and his associates said (J. Clin. Oncol. 2013 Dec. 30 [doi:10.1200/JCO.2013.50.8192]).

The authors reported having no relevant financial disclosures.

The diagnosis of renal cell cancer in a patient aged 46 or younger should prompt a referral for germline mutation testing and genetic counseling, according to a report published online in the Journal of Clinical Oncology.

"Early" onset is a known clinical factor for hereditary renal cell cancer (RCC), but this study establishes a proposed age threshold for genetic testing. Dr. Brian Shuch and his associates at the National Cancer Institute analyzed 106,224 cases of RCC from the general U.S. population in the SEER-17 (Surveillance, Epidemiology, and End Results–17) database, as well as 608 cases of hereditary RCC in an NCI database. This represents the largest cohort of patients with hereditary RCC studied to date, the researchers noted.

The age of presentation for hereditary forms of RCC was consistently much younger – typically 27 years younger – than that for sporadic RCC. The median age of onset was 37 years and the mean age of onset was 39 years for hereditary RCC, compared with 63 and 64 years, respectively, for sporadic RCC.

The researchers found that using the 10th percentile of the typical age of onset in the general population – age 46 years or younger – made a practical cutoff point that yielded the most sensitive and specific criterion for recommending genetic testing and counseling.

Once a syndrome is identified, specific recommendations can be given regarding nephron-sparing surgery, partial nephrectomy, the timing of interventions, and surveillance of the renal mass, as well as for the screening of relatives, Dr. Shuch and his associates said (J. Clin. Oncol. 2013 Dec. 30 [doi:10.1200/JCO.2013.50.8192]).

The authors reported having no relevant financial disclosures.