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<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_357"
                     title="Targeted Therapy Disappoints in Recurrent Brain Tumors (CME/CE)"
                     score="0.01"
                     href="http://www.medpagetoday.com/HematologyOncology/BrainCancer/tb/18237?impressionId=1265818269377"
                     
      &lt;p&gt;High hopes for treating recurrent glioblastoma with the novel, targeted antiangiogenic enzastaurin have been diminished by disappointing phase III results.&lt;/p&gt;
&lt;p&gt;The study failed its primary endpoint with a median progression-free survival of 1.5 months compared with 1.6 months on conventional lomustine (CeeNu, &lt;em&gt;P&lt;/em&gt;=0.08).&lt;/p&gt;
&lt;p&gt;Nor were there any other significant benefits, despite generally good tolerability, Wolfgang Wick, MD, of the University of Heidelberg, Germany, and colleagues reported online in the &lt;em&gt;Journal of Clinical Oncology&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;In an earlier &lt;a href=&quot;http://www.medpagetoday.com/HematologyOncology/BrainCancer/1062&quot; mce_href=&quot;http://www.medpagetoday.com/HematologyOncology/BrainCancer/1062&quot; target=&quot;_blank&quot;&gt;phase II study&lt;/a&gt;, the drug shrank tumors in 22% of heavily pretreated patients with recurrent glioblastoma, a heavily vascular cancer and one of the toughest to treat.&lt;/p&gt;
&lt;p&gt;The experimental agent is a potent and selective inhibitor of protein kinase C-beta, which mediates the most important regulator of vessel growth in glioma.&lt;/p&gt;
&lt;p&gt;Even so, jumping directly into a phase III study before the final results of a phase II study might have been premature, even with a strong preclinical rationale, the authors and an accompanying editorial said.&lt;/p&gt;
&lt;p&gt;Evanthia Galanis, MD, DSc, and Jan C. Buckner, MD, both of the Mayo Clinic in Rochester, Minn., wrote in an editorial that response rate &quot;can be particularly misleading as an indicator of antitumor activity of antiangiogenic agents.&quot;&lt;/p&gt;
&lt;p&gt;Reduced vascular permeability can appear as improvement on enhanced MRI, without true antitumor effect, the editorialists noted. Nor does response rate correlate well with progression-free or overall survival in this type of cancer, they wrote.&lt;/p&gt;
&lt;p&gt;Still, they cautioned, these negative phase III results aren&apos;t the final word on the drug whose modest activity was comparable to standard treatment  --  and with satisfactory tolerability.&lt;/p&gt;
&lt;p&gt;&quot;It would therefore still be worth incorporating enzastaurin in rationally designed combinatorial regimens, especially if based on a strong mechanistic rationale or preclinical demonstration of synergistic activity,&quot; Galanis and Buckner wrote.&lt;/p&gt;
&lt;p&gt;The study randomized patients with World Health Organization grade 4 glioblastoma to receive six-week cycles of open-label enzastaurin 500 mg/d (1,125-mg loading dose on day one) or lomustine (100 to 130 mg/m&lt;sup&gt;2&lt;/sup&gt; on day one).&lt;/p&gt;
&lt;p&gt;It was stopped at the planned interim futility analysis after enrollment of 266 patients.&lt;/p&gt;
&lt;p&gt;The researchers had powered the study for a 45% improvement in median progression-free survival, but found it actually tended to be 28% better with lomustine (HR 1.28, 95% CI 0.97 to 1.70).&lt;/p&gt;
&lt;p&gt;Six-month progression-free survival rates were 11.1% with the experimental treatment, compared with 19.0% among controls (&lt;em&gt;P&lt;/em&gt;=0.13).&lt;/p&gt;
&lt;p&gt;Overall survival, too, was similar at 6.6 and 7.1 months, respectively (HR 1.20, &lt;em&gt;P&lt;/em&gt;=0.25). Objective response rate showed no differences either (&lt;em&gt;P&lt;/em&gt;=0.501).&lt;/p&gt;
&lt;p&gt;Patient-reported time to deterioration  --  measured on the Functional Assessment of Cancer Therapy&amp;#8211;Brain questionnaire  --  was 2.27 months with enzastaurin compared with 2.33 months for lomustine (&lt;em&gt;P&lt;/em&gt;=0.54).&lt;/p&gt;
&lt;p&gt;Results likewise were similar between the groups for physical and functional well-being and for brain tumor&amp;#8211;specific concerns (&lt;em&gt;P&lt;/em&gt;&amp;gt;0.05).&lt;/p&gt;
&lt;p&gt;Adverse event rates were not different between groups, although more were drug-related in the lomustine group (62% versus 44%, &lt;em&gt;P&lt;/em&gt;=0.008).&lt;/p&gt;
&lt;p&gt;Enzastaurin did have the advantage of less hematologic toxicity overall (&lt;em&gt;P&lt;/em&gt;&amp;#8804;0.001), and specifically for grade 3 to 4 adverse events (one versus 46 events, &lt;em&gt;P&lt;/em&gt;&amp;#8804;0.001).&lt;/p&gt;
&lt;p&gt;Study deaths in the enzastaurin group totaled 11, including four due to adverse events and one drug-related; while the four deaths in lomustine-treated patients were disease-related.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by Eli Lilly, including writing and editorial support.&lt;/p&gt;&lt;p&gt;Wick and co-authors reported financial conflicts of interest with Eli Lilly, including employment and stock ownership for some.&lt;/p&gt;&lt;p&gt;Co-authors also reported financial conflicts of interest with Merck, Genentech, Enzon, Schering-Plough, and AstraZeneca.&lt;/p&gt;&lt;p&gt;Galanis reported conflicts of interest with Merck, Bristol-Myers Squibb, Gradalis, Genetech, and Bayer Pharmaceuticals.&lt;/p&gt;&lt;p&gt;Buckner reported conflicts of interest with Merck Serono, Genentech, Excelixis, Bayer Pharmaceuticals, Bristol-Myers Squibb, and Anti-Sense Pharma.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_391"
                     title="Rare Genetic Deletion Linked to Morbid Obesity (CME/CE)"
                     score="0.01"
                     href="http://www.medpagetoday.com/Genetics/GeneralGenetics/tb/18286?impressionId=1265818269377"
                     
      &lt;p&gt;Missing sections of DNA may have a powerful impact on weight for a small segment of the population, researchers said.&lt;/p&gt;
&lt;p&gt;Nearly all teens and adults found to have a particular deletion of roughly 30-genes on chromosome 16p11.2 were obese  --  most morbidly so  --  with a body mass index of at least 40 kg/m&lt;sup&gt;2&lt;/sup&gt;, Philippe Froguel, MD, PhD, of Imperial College London, and colleagues reported in &lt;em&gt;Nature&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;While the variant appeared to explain only a small proportion of morbid obesity  --  0.7% in the study population  --  it was never present in healthy, normal-weight controls.&lt;/p&gt;
&lt;p&gt;&quot;Although the recent rise in obesity in the developed world is down to an unhealthy environment, with an abundance of unhealthy food and many people taking very little exercise, the difference in the way people respond to this environment is often genetic,&quot; Froguel said in a prepared statement.&lt;/p&gt;
&lt;p&gt;But with further findings like these, it may be possible to identify such individuals through genetic testing, he said.&lt;/p&gt;
&lt;p&gt;If so, &quot;We can then offer them appropriate support and medical interventions, such as the option of weight-loss surgery, to improve their long-term health,&quot; Froguel declared.&lt;/p&gt;
&lt;p&gt;Although researchers speculate that one in 20 cases of obesity may have a genetic cause, the genetic component remains largely elusive.&lt;/p&gt;
&lt;p&gt;Even accounting for such a small fraction of cases, the newly discovered 16p11.2 variant would be the second most frequent known genetic cause of obesity, Froguel&apos;s group said.&lt;/p&gt;
&lt;p&gt;Extensive genome-wide association studies have linked numerous single nucleotide polymorphisms (SNPs) to obesity, but added all together they account for only a small fraction of the known heritable component, the researchers said.&lt;/p&gt;
&lt;p&gt;&quot;The &apos;common disease, common variant&apos; hypothesis is increasingly coming under challenge,&quot; they wrote.&lt;/p&gt;
&lt;p&gt;Their team first identified the genetic deletion in teen and adults with learning difficulties or delayed development.&lt;/p&gt;
&lt;p&gt;Because the 31 individuals who had the nearly identical deletions of at least 593 kilobases at chromosome 16p11.2 in one copy of their DNA all had a BMI of over 30 kg/m&lt;sup&gt;2&lt;/sup&gt;, the researchers decided to dig a little deeper.&lt;/p&gt;
&lt;p&gt;&quot;Cohorts with extreme phenotypes that include obesity may be enriched for rare but very potent risk variants,&quot; making them easier to discover, they wrote.&lt;/p&gt;
&lt;p&gt;So they undertook a case-control study among 312 patients at three centers in Britain and France who presented with congenital malformations, developmental delay, or both, in addition to obesity.&lt;/p&gt;
&lt;p&gt;The same deletions were seen in 2.9% of these individuals.&lt;/p&gt;
&lt;p&gt;The function of the missing genes are not well known, but some have previously been associated with delayed development, autism, and schizophrenia.&lt;/p&gt;
&lt;p&gt;Notably, though, the frequency of deletion of these genes in the obese case-control cohort was &quot;appreciably higher&quot; than the less than 1% seen in the autism and other studies that didn&apos;t include obesity as an inclusion criteria, the researchers said.&lt;/p&gt;
&lt;p&gt;A second independent survey of genetic data at eight cytogenetic centers in France, Switzerland, and Estonia turned up a 0.6% rate among 3,947 people with developmental delay, malformations, or both, but who were not selected for obesity (&lt;em&gt;P&lt;/em&gt;=0.00022 versus the cohort selected for obesity).&lt;/p&gt;
&lt;p&gt;Analysis of those with the missing genes revealed an age-dependent link to weight: All four teens and adults were obese. Children were often obese (four of 15) or overweight (two of 15). Children under 2 years all had normal weight.&lt;/p&gt;
&lt;p&gt;So to see whether the deletion was independent of neurodevelopmental problems, Froguel&apos;s group examined genome-wide association study data from general population cohorts totaling 11,856 individuals along with 2,772 from childhood obesity and adult morbid obesity case-control studies, 931 in an extreme early-onset obesity study, and 141 who had bariatric weight-loss surgery.&lt;/p&gt;
&lt;p&gt;All adult carriers of the deletion were obese with the exception of one who was apparently diabetic. Each of the seven children and adolescents who carried the variant had a BMI in the top 0.1% for their age and gender.&lt;/p&gt;
&lt;p&gt;None had any reported developmental or cognitive problems. Four had reported hyperphagia with excessive hunger and food intake.&lt;/p&gt;
&lt;p&gt;Altogether, the 16p11.2 deletions predicted 29.8-fold elevated risk of obesity (&lt;em&gt;P&lt;/em&gt;=0.00000058) and 43.0-fold elevated risk of morbid obesity (&lt;em&gt;P&lt;/em&gt;=0.000000064) compared with lean or normal weight.&lt;/p&gt;
&lt;p&gt;By extrapolation, the researchers extrapolated that about 0.4% of all morbidly obese cases are attributable to an inherited 16p11.2 deletion, with 0.3% arising from a de novo deletion in the same genetic region.&lt;/p&gt;
&lt;p&gt;&quot;Although they may be heterogeneous in nature, these deletions are highly likely to be the causal variants,&quot; they wrote.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by &quot;Le Conseil Regional Nord Pas de Calais/FEDER&quot; along with various governmental and industry supporters for the various component studies.&lt;/p&gt;&lt;p&gt;The researchers reported no financial conflicts of interest.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_202"
                     title="Survival Rates Vary with Congenital Anomalies (CME/CE)"
                     score="-0.004"
                     href="http://www.medpagetoday.com/Pediatrics/GeneralPediatrics/tb/18035?impressionId=1265818269377"
                     
      &lt;p&gt;Survival among children with congenital anomalies has increased in recent decades, but still varies notably depending on the condition, a British study found.&lt;/p&gt;
&lt;p&gt;Overall 20-year survival was 85.5% (95% CI 84.8 to 86.3) among children born with at least one congenital anomaly, Peter W.G. Tennant, MsC, of Newcastle University, and colleagues reported online in &lt;em&gt;Lancet&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;For specific conditions, the 20-year survival rates were as follows: &lt;ul&gt; &lt;li&gt;Orofacial clefts, 97.6% (95% CI 95.9 to 98.6)&lt;/li&gt; &lt;li&gt;Urinary system, 93.2% (95% CI 91.6 to 94.5)&lt;/li&gt; &lt;li&gt;Cardiovascular system, 89.5% (95% CI 88.4 to 90.6)&lt;/li&gt; &lt;li&gt;Digestive system, 83.2% (95% CI 79.8 to 86)&lt;/li&gt; &lt;li&gt;Chromosomal anomalies, 79.1% (95% CI 76.6 to 81.3)&lt;/li&gt; &lt;li&gt;Nervous system, 66.2% (95% CI 61.5 to 70.5)&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Congenital anomalies are recognized as a major cause of perinatal and infant mortality, but little is known about longer-term survival with conditions other than Down syndrome or spina bifida.&lt;/p&gt;
&lt;p&gt;So Tennant and colleagues analyzed data from the Northern Congenital Abnormality Survey, which is a population-based register for the north of England.&lt;/p&gt;
&lt;p&gt;Their study included 13,758 cases of congenital anomaly reported to the registry between January 1985 and December 2003, representing a prevalence of 20.8 per 1,000 births.&lt;/p&gt;
&lt;p&gt;Among these, 0.9% were late miscarriages, 16.3% were terminations after prenatal diagnosis, 3.1% were stillbirths, and 79.7% were live births.&lt;/p&gt;
&lt;p&gt;Of the 10,850 liveborn cases for whom survival status was known, 1,465 (13.5%) died during the course of the study.&lt;/p&gt;
&lt;p&gt;Year of birth was a highly significant predictor of survival, (HR 0.92, 95% CI 0.92 to 0.93, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001), which likely relates to important medical and surgical advances such as surfactant therapy and corticosteroid use for respiratory distress syndrome, as well as intrapartum treatment for chorioamnionitis.&lt;/p&gt;
&lt;p&gt;The rate of termination for fetal anomaly increased over time, rising from 12.4% (95% CI 9.8 to 15.5) in 1985 to 18.3% (95% CI 15.6 to 21.2) in 2003.&lt;/p&gt;
&lt;p&gt;The investigators further analyzed survival among specific subtypes of anomalies and found rates of 20-year survival exceeding 95% for the following: &lt;ul&gt; &lt;li&gt;Ventricular septal defects, 98.3% (95% CI 96.6 to 99.1)&lt;/li&gt; &lt;li&gt;Pulmonary valve stenosis, 98.1% (95% CI 96.1 to 99.1)&lt;/li&gt; &lt;li&gt;Cleft lip and palate, 97.7% (95% CI 94.6 to 99.1)&lt;/li&gt; &lt;li&gt;Atrial septal defects, 96.3% (95% CI 93.3 to 98)&lt;/li&gt; &lt;li&gt;Cleft palate, 96.3% (95% CI 92.8 to 98.1)&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;In contrast, subtypes with less than 50% one-year survival included arhinencephaly/holoprosencephaly, common arterial trunk, and hypoplastic left heart.&lt;/p&gt;
&lt;p&gt;Previous studies have found ten-year survival rates ranging from 76.5% to 88.6% for Down syndrome, 80.9% for all phenotypes of spina bifida, and 64% for spina bifida with hydrocephalus.&lt;/p&gt;
&lt;p&gt;In this study, the ten-year survival for Down syndrome was 83.9%, which probably reflects differences in care over time and by location, as well as surgical management and changing rates of terminations.&lt;/p&gt;
&lt;p&gt;The ten-year survival for spina bifida without hydrocephalus was 86.7% but fell to 53.3% with hydrocephalus, and 20-year survival remained 36.7% lower in those having hydrocephalus (95% CI 24 to 40, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001).&lt;/p&gt;
&lt;p&gt;Previous estimates of survival among children with cardiovascular anomalies ranged from 74.7% to 76.9% at five years, which are substantially lower than the 91.1% reported in the present study.&lt;/p&gt;
&lt;p&gt;As with Down syndrome, this may represent advances in care, but also may reflect the fact that the investigators stratified cases according to the presence of multiple anomalies.&lt;/p&gt;
&lt;p&gt;&quot;This effect is inconsequential for primary anomalies with a high mortality rate, such as hypoplastic left heart syndrome, since the effect of the primary anomaly is likely to overwhelm the effect of any additional anomalies. However, as the severity of the primary anomaly decreases, the confounding effect of any additional anomalies is likely to increase,&quot; they explained.&lt;/p&gt;
&lt;p&gt;For example, the 20-year survival of 98.3% for ventricular septal defect would have fallen to 91.7% if multiple anomalies had not been classified separately.&lt;/p&gt;
&lt;p&gt;The biggest limitation of the study was that only 10% of patients were born twenty years before the matching date of the study (Jan. 28, 2008) so that 20-year survival rates were only estimates for most of the anomaly subtypes.&lt;/p&gt;
&lt;p&gt;In an accompanying editorial, David H. Stone, MD, of the University of Glasgow, called for more research and funding for congenital anomalies.&lt;/p&gt;
&lt;p&gt;&quot;Birth-defect registries have had a chequered history since their initial proliferation after the thalidomide disaster,&quot; he wrote.&lt;/p&gt;
&lt;p&gt;They are a crucial source of data, but face an endless struggle for funding, with the result that good quality data on etiology, prevalence, and outcomes are sparse.&lt;/p&gt;
&lt;p&gt;&quot;The publication of today&apos;s findings from the north of England should provide a much-needed boost to the cause of congenital anomaly surveillance,&quot; Stone concluded.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;Funding for the study was provided by BDF Newlife.&lt;/p&gt;&lt;p&gt;All investigators and the editorialist declared no conflicts of interest.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_8_247"
                     title="Throwing the Tyrosine Kinase Kitchen Sink Against Glioblastoma"
                     score="-0.005"
                     href="