<?xml version="1.0" encoding="utf-8"?>
<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_452"
                     title="Study Backs Late Cardiotoxicity of Childhood Cancer Treatment (CME/CE)"
                     score="0.012"
                     href="http://www.medpagetoday.com/HematologyOncology/OtherCancers/tb/18384?impressionId=1265799087201"
                     
      A childhood cancer survivor&apos;s risk of dying from cardiovascular causes rises with the dose of radiation his heart received during treatment, researchers in France and the U.K. affirmed.&lt;br&gt;
&lt;br&gt;Those whose hearts were exposed had a 60% higher risk of cardiovascular death than the general population, even at a dose of 1 Gy (95% CI 20% to 250%), according to Florent de Vathaire, PhD, of L&apos;Institut National de la Sant&amp;#233; et de la Recherche M&amp;#233;dicale in Paris, and colleagues.&lt;br&gt;
&lt;br&gt;The risk jumped to 12.5-fold for a cumulative radiation dose to the heart of 5 to 14.9 Gy, and to 14.9-fold for a dose of more than 15 Gy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01 for trend), the researchers reported online in the &lt;em&gt;Journal of Clinical Oncology&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;The notion that exposing the heart to radiation increases the risk of cardiovascular disease and death is not surprising, according to an accompanying editorial.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;However, this study examined cardiovascular mortality effects of both the dose of radiation and the dose of anthracyclines given to childhood cancer victims in the same cohort.&lt;/p&gt;
&lt;p&gt;That&apos;s something previous studies haven&apos;t done, according to editorialists Steven E. Lipshultz, MD, of the University of Miami and Holtz Children&apos;s Hospital in Miami, and M. Jacob Adams, MD, MPH, of the University of Rochester, N.Y.&lt;/p&gt;
&lt;p&gt;&quot;These are pretty profound findings,&quot; Lipshultz told &lt;em&gt;MedPage Today&lt;/em&gt;. &quot;These are the exact concerns we&apos;ve had based on careful subclinical assessments of how the heart in these survivors has been working.&quot;&lt;/p&gt;
&lt;p&gt;His group was one of the first to report that survivors of childhood cancer faced not only acute cardiotoxicity from treatment, but also late cardiac effects.&lt;/p&gt;
&lt;p&gt;As more effective treatment for childhood cancers came into play, the dramatic jump in survival rates  --  from less than 50% in the mid-1970s to 80% today  --  yielded a large enough population of survivors to make chronic issues from treatment apparent, Lipshultz noted.&lt;/p&gt;
&lt;p&gt;&quot;It appears that for some of these survivors we have substituted one fatal disease of childhood  --  cancer  --  for another fatal disease of early adult life,&quot; he said.&lt;/p&gt;
&lt;p&gt;de Vathaire&apos;s group studied a cohort of 4,122 French and British children diagnosed with childhood solid cancer between 1942 and 1986 and who survived at least five years.&lt;/p&gt;
&lt;p&gt;Over an average of 27 years of follow-up, they were at 8.3-fold higher risk of dying from any cause compared with the general populations in France and the U.K. (95% CI 7.6 to 9.0).&lt;/p&gt;
&lt;p&gt;The majority of these excess deaths occurred early after diagnosis, five to nine years afterward in this analysis  --  in which all patients survived to five years.&lt;/p&gt;
&lt;p&gt;Based on just 32 deaths from cardiovascular diseases in the cohort, the childhood cancer survivors experienced five times the cardiovascular mortality (95% CI 3.3 to 6.7) expected from the general population (1.7% cumulative at 35 years versus 0.3%).&lt;/p&gt;
&lt;p&gt;This elevation in risk was similar to that seen in large studies from the U.S. and Nordic countries, suggesting generalizability of the results, Lipshultz said.&lt;/p&gt;
&lt;p&gt;Radiation therapy also conferred a 5.0-fold elevation in risk of cardiovascular disease-related death (95% CI 1.2 to 21.4).&lt;/p&gt;
&lt;p&gt;Like radiation, a higher cumulative dose of anthracycline chemotherapy also increased risk of dying from cardiac diseases, compared with the general population (RR 4.4 for a dose over 360 mg/m&lt;sup&gt;2&lt;/sup&gt;, 95% CI 1.3 to 15.3).&lt;/p&gt;
&lt;p&gt;However, radiotherapy and chemotherapy did not appear to interact for cardiovascular mortality (&lt;em&gt;P&lt;/em&gt;=0.4).&lt;/p&gt;
&lt;p&gt;Notably, the vinca alkaloids were also significantly linked to cardiovascular disease-related death risk among childhood cancer survivors, even after adjustment for sex, treatment period, age at diagnosis, follow-up, and all other treatment modalities (RR 3.6, 95% CI 1.0 to 12.9).&lt;/p&gt;
&lt;p&gt;Currently, guidelines support regular long-term cardiovascular screening for childhood cancer survivors who received anthracycline-based chemotherapy but provide little to no direction for those treated with nonanthracycline chemotherapy or radiation, Lipshultz noted.&lt;/p&gt;
&lt;p&gt;These results suggested all three groups should be getting cardiac follow-up, he told &lt;em&gt;MedPage Today&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;However, because other research has suggested that these individual treatments affect the heart in different ways, such as diastolic rather than systolic dysfunction with radiotherapy, screening modalities may need to account for this as well, he said.&lt;/p&gt;
&lt;p&gt;The researchers cautioned that cardiovascular disease was probably under-reported as a cause of death in the cohort.&lt;/p&gt;
&lt;p&gt;&quot;Indeed, 15 of the deaths classified as results of cancer as the principal cause had cardiovascular diseases as the immediate cause,&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 the Ligue Nationale Contre le Cancer; the Programme Hospitalier de Recherche Clinique; the Agence Fran&amp;#231;aise de S&amp;#233;curit&amp;#233; Sanitaire et Produit de Sant&amp;#233;; Electricit&amp;#233; de France; the Wyeth Foundation for childhood and adolescent health; and a grant from the Foundation of France.&lt;/p&gt;&lt;p&gt;The researchers reported no conflicts of interest.&lt;/p&gt;&lt;p&gt;The editorialists reported no 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_372"
                     title="Low Serotonin Eyed as Mechanism for SIDS (CME/CE)"
                     score="0.008"
                     href="http://www.medpagetoday.com/Neurology/GeneralNeurology/tb/18262?impressionId=1265799087201"
                     
      Low brainstem levels of serotonin and the enzyme that makes it could underlie sudden infant death syndrome (SIDS), researchers suggested.&lt;br&gt;
&lt;br&gt;In an autopsy study, SIDS cases showed 26% lower serotonin levels in two major components of the medulla&apos;s serotonin system  --  the raph&amp;#233; obscurus (&lt;em&gt;P&lt;/em&gt;=0.05) and paragigantocellularis lateralis (&lt;em&gt;P&lt;/em&gt;=0.04)  --  compared with age-adjusted controls who died from known causes.&lt;br&gt;
&lt;br&gt;These brainstem circuits control breathing, blood pressure, and heart rate during sleep, Hannah C. Kinney, MD, of Children&apos;s Hospital Boston, and colleagues reported in the Feb. 3 issue of the &lt;em&gt;Journal of the American Medical Association&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;A baby with an abnormality in control of these systems might not be able to respond to a life-threatening challenge like asphyxia by rousing from sleep or turning its head the researchers explained.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;SIDS occurs in the &quot;critical first year of life, when homeostatic systems are still maturing,&quot; they noted.&lt;/p&gt;
&lt;p&gt;Mary McClain, RN, MS, of Boston University Medical Center, who counsels families that have lost a baby to SIDS, commented that these findings help establish the biological basis for urging parents to place their babies on their backs to sleep.&lt;/p&gt;
&lt;p&gt;The researchers obtained tissue samples from autopsies of 41 children who died from SIDS, seven who died acutely from known causes (including a car accident, drowning, pneumonia, and unsuspected congenital heart disease), and five who died in the hospital with chronic conditions causing hypoxia-ischemia.&lt;/p&gt;
&lt;p&gt;SIDS cases had mean serotonin levels of 31.4 pmol/mg of protein in the paragigantocellularis lateralis, compared with 40.0 pmol/mg among the controls who died acutely (&lt;em&gt;P&lt;/em&gt;=0.04).&lt;/p&gt;
&lt;p&gt;Levels averaged 55.4 versus 75.5 pmol/mg of protein, respectively, in the raph&amp;#233; obscurus (&lt;em&gt;P&lt;/em&gt;=0.05).&lt;/p&gt;
&lt;p&gt;These abnormalities in the medulla did not appear to involve the catecholamine system. Catecholamine levels were similar between SIDS cases and controls.&lt;/p&gt;
&lt;p&gt;Nor was there evidence for excessive degradation of dopamine or neurotransmitter turnover in SIDS cases, supporting the idea that the key abnormality is reduced synthesis of serotonin, the researchers said.&lt;/p&gt;
&lt;p&gt;Another marker of serotonin function  --  tryptophan hydroxylase (TPH2), the key enzyme involved in synthesis of serotonin  --  also supported this conclusion, with 22% lower levels in the raph&amp;#233; obscurus in SIDS than in controls (&lt;em&gt;P&lt;/em&gt;=0.03).&lt;/p&gt;
&lt;p&gt;Serotonin receptor binding was 29% to 55% lower in three medullary nuclei that receive serotonin projections, notable for a decrease in binding with older age in SIDS cases, but not controls, the researchers noted.&lt;/p&gt;
&lt;p&gt;Given similar findings in three previous investigations, this &quot;may reflect a progressive decrease with age in those infants with the &apos;SIDS abnormality,&apos;&quot; they wrote. Or it&apos;s possible that those with a &quot;stronger abnormality take longer to outgrow the risk period for SIDS and continue to die at older ages,&quot; Kinney&apos;s group wrote.&lt;/p&gt;
&lt;p&gt;Likewise, serotonin receptor binding in infants who died from SIDS was significantly lower in those without known risk factors for SIDS, such as &lt;a href=&quot;http://www.medpagetoday.com/Pediatrics/GeneralPediatrics/17365&quot; mce_href=&quot;http://www.medpagetoday.com/Pediatrics/GeneralPediatrics/17365&quot; target=&quot;_blank&quot;&gt;sleeping face down&lt;/a&gt;, &quot;suggesting that additional risk factors are necessary to precipitate death when the medullary serotonin system is less compromised,&quot; they added.&lt;/p&gt;
&lt;p&gt;Although repetitive apnea and agonal &lt;a href=&quot;http://www.medpagetoday.com/Pulmonology/SleepDisorders/2817&quot; mce_href=&quot;http://www.medpagetoday.com/Pulmonology/SleepDisorders/2817&quot; target=&quot;_blank&quot;&gt;impaired gasping&lt;/a&gt; before death have been reported in some SIDS cases, chronic impaired oxygenation in the hospitalized children in the study produced a very different serotonin pattern than that seen in SIDS.&lt;/p&gt;
&lt;p&gt;Children who died with chronic hypoxia conditions had 55% higher serotonin levels in the raph&amp;#233; obscurus (&lt;em&gt;P&lt;/em&gt;=0.02) and 126% higher levels in the paragigantocellularis lateralis (&lt;em&gt;P&lt;/em&gt;=0.002) than the SIDS cases.&lt;/p&gt;
&lt;p&gt;They also had 640% higher dopamine levels in the raph&amp;#233; obscurus than the SIDS cases (&lt;em&gt;P&lt;/em&gt;=0.006).&lt;/p&gt;
&lt;p&gt;This suggested &quot;that the primary mechanisms underlying serotonin abnormalities in SIDS are not mediated by chronic hypoxia-ischemia,&quot; Kinney&apos;s group wrote.&lt;/p&gt;
&lt;p&gt;The researchers cautioned that their neurotransmitter measurements may have been off somewhat due to prolonged postmortem intervals.&lt;/p&gt;
&lt;p&gt;They also warned that the study was limited by inability to perform these measurements at the synapse in postmortem tissues and by the small sample of controls.&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 the First Candle/SIDS Alliance, CJ Martin Overseas Fellowship (National Health and Medical Research Council of Australia), CJ Murphy Foundation for Solving the Puzzle of SIDS, CJ Foundation for SIDS, National Institute of Child Health and Development, and the Developmental Disabilities Research Center at Children&apos;s Hospital Boston.&lt;/p&gt;&lt;p&gt;The researchers reported no conflicts of interest.&lt;/p&gt;&lt;p&gt;McClain provided no information on 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_357"
                     title="Targeted Therapy Disappoints in Recurrent Brain Tumors (CME/CE)"
                     score="0.007"
                     href="http://www.medpagetoday.com/HematologyOncology/BrainCancer/tb/18237?impressionId=1265799087201"
                     
      &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="20090101_3_274"
                     title="Childhood Leukemia and Brain Tumor Survivors Have Increased Stroke Risk"
                     score="-0.006"
                     href="