<?xml version="1.0" encoding="utf-8"?>
<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_465"
                     title="Genetic Pathways Play Role in NSCLC Survival (CME/CE)"
                     score="0.011"
                     href="http://www.medpagetoday.com/HematologyOncology/LungCancer/tb/18396?impressionId=1265811525897"
                     
      Researchers say they&apos;ve found genetic characteristics associated with age and sex differences observed in recurrence-free survival among non-small cell lung cancer patients.&lt;br&gt;
&lt;br&gt;Older patients at higher risk for recurrence had increased activation of wound-healing and invasiveness pathways, while high-risk women had increased activation of invasiveness and &lt;em&gt;STAT3&lt;/em&gt; pathways, Anil Potti, MD, of Duke University, and colleagues reported in the Feb. 10 issue of the &lt;em&gt;Journal of the American Medical Association&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;High-risk men had increased activation of the &lt;em&gt;STAT3&lt;/em&gt;, tumor necrosis factor, &lt;em&gt;EGFR&lt;/em&gt;, and wound-healing pathways, Potti the researchers found.&lt;br&gt;
&lt;br&gt;&quot;This analysis represents one of the first large-scale attempts to comprehensively characterize the biology of early-stage [non-small cell lung cancer] at a molecular pathway level and demonstrates a clear distinction in gene expression profiles within relevant age and sex categories,&quot; they wrote.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;There&apos;s lots of evidence that clinical and pathologic factors are clinically relevant, the researchers noted, but little is known about the underlying biological differences in lung tumor gene expression among patients with different characteristics, including age and gender.&lt;/p&gt;
&lt;p&gt;So Potti and colleagues conducted a retrospective analysis of 787 patients with predominantly early stage non-small cell lung cancer at Duke University from July 2008 to June 2009.&lt;/p&gt;
&lt;p&gt;They stratified their results by risk of recurrence, age, and gender.&lt;/p&gt;
&lt;p&gt;They found that high-risk patients under 70 had greater activation of the &lt;em&gt;Src&lt;/em&gt; and tumor necrosis factor pathways than low-risk patients (25% versus 6%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001; and 76% versus 42%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001, respectively).&lt;/p&gt;
&lt;p&gt;In patients 70 and older, those at high risk for recurrence had greater activation of the wound-healing and invasiveness pathways than low-risk patients (40% versus 24%, &lt;em&gt;P&lt;/em&gt;=0.02; and 64% versus 20%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001, respectively).&lt;/p&gt;
&lt;p&gt;&quot;Although this is a novel finding, biologically this is not entirely unexpected,&quot; the researchers wrote in reference to the data in older patients. &quot;The invasiveness and wound-healing gene signatures likely identify tumors at high risk of metastasis, along with the wound-healing signature identifying activation of angiogenesis pathways.&quot;&lt;/p&gt;
&lt;p&gt;Their findings also corroborated previous evidence that biology and clinical course of the disease are sex-specific, as the analysis found that women had significantly better progression-free survival than men (&lt;em&gt;P&lt;/em&gt;=0.008).&lt;/p&gt;
&lt;p&gt;In general, men had a higher probability of activation of these pathways than women:&lt;ul&gt;&lt;li&gt;Chromosomal instability (&lt;em&gt;P&lt;/em&gt;=0.001)&lt;/li&gt;&lt;li&gt;Epigenetic stem cell (&lt;em&gt;P&lt;/em&gt;=0.03)&lt;/li&gt;&lt;li&gt;Invasiveness (&lt;em&gt;P&lt;/em&gt;=0.005)&lt;/li&gt;&lt;li&gt;&lt;em&gt;Myc&lt;/em&gt; (&lt;em&gt;P&lt;/em&gt;=0.02)&lt;/li&gt;&lt;li&gt;Wound-healing (&lt;em&gt;P&lt;/em&gt;=0.004)&lt;/li&gt;&lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Women, meanwhile, had a higher probability of activation of the &lt;em&gt;E2F1&lt;/em&gt; pathway (&lt;em&gt;P&lt;/em&gt;=0.04).&lt;/p&gt;
&lt;p&gt;When stratified by risk, high-risk women had increased activation of the invasiveness and &lt;em&gt;STAT3&lt;/em&gt; pathways compared with low-risk women (99% versus 2%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001; and 72% versus 35%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001, respectively).&lt;/p&gt;
&lt;p&gt;Compared with low-risk men, those with high risk had increased activation of the following pathways:&lt;ul&gt;&lt;li&gt;&lt;em&gt;STAT3&lt;/em&gt; (87% versus 18%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001)&lt;/li&gt;&lt;li&gt;Tumor necrosis factor (90% versus 46%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) &lt;/li&gt;&lt;li&gt;&lt;em&gt;EGFR&lt;/em&gt; (13% versus 2%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001)&lt;/li&gt;&lt;li&gt;Wound-healing pathways (50% versus 22%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001)&lt;/li&gt;&lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Multivariate analyses confirmed pathway-based subphenotypes in women (HR 2.02, 95% CI 1.34 to 3.03, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) and in patients under 70 (HR 1.83, 95% CI 1.24 to 2.71, &lt;em&gt;P&lt;/em&gt;=0.003).&lt;/p&gt;
&lt;p&gt;&quot;While differences in clinical outcomes and the biology of [non-small cell lung cancer] based on age and sex have been previously noted, we were able to describe the molecular networks contributing to these differences,&quot; the researchers wrote.&lt;/p&gt;
&lt;p&gt;They said the findings are &quot;apt for therapeutic interventions when planning clinical trials with drugs that target specific pathway-related abnormalities or tumor biology.&quot;&lt;/p&gt;
&lt;p&gt;&quot;With genomic assays now being increasingly practical and clinically applicable, with turnaround times of five to seven days,&quot; they concluded, &quot;we believe our findings, while hypothesis generating and needing further validation, represent a step forward in defining pathway-driven cohorts of [non-small cell lung cancer] that likely explain the age-and sex-specific differences.&quot;&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 grants from the Emilene Brown Cancer Research Fund, the Harold and Linda Chapman Lung Cancer Fund, the Jimmy V Foundation, the American Cancer Society, and the National Cancer Institute.&lt;/p&gt;&lt;p&gt;The researchers 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_357"
                     title="Targeted Therapy Disappoints in Recurrent Brain Tumors (CME/CE)"
                     score="0.01"
                     href="http://www.medpagetoday.com/HematologyOncology/BrainCancer/tb/18237?impressionId=1265811525897"
                     
      &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_330"
                     title="Immune Cells Point to Skin Cancer Risk after Transplants (CME/CE)"
                     score="0.005"
                     href="http://www.medpagetoday.com/Nephrology/KidneyTransplantation/tb/18200?impressionId=1265811525897"
                     
      Monitoring two types of immune cells in kidney transplant recipients might identify patients with an increased risk of skin cancer, British investigators reported.&lt;br&gt;
&lt;br&gt;Increased levels of T-regulatory cells (Tregs) more than doubled the risk of squamous cell cancer of the skin. Decreased levels of natural killer (NK) cells were associated with more than a five-fold increased risk of skin cancer.&lt;br&gt;
&lt;br&gt;Both immune parameters had substantially greater predictive power than a history of squamous-cell skin cancer, according to an online report in the &lt;em&gt;Journal of the American Society of Nephrology&lt;/em&gt; by a team of Oxford University investigators.&lt;/p&gt;
&lt;p&gt;&quot;Squamous cell cancer of the skin affects about 30% of kidney transplant patients after 10 years of immunosuppression,&quot; Robert Carroll, MD, currently of Queen Elizabeth Hospital in Woodville, Australia, observed in a statement.&lt;/p&gt;
&lt;p&gt;&quot;A small number of patients develop multiple skin cancers per year, but there is no laboratory test to determine which transplant recipients will develop multiple skin cancers in the future.&quot;&lt;/p&gt;
&lt;p&gt;&quot;If a test can confirm high risk of skin cancer development, this may help clinicians to tailor immunosuppressive regimens for individual patients,&quot; he added.&lt;/p&gt;
&lt;p&gt;Long-term immunosuppression, such as that required for transplant recipients, confers an increased risk of squamous-cell skin cancer.&lt;/p&gt;
&lt;p&gt;Estimates of the magnitude have ranged as high as 200 times greater than the general population, the authors wrote. Additionally, 3% of organ transplant recipients require extensive plastic surgery each year as a result of skin cancer lesions.&lt;/p&gt;
&lt;p&gt;Age at transplantation and the immunosuppression dosage are the principal determinants of skin-cancer risk, and the dosage of immunosuppression also influences the risk of metastasis from squamous-cell cancer of the skin.&lt;/p&gt;
&lt;p&gt;In the general population, cancer has been associated with increased levels of Tregs, including CDR&lt;sup&gt;+&lt;/sup&gt;CD25&lt;sup&gt;high&lt;/sup&gt;FOXP3&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt;CD28&lt;sup&gt;-&lt;/sup&gt; cells. The same types of cells could play a role in the risk of skin cancer among organ transplant recipients, the authors wrote.&lt;/p&gt;
&lt;p&gt;Within the tumor microenvironment, Tregs may impair the antitumor activity of CD8&lt;sup&gt;+&lt;/sup&gt; and NK cell. However, in organ transplant recipients, Tregs help control or prevent rejections and may help improve long-term outcomes.&lt;/p&gt;
&lt;p&gt;Different immunosuppressive drugs affect Tregs differently, the authors continued. Sirolimus (Rapamune), for example, increases the number of FOXP3&lt;sup&gt;+&lt;/sup&gt; cells, whereas cyclosporine decreases Treg numbers.&lt;/p&gt;
&lt;p&gt;&quot;Tregs have not been assessed in relation to cancer after transplantation,&quot; the authors wrote. &quot;We therefore investigated the hypothesis that squamous-cell cancer in kidney transplant recipients would be associated with an increased number of Tregs.&quot;&lt;/p&gt;
&lt;p&gt;To examine the hypothesis, investigators phenotyped peripheral blood from 65 kidney transplant recipients with squamous skin cancer and 51 recipients without skin cancer, matched for age, sex, and duration of immunosuppression.&lt;/p&gt;
&lt;p&gt;They also quantified lymphocyte populations in skin cancer lesions from a subset of 25 patients and matched them with 25 other nontransplant patients with squamous cell cancer of the skin.&lt;/p&gt;
&lt;p&gt;The kidney transplant recipients had a median follow-up of 340 days. The investigators found that a concentration of &amp;gt;35 peripheral FOXP3&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt;CD127&lt;sup&gt;low&lt;/sup&gt; regulatory T cells/&amp;#181;L was associated with a hazard ratio for squamous cell skin cancer of 2.48 (95% CI 1.04 to 5.98).&lt;/p&gt;
&lt;p&gt;An NK cell count &amp;lt;100 cells/&amp;#181;L was associated with a skin cancer hazard ratio of 5.6 (95% CI 1.31 to 24). A history of squamous cell cancer of the skin increased the risk of skin cancer recurrence by a third (HR 1.33, 95% CI 1.15 to 1.53).&lt;/p&gt;
&lt;p&gt;&quot;If similar immune phenotypes are predictive in other kidney transplant recipient populations, then immune phenotype method has the potential to inform immunosuppressive regimen manipulation in kidney transplant recipients at high risk for developing multiple squamous cell cancers,&quot; the authors 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;The authors had no relevant disclosures.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_19_3986"
                     title="Cancer Report Card Reveals Decline in Disease and Death"
                     score="-0.005"
                     href="http://www.medpagetoday.com/HematologyOncology/Hematology/tb/17385?impressionId=1265811525897"
                     
      &lt;p&gt;Cancer incidence and mortality continue to decline, with the most dramatic decreases in lung, prostate, and colorectal cancers among men, and breast and colorectal cancers in women, according to the latest national report card.&lt;/p&gt;
&lt;p&gt;&quot;Overall cancer incidence rates for all racial/ethnic groups combined decreased by 0.7% per year during 1999-2006 for both sexes combined, by 1.3% per year during 2000-2006 for men, and by 0.5% per year during 1998-2006 for women,&quot; authors from the American Cancer Society, the CDC, the National Cancer Institute, and the North American Association of Central Cancer Registries concluded.&lt;/p&gt;
&lt;p&gt;The report, which has become an annual ritual, was published online in the ACS journal, &lt;em&gt;Cancer.&lt;/em&gt;&lt;/p&gt;
&lt;p&gt;There has been a decline in cancer death rates since the early 1990s and that trend appears to be durable.&lt;/p&gt;
&lt;p&gt;&quot;The decreases were slightly larger for men, who had declines of 1.5% per year during 1993-2001 and 2.0% per year during 2001-2006 compared with women, whose cancer death rates declined 0.8% per year during 1994-2002 and 1.5% per year during 2002-2006,&quot; the authors wrote.&lt;/p&gt;
&lt;p&gt;But the news was not all good. As men saw decreased rates of prostate, lung, oral, stomach, brain, and colorectal cancers, there was a concurrent increase in the cancers of the kidney, renal, liver, and esophagus  --  as well as increases in leukemia, myeloma, and melanoma of the skin.&lt;/p&gt;
&lt;p&gt;For women the story was similar -- decreased rates of breast, colorectal, ovarian, cervical, uterine corpus, and oral cancers, but an uptick in lung, thyroid, pancreas, bladder, and kidney cancers, as well as increases in non-Hodgkin lymphoma, melanoma, and leukemia.&lt;/p&gt;
&lt;p&gt;Colorectal cancer is a focus of this year&apos;s report, not a surprising choice because the news here is good: &quot;CRC death rates have declined since 1984 in both men and women, with an accelerated rate of decline since 2002 (for men) and 2001 (for women).&quot;&lt;/p&gt;
&lt;p&gt;And a &quot;microsimulation model&quot; suggests that death rates from colorectal cancer could be reduced by 36% over the next decade if &quot;1995-2000 trends for risk factor prevalence, screening, and treatment continue.&quot;&lt;/p&gt;
&lt;p&gt;But the authors point out that increased obesity among younger Americans could derail this trend.&lt;/p&gt;
&lt;p&gt;The annual report often paints a rosy picture based on a patchwork of data collected from a number of sources and analyzed using a complex array of statistical methods.&lt;/p&gt;
&lt;p&gt;The report&apos;s lead author, Brenda K. Edwards, PhD, of the National Cancer Institute, and her colleagues, provide detailed descriptions of potential problems  --  so much so that the report includes two pages of possible limitations.&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_27"
                     title="COX-2 Inhibitor May Ease Skin Cancer Burden (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/HematologyOncology/SkinCancer/tb/17793?impressionId=1265811525897"
                     
      &lt;p&gt;For people with a rare condition that puts them at high risk for skin basal cell carcinoma, the COX-2 inhibitor&lt;strong&gt; &lt;/strong&gt;celecoxib (Celebrex) could substantially cut down on the hundreds or thousands of tumors they develop over a lifetime, researchers said.&lt;/p&gt;
&lt;p&gt;In a phase II trial, the drug slowed the increase in basal cell carcinoma burden by an absolute 11% to 30% in patients with Gorlin syndrome, also known as basal cell nevus syndrome, according to Ervin H. Epstein, Jr., MD, of Children&apos;s Hospital of Oakland Research Institute, and colleagues.&lt;/p&gt;
&lt;p&gt;The COX-2 inhibitor appeared significantly effective only in patients with less severe disease, they reported in the January issue of &lt;em&gt;Cancer Prevention Research&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;The findings could have broader implications for skin cancer prevention in lower-risk individuals as well, commented Charles M. Rudin, MD, PhD, of Johns Hopkins, in an accompanying editorial.&lt;/p&gt;
&lt;p&gt;However, Epstein&apos;s group cautioned in the study that &quot;the potential cardiovascular risks associated with celecoxib would seem to preclude its widespread use.&quot;&lt;/p&gt;
&lt;p&gt;Although the risk with systemic COX-2 inhibition might be acceptable for patients with active cancers, for others, topical delivery could be feasible, Rudin suggested.&lt;/p&gt;
&lt;p&gt;Another possibility is development of several plant-derived small molecules, such as honokiol and curcumin, that have been shown to inhibit COX without causing cardiac toxicities, Jack L. Arbiser, MD, PhD, of Emory University in Atlanta, commented in a second editorial.&lt;/p&gt;
&lt;p&gt;COX enzymes are expressed at high levels in basal cell carcinoma, a finding which Epstein&apos;s group confirmed in mice with only one functioning copy of &lt;em&gt;PTCH1&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;This gene is seen to be malfunctioning in nearly all human cases of basal cell carcinoma. It encodes the primary inhibitor of the hedgehog pathway. Hedgehog is important in signaling the fate of cells during embryonic development, but activation thereafter helps tumor stem cells and contributes to malignant transformation.&lt;/p&gt;
&lt;p&gt;When these mice were exposed to radiation, they developed basal cell and other skin cancers much as Gorlin syndrome patients do.&lt;/p&gt;
&lt;p&gt;Overexpression of COX-2 yielded a twofold increase in microscopic basal cell carcinoma size compared with &lt;em&gt;COX&lt;/em&gt; wild-type mice.&lt;/p&gt;
&lt;p&gt;But knocking out COX-2 enzyme expression in the mouse model decreased overall basal cell tumor burden by 75%, largely because of significant decreases in size rather than number.&lt;/p&gt;
&lt;p&gt;Pharmacologically blocking COX-2 with celecoxib reduced microscopic basal cell carcinoma burden by about 30%, regardless of dose in the mice.&lt;/p&gt;
&lt;p&gt;So the researchers started a multicenter, phase II trial in 60 patients with Gorlin syndrome. The patients were randomized to placebo or oral celecoxib (200 mg twice daily) for 24 months.&lt;/p&gt;
&lt;p&gt;Celecoxib cut basal cell carcinoma burden (cumulative surface area) by an absolute 30% per year compared with placebo in patients with less severe Gorlin syndrome, as indicated by fewer than 15 tumors at baseline (50% versus 20% increase per year, &lt;em&gt;P&lt;/em&gt;=0.024).&lt;/p&gt;
&lt;p&gt;Although celecoxib produced a similar 30% reduction in new tumors overall in patients with Gorlin syndrome, the difference compared with placebo was not significant (&lt;em&gt;P&lt;/em&gt;=0.069).&lt;/p&gt;
&lt;p&gt;The reduction in basal cell carcinoma burden in patients overall was likewise not significant (26% versus 37% increase per year, &lt;em&gt;P&lt;/em&gt;=0.18).&lt;/p&gt;
&lt;p&gt;&quot;These prospective controlled results are consistent with prior observational data showing a modest effect of NSAIDs on squamous cell carcinomas and basal cell carcinomas,&quot; the researchers wrote.&lt;/p&gt;
&lt;p&gt;The greater effect on patients with lower baseline tumor burden was consistent with evidence for involvement of stromal COX-2 in the early stages of basal cell carcinoma development, they added.&lt;/p&gt;
&lt;p&gt;In his editorial, Rudin agreed that this finding suggested a primary effect on &quot;proliferation rate rather than on malignant transformation per se.&quot;&lt;/p&gt;
&lt;p&gt;Adverse events were similar between groups in the trial, with no cardiovascular signal.&lt;/p&gt;
&lt;p&gt;Further research using a combination approach with drugs that directly inhibit the hedgehog pathway may be warranted, Arbiser 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;The study was supported by grants by the National Institutes of Health and Office of the Director University of California at San Francisco&amp;#8211;Clinical and Translational Science Institute, and by the Mike Rainen Family Foundation, Patricia Hughes, and Stanley Eisenberg. Merck and Pfizer donated drugs for human and mouse treatments.&lt;/p&gt;&lt;p&gt;The researchers reported no conflicts of interest.&lt;/p&gt;&lt;p&gt;Rudin reported receiving support for research on the hedgehog pathway from the Burroughs Wellcome Fund but no conflicts of interest.&lt;/p&gt;&lt;p&gt;Arbiser reported receiving grant support from a Veterans Administration Merit Award, the National Institutes of Health, the Jamie Rabinowitch-Davis Foundation, and the Minsk Foundation. He reported pursuing patents on honokiol and Tris (dibenzylideneacetone) palladium.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
</recommendedContent>