Ibrahim Halil Sahin

Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer.

500 Background: Pts frequently treated with OC in the adjuvant, perioperative, or first-line setting for CRC may be retreated with oxaliplatin at the time of relapse or progression; the efficacy of retreatment is not known. Methods: Under an IRB-approved protocol, the pharmacy records identified 1,166 pts who received OC for CRC at our institution from 1/1/2004-12/30/2009. Pts were categorized as having previously received OC initially for the indication of adjuvant (group A, n=29), unresectable metastatic disease (group B, n=75), or perioperative therapy for metastasectomy (group C, n =22). Results: Four RECIST responses (14%) were seen in group A (2 of these pts received cetuximab in combination), four responses in group B (5%), and no responses in group C. Retreatment with OC following initial oxaliplatin exposure was associated with a low radiographic and biochemical response rate and a short time to progression or withdrawal of OC (Table). Retreatment duration was limited by cumulative neurotoxicity ...

Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.

Eukaryotic elongation factor 2 kinase (eEF-2K), through its phosphorylation of elongation factor 2 (eEF2), provides a mechanism by which cells can control the rate of the elongation phase of protein synthesis. The activity of eEF-2K is increased in rapidly proliferating malignant cells, is inhibited during mitosis, and may contribute to the promotion of autophagy in response to anti-cancer therapies. The purpose of this study was to examine the therapeutic potential of targeting eEF-2K in breast cancer tumors. Through the systemic administration of liposomal eEF-2K siRNA (twice a week, i.v. 150 µg/kg), the expression of eEF-2K was down-regulated in vivo in an orthotopic xenograft mouse model of a highly aggressive triple negative MDA-MB-231 tumor. This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth, the induction of apoptosis and the sensitization of tumors to the chemotherapy agent doxorubicin. eEF-2K down-modulation in vitro resulted in a decrease in the expression of c-Myc and cyclin D1 with a concomitant increase in the expression of p27Kip1. A decrease in the basal activity of c-Src (phospho-Tyr-416), focal adhesion kinase (phospho-Tyr-397), and Akt (phospho-Ser-473) was also detected following eEF-2K down-regulation in MDA-MB-231 cells, as determined by Western blotting. Where tested, similar results were seen in ER-positive MCF-7 cells. These effects were also accompanied by a decrease in the observed invasive phenotype of the MDA-MB-231 cells. These data support the notion that the disruption of eEF-2K expression in breast cancer cells results in the down-regulation of signaling pathways affecting growth, survival and resistance and has potential as a therapeutic approach for the treatment of breast cancer.

Rare Though Not Mutually Exclusive: A Report of Three Cases of Concomitant KRAS and BRAF Mutation and a Review of the Literature.

KRAS mutations occur frequently in colorectal cancers (CRC) and predict lack of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. CRC BRAF mutations, most commonly at V600E, occur less than 10% of the time, and occur usually in KRAS wild-type tumors, and more frequently in microsatellite instable tumors. Concomitant KRAS and BRAF mutant CRCs are rare (occurring in 0.001%); BRAF mutations should not be routinely tested in patients with KRAS mutant tumors, unless the patients is participating in a clinical trial enriching for the presence of a KRAS or BRAF tumor. Clinical trials treating patients with either KRAS or BRAF mutant tumors should address eligibility of patients with concomitant KRAS and BRAF mutations.

Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma.

Objective: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases. Methods: We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection. Results: Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4-77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil-interferon combination was the most frequently used systemic therapy. Conclusions: Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival.

Association of diabetes and perineural invasion in pancreatic cancer

Diabetes and perineural invasion are frequently observed in pancreatic cancer. In this study, we tested possible relations between diabetes and perineural invasion in patients with resected pancreatic cancer. We conducted a retrospective study in 544 cases of resected pancreatic adenocarcinoma seen at the University of Texas MD Anderson Cancer Center during 1996–2011. Information on tumor characteristics, diabetes history, and survival time was collected by personal interview and medical record review. Patients with diabetes before or at the time of the pancreatic cancer diagnosis were considered diabetes only. Pearson χ2 test was used to compare categorical variables in diabetic and nondiabetic groups. Kaplan–Meier plot, log‐rank test, and Cox proportional regression models were applied in survival analysis. The prevalence of diabetes and perineural invasion was 26.5% and 86.9%, respectively, in this study population. Patients with diabetes had a significantly higher prevalence of perineural invasion (92.4%) than those without diabetes (85%) (P = 0.025, χ2 test). Diabetes was not associated with other pathological characteristics of the tumor, such as tumor size, lymphovascular invasion, tumor grade, lymph node metastasis, and resection margin status. Diabetic patients had a significantly lower frequency of abdominal pain (P = 0.01), but a slightly higher frequency of weight loss (P = 0.078) as early symptoms of their cancer. Both diabetes and perineural invasion were related to worse survival and increased risk of death after adjusting for tumor grade and margin and node status (P = 0.036 and 0.019, respectively). The observed associations of diabetes and perineural invasion as well as reduced frequency of pain as early symptom of pancreatic cancer support the hypothesis that diabetes may contribute to pancreatic progression via the mechanism of nerve damage.

Aspirin, PIK3CA mutation, and colorectal-cancer survival [4]

To the Editor: Liao et al. (Oct. 25 issue)1 conclude that among patients with a diagnosis of colorectal cancer and mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit polypeptide gene that encodes the phosphatidylinositol 3-kinase [PI3K]), the use of aspirin was associated with longer colorectal cancer–specific survival and overall survival. However, patients with wild-type PIK3CA cancer who received the same treatment did not have longer survival. It might be interesting to know the distribution of the different mutations in the PIK3CA gene (exon 9, exon 20, or both) in this study. The existence of any of these mutations, especially in KRAS wild-type tumors,2 or the coexistence of the two best-known mutations implies an unfavorable prognosis in colorectal cancer.3 A further important aspect would be to analyze the specific benefit of aspirin in each group of patients with PIK3CA mutations (exons 9 and 20). Even more, in KRAS wild-type metastatic colorectal cancer, several studies4,5 have linked the exon 20 PIK3CA mutation to a lack of benefit from monoclonal antibodies against epidermal growth factor receptor (cetuximab or panitumumab). This molecular entity could be an exciting one in which to analyze the role of aspirin. Antonio Viúdez, M.D. Irene Hernandez, M.D. Ruth Vera, M.D.

High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: A single center retrospective study

PURPOSE Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature. METHODS Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies. RESULTS 196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0-19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P=0.047). CONCLUSIONS Based upon the patients risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery.

Predicting cetuximab efficacy in patients with advanced colorectal cancer

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 61–68 Current Biomarker Findings Dovepress

Obesity, Bisphosphonates, and Colorectal Cancer

fourstudiesinvestigatingtherelationshipbetweenbisphosphonate use and colorectal cancer risk and concluded that the use of oral bisphosphonates,whentheyareprescribed10ormoretimesinthe course of a year, is associated with a decreased risk of developing colorectal cancer. However, some confounding factors in the study may weaken this conclusion. Obesity (body mass index [BMI] 30) has been showntobeariskfactorforcolorectalcancer, 2 andhavingaBMImore than 26 to 28 is associated with a decreased risk of osteoporosis. 3 Therefore, obese patients included in this meta-analysis, who already hadanincreasedriskofdevelopingcolorectalcancer,mighthavebeen exposed less frequently to bisphosphonates. TheriskofcolorectalcancerwasadjustedforBMIinonlytwoof four studies examined in the meta-analysis (Rennert et al 4 and Green et al 5 ). Moreover, a recent study reported no association between exposuretobisphosphonatesandriskofcolorectalcancerafteradjusting for BMI. 6 Thus, the protective effects of oral bisphoshonates against colorectal cancer observed in the meta-analysis by Thosani et al 1 may have been related to the more frequent use of bisphosphonates in nonobese patients than the bisphosphonate use in

EGFR signalling and oncogenic pathway signature in colorectal cancer

Sun et al 1 reported a novel stratification model for classifying patients with colorectal cancer by characterising the gene expression profile of the tumours with wild type and mutant KRAS, BRAF and PIK3CA. The authors claimed that the combined transcription signature of these mutant signal molecules might help clinicians identify patients, whose tumour could have similar transcription signature without any mutation and who …