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Progressive renal dysfunction develops in patients with advanced HF. We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C compared with established markers of renal function in patients with heart failure (HF) because they might improve prognostic assessment of patients with HF.Serum samples were collected from 40 patients with stable HF (age: 58 ± 8 years, body mass index [BMI]: 28.4 ± 6.4 kg/m(2)), 40 HF patients undergoing ventricular assist device (VAD) implantation (age: 53 ± 11 years, BMI: 26.8 ± 5.5 kg/m(2)), 40 patients undergoing VAD removal at cardiac transplantation, and 24 controls (age: 48 ± 7 years, BMI: 29.4 ± 4.2 kg/m(2)). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease formula.Patients with stable HF showed elevated NGAL and cystatin C levels compared with controls (NGAL: 114.9 ± 48.3 ng/mL vs 72.0 ± 36.6 ng/mL, p0.0001; cystatin C: 1490.4 ± 576.1 ng/mL vs 954.7 ± 414.2 ng/mL, p = 0.0026). Unlike cystatin C, NGAL increased in advanced HF patients requiring VAD implantation (158.7 ± 74.8 ng/mL, p0.001). On VAD support, NGAL levels decreased (127.1 ± 80.4 ng/mL, p = 0.034). NGAL was higher in patients who developed right ventricular failure (187.8 ± 66.0 vs 130.9 ± 67.0 ng/mL, p = 0.03) and irreversible renal dysfunction (190.0 ± 73.8 ng/mL vs 133.8 ± 54.2 ng/mL, p0.05), whereas cystatin C, creatinine, and eGFR were not different. NGAL correlated with eGFR (r = -0.2188, p = 0.01).NGAL levels correlate with HF severity and hemodynamic improvement after VAD placement. Our findings suggest a role of this novel biomarker as a marker of severity and prognosis in patients with HF.

An automated system has been designed for routine amperometric testing of biosensor components for Cygnus Inc.'s GlucoWatch glucose monitoring device. Sensitivity of biosensors is measured as the amperometric response to hydrogen peroxide standards, across development lots, for lot release, and for stability testing. The automated system consists of five principal components: 1) a Gilson Model 223 liquid handling system with Model 402 syringe pump; 2) flow cells designed to hold biosensors; 3) programmable calibrated potentiostats; 4) valves, solenoids, and relays to direct flow and initiate potentiostats; and 5) software to control the liquid handling and potentiostat programming, and software for data acquisition. The system sequence consists of downloading potentiostat voltage-time programs, preconditioning the sensors under test, and then directing 0, 1, 5, and 10 µM H2O2 to the biosensors. The potentiostat is started after each injection, and the resulting current is measured at selected intervals. Sensor current is measured over 5 minutes, and the sensor response is determined using the observed current at selected intervals. Sensor sensitivity is measured as the slope of sensor response versus H2O2 concentration. The limit of quantitation of this automated method is 0.5 µM H2O2 and the analytical precision is less than 10 % RSD at 5 µM H2O2. Peroxide decline in standards is limited to less than 5 % over 8 h at room temperature, and less than 2 % over the typical analysis time of 4 h. This system provides a reliable, precise and easy procedure for multichannel amperometric biosensor testing.

International audience; The "Empire Youth Movement" (later known as the "Commonwealth Youth Movement") was the brainchild of Major Frederick James Ney, a "fervent imperialist" and a Canadian military man of English background who sought to solidify Britain's relationship with Canada. This paper delves into the little known history of this Movement from its inception in 1937 to the 1960s. In doing so, it addresses how Canada directly participated, directed and contributed in tangible ways towards the shifting of meanings and ideas of the British Empire and the Commonwealth for impressionable youth of different territories within the British sphere of influence.; Le mouvement de jeunesse « Empire Youth Movement » (rebaptisé « Commonwealth Youth Movement » par la suite) est une création du Major Frederick James Ney, "un fervent impérialiste" et un Canadien, militaire d'origine anglaise, qui chercha à renforcer les liens entre le Canada et la Grande-Bretagne. Cet article explore l'histoire peu connue de cette organisation, de sa naissance, dans les années trente jusqu'aux années soixante, et analyse comment le Canada a contribué culturellement au concept de Commonwealth. Cette contribution se focalise sur l'impact de ce mouvement sur des jeunes membres influençables venant des quatre coins du monde britannique.

An increased risk of prostate cancer is currently not considered a part of the Lynch syndrome spectrum. The purpose of this study was to retrospectively examine prostate cancer incidence in the Lynch syndrome cohort at the Ohio State University in comparison with that in the general population. We included all males diagnosed with Lynch syndrome from June 1998 to June 2012 at the Ohio State University and obtained baseline information including cancer history. If patients had not been seen in the 12 months before June 2012, they were contacted to document changes in their cancer history. We compared prostate cancer incidence among the Lynch syndrome families with that of the general population by using the Surveillance, Epidemiology, and End Results registry 1999–2009. Of the 188 males identified with Lynch syndrome, 11 males were diagnosed with prostate cancer during the study period. The ratio of observed to expected numbers of prostate cancer cases resulted in a standardized rate ratio of 4.87 (95% confidence interval: 2.43–8.71). Impaired mismatch repair expression and microsatellite instability were seen in one out of two prostate cancer specimens available for testing. Males with Lynch syndrome had a nearly fivefold increased risk of developing prostate cancer but did not appear to have earlier onset or a more aggressive phenotype. Genet Med 16 7, 553–557.

Colon cancer is among the most common cancers in the United States, and the median age of patients at diagnosis is 70. Medical oncologists are commonly asked to comprehensively evaluate elderly patients to estimate individual risk/benefit ratios for adjuvant treatment. Although 40% of patients with colon cancer are elderly, clinical trials enroll mainly younger patients. Consequently, we are forced to depend on subgroup analyses, observational studies, and personal experience to guide recommendations. Decision-making in adjuvant therapy for colon cancer is increasingly complex, as we subdivide patients with stage II to III colon cancer by molecular as well as anatomic staging to predict which are likely to benefit from chemotherapy and then whether the addition of oxaliplatin to 5-fluorouracil (5-FU) is worth the toxicity. It is likely that the tumor biology of younger and older patients differs, and more research is needed to dissect out the biologic heterogeneity of both the tumors and their elderly hosts to help guide treatment. We recognize that our evaluations should not solely be based on temporal age and factor physiology, pharmacology, psychology, functional status, and social support into these considerations. Older patients who are treated must be monitored closely for toxicities when undergoing treatment. Although there is a clear need for clinical trials in this population, treatment decisions confront us today in the absence of definitive evidence. How can we help our patients navigate through these important choices?

Introduction: 5-fluorouracil (5-FU)-based chemoradiation (CRT) is a standard neoadjuvant treatment strategy for the treatment of locally-advanced rectal adenocarcinomas (LARC). MEK-1/2 inhibition has been shown to radiosensitize Ras mutant tumors in preclinical models, including colorectal cancer. In this phase 1 trial, we will test MEK-1/2 inhibition in combination with neoadjuvant CRT for LARC. Methods: This trial is a standard 3+3 design testing 3 dose levels of the MEK-1/2 inhibitor trametinib (GSK1120212) in combination with CRT: 0.5 mg, 1.0 mg, and 2.0 mg daily, followed by an expansion cohort. All patients first receive a one week lead-in dosing of trametinib monotherapy, and undergo a tumor biopsy at the end of that week to assess pharmacodynamic inhibition by immunohistochemistry (IHC). Then, patients receive standard CRT (5-FU 225 mg/m2 per day by continuous infusion during radiotherapy, and 50.4 Gy in 28 fractions, 5 days/ week) in combination with trametinib (5 days/week). Patients have total mesorectal excision (TME) 6-10 weeks after completion of CRT. Results: The trial opened in 2013, and 31 patients have been screened for KRAS/BRAF/NRAS activating mutations, of which 11 (35.4%) tested positive for a mutation. Of these, 9 patients (8 male, 1 female) have been enrolled so far, with 3 patients accrued in each dose level. Regarding mutation status, six patients have KRAS mutations (five G12V, one G13D), two patients have BRAF mutations (one V600E, one D594N), and one patient is unknown (in dose level 1). Age of patients ranges from 38-64 years old (median 55). All patients have successfully completed neoadjuvant therapy and TME (5 low anterior resection, 4 abdominal-perineal resection). No dose-limiting toxicities were observed on dose levels 1 and 2, and additional patients are currently being accrued onto dose level 3 (2.0 mg). One patient in dose level 3 had pathologic complete response (pCR) at the time of TME. Examination of pre-treatment tumor tissue by IHC reveals baseline hyperactivation of ERK-1/2 (p42/44 MAPK) in most tumors with some heterogeneity in levels of phospho-ERK staining, reflecting hyperactivation of the RAS/RAF-MAPK pathway. Qualitatively, ERK-1/2 activity is reduced from pre-treatment to post-trametinib lead-in tumor tissue, particularly in patients on dose level 3. The patient who experienced a pCR had the most significant reduction in ERK-1/2 activity in tumor tissue and tumor-associated stroma. We will also present quantitative data demonstrating ERK-1/2 inhibition using Vectra quantitative immunohistochemistry. Conclusions: The combination of trametinib with 5-FU-based CRT for LARC is feasible with promising signs of clinical activity and tolerability. Ongoing enrollment will further assess safety, tolerability, and determine the maximally-tolerated dose of trametinib. Initial analysis of tumor tissue suggests dose-dependent pharmacodynamic inhibition of ERK-1/2 within 5 days of starting trametinib. Citation Format: Terence M. Williams, Evan Wuthrick, Christina Wu, Ryan Robb, Cynthia Timmers, Tanios Bekaii-Saab. A phase I trial combining MEK-1/2 inhibition in combination with 5-fluorouracil and radiation for KRAS, BRAF, and NRAS mutant locally advanced rectal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT025.

e14126Background: KRAS, NRAS, and BRAF mutations constitutively activate and dysregulate the MAPK pathway in colorectal cancer. Pre-clinical data suggest that MEK 1/2 inhibition radiosensitizes RAS...

e15148Background: MSI is detected in approximately 15% colorectal cancers, and associated with improved survival in early stage colon cancer. Heat shock protein 110 (HSP110) is a chaperone protein ...

584 Background: Tumor genomic profiling has become critical in the identification of targeted therapeutic options for patients (pts) with advanced malignancies. Mutational frequencies and their therapeutic importance vary among tumor types. This analysis was undertaken to characterize the landscape of genomic alterations in gastrointestinal (GI) malignancies found in a large academic institutional practice, and to determine the frequency of alteration-specific targeted therapy selection based on genomic profiling. Methods: Adult pts with GI malignancies presenting to the Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing through FoundationOne testing as part of routine clinical care. Institutional review board approval was obtained to retrospectively analyze results from FoundationOne testing performed between 2012 and 2015. Results: 265 pts with GI malignancies underwent successful genomic profiling. 1205 genomic alterations were found, with an average of 4.5 per tumor (range 0-20); 365 (30%) of these were potentially actionable and most often found in colorectal or gastroesophageal tumors. 14 pts (5.3%) had actionable alterations in MET, CDKN2A/B, FGFR2, KRAS, BRAF, or NF2 that led to enrollment in genotype-directed clinical trials or off label use of targeted therapies beyond standard of care. Pt performance status at the time of genomic alteration identification was a significant factor in precluding genotype-directed therapy. One variant of unknown significance involving FGFR2 identified at initial testing subsequently became actionable and led to pt enrollment on a clinical trial. One pt with rectal cancer was found to have a KRAS wild-type and BRAF mutant primary but KRAS mutant and BRAF wild-type liver metastasis. Conclusions: Genomic profiling of GI malignancies through next generation sequencing is feasible and can lead to genotype-directed therapy selection; however, it should be considered early in the pt’s course to optimize use of targeted therapies through clinical trials. Consideration should be given to serial tumor testing to identify emerging genomic alterations for optimal therapy selection.

4079Background: BTC are uncommon and associated with a dismal prognosis. Gemcitabine and platinum-combinations (GP) form the standard approach for treating advanced BTC with a modest improvement in...

287 Background: aBTC is uncommon and has a dismal prognosis with limited therapeutic options. First-line therapy for untreated aBTC is GC, with no approved therapies in the refractory setting. To assess for tumor-specific genetic variants that affect outcomes in patients (pts) who received GC in aBTC, we performed NGS in pts treated with who received GC as first-line therapy. Methods: Archival formalin-fixed, paraffin-embedded samples from pts with mBTC from Ohio State University and MD Anderson Cancer Center who received GC in the first-line and underwent NGS as part of routine care. 315 cancer-related genes plus select introns from 28 genes altered in solid tumors were included in the NGS panel. Univariate Cox regression model was used to determine the association between gene mutations with progression free survival (PFS) and (OS). Results: 80 evaluable pts with aBTC treated with first-line GC chemotherapy underwent successful genomic profiling. A total of 414 cancer-specific mutations were identified, where 49 (12%) genes had mutations with > 5% frequency. 17 of the 49 were known mutations. From the comprehensive analysis, somatic mutations in IDH1 (11 of 80 pts; 13%) (HR 0.31; p = 0.035) was associated with improved overall survival (OS) and progression free survival (PFS). Pts wild type for IDH1 had a median OS of 17.7 months and PFS of 4.5 months, while those with an IDH1 mutation had a median OS that was not reached and an improved PFS of 5.7 months. Conclusions: Somatic mutations in IDH1 were associated with improved clinical outcomes in pts with aBTC who received GC as first-line therapy which is consistent with other solid tumor malignancies. IDH1 is a therapeutic target of interest, where future prospective studies will be necessary to validate the predictive utility and its relevance in pt outcomes in aBTC.

196 Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.

215 Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer with a very dismal prognosis. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in progression free survival (PFS) and overall survival (OS) with acceptable toxicities when combined with 5-Fluorouracil (5FU)/ leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in APC. Methods: We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs) and Kaplan-Meier methods were used to calculate the median PFS and OS. Results: Forty patients were included in this analysis, 33% male. Patients had received 1 to 5 lines of prior therapy (27% with 1 prior and 25% with more than 3 lines of prior therapy). The mean age at diagnosis was 60 and 97% had ECOG of 1. The average CA 19-9 at the start of therapy was 33168 U/ml. The median PFS (from the start of FOLFIRI to disease progression or last follow up) was 2.59 months [95% confidence interval (CI); (1.90, 3.54)] and OS (from the start of FOLFIRI to death or least follow up) was 4.75 months [95% CI (3.14, 8.98)]. The most common AEs included fatigue (98%), neuropathy (83%), anorexia (68%), nausea (60%) and constipation (55%). Grade 3 toxicities included fatigue (13%) and rash (3%). There were no observed grade 4 toxicities that were observed. Conclusions: In this single institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in this heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC.

We thank Haufe et al for their insightful comments on our study of adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure (HF) and the impact of mechanical unloading.1 We appreciate the observation that incorrect homeostasis model of insulin resistance (HOMA-IR) values were listed in Table 3. Upon recalculation using the HOMA-IR formula, the correct values were found to be 1.0±0.6 for controls, 7.6±7.7 in advanced HF ( P =0.02 versus controls) and 4.5±3.6 after left ventricular assist device (LVAD) support ( P =0.01 versus HF). This supports the conclusion …

Aims Abnormal bone metabolism and progressive demineralization have been described in patients with heart failure (HF). We hypothesized that mechanical unloading through implantation of a ventricular assist device (VAD) with subsequent haemodynamic improvement would correct abnormal bone metabolism in patients with advanced HF. Methods and results Serum was collected from 14 controls, 20 patients with moderate HF, 34 patients with advanced HF undergoing VAD implantation, and 34 patients at the time of VAD explantation (mean duration: 169 ± 125 days). Bone metabolism markers were measured using enzyme-linked immunosorption assay (ELISA) or chemiluminescence immunoassay (CLIA). Compared with controls, HF patients showed increased parathyroid hormone (PTH: 42 ± 19 vs. 117 ± 117 pg/mL in HF; P < 0.02) with decreased 25-hydroxyvitamin D [25(OH)D: 29 ± 14 vs. 21 ± 11 ng/mL in HF; P = 0.05]. While procollagen-1 N-terminal peptide (P1NP) and osteocalcin were similar, cross-linked C- and N-telopeptides of type I collagen (CTX and NTX) were both higher in HF (NTX: 14 ± 6 vs. 20 ± 11 ng/mL; P < 0.05; CTX: 0.35 ± 0.13 vs. 1.05 ± 0.78 ng/mL; P < 0.01 for controls and HF, respectively). P1NP increased markedly after VAD implantation (49 ± 37 vs. 121 ± 62 ng/mL; P < 0.0001), with a mild decrease in CTX and NTX levels indicating a shift towards anabolic bone formation. Serum PTH correlated with estimated glomerular filtration rate (r = –0.245, P < 0.05). Conclusion Patients with advanced HF are characterized by increased levels of biochemical markers of bone resorption potentially as a result of secondary hyperparathyroidism and uncoupling of bone remodelling. Haemodynamic improvement and mechanical unloading after VAD implantation lead to correction of bone metabolism and increased levels of anabolic bone formation markers.

Background— Heart failure (HF) is characterized by inflammation, insulin resistance, and progressive catabolism. We hypothesized that patients with advanced HF also develop adipose tissue inflammation associated with impaired adipokine signaling and that hemodynamic correction through implantation of ventricular assist devices (VADs) would reverse adipocyte activation and correct adipokine signaling in advanced HF. Methods and Results— Circulating insulin, adiponectin, leptin, and resistin levels were measured in 36 patients with advanced HF before and after VAD implantation and 10 healthy control subjects. Serum adiponectin was higher in HF patients before VAD implantation compared with control subjects (13.3±4.9 versus 6.4±2.1 μg/mL, P =0.02). VAD implantation (mean, 129±99 days) reduced serum adiponectin (7.4±3.4 μg/mL, P P P 2 versus 5583±142 μm 2 in control subjects; P P Conclusions— Adipose tissue inflammation and adiponectin resistance develop in advanced HF. Mechanical unloading of the failing myocardium reverses adipose tissue macrophage infiltration, inflammation, and adiponectin resistance in patients with advanced HF.

There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice.

Gastrointestinal stromal tumors (GISTs) are rarely found in the anorectum and account for less than 0.3% of all rectal malignancies. The major treatment of rectal GISTs is complete resection of the primary tumor with negative microscopic margin. Here, we present an alternative method-laparoscopic-assisted local excision of rectal GIST. The patient had a 5x4x3 cm GIST located 4 cm above the dentate line in the right rectal wall. The tumor was mobilized by laparoscopic dissection with a clear safe margin and the specimen was removed from anus. The patient had a smooth recovery and no recurrence was observed 31 months after the procedure. This experience suggests that laparoscopic excision is a safe alternative for rectal GIST, offering the advantage of better visualization of structures and sparing the patient from unnecessary abdominoperineal resections.

Repeated oral stimulation with solutions of 2 ppm capsaicin increased time to maximum intensity, but yielded a decrease in sequential mouth-burn intensity due to a rising minimum irritation rating between stimuli. Two response patterns were observed: for 18 subjects mouth-burn increased, while 14 subjects showed depression upon repeated stimulation. Because of across-subject variability, there was little correlation between parotid salivary response and perceived sensory responses. Capsaicin-stimulated salivary flow was significantly higher than flow stimulated by distilled water in 9 high-flow subjects, but not in 14 low-flow subjects. Oral adaptation to capsaicin may attenuate parotid salivary response, although eaters and noneaters of chili peppers did not differ significantly in their perception of mouth-burn or in salivary flow.

Oral rinsing with different solutions significantly reduced mouth-burn of capsaicin solutions in both eaters and noneaters of chili peppers. Cold solutions (5 degrees C) were more effective in reduction of mouth-burn than solutions at 20 degrees C. Sucrose solutions (10%) at 20 degrees C and whole milk at 5 degrees C were equally effective while 5% ethanol was no more effective in mouth-burn reduction than water at 20 degrees C. Reduction of mouth-burn by sucrose was not dose dependent. Noneaters of chili peppers experienced a slightly greater reduction of mouth-burn from sucrose solutions than eaters. Oral rinsing with sweetened milk containing 0 and 10% fat, of varying globule size, resulted in similar degree of mouth-burn reduction. The first (control) sample was rated higher in intensity than subsequent ones, suggesting desensitization, which appears to be due to the interaction of stimulation of chemo-, mechano-, thermo- and gustatory receptors.

Meeting abstracts Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has a 5-year survival rate of less than 7% and is ultimately refractory to most treatments. An assessment of immunologic factors relevant to disease has not been performed in a comprehensive manner for treatment

KRAS is the most frequently altered gene in colorectal cancer (CRC), with mutations occurring in 30-40% of colorectal cancer. Although KRAS mutation is associated with poor prognosis and resistance to anti-epidermal growth factor receptor therapy, the mechanism by which it promotes tumor metastasis remains undefined. Our study explored a new hypothesis that targeting the Y-box binding protein-1 (YB-1)-insulin-like growth factor-I receptor (IGF-IR) signaling axis which is downstream of KRAS, with a novel integrin-linked kinase inhibitor, T315, represents a therapeutically relevant strategy to block KRAS mutation-driven tumor progression. In liver metastases from CRC patients, we observed that there was a preponderance (79/108) of over-expression in both YB-1 and IGF-1R by immunohistochemistry. In colon cancer cell lines HCT-116 and SW480, knockdown and over-expression of KRAS affected the protein and mRNA levels of IGF-1R in a dose-dependent manner. But KRAS only affected the protein level and not mRNA of YB-1, thus suggesting that KRAS regulated YB-1 expression at the post-transcriptional level. Manipulation of YB-1 via plasmid overexpression and siRNA affected IGF-1R protein and mRNA levels in a dose-dependent manner, and YB-1 and IGF-1R promoter binding was confirmed via ChIP assay. There was a dose-dependent decrease in YB-1 and IGF-1R protein levels with MEK162, a MEK inhibitor, but not with LY294002m a PI3K inhibitor. This demonstrated that the KRAS regulation of the YB-1- IGFR-1R signaling axis to be via the MEK signaling pathway and not PI3K/Akt. Our novel drug T315 targets YB-1, and was shown to inhibit cell viability and cell migration in a dose-dependent manner. T315 treatment of the colon cancer cells also decreased protein levels of YB-1 and IGF-1R and affected epidermal mesenchymal transition markers such as E-cadherin, vimentin, and snail. These results suggest that a combination of a MEK inhibitor and T315 may be an effective therapeutic strategy to target KRAS mutation driven CRC. Citation Format: Christina Wu, Peng-Chan Lin, Po-Chen Chu, Hsiao-Ching Chuang, Samuel Kulp, Tanios Bekaii-Saab, Ching-Shih Chen. Therapeutic targeting of KRAS mutation-driven tumor progression in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5424. doi:10.1158/1538-7445.AM2015-5424

e15012 Background: Targeting HER2 has improved outcomes in metastatic gastroesophageal (mGE) cancer. Recently, targeting patients (pts) with refractory c-Met amplified mGE tumors with AMG 337 has s...

366 Background: The combination of gemcitabine and nab-paclitaxel (GA) in first line treatment (tx) of MPC has a modest survival advantage over gemcitabine (gem) alone, but adds significant toxicities (tox) and increased cost. Based on data suggesting that biweekly administration (adm) of gem-based combinations preserves efficacy and improves tox profile, our institution adopted a modified regimen of GA (mGA). Methods: This is a retrospective analysis of a prospectively maintained database of patients (pts) with pancreatic cancer treated with gem (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1 and 15 of a 28-day cycle. Survival curves were estimated using Kaplan-Meier method, with alive pts censored at time of last follow-up. Cost of tx includes cost of drugs, adm, and tox. Results: Of total 69 pts treated with mGA for MPC, locally advanced, or borderline resectable disease, 63 pts were evaluable for tox (table 1). A total of 49 pts (47 evaluable for response) received mGA for previously untreated MPC, with median progression free survival of 4.8 months(mo) (95% CI 2.6,7.4) and overall survival of 11.1 mo (95% CI 5.3,not reached). Overall, 27% of pts experienced neurotoxicity with rate of grade 3 tox of < 2%, and 8% required growth factors (GF). Average cost savings was $5500/pt/month with mGA compared to standard GA, excluding GF cost which was lower with mGA. Conclusions: A less intense regimen of GA maintains efficacy while significantly improving tox profile and cost in pts with MPC. [Table: see text]

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta family, signal in many cells including neural precursors. Two receptors, types 1 and 2, coordinately mediate BMP signaling, and type 1 receptor has two forms: A and B. Using RT-PCR we found that neural crest-derived human melanocytes express BMP receptor-1A, -1B, and -2. Furthermore, melanocytes and the surrounding keratinocytes express BMP-4, suggesting both autocrine and paracrine effects of this molecule. Moreover, BMP-4 supplementation of cultured human melanocytes decreases melanin synthesis, tyrosinase mRNA, and protein. The mechanism of this BMP-4 effect on tyrosinase and ultimately on melanogenesis involves modest decreases of tyrosinase transcription rate and mRNA stability. Moreover, ultraviolet irradiation, the best recognized environmental stimulator of melanogenesis, down-regulated the mRNA of BMP receptor-1B in melanocytes. Our data provide evidence of a novel regulatory pathway for melanogenesis in human skin.

The cAMP-dependent pathway up-regulates MITF (microphthalmia-associated transcription factor), important for key melanogenic proteins such as tyrosinase, TRP-1 (tyrosinase-related protein 1) and TRP-2. We asked whether MITF is also a key transcription factor for PKC-beta (protein kinase C-beta), required to phosphorylate otherwise inactive tyrosinase. When paired cultures of human melanocytes were treated with isobutylmethylxanthine, known to increase intracellular cAMP, both protein and mRNA levels of PKC-beta were induced by 24 h. To determine whether MITF modulates PKC-beta expression, paired cultures of human melanocytes were transfected with dn-MITF (dominant-negative MITF) or empty control vector. By immunoblotting, PKC-beta protein was reduced by 63+/-3.7% within 48 h. Co-transfection of an expression vector for MITF-M, the MITF isoform specific for pigment cells, or empty control vector with a full-length PKC-beta promoter-CAT (chloramphenicol acetyltransferase) reporter construct (PKC-beta/CAT) into Cos-7 cells showed60-fold increase in CAT activity. Melanocytes abundantly also expressed MITF-A, as well as the MITF-B and MITF-H isoforms. However, in contrast with MITF-M, MITF-A failed to transactivate co-expressed PKC-beta/CAT or CAT constructs under the control of a full-length tyrosinase promoter. Together, these results demonstrate that MITF, specifically MITF-M, is a key transcription factor for PKC-beta, linking the PKC- and cAMP-dependent pathways in regulation of melanogenesis.

Purpose Galectin-3 (gal-3) is a novel biomarker implicated in cardiac fibrosis and is shown to correlate with the severity of heart failure (HF) and to independently predict mortality in HF. We investigated if hemodynamic improvement after left ventricular assist device (LVAD) implantation affects gal-3 levels. Methods and Materials Plasma samples were acquired from patients at time of LVAD implantation (HMII or Heartware, n=57), at 3 (n=17) and 6 months post-LVAD (n=14), and at explantation (n=23), as well as from healthy age and gender matched controls (n=30). Gal-3 was measured using a commercially available ELISA assay (BG Medicine, Waltham, MA). Data was analyzed with Prism 5. Events rates were calculated using the Kaplan-Meier method. Results At time of LVAD implantation, HF patients had significantly higher gal-3 levels compared to controls (29.2±14 ng/ml vs. 13±9 ng/ml; p figure 1 ] Conclusions Gal-3 levels are associated with HF state and predict survival on LVAD support. Distinct dynamics in gal-3 levels occur in patients following LVAD implantation with an initial decrease but subsequent increase. Gal-3 may serve as a new biomarker for risk assessment of patients before LVAD implantation.

In the past year, long-term follow-up of trials have confirmed and disproved paradigms in the treatment of colorectal cancer, and identified a chemoprevention agent. In metastatic disease, chemotherapy in unresected primary tumours was studied, and randomized phase III trials introduced new therapy options. Molecular characterization of colon and rectal tumours offers new drug targets.

Introduction The 5-year survival of pancreatic adenocarcinoma (PAC) with surgery alone is less than 10%, and with adjuvant chemotherapy increases to about 20%. The original GITSG adjuvant study demonstrated a survival benefit compared to surgery, and could have been attributed to the weekly IV bolus of 5FU for 2 years, in addition to chemoradiation. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest, and kill them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated patients at Georgetown University Hospital (GUH) who were treated with maintenance capecitabine, and compared to the patients who completed standard adjuvant gemcitabine at GUH and at the Ohio State University (OSU). Methods Patients in the Georgetown/Lombardi Cancer Center and the Ohio State University EMR were sought for PAC that was resected with curative intent, and had received standard adjuvant chemotherapy with or without chemoradiation. After 6 months of gemcitabine without recurrence, the study group received maintenance capecitabine for up to 2 years, and the control groups received no further therapy until disease relapse. Only patients with complete follow-up survival data were analyzed. Results 20 patients from GUH met the criteria as the maintenance group, and 58 and 14 patients from GUH and OSU respectively as the control group. In the maintenance group, capecitabine was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, up to 2 years. Patients received capecitabine for median duration of 12.5 months (2 to 24 months), and the median follow-up duration was 33 months (16 to 78 months). The median overall survival (OS) for the maintenance group was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. Four patients discontinued capecitabine due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea. The GUH control group was of comparable staging, and the median OS was 22 months, 2 year OS was 86.6%, 5 year OS rate was 16%, median RFS was 13 months, 2 year RFS was 19%. For the OSU control group, the median OS was 16.33 months, 2 yr OS was 35.7%, median RFS was 14.8 months, 2yr RFS was 20%. Conclusion In this retrospective controlled cohort study, capecitabine maintenance therapy following adjuvant therapy in resected PAC is associated with a significantly (p

Background Skeletal muscle dysfunction in patients with heart failure (HF) has been linked to impaired growth hormone (GH)/insulin-like growth factor (IGF)-1 signaling. We hypothesized that ventricular assist device (VAD) implantation reverses GH/IGF-1 axis dysfunction and improves muscle metabolism in HF. Methods Blood and rectus abdominis muscle samples were collected during VAD implantation and explantation from patients with HF and controls. Clinical data were obtained from medical records, biomarkers measured by enzyme-linked immunosorbent assay (ELISA), and gene expression analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). Grip strength was assessed by dynamometry. Oxidative capacity was measured using oleate oxidation rates. Muscle fiber type and size were assessed by histology. Results Elevated GH (0.27 ± 0.27 versus 3.6 ± 7.7 ng/ml in HF; p = 0.0002) and lower IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were found in HF (IGF-1, 144 ± 41 versus 74 ± 45 ng/ml in HF, p

Aim: Reovirus is a naturally occurring virus that causes oncolysis in tumor cells with a Ras-activated pathway. It acts synergistically with taxanes. Since most pancreas cancer cells have downstream activated Ras we hypothesized that pts with MAP are susceptible to reovirus. Methods: We conducted an NCI-sponsored phase II study with a goal of 70 evaluable MAP pts randomized in a 1:1 allocation to paclitaxel [P (175 mg/m2)], carboplatin [C (AUC 5)] on day 1 with reovirus [R (3 x 1010 TCID50) iv] on days 1-5 {Arm A} vs P/C alone {Arm B} on day 1 of a 21-day cycle. The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rate (ORR), and overall survival (OS). Pts progressing on B were allowed to crossover to A. Eligible pts had no prior chemotherapy. Pre-treatment tissue was required for KRAS mutation status from DNA analysis. Analyses of immunomodulatory effects of therapy were performed. Results: Refer to Table 1 for key characteristics. Most common grade 3-4 toxicities include neutropenia (53%) and leucopenia (36%) with no overall difference between arms. In evaluable pts, ORR/SD was 22%/59% (A) and 21%/47% (B). To date, 81% have progressed, and median follow-up of 3.75 mo in event-free pts. PFS was similar in both arms (A: median 4.63 vs B: 5.1 mos; HR = 1.07, p = 0.81). The results held after sensitivity analyses and adjusting for factors such as KRAS. In 60 patients with KRAS analysis, a trend toward improved overall PFS in KRAS WT (6.0 mo) vs MT (4.3 mo); p = 0.20. In the KRAS MT group, an early limited differential in PFS between arm A (4.63 mo) vs B (4.34 mo); p = 0.73. 16 pts crossed over from B to A with 1 PR, 6 SD, 7 PD and 2 NA. Characteristic Arm A Arm B p-value Total N = 73 36 37 Age (Median, yrs) 61.5 66 0.055 ECOG PS (0/1), N 20/16 17/20 0.49 Baseline Ca 19-9 of > 59x ULN, % 53% 75% 0.14 KRAS Status ( MT), % 70% 77% 0.99 Pancreas Tumor Location, % Head Body Tail NS 22 36 22 22 27 38 19 14 Number of Metastatic Sites, % 1 2 >2 19 30 51 22 14 66 0.51 Conclusions: Reovirus can be administered safely in combination with P/C in pts with MAP. Both arms performed better than historical control, but R did not seem to improve outcome when added to P/C in MAP. This is the first report of P/C in MAP, which proved to have higher activity than anticipated, suggesting that similar to other disease settings, a relatively inexpensive taxane is an acceptable choice in MAP. A pharmaco-economic analysis is underway. Disclosure: T. Bekaii-Saab: Research Funding: Oncolytics Biotech; M.A. Villalona-Calero: Research Grant : Oncolytics Biotech. All other authors have declared no conflicts of interest.

149 Background: Patients (pts) with relapsed or treatment-refractory E and GE cancers carry a poor prognosis. Inhibition of the vascular endothelial growth factor (VEGF) pathway may be a potential treatment approach. We conducted a phase II trial to assess the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGFR 1 and 2. Methods: Pts received sunitinib 37.5 mg orally, daily. Primary endpoint was progression free survival (PFS) at 24 weeks. Secondary endpoints included overall response rate (ORR), overall survival (OS), PFS, and toxicity. Pts underwent serial functional imaging with DCE-MRI and measurements of serum VEGF, PIGF, VEGFR 2 and 3. Gene expression profiling and somatic mutational analysis using next-generation sequencing were also performed on tumor specimens (results to be presented at the symposium). Results: Clinical results are in the table. The PFS in the group that had clinical benefit [partial response (PR) + stable disease (SD)] with sunitinib was 99 days (95% CI: 74-161) vs. 39 days (95% CI: 26-42; Log-rank test p-value is

415 Background: It has been argued that universal screening for LS should be performed on all patients (pts) diagnosed with CRC because screening LS pts and their relatives can detect early cancers and improve outcomes. This approach is being adopted by many comprehensive cancer centers around the country. The Ohio State University (OSU) began screening for deficient mismatch repair (dMMR) proteins by immunohistochemistry (IHC) on all CRC cases in 2006. This retrospective study aims to assess whether universal screening with IHC followed by conclusive testing (BRAF mutation in setting of MLH1 deficiency, and/or gene sequencing) affects pts survival. Methods: All CRC pts diagnosed at OSU from 3/2006-6/2012 with dMMR testing per IHC were included, and their charts were reviewed. Chi-square test was used to for categorical parameters, t-test was used for continuous variables, and the log-rank test for overall survival (OS) to compare the difference between pts with full conclusive testing vs those without full testing. Patients who expired within 4 weeks of diagnosis were excluded (n=10) from the OS analysis. Results: One hundred and twenty-two tumors (15.7% of 777 tumors tested) had dMMR by IHC during the study period. Fifty-one pts went on to have conclusive testing done; thirteen patients (25.5%) were diagnosed with LS, 29 patients (56.9%) had MLH1-hypermethylated tumors, and 9 patients (17.6%) were not found to have MMR mutations on gene sequencing. In an OS analysis, patients undergoing conclusive testing had significantly longer survival as compared to those with abnormal IHC without further testing (median OS not reached vs. 38 months, p=0.04). The difference was similar and remained marginally significant (p= 0.04-0.09) after correcting for age, stage and testing date using different models. Conclusions: Patients who had conclusive testing after initial abnormal universal screening with IHC had significantly longer OS compared to pts who had abnormal IHC without follow-up testing. It is possible that ascertainment bias and pts compliance influenced survival so larger prospective studies that document stage and treatment are needed to determine if increased surveillance in the setting of a LS diagnosis leads to better OS.

419 Background: LS, characterized by germline mutations in MLH1, MSH2, MSH6, or PMS2, leads to defective DNA mismatch repair (dMMR) and causes 2%-3% of CRC cases. Ohio State University (OSU) began immunohistochemistry (IHC) screening on all CRC cases in 2006. In 2006 results were reported in pathology reports without further follow-up. From 2007 to 2010 genetic clinic (GC) counselors contacted pts and recommended further testing. Since 2011, GC counselors met pts at a follow-up appointment. This retrospective study aims to assess if type of follow-up after abnormal IHC, affects rate of conclusive testing. Methods: All CRC pts diagnosed at OSU from 03/06-06/12 had MMR testing per IHC. All pts’ charts were reviewed. Conclusive testing, following the initial MMR IHC, includes either MLH1-hypermethylation testing and/or gene sequencing to identify LS from non-LS pts. Chi-square test was used for categorical parameters and t-test for continuous variables to compare differences between pts with conclusive test vs those without. Results: One-hundred and twenty two tumors of 777 (15.7%) tested had dMMR by IHC. The GC follow-up of abnormal results significantly affected the rate of conclusive testing. The rate of conclusive testing went from 14.3% in 2006 to 38.4% in 2007-2010 and after 2011, 90.5% of the pts had conclusive testing done. Among 51 pts undergoing full testing, 13 pts were diagnosed with LS, 29 pts had MLH1-hypermethylated tumors, and 9 pts were not found to have any mutations on gene sequencing. Conclusions: Conclusive testing rates after abnormal universal screening with IHC improved significantly with GC involvement and was most effective when GC counselors met with the pts during their appointment. [Table: see text]

275 Background: FOLFIRINOX exhibits a meaningful improvement in outcome measures in metastatic pancreatic cancer, making it an interesting regimen for BRPC and LAURPC. However, its use remains prohibitive due to toxicity. In this study, we examine the outcomes of mFOLFIRINOX as a neoadjuvant strategy for patients with BRPC and LAURPC. Methods: This is a retrospective analysis of a prospectively maintained database of patients who received mFOLFIRINOX for BRPC or LAURPC at Ohio State University. mFOLFIRINOX is as follows: irinotecan at 165 mg/m2; oxaliplatin at 85 mg/m2; 5-fluorouracil (5FU) at 2,400 mg/m2 over 46 hours and pegfilgrastim on day 4 of each 2-week cycle. Cases were thoroughly reviewed by a multidisciplinary team prior to initiation of therapy and at each restaging scan. The primary outcomes of this analysis were resection rate and grade 3/4 (G3/4) toxicities. Results: Since 1/1/2011, 43 patients (20 BRPC; 23 LAURPC) have received mFOLFIRINOX. Patients received gemcitabine-based chemoradiation (36 Gy in 15 fractions) only if their best response was stable disease after 4 months of mFOLFIRINOX. At the time of this abstract, 39 patients are evaluable for primary outcome. Overall resection rate was 53.8% including 45% of patients with initially unresectable disease. R0 resection was achieved in 85.7% of the surgeries. See table for more results. The rate of G3/4 toxicity was remarkably low with no episodes of febrile neutropenia, G3/4 neutropenia or thrombocytopenia. Toxicities lead to dose reductions in 46% of patients. Conclusions: Neoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen as part of an integrated, multimodality strategy in BRPC and LAURPC leading to high resection rates and high R0 resection frequency. [Table: see text]

Introduction: Antibody-dependent cellular cytotoxicity (ADCC) is one mechanism of action of monoclonal antibody (mAb) therapy. ADCC occurs via the innate immune system's ability to recognize mAb coated cancer cells and activate effector cells. Lenalidomide is an immunomodulatory agent with capacity to stimulate T cell proliferation, activate natural killer cells, and effect immune cytokines including IL-2, IL-12, and interferon gamma. Both preclinical and clinical data demonstrate the ability of lenalidomide to increase ADCC activity of mAb therapy. This Phase I CTEP sponsored trial aims to evaluate the combination of cetuximab with lenalidomide to enhance ADCC activity in advanced colorectal (CRC) and head and neck squamous cell cancers (HNSCC). Patients/Methods: This Phase I dose escalation trial included patients with locally advanced or metastatic CRC (KRAS wild type) or HNSCC. Treatment consisted of cetuximab 500 mg/m2 IV every 2 weeks with lenalidomide orally days 1-21 every 28 days. Cetuximab dose was the same in all cohorts although dose reductions were permitted for toxicity. Three dose levels of lenalidomide were evaluated (15 mg, 20 mg, and 25 mg). Prior treatment with cetuximab, panitumumab, or other EGFR directed therapy was allowed. Planned correlative studies include measurement of ADCC using an in vitro chromium release assay, serum interferon gamma and NK cytokine profiles, and Fc gamma receptor polymorphisms. Results: A total of 22 patients have been treated (19 CRC, 3 HNSCC). Grade 3 fatigue has been the only observed dose-limiting toxicity. One partial response was observed and 7 patients had stable disease as best response. Two patients remain on treatment. The recommended Phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily days 1-21. Conclusions: Cetuximab and lenalidomide was well-tolerated with minimal activity. Although response was not a primary endpoint, there is evidence of anti-tumor activity and clinical efficacy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A76. Citation Format: Erin M. Bertino, Jeffrey S. Rose, Christina Wu, Tanios Bekaii-Saab, Panayiotis S. Savvides, Richard M. Goldberg, Miguel Villalona, Gerard Lozanski, William Carson, Michael Grever, Gregory Otterson. Enhancement of cetuximab-induced antibody-dependent cellular cytotoxicity with lenalidomide in advanced solid tumors: A Phase I trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A76.