bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of the Optimata Virtual Patient (OVP) to predict effects of sunitinib malate in advanced pancreatic cancer.
Authors: Kleiman M. , Shacham S. , Kushnir M. , Chapnik E. , Agur Z.
Published: February 2017

341

Background: Pancreatic cancer is considered to be incurable by available treatment modalities, with 5-year survival rate <4%. Sunitinib malate (Sutent) significantly increased progression-free survival in patients with advanced islet cell tumors (pancreatic); however, it demonstrated only modest single-agent effect in a phase II study in patients with metastatic pancreatic adenocarcinoma (PaC) that progressed after first-line therapy with gemcitabine. To improve the response of PaC patients to drugs, the interplay between biologic, pathologic, and pharmacologic processes underlying drug-patient interactions have been mathematically modeled, predicting efficacy responses, different toxicities, and long-term tolerability in clinical trials, allowing for improved dosing regimens and patient selection (OVP engine) (Agur Z., 2010). The OVP engine was used to predict Sunitinib malate single-agent activity in advanced PaC.

Methods: OVP replicated the observed growth patterns of human PaC. Pharmacokinetics (PK) and pharmacodynamics (PD) of sunitinib malate were modeled based on literature (NDA 21-938). Effects of sunitinib malate on human PaC xenografts were scaled to model PK/PD in human. To evaluate drug efficacy in advanced PaC patient-population, a Virtual PaC Patient- Population was created by replacing the population averaged parameter values in the model by their distribution in the population. Using this procedure, a large set of virtual patients was generated. Model simulations with sunitinib malate therapy (50 mg QD/28 days; 14 days rest [1 cycle]) enabled the prediction and classification of patients' response according to RECIST criteria and compared with the actual clinical response (O'Reilly et al, 2008).

Results: Simulations of the FDA-approved schedule, predicted a stable disease in 81% of the patients following one treatment cycle and 54% following two treatment cycles. Stable disease was predicted to be the best observed response, which was confirmed in the clinical study.

Conclusions: Our model predictions are compatible with clinical results of a recent phase II trial with the same treatment regimen of sunitinib malate (O'Reilly et al, 2008) and further suggest the use of mathematical model during drug development.

[Table: see text]
EXPERT-C: A randomized phase II European multicenter trial of neoadjuvant chemotherapy (capecitabine/oxaliplatin) and chemoradiation (CRT) with or without cetuximab followed by total mesorectal excision (TME) in patients with MRI-defined high-risk rectal cancer.
Authors: Dewdney A. , Cunningham D. , Tabernero J. , Glimelius B. , Cervantes A. , Tait D. M. , Brown G. , Wotherspoon A. , Gonzalez de Castro D. , Chau I.
Published: February 2017

360

Background: We previously demonstrated the feasibility of administering neoadjuvant chemotherapy before CRT and TME in patients with MRI selected poor prognosis rectal cancer (Chua Y J et al Lancet Oncol 2010). This trial evaluates the addition of the anti-EGFR antibody cetuximab to this treatment strategy. KRAS and BRAF mutations have been established as predictive for lack of response to anti-EGFR therapy in metastatic colorectal cancer.

Methods: Patients with newly diagnosed, histologically confirmed, MRI defined high risk rectal adenocarcinoma were randomised to receive 4 cycles of capecitabine 1,700mg/m2 with oxaliplatin 130mg/m2 (CAPOX) followed by CRT, 45Gy/25# + 5.4Gy/3# boost with concurrent continuous capecitabine 1,650mg/m2/day, TME and 4 cycles of adjuvant CAPOX (EXPERT) or the same regimen with the addition of cetuximab (400mg/m2 loading dose week 1, followed by 250mg/m2/week) (EXPERT-C). The primary endpoint is complete response (CR) (defined as pathological complete response or radiological complete response in patients who decline surgery) in KRAS and BRAF wild type tumours. Secondary endpoints include radiological response to CRT, CR in both KRAS wild type and mutant patients, R0 resection rates, progression free and overall survival and safety.

Results: Between 2005-2008, 165 eligible patients were recruited from 15 centres (EXPERT n=81, EXPERT-C n=84). 99% of patients had performance status 0-1, 98% had ≥ T3 disease, 56% had an involved or threatened circumferential resection margin and 72% had evidence of extramural venous invasion determined by MRI. The current median follow up is 30 months. 72/81 (89%) and 79/84 (94%) of patients completed neoadjuvant CRT and 72/81 (89%) and 77/84 (92%) patients underwent curative-intent surgery on the EXPERT and EXPERT-C arms respectively. Two patients declined surgery.

Conclusions: The primary and secondary endpoints will be analyzed in October 2010 and will be presented at the meeting.

[Table: see text]
Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
Authors: Kachnic L. A. , Winter K. A. , Myerson R. J. , Goodyear M. D. , Willins J. , Esthappan J. , Haddock M. G. , Rotman M. , Parikh P. J. , Willett C. G.
Published: February 2017

368

Background: 5-Fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer is associated with high rates of acute morbidity. We have previously shown that dose-painted IMRT (DP-IMRT) significantly reduces grade 3+ GI and dermatologic acute toxicity, as compared to the RTOG 9811 5FU/MMC arm, which used non-conformal radiation techniques. We now report on the two-year outcomes of this DP-IMRT approach.

Methods: T2-4N0-3M0 anal canal cancers received 5FU (1,000 mg/m2/day 96 hour infusion) and MMC (10 mg/m2 bolus) days 1 and 29 of DP-IMRT prescribed as follows - T2N0: 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs), 28 fractions; T3-4N0-3: 45 Gy elective nodal, 50.4 Gy ≤ 3 cm and 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs, 30 fractions. The following two-year outcomes were assessed: local-regional (LRF) and colostomy failures (CF) using the cumulative incidence method, and disease-free (DFS), overall (OS) and colostomy-free survivals (CFS) using the Kaplan-Meier method.

Results: Of 63 accrued patients, 52 were analyzable. Median age was 58 years; 81% female; 54% stage II; 25% IIIA; 21% IIIB. Median follow-up was 23.2 months (0.2-33). Two-year LRF, CF, DFS and 95% confidence intervals are 20% (9%, 31%), 8% (0.4%, 15%) and 77% (62%, 86%), respectively. The causes of death for the 7 patients that died are: anal cancer in 5, morbidity in one and second primary outside the radiation field in one. Two-year comparison data from the RTOG 9811 5FU/MMC arm are shown in the table below.

Conclusions: DP-IMRT with 5FU/MMC for the treatment of anal canal cancer yields similar two-year outcomes as the RTOG 9811 conventional radiation, 5FU/MMC arm. Because of the associated acute toxicity sparing, DP-IMRT will be used as the platform, and may allow for radiation dose escalation, in future RTOG anal canal trials. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants.

[Table: see text]

No significant financial relationships to disclose.
A circulating microvesicle-based biosignature for the detection of colorectal cancer.
Authors: Spetzler D. , Tinder T. , Kankipati S. , Maheshwari M. , Kuslich C. D.
Published: February 2017

373

Background: Microvesicles are principally derived either from the endosomal pathway (as exosomes) or shed directly from the plasma membrane. They are between 40-500 nm in diameter and are secreted by most cell types, including tumor cells. In circulation, microvesicles appear to participate in cellular communication by transporting mRNAs, miRs and proteins from their cell of origin to target cells where they can elicit biological responses. The quantity and protein topography of microvesicles shed from cancer cells varies considerably compared to those shed from normal cells. Thus, the concentration of circulating plasma microvesicles with molecular markers indicative of the disease state can be used as a robust and informative blood-based biosignature. In this study we report the results of the application of a novel multiplexed method for quantifying and profiling microvesicles in plasma for the detection of colorectal cancer.

Methods: We have developed a versatile mulitplexed microvesicle-based discovery panel with 73 different antibodies that target surface proteins of various microvesicle subpopulations. This system was used to develop a microvesicle-derived biosignature composed of 2 different surface membrane protein biomarkers.

Results: In this study, we demonstrate that a combination of TMEM211 and CD24 provide a robust signature for the detection of colorectal cancer (CRC). We isolated microvesicles from plasma of 257 patients with CRC, 57 stage I, 104 stage II, 80 stage 3, 6 stage IV, and 11 of unknown stage; 327 self-described, age-range matched normal plasma specimens were used for the control population. The level of TMEM211 and CD24 containing microvesicles for these samples was determined using a multiplexed immunoassay. Thresholds were empirically determined to maximize the sensitivity and specificity of CRC detection, resulting in a sensitivity of 90% with a specificity of 85% with an AUC of .91.

Conclusions: This study demonstrates that it is possible to use circulating microvesicles for the development of a highly sensitive and specific blood-based assay to detect CRC.

[Table: see text]
Evaluation of physician knowledge and referral practices for colorectal cancer (CRC) genetic risk assessment: The experience at the Hospital of University of Pennsylvania (HUP).
Authors: Jenab-Wolcott J. , Tan K. , Heitjan D. F. , Giantonio B. J. , Garin M. , Powers J. , Stopfer J. , Hoops T. , Rustgi A.
Published: February 2017

379

Background: 3-5% of CRCs are due to inherited genetic mutations. We surveyed knowledge and practices of academic physicians for identification and care of individuals at risk for inherited CRC.

Methods: 264 physicians (oncologists (ON), gastroenterologists (GA), surgeons, internists, gynecologists, and radiation oncologists) at HUP were invited to participate in a web-based 9-min survey. The ability to obtain appropriate medical history and to make referral to genetic services was evaluated. Knowledge of hereditary CRC syndromes was examined both pre and post viewing of an educational web-page on inherited CRCs. Mantel-Haenszel, Fisher exact, and McNemar statistical tests were applied.

Results: Response rate was 33.3%; and of those, 97.4% accessed the educational webpage. In the cohort, 98.9 % obtained a medical history very frequently (VF), 88.6% obtained cancer history in 1st and 45.5% in the 2nd degree relatives VF, and 63.9% asked about the relatives' age at time of cancer diagnosis VF. Of those most likely to care for patients with CRC, the GA more frequently asked about relatives' age at cancer diagnosis (p=0.014) and family history of polyps (p< 0.001) than ON. GA were more likely than ON to refer patients for genetic counseling (73.9% vs. 36.8%, p=0.008). GA had superior knowledge of the availability of genetic testing for Lynch syndrome (LS) (95.6% GA vs. 63.2% ON, p=0.005) and for familial adenomatous polyposis (FAP) (100.0% GA vs. 65.8% ON, p<0.001). For the entire cohort, the educational intervention raised awareness of genetic testing for LS (64.5% pre vs. 94.7% post, p<0.001), FAP (69.7% pre vs. 97.4% post, p<0.001), and Peutz-Jeghers Syndrome (31.6% pre vs. 84.2% post, p<0.001); and it significantly improved recognition of LS family pedigrees and selection of appropriate surveillance.

Conclusions: Of the respondents, GA are more likely to obtain a detailed family history, utilize genetic services, and have a greater awareness of the availability of genetic testing, than ON. A simple educational intervention improves physician knowledge on inherited CRC risk recognition and surveillance recommendations.

No significant financial relationships to disclose.
Causes of suboptimal colorectal cancer screening (CRCS) in U.S. immigrants.
Authors: Shahidi N. C. , Homayoon B. , Cheung W. Y.
Published: February 2017

380

Background: Research shows that CRCS in U.S. immigrants is low, but causes for this poor uptake are unclear. Our aims were to 1) compare CRCS among U.S. born citizens (USB), naturalized citizens (NAC) and non-citizens (NOC), 2) evaluate clinical factors associated with CRCS, and 3) explore health system barriers to CRCS for immigrants.

Methods: Screening eligible patients were identified from the 2007 California Health Interview Survey. CRCS was defined as a fecal occult blood test within 1 year, a sigmoidoscopy within 5 years or a colonoscopy within 10 years. Using logistic regression, we determined the effect of immigrant status and other clinical factors on CRCS. We devised a 3-point composite scoring system based on survey responses to questions about health system barriers (where 0=worst and 3=best). Stratified analyses based on residence (urban vs rural), healthcare coverage (insured vs uninsured), English proficiency (good vs. poor), and composite score were conducted to assess their relationship with CRCS.

Results: We identified 30,434 respondents: USB 83%, NAC 13%, NOC 4%; mean age 66, 65, 61 years; male 39%, 41%, 48%; white 85%, 38%, 29%, respectively. Only 67% of USB, 61% of NAC and 46% of NOC underwent CRCS (p<0.001). Old age, male, high income earners, non-smokers, being married and those who visited their physicians frequently were more likely to receive CRCS (all p<0.05). When compared to USB, NAC and NOC were associated with decreased odds of CRCS (OR 0.88, 95%CI 0.73-1.05 and OR 0.67, 95%CI 0.52-0.87, respectively; global p=0.009). Stratified analyses revealed that the association between immigrants and decreased CRCS was more evident for immigrants who lived in rural areas, lacked insurance, or those who were not proficient in English (Table). Immigrants with a composite score ≤2 also reported worse CRCS.

Conclusions: CRCS remains suboptimal, especially in new U.S. immigrants. Inferior healthcare access and language barriers are potential drivers of this disparity. Addressing these system issues for immigrants may promote CRCS in this population.

[Table: see text]

No significant financial relationships to disclose.
Impact of colonoscopy screening on individuals at high risk of hereditary nonpolyposis colorectal cancer (HNPCC).
Authors: Guillen-Ponce C. , Martinez-Sevila C. , Jover R. , Perea R. , Molina-Garrido M. , Carrato A. ,   Hereditary Cancer Group of the Comunidad Valenciana, Spain
Published: February 2017

384

Background: Colonoscopy screening reduces the incidence of, and mortality from, colorectal cancer (CRC) in individuals with HNPCC. The aim of this study was to determine the impact of colonoscopic follow-up in individuals at high risk of HNPCC, in terms of detection of precursor lesions (adenomas) or cancer.

Methods: Between 2005-2008, 163 individuals with HNPCC were advised to undergo regular follow-up colonoscopy. Compliance and results of the scans were evaluated annually and were verified with medical documentation.

Results: Of the 125 individuals who underwent at least one colonoscopy during the follow-up period of colonoscopy screening, in 33 subjects (26%) at least one colonic adenoma was detected. The median number of adenomas detected per colonoscopy in individuals with polyps was 2. The number of colonoscopies with polyps did not differ between women and men. However, the number of polyps removed by colonoscopy and the total number of polyps removed during the follow-up period was significantly higher in men (p = 0.005, p = 0.05 bilateral, respectively). 5 individuals (4%) were diagnosed with CRC, one of whom had two synchronous tumors. Of these, four individuals had properly followed the screening recommendations with the recommended frequency. In the case where two synchronous tumors were detected, it was the first colonoscopy screening that had been performed on the individual. None had had cancer previously, they were healthy relatives of an index case. All except one belonged to families that fulfilled the Amsterdam criteria I / II. All the tumors were diagnosed at an early stage, except two, which exhibited positive nodes.

Conclusions: Colonoscopy screening is effective in diagnosing colorectal adenomas and cancer in individuals with HNPCC. Men with HNPCC have a greater number of colorectal adenomas. Screening allows the detection of colorectal cancer at an early stages. Funded by a young researcher's grant from the Spanish Society of Medical Oncology 2006.

No significant financial relationships to disclose.
A multiplex technology platform for the rapid detection of relevant mutations in the EGFR signaling pathway.
Authors: Labourier E. , Smith D. , Laosinchai-Wolf W. , Friar L. , Houghton J. , Hadd A. , Latham G.
Published: February 2017

386

Background: Determination of the mutational status of key gene effectors along the EGFR signaling pathway plays a critical role in the management of metastatic colorectal cancer (mCRC) and other cancer types. We previously reported the rapid, multiplex, and sensitive detection of 7 common KRAS mutations in mCRC FFPE specimens using the Signature KRAS Mutations (RUO) kit. We show here that the same technology platform can be applied to the detection of additional clinically relevant mutations in the EGFR, BRAF, KRAS, NRAS and HRAS genes.

Methods: Mutation panels were designed for multiplex PCR amplification of an internal control gene and discrete mutation regions in independent target genes. PCR products were hybridized on a liquid bead array carrying target-specific probes and sorted by flow cytometry using a Luminex 200 system. Genomic DNA was extracted from cell lines and representative flash frozen, FFPE or FNA clinical specimens using laboratory-validated extraction methods.

Results: Using model plasmids and cell lines we developed specific assays for distinct mutations in KRAS codon 12/13, KRAS 3' UTR (rs61764370), BRAF codon 600/601, HRAS codon 12/61, NRAS codon 61, and EGFR exon 19/20/21. The various assays reached 0.1 to 5% analytical sensitivity and could be further combined in multiplex panels relevant to specific applications. The Signature KRAS/BRAF Mutations (RUO) kit, an assay for 12 KRAS mutations in codon 12/13 and BRAF V600E, was validated in over 250 mCRC FFPE specimens with >99% agreement with clinically validated methods. Specific detection of these 13 mutations and 6 HRAS/NRAS mutations was also demonstrated in thyroid nodule FNA specimens. Single-well detection of EGFR deletions in exon 19 together with the point mutations L858R and T790M was also successfully evaluated in lung specimens.

Conclusions: The Signature technology platform is a specific, sensitive and flexible tool for the assessment of various mutations in different tissue types. The development and validation of broader mutation panels would likely facilitate the rapid molecular characterization of individual tumor specimens and the optimization of personalized treatments for mCRC and other cancer types.

[Table: see text]
Influence of KRAS mutation status in metachronous and synchronous metastatic colorectal adenocarcinomas.
Authors: Serna D. S. , Martin L. K. , Li X. , Weatherby L. M. , Rose J. S. , Bekaii-Saab T.
Published: February 2017

388

Background: Mutations in the KRAS oncogene are present in approximately 30-40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutational status is recognized to be predictive of tumor response with epidermal growth factor receptor-directed therapies such as cetuximab and panitumumab. Studies evaluating the prognostic value of KRAS status in localized (stage II and III) disease have been contradictory. The prognostic value in metastatic disease, either synchronous or metachronous, is less studied.

Methods: Consecutive patients with metastatic colorectal adenocarcinoma underwent tumor testing for KRAS exon 2 (codons 12 and 13) mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then retrospectively analyzed, stratified by synchronous or metastatic disease and KRAS mutational status (WT or mutated).

Results: For synchronous metastatic disease, KRAS WT patients (n = 39) had median overall survival (OS) of 34.3 months (95% CI, 21.8-58.3). KRAS mutated patients (n = 24) had median OS of 40.3 months (95% CI, 25.7-51.0; log-rank p = 0.55). By Kaplan-Meier survival analysis, 3-year OS was 48.9% (95% CI, 31.1-64.5) for KRAS WT and 51.1% (95% CI, 27.6-70.6) for KRAS mutated patients. Five-year OS was 27.8% (95% CI, 11.6-46.8) for KRAS WT and 9.7% (95% CI, 0.7-33.8) for KRAS mutated patients. For metachronous metastatic disease, from time of development of metastasis, KRAS WT patients (n = 29) had median OS of 33.2 months (95% CI, 28.3-40.7). KRAS mutated patients (n = 16) had median OS of 53.0 months (95% CI, 27.8-not applicable; log-rank p = 0.29). By Kaplan-Meier survival analysis, 3-year OS was 40.1% (95% CI, 19.9-59.7) for KRAS WT and 57.3% (95% CI, 25.0-80.0) for KRAS mutated patients. Five-year OS was 22.9% (95% CI, 7.6-43.2) for KRAS WT and 28.6% (95% CI, 1.7-68.1) for KRAS mutated patients.

Conclusions: KRAS mutation status does not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma.

No significant financial relationships to disclose.
Correlation between clinical-pathological parameters and family history to detect mutations in MLH1, MSH2, and MSH6.
Authors: Guillen-Ponce C. , Castillejo A. , Barbera V. M. , Alenda C. , Molina-Garrido M. , Carrato A. , Soto J. ,   Hereditary Cancer Group of the Comunidad Valenciana, Spain
Published: February 2017

391

Background: The Amsterdam I/II and Bethesda criteria are used to select individuals for the study of mutations in hereditary nonpolyposis colon cancer (HNPCC). The aim of this study was to analyze whether specific clinical features and family history of individuals suspected of HNPCC were correlated with the detection of germline mutations in MLH1, MSH2 and MSH6.

Methods: Between 2005-2008, the study of germline mutations in one or more of the genes MLH1, MSH2 or MSH6 was carried out on 124 individuals who fullfield the Amsterdam I/II criteria or Bethesda criteria with microsatellite instability (MSI) or loss of expression by immunohistochemistry (IHC) of any of the repair proteins of MMR genes. Subsequently, we applied univariate and multivariate analyses including clinicopathological characteristics and family history to see if they were related to the presence of germline mutations. The characteristics were: age, sex, age at diagnosis, whether they fulfilled the Amsterdam or Bethesda criteria, diagnosis of cancer, tumor type, presence of multiple tumors and age of first diagnosis of cancer in the family.

Results: Out of 124 patients studied, 29 gene mutations were detected (detection rate 25%). Of all the parameters studied, only endometrial cancer increased the risk of mutation 7.3 times (confidence interval [CI] 95%, from 1.83 to 29.2) for colorectal cancer (p = 0.005). 20.7% of mutations in MMR genes were explained by the type of cancer (R square Nagelkerke = 0.207). In the multivariate analysis none of the variables predicted the presence of mutation.

Conclusions: The most important clinical feature to predict the presence of a mutation in the genes MLH1, MSH2 and/or MSH6 in families with HNPCC is the diagnosis of endometrial cancer (univariate analysis).

No significant financial relationships to disclose.
Evaluation of glycolytic activity and HIF-1α expression in chemoresistant colorectal cancer cells.
Authors: Tozzi F. , Zhou Y. , Chen J. , Bose D. , Fan F. , Wang J. , Brusher H. , Widger W. , Weihua Z. , Ellis L. M.
Published: February 2017

415

Background: Overcoming drug resistance in colorectal cancer (CRC) involves understanding the mechanisms by which cancer cells adapt to the genotoxic stress. We established a model of oxaliplatin resistant cells derived from HCT116/HT29 (HCT116 OxR/HT29 OxR). How these resistant clones reprogram their energy metabolism to gain a survival advantage remains unknown. We hypothesized that chemoresistant CRC cells exhibit altered cellular metabolism to survive following chronic genotoxic stress.

Methods: The expression levels of glycolytic enzymes were detected by Western Blotting. Glucose and lactate concentrations were measured in the culturing media (CM). Intracellular ATP/ADP levels, oxygen consumption rate (OCR) and mitochondria ATP production were measured. In vivo xenograft study was used to compare the growth rate and angiogenesis of parental and oxaliplatin-resistant cells.

Results: Both HT29-OxR and HCT116-OxR cells compared to parental cells exhibit increased aerobic glycolysis. Consistently, Glut1, Hexokinase 2 and LDHA glycolytic enzymes are upregulated. The OxR cells are defective in mitochondria complex I/II substrate and ATP production despite increased OCR. Importantly, the OXR cells maintain higher intracellular ATP and ATP/ADP ratio, increased HIF1a and VEGF levels in the CM. In tumor xenograft model, HT29 OxR cells grow significant slower than parental HT29 cells. Interestingly, when OxR cells were mixed with parental HT29 cells (50:50 and 90:10), tumor growth and microvessel counts were significantly accelerated.

Conclusions: OxR cells demonstrate: 1) high aerobic glycolytic activity; 2) defective mitochondria functions; 3) increased ATP production; 4) increased HIF1a and angiogenesis. Likely, this metabolic switch contributes to the resistant phenotype. Metabolism intervention such as targeting HIF1a may provide a novel strategy to overcome drug-resistance in CRC.

No significant financial relationships to disclose.
CDH1 structural alterations as novel prognostic biomarker in gastric cancer patients.
Authors: Corso G. , Pascale V. , Marrelli D. , Pinheiro H. , Carvalho J. , Garosi L. , Seruca R. , Oliveira C. , Roviello F.
Published: February 2017

42

Background: Loss of CDH1 function occurs in sporadic gastric cancer (GC) progression by different molecular mechanisms. Hypermethylation and somatic mutations are considered the most frequent events. About 50% of sporadic diffuse GC shows CDH1 promoter of hypermethylation and 30% harbor somatic mutations; loss of heterozygosity (LOH) is documented in only 5% of diffuse GC cases. The present study aims to asses CDH1 alterations in 246 GC and study associated clinicopathologic features and family history of GC.

Methods: Bisulphite treated tumoral DNA was used for E-cad promoter methylation. A region of 221 bps was amplified using flanking primers and direct sequencing. To search for somatic mutations the hotspot region of E-cad was amplified and directly sequenced. For LOH analysis tumor and matched normal mucosae were amplified in three microsatellite markers (D16S3025, D16S496, D16S3067) flanking the CDH1 locus.

Results: Promoter hypermethylation was the most frequent event occurring in 20.7% (51 of 246) of the cases. We found 26 (10.6%) cases affected by structural alterations (three with somatic mutations and 23 with LOH). Promoter CDH1 methylation is associated with the diffuse type of GC (p = 0.017) and the presence of distant lymph node metastasis (p = 0.043). We identified association between male gender and structural CDH1 alterations (p = <0.001), R1/2 radicality of resection (p = 0.015). We verified a correlation between advanced stages and CDH1 promoter methylation (p = 0.033). Kaplan-Meier survival analysis estimates that CDH1 structural alterations participate as poor prognostic factor in GC patients (p = 0.017).

Conclusions: Considering the reversible nature of hypermethylation phenomena, demethylating drugs have emerged as possible chemopreventive strategies in solid tumors. Moreover, we verify that epigenetic changes of E-cadherin leading to its decrease protein expression induce an invasive behaviour to neoplastic cells; as structural alterations of CDH1 gene is assess as predictive of worse prognosis we found a new molecular biomarker of prognosis in GC that can be used to predict the clinical prognosis of the patients.

No significant financial relationships to disclose.
Cost-effectiveness of adjuvant therapy for treatment of stage II colon cancer in patients with diabetes.
Authors: Dinh T. , Alperin P. , O'Neil B. H.
Published: February 2017

421

Background: The decision to treat stage II colon cancer patients with adjuvant chemotherapy involves assessment of life expectancy, risk for recurrent disease, and the potential benefit and likelihood of adverse effects from treatment. This is a challenging task, particularly for patients with pre-existing chronic illnesses such as diabetes, which may increase side effects and potentially lessen response to chemotherapy.

Methods: We use the Archimedes Model to analyze cost effectiveness of adjuvant therapy in stage II colon cancer patients with pre-existing diabetes. The Archimedes Model is a large-scale, integrated mathematical model of human physiology, diseases, and healthcare systems, including pathways relating to diabetes, cardiovascular disease, and cancers of the breast, lung, and colon. The colon cancer model is built using the SEER, ACCENT databases and meta-analyses of clinical trials. Costs relating to colon cancer, diabetes and its complications are based on Medicare reimbursement rates. We simulate a trial in which stage II colon cancer patients are subjected to two treatment strategies: no treatment vs. adjuvant chemotherapy by FOLFOX regimen. We report incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life year (QALY) gained, of adjuvant therapy compared with no treatment.

Results: Cost effectiveness is strongly dependent on a patient's tumor profile, age and duration of diabetes. For instance, adjuvant therapy saves ∼0.2 QALYs per person in stage IIA patients who are 75 and older and have been diagnosed with diabetes >10 years, at an ICER of >$150,000/QALY gained. In contrast, it saves 1.1 QALYs per person in stage IIB patients aged 60-65, recently diagnosed with diabetes, at an ICER of <$30,000/QALY gained. Results are sensitive to assumptions on efficacy and side effects of chemotherapy in diabetic patients, as well as cost of adjuvant therapy.

Conclusions: The current study suggests that the decision to proceed with adjuvant chemotherapy requires careful assessment of severity of diabetes in stage II colon cancer patients with pre-existing diabetes.

No significant financial relationships to disclose.
Biomarker study in rectal cancer patients after 5FU-based radiochemotherapy: Evaluation of the prognostic capacity of thymidylate synthase in pretreatment biopsies and resected adenocarcinoma.
Authors: Conradi L. , Bleckmann A. , Schirmer M. , Sprenger T. , Homayounfar K. , Wolff H. A. , Becker H. , Ghadimi B. M. , Beissbarth T. , Liersch T.
Published: February 2017

435

Background: Fluorouracil (5FU) remains the backbone of neoadjuvant radiochemotherapy (RCT) as well as adjuvant therapeutic strategies in multimodal treatment of rectal cancer patients. Due to its central role as the major target of 5FU thymidylate synthase (TS) is a promising biomarker in rectal cancer. We assessed TS in 208 patients with regard to its predictive/prognostic capacity for disease free DFS and overall cancer specific survival (CSS).

Methods: 167 patients cUICC stages II (28%) and III (72%) received preoperative 5FU based RCT followed by total mesorectal excision (TME) A comparison group n = 41 received postoperative RCT after primary TME. All patients were treated after standardized protocols within phase-II/-III trials of the German Rectal Cancer Study Group. TS levels from pretreatment biopsies and corresponding resection specimens were assessed by immunohistochemical staining for their impact on DFS and CSS. Additionally, a TS gene polymorphism (28 bp repeat) was analysed in respect to intracellular protein expression levels and prognostic significance.

Results: Patients with low TS expression in pre-treatment biopsies showed a correlation with impaired CSS (p = 0.015). After neoadjuvant RCT there was evidence of lymph node metastases ypUICC stage III in 32.6%. Complete histopathologically confirmed tumor regression TRG 4 was achieved in 16 patients (9.5%). During follow-up (median 57 months) patients with low intratumoral TS expression and positive nodal status were at high risk for local and/or distant metastatic recurrence (p = 0.040). Analysis of the 28bp repeat revealed a correlation of *3/*3 genotype with high TS expression in pretherapeutical biopsies (p = 0.05).

Conclusions: TS represents a prognostic biomarker in locally advanced rectal cancer indicating an unfavourable outcome for patients with low TS expression and might help to adapt adjuvant therapy regimens by stratifying patients according to their risk for cancer recurrence.

No significant financial relationships to disclose.
Ten fractions of preoperative radiotherapy for advanced rectal cancer: Is it a new protocol to follow?
Authors: Gu J.
Published: February 2017

439

Background: This study is a retrospective analysis to investigate the efficiency of short-course preoperative radiotherapy following standardized total mesorectal excision (TME) for locally advanced rectal cancer.

Methods: Clinical data of locally advanced mid-low rectal cancer who received TME in Beijing Cancer Hospital from 2001 to 2005 were collected retrospectively. Survival analysis was performed between patients who had TME following short-course preoperative radiotherapy (biological equivalent dose: 36Gy) or TME alone at the corresponding period.

Results: Two hundred and sixty-three patients were eligible for analysis including 101 patients who received TME plus preoperative radiotherapy (PRT group) and 162 patients with TME alone (TME group). The occurrence of TNM downstaging in PRT group was 49.5%, including five percent who had complete response. The local reccurence rate was 4% in PRT group and 8.4% in TME group, with statistically different (p=0.04). An significant improved 5-year overall survival and disease-free survival was obtained in PRT group comparing with TME group (77.2% vs. 69.8%, p=0.04; 76.2% vs. 67.3%, p=0.03).

Conclusions: Improved local control and survival benefits could be achieved by short-course preoperative radiotherapy on the basis of standardized TME for locally advanced rectal cancer.

No significant financial relationships to disclose.
The optimum number of retrieved lymph nodes for locally advanced rectal cancer following short-course preoperative radiotherapy: A study by fat clearance.
Authors: Gu J. , Wang L.
Published: February 2017

449

Background: The optimum number of retrieved lymph nodes following preoperative radiotherapy and surgery for locally advanced rectal cancer is still controversial. This study is designed to confirm the least number of retrieved lymph nodes for locally advanced rectal cancer following 30Gy/10f short-course preoperative radiotherapy.

Methods: From Aug 2002 to Mar 2010, two hundred and twelve patients with locally advanced rectal cancer received 30Gy/10f preoperative radiotherapy (BED: 36Gy), standardized total mesorectal excision and fat-clearance based pathological evaluation in Beijing Cancer Hospital. The size of retrieved lymph nodes (LNs) was recorded. The sequence of LNs was arranged by a descending sort by retrieved nodes' size and the serial number of the largest metastatic lymph node (mLN) was recorded. The serial number of the first largest mLN is regarded as the least number of LNs to distinguish ypN+ status. The cumulative accuracy of ypN stage by variable numbers of LNs was calculated and analyzed.

Results: There were total 4,669 retrieved LNs and 354 mLNs. The median retrieved LNs number was 21 (range 4-61). The ypN positive rate was 40.6%. The peak-value of quantitive distribution of LNs and mLNs was observed in 1-2mm and 3-4mm level. The incidence of retrieving mLNs shows an intensifying tendency for increasing size of LNs. The analysis for sequence of LNs sorting suggested that 85.4% of cases could confirm their ypN stage by the first largest LN. The cumulative accuracy ascended to 95.1% or 98.1% when the first 5 or 9 largest LNs were retrieved.

Conclusions: For rectal cancer following 30Gy/10f preoperative radiotherapy, retrieving 12 or more lymph nodes seems not to be mandatory for confirming ypN stage. The accuracy in confirming negative ypN stage when retrieving 5 or 9 largest nodes is sufficient for majority of patients. In those cases that could not retrieve 5 or more nodes by routine fixation, fat clearance is indispensable.

No significant financial relationships to disclose.
Frequency of UGT1A1*28 gene polymorphism in Chinese gastrointestinal cancer patients and its relationship with irinotecan-related diarrhea.
Authors: Su Y. , Ma T. , Ye Z. b. , Zhang J. , Zhu Z. G.
Published: February 2017

451

Background: The incidence of irinotecan-related adverse events was associated with the polymorphism of uridine diphosphate glucuronosyltransferases (UGTs) gene, and demonstrated as obvious ethnic diversity. The aim of this study is to observe the frequency and severity of various adverse events in Han patients with advanced gastrointestinal cancer who was treated with irinotecan-based therapy. Simultaneously, the relationship between the severe adverse events and UGT1A1 gene promoter polymorphism (UGT1A1*28) was investigated.

Methods: A total of 109 patients (65 men and 44 women; median 57 years; range: 34-76 years) with advanced gastrointestinal carcinoma receiving irinotecan-based chemotherapy were enrolled. The adverse events during the course chemotherapy, the pretreatment serum bilirubin level, as well as the time to the Grade 3-4 toxicities occurrence were recorded. Genomic DNA was extracted from the peripheral blood to detect the polymorphism of UGT1A1*28 (TATA box thymine-adenine TA repeats). The relationship between the severity of adverse events and UGT1A1*28 polymorphism was investigated.

Results: Of all these 109 enrolled patients, 90 patients were identified with thymine-adenine (TA)6/(TA)6 genotype, 19 patients with the thymine-adenine (TA)6/(TA)7 genotype, and no (TA)7/(TA)7 genotype was found. Forty-six and 12 patients developed grade 3-4 neutropenia, while 8 and 5 patients occurred grade 3-4 diarrhea in (TA)6/(TA)6group and (TA)6/(TA)7 group, respectively. The occurrence of grade 3-4 diarrhea but not neutropenia was closely related with (TA)6/(TA)7 genotype in UGT1A1 promoter region in patients receiving irinotecan-based chemotherapy (P=0.033).

Conclusions: The frequency of UGT1A1*28 gene polymorphism in Han patients is 17.4%, which is lower than that reported in western populations. The marked increase in grade 3-4 diarrhea is related with (TA)6/(TA)7 genotype of UGT1A1 in patients receiving irinotecan-based chemotherapy.

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Effect of a gene expression-based tissue of origin test's impact on patient management for difficult-to-diagnose primary cancers.
Authors: Hornberger J. C. , Amin M. , Varadhachary G. R. , Henner W. D. , Nystrom J. S.
Published: February 2017

459

Background: An important step for a novel test is assessing its clinical utility and real-world effect on diagnosis and patient management. This report describes the results of a survey of physicians who have ordered a gene expression profile assay for identification of tumor tissue of origin (Pathwork Tissue of Origin Test) for patients with difficult-to-diagnose primary cancers.

Methods: The IRB-approved registry collects data from participating physicians who have ordered the Tissue of Origin test for their patients. To minimize recall bias, a detailed interview is conducted using both a web-based questionnaire and a confirmatory telephone interview with the physicians. Chart survey includes collection of data on patient demographics, diagnostic procedures including imaging and pathology including immunohistochemistry as well as therapy. The physicians are queried regarding their working diagnoses and treatment recommendations prior to and after Tissue of Origin Test result availability.

Results: Enrollment in the registry is ongoing. Fifty-nine patients (34 women) have been studied and 48 participating physicians have completed the interview. Survey results suggest that most patients have undergone extensive evaluation including multiple imaging tests (median, 6) and exhaustive immunohistochemistry (median, 10) prior to gene expression analysis. For these 59 pts, based on clinicopathologic evaluation, physicians reported working diagnoses for 46% of patients prior to test results and 83% after test results. Treatment recommendations were changed for 53% of patients. The majority (70%) of treatment changes were for chemotherapy. Physicians (n=26) reported that the Tissue of Origin test decreased the diagnosis associated anxiety in 62% of patients.

Conclusions: This ongoing registry study confirms that in patients with difficult-to-diagnose primary cancers, extensive baseline diagnostics is not uncommon and less than half of the patients have an established working diagnosis. Survey results suggest that the Tissue of Origin Test led to a change in working diagnosis and changed treatment recommendations in over half the patients.

[Table: see text]
Effect of platelet inhibition on the risk of development of metastatic disease in colorectal cancer.
Authors: Pulte D. , Chalasani S. B. , Bryan M. , Pliner L. F.
Published: February 2017

470

Background: Platelet inhibition has been shown to decrease the risk of metastatic disease in numerous animal models. The use of aspirin to decrease the risk of colorectal cancer (CRC) has been documented in several large studies. However, to date, no studies of whether the use of aspirin or other platelet inhibiting agent (PIA) will reduce the risk of recurrence in patients who develop CRC have been performed.

Methods: In this study, we reviewed the charts of all patients treated at the University of Medicine and Dentistry of New Jersey at Newark for stage II or III colon or rectal cancer. Data extracted included use of PIA, stage, treatment, recurrence, time of last contact, and patient characteristics. Patients were defined as having taken a PIA if any evidence of use could be documented. Statistical significance of differences observed was determined using a Fisher's exact test.

Results: 111 charts were initially identified. Use of PIA could not be determined for 6, six had metastatic disease at presentation, and one was stage I, leaving 98 patients for analysis. Of these, 35 had evidence of having used PIA, including 20 patients who were taking aspirin. Forty patients without history of use of a PIA had no metastatic disease, compared to 23 patients who developed metastatic disease. For patients taking PIA, 6 developed metastatic disease (Table).

Conclusions: Our results suggest that PIA may help decrease the likelihood of the development of metastatic disease in patients who are diagnosed with stage II or III CRC. The study was limited by the number of patients available, which was not large enough to allow consideration of all possible confounders. Further study of the effects of PIA in a translational and clinical setting including a larger, prospective trial of PIA in stage II/III CRC may lead to further insight into this question.

[Table: see text]

No significant financial relationships to disclose.
Outcome according to metastatic site in patients with KRAS wild-type tumors: Analysis from the CRYSTAL and OPUS studies.
Authors: Van Cutsem E. , Bokemeyer C. , Heeger S. , Sartorius U. , Rougier P. , Kohne C.
Published: February 2017

472

Background: The randomized CRYSTAL and OPUS studies showed that adding cetuximab (cet) to first-line chemotherapy (CT) significantly improved clinical benefit in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer (mCRC). R0 resection of colorectal liver metastases is a potentially curative option in this setting. In this descriptive analysis of these trials the benefit of adding cet to CT according to metastatic site was investigated.

Methods: KRAS wt pts were grouped according to liver-limited disease (LLD) and those with other metastatic sites (non-LLD). Treatment arms were compared for response rates (RR), R0 resection rates (R0R), progression-free (PFS) and overall survival (OS).

Results: The proportion of patients with LLD was comparable in each study and treatment arm (21%-30%). For most efficacy endpoints, pts with LLD derived greater benefit from CT alone or cet + CT compared with pts with non-LLD (Table). The highest R0R were seen in pts with LLD receiving cet + CT; increasing 2.3 and 3.7 fold from CT alone in the CRYSTAL and OPUS studies respectively. In pts with non-LLD adding cet to CT increased median OS by 5.1 and 3.4 months in the CRYSTAL and OPUS studies respectively (Table).

Conclusions: The addition of cet to standard CT increases the R0R, RR, PFS and prolongs OS in first-line mCRC in KRAS wt pts, regardless of LLD. In pts with non- LLD treated with cet and FOLFIRI median OS was prolonged by more than 5 months.

[Table: see text]

[Table: see text]
Axitinib or bevacizumab (bev) plus FOLFOX or FOLFIRI as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Bendell J. C. , Tournigand C. , Bednarczyk M. , Swieboda-Sadlej A. , Chung I. , Barone C. , Tarazi J. C. , Rosbrook B. , Ricart A. D. , Sobrero A. F.
Published: February 2017

478

Background: Axitinib (AG-013736,AG), an oral selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, shows activity in multiple tumor types including those refractory to front-line chemotherapy.

Methods: This multicenter, open-label, randomized phase II trial compared AG and bev in combination with FOLFOX or FOLFIRI in second-line mCRC. Pts previously treated with irinotecan were randomized to mFOLFOX6 plus AG 5 mg BID or bev 5 mg/kg q2wk; pts who received oxaliplatin were randomized to FOLFIRI with AG or bev at the same doses, with stratification by performance status and prior bev therapy. Primary endpoint was progression-free survival (PFS).

Results: 171 pts were randomized from March 2008 to July 2009. There were no significant differences in PFS or median overall survival (mOS) between the AG and bev arms with FOLFOX or FOLFIRI. However, there was a trend towards reduced mOS in the FOLFIRI arms with AG compared to bev, and a trend towards improved mOS with AG+FOLFOX vs bev+FOLFOX. There were more treatment discontinuations (DCs) and a higher incidence of grade ≥3 adverse events (AEs) in the AG arms (diarrhea, asthenia, fatigue; Table).

Conclusions: This study did not meet the primary endpoint, showing similar PFS with AG compared to bev when added to second-line chemotherapy. A potential factor in these results was earlier DCs in the AG versus bev arms, likely secondary to increased AEs. While VEGF inhibitors may have a role in second-line treatment of mCRC, at current dosing regimens AG-based chemotherapy shows no improvement in outcome compared to bev.

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[Table: see text]