bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective evaluation of patients with colorectal cancer (CRC) and type II non-insulin-dependent diabetes (NIDDM).
Authors: Hassabo H. , Hassan M. , George B. , Wen S. , Baladandayuthapani V. , Kopetz S. , Fogelman D. R. , Kee B. K. , Eng C. , Garrett C. R. 
Published: February 2017

507 Background: Patients with NIDDM have an increased risk of colorectal adenomas and CRC possibly mediated through the insulin growth factor receptor pathway. Metformin is associated with anticancer efficacy in preclinical models and a lower risk of cancer mortality in patients with NIDDM. We undertook to evaluate the difference in outcome in NIDDM patients with CRC based upon their medications taken for glycemic control. Methods: We conducted an IRB-approved (DR09-0719) retrospective analysis of 4,758 patients seen at a single institution (University of Texas M. D. Anderson) with CRC between the years of 2005-2008, to determine the prevalence of NIDDM in this patient population, in addition to determining whether patient survival differs based upon their diabetic therapy. Results: 425 out of 4,758 CRC patients (8.9%) were identified as having NIDDM. Gender, male:female 283:142 (67%, 33%), age, mean 62 years (range 31-91), stage I/II/III/IV 37:55:175:158 (8.7%, 12.9%, 41.2%, 37.2%). Overall survival (OS) for the 397 patients with follow-up data available, by univariable Kaplan Meier analysis, was 63.7 months (95% confidence interval (CI), 52.3-75.5). Patients with NIDDM and CRC treated with metformin as one of their diabetic medications had a survival of 76.9 months (95% CI, 61.4-102.4) as compared to 56.9 months in those patients not treated with metformin (95% CI, 44.8- 68.8), p = 0.048. By using a Cox regression model adjusted for age, sex, race, body mass index, and initial stage of disease we demonstrated that NIDDM patients treated with metformin had a 30% improvement in OS when compared to NIDDM patients treated with other diabetic agents. There was a non-statistically significant trend toward higher complete and minor pathologic response rate (≤ 10% residual tumor) in NIDDM patients with rectal cancer receiving chemoradiation who were treated with metformin when compared to those who were not (14/19, 74% vs. 9/19, 47%, p = 0.09). Conclusions: In this analysis the use of metformin in NIDDM patients with CRC was associated with an improved overall survival. While these results are consistent with the findings in other solid tumors they will need to be validated in other colorectal cancer data sets. No significant financial relationships to disclose.
Phase I study of the combination of everolimus (RAD001) with 5FU/LV in patients with refractory solid malignancies.
Authors: Davies J. M. , McRee A. J. , Sanoff H. K. , Triglianos T. , Keller K. , Ivanova A. , Bernard S. A. , Goldberg R. M. , Dees E. C. , O'Neil B. H. 
Published: February 2017

512 Background: mTOR is a controller of cellular growth and other processes that is activated by several oncogenic pathways in cancer. Everolimus is an oral inhibitor of mTOR activation. The mTOR inhibitor, temsirolimus, when combined with high dose 5FU, was limited by significant mucosal toxicity. Purpose: Phase I study to determine the maximum tolerated doses (MTD) and the safety of everolimus combined with 5FU/LV in patients with refractory solid tumors. Methods: Using a standard 3+3 design, starting doses were everolimus 15mg weekly, and q2 weekly 5FU 400mg/m2 bolus and 1800mg/m2 infusion (over 46 hours) and LV 400mg/m2. Daily dosing of everolimus was instituted during level 3 as data emerged about improved target inhibition and adverse event profile with daily dosing. Dose escalation to the maximum planned levels was achieved: everolimus 10mg daily, 5FU 400mg/m2 bolus and 2400mg/m2 infusion, and LV 400mg/m2. Dose limiting toxicities (DLT) were assessed in cycle 1 (4 weeks), defined as any grade 3/4 non-hematologic toxicity (except grade 3 skin rash, nausea and diarrhea), or complicated grade 3-4 heme toxicity. Tumors were measured every 8 weeks. Results: From 03/2008 and 11/2009, 21 patients were treated. Median age 58 (range 35-77), male/female 13/8, PS 0/1 10/11. One DLT was seen at dose level 1 (grade 3 hypersensitivity/angioedema); two at dose level 6 (grade 3 diarrhea, grade 3 hypophosphatemia). As such, dose level 5 is the MTD. Dose reductions were required in 4 patients for mouth sores (2), nasal sores (1), and grade 3 transaminitis (1). Responses are as follows: 11 stable disease and 8 progressive disease; 2 patients were not evaluable. Conclusions: MTD is everolimus 5mg daily, with q2 weekly 5FU 400mg/m2 bolus and 2400mg/m2 infusion and LV 400mg/m2. We are currently expanding the study to evaluate the addition of oxaliplatin and panitumumab to the 5-FU/LV and everolimus base. [Table: see text] [Table: see text]
KRN330, a fully human antibody against A33, in combination with irinotecan for patients with metastatic colorectal cancer (mCRC).
Authors: Bendell J. C. , Marshall J. , Berlin J. , Hochster H. S. 
Published: February 2017

534 Background: KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen on normal colonic epithelium, which is uniformly expressed in 95% of colorectal cancers. A KRN330 monotherapy phase I study showed over 1 year of stable disease in 2 pts with refractory mCRC. We report results of the phase I part of a phase I/II trial of KRN330 in combination with irinotecan in pts with mCRC. Methods: Pts with mCRC who progressed on one or more prior therapies received weekly (QW) or biweekly (Q2W) intravenous doses of KRN330 at 0.5 or 1.0 mg/kg with Q2W irinotecan at 180 mg/m2 in a standard 3+3 dose escalation design. Results: Nineteen pts were treated. Four pts received 1.0 mg/kg of KRN330 Q2W and irinotecan treatment. Three pts developed DLTs, which included G4 febrile neutropenia and G3 colitis, prolonged G3 diarrhea, and, G4 neutropenia with prolonged G3 diarrhea. KRN330 was then deescalated to 0.5 mg/kg Q2W and 0.5 mg/kg QW. There were no DLTs in 7 of 8 pts in the Q2W cohort. The 1 DLT in this cohort was G3 colitis. None of the 7 pts in the QW cohort experienced DLT. The most common G3/4 toxicities included diarrhea (26.3%) and febrile neutropenia (15.9%), leucopenia (10.5%), neutropenia (10.5%), abdominal pain (10.5%), and colitis (10.5%). Of the 16 pts evaluable for efficacy, 2 pts had PR, 8 SD and 6 PD as best response. The 2 pts with PR had previously received an irinotecan-containing regimen, one with PD on an irinotecan-containing regimen. The responses are being confirmed by independent adjudicator. Conclusions: QW and Q2W intravenous doses of KRN330 at 0.5 mg/kg KRN330 with irinotecan were tolerable and demonstrated antitumor effect in pts who had received previous irinotecan-containing regimens. The phase II part of the phase I/II study of QW KRN330 plus irinotecan in pts with second line mCRC is ongoing. No significant financial relationships to disclose.
Effect of inhibition of heat-shock protein 90 on mutant c-Kit protein as modulated by mRNA expression and protein degradation through both proteasome and autophagy-mediated pathways.
Authors: Chen L. , Hsueh Y. , Chiang N. , Yen C. , Shih N. 
Published: February 2017

54 Background: c-Kit is a known client protein of heat-shock protein 90 (Hsp90). Inhibition of Hsp90 can reduce the expression of c-Kit protein in human mastocytoma and gastrointestinal stromal tumor (GIST) cells, which is conceived through the proteasome degradation pathway. Methods: COS-1 cells transfected with vectors containing CMV promoter-driven various c-Kit mutants (imatinib- sensitive or imatinib-resistant) and human GIST882 cells (with endogenous exon 13 mutant c-Kit) were used to investigate the efficacy NVP-AUY922, a new class of Hsp90 inhibitor, on suppressing the constitutive activation of mutated c-Kit. Detail mechanisms of protein regulation, as RNA transcription, RNA stability, and protein degradation were studied. Results: NVP-AUY922 is more potent than 17-AAG to inhibit the proliferation of imatinib-sensitive GIST882 cells. Further study showed that NVP-AUY922 down-regulated both total and phosphorylated c-Kit proteins in dose- and time-dependent manners in both GIST882 cells and mutant c-Kit (including imatinib-resistant exon11/17 double mutants) expressed in COS-1 cells. Surprisingly, the NVP-AUY922-induced c-Kit degradation in both cell models could be reversed by proteasome-degradation inhibitor and autophagy inhibitor. The involvement of autophagy in NVP-AUY922-induced c-Kit protein degradation was further confirmed by co-localization of c-Kit and autophagosome by immuno-staining. In addition, NVP-AUY922 treatment resulted in a reduction of c-Kit mRNA level in GIST882 cells but not c-Kit expressing COS-1 cells, which could be explained by the use of CMV promoter in artificial COS-1 cell model. Conclusions: Taken together, these findings provide the first evidence that down-regulation of mutant c-Kit protein by Hsp90 inhibitor involved both transcription and post-translation levels. Of the latter, autophagy- as well as proteasome-mediated degradation pathways were involved. These observations highlight the use of NVP-AUY922 either alone or in combination with autophagy modulators in imatinib-refractory, c-Kit-expressing GIST. Supported by 99D1-TC-CADOH03. [Table: see text]
Distributions of FcγRIIa-131 and FcγRIIIa-158 polymorphisms and clinical response to cetuximab in Japanese patients with metastatic colorectal cancer (mCRC).
Authors: Fukushima H. , Yoshino T. , Yamazaki K. , Nishina T. , Yuki S. , Kadowaki S. , Shinozaki E. , Yokota T. , Kajiura S. , Yamanaka T. 
Published: February 2017

565 Background: Polymorphisms in fragment C receptor (FcγR) are expected as a predictive biomarker of cetuximab (Cmab). Previous studies have convincingly confirmed the distributions (dists) of FcγR polymorphisms in Western population and shown the existence of linkage disequilibrium (LD) between FcγRIIa and FcγRIIIa polymorphisms. Meanwhile, the dists in Asian population have been unknown but a few studies for non-cancer patients have suggested the difference in dists between Asian and Western populations. We investigated the dists of FcγR polymorphisms and their association with clinical response to Cmab in Japanese mCRC patients. Methods: Ninety-three patients with irinotecan/oxaliplatin/5-FU-refractory mCRC and treated by Cmab plus irinotecan or Cmab monotherapy were retrospectively registered from 8 centers in Japan. FcγR polymorphisms were determined from genomic DNA extracted from peripheral blood samples based on the Multiplex allele-specific PCR method. Comparisons according to FcγR polymorphisms were evaluated using Fisher's exact test for response rate (RR) and log-rank test for progression-free survival curves (PFS). Results: The dists of FcγRIIa HH/HR/RR and FcγRIIIa VV/VF/FF were 68/30/2% and 4/40/56%, respectively (Table). The absence of LD between FcγRIIa and FcγRIIIa polymorphisms was confirmed (GENEPOP, p=0.526; Linkdis, p=0.146). Of 74 patients with KRAS wild-type and treated by Cmab plus irinotecan, no difference according to FcγR polymorphisms was observed in either RR (IIa: HH 37% vs. HR/RR 36%, p=1.00; IIIa: VV/VF 39% vs. FF 35%, p= 0.81) or PFS curves (IIa: HH vs. HR/RR, p=0.84; IIIa: VV/VF vs. FF, p=0.09). Similar results were seen in patients treated by cetuximab monotherapy. Conclusions: This study clarified an ethnic difference in the frequencies of FcγR polymorphisms. Associations between the polymorphisms and clinical response to Cmab did not reach a statistical significance. [Table: see text] No significant financial relationships to disclose.
Interim analysis of a single-arm, phase II study of bevacizumab (BV) with modified OPTIMOX1 as first-line treatment of patients with metastatic colorectal cancer (mCRC): TCOG-GI0802.
Authors: Asano M. , Tanaka S. , Sato A. , Nakayama N. , Shimada K. , Konishi K. , Hibi K. , Sasaki E. , Kurihara M. 
Published: February 2017

578 Background: BV is widely used for treatment of metastatic colorectal cancer (mCRC) patients. Although BV was often administrated to mCRC patients in combination with oxaliplatin, optimal schedule remains unclear. Many mCRC patients cannot continue to use oxalipatin because of cumulative neurotoxity, which decreases patient's QOL and motivation.We postulated that modification of oxaliplatin schedule would improve TTF in intermittent oxaliplatin usage. Therefore, we planned to use BV with original OPTIMOX1 adiministration schedule; modified oxaliplatin dose (85 mg/m3). Methods: Patients were enrolled with the criteria excluding neuropathy, PS ≥ 1, or no previous usage of oxaliplatin and BV, and then were received modified FOLFOX6 regimen (L-OHP 85 mg/m2, l-LV 200 mg/m2, 5-FU 400 mg/m2 bolus, 5-FU 2,400 mg/m2 46h continuous infusion) plus BV (5 mg/kg) q2wks x 6 cycles, followed sLV5FU2 (omit L-OHP) plus BV x 12 cycles regimen. After that, oxaliplatin reintroduction was done and mFOLFOX6 plus BV regimen was continued until PD. The evaluation of antitumor effect was done according to RECIST Criteria. Results: 40 patients accrued this trial. Median age was 65 years old. PS0: 89.5%, male: 75%, female: 25%, colon: 65.8%, rectal: 31.6%,colon + rectal: 2.6%. During initial 6 cycles of chemotherapy, 90% patients could continue chemotherapy. Response rate was 50%, and clinical benefit (including SD) was 92.1%. During Intial 6 cycles, G3 neuropathy occurred 2.6%, and G2 were 5%. Most frequent toxicity (≥G3) was neutropenia (30.8%) and anorexia (5.3%). One patient could complete the scheduled regimen. This patient continued mFOLFOX6+BV for 12 cycles after reintroduction keeping with PS 0, and was received FOLFIRI+BV regimen as second-line chemotherapy. Further information are under examination. Conclusions: This administration schedule was well tolerated and could continue chemotherapy longer than usual method. sLV5FU2+BV regimen was not affected reintroduction rate and progression free survival. BV with mOPTIMOX1 regimen can be expected to become a good treatment options for mCRC patients. No significant financial relationships to disclose.
Association of hypersensitivity reactions to oxaliplatin with cumulative dose of oxaliplatin.
Authors: Saito M. , Yoshino T. , Kawamoto Y. , Bando H. , Arimura Y. , Fuse N. , Tahara M. , Doi T. , Ohtsu A. 
Published: February 2017

584 Background: The incidence of hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) in colorectal cancer patients (CRC) receiving the 5-fluorouracil/leucovorin plus L-OHP (FOLFOX) regimen is reported to be 10 to 17%. There are several reports of clinical features of HSRs to L-OHP, but the relationship between HSRs and the cumulative dose of L-OHP has not been clarified. Methods: From August 2005 to July 2009, a total of 54 CRC patients who developed HSRs during treatment with mFOLFOX6 or mFOLFOX6 plus bevacizumab regimen as first-line treatment, were reviewed retrospectively. Within this patient group, sixteen patients had an L-OHP-free interval of at least three months or more. We investigated the clinical features of HSRs associated with L-OHP in our institution, and evaluated the degree to which its occurrence is dependent upon the cumulative dose of L-OHP in patients who had an interruption of L-OHP. Results: Within the sample of 54 patients, HSRs occurred after a median treatment course number of 8 (range 2-19), and the median cumulative dose of L-OHP being 700 mg/m2 (range 170-1615). In these subjects, grade1/2/3 HSRs developed in 33/20/1 patients, respectively. Re-challenge of L-OHP combined with prophylactic agents was performed in 42 patients (78%). There were 16 patients who had an L-OHP- free interval, in whom the major reason for L-OHP withdrawal was neurotoxicity, with reintroduction because of tumor progression or recurrence. Of these 16 patients, 10 developed the first HSRs after reintroduction of L-OHP. Among these 10 patients, grade1/2/3 HSRs developed in 6/3/1 patients, respectively, and occurred at a median course number of 2.5 following re-infusion of L-OHP, or 12 treatments after the initial infusion. The median cumulative dose of L-OHP at HSRs in this patient group was 213 mg/m2 after the re-introduced infusion, and a total of 1088 mg/m2 since initial onset of treatment. Conclusions: Our results suggest that the development of HSRs during L-OHP treatment depends on the cumulative dose from the initial administration even in patients who experienced an L-OHP-free interval. No significant financial relationships to disclose.
Ultraradical surgery and heated intraperitoneal chemotherapy (HIPEC) as multimodal treatment of advanced colorectal cancer.
Authors: Nikolic S. , Zegarac M. , Inic M. , Martinovic A. 
Published: February 2017

585 Background: Examin does agressive surgical treatment in combination with HIPEC (oxaliplatin) could increase median survial in patients with advanced stage of colorectal cancer. Methods: Ultraradical surgery and HIPEC was applied in patients who were initialy with peritoneal carcinomatosis or infiltration in around organs. We evaluated the patients during the period 2000-2010 in this retrospective study. Results: During 2000 and 2010 we peformed 132 ultraradical surgical procedure. All patients were treated with HIPEC (40C) using oxaliplatin (410mg/m2) in 3l of perfusat during 90 minutes. The average duration of the procedure was 5h 57 minutes.The follow up period was 72 months. 120 had Ro and 12 had R1 resection. One year survival rate was 81.25% and three year survival rate was 56.25%, six year survival rate is 40.6%. Conclusions: Ultraradical surgery combined with HIPEC prolongs patient's survival and is considered to be a safe procedure if performed by the experience team of oncological surgeons. No significant financial relationships to disclose.
Vitamin K1 cream in the management of skin rash during anti-EGFR monoclonal antibody (mAb) treatment in patients with metastatic cancer: First analysis of an observational Italian study.
Authors: Pinto C. , Barone C. , Martoni A. , Di Tullio P. , Orlandi A. , Di Fabio F. , Cassano A. , Rojas Llimpe F. L. , Amoroso A. , Pini S. 
Published: February 2017

594 Background: Cutaneous toxicity, and especially skin rash, is a predictable side- effect of anti-EGFR mAb therapy. Preclinical studies have shown that vitamin K1 reactivated EGFR-mediated signal transduction after inhibition via EGFR receptor antagonists. The aim of this study was to evaluate the impact of vitamin K1 cream in skin rash management. Methods: In two Italian Oncology Centers sequential pts at the first therapy with cetuximab/panitumumab for metastatic cancer were treated with vitamin K1 cream at the first onset of grade ≥2 skin rash. Topical treatment with vitamin K1 (phytomenadione 0.1%) cream twice/die was administered continuously until the end of anti-EGFR treatment. Skin toxicity, according to NCI-CTC v3.0 grading system, was clinically evaluated every week and in a standardized way, taking pictures of 5 different body areas. Treatment benefit was evaluated according to symptom reduction and compliance to therapy. Results: From February to September 2010, 33 pts, 22M (66.6%) and 11F (33.4%), median age 63 years (range 27-79), were evaluated. The primary tumor site was 3 (9.1%) esophagus/stomach, 28 (84.8%) colon-rectum, 2 (6.1%) head-neck. Eighteen (54.5%) pts were treated as first-line and 15 (45.5%) were pretreated. The regimen contained cetuximab in 26 (78.7%) pts and panitumumab in 7 (21.3%). The combination regimens were platinum compounds-based in 23 (69.6%) pts, and irinotecan-based in 6 (18.2%); panitumumab was administered in monotherapy in 4 (12.2%) pts. The median time of vitamin K1 cream treatment was 24 weeks (range 6-28); the oral tetracyclines therapy was associated in 13 (39.4%) pts. The decrease in skin rash to grade 1-0 was observed in 12 (36.4%) pts, and 13 (39.4%) pts showed unchanged grade 2. The increase to grade 3 in skin rash was observed in 8 (24.2%) pts. Good skin rash symptom control was obtained in 69.2% of pts. Cetuximab/panitumumab dose reduction and treatment delays was required in 9 (27.3%) pts. Conclusions: These preliminary results suggest a favorable impact of vitamin K1 cream in skin rash management, which should be considered in a future clinical trial. No significant financial relationships to disclose.
The PARSC trial: A prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.
Authors: Salazar R. , Rosenberg R. , Lutke Holzik M. , Marshall J. , Van Der Hoeven J. J. , Glimelius B. , Bibeau F. , Stork-Sloots L. , Bender R. A. , Tabernero J. 
Published: February 2017

602 Background: Clinical trials have not yet shown convincingly if adjuvant chemotherapy is justified for stage II CC patients of whom 25% are at risk of recurrence. An 18-gene expression profile, ColoPrint, has been developed for identifying CC cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature has been validated in independent cohorts of 206 CC patients and in in-silico datasets (Salazar et al, JCO in press). The profile classified 63.2% of the stage II patients (n=134) as low risk. The HR for relapse free survival (RFS) was 3.34 (p=0.017) with a 5-year RFS rate of 90.9% (95%CI, 84.0 -97.8%) for low risk patients and 73.9% (95%CI, 59.2-88.6%) for high risk patients. Moreover, the profile stratified patients independent of ASCO clinical risk factors. Methods: A prospective trial, PARSC (Prospective Study for the Assessment of Recurrence Risk in Stage II CC Patients Using ColoPrint) has been initiated. The main objectives are: (1) determine risk assessment by ColoPrint profile versus clinical parameters based on local protocol and ASCO high-risk recommendations in stage II patients; (2) establish proportion of ′good prognosis′ and ′poor prognosis profile′ in various countries; and (3) validate the power of risk assessment and compare performance of ColoPrint and clinical risk assessment in estimating 3 year relapse rate. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II,no neoadjuvant systemic therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician. Results: The trial started in Sept. 2008 with currently 26 participating sites in 11 countries. So far, 223 stage II patients have been enrolled of whom 183 are eligible. 11 patients were rejected because of prior malignancies; 24 patients were rejected based on low tumor content of the sample (< 30% tumor cells), 3 patients had rectal cancer and 2 synchronous tumor. Conclusions: The aim is to enroll 600 stage II patients to differentiate between 3 year relapse- free survival predicted by ColoPrint versus clinical factors. [Table: see text]