bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of obesity in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas.
Authors: Lin B. S. , Zell J. A. , Madson N. , McLaren C. E. , Gerner E. W. , Meyskens F. L.
Published: February 2017

374

Background: Chemoprevention with difluoromethylornithine (DFMO) plus sulindac markedly reduces risk of recurrence in colorectal adenoma (CRA) patients. Obesity is associated with risk of CRA and colorectal cancer (CRC). This study investigates how obesity influences CRA characteristics at baseline and risk of recurrence after treatment with DFMO plus sulindac vs. placebo.

Methods: Our analysis included subjects enrolled in a phase III CRA prevention clinical trial investigating DFMO plus sulindac vs. placebo. Patients were classified by obesity (BMI > 30 kg/m2) status at baseline. Pearson's χ2 statistic or Fisher's exact test and Mann-Whitney U test were used to compare baseline characteristics with regard to obesity status. Log-binomial regression analysis was used to determine the relative risk of metachronous adenoma, adenoma with advanced histology, or multiple adenomas, adjusted for covariates.

Results: At baseline, obesity was associated with increased adenoma number (p =0.017), size (p =0.003), advanced histology (p =0.042), high-risk adenomas (p =0.0002), and distal adenomas (p =0.038). Obesity did not modify adenoma recurrence after treatment with DFMO plus sulindac or placebo (p =0.80).

Conclusions: Our results provide supporting evidence for the association of obesity with high-risk adenoma features at baseline; however, obesity does not substantially modify CRA risk reduction after treatment with DFMO plus sulindac vs. placebo.

[Table: see text]

[Table: see text]
Calcium and magnesium infusions for prevention of oxaliplatin-induced peripheral neuropathy.
Authors: Bupathi M. , Mahmud G. , Kovar J. , Wang E. , O'Brien T. E.
Published: February 2017

387

Background: Oxaliplatin plays an important role in chemotherapy regimens for colorectal and other GI malignancies. Debilitating peripheral neuropathy (PN) often develops with use of this drug. One study (Grothey A et al, ASCO 2009, abst #4025) has shown that pre- and post-oxaliplatin infusions with calcium (Ca) and magnesium (Mg) may reduce this toxicity. To confirm this in an unselected indigent minority population, a retrospective review was performed comparing development of PN in oxaliplatin exposed patients treated with or without Ca/Mg.

Methods: Records of patients who received oxaliplatin from 1/2008 to 12/2009 at MetroHealth Medical Center, a large safety net hospital in Cleveland, OH, were reviewed. 47 patients received Ca/Mg + oxaliplatin and 46 oxaliplatin alone. Data collected included age, race, gender, insurance status, performance status, tumor type, stage, concomitant diseases (DM and EtOH), number of cycles and cumulative dose of oxaliplatin. PN was determined using the Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. Patients were followed 6 months after completion of oxaliplatin.

Results: Demographic data was similar between the two groups. Colorectal cancer compromised 77% of the treatment group and 85% of control group. Patients who received Ca/Mg had significantly less PN in all three grades (1-3) compared with the control group (grade 1 89.4% vs. 71.7%, grade II 10.6% vs. 19.6%, grade 3 0% vs. 8.7%, respectively). The cumulative dose of oxaliplatin did not differ between the two groups (Ca/Mg median 1,143 range 260-2,169; control median 1,425 range 137-2,635). The combined total grades 2 and 3 in both the treatment and control (10.6% vs. 28.3%, p = 0.038) favored use of Ca/Mg.

Conclusions: This small, retrospective study confirms that Ca/Mg infusions reduce the incidence of clinically significant (grade 2/3) PN in pts receiving oxaliplatin.

No significant financial relationships to disclose.
Primary appendiceal mucinous adenocarcinoma in two first-degree relatives: Case report and retrospective chart review.
Authors: Racek A. R. , Rabe K. G. , Wick M. J. , Psychogios A. , Lindor N. M.
Published: February 2017

397

Background: Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for <0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare.

Methods: We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder: no DNA mismatch repair defect was evident and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases.

Results: Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member.

Conclusions: The occurrence of appendiceal cancer in siblings may represent a random occurrence. Adenocarcinomas of the most common type of appendiceal cancer and occur at older ages than other histologic subtypes. A strikingly rare predisposition syndrome cannot be ruled out.

[Table: see text]

No significant financial relationships to disclose.
Effect of surgeon education on lymphadenectomy in colon cancer.
Authors: Young S. E. , Cohn A. L. , Sellers G. , Gomez J. M. , Shapiro H. , Birdsey K. , Spaulding A.
Published: February 2017

423

Background: The most important determinant of prognosis for localized colon cancer is metastatic lymph node involvement. The American Joint Commission on Cancer and the College of American Pathologists have recommended examination ≥ 12 lymph nodes to ensure adequate staging. We hypothesized that surgeon education would improve the extent of lymphadenectomy in patients being treated for colon cancer. A large community based metropolitan health care system served as a model for testing this hypothesis.

Methods: 906 patients comprising AJCC stage I (n=265), stage II (n=304), and stage III (n=337) colon cancers were evaluated. Surgical approach was either open (n=567), laparoscopic (n=310), or unknown (n=29). Lymphadenectomy results obtained from post-operative pathology reports were tracked across four separate time periods: era 1 (1/1/02-1/31/04), era 2 (1/1/05-1/31/06), and era 3 (1/1/07-1/31/07). Results were then compared against a study endpoint measurement of 2008, era four.

Results: Upon analysis and comparison of individual era results, a significant improvement in lymphadenectomy (percentage of patients with ≥12 nodes harvested) was noted for all AJCC stages (p-values compare era 4 versus era 1): I (34.2% vs. 59% vs. 65% vs. 69%, P=0.0001), II (62% vs. 76% vs. 90% vs. 91%, P=0.0004), and III (55% vs. 72% vs. 84% vs. 86%, P<0.0001; see table). Surgical approach was not a significant factor. Neither age nor sex was significant.

Conclusions: Through physician education, we were able to increase awareness of optimal staging practice for lymphadenectomy in colon cancer. This resulted in significantly improved patient outcomes within a large metropolitan health care system.

No significant financial relationships to disclose.
Development of an assay to predict oxaliplatin sensitivity from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues.
Authors: Freedman J. A. , Osada T. , Tsamis K. A. , Morse M. , Clary B. M. , Lyerly H. K. , Nevins J. R. , Clay T. M. , Hsu S. D.
Published: February 2017

429

Background: Genomic profiling has improved our understanding of the underlying biology of tumors, accuracy of diagnosing disease, predictions of the courses of disease, and ability to determine the therapeutic agents that will be most effective in the treatment of particular tumors. However, in order for assays involving microarray data to be useful in the clinical setting, the ability to generate reliable and consistent data from FFPE tissues is essential.

Methods: Cancer cell lines from the NCI-60 collection exhibiting greatest sensitivity or resistance to oxaliplatin were identified. These cells were grown in culture, fixed for 24 hours in formalin, and paraffin-embedded. RNA from the FFPE cells was isolated, amplified, and hybridized to Affymetrix arrays. A Bayesian binary regression analysis was used to generate a predictor of oxaliplatin sensitivity from the gene expression data. Metastatic derived xenografts (MDXs) from resected colorectal tumors were established and treated with oxaliplatin. Samples from tumors prior to treatment were paraffin-embedded and used for RNA extraction, amplification, and hybridization to Affymetrix arrays. The gene expression signature predicting sensitivity to oxaliplatin was then validated with response data from MDXs treated with oxaliplatin.

Results: A predictor consisting of 300 genes that could predict sensitivity to oxaliplatin was generated using FFPE samples. Significant correlation was observed between the predicted probability of oxaliplatin sensitivity and the tumor growth inhibition measurement for a given MDX (p=0.0012).

Conclusions: Reliable and consistent predictions of oxaliplatin sensitivity can be obtained from gene expression data from FFPE tissues. This method has potential utility in the clinical setting. The ability to predict response to a therapeutic in a FFPE sample has the potential to guide the choice of therapeutics, resulting in an option that could be most effective in treating an individual with metastatic colorectal cancer.

No significant financial relationships to disclose.
PKM2 as a biomarker for sensitivity to oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).
Authors: Papadaki C. , Saridaki Z. , Tzardi M. , Sfakianaki M. , Sfakiotaki G. , Trypaki M. , Messaritakis I. , Mavroudis D. , Georgoulias V. , Sougklakos I.
Published: February 2017

434

Background: Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2), which is a key enzyme that regulates aerobic glycolysis in tumor cells. Use of RNA interfering (RNAi) targeting PKM2 significantly inhibits tumor growth when combined with cisplatin in xenograft models. We evaluated the predictive significance of PKM2 in patients with mCRC treated with oxaliplatin- based chemotherapy in the first-line setting.

Methods: FFPE primary tumors from 140 mCRC patients were analyzed for PKM2 mRNA expression by RT-qPCR. The analysis was performed with a set of primers and probes which amplify only the M2 isoform.

Results: The patients' characteristics were all typical for mCRC (median age 65 years, 61% males, 75% colon cancer 25% rectal cancer, 41% undifferentiated tumors, 21% mucinous features). PKM2 was successfully amplified in all specimens. Time to tumor progression (TTP) was significantly lower in patients with overexpression of PKM2 (6.7 vs. 9.1 months for high and low expression, respectively, p=0.004). Similarly, median overall survival (mOS) was significantly decreased in patients with upregulation of PKM2 (21.9 vs. 30.2 months for high and low expression, respectively, p=0.004). Multivariate analysis revealed PKM2 high mRNA expression (HR: 1.7, p=0.005) and the presence of undifferantited tumors (HR: 2.2, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, PKM2 high mRNA expression (HR: 1.8, p=0.005) and the presence of undifferantited tumors (HR: 2.5, p<0.0001) were revealed as independent prognostic factors for decreased mOS.

Conclusions: These results provide evidence that the PKM2 mRNA expression could be used as a predictive factor for sensitivity to oxaliplatin-based chemotherapy. The results should be validated prospectively in an independent patient cohort.

No significant financial relationships to disclose.
Impact of KRAS, BRAF, and PIK3CA mutations, PTEN, AREG, and EREG expression, and skin rash in metastatic colorectal cancer patients treated with cetuximab-containing salvage treatment.
Authors: Saridaki Z. , Tzardi M. , Papadaki C. , Sfakianaki M. , Pega F. , Kalikaki A. , Tsakalaki E. , Mavroudis D. , Georgoulias V. , Sougklakos I.
Published: February 2017

445

Background: To investigate the predictive significance of KRAS exon 2, BRAF V600E, PIK3CA exon 9 and 20 mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in patients with metastatic colorectal cancer (mCRC) treated with cetuximab containing salvage chemotherapy.

Methods: Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded.

Results: KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p=0.001 and p=0.026, respectively) or BRAF (p=0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p=0.018 and p=0.013, respectively) or EREG (p=0.002 and p=0.004, respectively) and in those with grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p=0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p=0.021 and p=0.004, respectively) or EREG (p=0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p=0.01) or lost PTEN (p=0.002). Multivariate analysis revealed KRAS (hazard ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low mRNA expression (HR: 1.6, p=0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p=0.01), BRAF mutation (HR: 3.0, p=0.001), EREG low mRNA expression (HR: 1.7, p=0.021), absecence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p=0.001) were revealed as independent prognostic factors for decreased OS.

Conclusions: These results underscore the potential of advanced CRCs genetic profiling in order to identify patients with different treatment response.

No significant financial relationships to disclose.
New analysis of the hypertension mechanism in bevacizumab-treated patients using 3-tesla dynamic contrast-enhanced magnetic resonance imaging.
Authors: Hirashima Y. , Yamada Y. , Tateishi U. , Kato K. , Miyake M. , Akiyoshi K. , Horita Y. , Nagashima K. , Shirao K.
Published: February 2017

450

Background: Vascular endothelial growth factor (VEGF) signaling inhibitors, such as bevacizumab (BV), leads to endothelial dysfunction and microvascular rarefaction in noncancer tissue. Angiotensin II has been reported to induce VEGF production by inhibiting VEGF, but the reasons for activation of angiotensin II are unclear. We conducted a study to examine the relationship between renin-angiotensin axis and renal blood perfusion using dynamic contrast magnetic resonance imaging (DCE-MRI) in colorectal cancer patients.

Methods: Sixteen patients with colorectal cancer were enrolled. They received BV+FOLFIRI regimen as second line. DCE-MRI was performed before the treatment and after 12th courses. Renin, angiotensin I, angiotensin II and aldosterone were examined before treatment and at 3, 5, 8, 12th courses. DCE-MRI parameters, Area under the time-intensity curve over the first 90 seconds after injection of contrast material (AUC90) and volume transfer constant of contrast material (Ktrans, Kep) were calculated in the normal kidney and examine the correlation with renin-angiotensin axis.

Results: All DCE-MRI parameters decreased significantly after 12th courses compared with before treatment (Variables median: Ktrans -1.51, Kep -2.30, AUC90 -26.0, P < 0.001, all). A decrease in Kep correlated with higher renin, angiotensin I and angiotensin II (renin: P =0.001, angiotensin I: P =0.003, angiotensin II: P =0.002, respectively). A decrease in AUC90 correlated with higher aldosterone (P =0.005). Blood pressure did not correlate with each DCE-MRI parameters.

Conclusions: VEGF inhibition decreases vessel permeability and raises interstitial pressure in normal kidney. Our data suggest that renin-angiotensin axis is also one mechanism of hypertension caused by BV.

No significant financial relationships to disclose.
Predictive and prognostic implications of KRAS genotype in patients with metastatic colorectal cancer (MCRC) treated with FIr-B/FOx association.
Authors: Bruera G. , Cannita K. , Di Giacomo D. , Troncone G. , Marchetti A. , Coletti G. , Sabourin J. , Tosi M. , Ficorella C. , Ricevuto E.
Published: February 2017

457

Background: FIr-B/FOx association, consisting of triplet chemotherapy (FIr/FOx) plus bevacizumab, increases activity, efficacy, and resection rate of liver metastases in MCRC patients (Bruera G et al, submitted 2010). Even if bevacizumab-containing chemotherapy is also active in KRAS m MCRC patients, ORR, PFS, and OS seem to be lower compared to KRAS wt patients (Hurwitz et al, Oncologist 2009). Present data evaluates activity and efficacy of FIr-B/FOX according to KRAS genotype.

Methods: Treatment schedule: weekly alternating bevacizumab (5 mg/kg days 1,15)/irinotecan (160 mg/m2) or oxaliplatin (80 mg/m2) associated to weekly 5- fluorouracil (12h-timed-flat-infusion, 900 mg/m2/d 1-2, 8-9, 15-16, 22-23); every 4 weeks. KRAS genotype was analyzed by direct sequencing or SNaPshot (Di Fiore et al, BJC'07) for KRAS codon 12 and 13 mutations.

Results: Forty-two (84%) out of 50 enrolled patients (pts) in the FIr-B/FOx phase II study were evaluated: ORR 86% (C.I. ± 11), median PFS 13 months (3-46+), median OS 28 months (8-47). Liver metastasectomies (LM) were performed in 11 pts (26%): 42% of the 26 liver-MCRC pts; 58% of the 19 pts with liver-only MCRC pts. Twenty-five pts (59.5%) were KRAS wild-type (wt), 17 pts (40.5%) KRAS mutated (m). Clinical features were balanced. Among the 25 KRAS wt pts: ORR 88% (C.I. ± 14); median PFS 14 months (3-46+); median OS 31 months (8-47). LM were performed in 9 KRAS wt pts (36%): 56% of the 16 liver-MCRC pts; 82% of the 11 liver-only MCRC pts. Among the 17 KRAS m pts: ORR 82% (C.I. ± 19); median PFS 12 months (4-37+); median OS 19 months (8-44). LM were performed in 3 KRAS m pts (18%): 30% of the 10 liver-MCRC pts; 37.5% of the 8 liver-only MCRC pts.

Conclusions: Triplet chemotherapy plus bevacizumab (FIr-B/FOx association) shows equivalent high activity (ORR) and efficacy (PFS) in KRAS wt and KRAS m MCRC pts; a trend toward a worse prognosis (OS) is confirmed in KRAS m pts.

No significant financial relationships to disclose.
Feasibility and potential benefit of neoadjuvant chemotherapy for colorectal liver metastasis: A single-centered retrospective study.
Authors: Kataoka K. , Kanazawa A. , Nakajima A. , Yamaguchi A. , Tuyuki S. , Arimoto A. , Kohno Y.
Published: February 2017

465

Background: Recently, several papers have reported the advantage of neoadjuvant chemotherapy for liver limited metastatic colorectal cancer. In these papers, most study groups used criteria for non-resectability due to size and/or number of metastases. Our criteria for resectability of colorectal liver metastases (CLM) depends on the size of remnant liver volume (>30%) and expected function after the removal of all metastases. Then, we assessed the feasibility and potential benefits of chemotherapy administered before surgery to patients with CLM retrospectively.

Methods: From January 2007 to April 2010, 67 chemotherapy-naive patients were diagnosed as CLM without extra-hepatic metastases. After chemotherapy, we assessed the resectability with radiological examination.Then, each case was divided in two groups, resected group and unresected group. Overall survival, median disease-free survival and postoperative complications were analyzed.

Results: 63 patients received oxaliplatin-based combination regimen and 4 patients other regimen. 30 patients (resected group) received R0 resection and 37 patients (unresected group) were considered as unresectable. No serious postoperative complications were observed. Overall survival was significantly higher in resected group than in unresected group (42.3 month and 29.1 month; P<0.001). Median disease-free survival was 18.8 months in resected group (95% CI:3.02 to 31.33). According to our retrospective review, resectable cases increased from 28 of 67 patients at baseline to 33 after chemotherapy (including 3 cases considered as CR after chemotherapy only).

Conclusions: Intensive treatment with neoadjuvant chemotherapy for CLM is well tolerated. Curative surgery improved significantly overall survival in patients with CLM. Neoadjuvant chemotherapy such as mFOLFOX6 may lead to increased resectability but do not increase postoperative complications. For most patients with resectable CLM, neoadjuvant chemotherapy should be considered the standard treatment.

No significant financial relationships to disclose.
Association of survivin expression following neoadjuvant radiochemotherapy in rectal cancer with distant metastases and survival.
Authors: Sprenger T. , Rödel F. , Beissbarth T. , Conradi L. , Homayounfar K. , Ghadimi B. M. , Yildrim M. , Becker H. , Rödel C. , Liersch T.
Published: February 2017

483

Background: Valid molecular markers need to be implemented in clinical trials to fulfill the demand of a risk-adapted and more individualized multimodal therapy of locally advanced primary rectal cancer. In the present study the expression of the inhibitor-of-apoptosis (IAP) protein Survivin was evaluated in pre-treatment biopsies and corresponding post-treatment resection specimens, and was correlated to histo-pathological tumor characteristics and clinical follow-up.

Methods: 116 patients with stage II/III rectal cancer treated with 5-FU-based neoadjuvant radiochemotherapy (RCT) within the German Rectal Cancer Trials were investigated. Survivin expression in pre-treatment biopsies and surgical resection specimens were determined by immunohistochemistry by two independent institutions and correlated with histopathologic parameters, tumor recurrences, disease-free and overall cancer-specific survival.

Results: In pre-treatment biopsies, a higher Survivin expression correlated with advanced ypT (p=0.026) and ypUICC (p=0.05) stage as well as decreased disease-free survival (p=0.038) after preoperative RCT. High post-treatment Survivin levels were associated with advanced ypT stage (p=0.03) and residual lymph node metastases (p=0.04). Moreover, neoadjuvant RCT resulted in a significant down-regulation of Survivin expression (p < 0.0001). A failure of RCT-induced down-regulation was associated with development of distant metastases (p=0.0056) and cancer-related death (p=0.026), and was significantly correlated with disease-free (p=0.011*/0.02**) and cancer-specific survival (p=0.0017*/0.01**) in uni*- and multivariate** analyses.

Conclusions: Survivin expression displays a marker with prognostic validity in rectal cancers. These results underline the usefulness of Survivin to monitor individual response to RCT in rectal cancer, and encourage anti-Survivin strategies in multimodal rectal cancer therapy within future randomised clinical trials.

No significant financial relationships to disclose.
Two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC following complete cytoreductive surgery for colorectal carcinomatosis.
Authors: Quenet F. , Goéré D. , Mehta S. , Roca L. , Dumont F. , Essissen M. , Sain-Aubert B. , Elias D.
Published: February 2017

486

Background: In treatment of peritoneal carcinomatosis (PC) of colorectal origin, studies combining cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC) have shown encouraging survival results. Intraperitoneal drugs usually used are mitomycin C or oxaliplatin in monotherapy. The aim of this study was to assess long-term survival in patients treated with a new combination of oxaliplatin and irinotecan (ox-irino) and to compare it with that obtained with oxaliplatin alone (ox-alone).

Methods: Two bi-institutional prospective studies were carried out. All patients with PC who had undergone CRS with HIPEC using either ox-alone 460 mg/m2 or ox-irino (ox: 300 mg/m2 and irino: 200 mg/m2) from January 1998 to December 2007 were included.

Results: 146 patient underwent CRS + HIPEC for PC from colorectal carcinoma. 103 patients received ox-irino and 43 patients received ox-alone HIPEC. The overall mortality rate was 4.1%. The overall morbidity rate was 47.2%. It was significantly lower in the ox-alone group compared to the ox-irino group (34.9% vs. 52.4%, p =0.05). After a median follow-up of 48.5 months, (95%CI 41.0-56.3), the median OS was 41 months (95%CI 32-60) and the median RFS was 15.7 months (95%CI 12-18). The median RFS of the ox-alone group was 16.8 months (95%CI 11-25) and was not significantly different from that of ox-irino group (15.7 months, 95%CI 11-18, p = 0.93). There was no significant difference between the median OS of the ox-alone group (40.83 months, 95%CI 29–61) and the ox-irino group (47 months, 95%CI 32-61, p = 0.94). At 5 years, the OS and the RFS rates were respectively 41.8% (95% CI 25.20-57.58) and 13.8% (95% CI 4.66-27.84) in the ox-alone group and 42.4% (95% CI 28.52-56.09) and 14.2% (95% CI 6.27-25.20) in the ox-irino group.

Conclusions: This study confirms the interesting survival results of CRS + HIPEC to treat colorectal PC. 460 mg/m2 of oxaliplatin alone HIPEC is as efficient as 300 mg/m2 of oxaliplatin associated with 200 mg/m2 of irinotecan, but with lower morbidity. Ox-alone HIPEC, should remain the current gold standard.

No significant financial relationships to disclose.
Catumaxomab therapy in peritoneal carcinomatosis from colon cancer: Clinical benefit in comparison to systemic chemotherapy alone and cytoreductive surgery/hyperthermic chemoperfusion.
Authors: Ströhlein M. A. , Heiss M. M.
Published: February 2017

488

Background: There is still no effective treatment for the majority of patients suffering from peritoneal carcinomatosis (PC) of colon cancer. Palliative chemotherapy (CHEM) had limited efficacy. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) showed promising results, but was manageable in early stage PC patients only. Catumaxomab therapy (CATU) offers a new option for intraperitoneal treatment in all stages of PC. Aim of the study was to evaluate CATU therapy in comparison to HIPEC and systemic therapy.

Methods: Between 2005 and 2008, 76 patients suffering from PC of colon cancer were included and treated with systemic chemotherapy alone (35), HIPEC +/- systemic chemotherapy (21) and CATU +/- chemotherapy (22). All patients were assessed for therapy-related severe side effects, incidence of intestinal obstruction-ileus and ascites and for overall survival.

Results: Grade IV side effects were observed in 9.1% of CATU patients, 14.3% after HIPEC and 5.7% after CHEM. Ascites was found in not a single patient after CATU vs. one patient after HIPEC (4.5%) and 7 patients after chemotherapy (20%, p<0.03). Intestinal obstruction was found in 22.7% of patients after CATU vs. 14.3% after HIPEC and in 42.9% of patients after chemotherapy (p<0.04). In comparison to systemic chemotherapy, overall survival was significantly increased after CATU (15.2 months, p=0.03) and HIPEC (20.1 months, p=0.02; median follow-up 17 months).

Conclusions: Catumaxomab therapy of patients with PC from colon cancer was associated with a preventive effect for accumulation of malignant ascites and intestinal obstruction. Patients receiving CATU or HIPEC therapy concepts showed a survival benefit compared to systemic chemotherapy alone. Therapy strategies containing intraperitoneal catumaxomab treatment may be beneficial in patients with PC from colon cancer, even in advanced PC disease, when HIPEC was not feasible.

[Table: see text]
Microsatellite instability status as a predictive marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer.
Authors: Zaanan A. , Flejou J. , Emile J. , Validire P. , Louvet C. , Rougier P. , De Gramont A. , Praz F. , Taïeb J.
Published: February 2017

493

Background: The addition of oxaliplatin to 5-fluorouracil (5-FU; FOLFOX regimen) was demonstrated to improve the adjuvant treatment of stage III colon cancer. For patients with microsatellite instability (MSI) tumors, several studies suggested a lack of benefit from 5-FU adjuvant chemotherapy but very little data are available regarding FOLFOX adjuvant therapy. The aim of this study was to further assess the value of MSI status as a marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer.

Methods: This multicentric retrospective study included 223 unselected patients with stage III colon cancer treated by FOLFOX adjuvant chemotherapy between 2003 and 2007. MSI status was determined by immunohistochemistry as the absence of MLH1, MSH2 or MSH6 expression. Disease-free survival (DFS) and relapse-free survival (RFS) were analyzed according to the MSI status using Kaplan Meier method and compared by log-rank test.

Results: Twenty three tumors (10.3%) were MSI. The rate of 3-year DFS was 88.6% and 76.6% for MSI and MSS groups, respectively (HR=0.64; 95% CI, 0.25 to 1.60; P=0.34). The rate of 3-year RFS was 88.6% and 76.7% for MSI and MSS groups, respectively (HR=0.52; 95% CI, 0.20 to 1.30; P=0.18).

Conclusions: A trend toward longer survival was observed for patients with MSI tumors compared with those with MSS tumors but the differences in survival were not significant. Interestingly, DFS at 3-years of patients with stage III MSI tumors treated by FOLFOX was higher in our series (88.6%) than in the largest study published for patients treated by 5-FU-based adjuvant chemotherapy (around 67.5%) or surgery alone (around 62.5%) (Sargent et al, JCO 2010). These observations suggest that adding oxaliplatin to 5-FU re-establishes a benefit of adjuvant treatment in the stage III MSI population. These results should be confirmed by analyzing materials of previously completed trials comparing FOLFOX to 5-FU such as the MOSAIC study.

[Table: see text]
Patterns of maintenance treatment (Tx) following first-line bevacizumab (bev) plus chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a large German community-based cohort study.
Authors: Arnold D. , Petersen V. , Kindler M. , Schulze M. , Seraphin J. , Hinke A. , Srock S. , Kutscheidt A.
Published: February 2017

502

Background: As a result of the long PFS with bev-containing combinations in first-line mCRC, discontinuation of at least one CT component after an “induction” period and continuation with “maintenance” Tx is common. It is anticipated that duration and patterns of maintenance Tx may affect PFS.

Methods: We analysed induction and maintenance Tx in a large observational cohort study of bev + various first-line CT regimens. Results of the entire cohort were reported earlier [Arnold et al. ASCO GI 2010].

Results: From Jan 05 to Jun 08, 1620 patients (pts) were enrolled at 261 sites. 1,307 pts (81% of total) received bev + fluoropyrimidine-oxaliplatin (n=306, 23.5%) or fluoropyrimidine-irinotecan (n=1,001, 76.5%). While Tx reduction was not predefined, after induction 271 pts (21%) received de-escalated maintenance Tx: bev alone (n=106; 8%), or bev + CT (n=165; 13%). Median Tx duration for pts receiving bev alone was 8.7 mo for induction and 3.2 mo for maintenance. Pts receiving bev + CT maintenance had shorter induction (5.1 mo) but longer maintenance (4.4 mo). Median PFS (after induction) with bev maintenance was 10.8 mo vs. 13.5 mo for bev + CT maintenance. Data are available from 161 pts with bev + CT maintenance after induction with oxaliplatin (n=97) or irinotecan (n=64). Median total Tx duration was 9.6 mo for oxaliplatin-based induction and 10.9 mo for irinotecan-based induction; median induction duration was 4.1 and 5.5 mo, and maintenance duration was 4.3 and 4.4 mo, respectively. Median PFS (after induction) was 12.8 and 14.1 mo, respectively. Progressive disease (PD) has not yet occurred in 165 pts (62% of maintenance cohort). A high proportion of pts received Tx until PD (74% and 79%, respectively).

Conclusions: Both de-escalation strategies led to long PFS and a high number of pts treated ′until PD′. A trend towards better PFS was observed in pts receiving bev + CT maintenance vs. single-agent bev. The ongoing randomized AIO KRK 0207 trial is prospectively evaluating three different maintenance strategies after induction with bev + fluoropyrimidine + oxaliplatin.

[Table: see text]
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.