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Introduction The oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC. Materials and methods We examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed. Results In the median follow-up duration after surgery of 60 months (3–120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32–28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27–27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01–6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06–29.93, P = 0.043). Conclusion NAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.

Background FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet. Patients and Methods This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety. Results A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004). Conclusions FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.

Background This study sought to evaluate the predictors of malignancy in the 2012 international consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) and validate their diagnostic value relative to the 2006 guidelines. Methods Between 2002 and 2014, 177 consecutive patients who underwent curative resection of IPMN were reviewed. Based on the 2012 guidelines, high-risk stigmata (mural nodule with enhancement, main pancreatic duct [MPD] ≥ 10 mm, and obstructive jaundice) and worrisome features (cyst size ≥ 30 mm, thickened cyst wall, mural nodule without enhancement, MPD 5–9 mm, an abrupt change in MPD diameter, and lymphadenopathy) were assessed, and predictive and diagnostic values were analyzed statistically. Results Multivariate analysis identified obstructive jaundice (odds ratio [OR], 23.9; P P = .017) and lymphadenopathy (OR, 5.84; P = .027) as independent predictive factors, with an accuracy of 69.8, 67.4, and 66.3%, respectively. Operative intervention was indicated in 156 patients (94.0%) using the 2006 guidelines, and in 130 (78.3%) using the 2012 guidelines. The accuracy of the 2006 guidelines was 35.5% compared with 44.8% for the 2012 guidelines. The area under the curve (AUC) for the 2006 and 2012 guidelines was 0.65 and 0.67, respectively; ΔAUC was 0.02, which was not statistically significant. When the worrisome features were combined with high-risk stigmata, the AUC increased to 0.79. Conclusion Obstructive jaundice, abrupt change in MPD diameter, and lymphadenopathy were independent predictive factors in the 2012 guidelines with high accuracy. Using the new guidelines, the number of patients with IPMN managed with observation and the predictive accuracy increased.

Background Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. We developed a novel technique to identify cancer-related genes of HCC as follows: triple-combination array analysis, which combines gene expression profiles, single nucleotide polymorphism arrays, and methylation arrays. Materials and methods Triple-combination array analysis was performed on one HCC sample from a 68-y-old female patient, and one candidate cancer-related gene was selected. Subsequently, we analyzed the identified gene by quantitative real-time reverse-transcriptase polymerase chain reaction (PCR) and methylation-specific PCR in nine HCC cell lines and in samples from 48 HCC patients. Additionally, we evaluated gene expression by immunohistochemistry and Western blotting. Results Using this method, protein tyrosine kinase 7 ( PTK7 ) was detected as a candidate cancer-related gene. PTK7 was revealed to be hypermethylated (methylation value 0.826, range 0–1.0) in cancer tissue, compared with that of adjacent noncancerous tissues (0.047) by methylation array. Of the 48 clinical samples, 30 HCC samples (62.5%) showed PTK7 promoter hypermethylation. Downregulation of PTK7 (expressions in tumor tissues decreased by ≥50% compared with the noncancerous tissues) was significantly associated with age >60 y ( P = 0.030) and elevation in serum protein induced by vitamin K absence or antagonists-II ( P = 0.033). Moreover, patients with downregulation were significantly inferior in overall survival ( P Conclusions Our data imply that PTK7 acts as a cancer-related gene and may be a potent prognostic marker for HCC. Triple-combination array analysis was once again found to be useful in identifying cancer-related genes.

Background Postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) leads to prolonged hospitalization and potentially fatal complications. We sought to determine whether estimated pancreatic parenchymal remnant volume (EPPRV) on preoperative computed tomography (CT) predicts clinically relevant POPF. Methods This retrospective study included 246 patients who underwent PD between 2008 and 2013. Pancreatic thickness, pancreatic width, and main pancreatic duct (MPD) diameter at the estimated transection line in addition to estimated whole pancreatic remnant volume (EWPRV) were measured on preoperative CT images. MPD volume was subtracted from EWPRV to determine EPPRV. The predictive ability of preoperative CT parameters for POPF was evaluated. Results EPPRV was an independent predictor of POPF and had a stronger association with POPF than EWPRV. Receiver operating characteristic curve analysis showed that EPPRV had the greatest area under the curve (0.885) for predicting POPF. EPPRV ≥25.5 cm 3 was the best cutoff value for predicting POPF, with a high negative predictive value (0.934) and low likelihood ratio of a negative result (0.235). Multivariate analysis including the preoperative CT parameters and well-known risk factors for POPF showed that EPPRV ≥25.5 cm 3 had the greatest odds ratio for POPF. EPPRV was correlated with pancreatic juice volume. Patients with EPPRV ≥25.5 cm 3 had a greater drainage fluid amylase concentration and greater duration of drainage tube placement than those with EPPRV 3 . Conclusion EPPRV from preoperative CT was highly predictive of POPF and may help in development of management for POPF after PD.

Background The aim of this study was to evaluate the efficacy and safety of CAPOX with planned oxaliplatin stop-and-go strategy compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods Patients with curative resection of colon cancerwere randomly assigned to receive eitherCAPOX with continuous use of oxaliplatin (8 cycles of CAPOX; continuous arm) or CAPOX intermittentuse of oxaliplatin (2 cycles of CAPOX – 4 cycles of capecitabine – 2 cycles of CAPOX; intermittentarm).The primary endpoints were frequency of peripheral sensory neuropathy (PSN) at 1-year after surgery and disease-free survival rate at 3-year after surgery. The secondary end points included overall survival (OS), compliance and safety. Results A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm,and 100 and 98 patients in the intermittentarm. Compliance: The overall treatment completion rate and relative dose intensity of oxaliplatin were 64% and 71% in the continuous arm vs.92% and 95% in the intermittentarm(p = 0.21 and 0.12, respectively). Efficacy: The 3-year DFS was 81.6% in the continuous arm vs.82.4% in the intermittentarm(HR, 0.82; 95% CI, 0.48-1.18). Safety: The incidence of PSN (>grade 2) was 33%in the continuous arm vs.15% in the intermittentarm (p Conclusions CAPOX withplanned oxaliplatin stop-and-go strategy could be equally effectiveas an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial identification 000012535 (09/December/2013). Legal entity responsible for the study Yasuhiro Kodera (Chubu Clinical Oncology Group, Japan). Funding Chubu Clinical Oncology Group. Disclosure All authors have declared no conflicts of interest.

Aim: Patients with hepatocellular carcinoma (HCC) have a poor prognosis, and novel molecular targets for treating recurrence and progression of the disease along with associated biomarkers are urgently required. In the present study, expression and the regulatory mechanism of TUSC1 (tumor suppressor candidate 1) were investigated to determine if it is a candidate tumor suppressor gene for HCC, which shows repressed transcription that involves aberrant DNA methylation. Methods: TUSC1 mRNA expression levels in HCC cell lines and 94 pairs of surgical specimens were determined using quantitative real-time reverse transcription polymerase chain reaction assay. Methylation status of HCC cell lines and clinical samples were analyzed to investigate the regulatory mechanism of TUSC1 transcription and the relationship between the methylation status of the TUSC1 gene and clinicopathological factors. The expression and distribution of the TUSC1 protein in liver tissues were determined using immunohistochemistry. Results: A majority of HCC cell lines (89%) and surgical specimens (84%) demonstrated reduced expression levels of TUSC1 mRNA compared with paired non-cancerous liver tissues. The mean mRNA expression level in HCC was significantly lower than in corresponding non-cancerous liver. In contrast, no significant difference was found in TUSC1 mRNA expression level between adjacent normal and cirrhotic liver tissue from HCC patients. The TUSC1 protein expression pattern in HCC and liver tissues was consistent with TUSC1 mRNA expression. Twenty-nine (31%) of 94 patients showed intragenic hypermethylation of the TUSC1 gene in HCC, and hypermethylation was significantly associated with advanced pathological stage. Subsequently, patients with hypermethylation of TUSC1 gene had a significantly poorer prognosis than patients without hypermethylation. Conclusions: Our results suggest that TUSC1 is a candidate tumor suppressor gene and intragenic hypermethylation is one of the suppressive mechanisms that regulate TUSC1 transcription in HCC. Intragenic methylation of the TUSC1 gene may serve as a novel prognostic marker of HCC. Disclosure: All authors have declared no conflicts of interest.

302 Background: The aim of this study was to investigate the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) with S-1 (oral fluoropyrimidine) followed by surgery for the treatment of borderline resectable pancreatic cancer that involved the major visceral artery or the portal venous system. Methods: Twenty-eight patients with pancreatic cancers that abutted the SMA in 10, the CHA in 7, the both SMA and CHA in 1, and occluded the SMV/PV in 10 were treated with NACRT at a single institution. Radiation therapy was delivered at a total dose of 50.4 Gy in 28 fractions. S-1 was administered orally at a dose of 80 mg/m(2)/day for 14 consecutive days followed by a 7-day rest period during radiation therapy. After radiotherapy and 2 courses of S-1, restaging was done to evaluate secondary resectability. Results: Of the all patients, 25 underwent a full course of NACRT, and NACRT terminated in 3 patients because of grade 3 leukopenia in 2 and tumor bleeding in 1. Partial response was achieved in 3 patients and stable disease in 22. Twenty-four patients (86%) underwent surgical resection, and all had margin-negative (R0) resections. Only two patients (8%) had major morbidity as Clavien-Dindo’s classification III or more, and there was no operative or in-hospital mortality. Pathological examination revealed that more than 50% of tumor cells had disappeared in 14 cases and all cases achieved Evans’ score IIa and more. Conclusions: Neoadjuvant chemoradiation with S-1 was feasible and promising therapy for borderline resectable pancreatic cancer that involves the major artery or the portal venous system.

Background The clinical significance of preservation of the pyloric ring in total pancreatectomy (TP) has not been elucidated.

s / Pancreatology 13 (2013) e1–e94 e76 Conclusion: Our study confirmed that IL-6, IL-8, IL-10, and sTNFr measured on admission, and CRP and pancreatic elastase measured on third day of admission represent valuable prognostic factors in the determination of severity in patients with AP.

s / Pancreatology 13 (2013) e1–e94 e26 were significantly more frequently observed in AZA+ compared to AZA-. In AZA+ group, relapse was observed in 16/17 (94%) before treatment and in 2/16 (12%) after treatment (mean follow-up 3 yrs range 1-8). Both AZA+ relapsing pts were treated with steroids, continuing AZA, and fully responded to therapy. 1 pts discontinued AZA for side effects (hepatitis). Conclusions: AZA seems to be an effective and safe treatment in AIP.

Objective Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known complication of hypertension. We studied the possible association between bevacizumab-related hypertension and gene polymorphisms links to determine the mechanism of this toxic effect and assure safer cancer therapy. Methods We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab containing chemotherapy from November 2007 to December 2011 and agreed to this study. Genotypes were determined for five well-known single nucleotide polymorphism (SNPs) of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C and C936T. SNPs were studied with the use of TaqMan SNP Genotyping Assays. Hypertension was graded by home blood pressure according to CTCAE v4.0. Results The VEGF -2578 C/C, -1498 T/T and -634 C/C polymorphisms were significantly associated with grade 2 or more severe bevacizumab-induced hypertension (P = 0.018, P = 0.035, P = 0.040, respectively). Conclusions The association of the three SNPs with bevacizumab-related hypertension was confirmed. All polymorphisms were related to a decreased risk of developing grade 2 or more severe bevacizumab-induced hypertension. These polymorphisms can possibly be used to confirm safer treatment of patients with bevacizumab containing chemotherapy.

Introduction A single nucleotide polymorphism (SNP) in the epidermal growth factor (EGF) has been investigated as a predictor of hepatocellular carcinoma (HCC). Previous reports demonstrated that an A to G transition at position 61 in the 5′ untranslated region of the EGF gene was identified, and that G/G genotype was associated with an increased risk of developing HCC compared with the A/G and A/A genotype. It has been reported that there are differences in the distribution of polymorphisms by race, there is no report in the Japanese population. Objectives To examine the relationship between EGF gene polymorphism genotype and the development and prognosis of HCC in the Japanese population. Methods Restriction fragment-length polymorphism was used to determine the EGF gene polymorphism genotype in two hundred and thirteen patients with HCC, who underwent resection in our department between 1996 and 2010. The correlation between these values and clinicopathological factors and prognosis were statistically analyzed. 2) The level of EGF mRNA expression in cancerous tissues was measured by quantitative reverse transcription-PCR. 3) EGF SNP was also analyzed in one hundred and forty patients with hepatitis and liver cirrhosis. Results 1) A/A, A/G, and G/G genotype were 5.2%, 43.7%, and 51.2% in the Japanese patients with HCC. A/A patients had better overall and disease-free prognosis than other genotypes, although no significant differences were found. 2) EGF mRNA expression in G/G patients was significantly higher than that in A/A patients (P = 0.04). 3) A/A, A/G, and G/G genotype were 7.1%, 34.3%, and 58.6% in patients without HCC. Analysis of the distribution of allelic frequencies revealed that odds ratio of developing HCC was 1.76 (95% CI 0.69-4.47, P = 0.23) in A/G patients, and 1.21 (95% CI 0.48-3.00, P = 0.68) in G/G patients, compared with A/A patients. Conclusions EGF 61*G allele was associated with greater transcript stability and EGF expression in the Japanese population. The EGF gene polymorphism genotype was associated with risk for development of HCC. Disclosure All authors have declared no conflicts of interest.

Purpose The aim of this study was to evaluate the efficacy and safety of the planned continuation of bevacizumab beyond first progression in Japanese patients with metastatic colorectal cancer (mCRC). Methods Previously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after second-line therapy. Secondary endpoints of the study were overall survival (OS), survival beyond first progression (SBP), progression free survival (PFS), response rate (RR), disease control rate (DCR) and safety. Results In the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7%, DCR of 89.4% and median PFS of 13.1 months (95% CI, 8.7 to 17.5 months). Thirty one patients went on to receive second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6%, DCR of 62.1% and median PFS of 7.5 months (95% CI, 5.5 to 9.5 months). Median 2nd PFS, the primary endpoint, was 18.0 months (95% CI, 13.7 to 22.3 months). The median OS was 30.8 months (95% CI, 27.7 to 33.9 months), and median SBP was 19.6 months (95% CI, 14.3 to 24.9 months), after median follow up period of 35.9 months. No critical events associated with bevacizumab were observed during the second-line therapy. Concluson The planned continuation of bevacizumab during second-line treatment is feasible for Japanese mCRC patients. A prospective randomized control study to confirm efficacy is warranted. Disclosure All authors have declared no conflicts of interest.

Background Chemokines and their receptors have been shown to play a critical role in cancer growth and metastasis. In particular, recent data have suggested that the chemokine CXCL12 and its receptor CXCR7 (also known as RDC1), which has been recently identified as a chemokine receptor, have key functions in promoting tumor development and progression. However, there is little information regarding their expression and clinical relevance in gastric cancer. Here we investigated for the first time the effects of combined CXCR7 and CXCL12 expression on the prognosis of patients with gastric cancer. Methods We studied CXCL12 and CXCR7 protein expression in 221 specimens of primary gastric cancer using immunohistochemistry, and investigated the relationaship between CXCL12/CXCR7 expression and clinicopathological features and clinical outcomes. Results Patients were categorized into four groups according to CXCR7 and CXCL12 expression: low CXCR7/low CXCL12, high CXCR7/low CXCL12, low CXCR7/high CXCL12, and high CXCR7/high CXCL12. No significant differences existed in age, gender, histology, tumor location, lymphovascular invasion among the four groups. However, high CXCR7/high CXCL12 expression in tumor cells was significantly associated with invasion depth of the tumor (T status; P 5 cm (P = 0.006) compared to tumors with low CXCR7/low CXCL12 expression or high CXCR7/low CXCL12–low CXCR7/high CXCL12 expression. Furthermore, patients with high CXCR7/high CXCL12 expression had the worst prognosis (5-year survival rate 30.6%; median, 2.3 years; range, 0.1 - 5.7 years) compared to those of other patient groups (5-year survival rate, 52.4%; median, not reached; log-rank test, P = 0.008) . Conclusions CXCR7 and CXCL12 are useful prognostic factors in gastric cancer, and the combination of high CXCR7 protein expression with high CXCL12 expression suggests a dismal prognosis. Disclosure All authors have declared no conflicts of interest.

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Background Epithelial-to-mesenchymal transition (EMT) was originally proposed as a process of organogenesis. In recent years, the association between EMT and cancer invasion and metastasis has been advocated and actively investigated in various cancers. In addition, chemoresistance and cancer stemness could be involved in EMT, and the elucidation of this association might contribute to improved outcomes of hepatocellular carcinoma (HCC). We utilized surgical specimens of HCC from our department to examine the clinical implications of EMT. Methods One hundred and one patients with hepatocellular carcinoma, who underwent resection in our department between 1994 and 2003 were analyzed. The mRNA expression of E-cadherin and Vimentin were measured by quantitative real-time PCR and EMT status of each patient was determined as follows: Vimentin/E-cadherin Results 1) AFP values were significantly higher in the epithelial group than in the mesenchymal group (P = 0.029). There was no difference in overall survival, but a significant difference was found in disease-free survival (P = 0.042), which showed that patients with a mesenchymal tumor were more prone to have an earlier recurrence than those with an epithelial tumor. 2) All transcription factors were more highly expressed in mesenchymal than in epithelial tumors, and in particular, Twist and Zeb-2 were significantly overexpressed (P = 0.0002, P = 0.0017, respectively). 3) IL-6 expression was also significantly higher in mesenchymal than in epithelial tumors, but there was no difference in IL-6R expression. Discussion Our study using resected surgical specimens suggest that EMT could be involved in cancer invasion and metastasis at the clinical level. In particular, Twist and Zeb-2 might be important for inducing EMT in HCC and patients with mesenchymal tumors are more prone to have early recurrence or metastases after resection. In addition, IL-6 might be an important factor for HCC EMT and could be a potential therapeutic target. Disclosure All authors have declared no conflicts of interest.