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Introduction This study aimed to review the farming activity and the administrative measure to successfully increase the distribution of heirloom vegetable “mizuna” nationwide by examining the paradigm shift in the use of its young less-branched form for salad. We also discussed that breeding programs of the young form ironically resulted in reduction the flavor and the antimutagenicity of this vegetable. Methods Through hearing survey, we explored reasons for the successful nationwide distribution of heirloom vegetable, mizuna. Through chemical analysis, the fragrant ingredients in mizuna, their antimutagenicity and the changes in their amount for one year were determined. Results and discussion The primary factor for commencing the distribution of mizuna includes the new idea of using young less-branched form of mizuna as salad ingredient, which has been recognized by most who were involved in promoting the distribution of mizuna among farmers, distributors, and employees of agricultural extension section at Kyoto Prefecture office. The secondary factor is the fact that the primary factor coincides on a time axis with other two factors: the occurrence of the boom of Kyoto's heirloom vegetables and the Vegetable Management Stabilization Project found as a measure of Kyoto Prefecture. We determined three fragrant compounds in mizuna, 3-butenyl isothiocyanate, 3-phenylpropionitrile, and phenylethyl isothiocyanate, of which their antimutagenic effects were also identified. Those amounts were highest at the best harvest season called ‘Syun’ in the past because of the cold temperature of Japanese winter in traditional open-field cultivation. Conclusion It implied that the successful nationwide distribution of mizuna resulted from the administrative measures based on the paradigm shift in the new use of mizuna for salad due to increase in demand of the vegetable in contemporary dishes. The traditional cultivation of mizuna might be suitable if wishing the flavor and antimutagenicity at the best harvest season ‘Syun’.

BACKGROUND Genetic variants in the CCL5/CCR5 pathway have been shown to predict regorafenib efficacy in patients with metastatic colorectal cancer (mCRC). This study investigated the biological role of CCL4 and CCL3 gene polymorphisms in patients with refractory mCRC treated using regorafenib. PATIENTS AND METHODS We analyzed the genomic DNA extracted from mCRC patients receiving regorafenib. Serum factor levels at baseline, day 21, and progressive disease (PD) were measured using ELISA. RESULTS Decreased CCL4 levels at day 21 or increased CCL3 levels at PD were associated with better clinical outcomes. In patients with any CCL5 rs2280789 G allele, CCL3 significantly increased between BL and day 21 compared with the A/A variant (72.7% vs. 23.1%, p=0.006), but CCL4 decreased (31.8% vs. 69.2%, p=0.043). CONCLUSION Increased CCL3 and decreased CCL4 seen in specific genotypes may serve as potential biomarkers of regorafenib in mCRC patients.

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44-0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19-0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.

OBJECTIVES: The enterocyte subtype of colorectal cancer (CRC) responds favorably to oxaliplatin-based adjuvant treatment for stage III CRC. We examined the clinical significance of single nucleotide polymorphisms (SNPs) in enterocyte-related genes MS4A12 and CDX2 in response to adjuvant treatment for stage III CRC. PATIENTS AND METHODS: A total of 350 patients with stage III CRC were included: 274 received adjuvant treatment with surgical resection (discovery cohort) and 76 received surgery alone (control cohort). In the discovery cohort, 68 patients received FOLFOX and 206 received oral fluoropyrimidine. SNPs were analyzed by PCR-based direct sequencing. Disease-free and overall survival were analyzed using Kaplan–Meier curves, log-rank test, and Cox proportional hazards regression. RESULTS: In the discovery cohort, the MS4A12 rs4939378 G/G variant was associated with lower 5-year survival than any A allele (70% vs. 90%, univariate: HR 2.29, 95%CI: 1.03–5.06, P=0.035; multivariate: HR 2.58, 95%CI: 1.15–5.76, P=0.021). Patients with the CDX2 rs3812863 G/G variant had better overall survival than those with any A allele, although this was not significant in multivariate analysis (5 year-survival: 95% vs. 82%, univariate: HR 0.34, 95%CI: 0.12–0.97, P=0.034; multivariate: HR 0.39, 95%CI: 0.13–1.11, P=0.078). The SNPs did not show significant association with overall survival in the control cohort, and significant interaction was observed between MS4A12 genotypes and groups (P=0.007). CONCLUSION: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in stage III CRC. However, the clinical significance of SNPs for response to oxaliplatin may differ by tumor stage.

Activin/myostatin signaling has a critical role not only in cachexia but also in tumor angiogenesis. Cachexia is a frequent complication among patients with advanced cancer and heavily pretreated patients. We aimed to evaluate the prognostic significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib. Associations between twelve single nucleotide polymorphisms in 8 genes (INHBA, MSTN, ALK4, TGFBR1, ALK7, ACVR2B, SMAD2, FOXO3) and clinical outcome were evaluated in mCRC patients of three cohorts: a discovery cohort of 150 patients receiving regorafenib, a validation cohort of 80 patients receiving regorafenib and a control cohort of 128 receiving TAS-102. In the discovery cohort, patients with any G variant in FOXO3 rs12212067 had a significantly lower response rate (P = 0.031) and overall survival (OS) than those with a T/T in univariate analysis (4.5 vs. 7.6 months, hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.09-2.46, P = 0.012). Among female patients, those with any G variant in INHBA rs2237432 had a significantly longer OS than those with an A/A in both univariate (7.6 vs. 4.3 months, HR = 0.57, 95%CI = 0.34-0.95, P = 0.021) and multivariable (HR = 0.53, 95%CI = 0.29-0.94, adjusted P = 0.031) analysis. This association was confirmed in female patients of the validation cohort, though without statistical significance (P = 0.059). Conversely, female patients with any G allele in the control group receiving TAS-102 did not show a longer OS. This was the first study evaluating the associations between polymorphisms in cachexia-associated genes and outcomes in refractory mCRC patients treated with regorafenib. Further studies should be conducted to confirm these associations.

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n = 146) and 2 (n = 70); irinotecan cohorts 1 (n = 228), and 2 (n = 276); and combination cohort (n = 230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P

Regorafenib confers the benefit of longer survival in metastatic colorectal cancer patients. The CCL5/CCR5 pathway modulates endothelial progenitor cell migration and vascular endothelial growth factor A production. Genetic variants of CCL4 and CCL3 may predict outcomes, and the different frequencies of CCL5 homozygote may explain ethnic differences in the development of severe hand–foot skin reactions. BACKGROUND: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. PATIENTS AND METHODS: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. RESULTS: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand–foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). CONCLUSION: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand–foot skin reaction in mCRC patients receiving regorafenib therapy.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a TP53 mutation and 17p deletion. Sixteen mutations were identified in OSBPL10 in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, TP53 mutations and TP53 deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. OSBPL10 mutations were validated as prognostic markers for excellent OS (P = 0.037) and PFS (P = 0.041). Significant differences in OS and PFS were observed when patients were stratified into three groups—OSBPL10 mutation (best prognosis), the coexistence of both TP53 mutation and TP53 deletion (poorest prognosis), and others. In this study, the presence of both TP53 mutation and 17p/TP53 deletion, but not the individual variants, was associated with poor prognosis in DLBCL patients after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or similar regimens. We also identified OSBPL10 mutation as a marker for patients with excellent prognosis in the R-CHOP era.

Background Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19–9 are used in clinical practice as tumor markers to diagnose or monitor colorectal cancer (CRC) patients, However, their specificities and sensitivities are not ideal, and novel alternatives are needed. In this study, mass spectrometry was used to search for screening markers, focusing on glycan alterations of glycoproteins in the sera of CRC patients. Methods Glycopeptides were prepared from serum glycoproteins separated from blood samples of 80 CRC patients and 50 healthy volunteers, and their levels were measured by liquid chromatography time-of flight mass spectrometry (LC–TOF–MS). Results Leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan (LRG–FTG) was identified as CRC marker after evaluating 30,000 candidate glycopeptide peaks. The average LRG–FTG level in CRC patients (1.25 ± 0.973 U/mL) was much higher than that in healthy volunteers (0.496 ± 0.433 U/mL, P

Early identification of patients at risk of postoperative pancreatic fistula (POPF) allows appropriate management after gastrectomy. Although some reports have suggested a correlation between POPF and the concentration of amylase in drained abdominal fluid (D-AMY), this has not been proven to impact sufficiently on clinical decision-making. A sustained high level of D-AMY is often assumed to be due to unsatisfactory drainage or excessive pancreatic leakage. We assessed the clinical utility of measuring D-AMY on postoperative day (POD) 1 and POD3 for prediction of POPF. Starting in April 2014, 801 patients who underwent radical gastrectomy with prophylactic drain placement were consecutively enrolled. We routinely measured D-AMY on POD1 and POD3, and compared the incidence of problematic POPF and clinical factors including D-AMY. We also attempted to clarify whether such two-point D-AMY measurement was clinically useful for patient management after gastrectomy. Fifty-one of the patients (6.4%) developed Clavien–Dindo grade III or worse POPF. Using D-AMY cutoffs of 2218 IU/L on POD1 and 555 IU/L on POD3, the patients were successfully classified. The highest risk group, in which D-AMY was higher than the cut-off value on both POD1 and POD3, showed a significantly high rate of occurrence (33/105, 31.4%) and high positive likelihood ratio (6.74). Multivariate analysis showed that classification into this highest risk group was an independent risk factor for development of severe POPF (odds ratio 15.2, 95% CI 7.92–29.0). Two-point measurement of D-AMY may be an efficient tool for achieving individualized management of POPF following radical gastrectomy.

Laparoscopic surgery for gastric cancer requires traction or compression of the pancreas, with the extent depending on the anatomical position of the pancreas. This study investigated the impact of the position of the pancreas on postoperative complications and drain amylase concentrations after laparoscopic distal gastrectomy (LDG). Gastric cancer patients who underwent LDG were assessed retrospectively. The following anatomical parameters were measured retrospectively in preoperative computed tomography sagittal projections: the length of the vertical line between the pancreas and the aorta (P–A length), representing the height of the slope looking down the celiac artery from the top of the pancreas, and the angle between a line drawn from the upper border of the pancreas to the root of the celiac artery and the aorta (UP–CA angle), representing the steepness of the slope. Correlations between each parameter and postoperative complications were analyzed by logistic regression analysis. Pearson’s product–moment correlation coefficients were calculated for scatter diagrams for each parameter and drain amylase concentration on postoperative day 1. Analyses were performed in 394 patients. P–A length [odds ratio (OR) 1.905; 95% confidence interval (CI) 1.100–3.300; P = 0.021] was significantly correlated with pancreatic fistula. P–A length (OR 2.771; 95% CI 1.506–5.098; P = 0.001), UP–CA angle (OR 2.323; 95% CI 1.251–4.314; P = 0.008), and low preoperative serum albumin (OR 2.082; 95% CI 1.050–4.128; P = 0.036) were significantly correlated with overall postoperative complications defined as Clavien–Dindo ≥ grade II. P–A length and UP–CA angle showed significant positive correlations with drain amylase concentration on postoperative day 1. The position of the pancreas is an independent predictor of pancreatic fistula and/or postoperative complications and correlates with drain amylase concentration after LDG for gastric cancer.

The occurrence of postoperative complications may have a significant negative impact on the prognosis of patients with gastrointestinal cancers. The inflammatory response releases systemic cytokines, which may induce residual cancer cell growth. Recently, neoadjuvant chemotherapy (NAC) was found to improve the prognosis of advanced gastric cancer (GC). We hypothesize that when postoperative complications occur after gastrectomy, NAC treatment of micrometastases can prevent residual cancer cell growth. This study included 101 patients who underwent curative resection after NAC for GC from 2005 to 2015. Clinical data, including intraoperative parameters, were collected retrospectively. Overall survival (OS) and relapse-free survival (RFS) were compared between the patients with complications and those without complications. Of the 101 patients, 35 (34.7%) had grade 2 or higher complications. Among those with complications, the 3- and 5-year OS rates were 63.5 and 58.2% and the 3- and 5-year RFS rates 41.7 and 41.7%, respectively. Among those without complications, the 3- and 5-year OS rates were 65.9 and 56.3% and the 3- and 5-year RFS rates 51.1 and 43.9%, respectively. There was no significant difference in prognosis between the patients with complications and those without complications. Our study is the first to demonstrate the potential of NAC to abolish the poor prognosis induced by postoperative complications after curative resection for GC.

Adherence has become an important issue in modern oncology treatment. Most studies have included heterogeneous target tumor types, regimens, and therapy settings. Our study focused on capecitabine during capecitabine plus oxaliplatin (XELOX) treatment as an adjuvant therapy for colorectal cancer. The main aims of this study were to evaluate real-life adherence to capecitabine and to investigate candidate factors that might decrease adherence. We studied 338 consecutive patients who received XELOX treatment between December 1, 2011, and April 30, 2015, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Our study assessed adherence to capecitabine through patient-reported treatment diaries and interviewed nonadherents to determine the reasons for not taking capecitabine at a pharmaceutical outpatient clinic. We calculated the adherence rate in a cycle as: number of times the patient took capecitabine/28. Relative dose intensities and factors associated with deteriorating adherence to capecitabine were retrospectively surveyed from electronic patient records. Uni- and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence. The study covered 282 patients who received 2,055 cycles of XELOX. Median adherence rate was 94.0% in the first cycle, and median relative dose intensity of capecitabine was 77.8%. The most common reasons for nonadherence were nausea/vomiting and diarrhea. The presence of the following factors was not significantly associated with adherence: ECOG performance status ≥1 (p = 0.715), clinical stage (p = 0.408), primary tumor site (p = 0.576), age ≥70 years at study entry (p = 0.757), female gender (p = 0.504), and not living alone (p = 0.579). The adherence rate from this study was significantly higher than the adherence from metastatic settings. Adherence-enhancing interventions for capecitabine in XELOX treatment as adjuvant therapy comprised management of nausea/vomiting and diarrhea.

Total pelvic exenteration (TPE) may be the only curative procedure for locally advanced rectal gastrointestinal stromal tumor (GIST) that is contiguous with the adjacent organs and pelvic wall. There is no previous report of laparoscopic TPE for advanced rectal GIST. Here, we describe our experience of performing laparoscopic TPE on a locally advanced rectal GIST after neoadjuvant imatinib chemotherapy. A 62-year-old Japanese man was diagnosed with locally advanced rectal GIST that was contiguous with the seminal vesicles, prostate, and left pelvic sidewall. He received imatinib mesylate for 5 months, after which the mass had shrunk but was still contiguous with adjacent organs. We therefore needed to perform TPE, and we accomplished the operation laparoscopically. The total operative time was 540 minutes and estimated blood loss was 280 mL. There were no intraoperative complications and not required conversion to open surgery. The patient had his first stool on the first postoperative day and discharged on the 21st postoperative day with no major complication. Pathologic examination of the resected specimen revealed negative margins. The patient had further adjuvant imatinib chemotherapy and had no recurrence for 20 months postoperatively. Laparoscopic TPE appears to be minimally invasive surgery and safe in the present case of rectal GIST. This is the first report of a case in the world that underwent laparoscopic TPE for advanced rectal GIST.

Background Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102. Patients and methods We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing. Results In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance. Conclusion Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.

// Yukiharu Hiyoshi 1 , Takashi Akiyoshi 1 , Ramu Inoue 2 , Keiko Murofushi 3 , Noriko Yamamoto 4 , Yosuke Fukunaga 1 , Masashi Ueno 1 , Hideo Baba 5 , Seiichi Mori 6 and Toshiharu Yamaguchi 1 1 Gastroenterological Center, Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan 2 Clinical Research Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan 3 Department of Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan 4 Division of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan 5 Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 6 Division of Cancer Genomics, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Correspondence to: Takashi Akiyoshi, email: takashi.akiyoshi@jfcr.or.jp Keywords: rectal cancer, chemoradiotherapy, serum, miR-143, prediction Received: January 10, 2017 Accepted: March 22, 2017 Published: March 31, 2017 ABSTRACT Recently, several circulating miRNAs have been reported as promising, minimally invasive biomarkers for the diagnosis or prediction of the prognosis in various types of cancer. However, the utility of circulating miRNAs as predictive markers of the cancer response to neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer is still unclear. To identify circulating serum miRNAs useful for predicting a pathological good response to nCRT, total 18 serum miRNAs of interest were analyzed by real-time polymerase chain reaction in 94 rectal cancer patients treated with nCRT and surgery. Pathological complete response (pCR; Dworak TRG4) and near-pCR (TRG3) were obtained in 12 (13%) and 9 (9%) patients respectively, and we regarded them as nCRT-responders. Of the 18 serum miRNAs, only the serum level of miR-143 was identified significantly associated with a pathological response to nCRT in 94 patients; the serum miR-143 level was significantly lower in nCRT-responders than in non-responders. A multivariate analysis incorporating other clinicopathological factors showed that only the serum miR-143 level was an independent predictor of a good pathological response. The circulating serum miR-143 level may be a novel, non-invasive predictive marker of a response to nCRT in locally advanced rectal cancer patients.

Background: It is still uncertain whether small cell lung carcinomas (SCLCs), pulmonary carcinoids, and the gastrointestinal neuroendocrine tumors (GI-NETs) have a common origin. MicroRNA (miRNA) expression may clarify their genetic relationships and origin. Methods: First, we compared the miRNA expression signature of formalin-fixed paraffin-embedded (FFPE) samples with frozen samples to verify the applicability of microarray analysis. Second, we compared the comprehensive miRNA expression patterns of pulmonary carcinoids and GI-NETs as well as other types of tumors and normal tissues from each organ using FFPE samples. These data were analyzed by hierarchical clustering and consensus clustering with nonnegative matrix factorization. Results: We confirmed that FFPE samples retained the miRNA signatures. In the first hierarchical clustering comparing carcinoids/NETs with adenocarcinomas and normal tissues, most of the carcinoids (48/50) formed 1 major cluster with loose subpartitioning into each organ type, while all the adenocarcinomas (9/9) and normal tissues (15/15) formed another major cluster. The nonnegative matrix factorization approach largely matched the classification of the hierarchical clustering. In the additional cluster analysis comparing carcinoids/NETs with SCLCs, most carcinoids/NETs (17/22) formed a major cluster, while SCLCs (9/9) grouped together with pulmonary adenocarcinomas (3/3) and normal tissues (6/6) in another major cluster. Furthermore, a subset of miRNAs was successfully identified that exhibited significant expression in carcinoids/NETs. Conclusion: Carcinoids/NETs had a characteristic pattern of miRNA expression, suggesting a common origin for pulmonary carcinoids and GI-NETs. The expression profiles of pulmonary carcinoids and SCLCs were quite different, indicating the distinct histogenesis of these neuroendocrine neoplasms.

Although laparoscopic gastrectomy (LG) is a widely accepted treatment for gastric cancer, conversion to laparotomy is sometimes required. The current study aimed to review the time trends of intraoperative conversions to open procedures during the decade in which the LG procedure was being developed. Cases in which LG was attempted at the Cancer Institute Hospital from 2005 to 2018 were retrospectively reviewed, and the details regarding conversions to open surgery were examined. Twenty-two (0.63%) of 3,498 patients required conversion to open surgery due to technical difficulties. The major reasons for conversions were difficulties in reconstruction (seven patients; 0.20%) and intraoperative bleeding (six patients; 0.17%). All conversions due to difficulties in reconstruction occurred in the introduction period of LG during the performance of esophagojejunostomy or esophagogastrostomy in laparoscopic total gastrectomy or proximal gastrectomy using a circular stapler. Five (71.4%) of the seven patients in whom conversion was performed due to difficulties in reconstruction developed postoperative severe complications. No conversions due to difficulties in reconstruction have been experienced since 2011, possibly due to the decrease in the number of laparoscopic total gastrectomy procedures and the introduction of the use of a linear stapler in esophagojejunostomy. To manage intraoperative bleeding in LG, hemostatic procedures were systematized and conversions were considered if visualization was not maintained following the procedures. None of the six patients who required laparotomy due to intraoperative bleeding required surgical or radiological intervention postoperatively. Over a decade of experience and procedural changes have markedly decreased the incidence of conversion to open surgery in LG. The main causes of conversion during the early period of LG introduction were difficulties in reconstruction and intraoperative bleeding; the incidences of these complications have been decreased by employing the appropriate procedures for LG.

Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/ CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24–0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26–0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.

Background and Aims Laparoscopic gastric resection is widely used for gastric submucosal tumors (SMTs). However, determining an appropriate resection line using only the laparoscopic approach is difficult. We developed a laparoscopic and endoscopic cooperative surgery (LECS) technique by combining laparoscopic gastric resection with endoscopic submucosal dissection, and we have used this procedure to resect gastric SMTs. In this study, the procedure is presented and its safety and feasibility for resecting gastric SMTs are evaluated. Methods This retrospective study included 100 patients who underwent LECS for SMTs at the Department of Gastroenterological Surgery, Cancer Institute, between June 2006 and November 2014. The demographics, tumor histopathologic characteristics, and operative and follow-up data were reviewed. Results Complete resection with negative surgical margins was achieved in all patients, and LECS was performed regardless of tumor location. The mean operation time was 174.3 minutes, with an estimated blood loss of 16.3 mL. In addition, the mean time until the initiation of oral intake was 1.4 days, and the mean postoperative hospital stay was 8.4 days. Moreover, no local or distant tumor recurrence was observed. The only severe adverse event was leakage, which was observed in 1 patient. Conclusions LECS was performed with a reasonable operation time, low blood loss, and minimal adverse events. Therefore LECS is safe and feasible for resecting gastric SMTs.

// Mitsukuni Suenaga 1 , Tetsuo Mashima 2 , Naomi Kawata 1, 2 , Takeru Wakatsuki 1 , Yuki Horiike 1 , Satoshi Matsusaka 1 , Shingo Dan 3 , Eiji Shinozaki 1 , Hiroyuki Seimiya 2 , Nobuyuki Mizunuma 1 , Kensei Yamaguchi 1 , Toshiharu Yamaguchi 4 1 Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan 2 Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan 3 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan 4 Department of Gastroenterological and Surgery Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan Correspondence to: Mitsukuni Suenaga, email: m.suenaga@jfcr.or.jp Keywords: regorafenib, metastatic colorectal cancer, VEGF-A, CCL5, prognostic marker Received: December 27, 2015 Accepted: April 16, 2016 Published: May 05, 2016 ABSTRACT Regorafenib is an oral multi-kinase inhibitor used as salvage therapy for metastatic colorectal cancer (mCRC). We tested whether serum cytokine levels are associated with clinical outcome in the mCRC patients receiving regorafenib. Serum samples were collected before treatment start, day 21, and progressive disease, and eleven angiogenic and inflammatory cytokine serum levels were examined. Fifty-four patients of a total of 62 enrolled patients were eligible for the analyses. The chemokine ligand 5 (CCL5) levels ≤ cut-off value (59959 pg/ml) at baseline was associated with relative tumor shrinkage ( P = 0.021), better progression-free survival (PFS) ( P = 0.036) and overall survival (OS) ( P = 0.019). Vascular endothelial growth factor A (VEGF-A) levels showing a decrease on day 21 were significantly associated with a better PFS ( P = 0.021). CCL5 levels ≤ cut-off was associated with any grade hand-foot skin reaction (HFSR) ( P = 0.025) and thrombocytopenia ( P = 0.013). Low chemokine ligand 2 levels at baseline were associated with grade 2 ≤ HFSR. High angiopoietin-2 and basic fibroblast growth factor (bFGF) levels at baseline were associated with grade 3 ≤ total bilirubin increase and transaminases increase, respectively. Low bFGF levels at baseline were associated with grade 3 ≤ hypertension. No correlation with severe events was observed. Baseline serum CCL5 levels and decrease of the serum VEGF-A levels may serve as potential predictive markers for survival or treatment-specific toxicities in mCRC patients receiving regorafenib.

Studies have demonstrated a relationship between clinical outcomes after curative resection for colorectal cancer (CRC) and gene mutations of the EGFR pathway; however, no studies have examined metastatic CRC (mCRC) patients with metastasectomy. The aim of this study was to evaluate the relationship between gene mutations of EGFR pathway and clinical outcomes after metastasectomy in mCRC patients. A total of 1,053 patients histopathologically confirmed CRC received a genotyping test for the EGFR pathway from February 2012 to October 2013. Detailed information was obtained through review of medical records. Gene mutations of EGFR pathway were analyzed by Luminex assay. Overall survival (OS) and recurrence free survival were estimated by the Kaplan-Meier method and the log-rank test was used to compare the survival outcomes by gene mutation status. A total of 132 patients received metastasectomy. The frequencies of KRAS exon 2, KRAS exon 3.4, NRAS, BRAF, and PIK3CA mutations were 38.6% (51/132), 3.6% (5/132), 5.1% (7/132), 5.1% (7/132), and 8.7% (12/132), respectively. With a median follow-up of 84.1 months (57.2-NA) for a survivor, the 4-year OS rate was 65.6% for mCRC with RAS mutation, and 81.3% for mCRC with wild-type RAS (p

The study sought the significance of resecting lymph nodes along the proper hepatic artery (station 12a) in gastric cancer surgery and the possibility of predicting station 12a involvement from clinicopathological factors or metastatic status in other regional lymph nodes of the stomach. Patients who underwent D2 gastrectomy were assessed retrospectively. Survivals were compared between the patients with and without station 12a metastasis among the patients with metastasis to any regional lymph nodes. Clinicopathological factors correlating with station 12a metastasis were sought by logistic regression analyses. The possibility of a predictor for station 12a metastasis was evaluated in each regional lymph node station. Metastasis to station 12a was observed in 21 of 1260 patients (1.7 %). The 5-year overall survival rate was 62.7 % in the patients without station 12a metastasis and 54.4 % in the patients with station 12a metastasis (P = 0.164). The lower third (OR 3.810, 95 % CI 1.507–9.631, P = 0.005), the lesser curvature or circumferential involvement (OR 4.099, 95 % CI 1.178–14.259, P = 0.027) and 81.5 mm or larger tumor diameter (OR 2.959, 95 % CI 1.212–7.224, P = 0.017) were identified as the independent risk factors of station 12a metastasis. Station 11p significantly correlated with station 12a metastasis (OR 13.469, 95 % CI 1.437–126.216, P = 0.023). The false negatives as predictors of station 12a metastasis ranged from 14.3 % (station 6) to 100.0 % (station 11d) for each regional lymph node station. Given the difficulty in predicting station 12a metastasis and the favorable survival in the patients with metastasis to the nodes, station 12a should be resected in a D2 gastrectomy.

To evaluate the clinicopathological features of and prognosis associated with sporadic colorectal cancer (CRC) in Japanese patients younger than 40 years old. The subjects of this study were patients with sporadic stage 0–III CRC, who underwent curative resection between 2004 and 2012 at the Cancer Institute Hospital. Clinicopathological characteristics and survival were compared between the young (

Background: A novel oral agent that consists of trifluridine and tipiracil hydrochloride (TFTD) has been established as salvage-line treatment for metastatic colorectal cancer (mCRC). Adherence to TFTD is crucial to maintaining appropriate curative effects. This study sought to clarify adherence to TFTD and identify candidate factors deteriorating adherence at our institution. Methods: A total of 50 consecutive mCRC patients who received TFTD monotherapy between June 1, 2014 and July 31, 2015 were analyzed in this study. Adherence to TFTD was checked by pharmacists using a self-reported treatment diary and interviewing nonadherents at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of patient intakes per 20 scheduled intakes in one cycle. We retrospectively surveyed the factors from the electronic patient record associated with reduced adherence. We measured relative dose intensity, defined as the dose intensity divided by the initial dose (each in milligrams per square meter per week). Results: Patient characteristics were as follows: males/females, 20/30; median age, 61 years (range, 34-83 years); performance status 0/1, 37/13. Median relative dose intensity of TFTD was 91.0%. Adherence rates were 95.0% for the first cycle of TFTD, 97.3% for the second cycle, 98.0% for the third cycle, and 98.2% for the fourth cycle. Factors associated with deteriorated adherence to TFTD were nausea/vomiting/decreased appetite (27.1%, 23 instances), pain (25.9%, 22 instances), neutropenia (11.8%, 10 instances), and missed dose (4.7%, 4 instances). Increased nonadherence to TFTD was associated with Eastern Cooperative Oncology Group performance status 1, while increased TFTD adherence in the first cycle was associated with prior regimens ≥4. Conclusions: The high frequency of treatment-related gastrointestinal disorder is the main factor affecting adherence to TFTD. Intensive supportive care in the management of these symptoms could assist adequate adherence to TFTD in mCRC patients.

Receptor tyrosine kinase (RTK)-related genes, including HER2, EGFR, MET, FGFR2 and KRAS, are target molecules that are clinically beneficial in gastric cancer (GC). We investigated the correlation between RTK-related genes and the curative effect of first-line S-1 plus cisplatin (SP) combination chemotherapy in metastatic and recurrent GC. We enrolled 150 patients with histopathologically confirmed metastatic and recurrent GC treated with SP. KRAS mutation was detected using direct sequencing. DNA copy number was measured by real-time PCR. Formalin-fixed paraffin-embedded specimens were examined immunohistochemically for HER2, EGFR, FGFR2 and MET. Among 144 patients, KRAS mutation was detected in five (3.5%) at codon 12 and one (0.7%) at codon 13. FGFR2, EGFR, HER2, MET and KRAS gene amplification was suggested in 4.4%, 5.9%, 9%, 3.7% and 10.3% of patients, respectively. KRAS mutation, but not KRAS amplification, was associated with significantly shorter overall and progression-free survival. MET membranous overexpression was associated with a significantly higher tumor response. MET amplification was associated with significantly shorter overall survival. We show for the first time that KRAS mutation and MET amplification are promising predictive markers in metastatic and recurrent GC patients treated with SP. KRAS status may be a useful prognostic marker in patients treated with SP.

In the original article on page 1636, first line, the reference cited for Kamikawa et al. is incorrect. The correct reference is as follows: Kamikawa Y, Kobayashi T, Kamiyama S, et al. A new procedure of esophagogastrostomy to prevent reflux following proximal gastrectomy (in Japanese). Shoukakigeka. 2001;24:1053-60.

Background/aim Past studies have suggested that adjuvant capecitabine and oxaliplatin (CAPOX) provides decreased tumor relapse and longer survival in patients with curatively resected colon cancer. We report the first evidence of the feasibility of adjuvant CAPOX in Japanese patients with early colon cancer. Patients and methods Eligible patients had histologically-confirmed stage II/III colon cancer and received curative resection. The primary endpoint was completion rate of treatment after 8 cycles of adjuvant CAPOX. Results Thirty-six patients were enrolled in this study. The completion rate of CAPOX and oxaliplatin were 77.8% and 61.1%, respectively. The incidence of grade ≥3 adverse events was neutropenia (n=6), thrombocytopenia (n=3), nausea (n=5), hand-foot syndrome (n=1) and peripheral sensory neuropathy (n=1). Three-year disease-free survival for stage II patients and stage III patients were 100% and 79.3%, respectively. Conclusion Adjuvant CAPOX can be safely administered to Japanese patients with stage II/III colon cancer.

Mitsukuni Suenaga,1 Nobuyuki Mizunuma,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Masato Ozaka,1 Mariko Ogura,1 Toshiharu Yamaguchi21Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanBackground: The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, PhaseII study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods: Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression≥6months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results: Thirty-three patients were enrolled. The median age was 62 (range: 35–77)years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths.Conclusion: Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6months previously during prior oxaliplatin-based therapy.Keywords: reintroduction, oxaliplatin, FOLFOX, advanced colorectal cancer, salvage-line

Thermal injury and unexpected bleeding caused by ultrasonic scalpels can lead to fatal complications in laparoscopic gastrectomy (LG), such as postoperative pancreatic fistulas (POPF). In this study, we developed the “Hit and Away” protocol for optimal usage of the ultrasonic scalpel, which in essence involves dividing tissues and vessels in batches using the tip of the scalpel to control tissue temperature. To assess the effectiveness of the technique, the surface temperature of the mesocolon of female swine after ultrasonic scalpel activations was measured, and tissue samples were collected to evaluate microscopic thermal injury to the pancreas. In parallel, we retrospectively surveyed 216 patients who had undergone LG before or after the introduction of this technique and assessed the ability of this technique to reduce POPF. The tissue temperature of the swine mesocolon reached 43 °C, a temperature at which adipose tissue melted but fibrous tissue, including vessels, remained intact. The temperature returned to baseline within 3 s of turning off the ultrasonic scalpel, demonstrating the advantage of using ultrasonic scalpel in a pulsatile manner. Tissue samples from the pancreas demonstrated that the extent of thermal injury post-procedure was limited to the capsule of the pancreas. Moreover, with respect to the clinical outcomes before and after the introduction of this technique, POPF incidence decreased significantly from 7.8 to 1.0 % (p = 0.021). The “Hit and Away” technique can reduce blood loss and thermal injury to the pancreas and help to ensure the safety of lymph node dissection in LG.

The feasibility of gastrectomy with standard lymphadenectomy for patients over 85 years of age is not known. This study investigated short- and long-term outcomes and the tolerability of gastrectomy with standard lymphadenectomy for patients over 85 years with gastric cancer. Altogether, 77 patients aged over 85 years underwent gastrectomy with lymphadenectomy for gastric cancer at the Cancer Institute Hospital, Japan from May 2000 to February 2012. Postoperative short-term outcomes and survivals were analyzed retrospectively. Standard lymphadenectomy was defined according to the Japanese Gastric Cancer Association guidelines. Lymphadenectomy without splenectomy during total gastrectomy was called “reduced” lymphadenectomy. Distal gastrectomy was performed in 51 patients, total gastrectomy in 20, remnant total gastrectomy in 5, and proximal gastrectomy in 1 patient. Gastrectomy with standard lymphadenectomy was initially planned for 50 (64.9 %) patients and completed in 42 (54.5 %) patients. The other 8 patients underwent reduced lymphadenectomy because they required R1 or R2 resection. There were no deaths. The morbidity rate was 55.8 % overall and 54.8 % with standard lymphadenectomy. The most frequent complication was intestinal hypoperistalsis (29.9 %). The mean postoperative hospital stay was 19 days (range 10–70 days). The median overall survival time was 46.8 months. Coupled with comprehensive postoperative medical care due to the relative high morbidity risk, gastrectomy with standard lymphadenectomy for gastric cancer may be acceptable for relatively healthy patients over 85 years of age. Decisions to reduce the extent of lymphadenectomy during gastrectomy should not be based on advanced age alone.

In radical operations for gastric cancer, a balance between the quality of lymph node dissection and safety of surgery must be ensured. During suprapancreatic lymphadenectomy in laparoscopic gastrectomy (LG), an adequate operative field should be safely and effectively established to reduce pancreas-related complications. We present a novel approach that avoids direct compression of the pancreas in LG and describe the surgical outcomes of this method. We historically compressed the pancreas during suprapancreatic lymph node dissection in LG to obtain an adequate operative field but have since modified our operative technique. In our new method introduced in March 2016, the operative field is established by pulling and controlling the connective tissues along the inferior border of the pancreas and the nerves along the common hepatic and splenic arteries, instead of directly compressing the pancreas itself. We compared 51 patients in the compression group (January 2015–February 2016) and 45 patients in the compressionless group (March 2016–January 2017) in terms of surgical outcomes, including the amylase concentration in the drainage fluid and postoperative complications. The amylase concentrations in the compressionless group were significantly lower on postoperative days 1 and 3 (p

BACKGROUND: Trifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102. PATIENTS AND METHODS: We investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing. RESULTS: In the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group. CONCLUSIONS: The combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.

There have been many studies that describe the value of diagnostic staging laparoscopy (DSL) in gastric cancer. However, different studies use different indications, making study results difficult to compare. This study aimed to clarify the diagnostic feasibility of DSL for gastric cancer in a prospective manner and investigated the impact of DSL on clinical decision-making in gastric cancer treatment. The study was a prospective cohort study based at a single institution between January 2010 and December 2013. We treated 2213 patients with potentially resectable gastric cancer during this period. DSL was primarily indicated for asymptomatic patients with: (1) large Borrmann type 3 tumours ≥8 cm, (2) Borrmann type 4 tumours (linitis plastica), (3) bulky lymph nodes or paraaortic lymph node swelling, or (4) clinical suspicion of peritoneal disease. The primary outcome is change in treatment strategy, and the secondary outcomes are diagnostic accuracy of the indications and false negative rate of DSL. DSL was performed on 156 (7%) of 2213 patients. Of these, peritoneal disease was found in 74 (47%) patients: (1) 56% for large type 3, (2) 54% for type 4, (3) 21% for bulky lymph nodes or paraaortic lymph node swelling, and (4) 20% for suspected peritoneal disease. The diagnostic accuracy of our indication for DSL was 92% for all patients and 74% for patients with cT3/T4 tumours. Among 82 patients without peritoneal disease, 66 patients (81%) underwent subsequent radical gastrectomy; peritoneal disease was discovered intraoperatively for 7 patients at laparotomy, indicating a false negative rate of 11%. We confirmed that DSL performed according to our indication, in the context of gastric cancer, possesses diagnostic feasibility. Approximately half of the patients who underwent DSL consequently avoided unnecessary laparotomy and were able to receive appropriate alternative treatment.

The optimal extent of lymph node (LN) dissection for gastric cancer with duodenal invasion is yet to be clarified. This study sought to evaluate the significance of gastrectomy with D2-plus lymphadenectomy including posterior LNs along the common hepatic artery (no. 8p), hepatoduodenal ligament LNs along the bile duct (no. 12b) and those behind the portal vein (no. 12p), LNs on the posterior surface of the pancreatic head (no. 13), LNs along the superior mesenteric vein (no. 14v) and para-aortic LNs around the left renal vein (nos. 16a2 and 16b1) dissection. Patients with gastric cancer with duodenal invasion undergoing R0 gastrectomy from January 2000 to December 2015 were enrolled. The therapeutic value index (TVI) of each LN dissection was calculated by multiplying the incidence of metastasis to each LN station by the 5-year overall survival (OS) rate of the patients with metastasis to the station. In total, 117 patients were eligible. The 5-year OS rates (and TVI) of the patients with metastasis to LNs were 40.4% (7.4) in no. 12b, 25.4% (6.8) in no. 13, 32.0% (6.1) in no. 14v, 50.0% (13.0) in no. 16a2 and 40.0% (10.0) in no. 16b1. None of the patients with metastasis in no. 8p or no. 12p survived 5 years or longer. In a potentially curative gastrectomy for gastric cancer with duodenal invasion, there may be some survival benefit in dissection of nos. 12b, 13, 14v, 16a2 and 16b1 LNs, while no benefit was seen in dissection of nos. 8p or 12p LNs.

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

Laparoscopic surgery has become the standard for colorectal cancers, but more minimally invasive surgery is continuously pursued. In June 2011, our institution started needlescopic surgery (NS). The aims of this study are to describe this technique and to investigate its feasibility for left-sided colorectal cancer surgery. From June 2011 to June 2013, 105 sigmoid colon and upper/middle rectal cancer patients underwent NS in our institution, involving one 5-mm port and three 3-mm ports, with the exception of an umbilical 12-mm port. A 10-mm scope is used through the umbilical 12-mm port, which will be extended to a small skin incision for specimen extraction. After dissection of the left colon, a 5-mm scope is inserted through the right lower 5-mm port and a linear stapler is inserted through the umbilical 12-mm port for rectal transection. The specimen is then extracted through umbilical incision, and the anastomosis is carried out by the double-staple technique. TNM staging is stage 0/I/II/III/IV = 0/31/32/31/11. Fifty-one patients underwent sigmoidectomy and 54 patients underwent anterior resection. There was no conversion to open surgery, but one patient required a change to a 5-mm port from one of the 3-mm ports. Mean operating time was 193 min and mean estimated blood loss was 12 ml. There were ten (9 %) postoperative complications: two anastomotic leaks requiring reoperation, two anastomotic hemorrhages, and one wound infection. There was no mortality. NS for left-sided colorectal cancer was a technically and oncologically feasible technique for selected patients.

This study assessed the feasibility and safety of laparoscopic surgery for metachronous colorectal cancer in patients who had previously undergone surgery for primary colorectal cancer. Of the 52 patients who underwent curative resection for metachronous colorectal cancer from August 2004 to April 2013, 26 each underwent laparoscopic and open surgery. Their clinical characteristics and surgical and postoperative outcomes were compared. The percentage of patients who underwent previous open surgery was significantly higher in the open group than in the laparoscopic group (92.3 vs. 65.4 %). The body mass index was higher in the laparoscopic group than in the open group (23.8 vs. 21.1 kg/m2), and the amount of blood loss was significantly smaller in the laparoscopic than in the open group (30 vs. 195 ml); however, the mean operative time did not differ significantly. The time to first flatus (1 vs. 3 days) and first stool (2 vs. 3.5 days), as well as the length of postoperative hospital stay (10 vs. 16 days), was significantly shorter in the laparoscopic group than in the open group, although the rates of postoperative complications did not differ (15.4 vs. 23.1 %). Laparoscopic surgery for metachronous colorectal cancer shows short-term benefits compared with open surgery and should be considered as a treatment option in these patients.

Laparoscopy-assisted total gastrectomy (LATG) is commonly performed for early gastric cancer (EGC) in the upper stomach; however, the incidence of anastomotic complications remains high, and postoperative nutritional status is not satisfactory. This study aimed to evaluate the feasibility and nutritional impact of a novel surgical procedure, laparoscopy-assisted subtotal gastrectomy (LAsTG). This was a retrospective study of 167 patients with EGC in the upper stomach. Of these, 57 patients underwent LAsTG, while 110 patients underwent LATG. Postoperative change in body weight, and serum concentration of albumin (Alb) and total protein (TP) were compared between the LAsTG and LATG groups. Analysis of covariance (ANCOVA) was used to assess the influence of potential confounding factors. Frequency of anastomotic complications was significantly higher in the LATG group (16.3 %) than in the LAsTG group (5.3 %, P = 0.040). Postoperative recovery of body weight at 12 months after surgery was significantly better in the LAsTG group (89.8 ± 1.4 %) than in the LATG group (82.1 ± 1.0 %, P

The feasibility, safety, and improved quality of postoperative life following laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) with a hand-sewn anastomosis via a mini-laparotomy for early gastric cancer (EGC) have been previously established. Here we describe the surgical procedure of totally laparoscopic pylorus-preserving gastrectomy (TLPPG) using an intracorporeal delta-shaped anastomosis technique, and the short-term surgical outcomes of 60 patients with EGC in the middle stomach are reported.After lymphadenectomy and mobilization of the stomach, intraoperative gastroscopy was performed in order to verify the location of the tumor, and then the distal and proximal transecting lines were established, 5 cm from the pyloric ring and just proximal to Demel's line, respectively. Following transection of the stomach, a delta-shaped intracorporeal gastrogastrostomy was made with linear staplers.There were no intraoperative complications or conversions to open surgery. Mean operation time and blood loss were 259 min and 28 mL, respectively. Twelve patients (20.0%) experienced postoperative complications classified as grade II using the Clavien-Dindo classification, with the most frequent complication being gastric stasis (6 cases, 10.0 %). The incidence of severe complications classified as grade III or above was 1.7%; only one patient required reoperation and intensive care due to postoperative intraabdominal bleeding and subsequent multiple organ failure.TLPPG with an intracorporeal delta-shaped anastomosis was found to be a safe procedure, although it tended to require a longer operating time than the well-established LAPPG with a hand-sewn gastrogastrostomy.

Abdominosacral resection may be the only curative procedure for locally advanced rectal cancer involving the presacral fascia or sacrum. Multimodal therapy might be necessary to prevent local and distant recurrence for such tumors. A 67-year-old man was diagnosed with locally advanced rectal cancer widely involving the right pelvic sidewall and presacral fascia near the S4/5 junction on the right posterolateral side. We performed laparoscopic abdominosacral resection (S4/5) with en bloc right lateral lymph node dissection and seminal vesicle resection to obtain a clear resection margin after systemic chemotherapy with mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) plus bevacizumab, followed by preoperative chemoradiotherapy. The total operative time was 660 min, and the estimated blood loss was 550 mL. The final pathological findings revealed no residual cancer cells (pathological complete response). Laparoscopic abdominosacral resection appears to be safe and feasible in selected patients.