Potential Molecular Cross Talk Among CCR5 Pathway Predicts Regorafenib Responsiveness in Metastatic Colorectal Cancer Patients.

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.

Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer.

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.

Intraoperative conversion from laparoscopic gastrectomy to an open procedure: a decade of experience in a Japanese high-volume center.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer.

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. 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: hazard ratio (HR) 2.29, 95% confidence interval (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). CONCLUSIONS: 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.

A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer.

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.

Should pylorus-preserving gastrectomy be performed for overweight/obese patients with gastric cancer?

BACKGROUND: Pylorus-preserving gastrectomy is an alternative to distal gastrectomy for early gastric cancer, and is expected to have postoperative advantages including maintenance of body weight. Overweight/obesity is a risk factor for chronic disorders, including hypertension and diabetes mellitus; in these conditions, body weight control is frequently required as part of treatment. It remains unknown whether pylorus-preserving gastrectomy should be performed in overweight/obese patients because excess body weight may be maintained postoperatively. METHODS: We retrospectively investigated body weight changes and postoperative nutritional status of overweight/obese patients who underwent laparoscopic distal gastrectomy (LDG) or laparoscopic pylorus-preserving gastrectomy (LPPG) between 2006 and 2015. Among 349 overweight patients (BMI ≥ 25 kg/m2), 101 LDG and 101 LPPG cases were compared after propensity score matching to adjust for patient characteristics. RESULTS: The mean relative body weight ratios (postoperative/preoperative ratios) were 87.5 ± 8.0% after LDG and 89.6 ± 6.7% after LPPG (difference not significant, p = 0.088). The prealbumin level at 2 years and hemoglobin levels at 6 months, 1 year and 2 years were significantly well maintained after LPPG than after LDG. Prealbumin and hemoglobin levels at 2 years had almost returned to baseline levels in the LPPG group. The superiority of LPPG in the hemoglobin level was confirmed regardless of reconstruction methods after LDG. CONCLUSIONS: For overweight/obese patients, LDG and LPPG resulted in similar degrees of postoperative weight loss, with patients achieving near-ideal body weight. The postoperative nutritional advantages of LPPG were confirmed. LPPG seemed to be better even for overweight/obese patients who meet indication criteria.

Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients.

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.

Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer.

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 < 0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P = 0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45-0.91, P = 0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47-0.78, P < 0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62-1.02, P = 0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin-based or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.

Correction to: Clinical Outcomes and Evaluation of Laparoscopic Proximal Gastrectomy with Double-Flap Technique for Early Gastric Cancer in the Upper Third of the Stomach.

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.

TP53 and OSBPL10 alterations in diffuse large B-cell lymphoma: prognostic markers identified via exome analysis of cases with extreme prognosis.

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.

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

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.

Serum leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan: a novel colorectal cancer marker.

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 < 10- 10), and its sensitivity and specificity exceeded those of CA19-9. The combination of CEA and LRG-FTG showed a complementary effect and had better sensitivity (84%), specificity (90%), and AUC (0.91 by ROC analysis) than each marker alone or any other previously reported marker. LRG-FTG alone or combined with CEA also corresponded well with patient response to treatment. CONCLUSIONS: We identified LRG-FTG as a new CRC marker, with a sensitivity and specificity exceeding CA19-9. The combination of LRG-FTG and CEA showed much higher sensitivity and specificity than each marker alone. Further validation beyond this initial exploratory cohort is warranted.

A Feasibility Study of Capecitabine and Oxaliplatin for Patients with Stage II/III Colon Cancer -ACTOR Study.

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.

Impact of anatomical position of the pancreas on postoperative complications and drain amylase concentrations after laparoscopic distal gastrectomy for gastric cancer.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Two-point measurement of amylase in drainage fluid predicts severe postoperative pancreatic fistula after gastric cancer surgery.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Two-point measurement of D-AMY may be an efficient tool for achieving individualized management of POPF following radical gastrectomy.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer.

Japanese mortality due to colorectal cancer is on the rise, surpassing 49,000 in 2015. Many new treatment methods have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2016 for the treatment of colorectal cancer (JSCCR Guidelines 2016) were 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 were prepared by consensus 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 2016.

Pulmonary Carcinoids and Low-Grade Gastrointestinal Neuroendocrine Tumors Show Common MicroRNA Expression Profiles, Different from Adenocarcinomas and Small Cell Carcinomas.

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.

Prophylactic effect of neoadjuvant chemotherapy in gastric cancer patients with postoperative complications.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Survival benefit of "D2-plus" gastrectomy in gastric cancer patients with duodenal invasion.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.