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Characteristics of selected SNPs in RBP encoding genes

Associations between selected SNPs and gene expression status in colon tissue from GTEx analysis

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RNA-binding proteins (RBPs) regulate many posttranscriptional cellular activities. Accumulating evidence suggests associations between RBPs with colonic tumorigenesis and chemosensitivity. We investigated the prognostic and predictive values of SNPs of genes encoding RBPs in metastatic colorectal cancer (mCRC), using clinical and genomic data from three randomized clinical trials of standard first-line chemotherapy for mCRC (TRIBE, FIRE-3, and MAVERICC). Genomic DNA extracted from blood samples was genotyped using an OncoArray. We tested 30 candidate SNPs of 10 major RBP-related genes with additive models. Prognostic values were estimated by meta-analysis approach. Treatment-by-SNP interactions were tested to estimate predictive values for targeted drugs and cytotoxic backbone chemotherapies. This study included 884 patients. The meta-analysis revealed prognostic values of LIN28B rs314277 [HR, 1.26; 95% confidence interval (CI), 1.06–1.49, P = 0.005, FDR-adjusted P = 0.072 for overall survival (OS)] and LIN28B rs314276 (HR, 1.25; 95% CI, 1.08–1.44, P = 0.002, FDR-adjusted P = 0.062 for OS). Although some SNPs showed potentially predictive values, these associations were not confirmed after FDR adjustment. In conclusion, the results of this study are warranting additional studies to provide the evidence that RBP-related SNPs may be associated with the prognosis of patients with mCRC treated with standard first-line chemotherapies. In addition, further studies are warranted to study the predictive value.

Supplementary Figure S1. Histopathological subtypes of AA. A: adenocarcinoma, not otherwise specified (NOS: common colonic type). B: low-grade mucinous adenocarcinoma (MU) with pseudomyxoma peritonei (PMP). C: mucinous adenocarcinoma (MU). D: signet ring cell carcinoma (SR). All images are with hematoxylin and eosin stain.

Supplementary Table S2. Patients characteristics.

Purpose:The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma.Experimental Design:A total of 183 samples from appendiceal adenocarcinoma [46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)], 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC.Results:We observed high mutation rates in appendiceal adenocarcinoma samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). Appendiceal adenocarcinoma exhibited higher mutation rates in KRAS and GNAS, and lower mutation rates in TP53, APC, and PIK3CA (6%) than colorectal cancers. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS (63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC.Conclusions:Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment.

Using a self-expanding metal stent as a bridge to surgery (BTS) is considered a reasonable strategy for patients with acute malignant large bowel obstruction. Since postoperative complications have a negative impact on patient survival, we aim to clarify the predictors of complications in patients undergoing BTS using a self-expanding metal stent.We conducted a retrospective review of 61 patients with colorectal cancer (CRC) who underwent stenting as a BTS at our institution. We analyzed the association of postoperative complications with clinicopathologic, surgical, and patient factors, and with the prestenting or preoperative laboratory data.Both postoperative complications in general and severe complications were significantly associated with a longer stenotic-section length (p = 0.007 and p = 0.003), lower preoperative hemoglobin levels (p 0.001 and p = 0.081), and lower prestenting hemoglobin levels (p = 0.006 and p = 0.042). Multivariate logistic regression analysis showed that lower prestenting (13.0 g/dl) and preoperative (11.5 g/dl) hemoglobin levels were independent predictive factors for postoperative complications (odds ratio [OR]: 4.15; 95% confidence interval [CI]: 1.07-18.90; p = 0.040; and OR: 4.93; 95% CI: 1.35-20.28; p = 0.016). A stenotic-section length of 5.0 cm or greater was predictive of severe complications (OR: 25.67; 95% CI: 1.95-1185.00; p = 0.011).Our data suggest that lower hemoglobin levels before stenting and a longer length of the stenotic section of bowel might predict postoperative complications in patients with CRC undergoing BTS for obstruction.

Activin A is a member of the transforming growth factor‑β superfamily of cytokines and displays various pathophysiological activities, including regulation of muscle catabolism and atrophy. Activin A expression is upregulated in several human cancer types and in certain pathologies, its expression is associated with poor prognosis. In the present study, activin A expression was assessed in colorectal cancer (CRC) tissue specimens from 157 patients with primary CRC and the relationship between activin A levels and clinicopathological characteristics, including skeletal muscle mass, and prognosis, was determined. Furthermore, the effects of knockdown of endogenous or exposure to exogenous activin A on the malignant behavior of human CRC cell lines were investigated

Colorectal cancer (CRC) is the most common cancer and the second leading cause of cancer death in Japan. Surgical resection is the only curative option for localized disease. However, undetectable micrometastases remaining after curative surgery may cause disease recurrence. Adjuvant chemotherapy aims to eradicate these micrometastases to improve the cure rate. Unfortunately, few reliable prognostic and predictive markers are available that identify patients at high risk for CRC during early‐stage disease. However, promising biomarkers may become available in the near future. Such biomarkers provide information for stratifying a patient's risk and for selecting the optimal treatment. Here, we provide an overview of current relevant prognostic and predictive biomarkers applicable to adjuvant treatment of early‐stage CRC and focus on the future of this field., During the last decade, numerous efforts have been made to develop precision medicine for patients with early colorectal cancer. We summarize prognostic and predictive biomarkers for adjuvant treatment of early colorectal cancer.

Background ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. Methods We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry. Results ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell–inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. Conclusions Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.

Background Advancements in chemotherapy for metastatic colorectal cancer (mCRC) have improved long-term outcomes, and median survival currently exceeds 30 months. The recommended treatment for mCRC is multidisciplinary, including a combination of surgical resection and chemotherapy. In this study, we report the case of a patient who has survived for more than 5 years after an initial diagnosis of mCRC while undergoing first-line chemotherapy and six repeat metastasectomies. Case presentation A 55-year-old man was diagnosed at our hospital with sigmoid colon cancer and hepatic metastasis. We performed laparoscopic sigmoidectomy and hepatic segmentectomy (segment 5 [S5] and S8). After resecting the primary tumor and liver metastasis, other metastases were found. Together with perioperative chemotherapy (CAPOX + bevacizumab), we performed repeated metastasectomies for liver metastasis (S4 and S7), pulmonary S1 metastasis, aortic lymph node metastasis, and right adrenal metastasis. With six metastasectomies, the patient has survived for more than 5.5 years. Conclusions Multidisciplinary treatment extends survival and improves the quality of life in patients with mCRC. Planned surveillance after metastasectomy may also be necessary to promote the early detection of recurrence in these patients.

Signet ring cell carcinoma (SRCC) is rare: about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however the underlying molecular characteristics are unknown. SRCCs were analyzed using NGS, immunohistochemistry, and in situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. A total of 8500 CRC and 1100 GC were screened. Seventy-six SRCC were identified from the CRC cohort (

Serum anti-p53 antibody is used clinically as a tumor marker of colorectal cancer. However, its prognostic significance in patients with metastatic colorectal cancer (mCRC) remains unclear. KRAS status may influence the host immune response against tumor progression. In the present study, we investigated the prognostic significance of serum anti-p53 in mCRC patients with wild-type KRAS and mutant KRAS treated with systemic chemotherapy. A retrospective study of 150 mCRC patients in whom serum anti-p53 antibody was measured before first-line chemotherapy was conducted. The patients were divided into two groups, high p53 and low p53, based on their serum anti-p53 antibody levels. Associations between serum anti-p53 level and clinical outcomes were evaluated in conjunction with KRAS status. There were 97 (64.7%) patients with wild-type KRAS and 53 (35.3%) with mutant KRAS. In an analysis of all patients, there was no significant difference in overall survival (OS) between the high p53 and low p53 groups. In patients with mutant KRAS, those in the high p53 group exhibited significantly longer OS than those in the low p53 group (p = 0.017, log-rank test). In the multivariate analysis, serum p53 antibody level was an independent predictor of OS in mCRC patients (high vs. normal; hazard ratio 0.438, 95% confidence interval 0.178–0.974, p

Lymph nodes (LNs) and distant metastases can arise from independent subclones of the primary tumor. Herein, we characterized the molecular landscape and the differences between LNs, distant metastases and primary colorectal cancers (CRCs). Samples were analyzed using next generation sequencing (NGS, MiSeq on 47 genes, NextSeq on 592 genes) and immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. In total, 11,871 samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs metastases (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant metastases (9 mut/MB, p p p = 0.017, respectively) classifications were more frequent in primaries and LNs vs distant metastases (9.5% and 8.8% vs 4.2%, p p = 0.001, respectively). TMB-high is significantly more common in LNs vs distant metastases and primaries (P APC, KRAS, PI3KCA, KDM6A, and BRIP1 (p

High MCV is suggested to be relevant to the incidence and prognosis of several malignancies. However, few studies investigating the correlation between MCV and survival outcome of esophageal cancer have been conducted. Methods This study included 570 patients with esophageal cancer who underwent radical esophagectomy between April 2005 and December 2017. Patients were divided into two groups according to the standard value of pretreatment MCV: normal (83–99 fL) and high (>99 fL) groups. Clinical backgrounds, short-term outcomes, and prognostic outcomes post-esophagectomy were retrospectively compared between the groups. Results Of all patients, 410 (71.9%) had normal MCV, and 160 (28.1%) had high MCV. High MCV was significantly associated with lower body mass index, higher frequency of habitual alcohol and tobacco use, and higher incidence of multiple primary malignancies other than esophageal cancer. High MCV also correlated with higher incidence of postoperative morbidity of the Clavien–Dindo classification ≥II and pulmonary morbidity. Overall survival was significantly worse in patients with high MCV. Multivariate analysis suggested that high MCV was an independent risk factor for worse survival outcome (hazard ratio, 1.54; 95% confidence interval, 1.098–2.151; p = 0.012). Conclusion Patients with high MCV have various disadvantages in clinical background that can adversely affect both short-term and long-term outcomes after esophagectomy. MCV can become a predictive marker to estimate survival outcome after esophagectomy for esophageal cancer.

KRAS status serves as a predictive biomarker of response to treatment in metastatic colorectal cancer (mCRC). We hypothesize that complex interactions between multiple pathways contribute to prognostic differences between KRAS wild-type and KRAS mutant patients with mCRC, and aim to identify polymorphisms predictive of clinical outcomes in this subpopulation. Most pathway association studies are limited in assessing gene–gene interactions and are restricted to an individual pathway. In this study, we use a random survival forests (RSF) method for identifying predictive markers of overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with FOLFIRI/bevacizumab. A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study. Two RSF approaches were used, namely variable importance and minimal depth. We discovered that Wnt/β-catenin and tumor associated macrophage pathway SNPs are strong predictors of OS and PFS in mCRC patients treated with FOLFIRI/bevacizumab independent of KRAS status, whereas a SNP in the sex-differentiation pathway gene, DMRT1, is strongly predictive of OS and PFS in KRAS mutant mCRC patients. Our results highlight RSF as a useful method for identifying predictive SNPs in multiple pathways.

AIM Patient body composition is an important indicator of metabolic status and is associated with cancer progression. Because body composition varies between men and women, we aimed to examine the difference in clinical impact of preoperative body composition according to sex. METHOD We used an integrated dataset of 559 colorectal cancer (CRC) patients. The association between preoperative body composition indices [body mass index (BMI), visceral to subcutaneous fat area ratio (VSR) and skeletal muscle index (SMI)] and patient outcome, clinicopathological factors and preoperative inflammation and nutritional status was analysed, comparing men and women. RESULTS Preoperative low BMI and low SMI in men was significantly associated with unfavourable overall survival (OS) [BMI: hazard ratio (HR) 2.22, 95% CI 1.28-4.14, P = 0.004; SMI: HR 2.54, 95% CI 1.61-4.07, P

Purpose: The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma. Experimental Design: A total of 183 samples from appendiceal adenocarcinoma [46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)], 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC. Results: We observed high mutation rates in appendiceal adenocarcinoma samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). Appendiceal adenocarcinoma exhibited higher mutation rates in KRAS and GNAS, and lower mutation rates in TP53, APC, and PIK3CA (6%) than colorectal cancers. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS (63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC. Conclusions: Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment.

Background Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. Patients and Methods We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 ( ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE ( ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed. Results In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort. Conclusion Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

Background The advanced lung cancer inflammation index (ALI), which comprehensively evaluates the patient body composition and inflammation/nutritional status, is reportedly associated with the patient outcome in lung cancer. However, the clinical significance in colorectal cancer (CRC) patients after curative resection remains unclear. Methods A total of 813 CRC patients after curative resection between April 2005 and June 2019 in a single institution were retrospectively enrolled. The association of the preoperative ALI (calculated as follows: body mass index × albumin value/neutrophil‐to‐lymphocyte ratio) with clinicopathological factors, postoperative complications, and survival was analyzed. Results A low ALI was significantly associated with male gender, older age, a higher depth of tumor invasion, progressed TNM stage, and preoperative carcinoembryonic antigen (CEA) positivity. Both postoperative complications and severe complications occurred more frequently in the ALI‐low group than in the ALI‐high group (P, The preoperative ALI may serve as a novel independent predictive index for severe postoperative complications and recurrence in CRC patients after curative resection.

Introduction The present study assessed the utility of a dry box time trial during laparoscopic surgical training to improve laparoscopic surgical skills and surgical outcomes. Methods In a monthly time trial, surgeon trainees twice completed a set task that involved grasping a suture, aligning a needle with a needle holder, passing the suture, making three knots, and cutting the two tails of the suture. The mean suturing time was then analyzed. To assess the utility of this time trial, we analyzed the short-term outcomes of patients with stage I to III colon cancer who had undergone laparoscopic colectomy before and after the introduction of the time trial. Results The monthly time trial was introduced in October 2018, and 52 surgeon trainees participated in the trials examined in this study. Within 6 months of the program's introduction, the mean suturing time had significantly declined to less than 70% of the time trial, while the standard deviations had declined to less than 30%. In comparisons of the short-term outcomes of laparoscopic colon cancer surgery before (n = 49) and after (n = 46) the introduction of the time trial, the operative time tended to decline (P = .074) after the introduction of the time trial, and blood loss was significantly reduced (P = .018). The rate of postoperative complications was similar before and after the introduction. Conclusion Regular time trials of laparoscopic surgical suture training using a dry box can be useful for improving laparoscopic surgical skills and surgical outcomes. Moreover, time trials can keep trainees motivated.

Purpose: GEP-NENs are rare malignancies with increasing incidence. Their molecular characteristics are still undefined. We explored the underlying biology of GEP-NENs and the differences between gastrointestinal (GI) and pancreatic (PNEN), high-grade (HG), and low-grade (LG) tumors. Experimental Design: GEP-NENs were analyzed using next-generation sequencing (NGS; MiSeq on 47 genes, NextSeq on 592 genes), IHC, and in situ hybridization. Tumor mutational burden (TMB) was calculated on the basis of somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 724 GEP-NENs were examined: GI (N = 469), PNEN (N = 255), HG (N = 135), and LG (N = 335). Forty-nine percent were female, and median age was 59. Among LG tumors, the most frequently mutated genes were ATRX (13%), ARID1A (10%), and MEN1 (10%). HG tumors showed TP53 (51%), KRAS (30%), APC (27%), and ARID1A (23%). Immune-related biomarkers yielded a lower prevalence in LG tumors compared with HG [MSI-H 0% vs. 4% (P = 0.04), PD-L1 overexpression 1% vs. 6% (P = 0.03), TMB-high 1% vs. 7% (P = 0.05)]. Compared with LG, HG NENs showed a higher mutation rate in BRAF (5.4% vs. 0%, P < 0.0001), KRAS (29.4% vs. 2.6%, P < 0.0001), and PI3KCA (7% vs. 0.3%, P < 0.0001). When compared with GI, PNEN carried higher frequency of MEN1 (25.9% vs. 0.0%, P < 0.0001), FOXO3 (8.6% vs. 0.8%, P = 0.005), ATRX (20.6% vs. 2.0%, P = 0.007), and TSC2 (6.3% vs. 0.0%, P = 0.007), but lower frequency of mutations in APC (1.0% vs. 13.8%, P < 0.0001). Conclusions: Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.

Background IgG4-related disease (IgG4-RD) is an immune-mediated disorder in which abundant IgG4-positive plasma cells infiltrate affected organs. There have been reported four cases of probable IgG4-RD presenting as a submucosal tumor of the stomach. We herein report the first case of definite IgG4-RD presenting as a submucosal tumor of the stomach resected with laparoscopic endoscopic cooperative surgery (LECS). Case presentation A 70-year-old woman with a 6-year history of autoimmune pancreatitis was referred to our department because a 15-mm submucosal tumor in the greater curvature of the lower part of the stomach had been identified via upper gastrointestinal endoscopy. Endoscopic ultrasonography showed a 10-mm low-echoic lesion derived from the submucosal layer of the stomach. A fine-needle aspiration biopsy was attempted, but the tumor was too hard for sampling. F-fluorodeoxyglucose (FDG) positron emission tomography showed an FDG uptake, suggesting a possibility of malignant disease. As the diagnosis could not be confirmed, LECS for both the diagnosis and curative treatment was performed. A histopathological examination showed a tumor with IgG4-positive lymphoplasmacytic infiltration and fibrosis. The ratio of IgG4+/IgG+ lymphoplasmacytic cells was > 80%. A laboratory examination showed elevation of the serum IgG4 levels preoperatively. Thus, the final diagnosis was IgG4-RD of the stomach. No recurrence was observed within 1 year after surgery. Conclusions We encountered a case of definite IgG4-RD presenting as a gastric SMT in which a correct diagnosis was achieved by a minimally invasive LECS technique. IgG4-RD may present as a gastric lesion and should be taken into consideration as a differential diagnosis.

Liver fibrosis influences liver regeneration and surgical outcomes, and several noninvasive models based on laboratory data have been developed to predict liver fibrosis. This study was performed to determine whether the Fibrosis-4 (FIB-4) index, a noninvasive fibrosis marker, can predict the prognosis in patients with colorectal liver metastases (CRLM) undergoing hepatectomy. This retrospective study involved 193 consecutive patients with CRLM who underwent hepatectomy. The FIB-4 index was calculated by laboratory data and age before hepatectomy and before preoperative chemotherapy. The FIB-4 cut-off was determined using survival classification and regression tree analysis. Patients were divided into two groups (high and low FIB-4 index), and post-hepatectomy overall survival (OS) and recurrence-free survival (RFS) were investigated. In total, 193 patients were evaluated. Chemotherapy before hepatectomy was performed in 105 (54.4%) patients. A high FIB-4 index (> 2.736) was found in 39 (20.2%) patients. OS was significantly shorter in patients with a high FIB-4 index than those with a low FIB-4 index in the univariate (45.9 vs. 74.4 months, log-rank p = 0.007) and multivariate analysis (hazard ratio 2.28, 95% confidence interval 1.39–3.74; p = 0.001). Among patients who received chemotherapy before hepatectomy, those with a high FIB-4 index had significantly shorter RFS (6.9 vs. 45.3 months, log-rank p = 0.047) and OS (23.9 vs. 55.0 months, log-rank p = 0.003) than those with a low FIB-4 index. This association was also confirmed by multivariate analysis (hazard ratio 4.28, 95% confidence interval 1.46–12.6; p = 0.008). Both the preoperative and prechemotherapy FIB-4 index can predict long-term outcomes after hepatectomy in patients with CRLM.

Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12-chemokine (CCL2, -3, -4, -5, -8, -18, -19, -21, CXCL9, -10, -11, -13) signature status from tumor tissue and the TLS expression. However, the potential significance of 12-chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12-chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12-chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12-chemokine signature status had a significant shorter relapse-free survival in discovery cohort (HR: 1.61, 95% CI: 1.11-2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33-10.08, p = 0.0087). High 12-chemokine signature status had significant associations with right-sided tumor, high tumor-localized TLS expression, BRAF mutant, CIMP-high status and MSI-high status. Furthermore, RNA-seq based analysis showed that high 12-chemokine signature status was strongly associated with inflammation-related, immune cells-related and apoptosis pathways (using gene set enrichment analysis), and more tumor-infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP-counter analysis). We investigated a promising effect of 12-chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.

The usefulness of quantitating tumor lesion glycolysis (TLG) from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings as a tool for determining the effect of neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC) has not yet been established. The cohort of this retrospective study comprised 46 patients who had undergone NAC and subsequent esophagectomy for locally advanced ESCC between January 2008 and December 2017. PET/CT was conducted before and after NAC to assess its therapeutic effect. Associations between changes in TLG values during NAC and clinicopathological findings, pathological tumor regression grade (TRG), and prognosis were assessed. Most patients received two courses of DCF (Docetaxel, Cisplatin, and Fluorouracil) as NAC. The mean TLG value of the primary tumor decreased significantly after NAC. The median follow-up period was 41 months. The Kaplan–Meier method, analyzed by log-rank test, showed that low TLG ratio (≤ 0.4) and low SUVmax ratio (≤ 0.6) were associated with favorable survival outcomes (P = 0.0073 and P = 0.032, respectively). Univariate and multivariate analysis revealed that TLG ratio and achievement of pathological cure were independent prognostic factors for overall survival. TLG ratio was also associated with pathological TRG (TRG 0–1a vs 1b–3) (P = 0.0016). TLG ratio before and after NAC is clinically useful in predicting both histological response and survival outcome after NAC and subsequent esophagectomy in patients with ESCC.

Accumulating evidence suggests that the inflammatory tumor microenvironment can potentiate tumor progression and metastasis. The C-reactive protein-to-albumin ratio (CAR) is a novel inflammation-based prognostic score. This study was performed to examine the associations of the preoperative CAR with clinical outcomes in patients with colorectal liver metastases (CRLM) after curative resection.We retrospectively assessed the preoperative CAR in 184 patients who underwent curative resection for CRLM from November 2001 to January 2018 at Kumamoto University (Kumamoto, Japan). The optimal cutoff level of the preoperative CAR was determined by survival classification and regression tree (CART) analysis. We compared clinicopathological factors and prognoses between the high-CAR and low-CAR groups. A Cox proportional hazards model was used to calculate hazard ratios (HRs), controlling for potential confounders.A higher preoperative CAR was associated with worse overall survival (OS) (p 0.0001) and recurrence-free survival (RFS) (p = 0.003). Applying survival CART analysis, the high-CAR group comprised 33 patients (17.9%). In the multivariate analyses, a high CAR was independently associated with shorter OS (HR, 2.82; 95% confidence interval, 1.63-4.72; p = 0.0004) and RFS (HR, 1.62; 95% confidence interval, 1.02-2.49; p = 0.040). A high CAR was associated with a large tumor size, high serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels, high intraoperative blood loss, and more postoperative complications.A high preoperative CAR is associated with shorter OS and RFS and might serve as a prognostic marker for patients with CRLM after curative resection.

Objective We retrospectively evaluated the impact of postoperative complications on long-term outcomes after curative resection for colorectal cancer (CRC), using propensity-score analysis (PSA). Patients and methods We reviewed data from 673 consecutive patients with stage I to III CRC, who underwent curative resections between 2005 and 2017. Patients were divided into the complication group (Clavien-Dindo [CD] grade ≥ 3) and the control group (others). We performed PSA to obtain unbiased estimates of the effects of the oncological background on each outcome. Results We matched for sex, age, American Society of Anesthesiologists grade, location (right colon/left colon/rectum), histology (tub1/tub2/por), pathological tumor depth, and lymph node metastases. Eighty-five patients (12.6%) developed postoperative complications with CD grade ≥ 3. After PSA, 81 patients were included in each group. The complication group showed significantly worse relapse-free survival (RFS) than the control group (5-year RFS rate: 62% vs 77%; P = .047). In multivariate analysis with inverse probability of treatment weights, the complication group had a higher risk of relapse or death than the control group (hazard ratio: 2.08, 95% confidence interval:1.3-3.3; P = .018). Conclusions Postoperative complications (CD grade ≥ 3) could cause poor long-term outcomes in patients with stage I to III CRC; their presence requires appropriate adjuvant chemotherapy and follow-up.

Background Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab. Patients and methods 773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated. Results RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009). Conclusion Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status.

Aim Preoperative anaemia is associated with adverse outcomes in colorectal cancer (CRC). To clarify the reason for this we aimed to comprehensively assess the association of preoperative anaemia with tumour characteristics, host systemic inflammation and nutrition status, and perioperative blood transfusion. Method We used an integrated database of 592 CRC patients. The association of preoperative anaemic subtype, calculated from haemoglobin and erythrocyte mean corpuscular volume levels, with patient outcome, preoperative serum data relating to systemic inflammation and nutrition and perioperative blood transfusion was analysed. Results Preoperative anaemia was significantly associated with poorer overall survival and relapse-free survival (RFS); in particular microcytic anaemia had a trend to poorer RFS than other forms of anaemia (P = 0.0648). In addition, preoperative anaemia was significantly correlated with right-sided tumours, greater depth of tumour invasion, use of neoadjuvant chemotherapy, poorer prognostic nutritional index and higher modified Glasgow Prognostic Score (mGPS). Microcytic anaemia in particular had a strong association with a greater depth of tumour invasion (P = 0.0072) and higher mGPS (P = 0.0058) than other causes of anaemia. Perioperative blood transfusion for CRC patients with anaemia was associated with adverse outcomes. Conclusions Preoperative anaemia, especially microcytic anaemia, was associated with poor patient outcomes, possibly due to poor systemic inflammatory and nutritional status, and it was not improved by perioperative blood transfusion. Our data suggest that preoperative anaemia and the anaemic subtype may serve as an easily available predictor of outcome in CRC.

Background Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). Methods The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. Results Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). Conclusion The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.

BACKGROUND/AIM The Controlling Nutritional Status (CONUT) score is a useful nutritional evaluation, that is calculated from serum albumin, total cholesterol concentrations, and total lymphocyte count. This study aimed to investigate the association between the CONUT score and prognosis in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS The CONUT score was retrospectively calculated in 211 patients with mCRC receiving first-line chemotherapy. The patients were divided into three groups: the CONUT low-group (0-1), intermediate-group (2-4), and high-group (5-). The associations of the CONUT score with clinicopathological factors and survival outcomes were evaluated. RESULTS The higher CONUT score was significantly associated with synchronous metastases, and no primary tumor resection. The higher CONUT score group showed a significant shorter progression-free survival (log-rank p