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Microsatellite instability (MSI) and tumor mutational burden (TMB) are indicators of the tumor mutational load, which can lead to immune cell recruitment. By contrast, the number of tumor-infiltrating T cells (TITs) is indicative of the host immune response to tumor cells. The present study evaluated if the expression of mismatch repair (MMR) proteins can be used as a precise tool to assess immunogenicity in the tumor microenvironment. A total of 73 colorectal cancer cases were enrolled in the present study. MMR protein expression was assessed using four-antibodies immunohistochemistry (IHC) targeting

Trousseau syndrome-related cerebral infarction rarely occurs during chemotherapy in patients with gastrointestinal (GI) cancer, and its clinical features remain unclear. The present study aimed to examine the clinical features of Trousseau syndrome-related cerebral infarction developed during chemotherapy for GI cancer. The present retrospective cohort study consecutively enrolled 878 patients with unresectable GI cancer who received chemotherapy at the Multidisciplinary Treatment Cancer Center, Kurume University Hospital (Kurume, Japan) between April 2014 and March 2020. Patients with colorectal cancer (n=308) were the most common, followed by those with pancreatic (n=242), gastric (n=222) and biliary tract (n=59) cancer, neuroendocrine tumors (n=34) and duodenal cancer (n=11). Among the 878 patients, Trousseau syndrome-related cerebral infarction occurred in 8 (0.9%) patients with a median age of 70.5 years (range, 58-75 years), and 50% of the patients were male (4/8). In total, 3 patients had gastric cancer, 3 had pancreatic cancer and 2 had biliary tract cancer. A greater percentage of patients with Trousseau syndrome-related cerebral infarction had hyperlipidemia (38.0%) than those without (8.2%; P=0.005). Hyperlipidemia was a risk factor for occurrence of Trousseau syndrome-related cerebral infarction with an odds ratio of 7.009 (95% confidence interval, 1.785-27.513). Trousseau syndrome-related cerebral infarction developed during GI chemotherapy was rare and hyperlipidemia may predict its onset.

Bevacizumab (BEV) requires an adequate withdrawal period to avoid BEV-related complications during major surgery. However, the safety of BEV administration immediately after surgical placement of the central venous (CV) port, a minor surgery, is still unclear. This study aimed to investigate whether BEV is safe when administered early after CV port placement. We retrospectively evaluated 184 patients with advanced colorectal cancer (CRC) treated with a BEV-containing regimen and divided them into two groups according to the interval between CV port implantation and chemotherapy initiation, with the early administration group being ≤7 days and late administration group being >7 days. Complications were then compared between the two groups. The early-administration group was significantly older and had a higher rate of colon cancer than the late-administration group. Overall, 24 (13%) patients developed CV port-related complications. Male sex was a risk factor for complications (odds ratio [OR], 3.154; 95% CI, 1.19–8.36). The two groups showed no significant difference in the frequency of complications (p = 0.84) or patient characteristics (after the inverse probability of treatment weighting, p = 0.537). In conclusion, the frequency of complications is not affected by the timing of BEV initiation after CV port implantation. Thus, early BEV administration after CV port placement is safe.

Background. The extent of lymph node dissection in advanced colorectal cancer varies according to regional guidelines. D3 lymphadenectomy is routinely performed in Japan but is associated with several risk factors. Metastases of the main lymph nodes (No.253 lymph nodes), which are located at the root of the inferior mesenteric artery, are rare in left-sided colorectal cancer. Tumor depth (T4) is an identifier of No.253 lymph node metastasis (LNM) risk, but other risk factors associated with No.253 LNM are unclear. This study was undertaken to investigate the frequency of No.253 LNM and to identify other clinicopathological risk factors associated with No.253 LNM in left-sided colorectal cancer. In this study, we aimed to evaluate the clinical benefit of routine D3 lymphadenectomy in surgically treated advanced colorectal cancer. Methods. A retrospective database of patients with colorectal cancer who underwent D3 dissection and R0 resection at Kurume University Hospital from 1978 to 2017 was constructed and used to search for the frequency and risk factors of No.253 LNM to investigate long-term prognosis. Clinicopathological factors associated with No.253 LNM, including age, sex, tumor location, T stage, tumor diameter, carcinoembryonic antigen levels, and various dissected lymph nodes, were analyzed. Results. Among 1,614 consecutive patients, No.253 LNM was observed in 23 cases (1.4%). The presence of three or more regional LNMs was an independent risk factor for No.253 LNM (odds ratio: 26.8). The 5-year overall survival rate was 49.1% in the No.253 LNM-positive group and 78.4% in the No.253 LNM-negative group (p=0.002). Conclusion. In left-sided colorectal cancer, No.253 LNM was a poor prognosis factor, and three or more regional LNMs were a risk factor for No.253 LNM. The No.253 LNM-positive group had a poor prognosis, but there are cases of long-term survival, with a 5-year survival rate of 49%. D3 lymphadenectomy is suitable when three or more metastatic LNs are identified prior to surgery.

The tumor immune response is dependent on the interaction between tumor cells and the T-cell subset expressing the T-cell receptor (TCR) repertoire that infiltrates into the tumor microenvironment. The present study explored the diversity and shared TCR repertoires expressed on the surface of locoregional T cells and identified the T lymphocyte subsets infiltrating into esophageal squamous cell carcinoma (ESCC), in order to provide insight into the efficiency of immunotherapy and the development of a novel immune-oriented therapeutic strategy. A total of 53 patients with ESCC were enrolled in the present study, and immunohistochemical analysis of CD3, CD8, CD45RO, FOXP3, CD274, HLA class I and AE1/AE3 was performed. Digital pathological assessment was performed to evaluate the expression level of each marker. The clinicopathological significance of the immuno relation high (IR-Hi) group was assessed. Adaptor ligation PCR and next-generation sequencing were performed to explore the diversity of the TCR repertoire and to investigate the shared TCR repertoire in the IR-Hi group. Repertoire dissimilarity index (RDI) analysis was performed to assess the diversity of TCR, and the existence of shared TCRα and TCRβ was also investigated. Further stratification was performed according to the expression of markers of different T-cell subsets. Patients were stratified into IR-Hi and immuno relation low (IR-Lo) groups. Cancer-specific survival and recurrence-free survival rates were significantly improved in the IR-Hi group compared with in the IT-Lo group. The diversity of the TCR repertoire was significantly higher in the IR-Hi group. TCR repertoire analysis revealed 27 combinations of TCRα and 23 combinations of TCRβ VJ regions that were shared among the IR-Hi group. The IR-Hi group was divided into three clusters. Overall, the current findings revealed that the IR-Hi group maintained the diversity of TCR, and a portion of the IR-Hi cases held the T cells with shared TCR repertoires, implying recognition of shared antigens. The prognosis of patients with ESCC was affected by the existence of immune response cells and may possibly be stratified by the T-cell subsets.

In colorectal cancer (CRC), the indication for immune checkpoint inhibitors is determined by the microsatellite instability status of the tumors. However, an optimal biomarker for their indication has not been fully identified to date. This study aimed to establish the clinicopathologic importance of the Immunoscore (IS) in CRC and to clarify the relationships between the IS, programmed death-ligand 1 (PD-L1) expression, and tumor-associated macrophages. In 132 cases, CRC was diagnosed and surgically treated in our department from 2009 to 2010. Immunohistochemical staining using primary antibodies PD-L1, CD3, CD8, CD68, and CD163 was performed. The IS was determined according to the proposal of an international task force. Statistical analyses were performed to investigate the correlation between the IS, clinicopathologic variables, and expression of immune checkpoint molecules. The overall survival (OS) and relapse-free survival (RFS) in the high-IS group (I3–4) were significantly better than in the low-IS group (I0–2) (OS: P = 0.0420; RFS: P = 0.0226). The positivity rate for PD-L1 on tumor cells (tPD-L1) was only 0.8%, whereas that for PD-L1 on interstitial tumor-infiltrating mononuclear cells (iPD-L1) was 18.2%. The iPD-L1-positive group showed significantly better survival in terms of both OS and RFS than the iPD-L1-negative group (OS: P = 0.0278; RFS: P = 0.0253). The findings showed significant correlation between the IS and iPD-L1 expression (P

Signet ring cell carcinoma (SRCC) is a rare pathological type of colorectal cancer, of which the clinicopathological features and genetic background have not yet been fully investigated. Previous research has focused on the optimization of colorectal cancer treatment utilizing consensus molecular subtyping (CMS). However, it is not known what type of CMS would be designated to SRCC treatment. In the current study, of 1,350 patients diagnosed with colorectal cancer who underwent surgery, 14 were diagnosed with SRCC. The case-control cohort that fit the clinical background of the SRCC case was constructed. Statistical comparison between the SRCC group and the case-control cohort was performed among clinicopathological variables. SRCC and well to moderately adenocarcinoma case mRNA were submitted to microarray analysis and CMS analysis. Compared with the case-control cohort, the SRCC group was located more in the right-sided colon, the lymphatic invasion was more severe and the peritoneal dissemination was more frequent. The cancer-specific survival and the progression-free survival were significantly worse in the SRCC group compared with the case-control cohort. Microarray and CMS analysis identified that one SRCC case was significantly well assigned in the CMS 4 group and the other case was assigned in the CMS 1 group. Gene set analysis revealed the upregulation of EMT related genes and the downregulation of fatty acid, glycolysis, differentiation, MYC, HNF4A, DNA repair genes. In conclusion, the clinical characteristics of SRCC are severe but there is a possibility of the presence of different phenotypes according to CMS analysis.

Background We investigated the correlation between surgery-related factors and the incidence of leakage after low anterior resection (LAR) for lower rectal cancer. Methods A total of 630 patients underwent colorectal surgery between 2011 and 2014 in our department. Of these, 97 patients (15%) underwent LAR, and are the subjects of this retrospective study. Temporary ileostomy was performed for each patient.Results Anastomotic leakage occurred in 21 patients (21.7%). Univariate analysis showed that operative duration (p=0.0051), transanal hand-sewn anastomosis (p=0.0141), and operation procedure (p=0.0191) were significantly associated with the incidence of leakage. Multivariate analysis showed that underlying disease (p=0.044), transanal hand-sewn anastomosis (p=0.0188), and drain type (p=0.0251) were significantly associated with the incidence of leakage. The propensity score analysis results showed that closed drainage was associated with 6.3 times more postoperative blood loss (mls) in patients experiencing anastomotic leakage compared with open drainage, in the inverse probability of treatment-weighted analysis.Conclusions Our results showed that underlying disease, transanal hand-sewn anastomosis, and the drain type may be risk factors for developing anastomotic leakage after LAR for lower rectal cancer. The notable finding was that the type of drainage was related to the incidence and volume of anastomotic leakage: open drainage was correlated with the incidence of leakage, and closed drainage was correlated with the volume of anastomotic leakage.

Background We investigated the correlations between surgery-related factors and the incidence of anastomotic leakage after low anterior resection (LAR) for lower rectal cancer. Methods A total of 630 patients underwent colorectal surgery between 2011 and 2014 in our department. Of these, 97 patients (15%) underwent LAR and were enrolled in this retrospective study. Temporary ileostomy was performed in each patient. Results Anastomotic leakage occurred in 21 patients (21.7%). Univariate analysis showed a significant association between operative duration (p = 0.005), transanal hand-sewn anastomosis (p = 0.014), and operation procedure (p = 0.019) and the occurrence of leakage. Multivariate regression reanalysis showed that underlying disease (p = 0.044), transanal hand-sewn anastomosis (p = 0.019) and drain type (p = 0.025) were significantly associated with the occurrence of leakage. The propensity-score analysis showed that closed drainage were 6.3 times more likely to have anastomotic leakage than open drainage in relation to the amount of postoperative drainage (ml), according to the inverse probability of treatment-weighted analysis. Conclusions Our results indicate that underlying disease, transanal hand-sewn anastomosis, and closed drain may be a risk and predictive factors for anastomotic leakage after LAR for lower rectal cancer. The notable finding was that closed drainage was related to the occurrence of anastomotic leakage and closed drainage was correlated with less volume of postoperative drain discharge than open drain.

We review 6 cases of diaphragmatic perforation, with and without herniation, treated in our institution. All patients with diaphragmatic perforation underwent radiofrequency ablation (RFA) treatments for hepatocellular carcinoma (HCC) performed at Kurume University Hospital and Tobata Kyoritsu Hospital. We investigated the clinical profiles of the 6 patients between January 2003 and December 2013. We further describe the clinical presentation, diagnosis, and treatment of diaphragmatic perforation. The change in the volume of liver and the change in the Child-Pugh score from just after the RFA to the onset of perforation was evaluated using a paired t-test. At the time of perforation, 4 patients had herniation of the viscera, while the other 2 patients had no herniation. The majority of ablated tumors were located adjacent to the diaphragm, in segments 4, 6, and 8. The average interval from RFA to the onset of perforation was 12.8 mo (range, 6-21 mo). The median Child-Pugh score at the onset of perforation (8.2) was significantly higher compared to the median Child-Pugh score just after RFA (6.5) (P = 0.031). All patients underwent laparotomy and direct suture of the diaphragm defect, with uneventful post-surgical recovery. Diaphragmatic perforation after RFA is not a matter that can be ignored. Clinicians should carefully address this complication by performing RFA for HCC adjacent to diaphragm.

A 70-year-old man was diagnosed with colon cancer with multiple liver metastases.He was administered modified FOLFOX6 plus panitumumab as first-line chemotherapy.He showed consciousness disturbance on the 3rd day during the 8 cycle and was hospitalized urgently.We diagnosed him with 5-FU-induced hyperammonemia.Administration of branchedchain amino acid preparation improved his consciousness disturbance.After changing the regimen of chemotherapy to another one containing oral fluoropyrimidine, the recurrence of hyperammonemic encephalopathy was not found.

Y‑box‑binding protein 1 (YB‑1) is a DNA/RNA‑-binding protein and an important transcription and translation factor in carcinogenesis. However, the biological function and molecular correlation of YB‑1 in colorectal cancer are not fully understood. The aim of the present study was to determine the significance of YB‑1 expression and its biological role in colorectal cancer. Cell proliferation, migration and apoptosis were examined upon knockdown of YB‑1 expression in different colon cancer cell lines that had different genetic backgrounds. Since the properties of different colon cancer cell lines with specific RAS/RAF gene mutations downstream epidermal growth factor receptor (EGFR) may differ from wild‑type colorectal cancer, it is critical to study the role of YB‑1 with respect to the mutational status of RAS. The results indicated that the suppression of YB‑1 decreased cell proliferation (P

Gemcitabine plus nab-paclitaxel (GnP) is widely used in clinical practice, despite a lack of prospective data to validate its efficacy in locally advanced pancreatic cancer (LAPC). We conducted a phase II study of GnP for LAPC to assess its efficacy and safety. We performed a single-arm, single-institution study with GnP in 24 patients with LAPC. The treatment protocol included successive administration of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2). The primary endpoint was the tumor overall response rate (ORR), and secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). The median PFS was 11.0 months, median OS was 21.2 months, ORR was 62.5%, and 37.5% of the patients had stable disease. Four (16.7%) of the patients were converted to surgical resection; 3 of these achieved R0 resection. Grade 3 to 4 AEs included hematological (neutropenia, 64%; thrombocytopenia, 12%), nonhematological (cholangitis, 16%), and sensory neuropathy (4%). These AEs were manageable and tolerable. The GnP treatment in patients with LAPC showed favorable tumor shrinkage, good toxicity profile, and enabled conversion to surgical resection in a subset of patients; therefore, GnP is an option for first-line chemotherapy in patients with LAPC.

Because of their rarity, there are no clear guidelines for the treatment of anal carcinomas; such tumors are normally subjected to the same modalities as recommended for rectal cancer. We report a patient with anal canal mucinous adenocarcinoma, with metastases in the pararectal and right inguinal lymph nodes, who was treated with abdominoperineal resection followed by mFOLFOX6 chemotherapy for 6 months (12 cycles). The patient has remained recurrence-free thus far, approximately 2 years since the surgery. As the optimal treatments for anal carcinomas have not been fully elucidated, we present this case to highlight a possible course of action for such patients that appears to be effective and promising.

Anal canal adenocarcinoma is a relatively rare malignancy without established diagnostic and treatment criteria. Case reports of chemotherapy for anal canal adenocarcinoma with distant metastasis are limited, and there is no convincing evidence for treatment effectiveness. A 62-year-old man complained of difficulty in defecation, anal pain, and bleeding during bowel movement. He was diagnosed with moderately differentiated primary anal canal adenocarcinoma. A computed tomography scan revealed multiple metastases in the lung and liver. The patient was treated with abdominoperineal resection to control local tumor growth and then with chemotherapy consisting of mFOLFOX6 + bevacizumab. Because he had an activating KRAS mutation, anti-EGFR therapy was not considered. A reduction in the size of lung and liver metastases was observed after 4 courses of mFOLFOX6 + bevacizumab, and after 22 courses, maximum reduction in the metastatic lesions was achieved. The patient demonstrated tolerable levels of oxaliplatin-related peripheral neurotoxicity (grades 1-2) and was considered as having partial response to treatment. He is currently at the partial response state for 1 year. We plan to continue the treatment unless the patient develops progressive disease or intolerable adverse reactions. This case demonstrates that anal canal adenocarcinoma with distant metastases could be successfully treated with mFOLFOX6 + bevacizumab therapy according to the guidelines for rectal carcinoma. However, as anal canal carcinoma has multiple histological subtypes, it is important to establish subtype-specific treatment strategies.

The case involved a 44-year-old man who underwent intersphincteric resection and lateral lymph node dissection for rectal cancer. Pathological diagnosis revealed a well-differentiated adenocarcinoma comprising KRAS wild type, and pT2N0M0 (pathological Stage I). CapeOX (capecitabine plus oxaliplatin[L-OHP]), and bevacizumab therapy was initiated because of local recurrence. Although a partial response (PR) was observed, the therapy was terminated after 6 courses because of the development of hand-foot syndrome. FOLFIRI and cetuximab therapy was initiated after cancer recurrence was observed during a follow up. As the therapeutic efficiency is characterized by stability (stable disease: SD), and the tumor reduction effect observed was not sufficient, we performed an abdominoperineal resection to achieve local control. However, a left hydronephrosis occurred due to the pelvic recurrence, necessitating the emergency hospitalization of the patient. Because resistance to L-OHP was not confirmed, mFOLFOX6 and bevacizumab therapy was introduced in hopes of the effect of the former. As Grade 2 allergy (erythema) appeared immediately after the L-OHP was administered during the 3 courses, treatment was discontinued. We the reinitiated the treatment along with the desensitization therapy from the 4 courses. A total of 27 courses of mFOLFOX6 and bevacizumab therapy were administered until the state of disease progression (progression disease: PD) was determined. PR was defined as the best therapeutic efficiency. In some cases, discontinuation of treatment is necessary as observed in the present case due to the onset of L-OHP allergies, even if the overall effect of the treatment is expected to be good. Our case is essentialas it demonstrates the successfulness of desensitization therapy for L-OHP allergies.

The aim of this study was to investigate the status of the c‑Myc‑related molecule Mina53 and the clinical impact of Mina53 nuclear localization in patients with stage II and III colorectal cancer (CRC). Patients (n=250) who underwent complete resection of CRC at our department were enrolled in this study, and tissue microarray samples were constructed from resected specimens. Mina53 expression in the nuclei of tumor cells was analyzed using immunohistochemistry (IHC). Patients were classified into Mina53 nuclear localization‑-positive and ‑negative groups, and statistical correlations with clinicopathological factors were investigated. Relapse‑free survival (RFS) was compared using the Kaplan‑Meier method and the Cox proportional hazard model. Tumor recurrence was significantly higher in the Mina53‑positive group than in the Mina53‑negative group. Moreover, in RFS analysis, patients in the Mina53‑positive group exhibited significantly poorer prognosis than patients in the Mina53‑negative group. In the univariate analysis, histological type, adjuvant chemotherapy status, carcinoembryonic antigen (CEA) status, and Mina53 status were prognostic factors for RFS. Furthermore, in the subgroup analysis, patients in the Mina53‑positive group with stage III disease treated with adjuvant chemotherapy exhibited significantly poorer prognosis in RFS than patients in the Mina53‑negative group. In the univariate and multivariate analyses, histological type and Mina53 status were significantly associated with RFS. Thus, our findings revealed that Mina53 was an important indicator of prognosis in patients with stage III CRC treated with adjuvant chemotherapy.

Background It has been shown that lenvatinib is effective in patients with radioactive iodine- (RAI) refractory differentiated thyroid cancer; however, there are few reports of its use in clinical practice. Purpose We investigated the efficacy, toxicity, and optimal dose of lenvatinib that had been administered for differentiated thyroid cancer in our hospital. Method We examined dose reduction, dose-limiting toxicity (DLT), optimal dose, response rate (RR), and disease control rate (DCR) in 10 patients who had received lenvatinib for differentiated thyroid cancer from January 2016 to December 2018. Results The mean patient age was 70.5 (50-80) years; there were four men and three women, and all had papillary thyroid cancer. Eight patients had received RAI. In all cases, the starting dose of lenvatinib was 24 mg/day; all patients required interruption and dose reduction. DLT was related to arthralgia in one patient, hand-foot syndrome in one, hypertension in one, and proteinuria in seven. The mean optimal dose of lenvatinib was 10.4 mg/day; 14 mg/day in two patients, 10 mg/day in six, and 8 mg/day in two. The mean interval to optimal dose was 2.4 (1.4-4.7) months. The RR was 40% (partial response in four patients and stable disease in six), making the DCR 100%. Seven patients continued receiving lenvatinib therapy. Discussion In the SELECT study, 67.8% of participants receiving lenvatinib required dose reduction; the mean dose was 17.2 mg/day. However, in the present study, dose reduction was required in all 10 patients, the mean optimum dose being 10.4 mg/day. Conclusion We consider that revision of starting doses and guidelines for reducing the dose of lenvatinib for differentiated thyroid cancer may be necessary.

In the original article, Akihiko Kawahara's first name is incorrect. It is correct as reflected here.

319 Background: Gene mutations of SMAD4, TP53 and CDKN2A( p16) have been reported to be associated with poor prognosis and metastatic burden in advanced pancreatic cancer (PC). On the other hand, the association between these gene mutations and recurrence in PC is still unclear. The present study aimed to whether the 3 gene mutations were related to the recurrence and the prognosis in PC patients. Methods: Formalin-fixed paraffin-embedded tumor samples were gathered from patients with PC who underwent curative resection between January 2014 and December 2015. We retrospectively evaluated a relationship between the mutation status of SMAD4, TP53 and p16 and the recurrence and prognosis in patients with PC. Results: Totally, fifty-six samples of patients with PC (Stage I/ II/ III: 5/6/45 (UICC 7th)) were included in this analysis. Recurrence was seen in 32 patients (57.1%). Patients with PC both recurrence and advanced pathological stage showed poor prognosis. Each 3 gene mutation did not show a significant association with recurrence. TP53 and p16 single mutations did not show significant association with prognosis. However, the patients with PC who have SMAD4 mutation showed a significant poor prognosis (Overall survival: 18.6 vs. 34.5 months, p = 0.03). Multivariate analysis showed only recurrence was a significant prognostic factor (p = 0.01) Conclusions: The present study suggested that there was no association between SMAD4 and recurrence, whereas in case of recurrence, SMAD4 mutation may be associated with prognosis in PC patients.