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Background Immune checkpoint inhibitors targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have demonstrated antitumor effects in patients with various malignancies, including esophageal cancer. Thus, a better understanding of local immunity in esophageal cancer is crucial for improving treatment and clinical outcomes. Methods We evaluated PD-1 expression on tumor-infiltrating lymphocytes (TILs), as well as PD-L1 expression on cancer cells, by immunohistochemistry and immunofluorescence using a nonbiased database of 433 curatively resected esophageal cancers. With the idea of application as liquid biopsy, PD-1 expression status on peripheral lymphocytes was evaluated by flow cytometry. Results The cutoff value of PD-1 expression was the median PD-1 count. Compared with cases of low PD-1 expression (n = 219), cases with high levels of PD-1 expression (n = 213) showed significantly worse overall survival (log-rank P = .0017). The prognostic effect of PD-1 differed according to the preoperative treatment status (P for interaction = .040); PD-1 expression was associated with high overall mortality among patients without preoperative therapy, while no such association was present among those with preoperative treatment. A stratification based on PD-1 and PD-L1 status was also significantly associated with overall survival (log-rank P = .0005). PD-1 expression on TILs was significantly associated with that on peripheral lymphocytes (P Conclusions PD-1 expression on TILs was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. The combination of PD-1 and PD-L1 expression enabled further classification of patients according to clinical outcome.

The present study assessed postoperative bowel dysfunction in Japanese patients with rectal cancer, including patients who underwent preoperative radiotherapy (RT).A total of 277 rectal cancer patients who underwent primary resection were included in the analyses. A questionnaire survey was administered using the low anterior resection syndrome (LARS) score and Wexner score. Scores were determined one year after rectal surgery or diverting ileostomy closure. The LARS score was categorized as minor LARS (21-29) and major LARS (30-42).The proportions of patients with minor and major LARS were significantly larger and Wexner scores significantly higher in patients with distal tumors and a lower anastomosis level than in those with proximal tumors and a higher anastomosis level. Among the patients with lower rectal cancer, the proportions with minor and major LARS were similar between those with and without preoperative RT. The Wexner scores in patients with preoperative RT were significantly higher than in patients without RT. A distal tumor location and lower anastomosis level were independent risk factors of major LARS in multivariate analyses.A distal tumor location, low anastomosis level, and preoperative RT might be associated with postoperative bowel dysfunction in rectal cancer patients.

Experimental evidence suggests a role of intratumour Fusobacterium nucleatum in the aggressive behaviour of gastrointestinal cancer through downregulating anti-tumour immunity. We investigated the relationship between intratumour F. nucleatum and immune response to oesophageal cancer.Utilising an unbiased database of 300 resected oesophageal cancers, we measured F. nucleatum DNA in tumour tissue using a quantitative polymerase chain reaction assay, and evaluated the relationship between the abundance of F. nucleatum and the densities of T cells (CD8 + , FOXP3 + and PDCD1 + ), as well as lymphocytic reaction patterns (follicle lymphocytic reaction, peritumoural lymphocytic reaction, stromal lymphocytic reaction and tumour-infiltrating lymphocytes) in oesophageal carcinoma tissue.F. nucleatum was significantly and inversely associated only with the peritumoural lymphocytic reaction (P = 0.0002). Compared with the F. nucleatum-absent group, the F. nucleatum-high group showed a much lower level of the peritumoural lymphocytic reaction (univariable odds ratio, 0.33; 95% confidence interval, 0.16-0.65; P = 0.0004). A multivariable model yielded a similar finding (multivariable odds ratio, 0.34; 95% confidence interval 0.16-0.69; P = 0.002).Intratumour F. nucleatum is associated with a diminished peritumoural lymphocytic reaction, providing a platform for further investigations on the potential interactive roles between intratumour F. nucleatum and host immunity.

Background The incidence of synchronous gastrointestinal neuroendocrine tumors (GI-NETs) and colorectal cancer is very low. Case presentation We present a 72-year-old man diagnosed with a rectal neuroendocrine tumor (NET) with multiple organ metastases and simultaneous sigmoid colon cancer. Although the NET was his prognostic factor, he underwent a laparoscopic sigmoidectomy at first because it was expected that the colon cancer would cause obstruction or bleeding during NET treatment. Subsequently, he started taking everolimus. Conclusions We should consider surgical resection of the synchronous cancer before systemic therapy for a GI-NET regardless of the difference in prognosis between synchronous tumors, if the cancer may impair the continuation of systemic therapy.

The large Maf transcription factors are expressed in immune cells including macrophages and lymphocytes. To investigate the distribution of Maf expression in human organs, immunostaining for Maf was performed using sections of several human organs. High Maf expression was seen in the nucleus of macrophages in the gastrointestinal tract and lymph node sinus macrophages (LySMs). Then, we assessed whether Maf expression in LySMs was correlated with CD169 expression and the clinical prognosis in patients with esophageal cancer. Maf expression was associated with CD169 expression, but Maf expression in LySMs was not associated with the clinical course in patients with esophageal cancer. We determined which cytokines stimulate Maf expression using cultured macrophages. Immunocytochemistry showed that Maf expression was significantly elevated by interferon-γ. These results are the first report of Maf expression in human samples. Maf expression may be a marker for the macrophage population in humans.

To evaluate the relationship between indoleamine 2, 3-dioxygenase (IDO1) expression and tumoral immune status and clinical outcome in esophageal cancer.IDO1 is a primary enzyme that generates immunosuppressive metabolites such as tryptophan and kynurenine. Like the PD-1/PD-L1 pathway, IDO1 plays a major role in tumor immunology and is a potential immune-based therapeutic target.The expressions of IDO1, CD8 (a marker of cytotoxic T cells), FOXP3 [a marker of regulatory T cells (Treg)], and PD-L1 in 305 curatively resected esophageal cancers were evaluated by immunostaining.Overall survival was significantly better in the IDO1 negative cases (n = 234) than in the IDO1 positive cases (n = 71) [log-rank P = 0.0041; hazard ratio (HR): 1.75; 95% confidence interval (CI): 1.12-2.67; P = 0.015]. CD8 high expression was significantly positively correlated with overall survival (log-rank P = 0.025) and low IDO1 expression (P = 0.044). The inverse correlation between CD8 and IDO1 expressions was confirmed by double immunostaining for IDO1 and CD8. Stratification based on IDO1 and CD8 expressions was also significantly associated with overall survival (log-rank P = 0.0024). In addition, the IDO1-positive group was correlated with high counts of FOXP3-positive cells (P = 0.020), but not with PD-L1 expression status (P = 0.19).IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. Combining the IDO1 and CD8 statuses enabled further classification of the clinical outcomes of patients.

Indoleamine 2, 3‐dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune‐based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5‐azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin‐fixed, paraffin‐embedded samples resected from esophageal cancer patients. We treated cell lines with 5‐azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P

Objective To examine the relationship between tumor long-interspersed nucleotide element-1 (LINE-1) methylation level and immune response to esophageal cancer. Background Evidence points to a correlation between the abundance of immune cells and a favorable prognosis in esophageal cancer patients. Accumulating evidence indicates a critical role of tumor LINE-1 hypomethylation in the aggressive behavior of esophageal cancer, which in turn leads to an unfavorable prognosis. Methods Utilizing a nonbiased database of 292 resected esophageal cancers, we measured tumor LINE-1 methylation level by pyrosequencing assay, and examined the relationship between LINE-1 methylation and the density of T cells (CD8 and FOXP3) and the lymphocytic reaction patterns (follicle lymphocytic reaction, peritumoral lymphocytic reaction, stromal lymphocytic reaction, and tumor-infiltrating lymphocytes) in esophageal carcinoma tissue. Results LINE-1 hypomethylation was associated with male gender and advanced stage cancer (P = 0.03 and P = 0.048, respectively). Tumor LINE-1 methylation level was significantly positively associated with peritumoral lymphocytic reaction (P = 0.004), but not with others. Compared with LINE-1 hypermethylation group, LINE-1 hypomethylation group showed much lower level of peritumoral lymphocytic reaction (univariable odds ratio 0.32, 95% confidence interval 0.16-0.64, P = 0.002). In multivariable model to control for potential confounders including disease stage, the similar finding was observed (multivariable odds ratio 0.31, 95% confidence interval 0.14-0.66, P = 0.004). Conclusions Tumor LINE-1 hypomethylation level is associated with a diminished peritumoral lymphocytic reaction, providing impetus for further investigations on potential interactive roles of tumor LINE-1 hypomethylation and host immunity in esophageal cancer development.

Introduction Tumour-associated macrophages (TAMs) in tumour microenvironments promote cancer cell proliferation, immunosuppression and angiogenesis, leading to tumour growth and metastasis. TAMs have become increasingly recognised as a cancer therapy target, such as in combination therapy with an immunity checkpoint inhibitor. However, the clinical and prognostic features of TAMs, and the relationship between TAMs and programmed death ligand 1 (PD-L1), remain unexplored in oesophageal cancer. Methods Using a non-biased database of 305 resected oesophageal cancer preparations, we evaluated the expression of two M2-like macrophage markers (CD163 and CD204) and PD-L1 on tumour cells by immunostaining. Through in vitro assays, we examined how TAMs influence phenotypic malignancy and PD-L1 expression. Results High density of CD163 (n = 160) or CD204 (n = 146) was associated with significantly worse overall survival than low expression (log rank P = 0.0025 and 0.018 for CD163 and CD204, respectively). The prognostic effect of TAMs was not significantly modified by any clinical factors (P > 0.05 for all interactions). High TAM density was significantly associated with increased PD-L1 expression. In in vitro assays, cell invasion and migration ability were significantly more upregulated in oesophageal cancer cell lines cocultured with activated macrophages than in control cell lines. Coculture with activated macrophages elevated the PD-L1 expression in cancer cells. Conclusions High TAM density in oesophageal cancer tissues was associated with shorter survival, suggesting a prognostic biomarker role for TAMs. TAMs also increase PD-L1 expression in tumour cells. Given the significant interest in cancer immunotherapies targeting TAMs and PD-L1, the current findings should have considerable clinical implications.

The effect of resection of the thoracic duct (TD) along with surrounding lymph nodes (LN) on short- and long-term outcomes of esophagectomy in esophageal cancer patients is not well defined. A total of 537 consecutive patients suffering from esophageal cancer who underwent three-incision esophagectomy between April 2005 and August 2018 were eligible for short-term outcome analysis. Among them, 487 patients who underwent surgery before August 2017 were eligible for analysis of long-term outcomes. Moreover, 164 patients who underwent esophagectomy after August 2012 and had no recurrence at 1-year postoperative follow-up were prospectively investigated for postoperative nutritional status. A total of 145 patients (27.0%) underwent TD resection with surrounding LN. Since the clinical stage was significantly more advanced in the removal group, preoperative treatment was more frequently performed in them. The operative time was significantly longer in the removal group. Intraoperative bleeding was higher in the removal group. Morbidity of Clavien–Dindo classification (CDc) ≥ II and pulmonary morbidities were frequently observed in the removal group. Multivariate analysis suggested that TD resection was an independent risk factor for pulmonary morbidities. Moreover, it may be associated with the incidence of CDc ≥ II morbidity. Greater numbers of LN were dissected in the thorax of patients in the removal group. However, overall survival was equivalent irrespective of the TD procedure in each stage. Nutritional status at 1-year follow-up was equivalent between the groups. On the basis of the present results, routine removal of the TD during esophagectomy is not recommended.

Thymic carcinoma, a rare mediastinal neoplasm, is characterized by extensive local invasion and distant metastasis. To our knowledge, this is the first case report demonstrating the efficacy of laparoscopic dissection for pelvic lymph node metastases from thymic carcinoma. A 64-year-old man was found to have a mediastinal mass by CT and underwent radical resection. Six months after resection of his thymic carcinoma, follow-up CT revealed a gluteal tumor and enlarged pelvic lymph nodes. The gluteal tumor was resected percutaneously. Two months after this procedure, PET showed that the three pelvic lymph nodes had abnormal uptake of 18 F-fluorodeoxyglucose and had enlarged further. The patient accordingly underwent laparoscopic dissection of these lymph nodes. Pathological examination of all resected specimens showed metastatic thymic carcinoma. We recommend laparoscopic dissection of pelvic lymph node metastases because it provides a clear intraoperative view and is minimally invasive.

Background: Regorafenib and TAS-102 are standard salvage-line treatment options for patients with chemorefractory metastatic colorectal cancer (mCRC). We aimed to evaluate the prognostic significance of skeletal muscle mass in mCRC patients receiving these salvage-line therapies. Methods: We conducted a retrospective analysis of 52 patients with mCRC who received regorafenib or TAS-102 as salvage-line treatment. Skeletal muscle cross-sectional area was measured by pretreatment CT to obtain the skeletal muscle index (SMI, cm2/m2). We divided patients into 2 groups (low-SM/high-SMI) based on the median value of SMI. Result: The median SMI was 51.8 cm2/m2 in males and 39.2 cm2/m2 in females. In Kaplan-Meier analysis, patients in the low-SMI group showed significantly shorter overall survival (3.7 vs. 7.3 months, log-rank p = 0.002) and progression-free survival (1.9 vs. 2.8 months, log-rank test p = 0.009) than those in the high-SMI group. Subsequent multivariate analysis revealed that the SMI was an independent prognostic factor (hazard ratio = 2.381, 95% CI 1.189–4.944, p = 0.014). Patients in the low-SMI group had significantly more grade 3 or 4 adverse events than those in the high-SMI group (46 vs.12%, p = 0.013). Conclusion: Low skeletal muscle mass is a negative factor for survival outcomes in mCRC patients treated with salvage-line chemotherapy.

Recent findings indicate CD169-positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti-cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer-specific survival (CSS). The density of tumor-infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity-related genes that are up-regulated by interferon in macrophages as well as CD169. Indoleamine 2,3-dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti-cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti-cancer immune reactions.

Aim This study aimed to investigate the prognosis after recurrence in patients with stage I–III colon cancer (CC) and rectal cancer (RC). Methods Cancer recurred in 116 (15.2%) out of 763 patients with stage I–III colorectal cancer. The overall survival (OS) after recurrence was evaluated based on the recurrence organs and patterns. Results The first recurrence occurred in the lungs, livers, lymph nodes, and other sites in 32, 22, 12, and 2 patients, respectively. It was localized, disseminated, and involved two or more organs in 14, 9, and 25 patients, respectively. Patients with CC had a shorter OS after recurrence as compared to those with RC (P = .0103). Compared to other organ metastasis, liver metastasis was associated with an earlier recurrence (P = .0026) and shorter OS after recurrence (hazard ratio [HR]: 2.216; 95% confidence interval [CI]: 1.052–4.459; P = .0370). Lung metastasis was associated with a more favorable prognosis as compared to other organ recurrences (HR: 0.338; 95% CI: 0.135–0.741; P = .0057). One‐organ recurrence and oligometastasis were observed in 78.4% and 49.1% of the patients, respectively. The 5‐y OS rates of patients with one‐organ recurrence and oligometastasis were 47.5% and 71.7%, respectively. Invasive treatment was associated with a favorable prognosis (P, One organ recurrence was observed in 78.4% of patients and oligometastasis in 49.1%. The 5‐y OS rates of patients with one organ recurrence and oligometastasis were 47.5% and 71.7%, respectively. Invasive treatment was associated with a favorable prognosis (P

Iron deficiency anemia is represented in colorectal cancer (CRC) patients. Iron surplus load to increase non-transferrin bound iron (NTBI), and NTBI promotes cancer progression and influences microbiota. This study investigated whether preoperative serum iron status was associated with prognosis after CRC resection.We evaluated preoperative iron and transferrin saturation (TSAT), which was calculated as iron divided by total iron-binding capacity, in 327 patients who underwent surgery for Stage II-III CRC. Fe 60 μg/dl and TSAT 40% were defined as low and high iron, respectively. The associations between iron status and overall survival (OS) were evaluated in univariate and multivariate Cox proportional hazards analysis.Of the 327 patients, 179 (54.7%), 124 (37.9%) and 24 (7.3%) had low, normal and high iron, respectively. In univariate analysis, low iron was associated with shorter OS (hazard ratio [HR] 2.821, 95% confidence interval [CI] 1.451-5.485, P = 0.002). High iron was also associated with shorter OS (HR 3.396, 95% CI 1.359-8.489, P = 0.009). In multivariate analysis, high age (P = 0.002), depth of invasion pT4 (P = 0.012), lymph-node metastasis presence (P = 0.035), low albumin (P = 0.011), low iron (HR 2.282, 95% CI 1.163-4.478, P = 0.016) and high iron (HR 3.757, 95% CI 1.486-9.494 P = 0.005) were independently associated with shorter OS. High iron was associated with the amount of intratumoral Fusobacterium nucleatum compared with normal iron.Both low and high preoperative iron in Stage II-III CRC patients were associated with unfavorable OS in univariate and multivariate analyses.

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.

Radiofrequency ablation (RFA) can be a minimally invasive therapeutic option in patients with lung metastasis from colorectal caner. We aimed to elucidate the safety and survival benefit of computed tomography (CT)-guided percutaneous RFA for lung metastasis from colorectal cancer. A total 188 lesions were ablated in 43 patients from 2005 to 2017. The clinicopathological and survival data of patients were collected retrospectively. The short- and long-term outcomes and prognostic factors were analyzed. Eight patients (18.6%) had viable extrapulmonary metastasis at RFA treatment. The median number of treated lung tumors was 2, and the median maximum diameter was 12 mm. Complications, such as pneumothorax, pleural effusion and subcutaneous emphysema, occurred in 24 (55.8%) patients. Although chest tube drainage for pneumothorax was needed in 6 patients (14.0%), there were no mortalities. Repeated RFA for lung recurrence after primary RFA was performed in 14 patients (32.6%). In a median follow-up of 24.3 months, the median progression-free and overall survival (OS) were 6.8 months and 52.7 months, respectively. The presence of extrapulmonary metastasis and a maximum tumors size of > 15 mm were independently associated with a worse disease-free survival and OS. The OS of patients who underwent repeated RFA was significantly better than that of patients who underwent RFA only once. CT-guided percutaneous RFA for lung metastasis from colorectal cancer is a safe and effective procedure in patients not eligible for surgery, particularly for lesions smaller than 1.5 cm without extrapulmonary metastasis.

This study investigated the predictors associated with early recurrence (i.e. within 12 months) after curative gastrectomy for gastric cancer (GC). We evaluated the clinicopathological factors in 429 patients who underwent curative gastrectomy for GC without preoperative chemotherapy and analyzed these factors’ associations with early recurrence. Of 429 patients, 57 experienced recurrences, which were associated with gender, diameter, depth of invasion, lymph node (LN) metastasis, the LN ratio (LNr; LNs with metastasis/dissected LNs), lymphatic invasion, vascular invasion, carbohydrate antigen 19-9 (CA19-9) levels, C-reactive protein levels and the neutrophil/lymphocyte ratio. Twenty-one patients (36.8%) recurred within 12 months. Early recurrence was associated with a high LNr (P = 0.0020) and high CA19-9 levels (P = 0.0415). The other factors were not significantly associated with early recurrence. The 12-month recurrence rate was 33.9% in patients with a high LNr and 1.9% in those with a low LNr and 20.3% in patients with high CA19-9 levels and 3.5% in those with low CA19-9 levels. The 12-month recurrence rate was 62.5% in patients with a high LNr and high CA19-9 levels, 18.4% in those with a high LNr or high-CA19-9 levels, and 1.4% in those with a low LNr and low CA19-9 levels. LNr ≥ 0.15 and CA19-9 ≥ 37 U/ml were effective surrogate markers for predicting early recurrence.

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.

Patients with gastric cancer (GC) are affected by changes in iron status. Before surgery, GC patients are likely to have iron-deficiency anemia; and after gastrectomy, patients suffer from low nutritional status and low iron. This study investigated preoperative iron status associated with prognosis after curative gastrectomy for gastric cancer. We evaluated preoperative serum hemoglobin (Hgb), Fe and total iron-binding capacity (TIBC) in 298 patients who underwent curative gastrectomy for GC without preoperative chemotherapy, and analyzed these factors’ associations with prognosis after surgery. Of the 298 patients, 129 (43.2%) had low Hgb levels, and 33 (11.1%) had low TIBC (

Programmed death ligand 1 (PD-L1) expression as a predictive biomarker for programmed cell death 1 (PD-1) inhibitor efficacy in gastric cancer (GC) remains controversial. We hypothesised that the conflicting results may be due to the inaccurate assessment of PD-L1 expression using biopsy samples. A total of 191 patients with GC who received radical resection were enrolled. PD-L1 expressions in biopsy and paired resected samples by immunohistochemistry staining were compared according to the number of biopsies. The numbers of PD-L1-positive patients determined by biopsy and resected samples were 89 (46.6%) and 135 (70.1%), respectively. The accordance rate was 64.4% (κ = 0.31). Single biopsy showed a lower accordance rate compared with multiple biopsies. Our study revealed that single biopsy cannot fully reflect PD-L1 expression in the whole tumour in GC. Multiple biopsies are recommended for accurate diagnosis of PD-L1 expression in GC.

The neutrophil-to-lymphocyte ratio (NLR) has been reported to predict the prognosis of various malignant tumors, including esophageal cancer. However, no previous reports have supported the use of the preoperative NLR as an independent prognostic marker focused on superficial (T1) esophageal cancer. The aim of this study was to elucidate the prognostic impact of the preoperative NLR in T1 esophageal cancer. This retrospective study recruited 245 consecutive patients with T1 esophageal cancer who underwent subtotal esophagectomy between 2005 and 2016. The relationship between the preoperative NLR and clinicopathological characteristics was analyzed. The preoperative NLR was significantly higher in male patients (p = 0.029), patients with T1b esophageal cancer (p = 0.0274), and patients with venous vessel invasion (p = 0.0082). In the Kaplan–Meier analysis, the elevated preoperative NLR was significantly associated with a poorer disease-free survival (p

The aim of this study was to elucidate the risk factors for and prognostic value of lateral pelvic lymph node (LPLN) metastasis in advanced rectal cancer patients, including those with stage IV disease. The treatment outcomes of 78 patients with advanced rectal cancer, the lower margin of which was located at or below the peritoneal reflection, who underwent curative-intent surgery with bilateral LPLN dissection from 2005 to 2018 were retrospectively analyzed. In total, 78 rectal cancer patients, including 13 patients with stage IV tumors, 9 patients (11.5%) had LPLN metastasis. A multivariate analysis to identify preoperative clinical factors associated with LPLN metastasis showed that tumor location (below the peritoneal reflection: Rb), LPLN metastasis on preoperative imaging and distant metastasis were independent predictors of LPLN metastasis. In addition, metastasis at the regional lymph nodes in the mesorectum was significantly associated with LPLN metastasis. Both the disease-free survival (DFS) and cancer-specific survival (CSS) of patients with LPLN metastasis were significantly worse in comparison to patients without LPLN metastasis, and the CSS of stage IV patients with LPLN metastasis was significantly worse in comparison to stage IV patients without LPLN metastasis. Tumor location (Rb), LPLN metastasis on preoperative imaging and distant metastasis were risk factors for LPLN metastasis. The prognosis of rectal cancer patients with LPLN metastasis is poor. There may not be the indication of LPLN dissection in stage IV lower rectal cancer except cases having complaints due to LPLN metastasis.

Respiratory morbidity is common after esophagectomy and can be a major cause of surgery-related mortality. Thus, it is important to identify novel predictors that can preoperatively estimate the incidence of postoperative respiratory morbidity. Asymptomatic sputum in the respiratory tract is sometimes observed on preoperative computed tomography (CT). This study aimed to determine the clinical importance of sputum in the respiratory tract as a predictor of postoperative morbidity after esophagectomy for esophageal cancer. The study included 609 consecutive patients who underwent three-incisional esophagectomy for esophageal cancer between April 2005 and November 2018. Among the patients, 76 (12.5%) had sputum in the respiratory tract on preoperative CT. This finding was significantly associated with older age, more extreme smoking habit, worse performance status, lower forced expiratory volume 1%, and more frequent pulmonary comorbidities. Additionally, the incidence of postoperative pneumonia was higher in these patients than in those without sputum (16 vs 8%, p = 0.028). Sputum in the main bronchus was associated with higher frequencies of morbidity of Clavien–Dindo classification (CDc) ≥ II (p = 0.019), severe morbidity of CDc ≥ IIIb (p = 0.058), pneumonia (p = 0.10), and pulmonary morbidity (p = 0.19) compared with the finding of sputum in the trachea alone. On multivariate analysis, sputum in the respiratory tract was an independent risk factor (hazard ratio, 2.07; 95% confidence interval, 1.019–4.207; p = 0.044) for postoperative pneumonia. Sputum in the respiratory tract is a novel predictor of postesophagectomy pneumonia. Patients with sputum in the more distal respiratory tract might have high risk of postoperative morbidities.

Few reliable prognostic markers have been established despite elucidation of the molecular mechanisms of gastrointestinal stromal tumor (GIST) development. We evaluated F-box and WD repeat domain-containing 7 (FBXW7), a cell-cycle-regulating and tumor suppressor, in GISTs. We aimed to determine the clinical relevance of FBXW7 in GISTs and characterize the molecular mechanism of FBXW7 in a GIST cell line. We measured FBXW7 expression in 182 GIST cases, correlated the expression levels with clinicopathological features, and characterized the molecular mechanism underlying suppressed FBXW7 expression in GIST cells in vitro. Of the 182 GISTs, 98 (53.8%) and 84 (46.2%) were categorized in the high and low FBXW7 expression groups, respectively. Compared with the high FBXW7 expression group, the low expression group showed a significantly poorer prognosis in terms of recurrence-free (P = 0.01) and overall (P = 0.03) survival. FBXW7 expression was a significant independent factor affecting the 10-year recurrence-free survival rate (P = 0.04). In vitro, FBXW7-specific siRNAs enhanced c-myc and Notch 1 protein expression and upregulated cell proliferation, invasion, and migration. FBXW7 is a potential predictive marker of recurrence after curative resection of GISTs. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely compared with a conventional risk stratification model.

To determine whether prognostic nutritional index (PNI) affects clinical outcome through local immunity in esophageal cancers.PNI is an indicator of nutritional status and systemic immune competence, and has attracted attention as a prognostic biomarker. Tumor-infiltrating lymphocytes (TILs) are a specific histological feature of human cancers, reflecting an individual's immunological tumor response.Using a nonbiased database of 337 curatively resected esophageal cancers, we evaluated the relationship between PNI, TILs status, CD8 expression by immunohistochemical staining, and clinical outcome.Compared with PNI-high cases (n = 220), PNI-low cases (n = 117) showed significantly worse overall survival (log-rank P0.001; hazard ratio: 2.23; 95% confidence interval: 1.56-3.18; P0.001; multivariate hazard ratio: 1.67; 95% confidence interval: 1.14-2.44; P = 0.008). The TILs status was also significantly correlated with overall survival (P0.001). In addition, PNI was significantly associated with TILs status (P0.001) and the CD8-positive cell count (P = 0.041). A significant relationship between the peripheral blood lymphocyte count and TILs status was also observed (P0.001).PNI and TILs score expression were associated with clinical outcome in esophageal cancer, supporting their roles as prognostic biomarkers. Considering the relationship between PNI and TILs, nutritional status and systemic immune competence may influence patient prognosis through local immune response.

Double tract reconstruction (DT) after proximal gastrectomy (PG) is considered beneficial for postoperative nutrition status by preserving the physiological passage of food. We conducted this study to assess postoperative nutrition status based on food passage after this operation. The subjects of this retrospective study were 63 patients who underwent PG with DT. The patients were divided into two groups according to whether they had postoperative malnutrition (PM) 1 year postoperatively (PM group) or not (non-PM group). PM was defined by both weight loss > 10% and a low body mass index of

Recent findings indicate CD169-positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti-cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer-specific survival (CSS). The density of tumor-infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity-related genes that are up-regulated by interferon in macrophages as well as CD169. Indoleamine 2,3-dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti-cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti-cancer immune reactions.

A simple and cost-effective cholinesterase assay is presented. Thiocholine (TCh), which is generated from substrates by the action of cholinesterase, promotes the electron transfer between [Fe(CN)6]3–/4– and Au electrodes. The electric current increases with the TCh concentration; therefore, the current decreases when cholinesterase is inhibited by neurotoxic chemicals, such as organophosphorus and carbamate compounds. First, we monitored the responses of acetylcholinesterase to cholinesterase inhibitors. The substrate acetylthiocholine was digested with acetylcholinesterase in Tris−HCl buffer, then the reaction mixture was combined with acetonitrile. A polished Au electrode was immersed in the mixed solution for 30 s to immobilize the enzymatic hydrolysis product, TCh, on the electrode surface. The electrode was then subjected to differential pulse voltammetry in 0.5 mM [Fe(CN)6]3– in the presence of KCl as a supporting electrolyte, with a concentration as low as 1 mM. The optimum conditions for the enzymatic treatment were for 10 min at 30 °C with 1.25 mU/mL acetylcholinesterase and 100 μM acetylthiocholine as final concentrations. The inhibition of acetylcholinesterase activities from DDVP (organophosphorus) and methomyl (carbamates) could be monitored. This system was applied to human serum samples containing butyrylcholinesterase. The inhibition of butyrylcholinesterase by DDVP and methomyl were successfully monitored even in human serum. Finally, real human blood donated by 10 volunteers were subjected to a cholinesterase assay using this system. The results from the present method showed good correlation with those obtained from the conventional method using 5,5′-dithiobis-(2-nitrobenzoicacid). The present method was considered valid as a novel ChE assay for human blood.

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Recently, depletion of skeletal muscle mass (sarcopenia) has been linked to poor prognosis in several types of cancers, but has not been investigated in esophageal squamous cell carcinoma (ESCC). This retrospective study investigates the relationship between sarcopenia and clinical outcome in ESCC patients treated by surgical resection or definitive chemoradiation therapy (dCRT). The study was retrospectively conducted in a single academic hospital in Kumamoto, Japan, and involved 325 ESCC patients (256 surgical cases and 69 dCRT cases) treated between April 2005 and April 2011. Skeletal muscle mass was quantified by radiologic measures using standard computed tomography scans. The skeletal muscle tissue in the 325 ESCC patients was distributed as follows: mean: 47.10; median: 46.88; standard deviation (SD): 7.39; range: 31.48-71.11; interquartile range, 46.29-47.90. Skeletal muscle tissue was greater in male patients than in female patients (P < 0.0001), but was independent of other clinical and tumor features. Sarcopenia was not significantly associated with overall survival (log rank P = 0.54). Lymph node involvement significantly altered the relationship between sarcopenia and survival rate (P for interaction = 0.026). Sarcopenia significantly reduced the overall survival of patients without lymph node involvement (log rank P = 0.035), but was uncorrelated with overall survival in patients with lymph involvement (log rank, P = 0.31). The anastomosis leakage rate was significantly higher in the sarcopenia group than in the non-sarcopenia group (P = 0.032), but other surgical complications did not significantly differ between the two groups. Sarcopenia in ESCC patients without lymph node involvement is associated with poor prognosis, indicating sarcopenia as a potential biomarker for identifying patients likely to experience an inferior outcome. Moreover, sarcopenia was associated with anastomosis leakage but no other short-term surgical outcome.

As cancer advances, changes in the systemic inflammatory response alter the relative levels of circulating white blood cell types and may contribute to the progression and outcomes of cancer. The aim of the current study is to clarify the impact of the preoperative neutrophil/lymphocyte ratio (NLR) on the prognosis and whether clinical and pathological features modify the influence of the NLR on the prognosis of esophageal squamous cell carcinoma (ESCC) patients. We retrospectively analyzed the mortality hazard ratios (HRs), including the preoperative NLR, obtained from data for 283 ESCC patients undergoing resection in the period from 2005 to 2011, adjusting for clinical and pathological features. A high NLR was associated with a significantly shorter overall survival (p = 0.0018) and cancer-specific survival (p = 0.0097). In the multivariate Cox model, we confirmed that the NLR was an independent prognostic marker for both overall survival (p = 0.0081) and cancer-specific survival (p = 0.028). The outcomes were not significantly modified by other diagnostic factors, including the tumor stage, in the survival analysis. The preoperative NLR is significantly associated with a poor prognosis in patients with ESCC, suggesting the utility of NLR as a cost-effective and broadly available independent prognostic marker of ESCC.

Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.

Evidence suggests that minimally invasive esophagectomy has several advantages with regard to short-term outcomes, compared to open esophagectomy in esophageal cancer patients. However, the impact of minimally invasive esophagectomy on long-term respiratory function remains unknown. The objective of this study is to assess the association between use of the minimally invasive esophagectomy and long-term respiratory dysfunction in esophageal cancer patients after esophagectomy. This retrospective single institution study using prospectively collected data included 87 consecutive esophageal cancer patients who had undergone esophagectomy. All patients underwent a respiratory function test before, and one year after esophagectomy. Logistic regression analysis was used to compute the hazard ratio for long-term respiratory dysfunction. Minimally invasive esophagectomies were performed in 53 patients, and open esophagectomies in 34 patients. The two groups showed no significant differences in terms of postoperative complications and postoperative course. Nor were any differences observed between the two groups in terms of volume capacity (L) and forced expiratory volume 1.0 (L) before esophagectomy (P > 0.34). However, one year after esophagectomy, the decreases in volume capacity and forced expiratory volume 1.0 were significantly less in the minimally invasive esophagectomy group than in the open esophagectomy group (P = 0.04 and P = 0.007, respectively). Multivariate analyses revealed that minimally invasive esophagectomy was an independent favorable factor for maintenance of forced expiratory volume 1.0 (hazard ratio = 0.17, 95% confidence interval 0.04-0.71; P = 0.01). Minimally invasive esophagectomy may be an independent favorable factor for maintenance of long-term respiratory function in esophageal cancer patients after esophagectomy.

The adenoma-carcinoma sequence, the sequential mutation and deletion of various genes by which colorectal cancer progresses, is a well-established and accepted concept of colorectal cancer carcinogenesis. Proteins of the polycomb repressive complex 2 (PRC2) function as transcriptional repressors by trimethylating histone H3 at lysine 27; the activity of this complex is essential for cell proliferation and differentiation. The histone methyltransferase enhancer of zeste homolog 2 (EZH2), an essential component of PRC2, is associated with the transcriptional repression of tumor suppressor genes. EZH2 expression has previously been reported to increase with the progression of pancreatic intraductal papillary mucinous neoplasm. Thus, we hypothesized that EZH2 expression also increases during the adenoma-carcinoma sequence of colorectal cancer. The present study investigated changes in EZH2 expression during the colorectal adenoma-carcinoma sequence. A total of 47 patients with colorectal adenoma, 20 patients with carcinoma in adenoma and 43 patients with colorectal carcinoma who underwent surgical or endoscopic resection were enrolled in this study. Non-cancerous tissue from the clinical specimens was also examined. The association between EZH2 expression, pathology and expression of tumor suppressor genes during colorectal carcinogenesis were analyzed. Each specimen was immunohistochemically stained for EZH2, proliferation marker protein Ki-67 (Ki-67), cyclin-dependent kinase inhibitor (CDKN) 1A (p21), CDKN1B (p27) and CDKN2A (p16). Total RNA was extracted from formalin-fixed paraffin-embedded blocks and reverse transcription-quantitative polymerase chain reaction analysis of these genes was performed. Ki-67 and EZH2 expression scores increased significantly during the progression of normal mucosa to adenoma and carcinoma (P=0.009), and EZH2 expression score was positively associated with Ki-67 expression score (P=0.02). Conversely, p21 mRNA and protein expression decreased significantly, whereas expression of p27 and p16 did not change significantly. During the carcinogenesis sequence from normal mucosa to adenoma and carcinoma, EZH2 expression increased and p21 expression decreased significantly. EZH2 may therefore contribute to the development of colorectal cancer from adenoma via suppression of p21.

Background: Immunotherapies targeting the PD-1/PD-L1 pathway have emerged as promising therapeutic strategies for many cancers. PD-L1 and PD-L2 are ligands of PD-1 on T-cells and prevent T-cells activation and proliferation. There have been reported that PD-L1 and PD-L2 are expressed on not only antigen-presenting cells but also some types of tumors. Clinical and prognostic features of the PD-L1 have been widely reported for many types of cancers but those of PD-L2 remain unclear in esophageal cancer. The aim of this study was to analyze the clinical significance and the difference between PD-L1 and PD-L2 in esophageal cancer. Methods: Using a database of 437 curatively resected esophageal cancer from April 2005 to March 2016, we evaluated PD-L1 and PD-L2 expression in tumor cells by immunohistochemical staining and analyzed the association between those with clinicopathological features. Double immunohistochemical staining for PD-L1 and PD-L2 was performed to confirm the localization of each positive cell. Results: Out of 437 cases of esophageal cancer, 69 cases (15.8%) showed PD-L1 positive and 71 cases (16.2%) showed PD-L2 positive expression. There was no significant relationship between PD-L1 and PD-L2 positive cases (p=0.18). In both PD-L1 and PD-L2 positive cases, double immunohistochemical staining for PD-L1 and PD-L2 showed that there was a heterogeneity for PD-L1 and PD-L2 positive tumor cell. PD-L1 positive cases were significantly associated with tobacco use (p=0.013), pathological stage (p=0.001), and preoperative therapy present cases (p=0.015). In the other hand, PD-L2 positive cases were significantly associated with younger age (p=0.029). Thus PD-L1 and PD-L2 patient characteristics were likely different. Overall survival rates of the patients with PD-L1 or PD-L2 positive were significantly worse than those with PD-L1 or PD-L2 negative (p=0.009 and p=0.013, respectively). Conclusion: There was no significant relationship between PD-L1 and PD-L2 expression, and patient characteristics of those were different in patients with esophageal cancer. But both PD-L1 and PD-L2 expression were significantly associated with prognosis, supporting their roles as prognostic biomarkers. Citation Format: Kazuo Okadome, Yoshifumi Baba, Taisuke Yagi, Yuki Kiyozumi, Kojiro Eto, Yukiharu Hiyoshi, Yohei Nagai, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Clinical significance and the difference between programmed death-1 ligand-1 and ligand-2 in patients with esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4123.

Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery.

Neuroendocrine tumors are neoplasms with various pathologic features. They occur in many areas such as the pituitary gland, digestive tract, and lung. Here, we report the case of a 68-year-old man who developed a neuroendocrine tumor in the Glissonean pedicle of the hepatic hilum. At a routine medical screening, the patient was found to have a hepatic tumor adjacent to the portal bifurcation measuring 2.0 cm in diameter. Results of laboratory and imaging studies were highly suggestive of well-differentiated hepatocellular carcinoma. The patient underwent excision of the tumor, which was located within the Glissonean pedicle. On immunohistochemical examination, the tumor was positive for synaptophysin, chromogranin A, and CD56 immunostaining. The final pathologic diagnosis was low-grade neuroendocrine tumor, according to the World Health Organization’s WHO Classification of Tumours of the Digestive System. The patient is doing well, with no evidence of recurrence, more than 1 year after the operation.

Trastuzumab in combination with cisplatin and capecitabine could be a new standard treatment for patients with HER2-positive advanced gastric cancer. We herein report a case of advanced gastric cancer with peritoneal dissemination that was successfully treated with trastuzumab combined with cisplatin and capecitabine followed by gastrectomy. A 49-year-old man complained of epigastric pain and was diagnosed with advanced gastric cancer. A staging laparoscopy revealed peritoneal dissemination that was overexpressing HER2 protein. After five courses of chemotherapy comprising trastuzumab, cisplatin and capecitabine, laparoscopic restaging was performed. The disseminated nodules had disappeared, and biopsy of the scar of peritoneal seeding and cytology of the peritoneal lavage fluid both found no malignant cells. Therefore, total gastrectomy with D2 lymph node dissection was performed. Pathologically, there were no residual tumor cells in the resected stomach or peritoneal wall. Trastuzumab in combination with chemotherapy may have curative potential for peritoneal dissemination from HER2-positive gastric cancer.

Pneumonia is a major cause of postesophagectomy mortality and worsens the long-term survival in resected esophageal cancer patients. Moreover, preoperative treatments such as chemotherapy or chemoradiotherapy (which have recently been applied worldwide) might affect the bacterial flora of the sputum. To investigate the association among preoperative treatments, the bacterial flora of sputum, and the clinical and pathological features in resected esophageal cancer patients, this study newly investigates the effect of preoperative treatments on the bacterial flora of sputum. We investigated the association among preoperative treatments, the bacterial flora of sputum, and clinical and pathological features in 163 resected esophageal cancer patients within a single institution. Pathogenic bacteria such as Candida (14.1%), Staphylococcus aureus (6.7%), Enterobacter cloacae (6.1%), Haemophilus parainfluenzae (4.9%), Klebisiella pneumoniae (3.7%), Methicillin-resistant Staphylococcus aureus (MRSA) (3.7%), Pseudomonas aeruginosa (2.5%), Escherichia coli (1.8%), Streptococcus pneumoniae (1.8%), and Haemophilus influenzae (1.2%) were found in the sputum. The pathogen detection rate in the present study was 34.3% (56/163). In patients with preoperative chemotherapy and chemoradiotherapy, the indigenous Neisseria and Streptococcus species were significantly decreased (P= 0.04 and P= 0.04). However, the detection rates of pathogenic bacteria were not associated with preoperative treatments (all P> 0.07). There was not a significant difference of hospital stay between the sputum-monitored patients and unmonitored patients (35.5 vs. 49.9 days; P= 0.08). Patients undergoing preoperative treatments exhibited a significant decrease of indigenous bacteria, indicating that the treatment altered the bacterial flora of their sputum. This finding needs to be confirmed in large-scale independent studies or well-designed multicenter studies.

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5+ human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs.

// Kenichi Nakamura 1 , Yoshifumi Baba 1 , Keisuke Kosumi 1 , Kazuto Harada 1 , Hironobu Shigaki 1 , Keisuke Miyake 1 , Yuki Kiyozumi 1 , Mayuko Ohuchi 1 , Junji Kurashige 1 , Takatsugu Ishimoto 1 , Masaaki Iwatsuki 1 , Yasuo Sakamoto 1 , Naoya Yoshida 1 , Masayuki Watanabe 2 , Mitsuyoshi Nakao 3 , Hideo Baba 1 1 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan 2 Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 3 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan Correspondence to: Hideo Baba, email: hdobaba@kumamoto-u.ac.jp Keywords: LINE-1, methylation, esophageal cancer, prognosis, UHRF1 Received: March 24, 2016 Accepted: July 19, 2016 Published: August 05, 2016 ABSTRACT Background: Global DNA hypomethylation contributes to oncogenesis through various mechanisms. The level of long interspersed nucleotide element-1 (LINE- 1) methylation is considered a surrogate marker of global DNA methylation, and is attracting interest as a good predictor of cancer prognosis. However, the mechanism how LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully elucidated. Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays a crucial role in DNA methylation. UHRF1 is overexpressed in many cancers, and UHRF1 overexpression may be a mechanism underlying DNA hypomethylation in cancer cells. Nonetheless, the relationship between UHRF1, LINE-1 methylation level, and clinical outcome in esophageal squamous cell carcinoma (ESCC) remains unclear. Results: In ESCC cell lines, vector-mediated UHRF1 overexpression caused global DNA (LINE-1) hypomethylation and, conversely, UHRF1 knockdown using siRNA increased the global DNA methylation level. In ESCC tissues, UHRF1 expression was significantly associated with LINE-1 methylation levels. Furthermore, UHRF1 overexpression correlated with poor prognosis in our cohort of 160 ESCC patients. Materials and Methods: The relationships between UHRF1 expression and LINE-1 methylation level (i.e., global DNA methylation level) were investigated using ESCC tissues and cell lines. In addition, we examined the correlation between UHRF1 expression, LINE-1 methylation, and clinical outcome in patients with ESCC. Conclusions: Our results suggest that UHRF1 is a key epigenetic regulator of DNA methylation and might be a potential target for cancer treatment.