Purpose Evidence on how nutritional, inflammatory, and body composition indices change during adjuvant chemotherapy for stage II/III colorectal cancer (CRC) is limited. This study aimed to evaluate these longitudinal changes and identify preoperative predictors of treatment discontinuation and overall survival (OS). Methods This was a retrospective, single-center study of stage II/III CRC patients who were curatively resected and received adjuvant chemotherapy. Nutritional, inflammatory, and body composition indices (including body mass index [BMI], psoas muscle index [PMI], Psoas Muscle Density [PMD], modified Intramuscular Adipose Tissue Content [mIMAC], Geriatric Nutritional Risk Index [GNRI], Prognostic Nutritional Index [PNI], hemoglobin, albumin, lymphocyte, and platelet [HALP] score, neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR]) were obtained preoperatively and 6 months after initiating adjuvant chemotherapy. Subgroup analyses contrasted doublet therapy (CAPOX/FOLFOX) and monotherapy (S-1, UFT/LV, capecitabine). Results Among 142 patients (median age 67 years), several indices (BMI, GNRI, PNI, and HALP score) increased, whereas inflammatory indices (NLR and PLR) decreased from baseline to follow-up. Adjuvant therapy was discontinued in 45 patients (31.7%). Discontinuation predictors differed by regimen: for doublet therapy, poor preoperative nutritional/inflammatory status was significant, whereas for monotherapy, only older age was a predictor. Lower preoperative muscle quality (PMD, mIMAC), but not quantity (PMI), was significantly associated with poorer OS, while other nutritional/inflammatory indices were not. Conclusion Nutritional and inflammatory status was not uniformly worsened after adjuvant chemotherapy, with several indices showing improvement. Muscle quality indices were prognostic for OS, and preoperative nutritional/inflammatory indices helped identify patients at risk for discontinuation, especially for doublet therapy.

Table S1. Clinical Characteristics of multiple cohorts Table S2. Association of MSI-H subtypes with clinical and genomic characteristics in multiple cohorts Table S3. Association of dMMR subtypes with clinical characteristics in Cohort 4 Supplementary Figure S1. Prognostic significance of MSI/MMR status in patients with colorectal cancer. Supplementary Figure S2. Prognostic significance of TGFB expression in patients with MSI-H colorectal cancer. Supplementary Figure S3. Expression z-scores for genes encoding immune checkpoint molecules for MSI-H-Stromal, MSI-H-Conventional and MSS tumors in Cohort 1. Supplementary Figure S4. Correlation of TGFβ-stromal signature (TBSS) z-score with stage of disease in Cohort 2 (A) and Cohort 3 (B). Supplementary Figure S5. Expression z-scores for genes encoding transcription factors that regulate Th cell differentiation, including TBX21 (Th1), GATA3 (Th2) and RORC (Th17) for MSI-H-Stromal, MSI-H-Conventional and MSS tumors in Cohort 1 (A), Cohort 2 (B) and Cohort 3 (C). Supplementary Figure S6. Genomic aberrations in 43 TGFβ pathway genes, including TGFβ superfamily ligands, receptors and receptor-associated proteins, SMADs, and adaptor molecules. Supplementary Figure S7. Correlation between RNA-seq-based transcriptomic TBSS and mass spectrometry-based proteomic TBSS in the CPTAC dataset.

cancers worldwide. Although approximately 30% of patients with CRC are diagnosed with stage II disease, there remains a challenging question of how to best manage those patients after surgery. We have recently identified a promising candidate, the expression of KRT17 (Keratin 17, K17) that may robustly stratify postoperative patients with stage II CRC into high and low risk of disease recurrence [1].

Circulating tumor cells (CTCs) are known to be a systemic process of malignant progression of cancer cells and there is a possibility that analysis for CTCs as a liquid biopsy become predictive or prognostic tools for cancer patients. In the present study with the novel CTCs detection system (Celsee system®), we performed quantitative and qualitative analysis of CTCs in patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemotherapy (NAC) with 5FU + CDDP regimen. CTCs are defined as having both DAPI positive and CD45 negative. Vimentin-positive CTCs were defined as mesenchymal-type CTCs (M-CTCs), while epithelial-type CTCs (E-CTCs) were only positive for pan-cytokeratin. At the baseline, there are detectable amounts of CTCs in all patients (n = 30) at all stages, and there were no significant differences of total CTCs, E-CTCs, or M-CTCs numbers between stages. Of importance, among total CTCs, M-CTCs are more dominant than E-CTCs in number. Also, there was no significant change of detectable amounts and phenotype of CTCs before and after NAC (n = 24). Of note, early recurrent group indicated that there was an elevated total CTCs number before NAC and an increased M-CTCs after NAC in comparison to those in non-recurrent group. Quantitative and qualitative analysis of CTCs may provide useful complementary predictive and prognostic information in ESCC.

Abstract Patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer represent a biomarker-defined population with distinct clinicopathologic features who are susceptible to immune checkpoint inhibitors (ICI). However, their survival outcomes vary considerably and nearly half of them exhibit primary resistance to current ICIs, suggesting substantial molecular heterogeneity even among tumors with dMMR/MSI-H. We conducted an extensive analysis of the tumor microenvironment (TME) using multiple transcriptomic, proteomic, and IHC cohorts of colorectal cancer, comprising 222 dMMR/MSI-H and 1440 MMR-proficient/microsatellite stable tumors. We developed a TGFβ-responsive stromal gene signature and then identified a unique poor prognostic subgroup of patients with dMMR/MSI-H colorectal cancers, characterized by the upregulation of transcriptional programs, including the TGFβ-rich active TME, angiogenesis, M2 macrophage polarization, and the extracellular matrix signature predictive of ICI resistance. The TGFβ-dependent stromal subset within dMMR/MSI-H tumors exhibiting poor survival outcomes was further recapitulated by proteomic datasets and IHC for VCAN protein expressed by cancer-associated fibroblasts. Meanwhile, this dMMR/MSI-H stromal subgroup was enriched neither with CD8+ T-cell infiltration nor common genomic alterations, such as mutation density and BRAF mutations, compared with dMMR/MSI-H tumors without TGFβ-dependent stromal activation. In conclusion, this study revealed a novel stromal subgroup of patients with dMMR/MSI-H colorectal cancer, demonstrating a TGFβ-rich tumor-promoting TME and unfavorable survival outcomes. Implications: Dual inhibition of immune checkpoints and TGFβ signaling may offer a promising strategy for these patients.

BACKGROUND:Tuberculous peritonitis (TBP) is uncommon in Japan, and its diagnosis with conventional methods is time taking and requires a high clinical index of suspicion. Laparoscopy with peritoneal biopsy is a tool for rapid and accurate diagnosis of TBP. However, few cases have mentioned the infectious control and prevention during the perioperative period. This case is written following the SCARE scale for case report writing. CASE PRESENTATION:A 30-year-old man from Southeast Asia with a past medical history of pulmonary tuberculosis at 3-year-old admitted to our institution with abdominal pain and slight fever lasting for a week. With the elevation of inflammatory response and CA125, we conducted CT (Computed tomography). Not only ascites, panniculitis with peritoneal nodules, and the thickening of the omentum were found. Considering the possibility of malignancy and TBP, we performed a diagnostic laparoscopy. Slightly cloudy ascites, peritoneal and thickening omentum with white nodules were seen, and pathological diagnosis from the omentum during the operation raised the possibility of TBP due to its caseating granuloma and these findings allowed us to start the rapid treatment. CONCLUSION:We reported the effectiveness of diagnostic laparoscopy along with the aspect of perioperative prevention for TBP.

AT-rich interactive domain 1A ( ARID1A ) functions as a tumor suppressor and several therapeutic targets in ARID1A -mutated cancers are under development. Here, we investigated the prognostic value of ARID1A for gastric cancer and its association with expression of PD-L1 and p53. ARID1A expression was examined by immunohistochemistry and negative expression of ARID1A was detected in 39 (19.5%) of 200 cases in a test cohort and in 40 (18.2%) of 220 cases in a validation cohort. Negative expression of ARID1A was associated with worse overall survival in undifferentiated cases, particularly early-stage cases. Negative expression of ARID1A was detected in 11 (50%) of 22 PD-L1-positive cases and in 68 (17.1%) of 398 PD-L1-negative cases in a combined cohort. Negative expression of ARID1A was detected in 45 (22%) of 205 p53-positive cases and in 34 (15.8%) of 215 p53-negative cases in a combined cohort. In addition, expression of EZH2, a potential synthetic lethal target in ARID1A -mutated tumors, was detected in 79 ARID1A-negative cases. An ARID1A-knockdown gastric cancer cell line was subjected to microarray analysis, but no actionable targets or pathways were identified. The present results indicate that ARID1A may serve as an early-stage prognostic biomarker for undifferentiated gastric cancer.

BackgroundLynch syndrome, is an autosomal dominantly inherited disease that predisposes individuals to a high risk of colorectal cancers, and some mismatch-repair genes have been identified as causative genes. The purpose of this study was to investigate the genomic rearrangement of the gene in a family with Lynch syndrome followed for more than 45years.Case presentationThe family with Lynch syndrome is family N, who received colorectal cancer treatment for 45years. The proband of family N had multiple colorectal and uterine cancers. Because the proband met the diagnostic Amsterdam criteria and was Microsatellite instability (MSI) - positive, we performed genetic testing several times. However, germline mutations in MLH1 and MSH2 genes were not found by long-distance PCR or RT-PCR/direct sequencing analysis within the 45-year follow-up. MLPA analysis showed that the genomes of the proband and proband's daughter contained a deletion from exon 4 through exon 19 in the MLH1 gene. Her son's son and her daughter's son were found to be carriers of the mutation.ConclusionsFor carriers of mismatch-repair gene mutation among families with Lynch syndrome, the onset risk of associated cancers such as uterine cancer is particularly high, including colorectal cancer. The diagnosis of carriers among non-onset relatives is important for disease surveillance.

Adjuvant chemotherapy is considered for patients with stage II colorectal cancer (CRC) characterized by poor prognostic clinicopathological features; however, current stratification algorithms remain inadequate for identifying high-risk patients. To develop prognostic assays, we conducted a step-wise screening and validation strategy using nine cohorts of stage II patients based on multiple platforms, including microarray, RNA-sequencing (RNA-seq) and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tissues. Four microarray datasets (total n = 458) were used as the discovery set to screen for single genes associated with postoperative recurrence. Prognostic values of candidate genes were evaluated in three independent microarray/RNA-seq validation cohorts (n = 89, n = 93 and n = 183, respectively), and then IHC for KRT17 was conducted in two independent FFPE series (n = 110 and n = 44, respectively). We found that high levels of KRT17 transcript expression were significantly associated with poor relapse-free survival (RFS) not only in the discovery set, but also in three validation cohorts, and its prognostic impact was independent of conventional factors by multivariate analyses. Positive staining of KRT17 protein was significantly associated with poor RFS in two independent FFPE cohorts. KRT17 protein expression had independent prognostic impact on RFS in a multivariate model adjusted for conventional variables, including high-risk clinicopathological features. In conclusion, using nine independent cohorts consisting of 997 stage II patients, we identified and validated the expression of KRT17 transcript and KRT17 protein as a robust prognostic biomarker that can discriminate postoperative stage II patients who are at high probability of disease recurrence, providing additional prognostic stratification beyond the currently available high-risk factors.

Although rectovaginal fistula is a rare complication of rectal cancer surgery, it is usually difficult to cure with conservative treatment, and patients generally need surgical intervention. A woman in her 70s underwent laparoscopic low anterior resection with right lateral lymph node dissection for rectal cancer. On postoperative day(POD)6, she had an anastomotic leakage and received conservative treatment. On POD 9, she underwent emergent laparotomy for urinary peritonitis as well as ileostomy and ureteral stenting. On POD 21, the rectovaginal fistula was confirmed with lower gastrointestinal tract fluoroscopic examination. The patient received conservative therapy for the rectovaginal fistula with estriol vaginal tablets and vaginal lavage for 2 weeks. Subsequently, the fistula was completely cured. After continuation of the estriol vaginal tablets for 4 weeks, the rectovaginal fistula has not recurred at the most recent follow-up.

e14204 Background: Although a causal relationship for inflammation and immunity of cancer is more widely accepted today, the precise cell mechanisms mediating this relationship have not been elucidated. Accumulating evidence suggests that myeloid-derived suppressor cells (MDSC), may contribute to the negative regulation of immune responses during cancer and inflammation. IL-17 is a pro-inflammatory cytokine that is primarily secreted by T helper (Th)17 cells and we have reported that IL-17 correlates with immunosuppressive conditions in patients with cancer. Methods: PBMC (peripheral blood mononuclear cells) were harvested from 106 patients including 43 with gastric and 63 with colorectal cancer. PBMC were stimulated with PHA (phytohemagglutinin) and the production of IL-17 was measured by ELISA. MDSC were detected by flow cytometry (CD11b+,CD14-,CD33+). The levels of CRP (C-reacting protein) and NLR (neutrophil to lymphocyte ratio) were used as inflammatory markers. Results: Both of MDSC and IL-17 production were increased in patients with advanced stages, and correlated with each other, inflammatory markers and immune suppression. The patients were divided with average levels of MDSC and IL-17 production and the prognosis were analyzed with Kaplan-Meier method. The overall survival of patients with high MDSC or high IL-17 production were significantly worse than those with low MDSC or low IL-17 production, respectively, in patients with stages III and IV, although the differences were not significant in patients with stages I and II. Conclusions: Thus these inflammatory markers are closely related with systemic inflammation involving IL-17 and with immunosuppression driven by MDSC, and are effective prognostic indicators in patients with stages III and IV gastric and colorectal cancer.

Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). The study aimed to identify miRNAs that posttranscriptionally control PD-L1 expression on tumor cells and also regulate immune evasion. A comprehensive miRNA screening using The Cancer Genome Atlas (TCGA) dataset (n = 260) combined with eight different miRNA target prediction programs resulted in the identification of a tumor suppressive miRNA, miR-148a-3p, as a potential negative regulator of PD-L1 expression, particularly in dMMR/MSI-H colorectal cancer. Using multiple cohorts of colorectal cancer, including TCGA data, a microarray dataset (n = 148), and formalin-fixed, paraffin-embedded samples (n = 395), we found that the expression of miR-148a-3p was decreased in dMMR/MSI-H tumors, correlating inversely with PD-L1 levels. We demonstrate that miR-148a-3p directly binds to the 3'-untranslated region of PD-L1, thereby reducing whole-cell and cell surface PD-L1 levels in HCT116 and SW837 cell lines. Overexpression of miR-148a-3p repressed IFNγ-induced PD-L1 expression on tumor cells and consequently diminished T-cell apoptosis in a coculture model of IL2-activated T cells and IFNγ-treated tumor cells. In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer. IMPLICATIONS: This study provides novel evidence that miR-148a-3p negatively regulates tumor cell PD-L1 expression and decreased levels of miR-148a-3p contributes to the immunosuppressive tumor microenvironment.

Introduction Recently in Japan, Ramucirumab (RAM) became the first anti-angiogenic agent to be approved for second-line treatment of gastric cancer. In the present study, we aimed to evaluate the efficacy and safety of RAM plus paclitaxel (PTX) in patients with unresectable and recurrent gastric cancer in our institution.Patients and Methods The subjects were 11 patients with unresectable and recurrent gastric cancer who received RAM plus PTX as a second- or later-line treatment at our hospital between June 2015 and September 2017, after the failure of previously-attempted treatments. We assessed the efficacy and safety of RAM plus PTX, and also compared them between patients aged <75 years (n=6) and those aged ≥75 (n=5), by performing a retrospective analysis based on the data obtained from daily clinical practice for gastric cancer treatment.Results Objective tumor response was observed in one of the 11 patients (9.1%) with partial response, and disease control was seen in the remaining 10 (90.9%). The median overall survival (OS) and progression-free survival (PFS) of the patients were 20.8 months (95% CI 7.8-NA (not applicable)) and 11.3 months (95% CI 6.5-NA), respectively. There were no serious adverse events. The median OS for the <75 years group and ≥75 years group was NA (due to short follow-up period) and 20.8 months (p = 0.336), respectively, and their respective median PFS rates were 9.4 and 11.3 months (p = 0.492). The difference of rate of adverse events was not significant between the two age groups in the present study, though the number of adverse events was not sufficient.Conclusion The results of the present study suggest that the combination chemotherapy of RAM and PTX was effective in unresectable and recurrent gastric cancer patients as a second- or later-line therapy, and has been shown to be safe and feasible in elderly patients.

We report 2 cases of superficial non-ampullary duodenal tumor resected using laparoscopic endoscopic cooperative surgery( LECS). A man in his5 0's underwent screening esophagogastroduodenoscopy. Endoscopy revealed a 0-Ⅱc lesion at the anal side of the papilla of Vater that measured 5 mm. We performed LECS, and pathologic examination revealed tubular adenoma with no tumor cellsat the edge of the specimen. A man in his 80's underwent screening esophagogastroduodenoscopy. Endoscopy revealed a 0-Ⅱc lesion at the posterior wall above the papilla of Vater that measured 10 mm. The biopsy showed a well-differentiated adenocarcinoma. We performed LECS, and the pathological examination revealed a tubular adenocarcinoma in the mucosal layer with no carcinoma cells at the edge of the specimen. As the treatment strategy for superficial duodenal tumors has not established yet, further accumulation of cases and investigation are necessary.

Cancer vaccines and immune checkpoint inhibitors (ICI) have recently been employed as immunotherapies for esophageal squamous cell carcinoma (ESCC). Cancer vaccines for ESCC have yielded several promising results from investigator-initiated phase I and II clinical trials. Furthermore, a Randomized Controlled Trial as an adjuvant setting after curative surgery is in progress in Japan. On the other hand, ICI, anti-CTLA-4 mAb and anti-PD-1 mAb, have demonstrated tumor shrinkage and improved overall survival in patients with multiple cancer types. For ESCC, several clinical trials using anti-PD-1/anti-PD-L1 mAb are underway with several recent promising results. In this review, cancer vaccines and ICI are discussed as novel therapeutic strategies for ESCC.

A 74-year-oldman underwent transthoracic esophagectomy andgastric tube reconstruction for esophageal cancer 15 years ago. Eleven years after the esophagectomy, he was diagnosedwith gastric tube cancer. He receivedproton beam irradiation therapy. Macroscopic clinical effect revealed complete response at that time. Four years later, due to his discomfort symptom, he was diagnosedwith recurrent gastric tube cancer. Total resection of the gastric tube was performedat our hospital. In pathology findings, poorly differentiated adenocarcinoma was found at the proton beam irradiated part with multiple lymph node metastases in the omentum. He died 8 months postoperatively because of carcinomatous pleurisy. Periodic screening of the gastric tube and early detection of gastric tube cancer at early stage are important.

Circulating tumor cells (CTCs) in patients with malignant tumors can be used as a prognostic marker. Recently the existence of mesenchymal CTCs have been detected by new methods. However, it has been not yet clarified how CTCs are associated with the treatment effects in esophageal cancer patients. We assessed CTCs in esophageal cancer patients and investigated the relationship between CTCs and treatment effect. Seven patients who had potential of curative resection have been enrolled and peripheral blood samples (10ml) were collected before and after treatment. All patients received chemotherapy (5-FU and cisplatin) and four patients of them received as neoadjuvant therapy. Other patients received only chemotherapy and radiation therapy without operation. CTCs were analyzed using a Microfluidic Chip devise provide with the Nihon Gene Research Laboratories. This system can isolates CTCs from blood samples, based on their size and deformability differences from blood cells. Phenotypes of CTCs are determined by staining and scanning systems. A previous report revealed that this method had higher sensitivity for CTCs than conventional methods (the Cell Search system) in 61 metastatic breast cancer. Treatments effects were stable disease or better in all cases. Multiple CTCs were detected in all cases before treatment. Five patients had epithelial CTCs and others had only mesenchymal CTCs. Total number of CTCs after treatment whose data can be available decreased except for two cases. One patient had no CTC after treatment. Two cases have been currently analyzing. CTCs may exist almost all patients of Stage II or more esophageal cancer. Decreasing the number of CTCs after treatment suggests some relationship between CTCs and treatment effect, and the accumulation of more cases is necessary. All authors have declared no conflicts of interest.

A case complicated with colorectal and prostate cancers in paraneoplastic(subacute)cerebellar degeneration(PCD)is extremely rare. We report a retrospective case of rectal carcinoma with paraneoplastic cerebellar degeneration. A 79-year-old man with Parkinson's disease was unable to walk because of paralysis. Brain MRI showed cerebellar atrophy. He was admitted to our hospital for anal bleeding and was diagnosed with colon cancer. An associated diagnosis of PCD was made. After resection, his paralysis and dysarthria were resolved to the extent of beingable to walk and speak fluently. Brain MP-RAGE showed no findings suggestive of metastasis or atrophy. He was treated surgically, which resulted in a transient improvement in PCD symptoms. Per blood testing, cytokines IL-6 and IL-10 were lower postoperatively. Immunosuppressive levels of myeloid- derived suppressor cells(MDSCs)were lower compared with the preoperative values. Thus, innate immunocompetence and resolution of paralysis followed the surgical intervention.

performed among patients with IHC from years 2004 to 2014.The median age of patients who had procedure was 66 years (Interquartile rage (IQR); 57-76).The number of procedures increased from 412 to 1055 (p<0.05) with greater than 90% being resections.During the time period there was a reduction in mortality and length of stay p<0.05.Conclusions: There has been a concordant increase in surgery for IHC with the increasing incidence of IHC.During the study period there was an improvement in mortality and length of stay. Tu1579