Identification of a unique subset of tissue-resident memory CD4+ T cells in Crohn's disease.

T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4+ tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4+ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4+ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4+ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4+ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Histological differentiation between sporadic and colitis-associated intestinal cancer in a nationwide study: A propensity-score-matched analysis.

BACKGROUND AND AIM: Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC. METHODS: We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data. RESULTS: A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01). CONCLUSION: CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer.

BACKGROUND: Tissue-resident memory T (Trm) cells are associated with cytotoxicity not only in viral infection and autoimmune disease pathologies but also in many cancers. Tumour-infiltrating CD103+ Trm cells predominantly comprise CD8 T cells that express cytotoxic activation and immune checkpoint molecules called exhausted markers. This study aimed to investigate the role of Trm in colorectal cancer (CRC) and characterise the cancer-specific Trm. METHODS: Immunochemical staining with anti-CD8 and anti-CD103 antibodies for resected CRC tissues was used to identify the tumour-infiltrating Trm cells. The Kaplan-Meier estimator was used to evaluate the prognostic significance. Cells immune to CRC were targeted for single-cell RNA-seq analysis to characterise cancer-specific Trm cells in CRC. RESULTS: The number of CD103+/CD8+ tumour-infiltrating lymphocytes (TILs) was a favourable prognostic and predictive factor of the overall survival and recurrence-free survival in patients with CRC. Single-cell RNA-seq analysis of 17,257 CRC-infiltrating immune cells revealed a more increased zinc finger protein 683 (ZNF683) expression in cancer Trm cells than in noncancer Trm cells and in high-infiltrating Trm cells than low-infiltrating Trm in cancer, with an upregulated T-cell receptor (TCR)- and interferon-γ (IFN-γ) signalling-related gene expression in ZNF683+ Trm cells. CONCLUSIONS: The number of CD103+/CD8+ TILs is a prognostic predictive factor in CRC. In addition, we identified the ZNF683 expression as one of the candidate markers of cancer-specific Trm cells. IFN-γ and TCR signalling and ZNF683 expression are involved in Trm cell activation in tumours and are promising targets for cancer immunity regulation.

Crohn's Disease-Associated Anorectal Cancer Has a Poor Prognosis With High Local Recurrence: A Subanalysis of the Nationwide Japanese Study.

INTRODUCTION: Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have involved only small numbers of patients, and no large series have been reported from Asia. The aim of this study was to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC. METHODS: A large nationwide database was used to identify patients with CD-CRC (n = 233) and sporadic CRC (n = 129,783) over a 40-year period, from 1980 to 2020. Five-year overall survival (OS), recurrence-free survival (RFS), and clinicopathological characteristics were investigated. The prognosis of CD-CRC was further evaluated in groups divided by colon cancer and anorectal cancer (RC). Multivariable Cox regression analysis was used to adjust for confounding by unbalanced covariables. RESULTS: Compared with sporadic cases, patients with CD-CRC were younger; more often had RC, multiple lesions, and mucinous adenocarcinoma; and had lower R0 resection rates. Five-year OS was worse for CD-CRC than for sporadic CRC (53.99% vs 71.17%, P < 0.001). Multivariable Cox regression analysis revealed that CD was associated with significantly poorer survival (hazard ratio 2.36, 95% confidence interval: 1.54-3.62, P < 0.0001). Evaluation by tumor location showed significantly worse 5-year OS and RFS of CD-RC compared with sporadic RC. Recurrence was identified in 39.57% of CD-RC cases and was mostly local. DISCUSSION: Poor prognosis of CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.

Deep Learning Analysis of Histologic Images from Intestinal Specimen Reveals Adipocyte Shrinkage and Mast Cell Infiltration to Predict Postoperative Crohn Disease.

Most patients with Crohn disease (CD), a chronic inflammatory gastrointestinal disease, experience recurrence despite treatment, including surgical resection. However, methods for predicting recurrence remain unclear. This study aimed to predict postoperative recurrence of CD by computational analysis of histopathologic images and to extract histologic characteristics associated with recurrence. A total of 68 patients who underwent surgical resection of the intestine were included in this study and were categorized into two groups according to the presence or absence of postoperative disease recurrence within 2 years after surgery. Recurrence was defined using the CD Activity Index and the Rutgeerts score. Whole-slide images of surgical specimens were analyzed using deep learning model EfficientNet-b5, which achieved a highly accurate prediction of recurrence (area under the curve, 0.995). Moreover, subserosal tissue images with adipose cells enabled highly accurate prediction. Adipose cell morphology showed significant between-group differences in adipose cell size, cell-to-cell distance, and cell flattening values. These findings suggest that adipocyte shrinkage is an important histologic characteristic associated with recurrence. Moreover, there was a significant between-group difference in the degree of mast cell infiltration in the subserosa. These findings show the importance of mesenteric adipose tissue in patient prognosis and CD pathophysiology. These findings also suggest that deep learning-based artificial intelligence enables the extraction of meaningful histologic features.

Identification of the Minimum Combination of Serum microRNAs to Predict the Recurrence of Colorectal Cancer Cases.

BACKGROUND: Serum microRNAs (miRNAs) have been recognized as potential stable biomarkers for various types of cancer. Considering the clinical applications, there are certain critical requirements, such as minimizing the number of miRNAs, reproducibility in a longitudinal clinical course, and superiority to conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9. This study aimed to identify serum miRNAs that indicate the recurrence of colorectal cancer (CRC), surpassing inter-tumor heterogeneity. METHODS: We conducted an analysis of 434 serum samples from 91 patients with CRC and 71 healthy subjects. miRNAs were obtained from Toray Co., Ltd, and miRNA profiles were analyzed using a three-step approach. miRNAs that were highly expressed in patients with CRC than in the healthy controls in the screening phase, and those that were highly expressed in the preoperative samples than in the 1-month postoperative samples in the discovery phase, were extracted. In the validation phase, the extracted miRNAs were evaluated in 323 perioperative samples, in chronological order. RESULTS: A total of 12 miRNAs (miR-25-3p, miR-451a, miR-1246, miR-1268b, miR-2392, miR-4480, miR-4648, miR-4732-5p, miR-4736, miR-6131, miR-6776-5p, and miR-6851-5p) were significantly concordant with the clinical findings of tumor recurrence, however their ability to function as biomarkers was comparable with CEA. In contrast, the combination of miR-1246, miR-1268b, and miR-4648 demonstrated a higher area under the curve (AUC) than CEA. These three miRNAs were upregulated in primary CRC tissues. CONCLUSION: We identified ideal combinatorial miRNAs to predict CRC recurrence.

Clinical Significance of Preoperative and Postoperative Serum CEA and Carbohydrate Antigen 19-9 Levels in Patients Undergoing Curative Resection of Locally Recurrent Rectal Cancer.

BACKGROUND: Local recurrence is common after curative resection for rectal cancer. Although one expects radical resection of locally recurrent rectal cancer to be curative, the postoperative re-recurrence rate is relatively high. Therefore, identifying risk factors for recurrence may improve the prognosis of locally recurrent rectal cancer with early therapeutic intervention. OBJECTIVE: This study aimed to evaluate the relationship between perioperative serum CEA/carbohydrate antigen 19-9 levels and prognosis in locally recurrent rectal cancer to validate their usefulness for postoperative surveillance in locally recurrent rectal cancer. DESIGN: This was a single-center retrospective cohort study. SETTING: The study is based on data obtained from procedures at the Osaka University Hospital. PATIENTS: Ninety patients underwent radical resection for locally recurrent rectal cancer between January 2000 and January 2015. MAIN OUTCOME MEASURES: We evaluated the correlation between perioperative serum CEA/carbohydrate antigen 19-9 levels and prognosis after complete resection of locally recurrent rectal cancer and the serum CEA and carbohydrate antigen 19-9 levels at the diagnosis of postoperative re-recurrence. RESULTS: The median preoperative serum CEA level was 4 ng/mL and carbohydrate antigen 19-9 level was 12 U/mL. Of the 90 patients, 43.3% had serum CEA ≥5 ng/mL, and 15.6% had serum carbohydrate antigen 19-9 ≥37 U/mL. Preoperatively, this serum carbohydrate antigen 19-9 level strongly correlated with poorer prognoses regarding cancer-specific survival. Postoperatively, serum CEA ≥5 ng/mL significantly correlated with a worse prognosis. At the time of diagnosis of re-recurrence after resection of locally recurrent rectal cancer, 53.2% of patients had serum CEA ≥5 ng/mL, and 23.4% of patients had serum carbohydrate antigen 19-9 ≥37 U/mL. LIMITATIONS: The study was limited by its single-center retrospective design, an insufficient sample size, and a relatively long study period. CONCLUSIONS: High serum levels of carbohydrate antigen 19-9 preoperatively and CEA postoperatively are associated with poor prognosis after locally recurrent rectal cancer. Furthermore, we found a high rate of serum CEA elevation in the diagnosis of postoperative re-recurrence. See Video Abstract at http://links.lww.com/DCR/C106 . IMPORTANCIA CLNICA DE LOS NIVELES SRICOS PREOPERATORIOS Y POSOPERATORIOS DE CEA Y CA EN PACIENTES SOMETIDOS A RESECCIN CURATIVA DE CNCER DE RECTO LOCALMENTE RECURRENTE: ANTECEDENTES:La recurrencia local es común después de la resección curativa del cáncer de recto. Aunque se espera que la resección radical del cáncer rectal localmente recurrente sea curativa, la tasa de recurrencia posoperatoria es relativamente alta. Por lo tanto, la identificación de los factores de riesgo de recurrencia puede mejorar el pronóstico del cáncer de recto localmente recurrente con una intervención terapéutica temprana.OBJETIVO:Evaluamos la relación entre los niveles séricos perioperatorios de CEA/CA19-9 y el pronóstico en el cáncer de recto localmente recurrente para validar su utilidad para la vigilancia posoperatoria en el cáncer de recto localmente recurrente.DISEÑO:Este fue un estudio de cohorte retrospectivo de un solo centro.AJUSTE:El estudio se basa en datos obtenidos de procedimientos en el Hospital Universitario de Osaka.PACIENTES:Noventa pacientes fueron sometidos a resección radical por cáncer de recto localmente recurrente entre Enero de 2000 y Enero de 2015.PRINCIPALES MEDIDAS DE RESULTADOS:Evaluamos la correlación entre los niveles séricos perioperatorios de CEA/CA19-9 y el pronóstico después de la resección completa del cáncer de recto localmente recurrente y los niveles séricos de CEA y CA19-9 en el diagnóstico de recurrencia posoperatoria.RESULTADOS:La mediana de los niveles séricos preoperatorios de CEA y CA19-9 fueron de 4 ng/mL y 12 U/mL, respectivamente. De los 90 pacientes, el 43,3 % tenía CEA sérico ≥5 ng/mL y el 15,6 % tenía CA19-9 sérico ≥37 U/mL. Antes de la operación, este nivel sérico de CA19-9 se correlacionó fuertemente con peores pronósticos con respecto a la supervivencia específica del cáncer. Después de la operación, el CEA sérico ≥5 ng/mL se correlacionó significativamente con un peor pronóstico. En el momento del diagnóstico de recurrencia después de la resección del cáncer de recto localmente recurrente, el 53,2 % de los pacientes tenían CEA sérico ≥5 ng/mL y el 23,4 % de los pacientes tenían CA19-9 sérico ≥37 U/mL.LIMITACIONES:El estudio estuvo limitado por su diseño retrospectivo de un solo centro, un tamaño de muestra insuficiente y un período de estudio relativamente largo.CONCLUSIONES:Los niveles séricos altos de CA19-9 antes de la operación y de CEA después de la operación están asociados con un mal pronóstico después del cáncer de recto localmente recurrente. Además, encontramos una alta tasa de elevación del CEA sérico en el diagnóstico de recurrencia posoperatoria. Consulte el Video Resumen en http://links.lww.com/DCR/C106 . (Traducción-Dr. Yesenia Rojas-Khalil ).

Efficacy, safety, and pharmacokinetics of teduglutide in adult Japanese patients with short bowel syndrome and intestinal failure: two phase III studies with an extension.

PURPOSE: The short- and long-term efficacy, safety, and pharmacokinetics of teduglutide were analyzed in adult Japanese patients with short bowel syndrome and intestinal failure (SBS-IF). METHODS: Patients received teduglutide 0.05 mg/kg/day in clinical trials (TED-C14-004, SHP633-306, and extension SHP633-307). Data were analyzed at 24 weeks and an interim data cut-off of 4.5 years. RESULTS: The parenteral support (PS) volume decreased by ≥ 20% for 9/18 patients at 24 weeks and in all 11 patients by data cut-off in SHP633-307. The mean (standard deviation) PS volume decreased from baseline at 24 weeks in TED-C14-004 (-30.1 ± 25.9%) and SHP633-306 (-25.6 ± 25.5%), and at data cut-off in SHP633-307 (-57.08 ± 28.49%). Teduglutide was absorbed quickly. The adverse events were consistent with the underlying disease and known adverse drug reactions. Anti-teduglutide antibody titers declined with long-term treatment. CONCLUSIONS: In Japanese adults with SBS-IF, teduglutide treatment was associated with clinically meaningful reductions in PS requirements, similar to findings in prior international studies. No new safety concerns specific to the Japanese SBS-IF patient population were identified with short- or long-term teduglutide treatment. Anti-teduglutide antibody titers disappeared in most Japanese adults with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date.

Simple Detection and Culture of Circulating Tumor Cells from Colorectal Cancer Patients Using Poly(2-Methoxyethyl Acrylate)-Coated Plates.

Here we aimed to establish a simple detection method for detecting circulating tumor cells (CTCs) in the blood sample of colorectal cancer (CRC) patients using poly(2-methoxyethyl acrylate) (PMEA)-coated plates. Adhesion test and spike test using CRC cell lines assured efficacy of PMEA coating. A total of 41 patients with pathological stage II-IV CRC were enrolled between January 2018 and September 2022. Blood samples were concentrated by centrifugation by the OncoQuick tube, and then incubated overnight on PMEA-coated chamber slides. The next day, cell culture and immunocytochemistry with anti-EpCAM antibody were performed. Adhesion tests revealed good attachment of CRCs to PMEA-coated plates. Spike tests indicated that ~75% of CRCs from a 10-mL blood sample were recovered on the slides. By cytological examination, CTCs were identified in 18/41 CRC cases (43.9%). In cell cultures, spheroid-like structures or tumor-cell clusters were found in 18/33 tested cases (54.5%). Overall, CTCs and/or growing circulating tumor cells were found in 23/41 CRC cases (56.0%). History of chemotherapy or radiation was significantly negatively correlated with CTC detection (p = 0.02). In summary, we successfully captured CTCs from CRC patients using the unique biomaterial PMEA. Cultured tumor cells will provide important and timely information regarding the molecular basis of CTCs.

[FOLFIRI plus RAM Therapy in Later Line of Unresectable Colorectal Cancer].

FOLFIRI plus ramucirumab(RAM)therapy has been reported to be effective and safe in the RAISE trial as second-line treatment for unresectable colorectal cancer. It is hypothesized that RAM may be effective in patients with PD treated with FOLFIRI plus bevacizumab(Bev)due to different mechanism of action from that of Bev, which is also an angiogenesis inhibitor. From January 2017 to December 2021, we conducted a retrospective study of 6 patients who had PD with 5-FU, oxaliplatin, irinotecan, or Bev as first or second-line treatment at our institution and who received FOLFIRI plus RAM in later line treatment. The 6 cases consisted of 3 patients in the third-line treatment, 1 patient in the fourth-line treatment, and 2 patients in the sixth-line treatment. The anti-tumor effect was PD in all cases in the third-line and fourth-line treatment, but the 2 patients of sixth-line treatment were controlled diseases.

[A Case Report-A Successful Case of Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Cancer with an Aberrant Right Hepatic Artery].

In cases of pancreatic cancer with anatomical variations of the hepatic artery, it is important to evaluate the hemodynamics of each case for surgical indication. We report the case of a 68-year-old man with locally advanced pancreatic cancer and an aberrant right hepatic artery who underwent distal pancreatectomy with celiac axis resection(DP-CAR). He was admitted to our institute due to abdominal discomfort. A CT scan showed pancreatic cancer invading the common hepatic artery. He underwent chemoradiotherapy with a diagnosis of locally advanced pancreatic cancer. After the tumor downstaging, we performed DP-CAR, which included a gastroduodenal artery and a proper hepatic artery resection. Even though delayed gastric emptying was observed after the operation, he was discharged on postoperative day 36.

Low G9a expression is a tumor progression factor of colorectal cancer via IL-8 promotion.

The histone methyltransferase G9a is expressed in various types of cancer cells, including colorectal cancer (CRC) cells. Interleukin 8 (IL)-8, also known as C-X-C motif chemokine ligand 8 (CXCL8), is a chemokine that plays a pleiotropic function in the regulation of inflammatory responses and cancer development. Here, we examined the relationship between G9a and IL-8 and the clinical relevance of this association. We immunohistochemically analyzed 235 resected CRC samples to correlate clinical features. Samples with high G9a expression had better overall survival and relapse-free survival than those with low G9a expression. Univariate and multivariate analyses demonstrated that low G9a expression remained a significant independent prognostic factor for increased disease recurrence and decreased survival (P < 0.05). G9a was expressed at high levels in commercially available CRC cell lines HCT116 and HT29. Knockdown of G9a by siRNA, shRNA or the G9a-specific inhibitor BIX01294 upregulated IL-8 expression. The number of spheroids was significantly increased in HCT116 cells with stably suppressed G9a expression, and the number of spheroids was significantly decreased in HCT116 cells with stably suppressed IL-8 expression. Thus, the suppression of IL-8 by G9a may result in a better prognosis in CRC cases with high G9a expression. Furthermore, G9a may suppress cancer stemness and increase chemosensitivity by controlling IL-8. Therefore, G9a is a potential novel marker for predicting CRC prognosis, and therapeutic targeting of G9a in CRC should be controversial.

PLXND1/SEMA3E Promotes Epithelial-Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer.

Colorectal cancer (CRC) is a major cause of cancer-related deaths. Metastasis is enhanced through epithelial-mesenchymal transition (EMT), a process primarily induced by the transforming growth factor beta (TGF-ß)-mediated canonical Smad pathway. This study focused on plexin D1 (PLXND1), a chemoreceptor for the ligand SEMA3E to mechanosensory, showing that PLXND1 induces EMT via activation of the PI3K/AKT pathway in CRC cells. The findings showed that PLXND1-knockdown decreases cell migration and invasion significantly, and that the binding of p61-SEMA3E to the PLXND1 enhances the invasiveness and migration through EMT. Furin inhibitor suppresses EMT, decreasing cell migration and invasion. Furin cleaves full-length SEMA3E and converts it to p61-SEMA3E, suggesting that furin inhibitors block PLXND1 and p61-SEMA3E binding. Furin is a potential therapeutic target for the purpose of suppressing EMT by inhibiting the binding of p61-SEMA3E to PLXND1. In vivo experiments have shown that PLXND1-knockdown suppresses EMT. Mesenchymal cells labeled with ZEB1 showed heterogeneity depending on PLXND1 expression status. The high-expression group of PLXND1 in 182 CRC samples was significantly associated with poor overall survival compared with the low-expression group (P = 0.0352, median follow-up period of 60.7 months) using quantitative real-time polymerase chain reaction analysis. Further research is needed to determine whether cell fractions with a different expression of PLXND1 have different functions.

Development and evaluation of a Japanese prediction model for low anterior resection syndrome after rectal cancer surgery.

BACKGROUND: Low anterior resection syndrome (LARS) is the most common complication after rectal cancer resection. We aimed to identify LARS' predictive factors and construct and evaluate a predictive model for LARS. METHODS: This retrospective study included patients with rectal cancer more than 1 year after laparoscopic or robotic-assisted surgery. We administered a questionnaire to evaluate the degree of LARS. In addition, we examined clinical characteristics with univariate and multivariate analysis to identify predictive factors for major LARS. Finally, we divided the obtained data into a learning set and a validation set. We constructed a predictive model for major LARS using the learning set and assessed the predictive accuracy of the validation set. RESULTS: We reviewed 160 patients with rectal cancer and divided them into a learning set (n = 115) and a validation set (n = 45). Univariate and multivariate analyses in the learning set showed that male (odds ratio [OR]: 2.88, 95% confidence interval [95%CI] 1.11-8.09, p = 0.03), age < 75 years (OR: 5.87, 95%CI 1.14-47.25, p = 0.03) and tumors located < 8.5 cm from the AV (OR: 7.20, 95%CI 2.86-19.49, p < 0.01) were significantly related to major LARS. A prediction model based on the patients in the learning set was well-calibrated. CONCLUSIONS: We found that sex, age, and tumor location were independent predictors of major LARS in Japanese patients that underwent rectal cancer surgery. Our predictive model for major LARS could aid medical staff in educating and treating patients with rectal cancer before and after surgery.

Comparison of clinical outcomes of single-incision versus multi-port laparoscopic surgery for descending colon cancer: a propensity score-matched analysis.

BACKGROUND: The clinical impact of single-incision laparoscopic surgery (SILS) for descending colon cancer (DCC) is unclear. The aim of this study was to evaluate the clinical outcomes of SILS for DCC compared with multi-port laparoscopic surgery (MPLS). METHODS: We retrospectively analyzed 137 consecutive patients with stage I-III DCC who underwent SILS or MPLS at two high-volume multidisciplinary tertiary hospitals between April 2008 and December 2018, using propensity score-matched analysis. RESULTS: After propensity score-matching, we enrolled 88 patients (n = 44 in each group). SILS was successful in 97.7% of the matched cohort. Compared with the MPLS group, the SILS group showed significantly less blood loss and a greater number of harvested lymph nodes. Morbidity rates were similar between groups. Recurrence pattern did not differ between groups. No significant differences were found between groups in terms of 3-year disease-free and overall survivals. CONCLUSION: SILS appears safe and feasible and can provide satisfactory oncological outcomes for patients with DCC.

Comparison of clinical outcomes of single-incision versus multi-port laparoscopic surgery for rectosigmoid or upper rectal cancer.

BACKGROUND: Single-incision laparoscopic surgery (SILS) for rectal cancer is technically challenging, and its clinical impact is unclear. The aim of this study was to evaluate clinical outcomes of SILS for rectal cancer compared with multi-port laparoscopic surgery (MPLS). PATIENTS AND METHODS: We retrospectively analyzed 357 consecutive patients with stage I-III rectal cancer located in the rectosigmoid or upper rectum who underwent SILS or MPLS between January 2012 and December 2016, using propensity score-matched analysis. RESULTS: After propensity score-matching, we enrolled 204 patients (n = 102 per group). Before matching, significant group-dependent differences were observed in tumor location (p < 0.001). After matching, preoperative clinical factors were similar between groups. SILS was successful in 73.5% of cases, an additional port was required in 23.5%, and 2.9% were converted to open surgery. Compared to the MPLS group, the SILS group showed shorter operative time (192 vs. 211 min, p = 0.015) and shorter postoperative hospital stay (9 vs. 11 days, p = 0.038). Other operative factors and morbidity rates did not differ significantly between groups. The number of harvested lymph nodes was smaller in the SILS group (24) than in the MPLS group (27, p = 0.008). Postoperative recurrence did not differ between groups, either before or after matching. No significant differences in 3-year disease-free, 3-year local recurrence-free, or 5-year overall survival were found between groups. CONCLUSIONS: SILS is safe, is feasible, and offers satisfactory oncological outcomes in selected patients with rectosigmoid or upper rectal cancer.

Fecal Stream Diversion Changes Intestinal Environment, Modulates Mucosal Barrier, and Attenuates Inflammatory Cells in Crohn's Disease.

BACKGROUND: The intestinal environment plays important roles in mucosal barrier homeostasis and intestinal inflammation, as clarified in studies using experimental animals but not in humans. AIMS: We investigated whether environmental changes in the fecal stream cause phenotypic changes in the human mucosal barrier. METHODS: We obtained human ileal samples after fecal stream diversions in patients with rectal cancer or Crohn's disease. We investigated the bacterial load and diversity in the human defunctioned ileum, defined as the anal side of the ileum relative to the ileostomy. We also examined the epithelium and lamina propria cell phenotypes in the defunctioned ileum. RESULTS: After fecal stream diversion, bacterial loads decreased significantly in the defunctioned ileum. Based on the Chao1, Shannon, and observed species indices, the diversity of mucosa-associated microbiota was lower in the defunctioned ileum than in the functional ileum. Moreover, the healthy defunctioned ileum showed reductions in villous height, goblet cell numbers, and Ki-67+ cell numbers. Additionally, interferon-γ+, interleukin-17+, and immunoglobulin A+ cell abundance in the lamina propria decreased. After the intestinal environment was restored with an ileostomy closure, the impaired ileal homeostasis recovered. The defunctioned ileum samples from patients with Crohn's disease also showed reductions in interferon-γ+ and interleukin-17+ cell numbers. CONCLUSIONS: Fecal stream diversion reduced the abundance and diversity of intestinal bacteria. It also altered the intestinal mucosal barrier, similar to the alterations observed in germ-free animals. In patients with Crohn's disease, Th1 and Th17 cell numbers were attenuated, which suggests that the host-microbiome interaction is important in disease pathogenesis.

Locally advanced rectal cancer receiving total neoadjuvant therapy combined with nivolumab: a case report and literature review.

BACKGROUND: The standard treatment for locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, it has been suggested that intensification of neoadjuvant treatment with polychemotherapy in addition to CRT instead of as an adjuvant chemotherapy is better tolerated and associated with a higher pathological complete response (pCR) rate. This concept is known as total neoadjuvant therapy (TNT). Recently, the addition of immunotherapy to preoperative CRT has been reported to be useful in LARC patients with mismatch-repair-deficiency and high levels of microsatellite instability (MSI-H), but there are no reports showing the therapeutic effect of nivolumab in combination with TNT. CASE PRESENTATION: A 23-year-old man had frequent diarrhea. Preoperative examination revealed two adenocarcinomas in the rectum. His maternal grandmother had a rectal cancer patient who developed the disease at age 70s. The larger tumor was located at the peritoneal reflection, and its anterior border close to the prostate (<1 mm); there were eight enlarged pararectal lymph nodes. Considering the size and depth of the tumor, it was judged that radical resection with sufficient margins would be difficult. Therefore, it was decided that TNT would be performed. At first, CAPOX (capecitabine and L-OHP) was administered, followed by preoperative CRT (RT:50.4 Gy and capecitabine). During this period, genetic testing diagnosed this patient as MSI-H, so additional nivolumab was administered after CRT. Colonoscopy revealed that the larger tumor was no longer detectable, so robot-assisted intersphincteric resection and bilateral lateral lymph node dissection was performed. The diagnosis of pCR was made for the larger tumor and partial response was achieved for the smaller tumor, and no lymph node metastasis was found. Major complications were not observed and the patient was discharged on the 14th day after surgery. He was followed up without adjuvant chemotherapy and is alive and recurrence-free after 9 months. CONCLUSION: A case of LARC with MSI-H was treated with TNT with nivolumab, resulting in pCR and complete radical resection. This result suggests that nivolumab in addition to TNT can be an option as a preoperative strategy for LARC with MSI-H.

Real-world etiologies and treatments of pediatric short bowel syndrome in Japan.

BACKGROUND: Short bowel syndrome (SBS) is a rare disease that can result in intestinal failure (IF). Short bowel syndrome intestinal failure leads to stunted growth and development and high mortality rates. The primary goal of treatment is to enhance intestinal adaptation and nutrient absorption. Parenteral nutrition (PN) is used to support this process until enteral autonomy can be restored. Some patients experience prolonged partial or complete dependency on PN and face an increased risk of life-threatening catheter-related bloodstream infections and intestinal failure-associated liver disease. This study aimed to provide real-world insights into the patient characteristics and treatment dynamics of PN-dependent children with SBS-IF in Japan. METHODS: This retrospective observational study used anonymized information from a large hospital-based medical insurance database to identify pediatric patients who received PN for ≥6 months between April 2008 and January 2020. The primary endpoint was weaning from PN. Secondary endpoints included duration and complications of PN. RESULTS: Forty-eight children (mean age, 2.9 years) were eligible for inclusion. The most common causes of SBS-IF were mechanical bowel obstruction, functional bowel disorders, and Hirschsprung's disease. Twenty-two patients (45.8%) were weaned from PN during the study. The mean time to first weaning was 464.2 days and five patients (22.7%) restarted PN. The mean total duration of PN was 692.6 days in weaned patients and 1,170.9 days in unweaned patients. The most frequent complications were sepsis, catheter infections (both 79.2%), and liver dysfunction (64.6%). CONCLUSIONS: Pediatric patients with SBS-IF faced difficulties when weaning off PN and rates of life-threatening complications were high.

Etiologies and treatments of chronic intestinal failure-short bowel syndrome (SBS) in Japanese adults: a real-world observational study.

PURPOSE: Short bowel syndrome (SBS) with intestinal failure (SBS-IF) requires long-term parenteral nutrition (PN). This study investigated the real-world etiologies of SBS, treatment patterns, and PN-related outcomes among adult patients with SBS-IF in Japan. METHODS: This retrospective, observational cohort study was based on data from April, 2008 to January, 2020 from one of the largest hospital-based claim databases in Japan. Analyzed patients were aged ≥ 16 years, had received continuous PN for ≥ 6 months, and had SBS or undergone SBS-related surgery with a diagnosis of a causative disease. The primary endpoint was PN weaning. RESULTS: We analyzed data for 393 patients. The most frequent causes of SBS-IF were ileus (31.8%), Crohn's disease (20.1%), and mesenteric ischemia (16.0%). Of 144/393 (36.6%) patients who were weaned off their PN, 48 (33.3%) were subsequently restarted on PN. Of 276/393 (70.2%) patients whose PN was initiated in hospital, 156 (56.5%) transitioned to home management. The mean duration of initial PN was 450.4 and 675.5 days for patients who were able or unable to be weaned off PN, respectively. Sepsis (67.4%), catheter-related bloodstream infections (49.1%), and liver disorders (45.0%) were the most reported PN-related complications. CONCLUSIONS: Most patients with SBS-IF in Japan could not be weaned off PN and suffered life-threatening complications.