Perioperative chemotherapy with docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) for the treatment of locally advanced gastric or gastro-esophageal junction adenocarcinoma (MATCH): an open-label, randomized, phase 2 clinical trial.

BACKGROUND: It remains unclear whether addition of docetaxel to the combination of a platinum and fluoropyrimidine could provide more clinical benefits than doublet chemotherapies in the perioperative treatment for locally advanced gastric/gastro-esophageal junction (LAG/GEJ) cancer in Asia. In this randomized, phase 2 study, we assessed the efficacy and safety of perioperative docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) in LAG/GEJ adenocarcinoma patients. METHODS: Patients with cT3-4 Nany M0 G/GEJ adenocarcinoma were randomized (1:1) to receive 4 cycles of preoperative DOS or SOX followed by D2 gastrectomy and another 4 cycles of postoperative chemotherapy. The primary endpoint was major pathological response (MPR). RESULTS: From Aug, 2015 to Dec, 2019,154 patients were enrolled and 147 patients included in final analysis, with a median age of 60 (26-73) years. DOS resulted in significantly higher MPR (25.4 vs. 11.8%, P = 0.04). R0 resection rate, the 3-year PFS and 3-year OS rates were 78.9 vs. 61.8% (P = 0.02), 52.3 vs. 35% (HR 0.667, 95% CI: 0.432-1.029, Log rank P = 0.07) and 57.5 vs. 49.2% (HR 0.685, 95% CI: 0.429-1.095, Log rank P = 0.11) in the DOS and SOX groups, respectively. Patients who acquired MPR experienced significantly better survival. DOS had similar tolerance to SOX. CONCLUSIONS: Perioperative DOS improved MPR significantly and tended to produce longer PFS compared to SOX in LAG/GEJ cancer in Asia, and might be considered as a preferred option for perioperative chemotherapy and worth further investigation.

Mechanism of Endogenous Peptide PDYBX1 and Precursor Protein YBX1 in Hirschsprung's Disease.

Endogenous peptides, bioactive agents with a small molecular weight and outstanding absorbability, regulate various cellular processes and diseases. However, their role in the occurrence of Hirschsprung's disease (HSCR) remains unclear. Here, we found that the expression of an endogenous peptide derived from YBX1 (termed PDYBX1 in this study) was upregulated in the aganglionic colonic tissue of HSCR patients, whereas its precursor protein YBX1 was downregulated. As shown by Transwell and cytoskeleton staining assays, silencing YBX1 inhibited the migration of enteric neural cells, and this effect was partially reversed after treatment with PDYBX1. Moreover, immunoprecipitation and immunofluorescence revealed that ERK2 bound to YBX1 and PDYBX1. Downregulation of YBX1 blocked the ERK1/2 pathway, but upregulation of PDYBX1 counteracted this effect by binding to ERK2, thereby promoting cell migration and proliferation. Taken together, the endogenous peptide PDYBX1 may partially alleviate the inhibition of the ERK1/2 pathway caused by the downregulation of its precursor protein YBX1 to antagonize the impairment of enteric neural cells. PDYBX1 may be exploited to design a novel potential therapeutic agent for HSCR.

Splenomegaly during oxaliplatin-based chemotherapy: impact on blood parameters and anti-neoplastic treatment.

Background: Oxaliplatin induces splenomegaly, which can cause blood sequestration and relevant cytopenia, leading to further dose reductions and schedule modifications of chemotherapy. Here, we aimed to explore the changes of spleen volume induced by oxaliplatin as well as its impact on blood parameters and anti-neoplastic treatment in patients with colon cancer. Methods: We conducted a retrospective analysis of patients with resectable stage II-IV colon cancer who were treated with oxaliplatin and capecitabine at our institution from January 2016 to December 2017. Laboratory tests and computed tomographic (CT) data before, during and up to 18 months after the end of chemotherapy were extracted. Spleen volume was determined by volumetric measurements. Splenomegaly was defined as an over 30% increase in spleen volume from baseline. Results: Out of 144 patients, 102 patients (70.8%) developed splenomegaly, and 75 (73.5%) recovered at 18 months after the end of chemotherapy. Higher cumulative dose intensity of oxaliplatin (P=0.001) and higher baseline platelet count (P=0.045) were risk factors associated with splenomegaly. Compared to those without splenomegaly, splenomegaly patients experienced more severe reduction in platelet (P<0.001), erythrocyte (P=0.010), neutrophil (P=0.002) and lymphocyte (P=0.006) counts and were more likely to undergo dose reductions of oxaliplatin (21.6% vs. 7.1%, P=0.038) as well as interruptions of chemotherapy (18.6% vs. 4.8%, P=0.040) due to thrombocytopenia. Conclusions: Splenomegaly was a common and partly irreversible side effect of oxaliplatin-based therapy in patients with colon cancer. It is correlated with more severe pancytopenia and might exert a negative impact on the efficacy of anti-neoplastic treatment.

Congenital hepatic cyst: Eleven case reports.

BACKGROUND: Liver cysts in infants are uncommon. With modern diagnostic imaging, we can achieve an early diagnosis of congenital hepatic cysts. Our purpose was to investigate the clinical features, surgical treatment methods and prognosis of infants with congenital hepatic cysts. Herein, we report a case series of congenital hepatic cysts. CASE SUMMARY: Eleven infants with hepatic cysts were retrospectively analysed. Ten of them had simple hepatic cysts, and a girl with a large hepatic mass was diagnosed with a solitary intrahepatic biliary cyst accompanied by a choledochal cyst. Among the ten simple hepatic cysts, eight were solitary and two were multiple. A total of 87.5% (7 of 8) of infants with solitary hepatic cysts were detected before delivery, and 86% (6 of 7) of those cysts were located in the right lobe of the liver. Surgical intervention was required for symptomatic hepatic cysts. Cyst resection or unroofing with fulguration of the cyst bed was employed. No recurrence of cysts was observed in these infants. CONCLUSION: Congenital hepatic cyst is a condition with a narrow differential diagnosis. Accurate diagnosis is essential for appropriate management. Unroofing is the favoured treatment in infants with symptomatic cysts. Most infants with congenital hepatic cysts have a good prognosis.

Intrauterine exposure to oxidative stress induces caspase-1-dependent enteric nerve cell pyroptosis.

PURPOSE: This study determined whether oxidative stress causes the developmental abnormalities of the enteric nervous system during the embryonic period. METHODS: Using the test results of tissue specimens of children with Hirschsprung disease (HSCR), we established a pregnant rat model of oxidative stress and a cellular oxidative stress model to conduct related molecular, cellular, and histopathological experiments for exploration and validation. RESULTS: The results of the quantitative real-time polymerase chain reaction assay indicated overexpression of pyroptosis markers (NLRP3, ASC, and caspase-1) in HSCR lesions and newborn pups in the oxidative stress group (treated with D-galactose). The expression of cathepsin D was significantly decreased in intestinal tissues of newborn pups in the oxidative stress group compared to the control group. Reactive oxygen species scavengers (N-acetyl-cysteine, NAC), the caspase-1 inhibitor (VX-765), and the NLRP3 siRNA could reverse the release of LDH, decrease the number of propidium iodide stained cells, and reduce the percentage of TUNEL/caspase-3 double-positive cells in the H2O2-treated group. CONCLUSION: Oxidative stress can induce the death of enteric nerve cells by activating caspase-1-dependent pyroptosis through NLRP3 inflammasomes, which may contribute to abnormal enteric nervous system development.

LncRNA-RMST Functions as a Transcriptional Co-regulator of SOX2 to Regulate miR-1251 in the Progression of Hirschsprung's Disease.

Hirschsprung's disease (HSCR) is a congenital disorder characterized by the absence of enteric neural crest cells (ENCCs). LncRNA rhabdomyosarcoma 2-associated transcript (RMST) is essential for the growth and development of neuron. This study aimed to reveal the role of RMST in the pathogenesis of HSCR. The expression level of RMST, miR-1251, SOX2, and AHNAK was evaluated with qRT-PCR or western blot. CCK-8 and transwell assays were applied to detect cell proliferation and migration. CHIP and RIP assays were applied to determine the combination relationship between SOX2 and promoter region of miR-1251 or RMST and SOX2, respectively. Dual-luciferase reporter assay was performed to confirm miR-1251 targeted AHNAK. As results have shown, RMST was downregulated in the aganglionic colon of HSCR patients. The knockdown of RMST attenuated cell proliferation and migration significantly. MiR-1251, the intronic miRNA of RMST, was also low expressed in HSCR, but RMST did not alter the expression of miR-1251 directly. Furthermore, SOX2 was found to regulate the expression of miR-1251 via binding to the promoter region of miR-1251, and RMST strengthened this function by interacting with SOX2. Moreover, AHNAK was the target gene of miR-1251, which was co-regulated by RMST and SOX2. In conclusion, our study demonstrated that RMST functioned as a transcriptional co-regulator of SOX2 to regulate miR-1251 and resulted in the upregulation of AHNAK, leading to the occurrence of HSCR. The novel RMST/SOX2/miR-1251/AHNAK axis provided potential targets for the diagnosis and treatment of HSCR during embryonic stage.

Multi-Center Analysis of Predictive Factors of Enteral Autonomy and Risk Factors of Complications of Pediatric Intestinal Failure in China.

OBJECTIVES: The aim of this study was to identify predictors for enteral autonomy and intestinal failure (IF)-related complications and evaluate the outcomes of a multi-center pediatric cohort in China. METHODS: The medical records of pediatric patients with IF treated at four medical centers in China from January 1, 2012 to November 31, 2020 were retrospectively reviewed. Enteral autonomy was defined as sustained growth and cessation of parenteral nutrition for >90 days. Multivariate logistic regression analysis was used to identify factors predictive of enteral autonomy and the risk factors of complications, such as IF-associated liver disease (IFALD) and catheter-related bloodstream infection (CRBSI). RESULTS: The study cohort of 92 pediatric patients with IF included 71 (77%) who underwent surgery and 21 (23%) who received non-surgical treatment. Eventually, 63 (68.5%) patients achieved enteral autonomy by the end of the follow-up period. Multivariate logistic regression analysis indicated that longer duration of parenteral nutrition (PN), sepsis, and non-breastfeeding were risk factors for enteral autonomy. When considering the detailed intraoperative data, the presence of an ileocecal valve (ICV) and greater residual small bowel (RSB) length were reaffirmed as predictors of achieving enteral autonomy. Medium/long-chain (MCT/LCT) lipids or sepsis were identified as negative predictors for IFALD. Univariate analysis revealed that the use of MCT/LCT lipids was associated with a greater likelihood of CRBSI. CONCLUSION: In this cohort, enteral autonomy was achieved at a percentage of 68.5%, and the risk factors for not achieving enteral autonomy were a longer duration of PN, sepsis, and non-breastfeeding. The presence of an ICV and a greater RSB length were important predictors of achieving enteral autonomy.

Risk factors for the occurrence and recurrence of acute cerebellar ataxia: a retrospective observational study.

OBJECTIVE: There is little evidence to support a correlation between abdominal surgery and acute cerebellar ataxia (ACA). We reviewed the records of children with ACA treated at our institution to analyze risk factors for ACA. METHODS: Clinical data of 442 children with ACA treated at Children's Hospital of Nanjing Medical University between November 2015 and June 2019 were retrospectively analyzed. Univariate and multivariate analyses were performed to determine risk factors for the occurrence and recurrence of ACA. RESULTS: In total, 442 children with ACA were included in this study. Multivariate logistic regression analysis showed age (p = 0.009), infection (p < 0.001), vaccination (p < 0.001), head trauma (p < 0.001), intussusception surgery (IS) (p < 0.001), operation for indirect inguinal hernia (p < 0.001), and operation for congenital gastrointestinal malformation (p < 0.001) were independent risk factors for ACA occurrence. Univariate analysis showed that only IS (p < 0.001) was associated with ACA recurrence. CONCLUSIONS: Surgeons should be aware that age, infection, vaccination, head trauma, and history of abdominal surgery are associated with ACA, while IS is a risk factor for ACA recurrence.

m6A demethylase ALKBH5 suppresses proliferation and migration of enteric neural crest cells by regulating TAGLN in Hirschsprung's disease.

OBJECTIVES: This study aims to investigate the role of demethylase ALKBH5 mediated demethylation of TAGLN mRNA in the occurrence of Hirschsprung's disease (HSCR), and to clarify how ALKBH5 reduces the m6A level of TAGLN mRNA and inhibits its degradation, thereby inhibiting the proliferation and migration of neural crest cells, and potentially contributing to the occurrence of HSCR. MATERIAL AND METHODS: Quantitative real-time PCR (qRT-PCR) and Western-Blot (WB) were conducted to test the expression level of ALKBH5 and TAGLN genes. Cell function assays were adopted to detect cell phenotypes. The qRT-PCR and methylated RNA immunoprecipitation (MeRIP-qPCR) were used to test the regulation of TAGLN by ALKBH5. RESULTS: 1. Compared with control intestinal tissue, the expression level of TAGLN and ALKBH5 in the aganglionic intestinal tissue of HSCR is increased. 2. The MeRIP-PCR and dualluciferase report confirmed that ALKBH5 could bind to m6A sites of TAGLN mRNA and reduce the m6A level of TAGLN mRNA. 3. In vitro cell experiments confirmed that overexpression of ALKBH5 can inhibit the degradation of TAGLN mRNA, increase the expression of TAGLN, thereby inhibiting cell proliferation and migration. 4. A zebrafish model of ALKBH5 overexpression was constructed. Studies have shown that ALKBH5 could inhibit the proliferation and migration of zebrafish enteric neurons. CONCLUSIONS: ALKBH5 could demethylate TAGLN mRNA and up-regulate TAGLN expression, leading to the inhibition of proliferation and migration of enteric neural crest cells and contributing to the occurrence of HSCR.

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. METHODS: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. RESULTS: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). CONCLUSIONS: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. IMPACT: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.

An integrated analysis of lymphocytic reaction, tumour molecular characteristics and patient survival in colorectal cancer.

BACKGROUND: Histological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer. Considering the lack of adequate statistical power, adjustment for selection bias and comprehensive tumour molecular data in most previous studies, we investigated the strengths of the prognostic associations of lymphocytic reaction in colorectal carcinoma by utilising an integrative database of two prospective cohort studies. METHODS: We examined Crohn's-like reaction, intratumoural periglandular reaction, peritumoural reaction and tumour-infiltrating lymphocytes in 1465 colorectal carcinoma cases. Using covariate data of 4420 colorectal cancer cases in total, inverse probability-weighted Cox proportional hazard regression model was used to control for selection bias (due to tissue availability) and potential confounders, including stage, MSI status, LINE-1 methylation, PTGS2 and CTNNB1 expression, KRAS, BRAF and PIK3CA mutations, and tumour neoantigen load. RESULTS: Higher levels of each lymphocytic reaction component were associated with better colorectal cancer-specific survival (Ptrend < 0.002). Compared with cases with negative/low intratumoural periglandular reaction, multivariable-adjusted HRs were 0.55 (95% CI, 0.42-0.71) in cases with intermediate reaction and 0.20 (95% CI, 0.12-0.35) in cases with high reaction. These relationships were consistent in strata of MSI status or neoantigen loads (Pinteraction > 0.2). CONCLUSIONS: The four lymphocytic reaction components are prognostic biomarkers in colorectal carcinoma.

Application of enhanced recovery after surgery during the perioperative period in infants with Hirschsprung's disease - A multi-center randomized clinical trial.

BACKGROUND & AIMS: Various enhanced recovery after surgery (ERAS) guidelines have been established for several kinds of adult surgeries. While the guidelines for pediatric surgeries remained to be explored. The aim of the study was to prospectively evaluate the safety and efficacy of an ERAS protocol for Hirschsprung's disease (HSCR) infants undergoing pull-through procedures. METHODS: An infant-specific ERAS protocol was developed and implemented at multiple centers from June 1, 2016 to December 31, 2017. The study included 145 consecutive patients who underwent pull-through surgery for HSCR in three Children's hospitals. Patients were primarily divided into three groups based on the clinical classification and surgical methods. Group I included patients with the short segment type who received transanal endorectal pull-through (TEPT) surgery. Group II comprised of patients with the classical type and long segment type who received laparoscopic-assisted pull-through (LAPT) surgery. Group III involved patients with the long segment type (who had received ileostomy or colostomy during the neonatal period) and total colonic aganglionosis who received open pull-through (OPPT) surgery. Patients in the three groups mentioned above were randomly and equally assigned into the ERAS group and traditional (TRAD) group with random number table row randomization. The primary outcome was the length of postoperative hospital stay (LOS). Secondary outcomes of interest included white blood cell (WBC) and C-reactive protein (CRP) on postoperative day 1 (POD 1), the blood glucose at the time of anesthesia and 24 h after surgery, time to first defecation, time to regular diet, plasma markers of nutrition status on POD 5, plasma natrium on POD 5, the mean intraoperative fluid volume, time to discontinuation of intravenous infusion, incidence of postoperative complications, re-admission within 30 days, hospitalization costs, parental satisfaction, and growth from admission to 6 months after surgery. RESULTS: 73 and 75 patients were assigned to the TRAD and ERAS groups, respectively. There were no significant differences in demographic data. The LOS decreased from 9.5 days in the TRAD group to 7.9 days (P < 0.001) in the ERAS group. WBC count on POD 1 showed no significant difference between the two groups. CRP on POD 1 in the ERAS group was significantly lower (P < 0.001). In the ERAS group, the blood glucose was higher at anesthesia compared to the TRAD group (P < 0.001). On the contrary, the blood glucose at 24 h after surgery was significantly lower in the ERAS group (P < 0.001). Intraoperative fluid volume was lower in the EARS group (P < 0.001). ERAS could also reduce the time to first defecation (P < 0.001), discontinuation of intravenous infusion (P < 0.001) and regular diet (P < 0.001). In the ERAS group, the concentrations of prealbumin and retinol conjugated protein on POD 5 were higher than those in the TRAD group (P < 0.001, P < 0.001, respectively). The plasma natrium had no difference in the two groups on POD 5 (P > 0.05). The rate of complications (P > 0.05) and 30-day re-admission (P > 0.05) were not significantly different between the two groups. Hospitalization costs were also reduced (P < 0.001). ERAS group has a higher parental satisfaction rate, although there was no statistical difference (96% vs 89%). There was no difference in growth between the ERAS and the TRAD groups from admission to 6 months after the surgery (weight for age z score: P > 0.05, weight for length z score: P > 0.05). We also found that the shortening of LOS by the application of ERAS protocol was more obvious in the OPPT group (-2.5 ± 1.0) than that in the TEPT (-1.9 ± 1.3) and LAPT (-1.3 ± 0.4) groups. CONCLUSIONS: Implementation of the ERAS protocol in infants undergoing HSCR pull-through operations is safe and efficient. The ERAS protocol is worthy of recommendation. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02776176.

Correction: Downregulation of lncRNA MEG3 and miR-770-5p inhibit cell migration and proliferation in Hirschsprung's disease.

[This corrects the article DOI: 10.18632/oncotarget.19207.].

Role of D2 gastrectomy in gastric cancer with clinical para-aortic lymph node metastasis.

BACKGROUND: Owing to the technical difficulty of pathological diagnosis, imaging is still the most commonly used method for clinical diagnosis of para-aortic lymph node metastasis (PALM) and evaluation of therapeutic effects in gastric cancer, which leads to inevitable false-positive findings in imaging. Patients with clinical PALM may have entirely different pathological stages (stage IV or not), which require completely different treatment strategies. There is no consensus on whether surgical intervention should be implemented for this group of patients. In particular, the value of D2 gastrectomy in a multidisciplinary treatment (MDT) approach for advanced gastric cancer with clinical PALM remains unknown. AIM: To investigate the value of D2 gastrectomy in a MDT approach for gastric cancer patients with clinical PALM. METHODS: In this real-world study, clinico-pathological data of all gastric cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Sciences between 2011 and 2016 were reviewed to identify those with clinically enlarged PALM. All the clinico-pathological data were prospectively documented in the patient medical record. For all the gastric cancer patients with advanced stage disease, especially those with suspicious distant metastasis, the treatment methods were determined by a multidisciplinary team. RESULTS: In total, 48 of 7077 primary gastric cancer patients were diagnosed as having clinical PALM without other distant metastases. All 48 patients received chemotherapy as the initial treatment. Complete or partial response was observed in 39.6% (19/48) of patients in overall and 52.1% (25/48) of patients in the primary tumor. Complete response of PALM was observed in 50.0% (24/48) of patients. After chemotherapy, 45.8% (22/48) of patients received D2 gastrectomy, and 12.5% (6/48) of patients received additional radiotherapy. The postoperative major complication rate and mortality were 27.3% (6/22) and 4.5% (1/22), respectively. The median overall survival and progression-free survival of all the patients were 18.9 and 12.1 mo, respectively. The median overall survival of patients who underwent surgical resection or not was 50.7 and 12.8 mo, respectively. The 3-year and 5-year survival rates were 56.8% and 47.3%, respectively, for patients who underwent D2 resection. Limited PALM and complete response of PALM after chemotherapy were identified as favorable factors for D2 gastrectomy. CONCLUSION: For gastric cancer patients with radiologically suspicious PALM that responds well to chemotherapy, D2 gastrectomy could be a safe and effective treatment and should be adopted in a MDT approach for gastric cancer with clinical PALM.

Circular RNA CCDC66 targets DCX to regulate cell proliferation and migration by sponging miR-488-3p in Hirschsprung's disease.

It has been suggested that circular RNAs play critical roles in natural growth and disease development. Nevertheless, whether the circular RNAs were related in Hirschsprung's disease (HSCR) remains unknown. Thus, we discovered the cir-CCDC66 was downregulated in HSCR compared with the normal gut tissues. The cir-CCDC66 reduction might inhibit cells' proliferation and migration in vitro. Then, we found that DCX transcript was putative cir-CCDC66 competing endogenous RNA. Furthermore, the function of cir-CCDC66 as a sponge for miR-488-3p to regulate DCX RNA expression was demonstrated by immunoprecipitation and luciferase reporter assays. In conclusion, this is the first report revealing that cir-CCDC66 modulates DCX expression through sponging miR-488-3p and thus participates in the onset of HSCR.

Erratum: LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR: Erratum.

[This corrects the article DOI: 10.7150/ijms.18392.].

The Amount of Bifidobacterium Genus in Colorectal Carcinoma Tissue in Relation to Tumor Characteristics and Clinical Outcome.

Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74-2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16-3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer.