Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition.

BACKGROUND AND AIM: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. METHODS: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. RESULTS: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. CONCLUSION: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

Therapeutic Drug Monitoring of Golimumab for the Prediction of Long-Term Clinical Remission in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: A considerable number of patients with ulcerative colitis (UC) who initially respond to golimumab (GLM), an anti-TNF-α antibody, gradually lose clinical response. Therapeutic drug monitoring has been proposed to optimize serum anti-TNF-α antibody concentrations before the loss of response; however, little is known about ideal serum GLM concentrations. We aimed to evaluate whether the serum GLM trough levels (TLs) early after the initiation of induction therapy affect the long-term outcomes in UC and to identify the early GLM TLs that should be targeted for better long-term outcomes. METHODS: Thirty-one patients were prospectively evaluated. The primary outcome was clinical remission at 54 weeks, and we measured the serum GLM TLs at weeks 6, 10, and 14. Receiver operating characteristic (ROC) curves were constructed to identify optimal GLM TL thresholds early after induction therapy that were associated with clinical remission at week 54. RESULTS: The GLM TL at week 14, but not at weeks 6 or 10, was significantly associated with clinical remission at week 54 (median [IQR] 1.6 [1.3-1.6] µg/mL vs. 0.9 [0.6-1.3] µg/mL; p = 0.04). The area under the ROC curve for GLM TLs at week 14 was 0.78. We identified a week-14 GLM TL of 1.1 µg/mL as the target threshold for achieving clinical remission at week 54. CONCLUSION: Our results demonstrate the value of early serum GLM TLs in predicting the long-term outcomes of GLM for patients with UC.

Risk Factors for Nephrotoxicity due to Tacrolimus Therapy for Ulcerative Colitis.

BACKGROUND AND AIMS: The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC. METHODS: We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months. RESULTS: Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016). CONCLUSION: We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment.

[Effect of an educational admission program for patients at the conservative phase of chronic kidney disease (CKD)].

PURPOSE: We have been conducting a 1-week educational admission program for patients at the conservative phase of chronic kidney disease (CKD) since 2006. In this study we evaluated the effect of the program. METHODS: We retrospectively reviewed 469 patients who could be followed for 12 months after a 1-week educational admission program for CKD out of a total of 700 patients who attended the program between October 2006 and April 2012. We compared the rates of decrease in renal function before and after the program. In addition, we divided the patients into two groups of diabetic nephropathy and non-diabetic nephropathy. We compared the rate of decrease in renal function in each group. RESULTS: The rate of decrease in renal function 12 months after discharge was improved compared with that 6 months before admission. (before: 0.316 mL/min/1.73 m2/month; after: 0.001 mL/min/1.73 m2/month.) The rate of decrease in renal function 6 months before admission of the diabetic nephropathy group was 72.3 times faster than that of the non-diabetic nephropathy group. However, the rate of decrease in renal function 12 months after admission was improved in both groups. CONCLUSION: It was revealed that the educational admission program is effective for preserving the renal function on patients at the conservative phase of CKD.

Serum IL-13 Predicts Response to Golimumab in Bio-Naïve Ulcerative Colitis.

A certain number of patients with ulcerative colitis (UC) are refractory to anti-TNF-α antibodies; biomarkers are thus needed to predict treatment efficacy. This study aimed to evaluate whether serum biomarkers that were reported to be associated with UC or anti-TNF-α antibody could predict the response to golimumab, a human anti-TNF-α monoclonal antibody, in bio-naïve patients with UC. We prospectively enrolled 23 consecutive patients with UC who were treated with golimumab. Serum samples were collected before the first golimumab dose. Eleven molecules were measured by electrochemiluminescence (ECL) or enzyme-linked immunosorbent assay (ELISA) and their association with efficacy after 10 weeks of golimumab treatment. Among the serum biomarkers, IL-13 levels were significantly higher in the non-remission group than in the remission group (p = 0.014). IL-15 levels were significantly lower in the non-response group than in the response group (p = 0.04). For clinical remission at week 10, the IL-13 0.20 concentration of pg/mL was associated with a sensitivity and specificity of 82.4% and 83.3%, respectively. Serum IL-13 may be a biomarker to predict golimumab efficacy in biologic-naïve patients with UC, and thus may help to tailor personalized treatment strategies.

Recurrence after ESD curative resection for early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is gaining ground as a minimally invasive treatment for early gastric cancer (EGC) that has a negligible risk of lymph node metastasis. According to the 5th edition of Japanese gastric cancer treatment guidelines, annual or biannual follow-up with endoscopy is recommended, but follow-up with abdominal ultrasonography or computed tomography (CT) for surveillance of metastases is not recommended after the eCuraA resection. However, we experienced a case of lymph node recurrence following ESD resulting in eCuraA. CASE PRESENTATION: A 76-year-old female received ESD for EGC in a previous hospital 4 years ago. Pathological findings were tub1, 30 mm, T1a (M), UL0, Ly0, V0, pHM-, pVM- (eCuraA) according to the 15th edition of Japanese Classification of Gastric Carcinoma. Follow-up esophagogastroduodenoscopy revealed submucosal tumor, which was suspected as a swollen lymph node by CT and endoscopic ultrasound fine-needle aspiration revealed the recurrence of gastric cancer. We performed total gastrectomy with D2 lymph node dissection. Postoperative pathological examination revealed no local recurrent tumor at the ESD site in the stomach. Swollen lymph node was diagnosed as metastasis and lymph node metastasis was limited near the cardia. CONCLUSION: This case provides valuable information about tumor with a minimum poorly differentiated adenocarcinoma component may develop lymph node metastasis even satisfying the guidelines criteria for curative resection.

Enhancement of O-linked N-acetylglucosamine modification promotes metastasis in patients with colorectal cancer and concurrent type 2 diabetes mellitus.

Reversible post-translational modification of serine and threonine residues by O-linked N-acetylglucosamine (O-GlcNAc), termed O-GlcNAcylation has been indicated to regulate the activities of a number of different proteins. Augmented O-GlcNAcylation contributes to the etiologies of type 2 diabetes mellitus (T2DM) and cancer. Moreover, diabetic conditions increase the risk of colorectal cancer. However, the effect of O-GlcNAcylation in patients with colorectal cancer and concurrent T2DM has not been elucidated. The current study evaluated the level of O-GlcNAcylation in patients with colorectal cancer with or without T2DM. Notably, O-GlcNAcylation levels were significantly higher in tissues from patients with T2DM compared with those in patients without T2DM, and higher in cancer tissues compared with corresponding adjacent tissues. O-GlcNAcylation and cancer stage were more strongly correlated in cancer tissues from patients with T2DM compared with those from patients without T2DM. Additionally, distant metastasis was significantly correlated with O-GlcNAcylation in cancer tissues from patients with T2DM. ß-catenin levels in colorectal cancer tissues were the highest in patients with advanced-stage cancer and concurrent T2DM. In SW480 human colon cancer cells, thiamet G (TMG) treatment and OGA silencing, which increased O-GlcNAcylation, significantly increased ß-catenin and SNAIL in high-glucose, but not during normal-glucose conditions. These data suggest that O-GlcNAcylation is closely associated with distant metastasis, most likely through upregulation of the ß-catenin/SNAIL signaling pathway in colorectal cancer patients with T2DM.

Superficial non-ampullary duodenal cancer identified by small-bowel capsule endoscopy: a case report (with video).

Herein, we report for the first time a case of a surficial superficial non-ampullary duodenal cancer causing obscure intestinal bleeding that was identified by small-bowel capsule endoscopy and treated by endoscopic mucosal resection. A 73-year-old man underwent upper gastrointestinal endoscopy to identify the cause of anemia. Although conventional duodenoscopy revealed a flat, elevated 5-mm lesion with a central recess and "milk-white mucosa" at the inferior duodenal angulus, capsule endoscopy revealed a white nodular 5-mm lesion with central recess at the duodenum slightly to the anal side from the major duodenal papilla. Pathohistological examination revealed a low-grade well-differentiated tubular adenocarcinoma growing locally in the mucosal layer. Although capsule endoscopy detected a nodular lesion, conventional endoscopy revealed a flat, elevated lesion. The cause of this difference in endoscopic findings is considered to be the degree of extension of the intestinal mucosa. In contrast, "milk-white mucosa" as a typical finding of superficial duodenal tumor in conventional endoscopy could be identified as a white mucosal color tone in capsule endoscopy. Conventional endoscopic findings of irregular surface structure in the lesion suggested malignancy. Pathohistologically, the ductal structure of the adenocarcinoma was also distorted. Unfortunately, it was difficult to suggest that the lesion was adenocarcinoma based on the endoscopic findings alone.

Approach for differentiating trophoblast cell lineage from human induced pluripotent stem cells with retinoic acid in the absence of bone morphogenetic protein 4.

INTRODUCTION: Placental transport is the first step in chemotherapeutic safety evaluations during pregnancy. However, a well-established in vitro model is not available. We previously reported that a trophoblast layer model using differentiating choriocarcinoma JEG-3 cells (DJEGs) can be used for placental drug transport studies. However, it was necessary to increase the similarities between the syncytiotrophoblast, the main layer of the placental barrier, and the in vitro evaluation model in order for the model to be useful for placental drug transport evaluations. We focused on in vivo similarities of differentiating induced pluripotent stem cells (iPSCs). iPSCs can achieve a syncytiotrophoblast-like form and secrete human chorionic gonadotropin (hCG) following bone morphogenetic protein 4 (BMP4) treatment. However, BMP4-treated iPSCs can differentiate into several cell types. In the placental transport model, a dense syncytiotrophoblast cell layer is necessary for appropriate differentiation. METHODS: The conditions permitting differentiation of iPSCs into syncytiotrophoblasts with retinoic acid (RA) treatment without BMP4 were investigated. The presence of syncytiotrophoblast-like cells was confirmed by measurement of mRNA expression levels of breast cancer resistance protein (BCRP) and paternally expressed 10 (PEG10) in syncytiotrophoblasts. In addition, immunofluorescence imaging of cytokeratin 7 (CK7) induced in trophoblasts was performed. RESULTS: and Discussion: RA-induced iPSCs exhibited these syncytiotrophoblast-like features and hCG secretion was maintained for at least 28 days after treatment with RA (500 nM) without BMP4. These results suggest that RA-induced iPSCs are a suitable in vitro syncytiotrophoblast model that can be used as an indicator of drug placental transport for pharmacotherapy during pregnancy.