Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation.

Inflammatory bowel diseases (IBDs), such as Crohn's disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-α) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-α Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-α (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-α Ab neutralized TNF-α inhibition in vitro. The effects of anti TNF-α Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.

Social capital in a time of uncertainty: A case study of COVID-19 in Maharashtra state, India.

A novel coronavirus disease (COVID-19) was reported in India in late January 2020, less than 50 days after the first case was reported in Wuhan, China. Knowingly or unknowingly, almost all aspects of humankind around the world are affected, including physical, mental, and financial aspects. We set out to investigate how local communities take preventive action and have a meaningful role in dealing with these impacts of COVID-19. This community role is absolutely based on trust, regular communication, and social networking among community members. We collected data from India to determine whether the community-level response to COVID-19 during the peak phase of the pandemic (January 1st to February 1st, 2021) depended on the level of social capital. The source of information on COVID-19 is one of the significant issues during the pandemic. People prefer to depend on and trust family members, who represent the only trustworthy source of information irrespective of where they bring the information. In general, regular participation in local activities plays a major role in preventing COVID-19 at the local level.

[A Resected Case of Cancer in the Ileum of the Blind Loop after an Ileotransverse Colostomy].

We report a resected case of cancer at the ileum of the blind loop. An 81-year-old male underwent an appendectomy for acute appendicitis and an ileotransverse colostomy for postoperative obstruction when he was 14 years old. He underwent radiation therapy for prostate cancer when he was 75 years old. Six years later, enhanced computed tomography revealed a 7 cm mass in the ileum of the blind loop. Colonoscopy showed wall thickening at the ileum of the blind loop, and biopsy revealed an adenocarcinoma. We performed partial resection of the ileum. The patient was discharged 17 days after surgery. Cancer at the ileum of the blind loop after an ileotransverse colostomy has rarely been reported.

Oral rehydration solution normalizes plasma renin and aldosterone levels in patients with ulcerative colitis after proctocolectomy.

OBJECTIVES: The possible effects and benefits of oral rehydration solution (ORS) on chronic dehydration after total proctocolectomy. METHODS: To evaluate the effect of ORS on the renin-angiotensin system after remnant proctocolectomy in patients with ulcerative colitis (UC), we selected 20 patients after remnant proctocolectomy, ileal J pouch-anal anastomosis, and construction of a diverting ileostomy for UC. Patients were randomly divided into two groups, A (n=9) or B (n=11), 2 weeks after the surgery. In group A, ORS (1000 mL/day) was given for the first 7 days and mineral water (1000 mL/day) for the next 7 days. In group B, mineral water (1000 mL/day) was given for the first 7 days and ORS (1000 mL/day) for next 7 days. Plasma levels of renin, aldosterone and excretion of sodium in urine were evaluated at days 0, 7, and 14. We defined day 0 as the day of beginning this study. RESULTS: Mean plasma renin levels on day 0 were six to eight times greater than the upper normal limit. In group A, ORS lowered plasma renin levels. In group B, plasma levels of renin and aldosterone after ORS were lower than those at days 0 and 7. CONCLUSIONS: ORS corrected increased plasma levels of renin and aldosterone to within the normal range in patients after proctocolectomy.

Tumescent TAPP: laparoscopic inguinal hernia repair after the preperitoneal tumescent injection of diluted lidocaine and epinephrine saline solution and carbon dioxide gas.

PURPOSE: Laparoscopic transabdominal preperitoneal inguinal hernia repair (TAPP) is technically difficult and not infrequently followed by postoperative complications and pain, especially when performed by inexperienced surgeons. To simplify TAPP and reduce postoperative pain, we devised a novel procedure whereby TAPP is carried out after the inguinal preperitoneal infiltration of diluted lidocaine and epinephrine saline solution and carbon dioxide gas (tumescent TAPP). This report introduces the concept of tumescent TAPP and summarizes its operative results. METHODS: About 120 ml of diluted lidocaine and epinephrine solution and 60 ml of CO2 gas were infiltrated into the inguinal preperitoneal space through a transabdominal needle before TAPP. Tumescent TAPP was performed for 400 patients (355 men, 45 women; mean age, 63.2 years). RESULTS: Using tumescent TAPP, we found it easier to confirm the inguinal anatomy and dissect the preperitoneal layer and inguinal floor, with less bleeding. The mean operation time was 101.9 min and there were few perioperative complications and minimal pain. CONCLUSIONS: Tumescent TAPP makes conventional TAPP easier and safer; however, this procedure should be verified by a comparative study with conventional TAPP.

Parastomal hernia repair with the Sugarbaker technique using e-PTFE mesh.

PURPOSES: Although surgery is commonly used to treat parastomal hernia, it is very difficult and has shown poor results. Recently, repair with prosthetic materials has been thought to be a more promising method. METHODS: The Sugarbaker technique with e-PTFE mesh (Dualmesh®) performed via open surgery was adopted for seven patients with parastomal hernia. Two of them were recurrent cases. Three of the patients experienced incarceration of the intestine and recovered conservatively before surgery. The median age of the patients at the parastomal hernia repair was 77.6 years old (range 37.7-84.7). RESULTS: The median operative time was 211 min (range 147-256). The median hernia size was 28 cm2 (range 7.5-60 cm2). The median amount of blood loss during the operation was 158 g (range 0-370 g). Surgical site infection was not observed. The postoperative median hospital stay was 17 days (range 13-40) and the median follow-up was 2.4 years (range 1.0-3.7). During the follow-up period, we did not observe recurrence or readmission. CONCLUSIONS: The surgical results were satisfactory with minimal morbidity and no recurrences. The Sugarbaker technique for parastomal repair using e-PTFE mesh may be suitable as a standard method for treating parastomal hernia.

[Surgical management of intestinal Crohn's disease].

Various intestinal conditions such as stricture, fistula, abscess, perforation, and hemorrhage are complications of Crohn's disease. Surgical intervention remains important, even in the era of biologic therapy. Limited surgical resection is essential to avoid short bowel syndrome after massive resection or multiple operations. Strictureplasty is effective for short, isolated stricture of the small intestine and provides good results equivalent to those of intestinal resection. Fecal diversion in the case of very complicated lesions not suitable for immediate resection can offer patients general and local improvement. Although bypass surgery is currently not performed because of the possibility of deterioration or carcinogenesis of the bypassed segment, bypass surgery is useful for avoiding stoma. Laparoscopic surgery is indicated for patients with nonperforating, localized ileocecal lesions, and for those presenting initially. The cumulative postoperative reoperation rate is about 50% to 60% at 10 years. The risk factors for early recurrence are smoking, perforating type, previous reoperation, and small intestinal disease. During postoperative follow-up and maintenance treatment, the importance of an algorithm comprising regular check-ups with ileocolonoscopy and the use of thioprines and biologics has been proposed.

Gastrointestinal toxicities of 5-fluorouracil increase the proportion of regulatory T cells in intestinal tract: advantages of alternate-day S-1 administration.

BACKGROUND: 5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy. METHODS: In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry. RESULTS: Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets. CONCLUSION: GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.

Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: a shorter drug-free interval leads to more efficient antitumor effects.

BACKGROUND: A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models. METHODS: Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis. RESULTS: Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP. CONCLUSION: Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.

Ileocecal ulcers accompanied by relapsing polychondritis: a case report.

INTRODUCTION: Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is a rare overlap syndrome that includes features characteristic of both Behçet's disease (BD) and relapsing polychondritis (RP). CASE DESCRIPTION: A 30-year-old female complained of lower abdominal pain and bloody stools during medical treatment for RP. Total colonoscopy revealed oval-shaped deep ulcers on the terminal ileum similar to those of intestinal BD. After performing the ileocecal resection, both RP and gastrointestinal lesions relapsed, but improved with infliximab treatment. DISCUSSION AND EVALUATION: During medical treatment for RP, we experienced a rare case with ileocecal ulcers similar to intestinal BD. Although our case did not meet the diagnosis criteria of intestinal BD because of the lack of BD's major clinical symptoms, intestinal lesions shared quite similar features with intestinal BD. Our case could possibly be a rare subtype of MAGIC syndrome that had the features characteristic of both intestinal BD and RP. CONCLUSIONS: We described a rare case of ileocecal ulcers without any BD symptoms but accompanied by RP, possibly be a subtype of MAGIC syndrome.

Adenocarcinoma associated with perianal fistulas in Crohn's disease.

AIM: The purpose of the present study was to examine the possible relation between anorectal carcinoma and infliximab therapy for Crohn's disease. PATIENTS AND METHODS: This study reviewed the medical records of patients with perianal Crohn's disease, who have required surgical intervention at the Tohoku University Hospital since May 2002, when infliximab was approved as a remedy for Crohn's disease in Japan. RESULTS: Ninety-two patients underwent surgery due to perianal Crohn's disease between May 2002 and December 2011. Four out of 92 patients were diagnosed as having anorectal carcinoma associated with perianal fistula. All four patients had advanced carcinoma, and received infliximab before the diagnosis of cancer was made. Infliximab was administered due to an exacerbated anal lesion in three patients. CONCLUSION: Careful inspection and obtaining of a biopsy sample under anesthesia is recommended for patients with Crohn's disease who have long-standing anal fistulas, especially before infliximab administration due to a possible exacerbation of anal symptoms.

Young-onset peri-anorectal leiomyomatosis: report of a case.

A 23-year-old female was referred with constipation that lasted for 2 years. Preoperative examinations revealed multiple submucosal tumors beside the anorectum, along with subcutaneous tumors in the left buttock. The pathological diagnosis was leiomyoma. Low anterior resection of the rectum with regional lymph node dissection, along with the resection of the subcutaneous tumors in the left buttock through the transdermal approach, was performed, since multiple tumor formation indicated a high malignant potential. The tumors were diagnosed as multiple leiomyomas with no malignancy. Disease categories such as intravenous leiomyomatosis, leiomyomatosis peritonealis disseminata, Alport syndrome, and Currarino syndrome have been reported to be associated with leiomyomatosis; however, the current case of "peri-anorectal leiomyomatosis" was not classified into any of these. The patient was monitored with careful checkups, and the postoperative course was satisfactory for over 5 years without any sign of recurrence or metastasis. Although the clinicopathological features of this case are quite rare and no therapeutic guidelines for such a disease have yet been established, radical resection should be considered, and the elucidation of the histogenesis of this disease will help establish future therapeutic guidelines.

[Therapeutic strategy for neuroendocrine tumor of the rectum].

The clinicopathological features of neuroendocrine tumor (NET) of the rectum were retrospectively analyzed in 25 patients( 17 men and 8 women; mean age, 57 years[ 30-78 years]) at Tohoku University Hospital from January 1998 to December 2012. The average diameter of 25 tumors was 15 mm (5-70 mm). Local resections and rectal resections with lymph node dissection were performed in 16 and 9 tumors, respectively. Three of the 9 tumors had lymph node metastases (33%), including 2 tumors with a diameter of 10 mm. In a median follow-up of 48 months, tumor recurrence was observed in 3 of 25 patients( 12%); local recurrence was observed in 1 patient; and liver metastasis was observed in 2 patients. Of the 2 patients with liver metastasis, liver metastasis recurred in a patient whose primary tumor, with a diameter of 10 mm, had been locally resected 40 months ago. According to histopathological analysis, 3 primary tumors with local recurrence or liver metastasis were categorized as G2 or G3 according to the World Health Organization (WHO) classification. Tumors with a diameter of ≥10 mm, in principle, may be removed by rectal resection with lymph node dissection. However, histopathological findings such as a proliferation of tumor cells should also be taken into consideration when deciding the treatment strategy for rectal NET.

Results of modified uncut Roux-en-Y reconstruction after distal gastrectomy for gastric cancer.

BACKGROUND/AIMS: The frequent occurrence of bile gastritis and esophagitis associated with dehiscence of 'uncut' jejunal portion was of concern for "uncut" Roux-en-Y reconstruction after distal gastrectomy. Our aim was to study if our technique of a modified, uncut Roux-en-Y procedure would decrease this dehiscence. METHODOLOGY: Ten patients with gastric cancer underwent distal gastrectomy with a modified, uncut Roux-en-Y reconstruction. Transmural silk stitches were added around the staples at the "uncut" portion in attempt to prevent dehiscence of the staple line. Dehiscence of the jejunum at the enterically closed site was investigated endoscopically or fluoroscopically. RESULTS: Mean operative time and intraoperative blood loss were 246 minutes and 381 mL, respectively. Morbidity occurred in three patients. No dehiscence was observed in any of the patients examined. CONCLUSIONS: These results suggest the possibility that our technique of a modified, uncut Roux-en-Y reconstruction after distal gastrectomy decreases dehiscence of enterically closed portion.

IL-23 directly enhances the proliferative and invasive activities of colorectal carcinoma.

Interleukin-23 (IL-23) plays an essential role in the mucosal immune system. It has been suggested that IL-23 is able to induce carcinogenesis as well as inflammation and a recent study revealed that IL-23R is expressed in colorectal carcinoma cells. However, neither the differences in the IL-23R expression among the patients nor the concrete functions of IL-23 in colorectal carcinoma cells have been revealed. The aim of the present study was to examine the characteristics of IL-23R expression in colorectal carcinoma and the direct effects of IL-23 on colorectal cancer cells. We examined the IL-23R expression in human colorectal cancer tissue samples by immunohistochemistry. Cell proliferation and invasion assays under IL-23 stimulation were performed using cultured cells derived from colorectal cancer. ELISA and real-time PCR were used to evaluate the transforming growth factor (TGF)-ß production due to IL-23 stimulation. All of the TNM stage IV patients were positive for IL-23R. IL-23R expression in the carcinoma tissue was also relatively high at the deepest point of invasion in certain cases. The proliferative and invasive activities and/or TGF-ß production of DLD-1 cells increased by IL-23 stimulation, whereas no change was observed in the activities of MIP101 and KM12c cells. IL-23 directly enhanced the malignancy of the colon carcinoma cells. An autocrine mechanism via TGF-ß production may underlie these effects. IL-23 is therefore a potential target for cancer immunotherapy. However, the homogeneity in IL-23R expression and the effects of IL-23 on colorectal carcinoma cells should be considered.

A shift from colon- to ileum-predominant bacteria in ileal-pouch feces following total proctocolectomy.

BACKGROUND: We previously investigated fecal flora of the pouch after total proctocolectomy using terminal restriction fragment polymorphism analysis. Although the results of the cluster analysis demonstrated clearly that bacterial populations, including an unidentified bacteria generating a 213-bp PCR fragment, moved toward a colon-like community in the pouch, it did not track changes in the individual species of fecal bacteria. AIMS: The aim of the present study was to estimate genome copy number of ten bacterial species, clusters, groups, or subgroups (including the bacteria generating 213-bp fragment in the previous study) in feces samples from pouches at various times following ileostomy closure. METHODS: A total of 117 stool samples were collected from patients with ulcerative colitis after surgery as well as healthy volunteers. We used real-time polymerase chain reaction of the 16S rRNA gene to estimate genome copy numbers for the nine bacterial populations and the bacteria generating 213-bp fragment after identification by DNA sequencing. RESULTS: We demonstrated a time-dependent increase in the number of anaerobic and colon-predominant bacteria (such as Clostridium coccoides, C. leptum, Bacteroides fragilis and Atopobium) present in proctocolectomy patients after stoma closure. In contrast, numbers of ileum-predominant bacterial species (such as Lactobacillus and Enterococcus faecalis) declined. CONCLUSIONS: Our data confirm previous findings that fecal flora in the pouch after total proctocolectomy changes significantly, and further demonstrate that the number and diversity of ileal bacteria decreases while a more colon-like community develops. The present data are essential for the future analysis of pathological conditions in the ileal pouch.

The long-term clinical course of pouchitis after total proctocolectomy and IPAA for ulcerative colitis.

BACKGROUND: Pouchitis is the most common long-term complication after restorative total proctocolectomy and IPAA for ulcerative colitis. OBJECTIVE: We examined the incidence, clinical aspects, and long-term outcome of patients with idiopathic pouchitis. DESIGN: This study was a retrospective review of medical records. PATIENTS: Included in the study were 284 patients with ulcerative colitis who underwent a total proctocolectomy and IPAA. MAIN OUTCOME MEASURES: We evaluated the cumulative risk and long-term outcome of pouchitis including the duration of disease, pattern of relapse, and responsiveness to antibiotic therapy. RESULTS: Sixty-four patients developed idiopathic pouchitis. The cumulative risk was 10.7% at 1 year, 17.2% at 2 years, 24.0% at 5 years, and 38.2% at 10 years. At their first pouchitis episode, 45 patients had acute pouchitis, 19 patients had chronic pouchitis, and all patients received antibiotic therapy with oral ciprofloxacin and/or metronidazole. The efficacy of the therapy was 96.6% initially. Forty-five patients had antibiotic-responsive pouchitis, 17 patients had antibiotic-dependent pouchitis, and 2 patients had antibiotic-refractory pouchitis at their first episode. Whereas 20 of 45 patients (44.4%) with initially acute pouchitis experienced 2 or more relapses, 16 of 19 patients (84.2%) with initially chronic pouchitis had 2 or more relapses. After taking into account the relapses, the number of patients with antibiotic-responsive pouchitis decreased from 45 to 40, the number with antibiotic-dependent pouchitis increased from 17 to 20, and the number with antibiotic-refractory pouchitis increased from 2 to 4. Among the 4 patients with antibiotic-refractory pouchitis, 3 patients had Clostridium difficile-associated pouchitis. LIMITATIONS: This study was retrospective. CONCLUSION: The patients with chronic pouchitis at the first episode tend to have a higher incidence of relapse. In some patients, the responsiveness to antibiotic therapy changes during follow-up. When patients with pouchitis do not respond to standard antibiotic therapy, then the occurrence of C difficile infection should be considered.

A unique variant of afferent limb syndrome after ileal pouch-anal anastomosis: a case series and review of the literature.

BACKGROUND: Afferent limb syndrome is a relatively rare cause of small bowel obstruction after restorative total proctocolectomy with ileal pouch-anal anastomosis for patients with ulcerative colitis or familial adenomatous polyposis. DISCUSSION: This report describes three patients who developed recurrent small bowel obstruction after ileal pouch-anal anastomosis. The bowel obstruction was caused by torsion of the ileum at the inlet of the ileal J-pouch, which was thought to be a variant of afferent limb syndrome. This variant of afferent limb syndrome is characterized by a flexible afferent limb of the pelvic pouch due to the lack adhesion of the ileum in the abdominal cavity. Preoperative diagnosis required multiple series of contrast small bowel enemas. Strictureplasty and ileopexy effectively resolved the recurrent bowel obstruction caused by this variant of afferent limb syndrome.

Inhibitor of apoptosis protein family as diagnostic markers and therapeutic targets of colorectal cancer.

The apoptosis and antiapoptotic signaling pathways are important for regulating carcinogenesis and cancer progression, and for determining prognosis. Molecules involved in apoptosis represent potential cancer diagnostic markers and therapeutic targets. The inhibitor of apoptosis protein (IAP) family includes several important molecules involved in apoptosis that might represent such targets. Increasing evidence has demonstrated that the IAP family of proteins is integral for antiapoptotic and nuclear factor-κB signal transduction, and enhanced expression of IAPs contributes to colon carcinogenesis and its poor prognosis, as well as to drug resistance of tumors. X-linked IAP, cIAP1, cIAP2, and survivin are prognostic markers of colorectal cancer, and survivin and cIAP2 are also utilized to predict the effect of anticancer treatment in colorectal cancer patients. Novel therapies such as YM155 and LY2181308 targeting survivin, AEG35156 and phenoxodiol targeting X-linked IAP, AT-406 as a Smac mimetic, and survivin peptides are currently being evaluated in clinical trials. This report reviews the involvement of the IAP family in colorectal adenocarcinoma in order to summarize the role of the IAP family members as diagnostic and therapeutic targets, and to provide an overview of the future course of research in this area.