MAP7D2 reduces CD8+ cytotoxic T lymphocyte infiltration through MYH9-HMGB1 axis in colorectal cancer.

Immune checkpoint inhibitors (ICIs) represent a new paradigm in cancer immunotherapy, but can be largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs) in colorectal cancer (CRC) patients with microsatellite stable (MSS) tumors. Here, through next-generation sequencing, we identify microtubule-associated protein 7 domain 2 (MAP7D2) as an exploitable therapeutic maneuver to improve the efficacy of ICIs for MSS CRC therapy. In human CRC tissues, MAP7D2 expression is significantly increased in MSS CRC, and MAP7D2 adversely correlates with the presence of antitumor T lymphocytes. In vitro and in vivo experiments demonstrate that MAP7D2 knockdown significantly increases the infiltration of CD8+ CTLs, thereby inhibiting tumor progression and improving the efficacy of ICIs in MSS CRC murine models. Mechanistically, MAP7D2 interacts with MYH9 and protects it from ubiquitin-mediated degradation, subsequently decreasing the secretion of HMGB1, which suppresses the infiltration of CD8+ CTLs in MSS CRC. These findings highlight the importance of MAP7D2 in determining the infiltration of CD8+ CTLs and indicate that targeting MAP7D2 in MSS CRC may present a novel antitumor immunotherapy.

Identification of CRKL as an oncogenic biomarker for prognosis and immunotherapy in melanoma, and its potential molecular mechanism.

CRKL (CRK Like Proto-Oncogene) belongs to the Crk family and is a 39-kDa adapter protein that encodes SH2 and SH3 (src homologs) domains. To identify its oncogenic role in malignant melanoma, we investigated the association between CRKL and mutation, prognosis, tumor mutation burden, immune cell infiltration of melanoma, and explored the associations between CRKL and immunotherapy response. Our results showed that abnormal CRKL expression is associated with poor prognosis in melanoma and is significantly correlated with immune-activated pathways and processes, immune cell infiltrations, and expression of immunoregulators. Importantly, we found that CRKL expression is a predictive biomarker for anti-PD1 therapy response in melanoma patients. Furthermore, inhibiting CRKL expression in melanoma cell lines suppressed their proliferation and metastasis, as well as activated the pyroptosis-related pathway. Our study provides potential mechanisms of melanoma pathogenesis, which may suggest new avenues for targeted therapy in this disease.

Baseline gut microbiome features prior to SARS-CoV-2 infection are associated with host symptoms in and post COVID-19.

The human gut microbiome varies substantially across individuals and populations and differentially tames our immunity at steady-state. Hence, we hypothesize that the large heterogeneity of gut microbiomes at steady-state may shape our baseline immunity differentially, and then mediate discrepant immune responses and symptoms when one encounters a viral infection, such as SARS-CoV-2 infection. To validate this hypothesis, we conducted an exploratory, longitudinal microbiome-COVID-19 study involving homogenous young participants from two geographically different regions in China. Subjects were recruited and sampled of fecal specimens before the 3-week surge window of COVID-19 (between December 11 and December 31, 2022) in China, and then were followed up for assessment of COVID-19 and post-COVID-19 manifestations. Our data showed that the baseline gut microbiome composition was intricately associated with different COVID-19 manifestations, particularly gastrointestinal involvement and post-COVID-19 lingering symptoms, in both an individual- and population-dependent manner. Our study intriguingly for the first time highlight that the gut microbiome at steady-state may prepare us differentially for weathering a respiratory viral infection.

A novel NF-κB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation.

BACKGROUND: Constitutive activation of nuclear factor-κB (NF-κB) signaling plays a key role in the development and progression of colorectal carcinoma (CRC). However, the underlying mechanisms of excessive activation of NF-κB signaling remain largely unknown. METHODS: We used high throughput RNA sequencing to identify differentially expressed circular RNAs (circRNAs) between normal human intestinal epithelial cell lines and CRC cell lines. The identification of protein encoded by circPLCE1 was performed using LC-MS. The function of novel protein was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel protein circPLCE1-411 encoded by circular RNA circPLCE1 was identified as a crucial player in the NF-κB activation of CRC. Mechanistically, circPLCE1-411 promoted the ubiquitin-dependent degradation of the critical NF-κB regulator RPS3 via directly binding the HSP90α/RPS3 complex to facilitate the dissociation of RPS3 from the complex, thereby reducing NF-κB nuclear translocation in CRC cells. Functionally, circPLCE1 inhibited tumor proliferation and metastasis in CRC cells, as well as patient-derived xenograft and orthotopic xenograft tumor models. Clinically, circPLCE1 was downregulated in CRC tissues and correlated with advanced clinical stages and poor survival. CONCLUSIONS: circPLCE1 presents an epigenetic mechanism which disrupts NF-κB nuclear translocation and serves as a novel and promising therapeutic target and prognostic marker.

Endoscopic treatment of pouch inlet and afferent limb strictures: stricturotomy vs. balloon dilation.

BACKGROUND: Strictures are common complications after ileal pouch surgery. The aim of this study is to evaluate the efficacy and safety of endoscopic stricturotomy vs. endoscopic balloon dilation (EBD) in the treatment of pouch inlet strictures. METHODS: All consecutive ulcerative colitis patients with the diagnosis of pouch inlet or afferent limb strictures treated in our Interventional Inflammatory Bowel Disease Unit (i-IBD) from 2008 to 2017 were extracted. The primary outcomes were surgery-free survival and post-procedural complications. RESULTS: A total of 200 eligible patients were included in this study, with 40 (20.0%) patients treated with endoscopic stricturotomy and 160 (80.0%) patients treated with EBD. Symptom improvement was recorded in 11 (42.3%) patients treated with endoscopic stricturotomy and 16 (13.2%) treated with EBD. Subsequent surgery rate was comparable between the two groups (9 [22.5%] vs. 33 [20.6%], P = 0.80) during a median follow-up of 0.6 years (interquartile range [IQR] 0.4-0.8) vs. 3.6 years (IQR 1.1-6.2) in patients receiving endoscopic stricturotomy and EBD, respectively. The overall surgery-free survival seems to be comparable as well (P = 0.12). None of the patients in the stricturotomy group developed pouch failure, while 9 patients (5.6%) had pouch failure in the balloon dilation group (P = 0.17). Procedural bleeding was seen in three occasions (4.7% per procedure) in patients receiving endoscopic stricturotomy and perforation was seen in three occasions (0.8% per procedure) in patients receiving EBD (P = 0.02). In multivariable analysis, an increased length of the stricture (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.0-1.8) and concurrent pouchitis (HR 2.5, 95% CI 1.0-5.7) were found to be risk factors for the requirement of surgery. CONCLUSION: Endoscopic stricturotomy and EBD were both effective in treating patients with pouch inlet or afferent limb strictures, EBD had a higher perforation risk while endoscopic stricturotomy had a higher bleeding risk.

Impact of pelvic dimensions on anastomotic leak after anterior resection for patients with rectal cancer.

AIM: The impact of pelvis on the development of anastomotic leak (AL) in rectal cancer (RC) patients who underwent anterior resection (AR) remains unclear. The aim of this study was to evaluate the impact of pelvic dimensions on the risk of AL. METHODS: A total of 1058 RC patients undergoing AR from January 2013 to January 2016 were enrolled. Pelvimetric parameters were obtained using abdominopelvic computed tomography scans. RESULTS: Univariate analyses showed that pelvic inlet, pelvic outlet, interspinous distance, and intertuberous distance were significantly associated with the risk for AL (P < 0.05). Multivariate analysis confirmed that pelvic inlet and intertuberous distance were independent risk factors for AL (P < 0.05). Significant factors from multivariate analysis were assembled into the nomogram A (without pelvic dimensions) and nomogram B (with pelvic dimensions). The area under curve (AUC) of nomogram B was 0.72 (95% CI 0.67-0.77), which was better than the AUC of nomogram A (0.69, [95% CI 0.65-0.74]), but didn't reach a statistical significance (P = 0.199). Decision curve supported that nomogram B was better than nomogram A. CONCLUSION: Pelvic dimensions, specifically pelvic inlet and intertuberous distance, seemed to be independent predictors for postoperative AL in RC patients. Pelvic inlet and intertuberous distance incorporated with preoperative radiotherapy, preoperative albumin, conversion, and tumor diameter in the nomogram might provide a clinical tool for predicting AL.

circCAMSAP1 Promotes Tumor Growth in Colorectal Cancer via the miR-328-5p/E2F1 Axis.

Increasing studies indicated that circular RNAs (circRNAs) play important roles in cancer progression. However, the roles of circRNAs in colorectal cancer (CRC) remain largely unknown. In this study, we determined the circRNA expression profile by next-generation RNA sequencing from eight CRC and paired non-cancerous matched tissues. circCAMSAP1 (originating from exon 2 to exon 3 of the CAMSAP1 gene, hsa_circ_0001900) was significantly upregulated in CRC tissues. Increased circCAMSAP1 expression was significantly correlated with advanced tumor/node/metastasis (TNM) stage and shortened overall survival. An elevation of circCAMSAP1 expression was detected via droplet digital PCR in the serum of CRC patients prior to surgery. Functionally, circCAMSAP1 promoted the malignant behavior of CRC. Mechanism study of upstream biogenesis of circCAMSAP1 indicated that circCAMSAP1 cyclization in CRC was mediated by splicing factor epithelial-splicing regulatory protein 1. Moreover, circCAMSAP1 acted as a sponge for miR-328-5p and abrogated its suppression on transcription factor E2F1. Taken together, our data indicated an essential role of the circCAMSAP1/miR-328-5p/E2F1 axis in the progression of CRC, which implied that circCAMSAP1 could serve as a diagnostic and prognostic biomarker as well as a potential therapeutic target for CRC.

The malignant role of exosomes in the communication among colorectal cancer cell, macrophage and microbiome.

Colorectal cancer (CRC) is a complex and heterogeneous malignant cancer characterized by its high prevalence and poor prognosis. Among different etiologies, impairment of immune surveillance and dysbiosis are important events to mediate the invasion and metastasis of CRC. Although aberrant distribution of macrophages and microbiota exhibits distinct properties to modulate the malignant behaviors of CRC, the crosstalk among macrophages, microbiomes and tumor cells remains unclear. Exosomes are intercellular messengers carrying different cargo to regulate the biological and pathologic changes of recipient cells. CRC-derived exosomes can educate macrophages and facilitate the angiogenesis and establishment of premetastatic niche. Meanwhile, exosomes from macrophages and microbiome can regulate the tumor microenvironment for tumor progression and dissemination. The aim of this review is to highlight the innovative role of exosomes in the pathogenesis of CRC. Theoretical elaboration of the underlying mechanism provides valuable treating targets of CRC.

Antiviral Treatment for Colonic Cytomegalovirus Infection in Ulcerative Colitis Patients Significantly Improved Their Surgery Free Survival.

BACKGROUND: The frequency of cytomegalovirus (CMV) colitis in steroid-refractory inflammatory bowel disease has been reported to range from 15.8% to 34.0%. Infected patients are more likely to become hospitalized, have longer lengths of stay, and higher mortality rates. Current data are limited to small scale studies and showed conflicting result regarding the role of antiviral therapy. AIMS: (1) To investigate the role of antiviral treatment in ulcerative colitis (UC) patients with CMV infection. (2) To investigate the role of viremia in the outcomes of these patients. MATERIALS AND METHODS: The Cleveland Clinic pathology database identified 1478 patients who had colon biopsy and were tested for CMV during 1990 to 2013. After inclusion and exclusion, 41 UC patients were selected. Among them, 24 (58.5%) received treatment, 17 (41.5%) did not. A total of 14 demographic data and 4 clinical outcomes (surgery free survival, hospitalization, rehospitalization, and mortality) were compared between treated and nontreated patients. The same outcomes were also compared in patients who received treatment based on their viremia status. RESULTS: All demographic variables are similar between those treated and nontreated groups. Antiviral therapy significantly improved the surgery free survival within 30 days, and lasted 70 months (P<0.01). In contrast, hospitalization, rehospitalization, and mortality were comparable (P>0.05). No significant difference was observed in any of the clinical outcomes based on viremia status. CONCLUSIONS: Our small scale study demonstrates that antiviral treatment for colonic CMV infection significantly improves the surgery free survival short-term and long-term in patients with UC.

Enteral nutrition is associated with a decreased risk of surgical intervention in Crohn's disease patients with spontaneous intra-abdominal abscess.

BACKGROUND: The impact of enteral nutrition (EN) on surgical risk in Crohn's disease (CD) patients suffering from spontaneous intra-abdominal abscess (IAA) was evaluated. METHODS: CD patients diagnosed with spontaneous IAA from 2008 to 2015 were included in the study. The impact of EN on surgical risk was evaluated using both univariate and multivariate analyses. RESULTS: A total of 87 patients were enrolled, 66 (75.9%) were male. The mean age at the development of an abscess was 30.2 ± 10.1 years and the median duration of illness from CD diagnosis until the development of an abscess was three (2-6) years. After a median follow-up of 1.9 (1.1-2.9) years, surgical intervention was performed in 42 patients (48.3%). Patients treated with EN were less likely to require surgical intervention (26.1% vs 56.3%, p = 0.01). Multivariate analysis showed that EN was an independent protective factor for the risk of surgery with a hazard ratio of 0.27 (95% confidence interval: 0.11-0.65, p = 0.004) after adjusting for abdominal pain, history of abdominal surgery, concomitant intestinal stenosis and prior use of antibiotics within three months. CONCLUSIONS: Surgical intervention is common for CD patients with IAA. Appropriate application of EN may help obviate the need for surgical treatment.

A Novel Immune Marker Model Predicts Oncological Outcomes of Patients with Colorectal Cancer.

BACKGROUND: The purpose of this study was to develop an in situ immune marker model to predict postoperative oncological outcomes in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry for 13 immune cell markers was performed on tumor tissue microarrays from 300 CRC patients who underwent curative resection from January 2000 to January 2006. Genetic algorithm was applied for the construction of an in situ immune marker model. RESULTS: The infiltration of CD3+ cells, CD45RO+ cells, and FOXP3+ cells, but not the infiltration of Tryptase+ cells, in the tumor was significantly associated with better clinical outcome in overall survival (OS) and disease-free survival (DFS) of CRC patients, as assessed by univariate analysis (P < 0.05). Based on the genetic algorithms, a total of 6 markers, including CD3, CD45RO, IL17, CD15, Tryptase, and FOXP3, were selected to construct an immune marker model. Our model was identified to have an independent predictive capability for both OS and DFS in Cox multivariable model (P < 0.001). This was further confirmed by the ROC analysis (area under curve: OS, 0.669; DFS, 0.684). CONCLUSIONS: The in situ immune marker model constructed in this study provides a novel approach to identify CRC patients who were at an increased risk for poor oncological outcomes.

Impact of Low Immunoglobulin G Levels on Disease Outcomes in Patients with Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs) are considered immune-mediated disorders with dysregulated innate and adaptive immunities. Secondary immunogloblin deficiency can occur in IBD and its impact on the disease course of IBD is not clear. AIMS: We sought to determine associations between low IgG/G1 levels and poor clinical outcomes in IBD patients. METHODS: This historic cohort study was performed on IBD patients with obtained IgG/IgG1 levels. The primary outcome was defined as any IBD-related bowel resection surgery and/or hospitalization. Subgroup analyses assessed particular surgical outcomes in Crohn's disease (CD), ulcerative colitis (UC) or indeterminate colitis (IC), and ileal pouch-anal anastomosis (IPAA). The secondary outcomes included IBD drug escalations and C. difficile or cytomegalovirus infections. RESULTS: A total of 136 IBD patients had IgG/G1 levels checked and adequate follow-up, 58 (42.6 %) with normal IgG/G1 levels and 78 (57.4 %) having low levels. A total of 49 patients (62.8 %) with low immunoglobulin levels had IBD-related surgeries or hospitalizations, compared to 33 patients (56.9 %) with normal levels [odds ratio (OR) 1.28, 95 % confidence interval (CI) 0.64-2.56; p = 0.49]. Low IgG/G1 levels were associated with IBD-related surgery in CD in univariate analysis [hazard ratio (HR) 4.42, 95 % CI 1.02-19.23; p = 0.048] and in Kaplan-Meier survival curve analysis (p = 0.03), with a trend toward significance on multivariate analysis (HR 3.07, 95 % CI 0.67-14.31; p = 0.15). IBD patients with low IgG/G1 levels required more small bowel resections (12.8 vs. 1.7 %, p = 0.024) and 5-aminosalicylate initiations (28.2 vs. 13.8 %, p = 0.045). CONCLUSIONS: Our study demonstrated a possible association between low IgG/G1 levels and poor outcomes in CD including surgery. Future implications include using immunoglobulin levels in IBD patients as a prognostic indicator or boosting humoral immunity as a treatment in this subset.

Restorative proctocolectomy with a handsewn IPAA: S-pouch or J-pouch?

BACKGROUND: The efferent limb on the S-pouch fits well into the anal canal while the body of the pouch lies on the levators. In contrast, the blunt end of a J-pouch may be distorted as it is forced into the muscular tube of the stripped anus. OBJECTIVE: The aim of this study is to compare the clinical outcomes and quality of life between patients with S- and J-pouches with a handsewn IPAA. DESIGN: This study was retrospective. SETTING: This study was conducted at a high-volume tertiary referral center. PATIENTS: Patients undergoing a primary handsewn IPAA from 1983 to 2012 were identified. MAIN OUTCOMES MEASURES: Demographics, operative details, functional outcomes, and quality of life were abstracted. RESULTS: A total of 502 patients, including 169 patients with an S-pouch (33.7%) and 333 patients with J-pouch (66.3%), met our inclusion criteria; 55.8% (n = 280) were men. Mean age at pouch construction was 37.8 ± 12.5 years. Patients with an S-pouch were younger (p = 0.004) and had a higher BMI (p = 0.035) at pouch surgery. There was no significant difference between patients with S- or J-pouches in other demographics. The frequencies of short-term complications in the 2 groups were similar (p > 0.05), but pouch fistula or sinus (p = 0.047), pelvic sepsis (p = 0.044), postoperative partial small-bowel obstruction (p = 0.003), or postoperative pouch-related hospitalization (p = 0.021) occurred in fewer patients with an S-pouch. At a median follow-up of 12.2 (range, 4.3-20.1) years, patients with an S-pouch were found to have fewer bowel movements (p < 0.001), less frequent pad use (p = 0.001), and a lower fecal incontinence severity index score (p = 0.015). The pouch failed in 62 patients (12.4%), but neither univariate nor multivariate analysis showed a significant association with pouch configuration. LIMITATIONS: The use of data from a single tertiary referral center was a limitation of this study. CONCLUSION: We recommend using an S-pouch when constructing an IPAA with a handsewn technique.

Management of sessile malignant polyps: is colonoscopic polypectomy enough?

BACKGROUND: The role of endoscopy in the management of malignant-pedunculated polyps has been well studied, but endoscopic management of malignant sessile polyps has not. Sometimes patients with malignant sessile polyps have comorbidities that make surgery exceptionally risky, and endoscopy beckons as a definitive management option. The aim of this study is to evaluate the potential role of endoscopy in the management of malignant sessile polyps. METHODS: Patients undergoing colonoscopic polypectomy for malignant sessile polyps by a single endoscopist from 1997 to 2010 were evaluated. Demographic data, clinicopathological variables as well as long-term outcomes were recorded. RESULTS: Sixteen patients had malignant sessile polyps. Six (37.5 %) were male and 10 (62.5 %) were female. Mean age at diagnosis was 72.9 ± 12.2 years. Six polyps were proximal to the splenic flexure (37.5 %) and 10 (62.5 %) were distal. The mean size of the polyps was 30.5 ± 15.9 mm. All polyps were removed endoscopically but 7 patients (43.8 %) had formal colectomy following colonoscopic resection. There were no demographic differences between patients with and without surgery. Piecemeal polypectomy was necessary in 8 patients, 4 from the surgery group, and 4 from the endoscopy group. More patients in the surgery group had poorly differentiated cancers (4/6 vs. 0/6) and incomplete margins (5/6 vs. 1/6) and more patients in the endoscopically treated group had serious comorbidity (5/9 vs. 3/7). There was no procedure-related morbidity or mortality. After a mean follow-up of 48.4 ± 27.2 months, one patient from the polypectomy group patient had a local recurrence and a liver metastasis, after originally declining surgery. In the surgery group, one patient had lung metastasis. The two patients who recurred with distant metastasis died. CONCLUSION: Endoscopic management of sessile colorectal polyps appears to be feasible and safe in patients with well/moderately differentiated cancer and negative margins. Larger studies are needed to confirm these findings.

Frequency, manifestations and management of bezoars in ileal pouches

Background and Aim To evaluate the frequency, diagnosis and management of ileal pouch bezoars. Methods Patients diagnosed with ileal pouch bezoars at the P ouch C enter at Cleveland Clinic from 2002 to 2013 were included. Demographic, clinical and endoscopic features, management and outcomes were evaluated. Results Twelve patients with ileal pouch bezoars were enrolled, including five (0.4%) of 1390 patients with J ­pouch and seven (13.0%) of 54 with continent ileostomy (P < 0.001). Males accounted for 25% (n = 3) of the cohort. Mean age at time of detection was 61.5 ± 10.3 years. Of the 12 patients, six (50.0%) had phytobezoars, four (33.3%) had lithobezoars, one (8.3%) had pharmacobezoar and one (8.3%) had a retained­J ackson­P ratt drain. Median number of harvested bezoars was one (range: 1­224), and mean diameter was 4.0 ± 2.4 cm. Bezoars were located at the pouch body in eight (66.7%) patients, pouch inlet in two (16.7%), pouch­anal anastomosis in one (8.3%) and efferent limb in one (8.3%). Ten patients (83.3%) were symptomatic, including seven (58.3%) with partial bowel obstructive symptoms. Eleven patients (91.7%) were initially managed with endoscopic treatment including basket, R othN et® , mechanical lithotripsy T ripod and snares. After a median of one (1­3) endoscopic therapy, bezoars were successfully removed in seven patients (58.3%). Surgical intervention was required in the remaining five patients (41.7%). Conclusions Ileal pouch bezoars appeared to be more frequently encountered in patients with continent ileostomies than in those with J ­pouches. Endoscopic management seemed to be effective in some patients, whereas surgical intervention was needed in others.

Comparable pouch retention rate between pediatric and adult patients after restorative proctocolectomy and ileal pouches.

BACKGROUND & AIMS: We compared long-term outcomes between adult and pediatric patients with inflammatory bowel disease (IBD) who underwent restorative proctocolectomy with ileal pouch-anal anastomosis. METHODS: We performed a retrospective study that analyzed data from consecutive patients with ileal pouches who presented to the subspecialty Pouch Center at the Cleveland Clinic from 2002-2011. Pouch outcomes of 104 pediatric patients (having pouch surgery at age <18 years; 53 male) were compared with those of 1135 adults (having pouch surgery at an age 18 years or older; 632 male). RESULTS: Pediatric patients had a shorter duration from time of IBD diagnosis to colectomy than adult patients. Fewer pediatric than adult patients had a history of smoking, concomitant extraintestinal manifestations, or dysplasia as the indication for colectomy. However, pediatric patients had higher rates of pouch procedure-related complications, postoperative pouch-associated hospitalization, and postoperative use of anti-tumor necrosis factor (TNF) agents. In multivariate analysis, risk factors for pouch failure included preoperative use of anti-TNF agents (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.05-3.13; P = .032), postoperative use of anti-TNF agents (HR, 2.07; 95% CI, 1.31-3.27; P = .002), Crohn's disease of the pouch (HR, 2.21; 95% CI, 1.28-3.82; P = .005), pouch procedure-related complications (HR, 2.68; 95% CI, 1.55-4.64; P < .001), and postoperative pouch-associated hospitalization (HR, 25.20; 95% CI, 14.44-43.97; P < .001). Being a pediatric patient was not significantly associated with pouch failure in univariate or multivariate analyses (HR, 0.6; 95% CI, 0.32-1.16; P = .13). CONCLUSIONS: On the basis of an analysis of patients with IBD who underwent restorative proctocolectomy and presented at a subspecialized Pouch Center, patients who had the surgery at a pediatric age tend to have a higher incidence of postoperative pouch complications than adults. However, long-term rates of pouch retention were comparable.

Significance of mTOR signaling and its inhibitor against cancer stem-like cells in colorectal cancer.

PURPOSE: To determine the role of the mammalian target of rapamycin (mTOR) signaling in sustaining cancer stem-like cells and its clinical values in colorectal cancer (CRC). METHODS: mTOR expression in CRC patients was analyzed by immunohistochemistry and survival analysis was used to confirm the clinical value of mTOR. Colorectal cell lines were treated by mTOR inhibitors rapamycin and PP242, and sphere formation assay and aldehyde dehydrogenase (ALDH) assay were utilized to determine the impact of mTOR inhibition in CRC stem-like cells, combined or not combined with chemotherapeutic drug (fluorouracil and oxaliplatin). RESULTS: mTOR expression was associated with outcomes of CRC patients and predicted poor prognosis in stage II CRC patients. mTOR signaling was activated in stem-like colorectal cancer cells, and mTOR inhibitors (rapamycin and PP242) decreased the capacity of sphere formation as well as ALDH activity. Furthermore, mTOR inhibitors also were demonstrated to suppress the stimulation of stem-like cells by chemotherapy. CONCLUSIONS: mTOR shared predictive significance in stage II CRC patients' outcomes and played a vital role in the maintenance of colorectal cancer stem-like cells. mTOR inhibitors might hold the potential to become a therapeutic target against CRC stem cells.

Twenty-year-old stapled pouches for ulcerative colitis without evidence of rectal cancer: implications for surveillance strategy?

BACKGROUND: The risk of anal transition zone dysplasia/cancer after stapled IPAA for ulcerative colitis might be cumulative over time. OBJECTIVE: The purpose of this work was to assess the long-term incidence and risk factors of anal transition zone dysplasia. DESIGN: This was a retrospective study from a prospectively maintained database. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Participants included those in our surveillance program of serial anal transition zone biopsies after stapled IPAA from 1986 to 1992. MAIN OUTCOME MEASURES: Anal transition zone dysplasia was the main measured outcome. RESULTS: Of 532 patients, 285 had 2 or more anal transition zone surveillance biopsies, including 73 with ≥20 years of regular follow-up. No adenocarcinoma was detected, and 15 patients died of unrelated causes after a median follow-up of 13.4 years (range, 2.9-19.5 years) without dysplasia. The estimated survival rates at 10, 15, and 20 years were 99.6% (95% CI, 96.9-99.9), 98.9% (95% CI, 95.7-99.7), and 92.6% (95% CI, 86.5-96.0). The estimated rates of anal transition zone dysplasia based on the 9 patients were 2.9% (95% CI, 1.5-5.7) and 3.4% (95% CI, 1.8-6.4) at 10 and 15 years. No new-onset dysplasia was identified beyond 125 months. Postoperative anal transition zone dysplasia was significantly associated with both preoperative and pathology findings of colorectal dysplasia (p < 0.001 for each) or cancer (p = 0.025 and p <0.001) and was managed expectantly or with mucosectomy (5 and 4 patients), depending on the number of positive biopsies and degree of dysplasia. Continued surveillance after detection of anal transition zone dysplasia showed no evidence of recurrent dysplasia during a median follow-up of 125 months (range, 9-256 months). LIMITATIONS: Approximately half of the eligible patients were excluded from the analysis because of insufficient follow-up. CONCLUSIONS: Long-term follow-up data corroborate the use of stapled IPAA for ulcerative colitis. Future studies should assess whether a less intensive surveillance strategy is safe 10 years after surgery.

Endoscopic and histologic abnormalities of gastrointestinal tract in patients with hereditary hemochromatosis.

BACKGROUND: Patients with iron overload frequently complained of upper gastrointestinal (GI) symptoms. This study aimed to systemically evaluate the association between hereditary hemochromatosis (HH) and gut inflammation. PATIENTS AND METHODS: HH patients were identified using the ICD-9 codes. Inclusion criteria were patients with primary HH who had esophagogastroduodenoscopy (EGD) and/or colonoscopy with GI biopsies (N=39). Patients undergoing EGD with duodenal biopsy for the indication of "rule out celiac disease" were included in the control group (N=40). GI biopsy specimens were rereviewed and scored. RESULTS: Of the 39 patients with genetically confirmed primary HH in the study group, 28 (71.8%) had liver biopsy and 25 (89.3%) of them showed iron deposition. Twenty-five patients (64.1%) had EGD and 23 (59.0%) had colonoscopy. Histologic inflammation was identified in the esophagus in 2 patients (8.0%), stomach in 11 (44.0%), duodenum in 2 (8.7%), and colon in 3 (13.0%). Duodenal biopsy specimen was available for rereview in 16 patients (41.0%). Patient demographics were comparable between the 16 cases in the study group and the 40 cases in the control group. On histology, the frequency of intraepithelial lymphocytosis of small intestine was 25.5% in the HH cases versus 2.5% in controls (P=0.020). HH patients also had a greater proportion of intraepithelial neutrophil infiltration (31.2% vs. 2.5%, P=0.006) and lamina propria lymphocyte infiltration (31.2% vs. 0%, P=0.001) than controls. CONCLUSIONS: GI inflammation was common in HH patients, which from the different perspective, supports the notion that iron overload may lead to GI inflammation.