MLH1 Inhibits Metastatic Potential of Pancreatic Ductal Adenocarcinoma via Downregulation of GPRC5C.

DNA mismatch repair gene MutL homolog-1 (MLH1) has divergent effects in many cancers; however, its impact on the metastasis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, MLH1 stably overexpressed (OE) and knockdowned (KD) sublines were established. Wound healing and transwell assays were used to evaluate cell migration/invasion. In vivo metastasis was investigated in orthotopic implantation models (severe combined immunodeficiency mice). RT-qPCR and western blotting were adopted to show gene/protein expression. MLH1 downstream genes were screened by transcriptome sequencing. Tissue microarray-based immunohistochemistry was applied to determine protein expression in human specimens. In successfully generated sublines, OE cells presented weaker migration/invasion abilities, compared with controls, whereas in KD cells, these abilities were significantly stronger. The metastasis-inhibitory effect of MLH1 was also observed in mice. Mechanistically, G protein-coupled receptor, family C, group 5, member C (GPRC5C) was a key downstream gene of MLH1 in PDAC cells. Subsequently, transient GPRC5C silencing effectively inhibited cell migration/invasion and remarkably reversed the proinvasive effect of MLH1 knockdown in KD cells. In animal models and human PDAC tissues, tumoral GPRC5C expression, negatively associated with MLH1 expressions, was positively correlated with histologic grade, vessel invasion, and poor cancer-specific survival. In conclusion, MLH1 inhibits the metastatic potential of PDAC via downregulation of GPRC5C.

Clinically Applicable Pan-Origin Cancer Detection for Lymph Nodes via Artificial Intelligence-Based Pathology.

INTRODUCTION: Lymph node metastasis is one of the most common ways of tumour metastasis. The presence or absence of lymph node involvement influences the cancer's stage, therapy, and prognosis. The integration of artificial intelligence systems in the histopathological diagnosis of lymph nodes after surgery is urgent. METHODS: Here, we propose a pan-origin lymph node cancer metastasis detection system. The system is trained by over 700 whole-slide images (WSIs) and is composed of two deep learning models to locate the lymph nodes and detect cancers. RESULTS: It achieved an area under the receiver operating characteristic curve (AUC) of 0.958, with a 95.2% sensitivity and 72.2% specificity, on 1,402 WSIs from 49 organs at the National Cancer Center, China. Moreover, we demonstrated that the system could perform robustly with 1,051 WSIs from 52 organs from another medical centre, with an AUC of 0.925. CONCLUSION: Our research represents a step forward in a pan-origin lymph node metastasis detection system, providing accurate pathological guidance by reducing the probability of missed diagnosis in routine clinical practice.

Preoperative H. pylori Eradication Therapy Facilitates Precise Delineation in Early Gastric Cancer with Current H. pylori Infection.

INTRODUCTION: Early gastric cancer with current Helicobacter pylori infection (HpC-EGC) is common, but it is still unclear whether H. pylori eradication therapy (Hp-ET) or endoscopic submucosal dissection (ESD) should be performed first. We evaluated Hp-ETs short-term effects on horizontal boundary delineations of HpC-EGC in ESD. METHODS: Prospectively enrolled HpC-EGC patients were randomly assigned to eradication or control groups. Operation scopes of HpC-EGC lesions were delineated with marking dots at 5 mm out of the endoscopic demarcation line by an independent endoscopist, unaware of eradication status, before formal circumferential incision. As representatives, precise delineation rate, the shortest distance of all marking dots to the pathological demarcation line in all slices of one intact resected specimen (Dmin), and negative marking dot specimen rate were examined. RESULTS: Twenty-three HpC-EGC patients (25 lesions) were allocated to eradication group and 26 patients (27 lesions) were allocated to the control group with similar eradication success rates and all were differentiated type. With improving background mucosa inflammation after Hp-ET and similar gastritis-like epithelium rates, 10 lesions (40.0%) in the eradication group were of precise delineation compared to control group with 2 lesions (7.4%) (relative risk = 5.40, 95% CI 1.31-22.28). Dmin of eradication and control groups were 4.17 ± 2.52 mm and 2.67 ± 2.30 mm (p = 0.029), accompanied by 4 (14.8%) and none (0.0%) specimens that exhibited positive marking dots (p = 0.11), respectively. CONCLUSION: For HpC-EGC patients, administrating eradication medication before ESD is beneficial for the precise delineation of lesions and reducing the risk of positive horizontal resection margins.

Diagnosing and grading gastric atrophy and intestinal metaplasia using semi-supervised deep learning on pathological images: development and validation study.

OBJECTIVE: Patients with gastric atrophy and intestinal metaplasia (IM) were at risk for gastric cancer, necessitating an accurate risk assessment. We aimed to establish and validate a diagnostic approach for gastric biopsy specimens using deep learning and OLGA/OLGIM for individual gastric cancer risk classification. METHODS: In this study, we prospectively enrolled 545 patients suspected of atrophic gastritis during endoscopy from 13 tertiary hospitals between December 22, 2017, to September 25, 2020, with a total of 2725 whole-slide images (WSIs). Patients were randomly divided into a training set (n = 349), an internal validation set (n = 87), and an external validation set (n = 109). Sixty patients from the external validation set were randomly selected and divided into two groups for an observer study, one with the assistance of algorithm results and the other without. We proposed a semi-supervised deep learning algorithm to diagnose and grade IM and atrophy, and we compared it with the assessments of 10 pathologists. The model's performance was evaluated based on the area under the curve (AUC), sensitivity, specificity, and weighted kappa value. RESULTS: The algorithm, named GasMIL, was established and demonstrated encouraging performance in diagnosing IM (AUC 0.884, 95% CI 0.862-0.902) and atrophy (AUC 0.877, 95% CI 0.855-0.897) in the external test set. In the observer study, GasMIL achieved an 80% sensitivity, 85% specificity, a weighted kappa value of 0.61, and an AUC of 0.953, surpassing the performance of all ten pathologists in diagnosing atrophy. Among the 10 pathologists, GasMIL's AUC ranked second in OLGA (0.729, 95% CI 0.625-0.833) and fifth in OLGIM (0.792, 95% CI 0.688-0.896). With the assistance of GasMIL, pathologists demonstrated improved AUC (p = 0.013), sensitivity (p = 0.014), and weighted kappa (p = 0.016) in diagnosing IM, and improved specificity (p = 0.007) in diagnosing atrophy compared to pathologists working alone. CONCLUSION: GasMIL shows the best overall performance in diagnosing IM and atrophy when compared to pathologists, significantly enhancing their diagnostic capabilities.

Endoscopic and histopathological hints on infections in patients of common variable immunodeficiency disorder with gastrointestinal symptoms.

BACKGROUND AND AIMS: Common variable immunodeficiency disorder (CVID) patients may have gastrointestinal (GI) involvement and suffer from infections, which are poorly understood. This study aimed to evaluate the clinical, endoscopic, and histopathological features of CVID patients with GI symptoms and determine their correlation with infections. METHODS: We performed a retrospective study on 21 CVID patients with GI symptoms who underwent endoscopic examination in Peking Union Medical College Hospital from 2000 to 2020. The clinical, infectious, endoscopic, and histopathological features were reassessed. RESULTS: Chronic diarrhea was the most prevalent GI symptom, observed in 95.2% of our CVID cohort. Over 85% of patients had low body weight and malabsorption. Small bowel villous atrophy was found in 90.5% of patients under endoscopy and mostly confirmed by histopathology. GI infections were identified in 9 (42.9%) patients. Of these, 7 patients with diffuse and obvious nodular lymphoid hyperplasia (NLH) of small bowel under endoscopy had significantly higher infection rate (85.7% vs 21.4%, p < 0.05), predominantly with Giardia and bacteria. Small bowel biopsies showed 95% of patients lacked plasma cells and 60% had increased intraepithelial lymphocytes (IELs), but not significantly different between GI infection and non-infection group. Most patients improved after intravenous immunoglobulin and anti-infection therapy. CONCLUSIONS: CVID could involve GI tract, particularly small bowel. Obvious NLH under endoscopy could be a hint for GI infection in CVID patients. Comprehensive endoscopic and histopathological evaluation may be helpful in CVID diagnosis and identification of potential co-infection, leading to proper treatment.

Recurrent spontaneous pneumoperitoneum secondary to intestinal dilatation caused by allied disorders of Hirschsprung's disease: a case report.

BACKGROUND: Allied disorders of Hirschsprung's disease (ADHD) mainly present with bowel obstruction, intestinal dilatation, and chronic constipation, while recurrent spontaneous pneumoperitoneum was rarely reported. We aimed to report a case of recurrent spontaneous pneumoperitoneum caused by ADHD. CASE PRESENTATION: A 59-year-old female patient presented with progressive and severe constipation in the past 30 years. She suffered from abdominal discomfort, which was described as 'gurgling' during the last three years. Radiography showed free-air and intestinal dilatation, without any other diseases, and she was identified with recurrent spontaneous pneumoperitoneum. Gastrointestinal transit test indicated gastrointestinal motility disorder, and anorectal manometry confirmed the presence of rectal anus-suppressing reflex. Subtotal colectomy was performed to relieve apparent constipation, and the postoperative pathological examination of the colon demonstrated proliferation of nerve fibers and hyperplasia of myenteric plexuses, as well as a relatively scarcity of ganglion cells in the myenteric plexus. Based on the presentations and the postoperative pathology, she was diagnosed with ADHD. The recurrent spontaneous pneumoperitoneum was regarded as the gas escape from dilated intestines, which was in high pressure. All the symptoms and her mental state were improved after the treatment with gastrointestinal decompression and enteral nutrition. However, during follow-up visits, she had intestinal infection, and suffered from severe diarrhea and water-electrolyte imbalance, and the patient eventually died at 17 months after the diagnosis. CONCLUSION: ADHD could be a rare cause of recurrent spontaneous pneumoperitoneum, and are mainly undiagnosed or misdiagnosed. A full-thickness biopsy of the gastrointestinal tract (especially the small intestine and sigmoid colon) and differential diagnosis are recommended for the definitive diagnosis. While the ADHD have shown a poor prognosis, timely and long-term treatment with intestinal decompression and nutritional therapy could help relieve symptoms and provide a better quality of life for such patients.

An MMP-based risk score strongly distinguishes prognosis in hepatocellular carcinoma after resection.

Aim: To first explore the prognostic value of MMP11 and MMP15 in hepatocellular carcinoma. Methods: MMP11/MMP15 expression was immunohistochemically detected and correlated with clinicopathologic variables and survival and confirmed in publicly available databases. An MMP-based risk score (MMPRS) was established. Results: Tumoral MMP11/MMP15 expression was higher and univariately associated with crucial clinicopathologic parameters, overall survival and disease-free survival in all patients and/or many subsets. Multivariately, MMP11/MMP15 expression remained significant. Their overexpression and prognostic value were confirmed in the Ualcan and Kaplan-Meier plotter databases. Critically, the novel MMPRS integrating MMP11, MMP15 and tumor-node-metastasis stage identified subgroups with the best and worst prognoses, with much higher predictive power. Conclusion: MMP11 and MMP15 served as prognosticators in hepatocellular carcinoma. MMPRS might work more accurately.

MMP11 and MMP15, involved in cancer dissemination, were found to have important biological functions in several cancers. However, their prognostic value in hepatocellular carcinoma (HCC) remains unknown. In the present study, it was found that MMP11 and MMP15 were overexpressed and predictive of the outcome of HCC. Moreover, the novel MMP-based risk score integrating MMP11, MMP15 and tumor­node­metastasis stage had much higher prognostic power. MMP11, MMP15 and especially the MMP-based risk score were identified as promising indicators of prognosis in HCC.

Elevated TIAM2 expression promotes tumor progression and is associated with unfavorable prognosis in pancreatic cancer.

BACKGROUND AND AIM: As a Rac1 guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 2 (TIAM2) has been reported to be correlated with malignant phenotypes in several cancers, but its prognostic significance and function in pancreatic ductal adenocarcinoma (PDAC) was not investigated. METHODS: The expression patterns of TIAM2 and patient survival were analyzed in a large cohort of 303 patients with radical surgical resection of PDAC, using immunohistochemical staining in tissue microarrays. Data mining was applied to evaluate TIAM2 expression and patient survival at the mRNA level. The function of TIAM2 in proliferation, motility and invasion of pancreactic cancer (PC) cells was also investigated. RESULTS: TIAM2 expression was significantly increased in PDAC compared with para-tumor tissues (p < .0001). The expression of TIAM2 was associated with histopathological grade (p = .008), tumor location (p = .013), and pathological T stage (p = .029). For survival, patients with high TIAM2 expression had significantly poor prognosis in some subgroups. In addition, multivariate analyses showed that the combination of TIAM2 and the pathological N stage largely enhanced the prognostic efficiency, and was found to be as an independent prognostic indicator in patients with PDAC. Data mining elucidated that TIAM2 mRNA expression level was increased in tumor tissues and correlated with patient survival. Furthermore, high TIAM2 expression was common in PC cells. Downregulation of TIAM2 suppressed cell proliferation, migration and invasion in PC. CONCLUSIONS: High expression of TIAM2 might be a meaningful prognostic factor for PDAC patients, and TIAM2 participates in tumor progression in PDAC.

IRAK-M Associates with Susceptibility to Adult-Onset Asthma and Promotes Chronic Airway Inflammation.

IL-1R-associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN-γ concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN-γ production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.

Clinicopathological and prognostic significance of ubiquitin-specific peptidase 15 and its relationship with transforming growth factor-ß receptors in patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND AIM: Ubiquitin-specific peptidase 15 (USP15) has been correlated to aggressive oncogenic behavior in several types of carcinomas, but its function in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the clinicopathological and prognostic value of USP15 and its relationship with transforming growth factor-ß (TGF-ß) receptors (TßRs) in PDAC. METHODS: By immunohistochemical staining of tissue microarrays, the expression patterns of USP15 and TßRs were retrospectively analyzed in 287 PDAC patients who underwent radical surgical resection without neoadjuvant therapy. Cancer-specific survival was compared based on USP15 expression, and the correlations between USP15 and TßRs were analyzed. RESULTS: Ubiquitin-specific peptidase 15 expression in tumor tissues was significantly higher than that in para-tumor tissues (P < 0.0001), and high USP15 expression was associated with the pathological N (pN) stage (P = 0.033). In addition, high USP15 expression was significantly associated with shorter cancer-specific survival (P = 0.019). Univariate analyses showed that high USP15 expression (P = 0.024), a poor histopathological grade (P = 0.003), and the pN1 stage (P = 0.009) were significantly correlated with shorter survival. Although the independent prognostic value of USP15 alone was not established, the combination of USP15 and the histological grade was identified as an independent prognostic factor in multivariate analyses (P = 0.015). USP15 expression was correlated with TßR-I, TßR-II, or TßR-III expression in PDAC. CONCLUSIONS: High USP15 expression is a potential prognostic indicator in patients with PDAC, and it might affect the TGF-ß signaling pathway in PDAC.

Ubiquitin-specific protease 4 predicts an unfavorable prognosis and promotes malignant behaviors in vitro in pancreatic cancer.

Ubiquitin-specific protease 4 (USP4), has been reported to participate in the progression of various cancers due to its role in post-translational modulation. However, the prognostic significance and mechanism of USP4 in pancreatic cancer (PC) have not been well elucidated before. In the present study, we found that USP4 expression was higher in PC tissues than that in adjacent normal tissues and PC patients with high level of USP4 expression have a poor prognosis via immunohistochemistry and bioinformatics analyses. In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion. Mechanistically, USP4 can activate nuclear factor kappa-B signaling pathway via stabilizing TNF receptor associated factor 6 at its protein level to promote the ability of proliferation, migration and invasion of PC cells. The results of this study revealed that USP4 plays a tumor-promoting role in PC and can be used as a prognostic indicator and therapeutic target for patients with resected PC.

Transanal endoscopic microsurgery with alternative neoadjuvant imatinib for localized rectal gastrointestinal stromal tumor: a single center experience with long-term surveillance.

BACKGROUND: Transanal endoscopic microsurgery (TEM) is widely used in the treatment of local rectal lesions and helps avoid radical surgery. This study evaluated the management and outcome in a long-term followed cohort of patients with localized rectal GIST underwent TEM with alternative neodajuvant imatinib (nIM). METHODS: A retrospective cohort study was undertaken of patients identified from a case database at Department of General Surgery, Peking Union Medical College Hospital (PUMCH) over a continuous period, from January 2006 to December 2017. RESULTS: Over 12 years, 42 patients presented with a primary rectal GIST in PUMCH. Median age was 49 (range 27-77) years. Neoadjuvant imatinib (nIM) therapy was used in 16 patients, significantly reducing mean tumor size from 4.41 to 2.46 cm (p < 0.001) and mitotic index (p = 0.041). All of these patients underwent TEM with no tumor rupture, nIM therapy enabled sphincter-preserving surgery to be undertaken in 16 (16/42) patients who would otherwise have required abdominoperineal resection or pelvic exenteration for tumor clearance and all patients (42/42) achieve R0 resection and negative margin. Imatinib was also used as postoperative adjuvant treatment in 15 patients with high-risk GIST. Median follow-up was 77 (range 14-144) and overall survival is 100%. In 42 patients, Local recurrence (LR) occurred in 3 of 42 patients and 1 of 42 patients developed distant metastasis (DM) in 112 months after TEM. In the univariate analysis, mitotic index (p = 0.028), NIH risk categories (p = 0.047) were predictive feature of local relapse. CONCLUSION: The application of nIM significantly decreased tumor size in large localized rectal GIST, which permitted TEM to preserve sphincter. The TEM procedure with alternative neoadjuvant imatinib therapy is a practicable treatment for patients with rectal GIST to preserve anus and have satisfied anal function.

Retrospective study of the differential diagnosis between cryptogenic multifocal ulcerous stenosing enteritis and small bowel Crohn's disease.

BACKGROUND: Being a rare disease, cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is easily misdiagnosed as small bowel Crohn's disease (SBCD). AIMS: This study was aimed to compare clinical features of CMUSE to SBCD. METHODS: Fourteen patients with CMUSE and 61 patients with SBCD were retrospectively analyzed. RESULTS: Hematochezia was more frequent in CMUSE patients (10, 71.4% vs 23, 37.7%, P = 0.022), while diarrhea was more common in SBCD patients (23, 37.7% vs 0, 0.0%, P = 0.015). More patients with CMUSE developed intestinal stenosis than with SBCD (14, 100% vs 37, 60.7%, P = 0.011). 30 (50.0%) SBCD patients and none CMUSE patients had an elevated erythrocyte sedimentation rate level (P = 0.001). Extra-enteric findings found by computed tomography enterography were significantly more prevalent in SBCD patients than in CMUSE patients (25,71.4% vs 3,25%, P = 0.013). Longitudinal ulcers found by endoscopy were more common in SBCD patients (16, 37.2% vs 0, 0.0%, P = 0.041), while circumferential ulcers were more common in CMUSE patients (6, 54.6% vs 8, 18.6%, P = 0.041). All ulcers observed in CMUSE patients were within mucosal and submucosal layers, but 8 (44.4%) SBCD patients had deep ulcers that reached beyond submucosal layers (P = 0.003). Ulcers were located at strictures in 9 (90.0%) CMUSE patients but only in 1 (5.6%) SBCD patient (P = 0.000). CONCLUSIONS: Gastrointestinal symptoms, erythrocyte sedimentation rate levels, radiologic, endoscopic and pathologic features help to distinguish CMUSE from SBCD.

The clinicopathologic features of chronic active Epstein-Barr virus infective enteritis.

Chronic active Epstein-Barr virus infective enteritis (CAEBV enteritis) is rare and has not been well described yet. Therefore, we reported the clinicopathologic features of 11 patients with chronic active Epstein-Barr virus infective enteritis and their differences from inflammatory bowel disease. The major clinical presentations of chronic active Epstein-Barr virus infective enteritis were intermittent fever over 39 °C (100%), diarrhea (73%), abdominal pain (64%), lymphadenopathy (64%), splenomegaly (64%), and hepatomegaly (27%). The main endoscopic findings included numerous shallow, small, and irregular ulcers, mainly involving colon and small intestine together, no cobble-like appearance, and longitudinal ulcers. Compared to inflammatory bowel disease patients, the frequency of intermittent fever, hepatomegaly, splenomegaly, lymphadenopathy, the value of C-reactive protein, and serum Epstein-Barr virus DNA (EBV DNA) were significantly higher in chronic active Epstein-Barr virus infective enteritis patients (p < 0.01). The histologic findings show transmural inflammation with extended lymphoid infiltration, fissuring ulcers, and intraepithelial lymphocytosis. But chronic active Epstein-Barr virus infective enteritis lacked granulomas and connective tissue changes such as neural hypertrophy and thickened muscularis mucosae. Three chronic active Epstein-Barr virus infective enteritis patients died within 5 years of disease onset, and those three patients have received total colectomy, two of them died within 1 month after surgery. In this study, clinicopathologic features have been summarized to better recognize chronic active Epstein-Barr virus infective enteritis. There are resemblances between chronic active Epstein-Barr virus infective enteritis and inflammatory bowel disease, but some symptoms, signs, and indexes like intermittent fever, hepatomegaly, splenomegaly, lymphadenopathy, and elevated C-reactive protein, Epstein-Barr virus DNA are characteristics to differentiate chronic active Epstein-Barr virus infective enteritis and inflammation. Histopathological features also help the discrimination. Serum Epstein-Barr virus DNA and intestinal tissue in situ hybridization for Epstein-Barr virus-encoded RNA are recommended to exclude chronic active Epstein-Barr virus infective enteritis.

Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS.

Oncogenic fusions are rare in colorectal carcinomas, but may be important for prognosis and therapy. An effective strategy for screening targetable oncogenic fusions in colorectal carcinomas is needed. Here, we investigate molecular genetic alterations in colorectal carcinomas based on their DNA mismatch repair status, and to effectively screen for targetable oncogenic fusions in colorectal carcinomas. In this retrospective study, the initial cohort included 125 consecutive mismatch repair-deficient and 238 randomly selected mismatch repair-proficient colorectal carcinomas diagnosed between July 2015 and December 2017 at Peking Union Medical College Hospital. Targeted sequencing was performed. MLH1 promoter hypermethylation analysis was further employed for subgrouping dMMR colorectal carcinomas. Clinicopathological characteristics, molecular features, and survival outcome of colorectal carcinomas harboring oncogenic fusions were assessed. A multicenter cohort comprised of 227 colorectal carcinomas with dual loss of MLH1/PMS2 was used to validate the efficacy of the proposed screening strategy for oncogenic fusions. Of the 363 patients in the initial cohort, 11(3.0%) harbored oncogenic fusions and were all mismatch repair-deficient colorectal carcinomas with hypermethylated MLH1 and wild-type BRAF and KRAS, comprising 55% (11/20) of this subgroup. These patients with oncogenic fusions showed poorer 3-year cancer-specific survival compared with other Stage III/IV mismatch repair-deficient colorectal carcinoma patients (40% vs. 97%), and significantly higher CD274(PD-L1) expression in tumor cells compared with other dMMR colorectal carcinoma patients (46% vs. 6.1%, P < 0.001). An easy-to-perform and cost-efficient strategy for screening targetable fusions was proposed based on the current molecular testing algorithms for colorectal carcinomas, and validated in an independent multicenter cohort. In conclusion, oncogenic fusions were highly enriched and frequently detected in mismatch repair-deficient colorectal carcinomas with MLH1 hypermethylation and wild-type BRAF and KRAS, and were associated with poor prognosis and high tumor CD274(PD-L1) expression.

A literature review and case report of severe and refractory post-colectomy enteritis.

BACKGROUND: Ulcerative colitis (UC)-related post-colectomy enteritis is a very rare condition that is characterized by diffuse small-bowel mucosal inflammation following colectomy and could be very dangerous. In previously reported cases, corticosteroid therapy seemed to be the optimal choice for inducing remission; however, the patient studied herein presented with severe diarrhoea and hypovolemic shock and failed to achieve full remission with corticosteroid therapy. CASE PRESENTATION: We describe the case of a patient with severe pan-enteritis presenting with life-threatening diarrhoea complicated with hypovolemic shock and acute kidney injury after colectomy and ileal pouch anal anastomosis (IPAA) for UC; this patient was successfully treated by ileostomy closure after failing to achieve full remission with corticosteroid therapy. Next, we review other cases of post-colectomy enteritis reported in the literature and propose a flow-chart for its diagnosis and initial treatment. CONCLUSION: Post-colectomy enteritis can be dangerous, and the early awareness of this condition plays a vital role. Additionally, in patients who do not respond well to corticosteroid or immunosuppressant therapy, early closure of the ileostomy and re-establishment of the natural faecal stream could be important considerations.

Endometriosis-associated recto-sigmoid cancer: a case report.

BACKGROUND: Endometriosis is a relatively common condition in women of reproductive age. Malignant transformation of intestinal endometriosis is a very rare event. We report a case in which a patient with a history of endometriosis underwent surgery for malignant intestinal endometriosis. CASE PRESENTATION: A 55-year-old woman complained of rectorrhagia and intermittent abdominal pain. A neoplasm was revealed by colonoscopy, CT scan and F18-FDG PET/CT of the recto-sigmoidal colon. The patient underwent a rectal anterior resection, hysterectomy and bilateral salpingo-oophorectomy for treatment. According to the histological and immunohistochemical presentation, the diagnosis of endometriosis-associated recto-sigmoid cancer was confirmed. The patient was treated with adjuvant chemotherapy for 6 months. During the follow-up appointment 22 months later, there was clinical and radiographic evidence of recurrence in the rectum. The patient received chemotherapy again and will receive another surgery after two more cycles of chemotherapy. CONCLUSION: We report a case of malignant intestinal endometriosis. Although there is no standard therapy for malignant intestinal endometriosis due to the rarity of this disease, surgery and adjuvant chemotherapy seemed to be rational. This case indicates that local recurrence may be a common situation after standard therapy.

Can Endorectal Ultrasound, MRI, and Mucosa Integrity Accurately Predict the Complete Response for Mid-Low Rectal Cancer After Preoperative Chemoradiation? A Prospective Observational Study from a Single Medical Center.

BACKGROUND: Patients with locally advanced rectal cancer could be managed by a watch-and-wait approach if they achieve clinical complete response after preoperative chemoradiotherapy. Mucosal integrity, endorectal ultrasound, and rectal MRI are used to evaluate clinical complete response; however, the accuracy remains questionable. Clinical practice based on those assessment methods needs more data and discussion. OBJECTIVE: The aim of this prospective study was to evaluate the accuracy of mucosal integrity, endorectal ultrasound, and rectal MRI to predict clinical complete response after chemoradiotherapy. DESIGN: Endorectal ultrasound and rectal MRI were undertaken 6 to 7 weeks after preoperative chemoradiation therapy. Patients then received radical surgery based on the principles of total mesorectal excision. Preoperative tumor staging achieved by endorectal ultrasound and rectal MRI was compared with postoperative staging by pathologic examination. Sensitivity, specificity, and accuracy of each evaluation method were calculated. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: Patients diagnosed with mid-low rectal cancer by biopsy between May 2014 and December 2016 were enrolled in this study. RESULTS: A total of 124 patients were enrolled in this study, and postoperative pathology revealed that 20 patients (16.13%) achieved complete response (ypT0N0). The sensitivity of mucosal integrity, endorectal ultrasound, and MRI to predict clinical complete response was 25%. The specificity of mucosal integrity, endorectal ultrasound, and MRI was 94.23%, 93.90%, and 93.27%. The combination of each 2 or all 3 methods did not improve accuracy. Regression analysis showed that none of these methods could predict postoperative ypT0. LIMITATIONS: The sample size is small, and we did not focus on the follow-up data and cannot compare prognosis data with previous research studies. CONCLUSIONS: Both single-method and combined mucosal integrity, endorectal ultrasound, and rectal MRI have poor correlation with postoperative pathologic examination. A watch-and-wait approach based on these methods might not be a proper strategy compared with radical surgery after neoadjuvant therapy. See Video Abstract at http://links.lww.com/DCR/A693.

High nuclear Survivin expression as a poor prognostic marker in pancreatic ductal adenocarcinoma.

BACKGROUND: Survivin, one of the key regulators of mitosis and apoptosis, has long been well recognized to play important biological roles in many neoplasms, including pancreatic ductal adenocarcinoma (PDAC). However, its prognostic value in PDAC remains controversial. PATIENTS AND METHODS: Nuclear expression of Survivin was detected, using tissue microarray-based immunohistochemistry, in paired-tumor and nontumor samples from 306 patients with radically resected PDAC. The staining H scores were further correlated with clinicopathologic features and disease-specific survival (DSS). RESULTS: Nuclear Survivin expression was much higher in tumor than in nontumor tissues (P < 0.001). No significant association between tumoral Survivin expression and clinicopathologic variables was found. For prognosis, high Survivin expression was associated with shortened DSS in all eligible patients and four subgroups, that is, male and nondiabetic patients as well as those with head-located and G1-2 tumors, shown by univariate analyses. In addition, a statistically marginal significance was revealed in eight subgroups. For the entire cohort and two subgroups, nuclear Survivin expression was also multivariate identified as an independent predictor for DSS. For patients with G1-2 tumors, it was the single prognostic marker. CONCLUSION: Our data suggest an association between high nuclear Survivin expression and poor prognosis in PDAC. However, further confirmation might be necessary.