Digital image analysis of Ki67 hotspot detection and index counting in gastroenteropancreatic neuroendocrine neoplasms.

The Ki-67 proliferative index plays a pivotal role in the subclassification of neuroendocrine neoplasm (NEN) according to the WHO Classification of Digestive System Tumors (5th edition), which designates neuroendocrine tumor (NET) grades 1, 2, and 3 for Ki-67 proliferative index of <3 %, 3-20 %, and >20 %, respectively. Proliferative index calculation must be performed in the hotspot, traditionally selected by visual scanning at low-power magnification. Recently, gradient map visualization has emerged as a tool for various purposes, including hotspot selection. This study includes 97 cases of gastrointestinal neuroendocrine neoplasms, with hotspots selected by bare eye and gradient map visualization (GM). Each hotspot was analyzed using three methods: eye estimation (EE), digital image analysis (DIA), and manual counting. Of the NENs studied, 91 % were NETs (26 % for G1, 55 % for G2, and 10 % for G3). Only 9 cases were neuroendocrine carcinoma (NEC). Between two hotspot selection methods, GM resulted in a higher grade in 14.77 % of cases, primarily upgrading from NET G1 to G2. Among the counting methods, DIA demonstrated substantial agreement with manual counting, both for pathologist and resident. Grading by other methods tended to result in a higher grade than MC (26.99 % with EE and 8.52 % with DIA). Given its clinical and statistical significance, this study advocates for the application of GM in hotspot selection to identify higher-grade tumors. Furthermore, DIA provides accurate grading, offering time efficiency over MC.

Detection of centroblast cells in H&E stained whole slide image based on object detection.

Introduction: Detection and counting of Centroblast cells (CB) in hematoxylin & eosin (H&E) stained whole slide image (WSI) is an important workflow in grading Lymphoma. Each high power field (HPF) patch of a WSI is inspected for the number of CB cells and compared with the World Health Organization (WHO) guideline that organizes lymphoma into 3 grades. Spotting and counting CBs is time-consuming and labor intensive. Moreover, there is often disagreement between different readers, and even a single reader may not be able to perform consistently due to many factors. Method: We propose an artificial intelligence system that can scan patches from a WSI and detect CBs automatically. The AI system works on the principle of object detection, where the CB is the single class of object of interest. We trained the AI model on 1,669 example instances of CBs that originate from WSI of 5 different patients. The data was split 80%/20% for training and validation respectively. Result: The best performance was from YOLOv5x6 model that used the preprocessed CB dataset achieved precision of 0.808, recall of 0.776, mAP at 0.5 IoU of 0.800 and overall mAP of 0.647. Discussion: The results show that centroblast cells can be detected in WSI with relatively high precision and recall.

Gastric villous adenoma: a case report and review of the literature.

BACKGROUND: Villous adenoma is the one subtype of adenomatous polyp that is very uncommon in the stomach. Data regarding clinical characteristics, natural history, and prognosis were scarce. CASE PRESENTATION: This report presented an 87-year-old Thai woman with a large gastric villous adenoma incidentally revealed in a computed tomography of chest for the evaluation of right pleural effusion. The esophagogastroduodenoscopy demonstrated a huge, glossy, proliferative polypoid mass involving gastric cardia, fundus, and a lesser curve of the upper body. The pathological report confirmed villous adenoma with low grade dysplasia. Although surgical resection was suggested, the patient denied any treatment due to advanced age and multiple comorbidities. She was generally well after 12 months of clinical and radiologic surveillance. CONCLUSION: From literature review, only 14 cases of gastric villous adenoma were reported to date. Most of the lesions were large and symptomatic. Malignancy presented in 43% of the cases. Nevertheless, our patient remained asymptomatic without surgical removal following a 12-month period.

Clinical characteristics and diagnosis of intestinal tuberculosis in clinical practice at Thailand's largest national tertiary referral center: An 11-year retrospective review.

BACKGROUND: Diagnosing intestinal tuberculosis (ITB) is challenging due to the low diagnostic sensitivity of current methods. This study aimed to assess the clinical characteristics and diagnosis of ITB at our tertiary referral center, and to explore improved methods of ITB diagnosis. METHODS: This retrospective study included 177 patients diagnosed with ITB at Siriraj Hospital (Bangkok, Thailand) during 2009-2020. RESULTS: The mean age was 49 years, 55.4% were male, and 42.9% were immunocompromised. Most diagnoses (108/177) were made via colonoscopy; 12 patients required more than one colonoscopy. Among those, the sensitivity of tissue acid-fast bacilli (AFB), presence of caseous necrosis, polymerase chain reaction (PCR), and culture was 40.7%, 13.9%, 25.7%, and 53.4%, respectively. Among patients with negative tissue histopathology, 4 (3.7%) and 13 (12.0%) were ITB positive on tissue PCR and culture, respectively. The overall sensitivity when all diagnostic methods were used was 63%. Seventy-six patients had stool tests for mycobacteria. The overall sensitivity of stool tests was 75.0%. However, when analyzing the 31 patients who underwent both endoscopy and stool testing, the sensitivity of stool testing when using tissue biopsy as a reference was 45.8%. Combining stool testing and tissue biopsy did not significantly increase the sensitivity compared to tissue biopsy alone (83.9% vs. 77.4%, respectively). CONCLUSION: Despite the availability of PCR and culture for TB, the overall diagnostic sensitivity was found to be low. The sensitivity increased when the tests were used in combination. Repeated colonoscopy may be beneficial. Adding stool mycobacteria tests did not significantly increase the diagnostic yield if endoscopy was performed, but it could be beneficial if endoscopy is unfeasible.

The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer.

Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFß signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes.

Performance of Cytomegalovirus Real-Time Polymerase Chain Reaction Assays of Fecal and Plasma Specimens for Diagnosing Cytomegalovirus Colitis.

INTRODUCTION: Cytomegalovirus (CMV) viral load detected by real-time polymerase chain reaction (PCR) in plasma or stool may facilitate detection of CMV colitis. METHODS: This prospective study enrolled 117 patients with clinically suspected CMV colitis. Patients presenting with gastrointestinal symptoms and having increased risk of CMV infection were eligible. All participants underwent colonoscopy with tissue biopsy. Five patients underwent colonoscopy twice because of clinical recurrence, resulting in a total of 122 colonoscopies. Stool CMV-PCR and plasma CMV-PCR were performed within 7 days before/after colonoscopy. Twenty asymptomatic volunteers also underwent the same protocol. RESULTS: Twenty-seven (23.1%) of 122 colonoscopies yielded positive for CMV colitis. The sensitivity and specificity was 70.4% and 91.6% for stool CMV-PCR and 66.7% and 94.7% for plasma CMV-PCR, respectively. The sensitivity of either positive plasma or positive stool CMV-PCR was 81.5%, which is significantly higher than that of plasma CMV-PCR alone ( P = 0.045). However, positive results from both tests yielded a specificity of 95.8%, which is significantly higher than that of stool CMV-PCR alone ( P = 0.045). There was a good and significant correlation between stool CMV-PCR and plasma CMV-PCR ( r = 0.71, P < 0.01), and both tests significantly correlated with the cytomegalic cell count ( r = 0.62, P < 0.01 for stool and r = 0.64, P < 0.01 for plasma). There were no positive stool or plasma CMV-PCR assays among volunteers. DISCUSSION: The results of this study strongly suggest that the combination of stool CMV-PCR and plasma CMV-PCR can be used to confidently rule in (both positive) or rule out (both negative) a diagnosis of CMV colitis.

Prognostic Relevance of Metabolic Dysfunction-associated Steatohepatitis for Patients with Chronic Hepatitis B.

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is prevalent in patients with chronic hepatitis B (CHB). The effect of the histologic MAFLD phenotype on long-term CHB outcomes is unknown. We performed a longitudinal study to determine the prognostic relevance of biopsy-proven hepatic steatosis and steatohepatitis for CHB patients. Methods: Clinical and laboratory data were obtained from CHB patients who underwent liver biopsy during 2002-2008 and were treated with antiviral drugs. A hepatopathologist reviewed the biopsy specimens. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (aHR) of outcomes, including all-cause mortality, liver transplantation, and liver-related events. Results: In accordance with Brunt's classification, 408 patients had steatohepatitis (n=34), "steatosis but not steatohepatitis" (n=118), or "non-steatosis" (n=256). All steatohepatitis patients had features of metabolic dysfunction. Over a mean follow-up of 13.8±3.1 years, 18 patients died or underwent liver transplantation. In multivariate-adjusted analysis, steatohepatitis (aHR, 6.37; 95% confidence interval [CI]: 1.59-25.5) compared with non-steatosis and advanced fibrosis (aHR, 11.3; 95% CI: 1.32-96.3) compared with no fibrosis were associated with overall mortality/liver transplantation. Thirty-five patients developed 43 liver-related events, among which 32 were hepatocellular carcinoma. These events were associated with steatohepatitis (aHR, 5.55; 95% CI: 2.01-15.3) compared with non-steatosis and advanced fibrosis (aHR, 6.23; 95% CI: 1.75-22.2) compared with no fibrosis. The steatosis but not steatohepatitis group had a non-significantly higher risk of overall mortality and liver-related events. Conclusions: Metabolic dysfunction-associated steatohepatitis increased the risk of long-term mortality/transplantation and liver-related events in CHB patients.

Cronkhite-Canada Syndrome: A Rare Case of Chronic Diarrhea With Ectodermal Changes.

Cronkhite-Canada syndrome (CCS) is a rare cause of chronic diarrhea and malabsorption where patients develop multiple polyps throughout the gastrointestinal (GI) tract, accompanied by ectodermal changes. Due to its rarity, early detection and diagnosis are challenging for physicians, inevitably leading to high mortality. CCS patients have a higher prevalence of GI cancer compared to the general population. Therefore, a follow-up endoscopy is necessary. We report a new case of CCS in an 85-year-old male who presented with chronic watery diarrhea, weight loss, and skin changes including alopecia, nail dystrophy, and hyperpigmentation. Laboratory results showed anemia and hypoalbuminemia. He underwent an endoscopy that found diffuse edematous polyposis in the stomach, duodenum, terminal ileum, and large intestine. The biopsy result confirmed the diagnosis of CCS. The patient received supportive treatment with total parenteral nutrition with improvement in his symptoms. He was placed on corticosteroid taper and azathioprine upon discharge. At the one-year follow-up, he was found in endoscopic remission.

Comparison of blue laser imaging and narrow band imaging for the differentiation of diminutive colorectal polyps: A randomized controlled trial.

BACKGROUND: To compare the diagnostic efficacy of blue laser imaging (BLI)- bright and narrow band imaging (NBI) modes of image enhanced endoscopy (IEE) in differentiating neoplastic and non-neoplastic lesions of diminutive colorectal polyps. METHODS: We conducted a prospective randomized controlled trial from September 2015 to July 2016. The participants were randomly assigned (1:1) for colonoscopy with polyp classification under NBI or BLI-bright mode without magnification. Histopathologic diagnosis was used as the gold standard. RESULTS: Three hundred and twenty-four diminutive polyps in 164 patients were included for analysis (BLI: 162 polyps in 73 patients, NBI: 162 polyps in 91 patients). These polyps were located at colon proximal to sigmoid (61.1 and 58.0%) and rectosigmoid colon (38.9 and 42.0%) in the BLI and NBI groups, respectively. Most polyps (71.9%) were adenomatous with one malignant polyp (0.3%). BLI achieved 86.4% accuracy, 98.3% sensitivity, 55.6% specificity, 85.2% positive predictive value (PPV), and 92.6% negative predictive value (NPV), similar to NBI which exhibited 90.1% accuracy, 99.1% sensitivity, 67.4% specificity, 88.5% PPV, and 96.9% NPV in the diagnosis of adenomatous polyps. Based on the location of the polyp, both modes of IEE provided ≥ 95% NPV for diagnosis of adenomatous polyps at the rectosigmoid colon. CONCLUSIONS: BLI-bright and NBI modes of IEE have similar accuracy in differentiation between neoplastic and non-neoplastic lesions of diminutive polyps. Both modes provided ≥ 90% NPV which allows for the adaptation of the American Society of Gastrointestinal Endoscopy "diagnose-and-leave" recommended strategy for diminutive polyps at the rectosigmoid colon.

Loss of CDX-2 expression is an independent poor prognostic biomarker in patients with early-stage deficient mismatch repair colorectal cancer.

AIM: To investigate the clinicopathological factors, molecular features, and prognostic implications associated with loss of Caudal-related homeobox transcription factor 2 (CDX-2) expression in colorectal cancer (CRC) patients. METHODS: Immunohistochemistry for CDX-2 expression was performed on formalin-fixed, paraffin-embedded primary CRC tissue samples from 449 patients. Correlation between CDX-2 expression and clinicopathological and molecular characteristics was evaluated. Univariate and multivariate survival analyses were performed to determine the prognostic value of loss of CDX-2 expression. RESULTS: Of 449 patients, 84% were stage I-III. CDX-2-negative expression was identified in 18 of 441 (4.1%) patients. Loss of CDX-2 expression was more commonly found in patients with right-sided tumors rather than left-sided tumors (odds ratio [OR] = 3.57; p = 0.009), deficient mismatch repair (dMMR) compared to proficient MMR (pMMR) (OR = 3.7; p = 0.012), and BRAF mutation compared to BRAF wild type (OR = 8.06; p = 0.002). Univariate analysis revealed that stage I-III CRC patients with loss of CDX-2 expression had significantly worse overall survival (OS) and disease-free survival (DFS) than those with positive CDX-2 expression (5-year OS = 33.3% vs. 74.6%, respectively; p < 0.001, and 5-year DFS: 42.9% vs. 69.5%, respectively; p = 0.004). Loss of CDX-2 expression remained significantly associated with worse OS compared to positive CDX-2 expression in multivariate analysis (hazard ratio [HR] = 2.4; 95% confidence interval [CI], 1.12-5.11; p = 0.023). CONCLUSIONS: Loss of CDX-2 expression was found to be associated with right-sided tumor, dMMR status, and BRAF mutation. Moreover, loss of CDX-2 expression is a poor prognostic factor for OS in stage I-III, even among patients with dMMR tumors.

Diagnostic yield of esophagogastroduodenoscopy, colonoscopy, and small bowel endoscopy in Thai adults with chronic diarrhea.

BACKGROUND: Gastrointestinal endoscopy is frequently recommended for chronic diarrhea assessment in Western countries, but its benefit in the Southeast Asia region is not well established. METHODS: Medical records of consecutive patients undergoing esophagogastroduodenoscopy (EGD), colonoscopy, and small bowel endoscopy for chronic diarrhea from 2008 to 2018 were reviewed. Small bowel endoscopy included push enteroscopy, balloon-assisted enteroscopy (BAE), and video capsule endoscopy (VCE). The diagnostic yield of each endoscopic modality and predictors for positive small bowel endoscopy were analyzed. RESULTS: A total of 550 patients were included. The mean age was 54 years, and 266 (46.3%) patients were male. The mean hemoglobin and albumin levels were 11.6 g/dL and 3.6 g/dL, respectively. EGD and colonoscopy were performed in 302 and 547 patients, respectively, and the diagnostic yield was 24/302 (7.9%) for EGD and 219/547 (40.0%) for colonoscopy. EGD did not reveal positive findings in any patients with normal colonoscopy. Fifty-one patients with normal EGD and colonoscopy underwent small bowel endoscopy. Push enteroscopy, BAE, and VCE were performed in 28, 21, and 19 patients with a diagnostic yield of 5/28 (17.9%), 14/21 (66.7%), and 8/19 (42.1%), respectively. Significant weight loss, edema, and hypoalbuminemia were independent predictors for the positive yield of small bowel endoscopy. CONCLUSION: Colonoscopy was an essential diagnostic tool in identifying the cause of chronic diarrhea in Thai patients, whereas EGD provided some benefits. Small bowel endoscopy should be performed when colonoscopy and EGD were negative, particularly in patients with significant weight loss, edema, and hypoalbuminemia.

Value and risk of percutaneous liver biopsy in patients with cirrhosis and clinical suspicion of autoimmune hepatitis.

OBJECTIVE: The decision regarding whether to perform a liver biopsy in patients with cirrhosis and clinically suspected autoimmune hepatitis (AIH) remains a challenge. This study aimed to assess the utility and complications of percutaneous liver biopsy in cirrhosis for differentiating AIH from other liver conditions. METHODS: A clinicopathological database of patients undergoing percutaneous liver biopsies for suspected AIH (unexplained hepatitis with elevated γ-globulin and autoantibody seropositivity) was reviewed to identify patients presenting with cirrhosis. Biopsy slides were reviewed by an experienced hepatopathologist who was blinded to clinical data. RESULTS: In 207 patients who underwent liver biopsy for suspected AIH, 59 patients (mean age: 59.0±12.0 years, 83.1% female) had clinically diagnosis of cirrhosis. Mean Child-Turcotte-Pugh score was 6.6±1.6, and 44% of patients had a Child-Turcotte-Pugh score≥7. According to the revised International AIH Group (IAIHG) criteria, histology assessment combined with clinical information facilitated a diagnosis of AIH or overlap syndrome of AIH and primary biliary cholangitis (PBC) in 81.4% of cases. Liver biopsy identified other aetiologies, including PBC (n=2), non-alcoholic steatohepatitis (n=6) and cryptogenic cirrhosis (n=3). A reliable diagnosis of AIH could be made using histological category of the simplified criteria in 69.2% and 81.8% of cases using IAIHG scores before biopsy of <10 and 10-15, respectively. Three patients with cirrhosis (5.1%) experienced bleeding following biopsy, but none of 148 patients with non-cirrhosis had bleeding complication (p=0.022). CONCLUSION: Liver biopsy provides important diagnostic information for the management of patients with cirrhosis and suspected AIH, but the procedure is associated with significant risk.

Cytomegalovirus enterocolitis with subsequent diagnosis of coexisting new-onset inflammatory bowel disease: Two case reports and review of the literature.

INTRODUCTION: Gastrointestinal (GI) cytomegalovirus (CMV) infection coexisting with or followed by a diagnosis of inflammatory bowel disease (IBD) is infrequently reported. Not recognizing this condition may delay IBD diagnosis in patients with GI-CMV disease who do not or partially respond to antiviral agents, which could consequently result in unsatisfied treatment outcomes. PATIENT CONCERNS: Two immunocompetent patients with no known underlying GI conditions presented with acute bloody diarrhea. The first patient developed diarrhea and hematochezia after admission to intensive care unit (ICU) because of severe alcoholic pancreatitis for 10 days duration. Computed tomography abdomen showed segmental jejunal thickening. The other patient presented with a 1-week history of severe bloody diarrhea which required ICU admission. Colonoscopy showed multiple ulcers along terminal ileum and colon. DIAGNOSIS: These 2 patients were initially diagnosed with CMV jejunitis and ileocolitis, respectively, based on endoscopic and histopathologic findings. Both had partial response to treatment with 3 weeks of intravenous ganciclovir. Crohn disease was suspected because of persistent ulcerations on the follow-up endoscopy with the presence of pathological features of chronic inflammation and disappearance of previously detected CMV-infected cells. INTERVENTION: Both patients were treated with systemic corticosteroids and azathioprine. OUTCOMES: Both patients had complete clinical improvement. Prednisolone could be tapered off in 6 months. Follow-up video capsule endoscopy (VCE) at 6 months showed improvement of mucosal inflammation and ulcers, but neither were completely healed in the first patient. Follow-up colonoscopy at 6 months showed complete resolution of ulcers and inflammation in the second patient. LESSONS: IBD should be suspected in patients with a diagnosis of GI-CMV disease who are immunocompetent and have a partial response to antiviral agents. This clinical scenario could be caused by either CMV infection activating immune response resulting in IBD onset, or CMV infection superimposed on pre-existing latent IBD.

Diffusion-weighted magnetic resonance imaging for the assessment of liver fibrosis in chronic viral hepatitis.

BACKGROUND: Accurate noninvasive methods for the assessment of liver fibrosis are urgently needed. This prospective study evaluated the diagnostic accuracy of diffusion-weighted magnetic resonance imaging (DWI) for the staging of liver fibrosis and proposed a diagnostic algorithm using DWI to identify cirrhosis in patients with chronic viral hepatitis. METHODS: One hundred twenty-one treatment-naïve patients with chronic hepatitis B or C were evaluated with DWI followed by liver biopsy on the same day. Breath-hold single-shot echo-planar DWI was performed to measure the apparent diffusion coefficient (ADC) of the liver and spleen. Normalized liver ADC was calculated as the ratio of liver ADC to spleen ADC. RESULTS: There was an inverse correlation between fibrosis stage and normalized liver ADC (p<0.05). For the prediction of fibrosis stage ≥2, stage ≥3, and cirrhosis, the area under the receiver-operating curve of normalized liver ADC was 0.603, 0.704, and 0.847, respectively. The normalized liver ADC value ≤1.02×10-3 mm2/s had 88% sensitivity, 81% specificity, 25% positive predictive value (PPV), and 99% negative predictive value (NPV) for the diagnosis of cirrhosis. Using a sequential approach with the Fibrosis-4 index followed by DWI, normalized liver ADC ≤1.02×10-3 mm2/s in patients with Fibrosis-4 >3.25 yielded an 80% PPV for cirrhosis, and a 100% NPV to exclude cirrhosis in patients with Fibrosis-4 between 1.45 and 3.25. Only 15.7% of patients would require a liver biopsy. This sequential strategy can reduce DWI examinations by 53.7%. CONCLUSION: Normalized liver ADC measurement on DWI is an accurate and noninvasive tool for the diagnosis of cirrhosis in patients with chronic viral hepatitis.

Clinicopathological Characteristics and Outcome of Adolescent and Young Adult-Onset Microsatellite Stable Colorectal Cancer Patients.

Purpose: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinicopathological characteristics and outcome of adolescent and young adult (AYA)-onset sporadic CRC patients. Methods: Medical records of patients who were diagnosed adenocarcinoma of colon or rectum at Siriraj Hospital between 2007 and 2018 were retrospectively reviewed. The patients were classified into two groups: AYA-onset CRC (age 15-39 years) and adult-onset CRC (age >50 years). Associations between sporadic microsatellite stable (MSS) AYA-/adult-onset CRC and clinicopathological features and outcome were evaluated. Results: A total of 203 patients were diagnosed with AYA-onset CRC with no known history of familial CRC syndromes, 119 had data on mismatch repair status; 98 confirmed MSS CRC. AYA-onset CRC patients were commonly found with left-sided rather than right-sided tumors (77.1% vs. 22%) and late stage of disease (80.7% in stage III-IV vs. 19.3% in stage I-II). Compared with adult-onset CRC (218 patients), AYA-onset MSS CRC had more patients with female gender (p = 0.038), perineural invasion (p = 0.003), and signet ring cell/mucinous histology (p = 0.132). On univariate analysis, male gender and mucinous/signet ring cell histology had worse overall survival (OS) (p = 0.004 and p = 0.072, respectively) and remained significant in multivariate analysis for signet ring cell histology (p = 0.008). There was no difference in disease-free survival and OS between both age groups. Conclusion: Sporadic MSS AYA-onset CRC patients were associated with female gender and aggressive pathological characteristics. However, there was no difference in survival outcome between AYA-onset and adult-onset groups.

Validation of models using basic parameters to differentiate intestinal tuberculosis from Crohn's disease: A multicenter study from Asia.

BACKGROUND: Data on external validation of models developed to distinguish Crohn's disease (CD) from intestinal tuberculosis (ITB) are limited. This study aimed to validate and compare models using clinical, endoscopic, and/or pathology findings to differentiate CD from ITB. METHODS: Data from newly diagnosed ITB and CD patients were retrospectively collected from 5 centers located in Thailand or Hong Kong. The data was applied to Lee, et al., Makharia, et al., Jung, et al., and Limsrivilai, et al. model. RESULTS: Five hundred and thirty patients (383 CD, 147 ITB) with clinical and endoscopic data were included. The area under the receiver operating characteristic curve (AUROC) of Limsrivilai's clinical-endoscopy (CE) model was 0.853, which was comparable to the value of 0.862 in Jung's model (p = 0.52). Both models performed significantly better than Lee's endoscopy model (AUROC: 0.713, p<0.01). Pathology was available for review in 199 patients (116 CD, 83 ITB). When 3 modalities were combined, Limsrivilai's clinical-endoscopy-pathology (CEP) model performed significantly better (AUROC: 0.887) than Limsrivilai's CE model (AUROC: 0.824, p = 0.01), Jung's model (AUROC: 0.798, p = 0.005) and Makharia's model (AUROC: 0.637, p<0.01). In 83 ITB patients, the rate of misdiagnosis with CD when used the proposed cutoff values in each original study was 9.6% for Limsrivilai's CEP, 15.7% for Jung's, and 66.3% for Makharia's model. CONCLUSIONS: Scoring systems with more parameters and diagnostic modalities performed better; however, application to clinical practice is still limited owing to high rate of misdiagnosis of ITB as CD. Models integrating more modalities such as imaging and serological tests are needed.

Predictive significance of cancer related-inflammatory markers in locally advanced rectal cancer.

BACKGROUND: Locally advanced rectal cancer is treated using neoadjuvant chemoradiation (nCRT), followed by total mesorectal excision (TME). Tumor regression and pathological post-treatment stage are prognostic for oncological outcomes. There is a significant correlation between markers representing cancer-related inflammation, including high neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte (MLR) and unfavorable oncological outcomes. However, the predictive role of these markers on the effect of chemoradiation is unknown. AIM: To evaluate the predictive roles of NLR, MLR, and PLR in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiation. METHODS: Patients (n = 111) with locally advanced rectal cancer who underwent nCRT followed by TME at the Minimally Invasive Surgery Unit, Siriraj Hospital between 2012 and 2018 were retrospectively analyzed. The associations between post-treatment pathological stages, neoadjuvant rectal (NAR) score and the pretreatment ratios of markers of inflammation (NLR, MLR, and PLR) were analyzed. RESULTS: Clinical stages determined using computed tomography, magnetic resonance imaging, or both were T4 (n = 16), T3 (n = 94), and T2 (n = 1). The NAR scores were categorized as high (score > 16) in 23.4%, intermediate (score 8-16) in 41.4%, and low (score < 8) in 35.2%. The mean values of the NLR, PLR, and MLR correlated with pathological tumor staging (ypT) and the NAR score. The values of NLR, PLR and MLR were higher in patients with advanced pathological stage and high NAR scores, but not statistically significant. CONCLUSION: In patients with locally advanced rectal cancer, pretreatment NLR, MLR and PLR are higher in those with advanced pathological stage but the differences are not significantly different.

High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma.

Interleukin 33 (IL-33) promotes cholangiocarcinoma (CCA) genesis in a mouse model, however, its function in human CCA has not been clearly understood. This study was aimed to investigate IL-33 level in CCA tissues and its clinicopathological correlations. The results revealed that IL-33 was found in both cancer cells and stromal cancer-associated fibroblast (CAFs) staining patterns which were divided into high (CH) and low level (CL) in cancer cells; and presence (FP) and absence (FA) in CAFs. Kaplan-Meier analysis showed that patients in the CL group were significantly correlated with a short 2-year survival time (P = 0.027). The CL/FP group had a shorter survival time compared to the other groups with statistical significance for 2-year (P = 0.030) and 5-year (P = 0.023) survivals. In contrast, CH/FP patients had significantly greater 2-year (P = 0.003) and 5-year (P = 0.003) survivals. Univariate and multivariate analysis confirmed that CL/FP was a significantly independent risk factor whereas CH/FP was a significant protective factor in CCA patients. High IL-33 expressing CCA cells had low migration, but they showed increased migration when IL-33 expression was knocked down. The low level of recombinant human IL-33 (rhIL-33) (0.002 - 2 ng/ml) could promote CCA cell migration, in contrast to the suppressive effect at a high dose (20 - 200 ng/ml). In conclusion, the combination of high IL-33 level in cancer cells and CAFs is a potentially good prognosis marker in CCA patients. The in vitro migration suppressive effect of IL-33 may be the potential mechanism supporting its role as a good prognostic marker in CCA patients. The obtained results strengthen IL-33 as a promising predictor and therapeutic target for CCA.

Periostin regulates autophagy through integrin α5ß1 or α6ß4 and an AKT-dependent pathway in colorectal cancer cell migration.

Colorectal cancer (CRC) is one of the most fatal cancers with highly invasive properties. The progression of CRC is determined by the driving force of periostin (PN) from cancer-associated fibroblasts (CAFs) in the tumour microenvironment. This present work aims to investigate autophagy-mediated CRC invasion via the receptor integrin (ITG) by PN. The level of PN in 410 clinical CRC tissues was found increased and was an independent poor prognosis marker (HR = 2.578, 95% CI = 1.218-5.457, P-value = .013) with a significant correlation with overall survival time (P-value < .001). PN activated proliferation, migration and invasion of CRC cells, but with reduced autophagy. Interestingly, the reduction of LC3 autophagic protein corresponded to the increased ability of CRC cell migration. The siITGα5-treated HT-29 and siITGß4-treated HCT-116 CRC cells attenuated epithelial-to-mesenchymal transitions (EMT)-related genes and pAKT compared with those in siITG-untreated cells. The reduction of pAKT by a PI3K inhibitor significantly restored autophagy in CRC cells. These evidences confirmed the effect of PN through either ITGα5ß1 or ITGα6ß4 and the AKT-dependent pathway to control autophagy-regulated cell migration. In conclusion, these results exhibited the impact of PN activation of ITGα5ß1 or ITGα6ß4 through pAKT in autophagy-mediated EMT and migration in CRC cells.

Periostin induces epithelial­to­mesenchymal transition via the integrin α5ß1/TWIST­2 axis in cholangiocarcinoma.

Periostin (PN) (also known as osteoblast­specific factor OSF­2) is a protein that in humans is encoded by the POSTN gene and has been correlated with a reduced survival of cholangiocarcinoma (CCA) patients, with the well­known effect of inducing epithelial­to­mesenchymal transition (EMT). The present study investigated the effect of PN, through integrin (ITG)α5ß1, in EMT­mediated CCA aggressiveness. The alterations in EMT­related gene and protein expression were investigated by real­time PCR, western blot analysis and zymogram. The effects of PN on migration and the level of TWIST­2 were assessed in CCA cells with and without siITGα5 transfection. PN was found to induce CCA cell migration and EMT features, including increments in Twist­related protein 2 (TWIST­2), zinc finger protein SNAI1 (SNAIL­1), α-smooth muscle actin (ASMA), vimentin (VIM) and matrix metallopeptidase 9 (MMP­9), and a reduction in cytokeratin 19 (CK­19) together with cytoplasmic translocation of E-cadherin (CDH­1). Additionally, PN markedly induced MMP­9 activity. TWIST­2 was significantly induced in PN­treated CCA cells; this effect was attenuated in the ITGα5ß1­knockdown cells and corresponded to reduced migration of the cancer cells. These results indicated that PN induced CCA migration through ITGα5ß1/TWIST-2­mediated EMT. Moreover, clinical samples from CCA patients showed that higher levels of TWIST­2 were significantly correlated with shorter survival time. In conclusion, the ITGα5ß1­mediated TWIST­2 signaling pathway regulates PN­induced EMT in CCA progression, and TWIST­2 is a prognostic marker of poor survival in CCA patients.