Correlation between intestinal stem cell niche changes and small bowel crypt failure in patients with treatment-naïve celiac disease.

OBJECTIVES: We hypothesized that crypt failure in the small bowel results in villous flattening in patients with celiac disease (CeD). We investigated whether alterations in the stem cell niche (ISC) are responsible for this phenomenon. MATERIALS AND METHODS: We included 92 duodenal (D2/3) biopsies from treatment-naive patients of CeD and 37 controls. All underwent screening for serum anti-tissue transglutaminase and endoscopic upper small bowel biopsy. Immunohistochemical markers were used to investigate ISC niche alterations, including LGR5 for crypt basal cells (CBC), Bmi1 for position 4+ cells, ß-Defensin for Paneth cells, R-spondin1 as WNT activator, transcription factor-4 as WNT transcription factor, BMP receptor1A as WNT inhibitor, fibronectin-1 as periepithelial stromal cell marker, H2AX as apoptosis marker, and Ki67 as proliferation marker. We also analyzed IgA anti-tTG2 antibody deposits by using dual-color immunofluorescence staining. RESULTS: We found that in biopsies from patients with treatment-naive CeD with modified Marsh grade 3a-3c changes, the epithelial H2AX apoptotic index was upregulated than in controls. LGR5+ crypt basal cells were upregulated in all modified Marsh grades compared to controls. However, the Ki67 proliferation index, expressions of WNT-activator RSPO1, and position-4 cell marker Bmi1 did not significantly alter in patients' biopsies as compared to controls ( P = 0.001). We also observed depletion of pericrypt stromal fibronectin-1 in patients with CeD compared to controls. In addition, we identified IgA anti-TG2 antibody deposits in pericrypt stroma. CONCLUSIONS: Our data suggests that ISC niche failure is a plausible hypothesis for villous flattening in patients with CeD, resulting from pericrypt IgA anti-TG2 antibody complex-mediated stromal depletion.

Novel Scoring Systems and Age-Based Hepatic Shear Wave Stiffness Cut-Offs for Improving Sonographic Diagnosis of Biliary Atresia.

OBJECTIVES: To make sonographic evaluation for biliary atresia (BA) more objective and reproducible using scoring systems, and evaluate hepatic shear wave elastography (SWE) as an adjunct in sonographic diagnosis of BA. METHODS: Sixty-four infants with cholestatic jaundice were enrolled between June 2016 and March 2018 in this prospective observational cohort study. Sonography and SWE was performed with SuperSonic Aixplorer system. Novel scoring systems were developed incorporating established sonographic parameters and hepatic stiffness values and analysed using SPSS software. RESULTS: Of the 18 patients confirmed as BA, 3 were misdiagnosed on conventional sonography (16.7%) as non-BA. Gall bladder (GB) wall irregularity and fasting GB length were the most accurate (93.8%) and most specific (97.8%) individual parameters, respectively. A significant difference was noted in the triangular cord (TC) thickness of BA and non-BA infants (p <0.001), with a high specificity of 95.6% for a 4 mm cut-off value for a positive TC sign. Comparison of hepatic SWE stiffness among age-matched groups of BA and non-BA showed significant differences (≤60 d: p = 0.003; >60 d: p <0.001) but with a reduced accuracy (93.8%). Diagnostic accuracy of greyscale scoring system (96.9%), greyscale + elastography scoring system in ≤60 d (94.4%) and >60 d (97.8%) were better than that of conventional sonographic diagnosis (93.8%). CONCLUSIONS: Grey scale scoring system improves the accuracy of sonographic diagnosis of BA without any additional cost or time penalty along with making it universally reproducible. SWE has only an adjunctive role, if any, in the sonographic diagnosis of BA.

Pancreatic Mass Characterization Using IVIM-DKI MRI and Machine Learning-Based Multi-Parametric Texture Analysis.

Non-invasive characterization of pancreatic masses aids in the management of pancreatic lesions. Intravoxel incoherent motion-diffusion kurtosis imaging (IVIM-DKI) and machine learning-based texture analysis was used to differentiate pancreatic masses such as pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumor (pNET), solid pseudopapillary epithelial neoplasm (SPEN), and mass-forming chronic pancreatitis (MFCP). A total of forty-eight biopsy-proven patients with pancreatic masses were recruited and classified into pNET (n = 13), MFCP (n = 6), SPEN (n = 4), and PDAC (n = 25) groups. All patients were scanned for IVIM-DKI sequences acquired with 14 b-values (0 to 2500 s/mm2) on a 1.5T MRI. An IVIM-DKI model with a 3D total variation (TV) penalty function was implemented to estimate the precise IVIM-DKI parametric maps. Texture analysis (TA) of the apparent diffusion coefficient (ADC) and IVIM-DKI parametric map was performed and reduced using the chi-square test. These features were fed to an artificial neural network (ANN) for characterization of pancreatic mass subtypes and validated by 5-fold cross-validation. Receiver operator characteristics (ROC) analyses were used to compute the area under curve (AUC). Perfusion fraction (f) was significantly higher (p < 0.05) in pNET than PDAC. The f showed better diagnostic performance for PDAC vs. MFCP with AUC:0.77. Both pseudo-diffusion coefficient (D*) and f for PDAC vs. pNET showed an AUC of 0.73. ADC and diffusion coefficient (D) showed good diagnostic performance for pNET vs. MFCP with AUC: 0.79 and 0.76, respectively. In the TA of PDAC vs. non-PDAC, f and combined IVIM-DKI parameters showed high accuracy ≥ 84.3% and AUC ≥ 0.84. Mean f and combined IVIM-DKI parameters estimated that the IVIM-DKI model with TV texture features has the potential to be helpful in characterizing pancreatic masses.

Role of Whole body PET/CT and Examination under anesthesia with multi-site biopsy in evaluating CUP.

To evaluate the role of 18FDG-WBPET-CT, Examination under anesthesia (EUA), and multiple-site biopsy in detecting the occult site in head & neck carcinoma of unknown primary (HN-CUP). In this prospective study, 22 patients with diagnosed CUP, after a thorough outpatient endoscopic evaluation of upper airway and radiological evaluation (CT/MRI) that ruled out a primary lesion were included. These patients subsequently underwent whole-body PET-CT and EUA. Based on the presence of suspicious findings ( +) or their absence (-) on 18FDG-WBPET-CT (P) and EUA (E), we divided the patients into 5 groups: P-E-, P-E + , P + E-, P + E + , and P + or E + . All these patients underwent bilateral palatine tonsillectomy, bilateral nasopharyngeal biopsy, and ipsilateral lingual tonsillectomy for identification of occult primary. Out of 22 patients, the primary could be detected in 4 patients (18%) after the workup (three in the oropharynx and one in the hypopharynx, all ipsilateral). 18FDG-PET-CT suspected primaries in 7 patients; biopsy was positive for three (sensitivity-75%, specificity-77%, PPV-43%, NPV-93%). Out of 5 patients, who had suspicious findings on EUA, 3 of the biopsies revealed malignancy (sensitivity-75%, specificity-88%, PPV-60%, NPV-94%). Both PET-CT and EUA when combined, yield a NPV of 100% if both are negative and PPV of 100% when both are positive for suspicious findings. No primary was identified in the absence of a suspicion by PET-CT or EUA. Without a suspicion on 18FDG-WBPET-CT and EUA, there is a limited role of multiple-site biopsies in patients of HN-CUP.

Impact of Cytomegalovirus Infection on Short-Term Clinical Outcomes and Operative Histopathology in Infants with Biliary Atresia: A Single-Center Prospective Cohort Study.

Background: There is limited information on the impact of cytomegalovirus (CMV) infection on clinical outcomes and operative histopathology in children with biliary atresia (BA). We hypothesized that CMV infection is associated with greater histopathological damage and unfavorable short-term clinical outcomes. Materials and Methods: A prospective single-center study was conducted with effect from January 2011-July 2012 including all infants with BA who underwent surgery. Diagnosis of CMV infection was confirmed by serum immunoglobulin M (IgM) positivity or the presence of CMV-deoxyribonucleic acid (DNA) in the liver tissue. Four short-term outcome variables were observed. The cohort was divided into subgroups on the basis of seropositivity (IgM + or IgM-); the presence of CMV-DNA in the liver (polymerase chain reaction [PCR]+ or PCR-); and composite CMV groups (Group 1 - IgM+, PCR+; Group 2 - IgM+, PCR-; Group 3 -- IgM-, PCR+; and Group 4 - IgM-, PCR-). Outcomes and histopathology were compared in these subgroups. Results: A total of 32 infants with BA were operated at a mean age of 3.5 (range: 1-6) months. Serum IgM+ and PCR+ were observed in 50% and 37.5% of the patients. Unfavorable outcomes showed a significant association with IgM+ and not PCR+. Similarly, outcomes were poor for CMV Groups 1 and 2 at 1-month follow-up. Infants with IgM+ and PCR+ showed a greater degree of histopathological damage in terms of bile duct proliferation and severe bile duct fibrosis, respectively. Conclusion: In the present study, there was a high incidence of serum IgM+ (50%) and PCR+ of biopsy specimens (37.5%) in infants with BA. This CMV-infected subgroup was associated with greater histopathological damage and unfavorable short-term outcomes after surgery.

Long-term outcomes of anti-tumor necrosis factor therapy and surgery in nonperianal fistulizing Crohn's disease.

BACKGROUND: Unlike perianal fistula, long-term outcomes of nonperianal fistulae (NPF) in Crohn's disease (CD) are not clear. We aimed to compare the outcomes of medical and surgical therapies in patients with NPF. METHODS: We retrospectively analyzed the records of patients of CD with NPF who were prospectively followed from January 2005 to December 2018. RESULTS: Of the 53 patients with NPF [mean age at presentation:29 ± 14 years; 54.7% male; median duration of follow-up: 47 months (interquartile range [IQR]:26-76 months)], enteroenteric fistula (37.8%) was the most common presentation. Of 22 patients treated with anti-tumor necrosis factor (TNF) therapy, complete response was achieved in 40.9% (n = 9). Overall probability of maintaining response was similar between the anti-TNF and surgical groups (95.2% vs 82.4%; 71% vs 76%; and 63% vs 69%% [P = 0.8] at 1, 2, and 3 years, respectively), with only 13.6% of patients treated with biologicals requiring surgery over 56 months. Twenty-one patients required upfront surgery (small bowel or ileocolonic resection with/without diversion; 28.5% emergent), with 47.6% postoperative recurrence over 36 months, of which nine patients required biologicals (77.7% response to anti-TNF therapy). Long-term outcome was comparable between medically and surgically treated patients; 6.4% developed tuberculosis on anti-TNF therapy. Two patients (3.7%) developed malignancy (one - enteroenteric, one - colovesical). CONCLUSION: Anti-TNF therapy appears to be as effective as surgery in this retrospective analysis of patients with NPFCD, and it may be indicated in the absence of abscess and other complications. These patients are at higher risk of fistula-associated malignancy, which requires a lower threshold for suspicion, especially over the long term in the presence of nonresponse to medical therapy.

NOVEL USE OF FLUORESCEIN DYE IN DETECTION OF ORAL DYSPLASIA AND ORAL CANCER.

BACKGROUND: India is now regarded as the country with one of the highest incidence of oral cancer in the world. Considering poor survival in cases with late diagnosis, early detection can reduce morbidity and mortality of cancer patients and may impede malignant transformation in cases of oral potentially malignant disorders (OPMD). Most of the diagnostic aids are expensive and not available for mass screenings in developing countries. There is a need to develop a sensitive and affordable technique for screening of oral cancer, which can be accurate even in hands of health care workers with limited experience. Fluorescein dye has been used for tumour detection in colon, stomach, breast and brain. However, its utility in the diagnosis of oral cancer and OPMD has not yet been explored. METHODS: This is the first study to report the role of fluorescein in the detection of oral cancer and OPMD. The present cross sectional study was conducted at a tertiary care dental centre. It included 100 individuals presenting with 42 OPMDs, 40 oral squamous cell carcinoma (OSCC) and 18 controls. RESULTS: The sensitivity and specificity for the fluorescein detection method for OPMDs and OSCC was found to be 96.6% and 52.4% respectively. The positive predictive value was 73.7% and the negative predictive value was 91.7% for the fluorescein method. The likelihood ratios stood at 2.03 for a positive test and 0.066 for a negative test. CONCLUSION: We conclude that fluorescein staining along with blue light is likely to improve detection of early oral cancers and dysplasia and can play a vital role in mass screening programmes of oral cancer.

SPARC expression in desmoplastic and non desmoplastic pancreatic carcinoma and cholangiocarcinoma.

BACKGROUND: The pancreatobiliary carcinomas are characterized by presence of desmoplastic stroma. Overexpression of secreted protein acid and rich in cysteine (SPARC), a matrix producing agent has been documented in pancreatic ductal adenocarcinomas, with survival benefits. This study was targeted to see if SPARC expression in pancreatobiliary carcinomas is responsible for stromal desmoplasia and its prognostic significance. METHODS: In this retrospective study 48 cases of pancreatic cancer and 27 cases of cholangiocarcinoma were analyzed. The expression pattern of SPARC and vascular endothelial growth factor (VEGF) (angiogenic factors) was evaluated by immunohistochemistry on formalin fixed paraffin embedded tissues. Immunoreactivity was scored semi quantitatively based on stain intensity and stain distribution. SPARC expression was correlated with tumor histology, stromal desmoplasia, VEGF expression, various histological parameters and overall survival in patients. Real time polymerase chain reaction was performed in few cases to validate the immunohistochemistry expression pattern. RESULTS: SPARC expression was high in peritumoral stroma in pancreatic carcinoma than in pancreatic controls; however, SPARC expression pattern was not grossly different in desmoplastic and non-desmoplastic pancreatobiliary carcinomas and in cholangiocarcinomas. No definite correlation was noted between SPARC expression and histological markers of severity and overall survival data. CONCLUSIONS: The relevance of SPARC expression in pancreato-biliary carcinomas though may still be important for therapeutic decision making, it is not responsible for peritumoral stromal desmoplasia in these tumors and it does not have any significant prognostic implication.

Duodenal mucosal immune cells in treatment-naive adult patients with celiac disease having different histological grades and controls.

BACKGROUND: It is hypothesized that the duodenal mucosal damage in patients with celiac disease (CeD) is caused by the mucosa-infiltrating lymphoid cells. This study aimed to analyze the immune effective and regulatory T (Treg) cells in duodenal biopsies from treatment-naive adult patients with CeD having different histological grades and controls. PATIENTS AND METHODS: Dual-color immunohistochemical staining was done in a total of 234 duodenal biopsies, including 132 controls and 102 adult patients with CeD using CD20, CD3:CD4, CD3:CD8, CD4:FoxP3, CD8:FoxP3, and TCRαß:TCRγδ antibodies. The density of these lymphoid cells in lamina propria and mucosal epithelium was compared between controls and CeD, with different modified Marsh grades. RESULTS: Densities of CD4+ T cells in lamina propria and CD8+γδ intraepithelial lymphocytes (IELs) were significantly more in biopsies from patients with CeD, than in controls. An increasing linear pattern of IELs, CD3+ T cells, and CD20+ B cells was observed with increasing grades of villous abnormalities. Although CD8+ FoxP3+ Treg cells were significantly more in biopsies from patients with CeD, there was no significant difference in CD4+ FoxP3+ Treg cell infiltrate between both the groups. CONCLUSION: Our finding in this observational study generates interest to study the local intestinal mucosal immunity in CeD in detail. A study to prove the failure of CD4+ FoxP3+ Treg cell recruitment in CeD and its direct functional impact may yield valuable information regarding loss of mucosal tolerance.

Microvillous Inclusion Disease as a Cause of Protracted Diarrhea.

Microvillous inclusion disease (MVID), also known as congenital microvillus atrophy, was first described by Davidson et al. in 1978. Till date, only a handful of cases with MVID have been described in English literature. It is an autosomal recessive disorder with no sex predisposition and more commonly noted in countries with prevalent consanguineous marriages. These patients usually present with intractable secretory diarrhea in early days of life. The pathognomonic findings of MVID are villous atrophy along with the formation of intracellular microvillous inclusions on electron microscopy. Till date, no curative therapy exists, and prognosis mainly depends upon parenteral nutrition. Small bowel transplantation is one of the treatment options. Clinician and pathologist should consider the possibility of MVID in the differential diagnosis of chronic intractable diarrhea in an infant. Herein, authors are describing a case of intractable diarrhea with MVID phenotype diagnosed in a 3-mo-old male child who presented with intractable diarrhea in an outside hospital, and the diagnostic workup was performed by the authors on endoscopic biopsy sample.

Quantitative histology-based classification system for assessment of the intestinal mucosal histological changes in patients with celiac disease.

BACKGROUND/AIMS: The existing histological classifications for the interpretation of small intestinal biopsies are based on qualitative parameters with high intraobserver and interobserver variations. We have developed and propose a quantitative histological classification system for the assessment of intestinal mucosal biopsies. METHODS: We performed a computer-assisted quantitative histological assessment of digital images of duodenal biopsies from 137 controls and 124 patients with celiac disease (CeD) (derivation cohort). From the receiver-operating curve analysis, followed by multivariate and logistic regression analyses, we identified parameters for differentiating control biopsies from those of the patients with CeD. We repeated the quantitative histological analysis in a validation cohort (105 controls and 120 patients with CeD). On the basis of the results, we propose a quantitative histological classification system. The new classification was compared with the existing histological classifications for interobserver and intraobserver agreements by a group of qualified pathologists. RESULTS: Among the histological parameters, intraepithelial lymphocyte count of ≥25/100 epithelial cells, adjusted villous height fold change of ≤0.7, and crypt depth-to-villous height ratio of ≥0.5 showed good discriminative power between the mucosal biopsies from the patients with CeD and those from the controls, with 90.3% sensitivity, 93.5% specificity, and 96.2% area under the curve. Among the existing histological classifications, our quantitative histological classification showed the highest intraobserver (69.7%-85.03%) and interobserver (24.6%-71.5%) agreements. CONCLUSIONS: Quantitative assessment increases the reliability of the histological assessment of mucosal biopsies in patients with CeD. Such a classification system may be used for clinical trials in patients with CeD. (Intest Res, Published online).

Clinical, endoscopic, and histological differentiation between celiac disease and tropical sprue: A systematic review.

BACKGROUND AND AIM: While the prevalence of celiac disease (CD) is increasing globally, the prevalence of tropical sprue (TS) is declining. Still, there are certain regions in the world where both patients with CD and TS exist and differentiation between them is a challenging task. We conducted a systematic review of the literature to find out differentiating clinical, endoscopic, and histological characteristics between CD and TS. METHODS: Medline, PubMed, and EMBASE databases were searched for keywords: celiac disease, coeliac, celiac, tropical sprue, sprue, clinical presentation, endoscopy, and histology. Studies published between August 1960 and January 2018 were reviewed. Out of 1063 articles available, 12 articles were included in the final analysis. RESULTS: Between the patients with CD and TS, there was no difference in the prevalence and duration of chronic diarrhea, abdominal distension, weight loss, extent of abnormal fecal fat content, and density of intestinal inflammation. The following features were more common in CD: short stature, vomiting/dyspepsia, endoscopic scalloping/attenuation of duodenal folds, histological high modified Marsh changes, crescendo type of IELosis, surface epithelial denudation, surface mucosal flattening, thickening of subepithelial basement membrane and celiac seropositivity; while those in TS include anemia, abnormal urinary D-xylose test, endoscopic either normal duodenal folds or mild attenuation, histologically decrescendo type of IELosis, low modified Marsh changes, patchy mucosal changes, and mucosal eosinophilia. CONCLUSIONS: Both patients with CD and TS have overlapping clinical, endoscopic, and histological characteristics, and there is no single diagnostic feature for differentiating CD from TS except for celiac specific serological tests.

Detection of Solitary Axillary Lymph Node Metastases from Hürthle Cell Carcinoma of the Thyroid on 18F-FDG PET/CT.

Thyroid carcinoma is the most common neoplasm of endocrine malignancies. Differentiated thyroid carcinoma (DTC) constitutes 90% of the thyroid carcinomas, rest being medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). Distant metastases occur in up to 10% of patients with DTC. Metastases to axillary lymph nodes (ALN) are very rare. As per literature, only 25 cases have been reported. We report an unusual case of 47-year-old male with Hürthle cell carcinoma of the thyroid presenting with a solitary axillary lymph node metastasis 17 years after thyroidectomy, along with review of literature.

Selective M1 macrophage polarization in granuloma-positive and granuloma-negative Crohn's disease, in comparison to intestinal tuberculosis.

BACKGROUND/AIMS: Classical M1 macrophage activation exhibits an inflammatory phenotype while alternative M2 macrophage activation exhibits an anti-inflammatory phenotype. We aimed to determine whether there are discriminant patterns of macrophage polarization in Crohn's disease (CD) and intestinal tuberculosis (iTB). METHODS: Colonic mucosal biopsies from 29 patients with iTB, 50 with CD, and 19 controls were examined. Dual colored immunohistochemistry was performed for iNOS/CD68 (an M1φ marker) and CD163/CD68 (an M2φ marker), and the ratio of M1φ to M2φ was assessed. To establish the innate nature of macrophage polarization, we analyzed the extent of mitochondrial depolarization, a key marker of inflammatory responses, in monocyte-derived macrophages obtained from CD and iTB patients, following interferon-γ treatment. RESULTS: M1φ polarization was more prominent in CD biopsies (P=0.002) than in iTB (P=0.2) and control biopsies. In granuloma-positive biopsies, including those in CD, M1φ predominance was significant (P=0.001). In iTB, the densities of M1φ did not differ between granuloma-positive and granuloma-negative biopsies (P=0.1). Interestingly, higher M1φ polarization in CD biopsies correlated with high inflammatory response exhibited by peripheral blood-derived monocytes from these patients. CONCLUSIONS: Proinflammatory M1φ polarization was more common in colonic mucosa of CD patients, especially in the presence of mucosal granulomas. Further characterization of the innate immune system could help in clarifying the pathology of iTB and CD.

Histological assessment & use of immunohistochemical markers for detection of dysplasia in Barrett's esophageal mucosa.

BACKGROUND: Histological assessment of dysplasia in Barrett's esophagus (BE) has high inter-observer variability. Hence, use of ancillary markers for early detection of dysplasia in BE is an important clinical question. METHODS: In this retrospective study consecutive cases of BE (n = 59), over a period of 4 years were included. Hematoxylin and eosin stained sections were reviewed independently by 3 senior qualified pathologists, who graded the dysplasia according to the Vienna Classification system and inter-observer agreement was analysed using the Kappa statistics. Subsequently Alpha-Methyl Acyl-CoA Racemase (AMACR), p53, CyclinD1, ß-catenin, H2AX and M30 immunohistochemical (IHC) stains were examined on the following disease categories: BE with no dysplasia [NFD] (45), BE with indefinite for dysplasia (IFD) (4), low grade dysplasia (LGD) (3), high grade dysplasia (HGD) (2) and in adenocarcinomas (5). H score was calculated by adding up products of different grades of stain distribution and stain intensities (range of scores 0-300). RESULTS: Among the 3 pathologists, overall agreement was poor (k 0.06; 95% CI -0.089 to 0.145), with highest disagreement noted for differentiating the LGD and IFDs (k = 0.21). After revising the histological criteria, the kappa improved to 0.53. Among the IHC stains performed, p53, ß-catenin, H2AX and M30 stains were significantly useful to differentiate between IFD and LGD (P values: 0.04, 0.004, 0.05 & 0.04, respectively). AMACR and ß-catenin stains though were up-regulated in HGD/adenocarcinomas than in other categories, their expression were not statistically different between the IFD and LGDs. CONCLUSIONS: A detail histological scoring system may bring uniformity in histological interpretation of dysplasia in BE. Using a combined panel of IHC stains seems helpful in detection of dysplasia in BE, especially to differentiate the IFD and LGD changes in BE.

Ratio of Preoperative and Postoperative Serum Bilirubin Levels Predicts Early Outcome Following Biliary Atresia Surgery.

AIM: This study investigates the fall in total serum bilirubin levels within 1 week after surgery, as a marker to predict early outcome in biliary atresia (BA) patients post-Kasai portoenterostomy (KP). METHODS: The ratio of total serum bilirubin levels at the 7th postoperative day to the preoperative level (TB7/TB0) in patients undergoing KP was calculated (January 2011-July 2015). Patients were stratified after 3-months follow-up into outcome groups depending on the clinical clearance of jaundice and TB7/TB0 ratio was correlated to outcome and liver histopathological changes in these groups. RESULTS: Sixty-one patients (M:F = 44:17), median age 75 days were included. At the end of 3 months, 27 (44.39%) were anicteric while 26 (42.6%) were still clinically jaundiced. Patients with a higher median value of TB7/TB0, that is, 0.856 were more likely to have jaundice at the end of 3 months as compared to patients with a lower median value of 0.615 (P < 0.0001). A cutoff TB7/TB0 ratio >0.723 predicted the KP outcome with 84.6% sensitivity and 81.5% specificity. The difference in TB7/TB0 ratio between patients with varying severity of liver histopathological changes was also significant, namely, cholestasis (P = 0.01), hepatocellular damage (P = 0.03), portal inflammation (P = 0.04), and portal fibrosis (P = 0.02). CONCLUSIONS: The rapidity of fall in the total serum bilirubin levels within 1 week post-KP was able to predict the likely outcome in BA patients.

Topographic, histological and molecular study of aberrant crypt foci identified in human colon in different clinical groups.

BACKGROUND/AIMS: Aberrant crypt foci (ACF) are early microscopic lesions of the colonic mucosa, which can be detected by magnified chromoendoscopy. Herein, we have investigated whether ACF identified in different clinical groups can be differentiated based on their characteristics. METHODS: Macroscopically unremarkable mucosal flaps were collected from 270 fresh colectomies and divided into 3 clinical groups: colorectal carcinoma (group A), disease controls having known pre-neoplastic potential (group Bc), and disease controls without risk of carcinoma development (group Bn). Topographic and histologic analysis, immunohistochemistry, and molecular studies (high-resolution melt curve analysis, real-time polymerase chain reaction, and Sanger sequencing) were conducted for certain neoplasia-associated markers. RESULTS: ACF were seen in 107 cases, out of which 72 were left colonic ACF and 35 right colonic ACF (67.2% vs. 32.7%, P=0.02). The overall density of left colonic ACF was 0.97/cm, which was greater than the right colonic ACF density of 0.81/cm. Hypercrinia was present in 41 out of 72 left colonic ACF and in 14 out of 35 right colonic ACF (P=0.01). Immunohistochemical expression of p53 was also greater in left colonic ACF than in right colonic ACF (60.5% vs. 38.2%, P=0.03). However, ACF identified among the 3 clinical groups did not show any distinguishing topographic, histological, or genetic changes. CONCLUSIONS: Left colonic ACF appear to be high-risk based on their morphological and prototypic tumor marker signature. ACF identified in different clinical groups do not show significant genotypic or topographic differences. Further detailed genetic studies are required to elucidate them further.

Acute Traumatic Endotheliopathy in Isolated Severe Brain Injury and Its Impact on Clinical Outcome.

STUDY DESIGN: Prospective observational cohort. OBJECTIVE: To investigate the difference in plasma levels of syndecan-1 (due to glycocalyx degradation) and soluble thrombomodulin (due to endothelial damage) in isolated severe traumatic brain injury (TBI) patients with/without early coagulopathy. A secondary objective was to compare the effects of the degree of TBI endotheliopathy on hospital mortality among patients with TBI-associated coagulopathy (TBI-AC). METHODS: Data was prospectively collected on isolated severe TBI (sTBI) patients with Glasgow Coma Scale (GCS) ≤8 less than 12 h after injury admitted to a level I trauma centre. Isolated sTBI patients with samples withdrawn prior to blood transfusion were stratified by conventional coagulation tests as coagulopathic (prothrombin time (PT) ≥ 16.7 s, international normalized ratio (INR) ≥ 1.27, and activated partial thromboplastin time (aPTT) ≥ 28.8 s) and non-coagulopathic. Twenty healthy controls were also included. Plasma levels of thrombomodulin and syndecan-1 were estimated by ELISA. With receiver operating characteristic curve (ROC) analysis, we defined endotheliopathy as a syndecan-1 cut-off level that maximized the sum of sensitivity and specificity for predicting TBI-AC. RESULTS: Inclusion criteria were met in 120 cases, with subjects aged 35.5 ± 12.6 years (88.3% males). TBI-AC was identified in 50 (41.6%) patients, independent of age, gender, and GCS, but there was an association with acidosis (60%; p = 0.01). Following isolated sTBI, we found insignificant changes in soluble thrombomodulin (sTM) levels between patients with isolated TBI and controls, and sTM levels were lower in coagulopathic compared to non-coagulopathic patients. Elevations in plasma syndecan-1 (ng/mL) levels were seen compared to control (31.1(21.5-30.6) vs. 24.8(18.5-30.6); p = 0.08). Syndecan-1(ng/mL) levels were significantly elevated in coagulopathic compared to non-coagulopathic patients (33.7(21.6-109.5) vs. 29.9(19.239.5); p = 0.03). Using ROC analysis (area under the curve = 0.61; 95% Confidence Interval (CI) 0.50 to 0.72), we established a plasma syndecan-1 level cutoff of ≥30.5 ng/mL (sensitivity % = 55.3, specificity % = 52.3), with a significant association with TBI-associated coagulopathy. CONCLUSION: Subsequent to brain injury, elevated syndecan-1 shedding and endotheliopathy may be associated with early coagulation abnormalities. A syndecan-1 level ≥30.5 ng/mL identified patients with TBI-AC, and may be of importance in guiding management and clinical decision-making.

Prebiopsy multiparametric MRI-based risk score for predicting prostate cancer in biopsy-naive men with prostate-specific antigen between 4-10 ng/mL.

BACKGROUND: Risk calculators have traditionally utilized serum prostate-specific antigen (PSA) values in addition to clinical variables to predict the likelihood of prostate cancer (PCa). PURPOSE: To develop a prebiopsy multiparametric MRI (mpMRI)-based risk score (RS) and a statistical equation for predicting the risk of PCa in biopsy-naive men with serum PSA between 4-10 ng/mL that may help reduce unnecessary biopsies. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: In all, 137 consecutive men with PSA between 4-10 ng/mL underwent prebiopsy mpMRI (diffusion-weighted [DW]-MRI and MR spectroscopic imaging [MRSI]) during 2009-2015 were recruited for this study. FIELD STRENGTH/SEQUENCE: 1.5T (Avanto, Siemens Health Care, Erlangen, Germany); T1 -weighted, T2 -weighted, DW-MRI, and MRSI sequences were used. ASSESSMENT: All eligible patients underwent mpMRI-directed, cognitive-fusion transrectal ultrasound (TRUS)-guided biopsies. STATISTICAL TESTS: An equation model and an RS were developed using receiver operating characteristic (ROC) curve analysis and a multivariable logistic regression approach. A 10-fold crossvalidation and simulation analyses were performed to assess diagnostic performance of various combinations of mpMRI parameters. RESULTS: Of 137 patients, 32 were diagnosed with PCa on biopsy. Multivariable analysis, adjusted with positive pathology, showed apparent diffusion coefficient (ADC), metabolite ratio, and PSA as significant predictors of PCa (P < 0.05). A statistical equation was derived using these predictors. A simple 6-point mpMRI-based RS was derived for calculating the risk of PCa and it showed that it is highly predictive for PCa (odds ratio = 3.74, 95% confidence interval [CI]: 2.24-6.27, area under the curve [AUC] = 0.87). Both models (equation and RS) yielded high predictive performance (AUC ≥0.85) on validation analysis. DATA CONCLUSION: A statistical equation and a simple 6-point mpMRI-based RS can be used as a point-of-care tool to potentially help limit the number of negative biopsies in men with PSA between 4 and 10 ng/mL. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1227-1236.

Prevalence of eosinophilic esophagitis in patients with gastroesophageal reflux symptoms: A cross-sectional study from a tertiary care hospital in North India.

BACKGROUND: Eosinophilic esophagitis (EoE) is being recognized increasingly all over the globe; Indian data is however sparse. We screened patients with symptoms of gastroesophageal reflux disease (GERD) for presence of EoE in them. METHODS: Consecutive patients with symptoms suggestive of GERD underwent gastroduodenoscopy and esophageal biopsies, obtained from both the upper esophagus (5 cm below the upper esophageal sphincter) and lower esophagus (5 cm above gastroesophageal junction), as well as from any other endoscopically visible abnormal mucosa. Demographic and clinical characteristics, endoscopic findings, peripheral blood eosinophilic count, and history of use of proton-pump inhibitors (PPIs) were analyzed. Stool examination was done to rule out parasitoids. EoE was diagnosed if number of mucosal eosinophil infiltrate was >20 per high-power field. In the latter, Warthin-Starry stain was performed to rule out presence of H elicobacter pylori. RESULTS: Of 190 consecutive patients with symptoms of GERD screened, esophageal biopsies were available in 185 cases. Of them, 6 had EoE, suggesting a prevalence of 3.2% among patients with GERD. On univariate analysis, history of allergy, non-response to PPI, and absolute eosinophil counts and on multivariable analysis, history of allergy and no response to PPIs were significant predictors of EoE. Presence of EOE did not correlate with severity of reflux symptoms. CONCLUSION: In this hospital-based study from northern part of India, prevalence of EoE in patients with GERD was 3.2%. EoE should be considered as a diagnostic possibility, especially in those with history of allergy, no-response to PPI, and absolute eosinophil count of ≥250/cumm.