Ananya Pongpaibul

Histopathology of de novo autoimmune hepatitis

De novo autoimmune hepatitis (DAIH) is a well‐recognized complication of pediatric liver transplantation (LT). The diagnosis is largely based on elevated liver function test results and the development of autoimmune antibodies. The histology of DAIH was first described in 1998. We present detailed histological data from the largest series to date of pretreatment and posttreatment biopsy samples from pediatric LT patients with DAIH. The histological evaluation included first an assessment of the predominant pattern of injury (hepatitis, rejection, or bile duct obstruction). Then, the necroinflammatory activity (interface, lobular, and perivenular), plasma cell density, rejection activity index, and fibrosis were scored. Seventy of 685 pediatric patients (10.2%) who underwent LT developed DAIH according to clinical and biopsy findings. Fifty‐one pretreatment biopsy samples and 38 posttreatment biopsy samples were available for a retrospective review. The predominant pattern of injury (hepatitis, rejection, or bile duct obstruction) was determined, and biopsy samples were scored for the necroinflammatory activity (interface, lobular, and perivenular), plasma cell density, rejection activity index, and fibrosis. The most common pattern of injury was lobular hepatitis, which was frequently unaccompanied by interface necroinflammatory activity or prominent plasma cell infiltrates. Seven of the 51 cases had features strongly suggestive of acute rejection. Posttreatment biopsy samples showed a reduction in the degree of necroinflammatory activity and plasma cell infiltrates. In most patients, the degree of fibrosis was stable or had regressed. Because the histological features of DAIH are variable and nonspecific, a high index of suspicion and correlation with autoimmune antibodies are necessary to establish the diagnosis. In the majority of patients with DAIH, treatment appears to yield good clinical outcomes and histological improvements. Liver Transpl, 2012.

Meta-Analytic Bayesian Model For Differentiating Intestinal Tuberculosis from Crohn's Disease.

Objectives:Distinguishing intestinal tuberculosis (ITB) from Crohns disease (CD) is difficult, although studies have reported clinical, endoscopic, imaging, and laboratory findings that help to differentiate these two diseases. We aimed to produce estimates of the predictive power of these findings and construct a comprehensive model to predict the probability of ITB vs. CD.Methods:A systematic literature search for studies differentiating ITB from CD was conducted in MEDLINE, PUBMED, and EMBASE from inception until September 2015. Fifty-five distinct meta-analyses were performed to estimate the odds ratio of each predictive finding. Estimates with a significant difference between CD and ITB and low to moderate heterogeneity (I2<50%) were incorporated into a Bayesian prediction model incorporating the local pretest probability.Results:Thirty-eight studies comprising 2,117 CD and 1,589 ITB patients were included in the analyses. Findings in the model that significantly favored CD included male gender, hematochezia, perianal disease, intestinal obstruction, and extraintestinal manifestations; endoscopic findings of longitudinal ulcers, cobblestone appearance, luminal stricture, mucosal bridge, and rectal involvement; pathological findings of focally enhanced colitis; and computed tomographic enterography (CTE) findings of asymmetrical wall thickening, intestinal wall stratification, comb sign, and fibrofatty proliferation. Findings that significantly favored ITB included fever, night sweats, lung involvement, and ascites; endoscopic findings of transverse ulcers, patulous ileocecal valve, and cecal involvement; pathological findings of confluent or submucosal granulomas, lymphocyte cuffing, and ulcers lined by histiocytes; a CTE finding of short segmental involvement; and a positive interferon-γ release assay. The model was validated by gender, clinical manifestations, endoscopic, and pathological findings in 49 patients (27 CD, 22 ITB). The sensitivity, specificity, and accuracy for diagnosis of ITB were 90.9%, 92.6%, and 91.8%, respectively.Conclusions:A Bayesian model based on the meta-analytic results is presented to estimate the probability of ITB and CD calibrated to local prevalence. This model can be applied to patients using a publicly available web application.

Deficient DNA mismatch repair is associated with favorable prognosis in Thai patients with sporadic colorectal cancer

AIM To determine the prognostic significance of deficient mismatch repair (dMMR) and BRAF V600E in Thai sporadic colorectal cancer (CRC) patients. METHODS We studied a total of 211 out of 405 specimens obtained from newly diagnosed CRC patients between October 1, 2006 and December 31, 2007 at Siriraj Hospital, Mahidol University. Formalin-fixed paraffin-embedded blocks of CRC tissue samples were analyzed for dMMR by detection of MMR protein expression loss by immunohistochemistry or microsatellite instability using polymerase chain reaction (PCR)-DHPLC. BRAF V600E mutational analysis was performed in DNA extracted from the same archival tissues by two-round allele-specific PCR and analyzed by high sensitivity DHPLC. Associations between patient characteristics, MMR and BRAF status with disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier survival plots and log-rank test together with Coxs proportional hazard regression. RESULTS dMMR and BRAF V600E mutations were identified in 31 of 208 (14.9%) and 23 of 211 (10.9%) tumors, respectively. dMMR was more commonly found in patients with primary colon tumors rather than rectal cancer (20.4% vs 7.6%, P =0.01), but there was no difference in MMR status between the right-sided and left-sided colon tumors (20.8% vs 34.6%, P = 0.24). dMMR was associated with early-stage rather than metastatic disease (17.3% vs 0%, P = 0.015). No clinicopathological features such primary site or tumor differentiation were associated with the BRAF mutation. Six of 31 (19.3%) samples with dMMR carried the BRAF mutation, while 17 of 177 (9.6%) with proficient MMR (pMMR) harbored the mutation (P = 0.11). Notably, patients with dMMR tumors had significantly superior DFS (HR = 0.30, 95%CI: 0.15-0.77; P = 0.01) and OS (HR = 0.29, 95%CI: 0.10-0.84; P = 0.02) compared with patients with pMMR tumors. By contrast, the BRAF V600E mutation had no prognostic impact on DFS and OS. CONCLUSION The prevalence of dMMR and BRAF V600E in Thai sporadic CRC patients was 15% and 11%, respectively. The dMMR phenotype was associated with a favorable outcome.

The prevalence of steatohepatitis in chronic hepatitis B patients and its impact on disease severity and treatment response.

The clinical significance of steatohepatitis in chronic hepatitis B remains unclear. This study aimed to determine the prevalence and risk factors for steatohepatitis in chronic hepatitis B, and to determine its correlation with liver fibrosis and response to antiviral therapy.

The microRNA-15a-PAI-2 axis in cholangiocarcinoma-associated fibroblasts promotes migration of cancer cells

BackgroundCholangiocarcinoma (CCA) has an abundance of tumor stroma which plays an important role in cancer progression via tumor-promoting signals. This study aims to explore the microRNA (miRNA) profile of CCA-associated fibroblasts (CCFs) and the roles of any identified miRNAs in CCA progression.MethodsmiRNA expression profiles of CCFs and normal skin fibroblasts were compared by microarray. Identified downregulated miRNAs and their target genes were confirmed by real-time PCR. Their binding was confirmed by a luciferase reporter assay. The effects of conditioned-media (CM) of miRNA mimic- and antagonist-transfected CCFs were tested in CCA migration in wound healing assays. Finally, the levels of miRNA and their target genes were examined by real-time PCR and immunohistochemistry in clinical CCA samples.ResultsmiR-15a was identified as a downregulated miRNA in CCFs. Moreover, PAI-2 was identified as a novel target gene of miR-15a. Recombinant PAI-2 promoted migration of CCA cells. Moreover, CM from miR-15a mimic-transfected CCFs suppressed migration of CCA cells. Lower expression of miR-15a and higher expression of PAI-2 were observed in human CCA samples compared with normal liver tissues. Importantly, PAI-2 expression correlated with poor prognosis in CCA patients.ConclusionsThese findings highlight the miR-15a/PAI-2 axis as a potential therapeutic target in CCA patients.

Eosinophilic pseudotumour of the liver.

A 50-year-old woman presented with a 3-month illness with intermittent high-graded fever and significant weight loss. On admission, the physical examination revealed hepatomegaly with mild tenderness. Initial evaluation showed mild liver dysfunction and eosinophilia (1,900/ml). Abdominal ultrasonography revealed a 9-cm diameter hypoechoic lesion in the right hepatic lobe. Contrast-enhanced computed tomography demonstrated conglomerate hypodense lesions with lobulated surface and minimal peripheral enhancement at the inferior segment of the right hepatic lobe with subcapsular haemorrhage (arrow) (Fig. 1A). Enlarged lymph nodes were also observed in the porta hepatis. Subsequently, patient underwent percutaneous liver biopsy because the possibility of cystic neoplasm was not entirely excluded. Histological examination of the specimen showed necrotizing eosinophilic granulomas (Fig. 1B) with Charcot-Leyden crystals (arrows) in the absence of identifiable organisms and malignancy (Fig. 1C). Repeated examinations of stool specimens were negative for ova and parasites. The diagnosis of acute fascioliasis was established by a positive immunoserological test. Patient was a habitual consumer of watercress, which may explain the Fasciola hepatica infection. After therapy with a single dose of 10 mg/kg triclabendazole, patient had clinical improvement and disappearance of eosinophilia. One year later, she remained asymptomatic and liver imaging showed almost complete resolution of the lesions. Some clinical features of acute-stage fascioliasis can mimic tumours and is characterized by eosinophilia accompanied with eosinophilic-rich granulomatous lesions in an enlarged liver (1, 2). The identification of eosinophilic granulomatous hepatitis should suggest the diagnosis of visceral larva migrans and prompt a search for the causative organism with serologic tests for parasites (3).

Severe enteropathy with villous atrophy in prolonged mefenamic acid users – a currently under-recognized in previously well-recognized complication: Case report and review of literature

Rationale: Mefenamic acid-induced enteropathy may be an under-recognized condition because few reported cases and no review of literature to comprehensively describe all reported cases exist. From inception until February 2017, a systematic literature search identified twenty original reports of cases of mefenamic acid-induced enteropathy. Additional five cases were identified at our hospital. All cases were included in the analyses. Patient concerns: Most patients had been regularly taking therapeutic dosages of mefenamic acid for at least three months before symptoms developed. All patients presented with chronic diarrhea with significant weight loss. Approximately one-third of the cases had some degree of anemia and hypoalbuminemia. Diagnoses: Endoscopic findings could range from very mild abnormalities, such as mild atrophic mucosa, to marked abnormalities, such as blunted villi with scalloping appearance in the small intestine and inflamed mucosa with a few superficial ulcers in the ileum and colon. Pathological findings included flattened small intestinal villi and mixed inflammatory infiltrates including eosinophils in lamina propria. Intervention: After identifying history of prolong mefenamic acid exposure, all patients were prescribed to stop this medication. Nutritional support and substitutional treatment for mefenamic acid were provided as well. Outcomes: All symptoms responded dramatically to drug withdrawal. Some patients could change to use other nonsteroidal anti-inflammatory drugs (NSAIDs) without symptoms reoccurring. Lessons: Unlike other traditional NSAIDs, mefenamic acid could induce intestinal villous atrophy. An adequate drug history is crucial to identifying the condition. Protracted diarrhea occurring during treatment should be the indication to cease the medicine promptly.

Does Extending the Waiting Time of Low-Rectal Cancer Surgery after Neoadjuvant Chemoradiation Increase the Perioperative Complications?

Background. Traditionally, rectal cancer surgery is recommended 6 to 8 weeks after completing neoadjuvant chemoradiation. Extending the waiting time may increase the tumor response rate. However, the perioperative complication rate may increase. The purpose of this study was to determine the association between extending the waiting time of surgery after neoadjuvant chemoradiation and perioperative outcomes. Methods. Sixty patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiation followed by radical resection at Siriraj hospital between June 2012 and January 2015 were retrospectively analyzed. Demographic data and perioperative outcomes were compared between the two groups. Results. The two groups were comparable in term of demographic parameters. The mean time interval from neoadjuvant chemoradiation to surgery was 6.4 weeks in Group A and 11.7 weeks in Group B. The perioperative outcomes were not significantly different between Groups A and B. Pathologic examination showed a significantly higher rate of circumferential margin positivity in Group A than in Group B (30% versus 9.3%, resp.; P = 0.04). Conclusions. Extending the waiting to >8 weeks from neoadjuvant chemoradiation to surgery did not increase perioperative complications, whereas the rate of circumferential margin positivity decreased.

Gastrointestinal: Ogilvie's syndrome: A rare complication of cytomegalovirus infection in an immunocompetent patient

Ogilvie’s syndrome is a disorder characterized by the acute dilatation of the colon in the absence of any mechanical obstruction in the debilitated patient. We herein present a rare case of Ogilvie’s syndrome coincided with cytomegalovirus (CMV) infection occurring in pregnancy. A 38-year-old primigravida presented at 18 weeks estimated fetal gestational age with vaginal bleeding and was found to have intrauterine fetal death requiring uterine curettage. Her course was complicated by increasing abdominal discomfort, passage of mucous stools, and subfebrile temperature. Physical examination revealed generalized abdominal distention with mild tenderness and absent bowel sounds. Abdominal X-ray and computed tomography scan demonstrated diffuse dilatation of intestines and thickened colonic wall without evidence of mechanical obstruction, suggesting pseudo-obstruction. She was treated conservatively with nothing by mouth, intravenous fluids, and nasogastric and rectal tube decompression without improvement after 72 h. Therefore, a 2-mg of neostigmine was given intravenously. The patient yet continued to suffer from abdominal distention without appreciable clinical response. Given failure of medical treatment, a decompressive colonoscopy was performed without bowel preparation. The colonoscope reached the splenic flexure and revealed multiple large clean-based ulcers with well-defined border in the sigmoid colon (Figs 1,2, arrow). Based on endoscopic findings, ganciclovir was administered intravenously for the presumptive diagnosis of CMV infection resulting in significant improvement of abdominal symptoms in a few days. Histopathological examination of the mucosal biopsies showed superficial erosion with acute and chronic inflammation in the lamina propria and granulation tissue containing a cytomegalic cell with intranuclear inclusion confirmed by immunoperoxidase staining for CMV (Fig. 3). Additional laboratory showed absence of human immunodeficiency virus antibodies and normal determination for helper and cytotoxic T lymphocytes. The patient remained well, and colonic lesions were completely resolved on the follow-up colonoscopy at 6 months after discharge. Most of reported patients with CMV disease of the gastrointestinal tract suffered from severe life-threatening complications including profuse bleeding necessitating resection, toxic megacolon, and perforation. There are few reported cases of CMV infection associated with Ogilvie’s syndrome, and they are mostly confined to transplant recipients. The precise mechanism by which colonic dysmotlity occurs in CMV infection remains unknown. Nonetheless, infection of the myenteric plexus could lead to an imbalance in the autonomic innervation of the colon, which may be augmented by an increased sympathetic drive in an ill patient, resulting in acute colonic pseudo-obstruction. Early diagnosis and appropriate treatment for CMV-related colonic dilatation may result in faster recovery and avoid complications.

A 53-year-old woman with progressive headaches.

A 53-year-old woman presented with a 1-month history of severe headache and intractable vomiting. Physical examination revealed left facial palsy and generalized weakness of the extremities (grade IV/V all extremities) without other localizing signs. She had no known underlying disease and there was no significant family history. MRI of the brain disclosed multiple ill-defined high signal lesions in T2W at left lower pons, left thalamus, subcortical regions of temporal, parietal, and frontal lobes bilaterally, and periventricular white matter. Nodular enhancement was noted in the left frontal lobe lesion (Figure 1a), left thalamus (not shown) and left pons (Figure 1b). Irregular leptomeningeal enhancement was also noted diffusely. The largest mass present at the left frontal lobe was 2 cm in largest dimension and showed marked peritumoral vasogenic edema (Figure 1a). High resolution chest CT revealed an ill-defined mass at the posterior basal segment of the right lower lobe, 3.2 cm in greatest dimension (not shown). There were also multiple small nodules involving both lungs, ranging from 0.4 to 0.5 cm. Stereotactic biopsy of the left frontal lobe lesion was performed. MICROSCOPIC PATHOLOGY