Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Diagnostic dilemma in a patient with history of medullary thyroid carcinoma and abnormal serum liver enzymes; a case report with six years follow up.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that originates from parafollicular C-cells. Calcitonin (Ctn) and carcinoembryonic antigen (CEA) are useful biomarkers for monitoring MTC cases. CASE PRESENTATION: Here, we describe a 48-year-old woman, who presented in 2014 with bilateral thyroid nodules. Report of fine needle aspiration was suspicious for MTC; initial laboratory evaluation showed serum Ctn level of 1567 pg/mL. After excluding type 2 multiple endocrine neoplasia syndrome clinically, total thyroidectomy and neck lymph node dissection were performed. The final histopathological diagnosis was right lobe MTC with neither vascular invasion nor lymph node involvement. On regular follow-up visits, Ctn and CEA levels have been undetectable, and repeated cervical ultrasonographic exams were unremarkable from 2014 to 2021. As liver enzymes became elevated in 2016, the patient was further evaluated by a gastroenterologist. Abdominopelvic ultrasonography revealed a coarse echo pattern of the liver parenchyma with normal bile ducts. A liver fibroscan showed a low fibrosis score (7kPa). The patient was recommended to use ursodeoxycholic acid. According to the progressive rise of liver enzymes with a cholestatic pattern in October 2020, a liver biopsy was performed that showed tiny nests of neuroendocrine-like cells with a background of primary biliary cholangitis (PBC). Immunohistochemical stainings were positive for chromogranin A (CgA), and synaptophysin and negative for Ctn, CEA, and thyroglobulin. Further imaging investigations did not reveal any site of a neuroendocrine tumor in the body. Considering normal physical exam, imaging findings, as well as normal serum levels of Ctn, CEA, CgA, and procalcitonin, the patient was managed as a PBC. CONCLUSION: In follow-up of a patient with MTC, we reported progressively increased liver enzymes with a cholestatic pattern. Liver biopsy revealed nests of neuroendocrine-like cells with a background of PBC, the findings that might suggest acquiring neuroendocrine phenotype by proliferating cholangiocytes.

Evaluation of multimodal MR imaging for differentiating infiltrative versus reactive edema in brain gliomas.

OBJECTIVE: To determine the border of glial tumors by diffusion weighted imaging (DWI), apparent diffusion co-efficient (ADC), magnetic resonance spectroscopy (MRS) and perfusion brain MRI. PATIENTS AND METHODS: Ten patients with brain gliomas were enrolled [mean age: 35.3 ± 13.2, range: 20-62]. Conventional MRI was performed for all patients. Besides, tumor mapping based on Choline (Cho)/Creatine (Cr) color map in MRS, perfusion and diffusion color maps, were gathered. Different tumoral and peritumoral regions [normal tissue, reactive edema, infiltrative edema, and tumor core] were defined. MRI criteria were evaluated in areas targeted for biopsy and histopathologic evaluation was determined. RESULTS: Tumor cell positive samples [one necrosis, 26 infiltrative and nine tumor cores] composed 36 (75%) of the 48 samples. Seven (19.4%) of the positive samples were interpreted as not tumor on MRI. Five were identified as reactive edema and two as normal tissue] [kappa: .67, p-value < .001]. Mean of ADC, median of N-acetylaspartate (NAA) and NAA/Cho were statistically different between positive and negative samples (p = .02 and p < .001, respectively). Mean ADC and median Cho/NAA were statistically different in missed tumor containing tissue presented as reactive edema compared to normal and correctly diagnosed reactive edema samples together (p-values < .05). CONCLUSIONS: Multimodal MRI could define infiltrated borders of brain gliomas.

Characterization of active and infiltrative tumorous subregions from normal tissue in brain gliomas using multiparametric MRI.

BACKGROUND: Targeted localized biopsies and treatments for diffuse gliomas rely on accurate identification of tissue subregions, for which current MRI techniques lack specificity. PURPOSE: To explore the complementary and competitive roles of a variety of conventional and quantitative MRI methods for distinguishing subregions of brain gliomas. STUDY TYPE: Prospective. POPULATION: Fifty-one tissue specimens were collected using image-guided localized biopsy surgery from 10 patients with newly diagnosed gliomas. FIELD STRENGTH/SEQUENCE: Conventional and quantitative MR images consisting of pre- and postcontrast T1 w, T2 w, T2 -FLAIR, T2 -relaxometry, DWI, DTI, IVIM, and DSC-MRI were acquired preoperatively at 3T. ASSESSMENT: Biopsy specimens were histopathologically attributed to glioma tissue subregion categories of active tumor (AT), infiltrative edema (IE), and normal tissue (NT) subregions. For each tissue sample, a feature vector comprising 15 MRI-based parameters was derived from preoperative images and assessed by a machine learning algorithm to determine the best multiparametric feature combination for characterizing the tissue subregions. STATISTICAL TESTS: For discrimination of AT, IE, and NT subregions, a one-way analysis of variance (ANOVA) test and for pairwise tissue subregion differentiation, Tukey honest significant difference, and Games-Howell tests were applied (P < 0.05). Cross-validated feature selection and classification methods were implemented for identification of accurate multiparametric MRI parameter combination. RESULTS: After exclusion of 17 tissue specimens, 34 samples (AT = 6, IE = 20, and NT = 8) were considered for analysis. Highest accuracies and statistically significant differences for discrimination of IE from NT and AT from NT were observed for diffusion-based parameters (AUCs >90%), and the perfusion-derived parameter as the most accurate feature in distinguishing IE from AT. A combination of "CBV, MD, T2 _ISO, FLAIR" parameters showed high diagnostic performance for identification of the three subregions (AUC ∼90%). DATA CONCLUSION: Integration of a few quantitative along with conventional MRI parameters may provide a potential multiparametric imaging biomarker for predicting the histopathologically proven glioma tissue subregions. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:938-950.

Gastrointestinal basidiobolomycosis - A rare fungal infection: Challenging to diagnose yet treatable - Case report and literature review.

Gastrointestinal Basidiobolomycosis is a rare manifestation of Basidiobolus ranarum infection. In this report, we present two cases of gastrointestinal Basidiobolomycosis. The first patient presented with obstructive symptoms, fever, and weight loss. The diagnosis of Basidiobolomycosis was not made until after surgery, when Liposomal amphotericin-B combined with itraconazole were administered, leading to the resolution of laboratory markers of inflammation and patient's symptoms. The second case involves a young woman who presented with hematochezia, perianal induration, and abdominal pain. The patient had previously been diagnosed with Crohn's disease and treated accordingly, but her symptoms did not improve. Due to the endemicity of tuberculosis in Iran, the patient was treated for TB but still showed no improvement. However, a perianal biopsy sample revealed the Splendore Hoeppli phenomenon and fungal elements in GMS staining, leading to the diagnosis of gastrointestinal Basidiobolomycosis. Treatment with itraconazole and co-trimoxazole led to a significant improvement in symptoms and laboratory indices after one week, including the resolution of perianal induration. The key takeaway from this report is the importance of considering rare infections in the differential diagnosis of gastrointestinal conditions such as IBD and GI obstruction.

Extramedullary hematopoiesis (EMH) in the liver allograft presenting with a mass-like lesion.

This is a rare case of extramedullary hematopoiesis (EMH) presenting as a mass-like lesion in liver allograft. Our patient was a 57-year-old woman who had undergone liver transplantation due to hepatic epithelioid hemangioendothelioma. She presented with an ill-defined hypoechoic lesion on ultrasound which showed features of focal EMH on pathologic examinations. While transient intrahepatic hematopoiesis has been reported in liver transplant patients, focal EMH mass lesion is a rarely encountered phenomenon. Therefore, focal EMH may need to be considered as a differential diagnosis when encountering a mass in post liver transplant patients.

Prognostic impact of MUC1 and potential regulatory miR-145 and miR-21 expression in salivary mucoepidermoid carcinoma.

BACKGROUND: Salivary gland mucoepidermoid carcinoma (MEC) poses a considerable risk of locoregional and distant metastasis after conventional treatments. There is an evident need for specifying prognostic biomarkers to identify patients who are in need of more intensive and prolonged follow-ups. This study aimed to assess the mucin 1 (MUC1) expression level and its potential regulatory microRNAs in salivary gland MEC and their prognostic potentials. MATERIALS AND METHODS: The expression of MUC1 in salivary gland MEC tissues was assessed in 47 samples using immunohistochemistry. Related microRNA (miR-145 and miR-21) were evaluated using quantitative Reverse Transcription PCR. The associations between MUC1 and microRNAs expressions and clinicopathological parameters were investigated. RESULTS: MUC1 expression levels positively correlated with histologic grade (p < 0.001), clinical stage (p = 0.04), risk of nodal metastasis (p = 0.02), as well as the likelihood of opting for radical treatment (p = 0.01). Increased expression of miR-21 (p < 0.001) and decreased expression of miR-145 (p < 0.001) were observed in MECs compared to normal salivary gland tissue. MiR-145 negatively (p = 0.01) and miR-21 positively (p = 0.01) correlated with MUC1 overexpression. Based on the univariate cox proportional hazard model, histologic grade and MUC1 expression level were significantly associated with disease-free, cancer-specific, and overall survival. However, the multivariable cox proportional hazard model indicated tumor grade as the only prognostic factor associated with disease-free survival. CONCLUSION: Our results support the tumor suppressor role of miR-145 and the oncogenic role of miR-21 in salivary gland MEC. Also, MUC1 and miR-145 overexpression, as well as miR-21 suppression, show promising association with histologic tumor grade and clinical stage.

Online Assessment for Pathology Residents during the COVID-19 Pandemic: Report of an Experience.

BACKGROUND & OBJECTIVE: The world is facing COVID-19 pandemic, and medical education system and consequently the evaluation of students at different levels have been overshadowed. Residency students are among those affected. In the present study, we aim to share our experiences regarding holding exams for pathology residents before and during the pandemic. METHODS: This cross-sectional study was carried out in Tehran University of Medical Sciences. The online exam, which consisted of 30 multiple-choice questions, was designed and held in April 2020 to evaluate pathology residents. To assess the quality of the exam, indices such as the number of questions, highest and lowest scores, the average score, the standard deviation, the variance, Cronbach's alpha reliability coefficient, standard error of measurement, discrimination index, difficulty index, number/percentage of questions on three difficulty levels of easy, normal, hard were reviewed and analyzed. RESULTS AND DISCUSSION: The average score of the participants in the January exam which was held in the university's exam center was 16.23 (±5.03), while the average score in the online exam which was held after the onset of the pandemic was 20.86 (±5.18). The average discrimination indices in the first and second exams were 0.36 and 0.38, respectively, and the average difficulty indices in the first and second exams were 0.54 and 0.70, respectively. We found the administration of this online examination would be a positive experience. By sharing it, we hope to pave the way for similar ventures in the other departments.

Colonic Mucosal Infiltration of IgG4 Plasma Cells and Ulcerative Colitis: Determinant of Presence, Activity, Extension, and Duration of Disease.

BACKGROUND Infiltration of IgG4 positive plasma cells has been detected in the colonic mucosa of patients with ulcerative colitis (UC). The aim of the study was to investigate the association between colonic mucosal infiltration of IgG4 plasma cells and the presence, activity, extension, and duration of UC. METHODS In this case-control study (2009-2014), 102 subjects (84 with UC/18 controls) were enrolled. Clinical records and rectosigmoid biopsies of UC patients were selected, and biopsies were stained with IgG4 monoclonal antibodies. IgG4 positive plasma cells were counted by a single pathologist. RESULTS Amongst 84 patients with UC, 73.8% had UC without primary sclerosing cholangitis (PSC), and 26.2% had UC with PSC. IgG4 plasma cells were seen in 35 (41.7%) patients with UC and 0% of controls (p = 0.001). The mean amount of IgG4 containing plasma cells was significantly different between active and inactive patients with UC, although it was not significantly different between UC patients with and without PSC. The presence of IgG4 infiltration was significantly associated with the extension and duration of the disease. Furthermore, IgG4 count had a sensitivity/specificity of 78.6%/83.3% for the diagnosis of UC. CONCLUSION Our study revealed the diagnostic role of IgG4 plasma cells in the colonic mucosa of patients with UC and its association with activity, extension, and duration of disease.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Orthotopic Liver Transplantation for Etanercept-induced Acute Hepatic Failure: A Case Report.

Occurrence of hepatotoxicity following prescription of etanercept, a tumor necrosis factor-alpha (TNF-α) antagonist, is a relatively well-known issue. On the other hand, acute hepatic failure which could lead to liver transplantation is extremely rare to the best of our knowledge, and there is no previously published case in the literature. In this article, we presented a case of acute liver failure followed by liver transplantaion, in a 32- year old man with a previous history of ankylosing spondylitis after etanercept usage. On pathologic examination of the explanted liver of the patient, extensive confluent necrosis in all liver segments with prominent infiltration of a mixed population of inflammatory cells in portal tracts was noticed. In conclusion, close follow-up of patients who are receiving etanercept is crucial, since its liver complications could be severe enough to subject the patients for liver transplantation.

A Comparative Evaluation of Regulatory T Cells Profile among Acute and Chronic Cutaneous Leishmaniasis Using Flow Cytometry.

BACKGROUND: Cutaneous leishmaniasis (CL) is described as a major health problem in many countries of the world. Regulatory T cells (Tregs) are characterized as one of immunologic indexes. One of the best methods to determine of Tregs percentage is flow cytometry. The aim of this study was determination of the role of Tregs profile among acute and chronic forms of human CL using flow cytometry analysis. METHODS: This study was conducted on 24 patients referred to Laboratory of Leishmaniasis, Tehran University of Medical Sciences, Tehran, Iran with acute and 14 patients with chronic phases of CL as well as 15 healthy individuals as control group in 2015-2016. After microscopic examination, 2 ml of peripheral blood samples were collected for determining percentage of CD4 + CD25 + CD127 low Tregs by using flow cytometry method. RESULTS: Using flow cytometry analysis, the average percentage of Tregs were calculated 5.73, 6.71 and 6.61 for acute, chronic and healthy individuals, respectively. With SPSS software and Scheffe multiple comparison tests, the differences within in these groups are statistically significant (P=0.04) and between the acute and chronic group, there was marginally significant with approximately 91% of confidence level (P=0.088). CONCLUSION: Marginally differences were found significantly among averages of Regulatory T cells, acute and chronic phases of CL. Further comprehensive studies can be needed to verify the role of Tregs in both phases of CL cases.

Effects of Opium Dependency on Testicular Tissue in a Rat Model: An Experimental Study.

PURPOSE: This study is aimed to evaluate the effects of opium dependency on testicular tissue in a rat model. METHODS: Thirty-two Wistar male rats (aged 30 days and weighing 200-250 grams) were randomized into two groups. Group A, consisting of 16 rats, received dissolved oral opium tablets in drinking water for 45 days, whereas group B (control group) consisted of 16 rats that received opium-free water. After 45 days vertical and horizontal diameters of testis, number of seminiferous tubules, mean seminiferous tubule diameter, number of germ cells, height of germinal epithelium, percentage of degenerating Leydig and germ cells and glutathione density of testicular tissue (µmol/g of tissue) were compared between study groups. RESULTS: Morphological evaluation of testicular tissue revealed a significantly higher percentage of degenerating Leydig and germ cells in the treated group compared to control group. (10.08 ± 0.351 vs. 1.83 ± 0.88, 4.50 ± 0.769 vs. 0.607 ± 0.118, respectively) (P-value<0.001 for each) Interestingly, vertical and horizontal diameter of testis, the average number of germ cells, height of germinal epithelium and number of seminiferous tubules, were significantly higher in the treated group compared to control group. Seminiferous tubule diameter and glutathione density of testicular tissue were not statistically significantly different between the groups. CONCLUSIONS: Applying a rat model, we noted that opium has a substantial effect on testicular structure and function. A significantly higher proportion of Leydig and germ cells were degenerated in treated rats despite an increase in the average number of seminiferous tubules and germ cells. These findings support the hypothesis that opium consumption adversely affects male fertility.

Dicrocoelium Dentriticum in Explanted Liver: Report of an Unusual Finding.

Dicrocoelium dentriticum, a member of trematode type helminths, is a liver parasite of ruminants. Humans are infected accidentally by ingestion of intermediate host, through infected ants via eating of raw vegetables or drinking of contaminated water. Infection is often asymptomatic or results in subtle symptoms; therefore, infections are usually unrecognized. However, it can produce chronic cholangitis and swelling or adenomatous proliferation in the bile ducts and lead to abdominal pain, diarrhea, fatigue, jaundice, and other symptoms. We report a 49-year-old female patient with end-stage hepatic cirrhosis from viral hepatitis B and D coinfection who underwent liver transplant. Shortly after transplant, she developed symptoms suggesting an obstructed biliary duct. Liver needle biopsy was done 24 hours after transplant to rule out rejection. Biopsy of her explanted liver was also examined pathologically. Microscopic examination of the liver needle biopsy ruled out rejection. Prepared sections of explanted liver revealed a helminth in the common bile duct. Morphologic reconstruction of helminth by microscopic findings and consultation with an expert parasitologist supported the diagnosis of Dicrocoelium dentriticum.

Intraoperative consultation of central nervous system lesions. Frozen section, cytology or both?

OBJECTIVE: Frozen section is the traditional method of assessing central nervous system (CNS) lesions intraoperatively. Our aim is to determine the diagnostic accuracy of frozen section and/or cytological evaluation of CNS lesions in our center. STUDY DESIGN: A total of 157 patients with CNS lesions underwent open surgical biopsy or excision in our center during a period of 2 years (2012-2013). All specimens were studied cytologically; of these specimens, 146 cases were also examined by frozen section. Cytology and frozen section slides were studied separately by two general pathologists who were blind to final diagnoses. The final diagnoses were based on permanent sections and IHC studies. RESULTS: The accuracy rates of frozen section analysis and cytological evaluation were 87% and 86%, respectively. If the two methods were considered together, the accuracy rate improved to about 95%. CONCLUSIONS: Cytological evaluation is an acceptable alternative to frozen section analysis and also a great supplement to the diagnosis of CNS lesions.

Correlation of Histopathologic Findings of Non-Graft Threatening Preservation/Reperfusion Injury in Time-Zero Liver Needle Biopsies With Short-Term Post-transplantation Laboratory Alterations.

BACKGROUND: Early post-transplantation alterations in liver tests are caused by a variety of etiologies including rejection, biliary or vascular complications, and preservation/reperfusion injury (PRI). OBJECTIVES: The aim of this study was to show the correlation between histopathologic changes of PRI and the alterations in liver tests in the early post-transplantation period. MATERIALS AND METHODS: Between April 2013 and August 2014, histopathologic findings of protocol, time-zero, Tru-Cut, liver needle biopsies were evaluated in 94 cases of cadaveric liver transplantation. The histopathologic changes included ballooning degeneration, micro- and macro-vesicular steatosis, bilirubinostasis, apoptotic cells, bile plugs and neutrophilic infiltration. These histopathologic changes were compared with the early (15 days) post-transplantation liver laboratory findings. RESULTS: Clinico-pathologic evaluation of all 94 cases was done by assessment of PRI findings in time-zero biopsies and possible causes of allograft injury were appraised. In 21 patients, a specific cause for allograft injury was found including rejection and/or surgical complications. In the remaining 73 cases, there was no specific cause for allograft injury and histopathologic findings of time-zero liver needle biopsies supported PRI. We classified liver laboratory tests alterations as: hepatocellular damage (elevation of transaminases and lactate dehydrogenase), cholestatic damage (elevation of alkaline phosphatase and total bilirubin) and mixed. Hepatocellular and cholestatic alterations in liver function tests were associated with the presence of marked apoptotic bodies and neutrophilic aggregates in time zero biopsies, respectively. On the other hand, macrovesicular steatosis was dominantly associated with mixed (hepatocellular and cholestatic) laboratory alterations of liver tests. CONCLUSIONS: Any discrepancy between histopathologic changes in time-zero biopsies and pattern of early liver laboratory alterations may be considered as a warning for causes other than PRI.

Parathyroid Hormone Levels May Predict Nonalcoholic Steatohepatitis in Morbidly Obese Patients.

BACKGROUND: Obesity as a worldwide health problem is associated with nonalcoholic steatohepatitis (NASH). Since severe liver injury may be present in asymptomatic obese patients and a definite diagnosis of nonalcoholic steatohepatitis can only be made after an invasive procedure of liver biopsy, there is a need for noninvasive methods to predict the probability of NASH. OBJECTIVES: To investigate the role of vitamin D endocrine system in predicting the probability of presence of NASH in asymptomatic morbidly obese candidates of bariatric surgery. PATIENTS AND METHODS: From December 09 to March 11, every patient undergoing bariatric surgery had a liver biopsy. Nonalcoholic steatohepatitis was diagnosed using the Lee's criteria, the baseline labs obtained and the association between laboratory data and presence of NASH assessed. RESULTS: Forty-six patients (34 women, aged 36.5 ± 10.6 years) were analyzed. The mean levels of liver enzymes were significantly higher in the group with NASH (P value < 0.01). In an unadjusted logistic model, PTH was the only variable in vitamin D endocrine system which was significantly associated with NASH (odds ratio (OR): 1.04, 95%CI: 1.01 - 1.07). After adjustment for possible confounding factors, age (OR: 1.22, 95%CI: 1.00 - 1.50) and PTH (OR: 1.08, 95%CI: 1.01 - 1.16) were predictive factors for NASH (P value < 0.05). CONCLUSIONS: Elevated serum PTH level was the predictive factor for NASH in morbidly obese patients. Also, we reported elevated serum liver enzymes, high serum PTH levels and older age as predictors of NASH in patients seeking obesity surgical treatments.