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Objective The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD. Design The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) 10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069). Conclusions Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. Lay summary NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD. ©

Background: Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in Western countries, and in particular in obese patients the prevalence is higher than in general population. It has a large clinical spectrum, ranging from simple steatosis to steatohepatitis (NASH) and cirrhosis. Aim of the study: To evaluate in obese patients who underwent bariatric surgery in the last 3 years: 1) the histological prevalence and severity of liver steatosis (LS) and fibrosis; 2) the reliability of ultrasound (US) in diagnosing steatosis. Patients and methods: We reviewed preoperative liver US and intraoperative liver biopsy results in 57 bariatric surgery patients (age 42 ± 12.0 years, Body Mass Index (BMI) 43.5 ± 7.1), along with their clinical characteristics. Steatosis was diagnosed when more than 5 % of liver parenchyma was involved, the NAFLD activity score (NAS) and grade of fibrosis were determined according to Clinical Research Network system for scoring activity and fibrosis in non-alcoholic fatty liver disease (NASH CRN). US was performed after a 12-hour fast. US diagnosis of LS was evaluated with bright liver echopattern. Results: The prevalence of liver steatosis was 81 % (CI 95 %: 71-90), in patients with LS, the NAS Score was: 0-2 (not NASH) in 11 patients (24%; 13-37); 3-4 (borderline) in 20 patients (43 %; 30-58); ≥ 5 (NASH) in 15 patients, (33 %; CI 95 %: 21-46). Fibrosis was present in 40 patients (87 %; CI 95 %:75-95), bridging fibrosis (F= 3) in 3 patients, cirrhosis in 1 patients. The Sensitivity of US in steatosis diagnosis was 93% (CI 95 %:81-98), Specificity 42% (CI 95 %:9-75), Positive Predictive Value 89.3% (CI 95 %:83-93), Negative Predictive Value 50 % (CI 95 %:13-72), Accuracy 84.9% (CI 95 %:72- 93). Conclusions: In obese patients the prevalence of steatosis was higher than in the general population (82%), NASH and borderline-NASH were present in 24 and 43%, respectively. Finally, severe fibrosis or cirrhosis was present in 3 and 1 patient, respectively (in total 10 %); this low prevalence may be due to the young age of patients, confirming that earlier therapy could be associated with less irreversible liver damage. The US in diagnosing liver steatosis showed a good sensitivity, but insufficient specificity, confirming that in severe obesity the US reliability is low.

FIBROSIS DIAGNOSTIC SCORES VALIDATION IN OBESE PATIENTS WITH NON-ALCOHOLIC LIVER DISEASE

Background: Blood tests of liver injury are less well validated in non-alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. Aims: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. Methods: We pre-included new NAFLD patients with biopsy and blood tests from a single-centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary-ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. Results: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). Conclusions: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non-invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

Background: Metabolic factors have been associated with liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Aims To test a new marker of adipose dysfunction, the visceral adiposity index (VAI), in NAFLD patients to assess whether or not it is associated with host factors, and to investigate a potential correlation with histological findings. Methods One hundred and forty-two consecutive NAFLD patients were evaluated by liver biopsy, and clinical and metabolic measurements, including insulin resistance with the homeostasis model assessment (HOMA), and VAI by using waist circumference, body mass index, triglycerides and HDL. Serum levels of TNFα, IL-6, adiponectin and leptin were also assessed. All biopsies were scored for NAFLD activity score (NAS) and its components, and for staging (Kleiner). Results By multiple linear regression analysis, VAI was independently associated with higher HOMA (P = 0.04), and fibrosis (P = 0.04). In addition, an independent association was found between higher VAI and lower adiponectin levels (P = 0.002). Higher HOMA (OR 1.149, 95% CI 1.003-1.316, P = 0.04), higher VAI (OR 1.446, 95% CI 1.023-2.043, P = 0.03), lobular inflammation (OR 3.777, 95% CI 1.771-8.051, P = 0.001), and ballooning (OR 2.884, 95% CI 1.231-6.757, P = 0.01) were correlated with significant fibrosis (F2-F4) on multiple logistic regression analysis. In particular, the prevalence of significant fibrosis progressively increased from patients with a VAI ≤ 2.1 and HOMA ≤ 3.4 (26%) to those with a VAI > 2.1 and HOMA > 3.4 (83%). Conclusions In NAFLD patients, visceral adiposity index is an expression of both qualitative and quantitative adipose tissue dysfunction and, together with insulin resistance, is independently correlated with significant fibrosis. © 2011 Blackwell Publishing Ltd.

The current standard of care (SoC) for chronic hepatitis C, i.e. the combination of a pegylated-interferon (PEG-IFN) with ribavirin (RBV), may activate underlying autoimmune conditions. Particularly, interferon (IFN) has been known to induce or exacerbate autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) in hepatitis C virus patients. We describe a severe, acute-onset antimitochondrial antibody (AMA)-M2 positive AIH appearing during the last weeks of SoC in a woman with chronic hepatitis C and no previous history of autoimmunity, and resolving on protracted steroids. In this context, the relevance of the characterization of the immunoglobulin isotype of portal plasma cells for a more appropriate diagnosis of autoimmune liver diseases can be emphasized.

Mycotic infection of the alimentary canal are rare and usually involve the upper digestive tract. Mycetes, especially of Candida family, are habitual saprophytes in the digestive tract of healthy individuals. Under certain conditions, fungal flora may overgrowth, resulting in lesions of the digestive mucosa, which, rarely, might evolve to local diffusion and/or systemic lympho-hematogenous spreading. In the stomach, sometimes, mycotic infections may appear like benign gastric ulcers. we described a case of woman, aged 64, affected by psoriasis, in chronic treatment with cyclosporine and type 2 diabetes mellitus, a well-known immunosoppressive condition, with endoscopic evidence of ulcerated vegetating gastric lesion, strongly suggestive for malignancy, due to Candida albicans infection, and completely healed after cyclosporine withdrawal and administration of oral antifungal drugs.

Background and aim: Steatosis and insulin resistance (IR) are the major disease modifying in patients with chronic hepatitis C (CHC). Only few studies evaluated these features in patients with chronic hepatitis B (CHB). We aimed to assess the prevalence and the characteristics of steatosis and IR in CHB patients, compared to CHC subjects, and to evaluate the potential association between these features and fibrosis severity. Material and methods: 170 consecutive patients with CHB (28 HBeAg positive, 128 HBeAg negative, and 14 HBeAg negative/anti-HDV positive), and 170 sex, age and BMI matched genotype 1 CHC patients were evaluated by liver biopsy and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Insulin resistance was defined if HOMA-IR>2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer). Steatosis was considered significant if ≥10%. Results: The prevalence of significant steatosis was similar in both CHB and CHC patients (31% vs. 38%; p=0.14). IR rate was significantly higher in CHC than in CHB patients (42% vs. 26%; p=0.002). In CHB patients, at multivariate analysis, severe fibrosis (F3-F4) was independently associated with older age (OR 1.054,95%CI 1.007–1.103, p=0.02), low platelet levels (OR 0.984,95%CI 0.973–0.994, p=0.003), high GGT (OR 1.019,95%CI 1.001– 1.039, p=0.04), steatosis>10% (OR 3.601,95%CI 1.272–10.194, p=0.01), and moderate-severe necroinflammatory activity (OR 8.111,95%CI 1.884–34.925, p=0.005), regardless HBeAg status and HDV co-infection. Conclusions: CHB patients had high steatosis prevalence, similar to CHC controls, but lower IR rate. Steatosis, is independently associated with severe fibrosis in CHB patients.

BACKGROUND: The role of Barrett esophagus in carcinogenesis is widely accepted, but the significance of esophageal columnar mucosa without histological intestinal metaplasia, known as columnar-lined esophagus, is debated. MATERIAL/METHODS: We studied 128 patients free of Helicobacter pylori with reflux-related symptoms and columnar mucosa in the esophagus at endoscopy, 106 patients with Barrett esophagus (referred to as the Barrett group) and 22 patients without intestinal metaplasia (columnar group). Samples from 20 subjects free of H. pylori were used as controls. Immunostaining for keratin 7 (KRT7), keratin 20 (KRT20), caudal type homeobox 2 (CDX2), mucin 2, oligomeric mucus/gel-forming (MUC2), and tumor protein p53 (TP53) was assessed. RESULTS: Samples taken 1 cm above the gastroesophageal junction showed KRT7 staining in all cases in the Barrett and columnar groups and none in the control group. Immunostaining for TP53 was absent in the control group, and more frequent in the columnar group (7, 31.8%) compared with the Barrett group (14, 13.2%, P=0.033). In the columnar group, low grade dysplasia and TP53 expression was seen in 7 of 22 biopsy specimens (31.8%) at baseline and in 4 additional specimens after 2 years, for a total of 11 specimens (50.0%). CONCLUSIONS: The expression of KRT7 might help to explain the pathological, reflux-related nature of columnar-lined esophagus, as aberrant expression in a very early stage of the multistep Barrett esophagus progression. Expression of KRT7 may occur in basal glandular cells as a result of their multipotentiality and susceptibility to immunophenotype changes induced by reflux.

Background: Neurofibromas are sporadic or associated with type 1 neurofibromatosis (NF1), with a higher risk of malignant progression. Materials and Methods: We investigated CD10 immunoexpression in 39 peripheral nerve sheath lesions. They were 18 typical, solitary, sporadic neurofibromas (group A) and 21 cases (group B) consisting of 11 NF1-associated cases, 3 malignant peripheral sheath tumors (MPNST) and 8 atypical neurofibromas. Results: CD10 immunopositivity was absent or very weak and focal in group A. On the contrary, CD10 was strongly expressed in group B, including all the MPNST and their metastases, with 95% sensitivity and 72% specificity in distinguishing between the two groups. Conclusion: CD10 is useful in the assessment of peripheral sheath tumors and could give evidence that atypical myxoid and/or diffuse neurofibromas, sometimes histologically difficult to distinguish from low-grade MPNST, represent not only a histological but also an immunohistochemical continuum with MPNST

Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance in classification increased in Group 1 from moderate (κ=0.54) to substantial (κ=0.66) and from fair (κ=0.35) to substantial (κ=0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ=0.61), activity (κ=0.75), and almost perfect for fibrosis (κ=0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ=0.54 for S, κ=0.68 for A, and κ=0.72 for F). Conclusion: The FLIP algorithm based on the SAF score should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565-575) © 2014 by the American Association for the Study of Liver Diseases.

Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p

BACKGROUND: To date an accurate evaluation of predictive markers in breast cancer is mainly conducted at the primary site, although the main goal of the adjuvant therapy is the control of micrometastases. Adjuvant therapy drugs need a high proliferative cell rate to be effective. The proliferating activity can be evaluated by the Ki-67 marker and even by thymidylate synthase (TS), a cell cycle enzyme present in proliferating cells. In this study the TS levels in primary tumours were compared to those of their metastases. PATIENTS AND METHODS: The TS expression and Ki-67 were evaluated by means of immunohistochemistry in 80 primary breast tumours (PTs) and in their matched axillary metastatic lymph-nodes (ALNs). RESULTS: In 16% of patients, malignant cells of involved nodes showed a lower TS expression than the PTs. In the same group, we also found a lower number of Ki-67 immunoreactive cells in lymph node metastases when compared with primary tumours. CONCLUSION: The group of patients with lower TS and Ki-67 expression in lymph node metastatic cells may be less sensitive to 5-fluorouracil and high dose methotrexate requiring them to be treated with other drug combinations.

BACKGROUND: Lichen planus (LP) is a mucocutaneous inflammatory dermatosis that frequently involves the oral and genital mucosae. Patients with LP affecting these sites are often seen by oral medicine specialists or gynaecologists who work in isolation and depend heavily on histopathologists to help them in confirming the diagnosis. There are few studies in the literature combining the experiences of these specialists who share the care of patients with both oral and genital LP. OBJECTIVES: To estimate the prevalence of vulval LP (VLP) in a cohort of patients with histologically confirmed oral LP (OLP). METHODS: The study group consisted of 42 women histologically diagnosed with OLP. The mean age was 60.5 years (range 27-81). They underwent genital examination, colposcopy and vulvoscopy. For the histological confirmation of clinical VLP biopsies were performed whenever a clinical lesion was found. Oral and genital biopsy specimens were processed through histological and immunohistochemical staining. Histological diagnoses of LP were made according to the modified World Health Organization histopathological criteria proposed by van der Meij and van der Waal for the diagnosis of OLP, and extended to VLP. Patients with clinical evidence, but without the histological confirmation of OLP and VLP, were excluded from the study group. RESULTS: Thirty-two vulval and one vaginal biopsy specimens were obtained. Histological diagnoses were confirmed in 24 of 32 (75%) patients who underwent a vulval biopsy: these represent 57% (24 of 42) of the study group. Of the 12 patients free of symptoms such as itching, burning and dyspareunia, but with clinical vulval lesions, 11 (92%) had histological confirmation of VLP. Vulval lichen sclerosus was ascertained in five of 32 (16%) cases. CONCLUSIONS: This study showed a 57% prevalence of VLP in selected patients with OLP. The high prevalence of VLP of 92% in the women who were free of vulval symptoms confirmed the usefulness of this careful integrated approach.

We report a case of peritoneal biphasic mesothelioma with cystic areas in a patient with professional exposure to asbestos. It showed focal epithelial glandular and papillary proliferations, also presenting fluid filled cysts, whose wall consisted of a proliferation of spindle cells. Atypia and mitoses were very scanty. EMA, vimentin, CK5/6, D2-40, calretinin and P53 were positive and desmin was negative in both epithelial and spindle areas, including the ones surrounding the cystic spaces. These findings gave an essential aid in the differential diagnosis with a benign cystic mesothelioma and with a cystic epithelial mesothelioma with secondary pseudosarcomatous myofibroblastic proliferation. The presence of cystic areas in a malignant mesothelioma could make difficult the diagnosis. A large amount of tumour tissue is necessary for confirming the biphasic histotype, an aggressive histotype, even in the presence of mild histological features and of some others favourable clinical prognostic indices as in this case. To our knowledge this is the first case of malignant peritoneal biphasic mesothelioma with cystic features reported in the literature.Cystic Mesothelioma, Immunohistochemistry, Malignant Mesothelioma, Peritoneal Diseases, Mesothelial Neoplasms.Il mesotelioma peritoneale maligno è una patologia rara la cui diagnosi è resa particolarmente difficile dalla molteplicità delle possibili presentazioni cliniche e morfologiche. A differenza della patologia pleurica, questa sembra avere una minore correlazione con l’esposizione all’asbesto. La prognosi è sfavorevole con una sopravvivenza media di 5.4 mesi. Riportiamo un caso di mesotelioma peritoneale in un paziente di 73 anni con esposizione professionale all’asbesto. La diagnosi è verosimilmente avvenuta dopo diversi inquadramenti clinici, che hanno compreso addominalgie attribuite ad IBD, poi non accertate istologicamente, e ad un’appendicite acuta. Per ultimo il paziente è giunto alla nostra osservazione con un quadro subocclusivo che l’indagine TC attribuiva ad una verosimile carcinosi peritoneale a primitivo sconosciuto. La laparoscopia esplorativa, poi convertita in approccio laparotomico, ha mostrato un quadro di peritonite incapsulante che coinvolgeva estesamente l’intestino tenue. È stata eseguita una resezione intestinale del tenue coinvolto ed una asportazione di un’area nodulare peri-splenica. L’esame istologico con l’integrazione di indagini immunoistochimiche ha permesso la diagnosi di mesotelioma peritoneale cistico maligno con istotipo bifasico che risulta essere il primo descritto in letteratura. Le aree cistiche avevano inizialmente fatto propendere per una diagnosi di mesotelioma multicistico benigno o di mesotelioma cistico con secondaria proliferazione miofibroblastica pseudosarcomatosa. Negli ultimi anni la prognosi di questa patologia ha trovato nell’utilizzo della chirurgia citoriduttiva e della chemioterapia intraperitoneale un miglioramento prognostico, queste nuove tecniche sono disponibili in centri di riferimento e trovano ad oggi indicazione solo in casi selezionati e in istotipi poco aggressivi. Il nostro paziente a causa dell’estensione della malattia, dell’istotipo non favorevole e dell’età avanzata è stato riferito al servizio di oncologia per il prosieguo delle cure. E’ stato sottoposto a chemioterapia con Pemetrexed e Cisplatino e dopo sei mesi presenta soddisfacenti condizioni cliniche generali e la TC di controllo non ha mostrato progressione di malattia.

The study underlines the importance of the differential diagnosis between primary Epstein- Barr virus EBV associated hepatitis with features of autoimmunity, in which there is a direct pathogenetic role of the virus, and EBV related autoimmune hepatitis, in which EBV could act as the trigger of the immune-mediated damage with probable differences between the two conditions with regard to the prognosis and the responsiveness to immunosuppressive treatment. Moreover we hypothesise that the favourable outcome in our patient, better than the most of autoimmune hepatitis cases, may be related either to the moderate necroinflammatory activity and to the low level of fibrosis at the beginning of the disease or to the role of EBV as a trigger of autoimmune hepatitis. The hypothesis that EBV-related autoimmune hepatitis could have a more favourable prognosis than the most of autoimmune hepatitis cases in general need to be confirmed on a larger series of studies.

Skin melanoma can metastasize to any organ or tissue. The median survival in patient with intestinal metastases is inferior to 7 months compared to other sites metastasis. A wide intestinal resection including the resection of the mesentery with lymph nodes remains the main treatment due to the low morbidity and mortality rate it is also associated with.We took under analysis a recent case of acute abdomen for small bowel perforation from intestinal metastases in a patient with metastatic melanoma who was under treatment with Pemrolizumab. A bowel resection was performed and no other lesions were found in the abdominal examination. However, the chemotherapy was stopped due to the advanced age of the patient, presence of brain metastases that worsening his performance status and the bowel involvement.Preoperative diagnoses of metastatic or small intestine melanoma tend to often be difficult to perform. Before considering a possible elective surgery, in case of non-urgent symptoms, it is important to value first intestinal or extraintestinal spread. The previous report of bowel perforation from melanoma metastases showed an intraoperative finding of multiple widespread brown lesions. There are not reports about the possible involvement of Pembrolizumab in bowel perforation, which leads to the conclusion that it was probably the ingrown of the metastasis to cause it.The treatment of metastatic melanoma includes chemotherapy, immunotherapy and target-therapy. It will be useful to do a multicenter study on the survival after complete resection to better define the surgical indication for the treatment of the metastatic disease.Intestinal perforation, Melanoma, Metastasis.Il melanoma cutaneo può metastatizzare a qualsiasi organo o tessuto. La sopravvivenza media dei pazienti con metastasi intestinali è inferiore a 7 mesi. Una resezione intestinale ampia comprendente i relativi mesentere e linfonodi rimane il trattamento di scelta e sembra essere associato con bassa morbilità e la mortalità. Descriviamo un recente caso di addome acuto da perforazione intestinale causato da una localizzazione metastatica unica di un già noto melanoma cutaneo in un paziente in trattamento con Pemrolizumab. In urgenza il paziente è stato sottoposto a resezione dell’intestino interessato dalla lesione e comprendente il relativo mesentere. Non sono state evidenziate all’esplorazione altre lesioni addominali. Data la compresenza di una metastasi cerebrale, di un non soddisfacente performance status e dell’età avanzata del paziente la chemioterapia precedentemente praticata è stata interrotta. La diagnosi preoperatoria di secondarismi intestinali da melanoma cutaneo è spesso difficile da eseguire. Prima di considerare un possibile intervento chirurgico elettivo, in caso di sintomi non urgenti, è importante valutare la diffusione sia intestinale che extra-intestinale. I casi di perforazione intestinale da metastasi di melanoma riportati in letteratura spesso riportano il reperto intra-operatorio di multiple e diffuse lesioni. Non sono stati presentati dati circa il possibile coinvolgimento di Pembrolizumab nell’insorgenza di perforazioni intestinali. Probabilmente è stata la crescita infiltrante della metastasi a causare la perforazione nel nostro caso. Il trattamento del melanoma metastatico comprende la chemioterapia, l’immunoterapia e target terapia. La chirurgia nel caso di lesioni isolate sembra offrire buone prognosi. Data la rarità delle lesioni, l’indicazione chirurgica si gioverebbe della presenza di uno studio multicentrico sulla sopravvivenza dopo resezione completa per definirne al meglio l’indicazione.

The aim of the study was to verify by Ki-67 immunostaining if any difference exists in the cell proliferating fraction between primary breast tumors (PTs) and matching positive axillary lymph nodes (ALNs). PATIENTS AND METHODS: Immunohistochemistry with the monoclonal antibody against Ki-67 was performed in 160 node-positive breast carcinomas and in their respective lymph node metastases. RESULTS: An increase of Ki-67 immunoreactive cells in ALN compared with that of PTs was observed in 84% of cases (ALN: mean 17%, PTs: mean 8%; p < 0.001), whereas 16% of the cases showed Ki-67 value two to six times lower in the ALNs than in the corresponding PTs (ALN: mean 3.2%, PTs mean 12.5%; p < 0.005). The decrease of Ki-67 positive cells in the ALN was independent from the histotype and the histological grade of the tumor. CONCLUSION: A different cell proliferation fraction between PTs and matching positive ALNs was demonstrated and underlined that the existence of a group of patients with decreased number of Ki-67 immunoreactive cells in lymph node metastases compared with that of the primary tumors could be taken into account in the choice of therapeutic strategy.

Exosomes (EXs) secreted from cells to the extracellular environment play an important role in intercellular communication in normality and pathology. In particular, EXs contribute to cancer progression through the modulation of tumor microenvironment. Heat Shock Proteins (Hsps) are implicated in the development of carcinogenic process because they interact with many metabolic and biomolecular mechanisms of cancer cells [1]. Different studies shown that they can be released by tumors cells and that the mechanism of release is mediated by EXs pathway. In this study we performed an immunomorphological and biomolecular analysis to investigate Hsp27, Hsp60, Hsp70, Hsp90 levels expression profile in thyroid tissue and in plasma samples from patients undergoing thyroidectomy. We studied two groups of patients, one surgically treated for benign goiter, another surgically treated for papillary carcinoma. Samples of thyroid tissue of benign goiter and papillary carcinoma were used for IHC analysis. Two blood samples from each subjects were taken, the first one day prior to the surgical removal of the thyroid, and the second, one week after, on the day of medication. These blood samples were used for exosomal isolation. The immunoistochemistry shown an overexpression of Hsp27, Hsp60 and Hsp90 in the PTC cases comparison with peritumoral tissue and with goiter samples. Hsp70 expression level has not shown significant difference between two groups studied. In particular Hsp27, Hsp60 and Hsp90 were visible at cytoplasmic and membrane levels. The membrane localization of these HSP suggested their release in tumor microenviroment. The exosomes, obtained from the plasma, were analyzed by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), and Atomic Force Microscopy (AFM) in order to estimate the exosomes size/diameter and morphology. After, we performed Western Blotting analysis for Alix and CD81, as exosomal markers, and for Hsp27, Hsp60 and Hsp90. The levels of Hsp27, Hsp60 and Hsp90 in the exosomes of patients with PTC before surgery were significantly higher than in the exosomes from the same patients after surgery. The data obtained shown that, as demonstrated in human large bowel cancer [2], the Hsp levels studied increased in PTC specimens respect to goiter specimens.

Background: Familial chylomicronemia syndrome (FCS) is characterized by severe fasting hypertriglyceridemia, abdominal pain, and recurrent acute pancreatitis. Available triglyceride-lowering drugs are insufficient to avoid pancreatitis. Therefore, there is a significant unmet medical need for effective triglyceride-lowering drugs for patients with FCS. Case report: We report the second case of a patient with FCS and recurrent pancreatitis treated with lomitapide. Lomitapide treatment resulted in a reduction of fasting TG levels from 2897 mg/dL (32.71 mmol/L) to an average of 954 mg/dL (10.77 mmol/L) on the 30 mg lomitapide equating to a 67% reduction from baseline. After 26 months of lomitapide treatment, histological activity score for hepatic fibrosis was stable although liver biopsy showed a marked increase of liver steatosis and mild perivenular and perisinusoidal fibrosis. Conclusions: Lomitapide is effective in reducing triglycerides in FCS and preventing the recurrence of acute pancreatitis. A longer follow-up is necessary to evaluate long-term risk of progression toward severe stages of liver fibrosis. A prospective clinical trial may identify which subgroup of FCS patients would benefit from lomitapide treatment in the absence of significant liver adverse effects.

Background and Aim To evaluate if the presence of carotid atherosclerosis in patients with NAFLD, could be related to gene variants influencing hepatic fat accumulation and the severity of liver damage. Methods We recorded anthropometric, metabolic and histological data(Kleiner score) of 162 consecutive, biopsy-proven Sicilian NAFLD patients. Intima-media thickness(IMT), IMT thickening(IMT≥1 mm) and carotid plaques(focal thickening of >1.3 mm at the level of common carotid artery) were evaluated using ultrasonography. IL28B rs12979860 C>T, PNPLA3 rs738409 C>G, GCKR rs780094 C>T, LYPLAL1 rs12137855 C>T, and NCAN rs2228603 C>T single nucleotide polymorphisms were also assessed. The results were validated in a cohort of 267 subjects with clinical or histological diagnosis of NAFLD from Northern Italy, 63 of whom had follow-up examinations. Results Carotid plaques, IMT thickening and mean maximum IMT were similar in the two cohorts, whereas the prevalence of diabetes, obesity, NASH, and PNPLA3 GG polymorphism(21%vs.13%, p = 0.02) were significantly higher in the Sicilian cohort. In this cohort, the prevalence of carotid plaques and IMT thickening was higher in PNPLA3 GG compared to CC/CG genotype(53%vs.32%, p = 0.02; 62%vs.28%, p

Background & Aims: Unhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology. Methods: Anthropometric and metabolic factors, including waist circumference (WC), waist-to-hip ratio (WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1 CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading (Scheuer classification), and graded for steatosis, which was considered moderate-severe if P20%. Features of non-alcoholic steatohepatitis (NASH) in CHC were also assessed (Bedossa classification). Results: Mean daily intake of total, industrial and fruit fructose was 18.0 ± 8.7 g, 6.0 ± 4.7 g, and 11.9 ± 7.2 g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR (p = 0.02) and hypercaloric diet (p

Hurthle cell (HC), anaplastic (AC), and medullary (MC) carcinomas are low frequency thyroid tumors that pose several challenges for physicians and pathologists due to the scarcity of cases, information, and histopathological images, especially in the many areas around the world in which sophisticated molecular and genetic diagnostic facilities are unavailable. It is, therefore, cogent to provide tools for microscopists to achieve accurate diagnosis, such as histopathological images with reliable biomarkers, which can help them to reach a differential diagnosis. We are investigating whether components of the chaperone system (CS), such as the molecular chaperones, can be considered dependable biomarkers, whose levels and distribution inside and outside cells in the tumor tissue could present a distinctive histopathological pattern for each tumor type. Here, we report data on the chaperones Hsp27, Hsp60, and Hsp90. They presented quantitative levels and distribution patterns that were different for each tumor and differed from those of a benign thyroid pathology, goiter (BG). Therefore, the reported methodology can be beneficial when the microscopist must differentiate between HC, AC, MC, and BG.

[Objective] The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD., [Design] The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI), [Results] Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069)., [Conclusions] Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. [Lay summary] NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD., This study has been supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 and the Newcastle NIHR Biomedical Research Centre. The authors are contributing members of The European NAFLD Registry. The study was also supported by the Italian Ministry of Health, grant RF-2016-02364358 (Ricerca Finalizzata, Ministero della Salute). ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422).

Long noncoding RNAs (lncRNAs) are emerging as key regulators of genetic and epigenetic networks, and their deregulation may underlie complex diseases, such as carcinogenesis. Several studies described lncRNA alterations in patients with solid tumors. In particular, HOTAIR upregulation has been associated with tumor aggressiveness, metastasis, and poor survival in gastrointestinal stromal tumor (GIST) patients. We analyzed expression levels of other lncRNAs, H19 and MALAT1, in FFPE tissue specimens from 40 surgically resected and metastatic GIST patients, using real-time PCR analysis. H19 and MALAT1 were both upregulated in 50% of GIST patients. MALAT1 lncRNA expression levels seem to be correlated with c-KIT mutation status. The percentage of both H19 and MALAT1 upregulation was significantly higher in patients with time to progression (TTP) 6 months. The median TTP was significantly lower in patients with both H19 and MALAT1 lncRNA upregulation as compared to those with lncRNA downregulation. These data suggest a potential role for both H19 and MALAT1 lncRNAs as prognostic biomarker for the clinical selection of the best candidate to first-line treatment with imatinib.

Background and aims: The LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology. Methods and results: Forty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH. Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18–6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm. Conclusions: ezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone. Trial accession number: ClinicalTrial.gov: NCT01950884.

In previous studies on localized GISTs, KIT exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of KIT and PDGFRA mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the KIT exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of KIT exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) (p &lt, 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (&gt, 7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PDGFRA PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier.

Background and AimsNon-alcoholic fatty liver disease and related hepatic syndromes affect up to one third of the adult population. The molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs and recently we report its active participation in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.MethodsWe used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analysed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with either simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild type (Nupr1+/+) or Nupr1 knockout mice (Nupr1-/-) fed ad libitum with a high fat diet (HFD) for up to 15 weeks.ResultsNUPR1 expression is inversely correlated to hepatic steatosis progression. We found that NUPR1 participates in the activation of PPAR-α signalling via UPR. PPAR-α signalling, is involved in the maintenance of fat metabolism and proper lipid homeostasis and energy balance. As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.ObjectiveNon-alcoholic fatty liver (NAFL) disease and related hepatic syndromes affect up to one third of the adult population in industrialised and developing countries. However, the molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including the liver. Recently, we report NUPR1 actively participates in activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.DesignWe used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analysed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with either simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild type (Nupr1+/+) or Nupr1 knockout mice (Nupr1-/-) fed ad libitum with a high fat diet (HFD) for up to 15 weeks.ResultsNUPR1 expression is inversely correlated to hepatic steatosis progression. Mechanistically, we found NUPR1 participates in the activation of PPAR-α signalling via UPR. PPAR-α signalling, is involved in the maintenance of fat metabolism and proper lipid homeostasis and energy balance. As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.ConclusionsAs PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.Lay summaryNUPR1 is activated during high caloric intake in both mice and patients. Decrease in expression or inhibition of NUPR1 worsens lipid deposition and hepatic damage.Graphical abstractHighlightsNUPR1 protects liver from high caloric intake hepatic damageThe function of NUPR1 in this context is to control the lipid homeostasis through the UPR and more specifically through PPAR-α signalling.NUPR1 could be used as a predictive marker for the gravity of NAFL progression. Moreover, as clinical interest is being raised around NUPR1 inhibitors to treat liver and pancreatic cancer, care should be taken in monitoring lipotoxic parameters.