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Sarcoidosis is a granulomatous disease that can potentially involve all body tissues, including the liver in about 10-20% of cases (1-4). High quality data on the management of hepatic sarcoidosis (HS) are scarce. In absence of national and international guidelines, management of HS is still experienced-based. This survey was carried out amongst Italian hepatologists to describe their practices in the management of patients with HS. 1985 questionnaires were forwarded, of which 37 were completed and returned. Thirty-three centers reported managing patients with HS, 17 (51%) of these reported managing more than one patient. Twenty-seven (81%) centers obtained the diagnosis by liver biopsy, the remaining centers by radiological techniques or biopsy in other sites. In coexistence with HS, the pulmonary sarcoidosis was reported from 18 (54%) centers, while patients with no other localization, except for the hepatic one, were followed up in 6 (18%) centers. Twenty-two (66%) centers treated such patients with first-line steroid therapy, the remainders reported using other drugs. Finally, 3 (9%) centers reported the presence of transplant patients, other 3 (9%) centers of deceased patients. HS is a rare entity in Italy and there is a wide variation in diagnostics and therapeutics. A multicentric, prospective, national cohort study is needed to study this disease. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). Salvage liver transplantation (LT) may be an option provided that a transplantable recurrence has occurred. We aimed to assess incidence and preoperative predictors of recurrence beyond Milan criteria (MC) in patients with small (≤ 5 cm) single HCC treated with first-line LR. Data of 512 patients with single HCC ≤5 cm treated with frontline LR were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Incidence and predictors of recurrence beyond MC was compared across two groups according to tumor diameter (HCC ≤3 cm vs. >3 cm). During a median follow-up of 4.2 years, the overall recurrence rate was 55.9%. Only 18.0% of patients had a first recurrence beyond MC (14.0% in the ≤3 cm group and 23.9% in the >3 group; p=0.005), while the overall recurrence rate beyond MC was 30.3% (25.1% and 38.0% patients in the ≤3 cm and >3 cm groups, respectively; p=0.002) (Figure). Compared to those with larger tumors, patients with HCC ≤3 cm had a longer recurrence-free survival (4.0 [95% CI 3.3-4.7] vs. 2.5 [95% CI 2.0-3.0] years; p=0.002) and overall survival (9.9 [95% CI 6.5-13.4] vs. 7.8 [95% CI 5.7-9.9] years; p=0.008). HCC size and alpha-fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC. A subanalysis in patients with "ab initio" potentially transplantable HCC confirmed these results. Despite the high recurrence rate, LR for single HCC ≤ 5 cm offers excellent long-term survival. Recurrence beyond MC is predicted by HCC size and AFP levels. Referral for salvage LT should be immediate at the first HCC recurrence, but high-risk patients (HCC >3 cm and high AFP) could be considered for frontline LT or listed for transplantation even before recurrence. [ABSTRACT FROM AUTHOR]

Even though hepatocellular carcinoma (HCC) is mainly characterized by a locoregional progression, the prognosis of some patients is burdened by the development of metastases. We aimed to identify risk factors of extrahepatic progression (EHP) in HCC patients undergoing transarterial chemoembolization (TACE). From the ITA.LI.CA database, 890 patients treated with first-line TACE were retrieved. Incidence and predictors of EHP were compared between patients with tumor burden score (TBS) ≤4.2 and >4.2 (cut-off determined by ROC curve analysis). Validation (n=442) and derivation (n=448) cohorts were used to create a predictive model for EHP after TACE (EHPaT score). During a median follow-up of 28.6 months (IQR, 14.0-50.0), 76.2% of patients showed progression after treatment. In the TBS >4.2 group, a significantly higher proportion of patients demonstrated extrahepatic spread at first progression (11.2% vs. 4.3%; p<0.001) and overall during follow-up (35.4% vs. 19.3%; p<0.001). The most common sites of metastases were lymph nodes and lung. Patients with TBS ≤4.2 had a significantly longer progression free survival (11.6 vs. 9.0 months; p<0.001) and overall survival (54.1 vs. 31.1 months; p<0.001). Independent predictors of EHP were TBS, radiological response and alpha-fetoprotein (AFP) levels. The Cox Score for the prediction of EHP (incorporating TBS, AFP, radiological response and etiology) yielded an AUROC of 0.743 (95% CI 0.656-0.830) at first progression and an AUROC of 0.701 (95% CI 0.645-0.757) overall during the follow-up in the derivation cohort. Similar results were obtained in the validation cohort. Although HCC is characterized by predominantly locoregional progression, identifying risk factors for metastases development is relevant for prognostic prediction and treatment allocation. Tumor burden, together with radiological response and AFP, has to be considered in the prediction of EHP after TACE. The EHPaT score revealed to be a useful tool in predicting of metastases development. [ABSTRACT FROM AUTHOR]

CD8 T-cells are the main effectors of the adaptative immune system and are characterized by cytotoxic and regulatory functions, thus constituting the most relevant line of defense against viral infections and tumors. The tumor immune microenvironment is able to release soluble factors or exert other regulatory mechanisms capable of intervening on different immunological pathways. Functional defects of CD8 T-cell response have been described in HCC showing correlation with disease stage and clinical outcome, however the molecular bases of CD8 cell dysfunction are still not completely known. the aim of this study was to define the molecular profile of tumor-infiltrating CD8 T-cells, their metabolic, phenotypic and functional alterations associated with CD8 T-cell exhausted phenotype. by comparison with CD8 cells from the non-tumorous counterpart, genomic profiling of tumor-infiltrating CD8 T-cells showed upregulation of several pathways among which hypoxic and oxidative stress response, DNA damage response and TGF-β pathway. We performed phenotypic analysis, staining tumor and liver infiltrating CD8 T-cells for CD103, CD39, PD-1, TIM-3, TIGIT, CXCR6. An enhanced expression of check point molecules such as PD-1, CD-39 and TIM-3 was evident in the tumor. Moreover, infiltrating CD8 cells showed depolarized mitochondrial membrane and higher levels of phosphorylation of the histone H2AX and ATM suggesting dysfunctional mitochondria and DNA damage, in agreement with the genomic profiling of CD8 T-cells. the discovery of metabolic and functional alterations of tumor infiltrating CD8 T-cells, provides the basis for further investigations aimed at identifying new therapeutic strategies to restore tumor-specific CD8 T cells response in HCC patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Immunohistochemical changes associated with development of cancer in Barrett''s esophagus offer potential areas of intervention to prevent and manage esophageal cancer. Aims: To assess the role of cyclooxygenase 2, caudal-type homeobox transcription factor 2 and cell division cycle 2/cyclin-dependent kinase 1 in the Barrett''s metaplasia–dysplasia–adenocarcinoma sequence. Patients and methods: Specimens from 46 patients with Barrett''s esophagus (39% without dysplasia, 33% with dysplasia and 28% with adenocarcinoma) were stained for cyclooxygenase 2, caudal-type homeobox transcription factor 2 and cell division cycle 2. Results: Cyclooxygenase 2: No expression differences between groups were found, except for adenocarcinomas (p =0.04). Caudal-type homeobox transcription factor 2: Nuclear positivity decreased from Barrett''s esophagus without dysplasia (71.6%), to Barrett''s esophagus with low grade dysplasia (35.3%), to Barrett''s esophagus with high grade dysplasia (17.14%); in adenocarcinoma these percentages were intermediate between high and low grade dysplasia (30.5%). Cell division cycle 2: Expression on deeper glandular structures was 40% in Barrett''s esophagus without dysplasia, 55.47% in Barrett''s esophagus with dysplasia, and 63.84% in adenocarcinoma, with no statistical differences between groups. Concerning cells of the superficial layer, Barrett''s esophagus with low grade dysplasia expressed focal positivity (p =0.0001 vs. no dysplasia); Barrett''s esophagus with high grade dysplasia displayed diffuse positivity (p =0.0001 vs. no dysplasia and low grade dysplasia). A diffuse positivity was found in Barrett''s esophagus with adenocarcinoma (p =0.0001 vs. no dysplasia and low grade dysplasia). Conclusions: Further evaluation of cyclooxygenase 2, cell division cycle 2 and caudal-type homeobox transcription factor 2, in association with morphology, might help to improve the accuracy of diagnosis and be useful for the clinical–pathological assessment of patients with Barrett''s esophagus. [Copyright &y& Elsevier]

Abstract: Incidence of hepatocellular carcinoma has been rising in the last two decades because of the wide exposure to hepatitis C virus during 1960s and 1970s. Improvement in treatment has been achieved by local ablative therapies, however because of early recurrence and lack of effective chemotherapies, alternative treatments based on stimulation of the anti-tumour immune response could represent new strategies to control hepatocellular carcinoma spread and recurrence. Proof of principle of an effective immunotherapy has been achieved for other solid tumours such as melanoma and several results could be transferred to the immunotherapy of hepatocellular carcinoma. Specific tumour antigens have been identified in hepatocellular carcinoma, such as cancer testis antigens expressed in a large part of hepatocellular carcinomas and alpha-fetoprotein that has been already employed in clinical trials demonstrating immunogenicity without however significant clinical efficacy. Better results have been achieved by non-antigen-specific immunotherapies that demonstrated improvement in recurrence and recurrence-free survival in patients undergoing surgical resection for hepatocellular carcinoma. Passive immunotherapy and targeted therapies blocking tumour cell receptors or enzymatic pathways are already in the clinic for other malignancies and the near future will see these new treatments applied to hepatocellular carcinoma patients along with the development of efficacious active immunotherapies aimed at reducing disease recurrence and improving survival. [Copyright &y& Elsevier]