Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

Muir-Torre syndrome (MTS) is defined as the association of a sebaceous tumor or keratoacanthoma and an extracutaneous neoplasm, mainly from the gastrointestinal or genitourinary tracts. MTS is related to hereditary non-polyposis colorectal cancer (HNPCC), a syndrome with germline mutations in the mismatch repair (MMR) gene(s), leading to microsatellite instability (MSI). In this study, using immunohistochemistry and a microsatellite instability assay, we analyzed the incidence of MMR gene abnormalities in 79 sebaceous lesions from 70 patients, 26 of whom also had an extracutaneous visceral neoplasm. We were unable to investigate the family histories of our patients regarding other tumors in order to assess which of our cases met the Amsterdam criteria. Defective MMR protein expression (MMR-) was found in 18/70 (25.7%) patients, with an identical distribution between those having an isolated skin tumor (11/44, 25.0%) and those with an extracutaneous cancer (7/26, 25.4%). In the sporadic group, MMR negative lesions were significantly more frequent in extrafacial areas (P = 0.03). High concordance was found between MMR expression in sebaceous lesions and the extracutaneous neoplasm in the same patient (20/23, 86.9%), as well as between MMR expression and microsatellite status (18/20, 90%). In conclusion, this study confirms the value of immunohistochemistry to identify MMR defective tumors. However, since only a minority of sebaceous neoplasms in patients who also have an extracutaneous cancer display MMR defects, these techniques are of limited value for the identification of "clinically defined" MTS.

Background: Lung cancer stem cells (CSCs) share many characteristics with normal stem cells, such as self-renewal and multipotentiality. High expression of aldehyde dehydrogenase (ALDH) has been detected in many tumors, particularly in the CSC compartment, and it plays an important role in tumor proliferation, metastasis, and drug resistance. CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumors. The aim of this study was to isolate and analyze cancer stem-like cells from surgically removed specimens to compare lung adenocarcinoma (ADENO) and squamous (SQUAMO) cell carcinoma. Methods: The ALDEFLUOR assay was used to identify and sort ALDH high and ALDH low human lung cancer cells following tissue digestion. Fluorescence-activated cell sorting analysis for CD44 was performed with tumor cells. Quantitative real-time PCR was performed to assess the expression of SOX2 and NANOG as stemness markers. ALDH1A1 expression was additionally determined by immunohistochemistry. Anchorage-independent ALDH high cell growth was also evaluated. ALDH high ADENO and SQUAMO cells were cultured to analyze spheroid formation. Results: All specimens contained 0.5-12.5% ALDH high cells with 3.8-18.9% CD44-positive cells. SOX2 and NANOG relative expression in ALDH high compared to ALDH low cells in ADENO and SQUAMO was analyzed and compared between the histotypes. Immunohistochemistry confirmed the presence of ALDH1A1 in the sections. SOX2 and NANOG were expressed at higher levels in the ALDH high subpopulation than in the ALDH low subpopulation only in ADENO cells, and the opposite result was seen in SQUAMO cells. In vitro functional assays demonstrated that ALDH high cells exhibited migration capacity with distinct behaviors between ALDH high spheres in ADENO vs. SQUAMO samples.

In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial–mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state.

Annular lichenoid dermatitis of youth (ALDY) is a clinico-pathologic entity described in children and young patients, clinically reminiscent of morphea, annular erythema, vitiligo or mycosis fungoides. We report on six patients presenting single or multiple lesions, distributed particularly on the flanks and abdomen, with clinical and histologic features consistent with ALDY. Two patients were young girls and four were adults males. Three patients received topical therapy and four showed complete resolution of the lesions after a 24-65 months follow-up. Analogously to the cases reported so far, immunohistochemistry showed a T cell infiltrate with a predominance of CD8+ lymphocytes, while T cell receptor rearrangement was absent in all cases. It seems appropriate to include annular lichenoid dermatitis of youth among the dermatoses with a lichenoid pattern. For the first time, we found that it can affect also adult patients, therefore we propose to rename the disease annular lichenoid dermatitis. The differential diagnosis with mycosis fungoides, especially in adult patients, is particularly crucial for their proper management and treatment.