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Somatic mutations in genes such as ASXL1 , RUNX1 , TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death. Supporting the potential for ABT-199 treatment in MDS, high-risk MDS patient samples specifically underwent cell death in response to ABT-199 even when harbouring mutations in ASXL1 , RUNX1 , TP53 or EZH2 . ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in ASXL1 , RUNX1 , TP53 or EZH2 and even proved effective in patients harbouring more than one of the defined high-risk mutations. Moreover, we utilized the protein abundance of BCL-2 family members in primary patient samples using flow cytometry as a biomarker to predict ABT-199 treatment response. Our data demonstrate that ABT-199 effectively induces apoptosis in progenitors of high-risk MDS/sAML despite the presence of adverse genetic mutations supporting the notion that pro-apoptotic intervention will hold broad therapeutic potential in high-risk MDS patients with poor prognosis., Competing Interests: CONFLICTS OF INTEREST None.

Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis and additional therapeutic strategies must be implemented to optimize ESCC treatment. Meanwhile, the important biologic role and potential prognostic and therapeutic implications of a tumors immunologic microenvironment (IM) have been recognized in various cancers.In order to investigate the contexture and the prognostic relevance of the IM in ESCC, we immunohistochemically evaluated the extent of overall/intraepithelial TILs (CD3+/CD8+) and of PD-1 / PD-L1 expression in a cohort of 125 therapy-naive ESCCs, additionally assessing PD-L1 copy number status via fluorescence in-situ hybridization.High intraepithelial CD3+ TILs (CD3ihigh) and high PD-L1 expression on tumor cells (PD-L1high) were each significantly associated with improved overall- (OS) (CD3+: p = 0.019; PD-L1: p = 0.028), disease specific- (DSS) (CD3+: p = 0.05; PD-L1: p = 0.006) and disease free survival (DFS) (CD3+: p = 0.009; PD-L1: p < 0.001). CD3ihigh- and PD-L1high cases were significantly associated with one another (p < 0.001). Subgrouping of ESCC revealed decreased OS (p = 0.031), DSS (p = 0.012) and DFS (p < 0.001) for CD3ilow/PD-L1low cancers.Our data not only associate CD3ihigh- and PD-L1high ESCC with a beneficial outcome, but also demonstrate PD-L1high- and CD3ihigh status to be closely intertwined. Furthermore, our study demarcates a prognostically unfavorable, "non-immunoreactive" CD3ilow / PD-L1low ESCC-subgroup, potentially forming the basis for an immune-based stratification of ESCC.

Autophagy is a lysosomal degradation and recycling process implicated in cancer progression and therapy resistance. We assessed the impact of basal autophagy in colon cancer (CC) in vitro and ex vivo . Functional autophagy was demonstrated in CC cell lines (LoVo; HT-29) showing a dose-dependent increase of the autophagy markers LC3B, p62 and autophagic vesciles upon increasing concentrations of the autophagy inhibitor chloroquine, which was demonstrated by immunoblotting, immunofluorescence and electron microscopy. Next, tissue microarrays with 292 primary resected CC, with cores from different tumor regions, and normal mucosa were analyzed by immunohistochemistry for LC3B and p62. CC tissue showed LC3B dot-like, p62 dot-like, cytoplasmic and nuclear staining in various levels without significant intratumoral heterogeneity. Tumoral LC3B and p62 expression was significantly higher than in normal tissue (p<0.001). No associations between staining patterns and pathological features (e.g. TNM categories; grading) were observed. Both low LC3B dot-like and low p62 dot-like-cytoplasmic staining were associated with worse overall survival (p=0.005 and p=0.002). The best prognostic discrimination, however, was seen for a combination of LC3B dot-like/p62 dot-like-cytoplasmic staining: high expression of both markers, indicative of impaired activated autophagy, was associated with the best overall survival. In contrast, high LC3B dot-like/low p62 dot-like-cytoplasmic expression, indicative of intact activated autophagy, was associated with the worst outcome (p<0.001 in univariate and HR=0.751; CI=0.607-0.928; p=0.008 in multivariate analysis). These specific expression patterns of LC3B and p62 pointing to different states of autophagy associated with diverging clinical outcomes highlighte the potential significance of basal autophagy in CC biology., Competing Interests: CONFLICTS OF INTEREST The authors declare that there is no conflicts of interest.

Objectives: The occurrence of squamous cell carcinoma of the tongue (SCCT) of young patients increased. There are still controversies about patient prognosis. The underlying molecular mechanisms remain unclear., Methods: 276 patients (66 ≤45, 210 >45 years) with SCCT were included. Clinical parameters and survival data were assessed. Oncogenes and tumor suppressors were analyzed via immunohistochemistry (p53, CXCR4, p16, EGFR) and qPCR (CDK4, CDKN2A, TP53, MDM2, AKT1, PIK3CA, NRAS, HRAS, KRAS, HGF, MET, EGF, ATM, BRCA1, E2F1, FHIT, RUNX3, STK11, BCL2, CTNNB1)., Results: The median overall survival was 142 (≤45 years) and 34 months (>45 years) (p < 0.0001; HR [95%CI]: 0.37 [0.30-0.58]). Disease specific survival in patients ≤45 years was with 181 months significantly higher than in patients >45 years (p < 0.0001; HR [95%CI]: 0.33 [0.26-0.57]). Immunhistochemistry visualized a comparable expression of analyzed proteins. QPCR demonstrated in patients ≤45 years a higher expression of genes that are associated with carcinogenesis (CTNNB1, STK11, CDKN2A, HGF, MET) as well as tumor suppressors that constitute an enhanced radio-sensitivity (ATM, BRCA1E2F1, FHIT)., Conclusion: Derogation of the WNT-CTNNB1-STK11 and CDKN2A-HGF-MET pathway can constitute the carcinogenesis, while the higher expression of radio-sensitizers ATM, BRCA1E2F1 and FHIT can explain the better OS/DSS in young patients.