Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. Methods: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. Results: Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte reprogramming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14 + cells. Conclusion: MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.

The new proposed ultrashort triple therapy, including lansoprazole, low dose azithromycin for 3 days, and a single dose of tinidazole, appears to be a very effective anti-H. pylori regimen, a simpler, cheaper, well-tolerated, and equally effective alternative to 1-wk triple therapy.

Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor−/− knockout mouse model characterized by impaired erythroid development (macrocytosis and anemia) and enhanced thrombopoiesis, which are both features of myelodysplasia/myeloproliferative neoplasms. We then created and characterized double Bcor−/−/Dnmt3a−/− knockout mice. Interestingly, these animals developed a fully penetrant acute erythroid leukemia (AEL) characterized by leukocytosis secondary to the expansion of blasts expressing c-Kit+ and the erythroid marker Ter119, macrocytic anemia and progressive reduction of the thrombocytosis associated with loss of Bcor alone. Transcriptomic analysis of double knockout bone marrow progenitors revealed that aberrant erythroid skewing was induced by epigenetic changes affecting specific transcriptional factors (GATA1-2) and cell-cycle regulators (Mdm2, Tp53). These findings prompted us to investigate the efficacy of demethylating agents in AEL, with significant impact on progressive leukemic burden and mice overall survival. Information gained from our model expands the knowledge on the biology of AEL and may help designing new rational treatments for patients suffering from this high-risk leukemia.

Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

Background: 1‐week proton pump inhibitor‐based triple therapies are considered the most effective and convenient drug combinations for curing Helicobacter pylori infection. Short therapies, lasting less than 1 week have been investigated rarely. Aim: To assess the efficacy and tolerability of a 3‐day lansoprazole triple therapy after 1 day of lansoprazole pre‐treatment. Methods: Seventy H. pylori‐positive (rapid urease test and histology) patients received LAzT3 regimen (lanzoprazole 30 mg b.d. and azithromycin 500 mg o.m. for 3 days; tinidazole 2000 mg o.m. on day 1 and 1000 mg o.m. on days 2–3) after 1 day of lansoprazole pre‐treatment. Patients with active ulcer received lansoprazole 30 mg o.m. for an additional 4 weeks. Follow‐up gastroscopy was carried out 4–6 weeks after completion of therapy. Eradication was defined as negative histology and rapid urease test. Results: Four patients failed to attend the follow‐up endoscopy. One patient complained of minor side‐effects. H. pylori was eradicated in 57 of 66 patients suitable for evaluation, with a per‐protocol cure rate of 86.3% (95%CI: 76–94%), and an intention‐to‐treat cure rate of 81.4% (95%CI: 70–90%). Conclusions: This new ultrashort triple therapy including lansoprazole, azithromycin and tinidazole seems to be effective in eradicating H. pylori. It is safe and well‐tolerated, and may be taken into consideration as a valid alternative to the better known and widely used 1‐week proton pump inhibitor‐based triple therapies.