The classic, chronic Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPN)- mainly essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)— represent a heterogeneous group of stem cell disorders characterized by clonal proliferation of one or more hematopoietic cell lineages with organomegaly and constitutional symptoms. Several studies have shown that the presence of chronic inflammation and a dysregulated immune system play indisputable roles in the pathogenesis of these diseases. Lately, the treatment of cancer including hematological malignancy has progressed on the agents targeting the immune system, cytokine milieu, immunomodulatory agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cells function in the tumor microenvironment (TME). The fully unraveled primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) is based on blocking the inhibitory pathways in T cells to promote anti-tumor immune responses and has revolutionized cancer treatment paradigms. Despite the impressive clinical success of ICIT, tumor intrinsic resistance remains a daunting challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A phase II trial on Nivolumab for patients with Primary Myelofibrosis, post-Essential thrombocythemia myelofibrosis, or post- Polycythemia myelofibrosis has been performed (ClinicalTrials.gov Identifier: NCT02421354). This clinical trial, on the efficacy of PD-1 blockade using the monoclonal antibody Nivolumab, was prematurely terminated due to a lack of efficacy and adverse events. A multicenter, open-label, phase 2, single-arm study was conducted including pembrolizumab in patients with Dynamic International Prognostic Scoring System category of intermediate-2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with Ruxolitinib. Pembrolizumab treatment was well tolerated, but there were no objective clinical responses, so the study closed after the first stage was completed. To permit more patients to benefit from immunotherapy, the focus has changed to targeting alternative novel immune checkpoints in the tumor microenvironment such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin, and mucin domain 3 (TIM-3), V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA), T cell immunoglobulin and ITIM domain (TIGIT) and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. Our article aims at emphasizing and discovering the role of next-generation ICIT in MPN as targeted immunotherapy involving monoclonal antibodies, checkpoint inhibitors, or therapeutic vaccines against selected MPN epitopes that could further enhance tumor-specific immune responses. Immunotherapeutic approaches are expanding and hopefully will extend the therapeutic armamentarium in patients with myeloproliferative neoplasms. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.

Relapsed acute lymphoblastic leukemia (ALL) represents a continuous challenge for the clinician. Despite recent advances in treatment, the risk of relapse remains significant. The clinical, biological, cytogenetic, and molecular characteristics may be different at the time of relapse. Current comprehensive genome sequencing studies suggest that most relapsed patients, especially those with late relapses, acquire new genetic abnormalities, usually within a minor clone that emerges after ALL diagnosis. We report the case of a 23-year-old young woman diagnosed with Philadelphia chromosome negative B-cell acute lymphoblastic leukemia. The patient underwent allogeneic stem cell transplantation (allo-HSCT) after complete remission. Although having favorable prognostic factors at diagnosis, the disease relapsed early after allo-HSCT. The cytogenetic and molecular exam at relapse was positive for the Philadelphia chromosome, respectively for the bcr-abl transcript. What exactly led to the relapse of this disease in a more aggressive cytogenetic and molecular form, although there were no predictive elements in the diagnosis of this relapse?

Performance of flow through orifices on a perforated distribution pipe between periods with and without partial clogging (submersion of part of the distribution pipe) was compared. The distribution pipe directly receives runoff and delivers it to an underground infiltration bed. Partial clogging appeared in winter but reduced in summer. Performance was defined as flow rate divided by l_eff (h_(d,mean)^0.5) where h_(d,mean) is the mean pressure head that drives flow and l_eff is the effective pipe length (length of water column with pipe water volume and the pipe cross-sectional area). ANCOVA (ANalysis of COVAriance) was adopted to examine the clogging effects with flow rate plotted against l_eff (h_(d,mean)^0.5) . Partial clogging had a significant effect on pipe performance during periods of low or no rainfall. However, if only data during larger storms was considered, little evidence showed that partial clogging had effects on pipe delivery performance. Partial clogging might be caused by leaves accumulated in the lower section of the pipe in winter, and its effect was insignificant when water level rose in the pipe, utilizing significantly more orifices on the distribution pipe, thus the effect from the clogged portion had negligible impact on system performance. Larger storms might also provide the required flow rate to move the debris block thus exposing the orifices. Partial clogging did not increase the tendency of overflow; therefore, current maintenance schedule was sufficient to keep the distribution pipe at satisfactory performance even though partial clogging can exist.