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The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug-drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography-tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration-time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone-the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring.

Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia., Methods: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here., Results: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event., Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Acute leukemia of ambiguous lineage (ALAL) is a rare type of leukemia and represents an unmet clinical need. In fact, due to heterogeneity, substantial rarity and absence of clinical trials, there are no therapeutic guidelines available. We investigated the genetic basis of 10 cases of ALAL diagnosed at our centre from 2008 and 2020, through a targeted myeloid and lymphoid sequencing approach. We show that this rare group of acute leukemias is enriched in myeloid-gene mutations. In particular we found that RUNX1 mutations, which have been found double mutated in 40% of patients and tend to involve both alleles, are associated with an undifferentiated phenotype and with lineage ambiguity. Furthermore, because this feature is typical of acute myeloid leukemia with minimal differentiation, we believe that our data strengthen the idea that acute leukemia with ambiguous lineage, especially those with an undifferentiated phenotype, might be genetically more closer to acute myeloid leukemia rather than acute lymphoblastic leukemia. These data enrich the knowledge on the genetic basis of ALAL and could have clinical implications as an acute myeloid leukemia (AML) - oriented chemotherapeutic approach might be more appropriate., Competing Interests: Author ER was employed by the company enGenome srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Merati, Rossi, Gallì, Roncoroni, Zibellini, Rizzo, Pietra, Picone, Rocca, Cabrera, Gelli, Santacroce, Arcaini and Zappasodi.)

Study Design: Multi-centre mixed-method study design organised into several phases., Background: The Veneto region has recently defined a set of policies on nursing care by determining the needed amount of daily care in minutes and by initiating a systematic measurement of nursing outcomes; also, with a more recent policy, missed nursing care (MNC) has been established as a process measure of interest. To measure the effect of these policies, a research protocol - aimed at evaluating several end points - has been designed, involving a large target population and hospital units. The aim of this manuscript is to briefly present the research protocol and to discuss the public health implications of its expected end-points., Methods: The endpoints of the protocol are: (a) to describe the frequency of MNC as perceived by nurses; (b) to identify contributing factors; (c) to identify practices adopted in low-occurrence MNC units and to assess the effectiveness of implementing them in units with higher levels of MNC; (d) to explore the relationship between the amount of nursing care provided, MNC, and patient outcomes; and (e) to validate a tool that measures MNC as perceived by patients/caregivers. A total of 3,460 nurses, 5,000 patient/day and 160 nursing coordinators of the medical and surgical units of public hospitals in the Veneto Region will be included., Conclusions: Measuring the association between the amount of nursing care and patient outcomes, as well as evaluating the role of MNC as perceived by nurses and patients in hindering or increasing the risk of some patient outcomes can provide a body of evidence capable of further informing policies in the field, both at the national and at the international level. Moreover, emerging good practices capable of preventing or minimising MNC, sharing and implementing them in other units where high levels of missed care are reported and evaluating their effectiveness, can also inform public health policies.

Introduction: The indicators used in the Italian National Outcome Strategy does not include measurement of nursing care outcomes so these have not yet been assessed systematically in our country but only in the context of specific research projects. Positive and negative outcomes of nursing care have been documented in the literature, the latter associated with missed nursing care, a phenomenon that occurs when conditions are such that nurses are unable to deliver planned care to patients., Objectives: To describe the rationale, methodology and main results achieved to date in the development of a regional policy aimed at establishing a panel of indicators for monitoring nursing care-sensitive outcomes hospitals in publicly funded hospitals in the Veneto Region (northern Italy)., Methods: A plurennial, multi-method project based on [1] identification of selection criteria for a Minimum Data Set of indicators; [2] a rapid review of the literature and of the policies established internationally to measure nursing care-sensitive outcomes; [3] the establishment of an initial panel of indicators and evaluation of any critical issues with the chosen indicators, and [4] identification of the most appropriate tool for measuring missed nursing care., Results: The medical and surgical units were considered to be the most suitable settings for the pilot study. Following the literature review, indicators that were already being monitored in the current regional information system were chosen, with the intent to prevent an additional administrative burden to nurses. By using a progressive consensus process, five outcome indicators (functional status, falls, pressure sores, urinary tract infections, aspiration pneumonia) and one process indicator (missed nursing care) were selected., and the tools for measuring the above-mentioned indicators and their related risks, were identified. A regional policy was then established to measure these indicators in a pilot phase, with the intent of implementing them as stable indicators to be measured in the new computerized hospital information system., Conclusions: An initial panel of nursing-sensitive outcome indicators has been defined to be used in Internal Medicine and General Surgery units of hospitals in Italy's Veneto Region. Despite its limitations, the project represents the first effort to create a regional policy to measure the contribution of nursing care to the health outcomes of patients and that will also the identification of potential relations with other variables such as personnel staffing and/or skill mix.

Introduction: The 2016 WHO classification comprises two stages of primary myelofibrosis (PMF): early/prefibrotic primary myelofibrosis (pre-PMF) and overt fibrotic PMF (overt PMF). Diagnostic criteria rely on bone marrow morphology, fibrosis grade (0-1 in pre-PMF, 2-3 in overt PMF), and clinical features (leukoerythroblastosis, anemia, leucocytosis, increased lactate dehydrogenase, and palpable splenomegaly). An accurate differentiation from essential thrombocythemia (ET) is pivotal because the two entities show different clinical presentation and outcome, in terms of survival, leukemic evolution, and rates of progression to overt myelofibrosis. Areas covered: The current review provides an overview on how to diagnose and stratify patients with pre-PMF, taking into account their definite and peculiar risk of vascular event, which is often neglected, and their milder disease course, compared with overt PMF, with the aim of improving and individualizing their counseling and management. Expert commentary: Pre-PMF is a new entity characterized by a unique combination of both a thrombo-hemorrhagic risk (that brings it closer to PV and ET) and a definite risk of disease evolution (that places pre-PMF somewhat closer to the overt PMF variant).

Presented here is the approach used by a multidisciplinary working group fo the drafting of the "core" competence profile of the healthcare professions manager in the Veneto Region. Defining a competence profile allows for specifying a standard for measuring the skills acquired by a professional and the gap level from what is expected by the organization, as well as orienting the preparatory education to carry out the related role.

The recently revised World Health Organization (WHO) classification of myeloid neoplasms recognizes prefibrotic myelofibrosis (prePMF) as a distinct entity, characterized by well-defined histopathologic features together with minor clinical criteria (leukocytes, anemia, increased LDH, splenomegaly). The aim of the study was to examine the clinical relevance of distinguishing prePMF from essential thrombocythemia (ET). We identified in our database all patients affected with ET, prePMF and primary myelofibrosis (PMF) diagnosed according to 2008 WHO criteria with a bone marrow fibrosis grade 0-1 at diagnosis and one DNA sample to define the mutational status. The bone marrow morphology of all 404 identified patients was reviewed by an expert pathologist and patients were reclassified according to the 2016 WHO criteria. After reclassification, our cohort included 269 ET, 109 prePMF, and 26 myeloproliferative neoplasm unclassificable. In comparison with ET, patients with prePMF had higher leukocyte count, lower hemoglobin level, higher platelet count, higher LDH values, and higher number of circulating CD34-positive cells; they showed more frequently splenomegaly (all P values < ·001). CALR mutations were more frequent in prePMF than in ET (35·8% vs 17·8%, P < ·001). PrePMF patients had shorter overall survival ( P < ·001) and a trend to a higher incidence of leukemic evolution ( P ·067) compared to ET patients, while they did not differ in terms of thrombotic and bleeding complications. In conclusion, ET and prePMF diagnosed according to 2016 WHO criteria are two entities with a different clinical phenotype at diagnosis and a different clinical outcome., Competing Interests: CONFLICTS OF INTEREST Authors do not have competing financial interests.

We investigated the variation of CALR-mutant burden during follow-up in 105 CALR-mutant MPN and compared it to the variation of JAK2-mutant burden in 226 JAK2-mutant MPN.The median allele burden at last evaluation was significantly higher than at first evaluation in essential thrombocythemia (ET) (49.5% vs 45%, P < .001) but not in primary myelofibrosis (PMF) (52% vs 51%, P 0.398). Median values of slope were positive both in ET (0.071) and in PMF (0.032). In CALR-mutant ET there was a difference between natural and therapy-related slope (P 0.006).In the JAK2-mutated cohort, the median allele burden at last evaluation was not different respect to that at first evaluation, neither in ET (22.9% vs 23.2%, P = 0.216) nor in PMF (50.5% vs 45.0%, P = 0.809), despite a positive slope. Multivariate analysis to evaluate the effect of mutation (CALR vs JAK2) on the slope of mutant burden in not treated pts with a positive slope adjusting for diagnosis (ET vs PMF) showed a trend toward a higher increase of mutant burden in CALR vs JAK2 (β = 0.19, P = 0.061) with no difference between diagnosis (P = 0.419). The findings of this study suggest that clonal expansion in CALR-mutant MPN is faster than that observed in JAK2-mutant MPN.

Purpose: Despite the lack of major improvements in the treatment of primary myelofibrosis (PMF), there are recent indications that the survival of patients might have increased over the years. This study was aimed at ascertaining whether survival prolongation has actually occurred in PMF., Patients and Methods: A total of 802 patients diagnosed with PMF in four European countries were compared for the presentation of features and survival according to the diagnostic periods 1980 to 1995 (n = 434) and 1996 to 2007 (n = 368); relative survival was estimated for the two groups., Results: Patients diagnosed between 1996 and 2007 more often had constitutional symptoms (31% v 23%) but a lower incidence of marked anemia (31% v 39%), leukocytosis greater than 25 × 10(9)/L (9% v 13%), and blood blasts (27% v 33%); risk distribution was comparable between the two groups. Median survival was 4.6 years (95% CI, 4.0 to 5.1) for patients from 1980 to 1995 and 6.5 years (95% CI, 5.5 to 7.4) for patients from 1996 to 2007 (P < .001). The latter group of patients showed improved relative survival, especially for women, patients younger than age 65 years, and patients with low or intermediate-1-risk disease. Rates of PMF-attributable mortality at 5 and 10 years were significantly lower in the second period; this reduction in disease-specific mortality occurred across all patient subgroups, except in intermediate-2-risk or high-risk patients., Conclusion: Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations.