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The introduction of pediatric-inspired regimens in adult Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL) has significantly improved patients' prognosis. Within the Campus ALL network, we analyzed the outcome of adult Ph- ALL patients treated according to the GIMEMA LAL1913 protocol outside the clinical trial to compare the real-life data with the study results. We included 421 consecutive patients; median age 42 years. The complete remission (CR) rate after the first course of chemotherapy was 94%, and measurable residual disease (MRD) negativity after the third course was achieved in 72% of patients. The 3-year overall survival (OS) and disease-free survival (DFS) were 67% and 57%, respectively. In a multivariate analysis, MRD positivity negatively influenced DFS. In a time-dependent analysis including only very high-risk (VHR) and MRD positive cases, transplanted (hematopoietic stem cell transplantation [HSCT]) patients had a significantly better DFS than non-HSCT patients (P=0.0017). During induction, grade ≥2 pegaspargase-related hepato-toxicity was observed in 25% of patients (vs. 12% in the GIMEMA LAL1913 trial, P=0.0003). In this large, real-life cohort of Ph- ALL, we confirmed the very high CR rate and a superimposable OS and DFS compared to the GIMEMA LAL1913 clinical trial (CR rate after C1, 94% vs. 85%, P=0.0004; 3-year OS, 67% vs. 67%, P=0.94; 3-year DFS, 57% vs. 63%, P=0.17). HSCT confirms its important role in VHR and MRD-positive patients. The rate of pegaspargase-related toxicity was significantly higher in the real-life setting, emphasizing the importance of dose adjustment in the presence of risk factors to avoid excessive toxicity.

Natural Health Products (NHPs) have long been considered a valuable therapeutic approach for the prevention and treatment of various diseases, including cancer. However, research on this topic has led to inconclusive and often controversial results. This review aims to provide a comprehensive update of the effects and mechanisms related to the use of NHPs, to describe the results of randomized clinical trials (RCTs) on their effects in cancer patients, and to critically discuss factors influencing clinical outcomes. RCTs available in the literature, even those studying the same NHP, are very heterogeneous in terms of indications, doses, route and timing of administration, and outcomes evaluated. Silymarin, ginsenoside, and vitamin E appear to be useful in attenuating adverse events related to radiotherapy or chemotherapy, and curcumin and lycopene might provide some benefit in patients with prostate cancer. Most RCTs have not clarified whether NHP supplementation provides any real benefit, while harmful effects have been shown in some cases. Overall, the available data suggest that although there is some evidence to support the benefits of NHPs in the management of cancer patients, further clinical trials with the same design are needed before their introduction into clinical practice can be considered.

Introduction: Since COVID-19 patients are often polytreated, monitoring drug-drug interaction (DDIs) is necessary. We evaluated whether drugs used after the second COVID-19 pandemic wave were associated with DDI-related adverse events and the role of drug interaction checkers in identifying them., Methods: The study (PROSPERO-ID: CRD42024507634) included: 1) consulting the drug interaction checkers Drugs.com, Liverpool COVID-19 Interactions, LexiComp, Medscape, and Micromedex; 2) systematic review; 3) reviewed studies analysis; 4) evaluating drug interaction checkers potential to anticipate DDI-related adverse events.The systematic review was performed searching PubMed, Scopus, ScienceDirect, and Cochrane databases from 1 March 2022 to 11 November 2023. Observational studies, and clinical trials were included. Article without reporting direct association between DDIs and adverse events were excluded. The risk of bias was assessed by Newcastle-Ottawa scale., Results: The most frequent DDIs involved nirmatrelvir/ritonavir (N/R) and fluvoxamine. Fifteen studies, including 150 patients and 35 DDI-related outcomes, were analyzed. The most frequent DDIs involved tacrolimus with N/R, resulting in creatinine increase.Eighty percent of reported DDI-related adverse events would have been identified by all drug-interaction checkers, while the remaining 20% by at least 2 of them., Conclusions: Drug interaction checkers are useful but show inconsistencies. Multiple sources are needed to tailor treatment in the context of COVID-19.

Purpose: There is increasing evidence that photobiomodulation (PBM) therapy is both an effective and safe approach in hematopoietic stem cell transplantation (HSCT) for both prevention and management of oral mucositis (OM), but its use in clinical practice is still limited and the timing of application is under discussion. The aim of this retrospective study was to evaluate possible differences between patients treated either with preventive or curative PBM therapy., Methods: The retrospective case series included 24 patients suffering from multiple myeloma who underwent the same conditioning and transplantation protocol. Patients were treated either with preventive PBM starting from the first day of conditioning up to two days post-HSCT or with curative PBM (starting at OM onset for four consecutive days). OM score, pain, and functional parameters were recorded., Results: All patients developed OM. Preventive PBM was significantly more effective in reducing OM severity (p < 0.0001) and pain (p < 0.0001) post-HSCT than curative PBM. Furthermore, we found a lower number of patients reporting discomfort in all subjective parameters (pain during swallowing, chewing, and speaking) in the preventive PBM group. No adverse events related to PBM therapy were recorded in both groups., Conclusion: The timing for PBM therapy in patients undergoing HSCT is crucial: when started on the first day of conditioning, it significantly reduces both pain and OM severity, providing an important benefit also in subjective oral functions such as speaking, swallowing, and chewing, thus increasing the overall adherence to the oncological therapies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Understanding the link between COVID-19 and patient immune characteristics is crucial. We previously demonstrated that high levels of the soluble Programmed Death-Ligand1 (sPD-L1) at the beginning of the infection correlated with low lymphocyte number and high C-reactive protein (CRP), longer length of stay (LOS), and death. This study investigated whether sPD-L1 can be a prognosis biomarker during COVID-19. Severe and non-severe COVID-19 patients were enrolled at the University Hospital of Salerno. During hospitalization, at admission, and after 12-14 days, patients' data were collected, and sPD-L1 levels were measured by enzyme-linked immunosorbent assay. The peripheral lymphocyte number negatively correlated with the time of negativization ( p = 0.006), length of stay (LOS) ( p = 0.032), and CRP ( p = 0.004), while sPD-L1 positively correlated with LOS ( p = 0.015). Patients with increased sPD-L1 and lymphocyte number showed a shorter LOS than those with decreased sPD-L1 and lymphocyte number ( p = 0.038) and those with increased sPD-L1 and decreased lymphocyte number ( p = 0.025). Moreover, patients with increased sPD-L1 and decreased CRP had a shorter LOS than those with increased sPD-L1 and CRP ( p = 0.034) and those with decreased sPD-L1 and CRP ( p = 0.048). In conclusion, while at an early phase of COVID-19, sPD-L1 promotes an immune escape, later, it might act to dampen an excessive immune response, proving its role in COVID-19 prognosis.

messenger RNA (mRNA)-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccines such as BNT162b2 became available in late 2020, but hematological malignancy patients (HM pts) were not evaluated in initial registration trials. We hereby report the results of a prospective, unicentric, observational study Response to COVID-19 Vaccination in hEmatological malignancies (CERVAX) developed to assess the postvaccine serological and T-cell-mediated response in a cohort of SARS-CoV2-negative HM pts vaccinated with BNT162b2. Patients with lymphomas [non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL)], chronic lymphocytic leukemia (CLL), and multiple myeloma (MM); off-therapy for at least 3 months; in a watch-and-wait program; or in treatment with ibrutinib, venetoclax, and lenalidomide were included. Different time points were considered to assess the serological response to the vaccine: before the second dose (T1), at 3-6-12 months after the first dose (T2-3-4, respectively). Since March 2021, 39 pts have been enrolled: 15 (38%) NHL, 12 (31%) CLL, and 12 (31%) MM. There were 13 of the 39 pts (33%) seroconverted at T1; an increase of the serological response was registered after the second dose (T2) (22/39 pts, 56%) and maintained after 6 months (22/39 pts, 56%) and 12 months (24/39 pts, 61%) from the first dose (T3-T4, respectively). Non-serological responders at T4 were 7/39 (18%): 0/15 NHL, 1/12 MM (8%), and 6/12 CLL (50%). All of them were on therapy (one lenalidomide, three ibrutinib, and three venetoclax). SARS-CoV2-reactive T-cell analysis (interferon gamma release assays) was available since June 2022 and was evaluated at 12 months (T4) from the first dose of vaccine in 31/39 pts (79%). T-cell-mediated-responders were 17/31 (55%): most of them were NHL and MM (47%, 41% and 12% for NHL, MM, and CLL, respectively). Both serological and T-cell non-responders were represented by pts on active therapy (venetoclax/ibrutinib). During the period of observation, eight (20.5%) pts developed mild SARS-CoV2 infection; no coronavirus disease 19 (COVID-19)-related deaths or hospitalizations were registered. In conclusion, in our cohort of lymphoproliferative pts receiving BNT162b2, CLL diagnosis and venetoclax/ibrutinib seem to be related with a lower humoral or T-mediated response. Nevertheless, the efficacy of mRNA vaccine in HM pts and the importance to continue the vaccine program even in non-responders after the first dose are supported in our study by demonstrating that a humoral and T-cell-mediated seroconversion should be observed even in the subsets of heavily immunocompromised pts., Competing Interests: The 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 © 2023 Mohamed, Lucchini, Sirianni, Porrazzo, Ballotta, Ballerini, De Sabbata, De Bellis, Cappuccio, Granzotto, Toffoletto, Fortunati, Russignan, Florea, Torelli and Zaja.)

The Waterhouse-Friderichsen syndrome represents a critical condition characterized by a septic shock associated with a disseminated intravascular coagulation causing the plugging of the microvascular network virtually all organs and systems, including the skin, the kidneys, the liver, and adrenal glands; the mortality rate is elevated, and survivors often must undergo multiple limb amputations. Here, we describe the uncommon case of an asplenic patient who developed this syndrome after a superficial wound caused by a dog bite causing an initial infection due to Capnocytophaga canimorsus that is part of the normal oral microbiome of pets. The clinical and pathological findings and the current and future therapeutic options are reviewed and discussed., (© 2023. The Author(s).)

Hand-Foot syndrome (HFS) and diarrhoea are dose-limiting Adverse Drug Reactions (ADRs) of capecitabine-based chemotherapy. Four polymorphisms in the dihydropyrimidine dehydrogenase ( DPYD ) gene, encoding the DPD enzyme responsible for the metabolism of fluoropyrimidines, such as capecitabine, are strongly associated with severe ADRs, and their screening should be performed before starting treatment. Moreover, capecitabine-related toxicity may worsen due to drug-drug and drug-supplement interactions. Here we investigated factors responsible for severe HFS and diarrhoea presented by two patients, non-carriers of the recommended DPYD single nucleotide polymorphisms (SNPs) but carriers of other genetic variants suggested to increase the risk of capecitabine-related ADRs. Through careful therapy recognition, we demonstrated that, unbeknownst to the oncologists, the patients were taking folic acid during the treatment with capecitabine at a dosage higher than 2000 mg/m 2 , which is the maximum tolerated dose when folate is administered. To resolve the ADRs, the therapy had to be drastically changed. In one case, dose reduction of capecitabine and discontinuation of lipid-lowering agents were carried out. In the other case, discontinuation of capecitabine and folic acid and capecitabine re-administration were performed after a month. Genetic and environmental factors should be considered good predictors of severe capecitabine-related toxicity. Medication reconciliation should be encouraged to avoid the harmful consequences of inappropriate treatments.

Vitamin K antagonists (VKAs) are used in the prophylaxis and treatment of thromboembolic disorders. Despite a high efficacy, their narrow therapeutic window and high response variability hamper their management. Several patients experience fluctuations in dose−response and are at increased risk of over- or under-anticoagulation. Therefore, it is essential to monitor the prothrombin time/international normalized ratio to determine the so-called stable dose and to adjust the dosage accordingly. Three polymorphisms, CYP2C9∗2, CYP2C9∗3 and VKORC1-1639G>A, are associated with increased sensitivity to VKAs. Other polymorphisms are associated with a request for a higher dose and VKA resistance. We described the clinical cases of two patients who were referred to the Clinical Pharmacology and Pharmacogenetics Unit of the University Hospital of Salerno for pharmacological counseling. One of them showed hypersensitivity and the other one was resistant to VKAs. A systematic review was performed to identify randomized clinical trials investigating the impact of pharmacogenetic testing on increased sensitivity and resistance to VKAs. Although international guidelines are available and information on the genotype-guided dosing approach has been included in VKA drug labels, VKA pharmacogenetic testing is not commonly required. The clinical cases and the results of the systematically reviewed RCTs demonstrate that the pharmacogenetic-based VKA dosing model represents a valuable resource for reducing VKA-associated adverse events.

Non-steroidal anti-inflammatory drugs (NSAIDs) [cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors] and COXIBs (the COX-2 selective inhibitors) may induce several potentially severe and life-threatening issues especially in elderly patients. The use of low-dose NSAIDs is associated with lower risk of side effects compared to the standard dosage. Low-dose NSAIDs could minimize the side effects of these drugs while maintaining their clinical efficacy and effectiveness. The present study evaluates the effectiveness and safety of low-dose NSAIDs in musculoskeletal applications., Competing Interests: Disclosure: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Acute Myeloid Leukaemia (AML) is a haematological malignancy showing a hypervariable landscape of clinical outcomes and phenotypic differences, explainable by heterogeneity at the cellular and molecular level. Among the most common genomic alterations, CBFB-MYH11 rearrangement and FLT3-ITD gene mutations, have opposite clinical significance and are unfrequently associated. We present here a Molecular Case Report in which these two events co-exist an ultra-aggressive phenotype resulting in death in 4 days from hospital admittance. Somatic and germline Whole Exome Sequencing analysis was performed to uncover other putative driver mutations, de-novo genomic structural events or germline clusters increasing cancer insurgence. Only three mutations in LTK, BCAS2 and LGAS9 were found, unlikely causative of the exhibited phenotype, prompting to additional investigation of the rare CBFB-MYH11/ FLT3-ITD scenario., (© 2022. The Author(s).)

Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of therapy-related myeloid neoplasms (t-MN). Using target next-generation sequencing (t-NGS) panels and digital droplet polymerase chain reactions (ddPCR), we studied the myeloid gene mutation profiles of patients with chronic lymphocytic leukaemia (CLL) who developed a t-MN after treatment with chemo-(immuno)therapy. Using NGS, we detected a total of 30 pathogenic/likely pathogenic (P/LP) variants in 10 of 13 patients with a t-MN (77%, median number of variants for patient: 2, range 0-6). The prevalence of CHIP was then backtracked in paired samples taken at CLL diagnosis in eight of these patients. Six of them carried at least one CHIP-variant at the time of t-MN (median: 2, range: 1-5), and the same variants were present in the CLL sample in five cases. CHIP variants were present in 34 of 285 patients from a population-based CLL cohort, which translates into a significantly higher prevalence of CHIP in patients with a CLL who developed a t-MN, compared to the population-based cohort (5/8, 62.5% vs. 34/285, 12%, p = 0.0001). Our data show that CHIP may be considered as a novel parameter affecting treatment algorithms in patients with CLL, and highlight the potential of using chemo-free therapies in CHIP-positive cases., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Vitamin C has been shown to play a significant role in suppressing progression of leukemia through epigenetic mechanisms. We aimed to study the role of vitamin C in acute myeloid leukemia (AML) biology and clinical course. To this purpose, the plasma levels of vitamin C at diagnosis in 62 patients with AML (including 5 cases with acute promyelocytic leukemia, APL),7 with myelodysplastic syndrome (MDS), and in 15 healthy donors (HDs) were studied. As controls, vitamins A and E levels were analysed. Expression of the main vitamin C transporters and of the TET2 enzyme were investigated by a specific RQ-PCR while cytoplasmic vitamin C concentration and its uptake were studied in mononuclear cells (MNCs), lymphocytes and blast cells purified from AML samples, and MNCs isolated from HDs. There were no significant differences in vitamin A and E serum levels between patients and HDs. Conversely, vitamin C concentration was significantly lower in AML as compared to HDs (p<0.0001), inversely correlated with peripheral blast-counts (p=0.029), significantly increased at the time of complete remission (CR) (p=0.04) and further decreased in resistant disease (p=0.002). Expression of the main vitamin C transporters SLC23A2 , SLC2A1 and SLC2A3 was also significantly reduced in AML compared to HDs. In this line, cytoplasmic vitamin C levels were also significantly lower in AML-MNCs versus HDs, and in sorted blasts compared to normal lymphocytes in individual patients. No association was found between vitamin C plasma levels and the mutation profile of AML patients, as well as when considering cytogenetics or 2017 ELN risk stratification groups. Finally, vitamin C levels did not play a predictive role for overall or relapse-free survival. In conclusion, our study shows that vitamin C levels are significantly decreased in patients with AML at the time of initial diagnosis, further decrease during disease progression and return to normal upon achievement of CR. Correspondingly, low intracellular levels may mirror increased vitamin C metabolic consumption in proliferating AML cells., Competing Interests: The 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 © 2022 Ottone, Faraoni, Fucci, Divona, Travaglini, De Bellis, Marchesi, Angelini, Palmieri, Gurnari, Giansanti, Nardozza, Montesano, Fabiani, Lindfors Rossi, Cerretti, Cicconi, De Bardi, Catanoso, Battistini, Massoud, Venditti and Voso.)

IDH1/2 mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of IDH1/2 mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19−86). Of these, 38 (14%) harbored IDH1 and 51 (18%) IDH2 mutations. IDH1/2 mutations were significantly associated with WHO PS >2 (p < 0.001) and non-complex karyotype (p = 0.021) when compared to IDH1/2-WT. Furthermore, patients with IDH1 mutations were more frequently NPM1-mutated (p = 0.007) and had a higher platelet count (p = 0.036). At relapse, IDH1/2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of IDH1/2-mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to IDH1/2-WT. In IDH1/2-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that IDH1/2 mutations are frequently detected at diagnosis and underlines the importance of recognizing IDH1/2-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors.

Background: Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug's effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD., Materials and Methods: This is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t 1/2 ), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters., Results: Thirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men ( p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t 1/2 . Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = -0.0970631, 95% CI -0.1733004 -0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t 1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t 1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men., Conclusion: This study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD., Competing Interests: The 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 © 2022 Conti, Izzo, Russillo, Picillo, Amboni, Scaglione, Nicoletti, Cani, Cicero, De Bellis, Charlier, Giudice, Somma, Corbi, Barone, Filippelli and Pellecchia.)

Importance: During the COVID-19 pandemic, urgent clinical management of patients has mainly included drugs currently administered for other diseases, referred to as repositioned drugs. As a result, some of these drugs have proved to be not only ineffective but also harmful because of adverse events associated with drug-drug interactions (DDIs)., Objective: To identify DDIs that led to adverse clinical outcomes and/or adverse drug reactions in patients with COVID-19 by systematically reviewing the literature and assessing the value of drug interaction checkers in identifying such events., Evidence Review: After identification of the drugs used during the COVID-19 pandemic, the drug interaction checkers Drugs.com, COVID-19 Drug Interactions, LexiComp, Medscape, and WebMD were consulted to analyze theoretical DDI-associated adverse events in patients with COVID-19 from March 1, 2020, through February 28, 2022. A systematic literature review was performed by searching the databases PubMed, Scopus, and Cochrane for articles published from March 1, 2020, through February 28, 2022, to retrieve articles describing actual adverse events associated with DDIs. The drug interaction checkers were consulted again to evaluate their potential to assess such events., Findings: The DDIs identified in the reviewed articles involved 46 different drugs. In total, 575 DDIs for 58 drug pairs (305 associated with at least 1 adverse drug reaction) were reported. The drugs most involved in DDIs were lopinavir and ritonavir. Of the 6917 identified studies, 20 met the inclusion criteria. These studies, which enrolled 1297 patients overall, reported 115 DDI-related adverse events: 15 (26%) were identifiable by all tools analyzed, 29 (50%) were identifiable by at least 1 of them, and 14 (24%) remained nonidentifiable., Conclusions and Relevance: The main finding of this systematic review is that the use of drug interaction checkers could have identified several DDI-associated adverse drug reactions, including severe and life-threatening events. Both the interactions between the drugs used to treat COVID-19 and between the COVID-19 drugs and those already used by the patients should be evaluated.

The addition of venetoclax to hypomethylating agents (HMA-V) improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment. The aim of our study was to confirm data reported in literature, in a real-life multicenter experience. We retrospectively evaluated 56 naïve AML patients who received HMA-V at 8 different collaborating Hematology Units in the North-East of Italy, from September 2018 to October 2020. Patients received azacitidine or decitabine at standard dose, adding venetoclax starting from cycle 1-3. The median time-to-response was 2 cycles and composite complete remission rate (CCR) was 67.9%. Thirteen out of 38 responders (34.2%) relapsed, with a median response duration of 13.7 months. Transfusion independence (TI) was obtained in 27 (87.0%) and 28 (90.3%) out of 31 patients for red blood cells and platelets, respectively. Median OS was 12.3 months (95% CI, 8.1-16.5), and median PFS was 11.3 months (95% CI, 4.6-17.9). Cytogenetic risk was the only variable impacting on survival, while no differences were observed stratifying patients by age, bone marrow blasts, WHO classification or type of HMA. In conclusion, our real-life multicenter experience indicates that HMA-V treatment allows achieving good response rates in naïve AML patients, ineligible for intensive chemotherapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Data supporting the use of Tocilizumab (TCZ) in COVID-19 are contrasting and inconclusive. This meta-analysis aimed to assess TCZ effectiveness in reducing the mortality rate in COVID-19 patients. PubMed, Scopus, Embase, Cochrane, WILEY, and ClinicalTrials.gov were searched to evaluate observational studies and RCTs. The outcome was the mortality rate. Forty observational studies and seven RCTs, involving 9640 and 5556 subjects treated with Standard Therapy (ST) + TCZ or ST alone, respectively, were included. In patients treated with ST+TCZ, a higher survival (Log odds ratio = -0.41; 95% CI: -0.68 -0.14; p < 0.001) was found. Subgroups analyses were performed to better identify the possible interference of some parameters in modifying the efficacy of TCZ therapy on COVID-19 mortality. Separating observational from RCTs, no statistically significant ( p = 0.70) TCZ-related reduction of mortality regarding RCTs was found, while a significant reduction (Log odds ratio = -0.52; 95% CI: -0.82 -0.22, p < 0.001) was achieved regarding the observational studies. Stratifying for the use of Invasive Mechanic Ventilation (IMV), a higher survival was found in patients treated with TCZ in the No-IMV and IMV groups (both p < 0.001), but not in the No-IMV/IMV group. Meta-regression analyses were also performed. The meta-analysis of observational studies reveals that TCZ is associated with reducing the mortality rate in both severe and critically ill patients. Although the largest RCT, RECOVERY, is in line with this result, the meta-analysis of RCTs failed to found any difference between ST + TCZ and ST. It is crucial to personalize the therapy considering the patients' characteristics.

Acute promyelocytic leukaemia (APL) represents a modern success of precision medicine. However, fatalities occurring within the first 30 days of induction treatment, in particular intracranial haemorrhage (ICH), remain the main causes of death. We studied the clinico-biological characteristics of 13 patients with APL who experienced ICH. Compared to 85 patients without this complication, patients with ICH were older and more frequently had high-risk APL. Moreover, positivity for the 'swirl' sign at neuroradiological imaging and hydrocephalus were predictors of a fatal outcome, together with lower fibrinogen, prolonged international normalized ratio (INR) and higher lactate dehydrogenase levels., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Pharmacogenetics investigates the response to pharmacological treatments based on individual genetic background. Actually, numerous pharmacogenetic tests help to predict the response to drugs used in different medical areas, contributing to the so-called personalized medicine., Objective: This review aims to update the available data on the genotype-guided treatment with both the anticoagulant and antiplatelet agents. Moreover, it sheds light on the pitfalls in the implementation of cardiovascular pharmacogenetics., Methods: A review of the literature on the studies investigating the effects of the genotype- guided anticoagulant and antiplatelet treatment was performed., Results: Considering the extensive use of antithrombotic drugs, pharmacogenetics has particular importance in this field. Several polymorphisms influence the response to both anticoagulant and antiplatelet agents, and tests, based on their identification, are now available., Conclusion: Recent randomized clinical trials demonstrated that pharmacogenetics might successfully contribute to optimizing the antiplatelet therapy also in patients particularly complicated to treat. However, despite accumulating evidence on the utility and feasibility of some pharmacogenetics tests, several barriers still exist in their implementation in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is very complex and heterogeneous. If not adequately treated, RA patients are likely to manifest excess of morbidity and disability with an important impact on the quality of life. Pharmacological treatment is based on the administration of the disease-modifying antirheumatic drugs (DMARDs), subdivided into conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs). bDMARDs are now frequently administered in patients, both as alternative treatment and together with csDMARDs. Unfortunately, there is a therapeutic response variability both to old and new drugs. Therefore, to identify pre-therapeutic and on-treatment predictors of response is a priority. This review aims to summarize recent advances in understanding the causes of the variability in treatment response in RA, with particular attention to predictive potential of autoantibodies and DMARD pharmacogenetics. In recent years, several biomarkers have been proposed to personalize the therapy. Unfortunately, a magic bullet does not exist, as many factors concur to disease susceptibility and treatment outcomes, acting around the patient's congenital background. Models integrating demographic, clinical, biochemical, and genetic data are needed to enhance the predictive capacity of specific factors singularly considered to optimize RA treatment in light of multidisciplinary patient management.

The terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in acute myeloid leukemias (AMLs), where it may be involved in the generation of NPM1 and FLT3-ITD mutations. We studied the correlations between TdT expression and FLT3-ITD or NPM1 mutations in primary AML samples, and the impact on patients' survival. TdT expression was analyzed in 143 adult AML patients by flow cytometry as percentage of positivity and mean fluorescence intensity (MFI) on blasts. TdT was positive in 49 samples (34.2%), with a median of 48% TdT-positivity (range 7-98) and a median MFI of 2.70 (range 1.23-30.54). FLT3-ITD and NPM1 mutations were present in 24 (16.7%) and 34 (23.7%) cases, respectively. Median TdT expression on blasts was significantly higher in FLT3-ITD+, as compared with FLT3-ITD- AMLs (median 8% vs 0% respectively, p = 0.035). NPM1 mutational status, FLT3-ITD allelic ratio, karyotype, and ELN risk groups, did not correlate with TdT expression or MFI on blasts. TdT + patients had poorer survival as compared to TdT-, but this result was not confirmed by the multivariable analysis, where ELN risk stratification as well as age and type of treatment remained independent prognostic factors for OS. In summary, our results support the possible implication of TdT enzyme in the generation of FLT3-ITD mutations in AML., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Heart Failure (HF) is a syndrome, which implies the existence of different phenotypes. The new categorization includes patients with preserved ejection fraction (HFpEF), mid-range EF (HFmrEF), and reduced EF (HFrEF) but the molecular mechanisms involved in these HF phenotypes have not yet been exhaustively investigated. Sirt1 plays a crucial role in biological processes strongly related to HF. This study aimed to evaluate whether Sirt1 activity was correlated with EF and other parameters in HFpEF, HFmrEF, and HFrEF. Seventy patients, HFpEF ( n = 23), HFmrEF ( n = 23) and HFrEF ( n = 24), were enrolled at the Cardiology Unit of the University Hospital of Salerno. Sirt1 activity was measured in peripheral blood mononuclear cells (PBMCs). Angiotensin-Converting Enzyme 2 (ACE2) activity, Tumor Necrosis Factor-alpha (TNF-α) and Brain Natriuretic Peptide (BNP) levels were quantified in plasma. HFpEF showed lower Sirt1 and ACE2 activities than both HFmrEF and HFrEF ( p < 0.0001), without difference compared to No HF controls. In HFmrEF and HFrEF a very strong correlation was found between Sirt1 activity and EF (r 2 = 0.899 and r 2 = 0.909, respectively), and between ACE2 activity and Sirt1 (r 2 = 0.801 and r 2 = 0.802, respectively). HFrEF showed the highest TNF-α levels without reaching statistical significance. Significant differences in BNP were found among the groups, with the highest levels in the HFrEF. Determining Sirt1 activity in PBMCs is useful to distinguish the HF patients' phenotypes from each other, especially HFmrEF/HFrEF from HFpEF.

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms ( DPYD -PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD -PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD -PGx. We describe a case series of patients in whom we performed DPYD -PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD -PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

Acute myeloid leukemia (AML), with an incidence increasing with age, is the most common acute leukemia in adults. Concurrent comorbidities, mild to severe organ dysfunctions, and low performance status (PS) are frequently found in older patients at the onset, conditioning treatment choice and crucially influencing the outcome. Although anthracyclines plus cytarabine-based chemotherapy, also called "7 + 3" regimen, remains the standard of care in young adults, its use in patients older than 65 years should be reserved to selected cases because of higher incidence of toxicity. These adverse features of AML in the elderly underline the importance of a careful patient assessment at diagnosis as a critical tool in the decision-making process of treatment choice. In this review, we will describe selected recently approved drugs as well as examine prognostic algorithms that may be helpful to assign treatment in elderly patients properly., Competing Interests: The authors declare no conflict of interest.

Introduction : Multiparametric flow cytometry immunophenotype (MFCI) plays a crucial role in the diagnosis of acute leukemia (AL). Through the comprehensive assessment of surface and intracellular antigens expressed by blasts, MFCI permits to distinguish myeloid or B/T lymphoid AL, or AL of ambiguous lineages. By means of MFCI, the blasts can be characterized in bone marrow, peripheral blood, and body fluids, such as cerebrospinal fluid. Area covered : This review discusses how MFCI is currently applied in the diagnostic evaluation of AL; it also focuses on 'peculiar' issues such as the role of MFCI for the diagnosis of central nervous system leukemic involvement. Expert commentary : Despite the improved knowledge about the biology of AL, MFCI remains a fundamental tool to make a prompt and accurate diagnosis. MFCI also provides prognostic information for some antigens are associated with specific cytogenetic/genetic abnormalities and, recently, it became a powerful tool to evaluate the quality and depth of response (the so called 'measurable residual disease'). Its role as an efficient detector of residual disease paved the way to the investigation of tissues other than bone marrow and peripheral blood, demonstrating that even small amounts of AL appear to have a prognostic impact and may require personalized intervention.

Background: Although bronchoalveolar lavage (BAL) measurements of galactomannan antigen (GM) seems to be more sensitive than serum testing to detect invasive fungal infection (IFI), a consensus on the most appropriate diagnostic threshold of the BAL GM test is still unclear. Moreover, there is uncertainty as to whether BAL is a safe procedure in patients with hematological malignancies (HM) and thrombocytopenia., Objectives: Based on this background, 102 adult patients with HM and associated thrombocytopenia were retrospectively analyzed with the dual aim of 1) determining whether BAL is a safe and feasible procedure; and, 2) identifying the most appropriate threshold for GM positivity in the diagnosis of IFI., Patients/methods: each BAL was considered as one case/patient. One hundred twelve BALs were carried out in 102 HM patients: at the time of the BAL, the median platelet count (PLTs) in all patients was 47×10 9 /L (1-476), and 31 patients (27%) had PLTs< 20×10 9 /L., Results: complications from the BAL were infrequent (3.5%) and mild. No bleeding was reported. The BAL GM cut off of >0.8 was associated with the best diagnostic accuracy (sensitivity 72.97% and specificity 80%). Antifungal treatment of patients with BAL GM >0.8 resulted in a clinical-radiological improvement in 35/41 patients (85%)., Conclusions: BAL was a safe procedure also in thrombocytopenic patients, permitting an IFI diagnosis not otherwise identifiable using EORTC/MSG criteria. Our data suggest that a BAL GM value of>0.8 represents the most useful cut-off in terms of sensibility and specificity. Further prospective studies on a more significant number of patients are needed to confirm these results., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid leukemia (AML). FOX proteins are widely involved in AML biology, including leukemogenesis, relapse and drug sensitivity. Here we explore the role of FOX transcription factors in the major AML entities, according to "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia", and in the context of the most recurrent gene mutations identified in this heterogeneous disease. Moreover, we report the new evidences about the role of FOX proteins in drug sensitivity, mechanisms of chemoresistance, and possible targeting for personalized therapies.