Statistics of extremes through m-component distribution

Cet article presente un modèle probabiliste à composantes multiples en s'appuyant sur l'analyse des chroniques de crues mesurées sur 19 rivières du sud de l'Italie. Un tel modèle peut être modifié si des points aberrants figurent dans l'échantillon considéré. L'identification de tels points aberrants est menée au moyen d'une estimation empirique de deux seuils appropriés, valables pour les rivières du sud de l'Italie. La combinaison de ces seuils permet de déterminer quatre classe de distribution caractérisées par le nombre de composantes (m=1, 2 et 3) du modèle probabiliste. (Résumé d'auteur

Investigations on Arthropods Associated with Decay Stages of Buried Animals in Italy

Burial could be used by criminals to conceal the bodies of victims, interfering with the succession of sarcosaprophagous fauna and with the evaluation of post-mortem interval. In Italy, no experimental investigation on arthropods associated with buried remains has been conducted to date. A first experimental study on arthropods associated with buried carcasses was carried out in a rural area of Arcavacata di Rende (Cosenza), Southern Italy, from November 2017 to May 2018. Six pig carcasses (Sus scrofa Linnaeus) were used, five of which were buried in 60-cm deep pits, leaving about 25-cm of soil above each carcass, and one was left above ground. One of the buried carcasses was periodically exhumed to evaluate the effects of disturbance on decay processes and on arthropod fauna. The other four carcasses were exhumed only once, respectively after 43, 82, 133, and 171 days. As expected, the decay rate was different among carcasses. Differences in taxa and colonization of arthropod fauna were also detected in the above ground and periodically exhumed carcasses. In carcasses exhumed only once, no arthropod colonization was detected. The results showed that a burial at about 25 cm depth could be sufficient to prevent colonization by sarcosaprophagous taxa and these data could be relevant in forensic cases involving buried corpses

Necrodes littoralis (Coleoptera: Silphidae) visiting and breeding on a carcass in Italy

The community that progressively colonizes a decaying corpse can be considered a small ecosystem mostly composed of sarcosaprophagous arthropods belonging to the orders Diptera and Coleoptera. Studies on these species are often performed through animal models to obtain data on their succession, behaviour and life cycle, together with information on habitat, corpse conditions, season and association with other species. These data may be relevant for forensic investigations, especially concerning the estimation of Post Mortem Interval (PMI). An investigation on the sarcosaprophagous insect community in a rural area was set in Calabria (Southern Italy), using a pig, Sus scrofa Linnaeus, 1758 (Artiodactyla: Suidae) as experimental model. Analyses of the community of Diptera and Coleoptera revealed the massive presence of Necrodes littoralis (Linnaeus, 1758) (Coleoptera: Silphidae). Adults of this species reached the carcass during the bloated stage and a large amount of larvae was detected from the decay stage onwards, simultaneous to the sharp decrease in dipteran larvae and pupae. The occurrence and the activity of N. littoralis should be considered to avoid misinterpretation and errors in estimating PMI in forensic investigation

Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

Over the past 10 years, the treatment of multiple myeloma (MM) dramatically changed due to the introduction of a number of new agents and combination regimens both in the frontline and in the relapsed/refractory setting. Currently, at least 11 classes of therapeutic agents, including steroids, alkylators (melphalan and cyclophosphamide), proteasome inhibitors (PI: bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), monoclonal antibodies (mAbs: elotuzumab, daratumumab), HDAC-inhibitors (panobinostat), BCL2 inhibitors (venetoclax), selective inhibitors of nuclear export (selinexor), drug-conjugated mAbs (belantamab mafodotin), bispecific agents and CAR-T, are approved (or are going to be approved) alone or in different combinations for the treatment of this disease, while few or no data are available to guide the therapeutic strategy to adopt at diagnosis or relapse (1). The choice of the treatment at relapse (2), in particular, poses particular challenges, and is currently dependent on patients (age, comorbidities, fitness, renal impairment, frailty) and disease characteristics (aggressive vs biochemical relapse, cytogenetics, presence of extra-medullary disease), previous treatments (classes of agents, duration of response, progression while on therapy), regional drug access (approval of combinations, reimbursement, costs) and, finally, patient’s choice. Unfortunately, there is a lack of trials specifically designed to help in this choice, and often, pre-planned subgroup analyses, do not include a sufficient number of patients to reach statistical evidence. Recently, since lenalidomide is progressively becoming the preferred one-line option to treat MM patients (and often, it is administered until progression), the choice of the treatment to be offered at relapse should be carefully evaluated. Interestingly, it has been reported that the longest prior lenalidomide treatment duration (>12 months) and IMiD-free interval (>18 months) could positively impact patients’ outcome (3), making the choice of a lenalidomide-sparing regimen of particular interest in this setting. On the bases of these premises, we performed a systematic review and a frequentist network meta-analysis in R [by using the netmeta package (4)] comparing direct and indirect evidence on the efficacy of seven different lenalidomide-sparing regimens (bortezomib-dexamethasone, VD; daratumumab-VD, DVD; carfilzomib-D, KD; daratumumab-KD, KdD; pomalidomide-VD, PVD; isatuximab-KD, IKD; selinexor-VD, SVD) in lenalidomide-exposed and lenalidomide-refractory patients, to provide statistical evidence to support clinical decision makin

Mechanisms of immune evasion in multiple myeloma: Open questions and therapeutic opportunities

Multiple myeloma (MM) is the second most common hematologic malignancy, charac-terized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immuno-suppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients

Long-Term Remission Achieved by Ponatinib and Donor Lymphocytes Infusion in a Ph+ Acute Lymphoblastic Leukemia Patient in Molecular Relapse After Allogenic Stem Cell Transplant and Dasatinib: A Case Report

Currently, the prognosis of Ph+ acute lymphoblastic leukemia (Ph+ ALL) patients relapsing after an allogenic hematopoietic stem cell transplantation (allo-SCT) remains poor, with few therapeutic options available. Here we present the case of a 32 years old patient with dasatinib-resistant post-transplant molecular relapse of ALL, who received, as second-line therapy, the combination of ponatinib and donor lymphocyte infusion (DLI). The therapy was safe and the patient achieved a sustained minimal residual disease negative disease, still ongoing after 22 months, which was accompanied by several changes in the immune populations distribution within the bone marrow (i.e., the increase in the CD8/CD4 lymphocytes ratio). Our report provides evidence of the efficacy of the third generation TKI inhibitor ponatinib in combination with DLI as second line therapy for Ph+ ALL relapsing after an allo-SCT

Survival Risk Scores for Real-Life Relapsed/Refractory Multiple Myeloma Patients Receiving Elotuzumab or Carfilzomib In Combination With Lenalidomide and Dexamethasone as Salvage Therapy: Analysis of 919 Cases Outside Clinical Trials

The present study aimed to develop two survival risk scores (RS) for overall survival (OS, SRSKRd/EloRd) and progression-free survival (PFS, PRSKRd/EloRd) in 919 relapsed/refractory multiple myeloma (RRMM) patients who received carfilzomib, lenalidomide, and dexamethasone (KRd)/elotuzumab, lenalidomide, and dexamethasone (EloRd). The median OS was 35.4 months, with no significant difference between the KRd arm versus the EloRd arm. In the multivariate analysis, advanced ISS (HR = 1.31; P = 0.025), interval diagnosis–therapy (HR = 1.46; P = 0.001), number of previous lines of therapies (HR = 1.96; P < 0.0001), older age (HR = 1.72; P < 0.0001), and prior lenalidomide exposure (HR = 1.30; P = 0.026) remained independently associated with death. The median PFS was 20.3 months, with no difference between the two strategies. The multivariate model identified a significant progression/death risk increase for ISS III (HR = 1.37; P = 0.002), >3 previous lines of therapies (HR = 1.67; P < 0.0001), older age (HR = 1.64; P < 0.0001), and prior lenalidomide exposure (HR = 1.35; P = 0.003). Three risk SRSKRd/EloRd categories were generated: low-risk (134 cases, 16.5%), intermediate-risk (467 cases, 57.3%), and high-risk categories (213 cases, 26.2%). The 1- and 2-year OS probability rates were 92.3% and 83.8% for the low-risk (HR = 1, reference category), 81.1% and 60.6% (HR = 2.73; P < 0.0001) for the intermediate-risk, and 65.5% and 42.5% (HR = 4.91; P < 0.0001) for the high-risk groups, respectively. Notably, unlike the low-risk group, which did not cross the median timeline, the OS median values were 36.6 and 18.6 months for the intermediate- and high-risk cases, respectively. Similarly, three PRSKRd/EloRd risk categories were engendered. Based on such grouping, 338 (41.5%) cases were allocated in the low-, 248 (30.5%) in the intermediate-, and 228 (28.0%) in the high-risk groups. The 1- and 2-year PFS probability rates were 71.4% and 54.5% for the low-risk (HR = 1, reference category), 68.9% and 43.7% (HR = 1.95; P < 0.0001) for the intermediate-risk, and 48.0% and 27.1% (HR = 3.73; P < 0.0001) for the high-risk groups, respectively. The PFS median values were 29.0, 21.0, and 11.7 months for the low-, intermediate-, and high-risk cases. This analysis showed 2.7- and 4.9-fold increased risk of death for the intermediate- and high-risk cases treated with KRd/EloRd as salvage therapy. The combined progression/death risks of the two categories were increased 1.3- and 2.2-fold compared to the low-risk group. In conclusion, SRSKRd/EloRd and PRSKRd/EloRd may represent accessible and globally applicable models in daily clinical practice and ultimately represent a prognostic tool for RRMM patients who received KRd or EloRd

Direction of the oblique medial malleolar osteotomy for exposure of the talus

A medial malleolar osteotomy is often indicated for operative exposure of posteromedial osteochondral defects and fractures of the talus. To obtain a congruent joint surface after refixation, the oblique osteotomy should be directed perpendicularly to the articular surface of the tibia at the intersection between the tibial plafond and medial malleolus. The purpose of this study was to determine this perpendicular direction in relation to the longitudinal tibial axis for use during surgery. Using anteroposterior mortise radiographs and coronal computed tomography (CT) scans of 46 ankles (45 patients) with an osteochondral lesion of the talus, two observers independently measured the intersection angle between the tibial plafond and medial malleolus. The bisector of this angle indicated the osteotomy perpendicular to the tibial articular surface. This osteotomy was measured relative to the longitudinal tibial axis on radiographs. Intraclass correlation coefficients (ICC) were calculated to assess reliability. The mean osteotomy was 57.2 ± 3.2° relative to the tibial plafond on radiographs and 56.5 ± 2.8 on CT scans. This osteotomy corresponded to 30.4 ± 3.7° relative to the longitudinal tibial axis. The intraobserver (ICC, 0.90-0.93) and interobserver (ICC, 0.65-0.91) reliability of these measurements were good to excellent. A medial malleolar osteotomy directed at a mean 30° relative to the tibial axis enters the joint perpendicularly to the tibial cartilage, and will likely result in a congruent joint surface after reductio

Predictors of Response to Hydroxyurea and Switch to Ruxolitinib in HU-Resistant Polycythaemia VERA Patients: A Real-World PV-NET Study

: In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised