Covering Hierarchical Dirichlet Mixture Models on binary data to enhance genomic stratifications in onco-hematology.

Onco-hematological studies are increasingly adopting statistical mixture models to support the advancement of the genomically-driven classification systems for blood cancer. Targeting enhanced patients stratification based on the sole role of molecular biology attracted much interest and contributes to bring personalized medicine closer to reality. In onco-hematology, Hierarchical Dirichlet Mixture Models (HDMM) have become one of the preferred method to cluster the genomics data, that include the presence or absence of gene mutations and cytogenetics anomalies, into components. This work unfolds the standard workflow used in onco-hematology to improve patient stratification and proposes alternative approaches to characterize the components and to assign patient to them, as they are crucial tasks usually supported by a priori clinical knowledge. We propose (a) to compute the parameters of the multinomial components of the HDMM or (b) to estimate the parameters of the HDMM components as if they were Multivariate Fisher's Non-Central Hypergeometric (MFNCH) distributions. Then, our approach to perform patients assignments to the HDMM components is designed to essentially determine for each patient its most likely component. We show on simulated data that the patients assignment using the MFNCH-based approach can be superior, if not comparable, to using the multinomial-based approach. Lastly, we illustrate on real Acute Myeloid Leukemia data how the utilization of MFNCH-based approach emerges as a good trade-off between the rigorous multinomial-based characterization of the HDMM components and the common refinement of them based on a priori clinical knowledge.

Incidence of blast phase in myelofibrosis according to anemia severity.

Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids.

Optimization of CRISPR/Cas9-mediated genome engineering has resulted in base editors that hold promise for mutation repair and disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived organoids. First we show efficacy of cytosine and adenine base editors in modeling CTNNB1 hot-spot mutations in hepatocyte organoids. Next, we use C > T base editors to insert nonsense mutations in PTEN in endometrial organoids and demonstrate tumorigenicity even in the heterozygous state. Moreover, drug sensitivity assays on organoids harboring either PTEN or PTEN and PIK3CA mutations reveal the mechanism underlying the initial stages of endometrial tumorigenesis. To further increase the scope of base editing we combine SpCas9 and SaCas9 for simultaneous C > T and A > G editing at individual target sites. Finally, we show that base editor multiplexing allow modeling of colorectal tumorigenesis in a single step by simultaneously transfecting sgRNAs targeting five cancer genes.

Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations.

Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell-associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.

The impact of income-support interventions on life course risk factors and health outcomes during childhood: a systematic review in high income countries.

BACKGROUND: In high income countries one in five children still lives in poverty, which is known to adversely shape the life course health trajectory of these children. However, much less is understood on whether social and fiscal policies have the capacity to reverse this damage, which intervention is likely to be most effective and when these interventions should be delivered to maximise their impact. This systematic review attempts to address these questions by looking at the impact of income-support interventions, delivered during the first 1,000 days of life, on cardiovascular, metabolic, respiratory and mental health outcomes. METHODS: The review was restricted to experimental or quasi experimental studies conducted in high income countries. Studies were retrieved from multidisciplinary databases as well as health, economic, social sciences-specific literature browsers. All papers retrieved through the search strategy were double screened at title, abstract and full text stage. Relevant data of the selected studies were extracted and collected in tables, then summarised via narrative synthesis approach. Robustness of findings was assessed by tabulating impact by health outcome, type of intervention and study design. RESULTS: Overall, 16 relevant papers were identified, including 15 quasi-experimental studies and one randomized control trial (RCT). Income-support interventions included were unconditional/conditional cash transfers, income tax credit and minimum wage salary policies. Most studies were conducted in United States and Canada. Overall, the evidence suggested limited effect on mental health indicators but a positive, albeit small, effect of most policies on birth weight outcomes. Despite this, according to few studies that tried to extrapolate the results into public health terms, the potential number of negative outcomes averted might be consistent. CONCLUSIONS: Income-support interventions can positively affect some of the health outcomes of interest in this review, including birth weight and mental health. Given the large number of people targeted by these programs, one could infer that - despite small - the observed effect may be still relevant at population level. Nonetheless, the limited generalisability of the evidence gathered hampers firm conclusions. For the future, the breadth and scope of this literature need to be broadened to fully exploit the potential of these interventions and understand how their public health impact can be maximised.

The perceived impact of Covid-19 pandemic on the children with cerebral palsy: the parents' perspective explored within the "6-F words" framework.

BACKGROUND: In 2020 the world faced the spread of the coronavirus infection disease (Covid-19). This was a general public health emergency but many people with disabilities might have been particularly affected. OBJECTIVE: This paper aims to investigate the impact of the Covid-19 pandemic on children with Cerebral Palsy (CP) and their families. METHODS: 110 parents of children with CP (aged 2 to 19) who completed a questionnaire were included. These children were under the care of one of the Italian Children Rehabilitation Centers. Socio-demographic and clinical information about patients and their families were collected. In addition, difficulties on adopting protective measures and in respecting lockdown rules by children were explored. We adopted the ICF (International Classification of Functioning, Disability and Health) framework to create multiple choice questions. Descriptive statistics were reported and logistic regression analyses were run in order to identify the predictors of perceived impairment in motor, speech, manual and behavioral abilities. RESULTS: Daily activities of children, as well as rehabilitation and fitness sessions, underwent a change during the pandemic. Spending more time with family due to lockdown measures, has had, in some cases a positive effect however there was a perceived decrease in rehabilitation support and school activities. The age range (between 7 and 12 years) and difficulty in respecting rules emerged as significant predictors of the perceived impairment due to Covid-19 pandemic. CONCLUSIONS: The pandemic has had different impacts on children and their families on the basis of children's characteristics. Rehabilitation activities during a hypothetic lockdown should consider these characteristics.

Molecular landscape of myelodysplastic neoplasms in disease classification and prognostication.

PURPOSE OF REVIEW: The aim of this review is to provide a complete perspective of the evidence that led to the three recent new landmarks of myelodysplastic syndromes (MDS) definition and prognostication: the WHO 2022 and International Consensus Classification (ICC) 2022 classification and the Molecular Intermational Prognostic Scoring System (IPSS-M) score. RECENT FINDINGS: The molecular founding lesions of MDS are strongly linked with disease phenotype and prognosis, therefore the genetic assessment have become part of MDS classifications and prognostication. SUMMARY: The WHO 2022 now recognizes the class 'MDS with defining genetic abnormalities'. It includes 'MDS with SF3B1 mutation', and 'MDS with biallelic TP53 inactivation'. The ICC 2022 further introduces the category 'MDS/acute myeloid leukemia (AML)' emphasizing the biological continuum existing between the diseases, with the aim to expand therapeutic possibilities for MDS patients with more than 10% of blasts; it further identifies 9 MDS-funding lesions, defying the 'MDS/AML with myelodysplasia-related gene mutations' class. In recent years, many efforts have been done in order to specify and weight the role of mutations in disease prognostication; the IPSS-M proposed in 2022 finally integrates the molecular profile of the disease with the clinical and cytogenetic data, providing a better prognostication at patient level compared to IPSS-R.

Multiparameter flow cytometry in the evaluation of myelodysplasia: Analytical issues: Recommendations from the European LeukemiaNet/International Myelodysplastic Syndrome Flow Cytometry Working Group.

Multiparameter flow cytometry (MFC) is one of the essential ancillary methods in bone marrow (BM) investigation of patients with cytopenia and suspected myelodysplastic syndrome (MDS). MFC can also be applied in the follow-up of MDS patients undergoing treatment. This document summarizes recommendations from the International/European Leukemia Net Working Group for Flow Cytometry in Myelodysplastic Syndromes (ELN iMDS Flow) on the analytical issues in MFC for the diagnostic work-up of MDS. Recommendations for the analysis of several BM cell subsets such as myeloid precursors, maturing granulocytic and monocytic components and erythropoiesis are given. A core set of 17 markers identified as independently related to a cytomorphologic diagnosis of myelodysplasia is suggested as mandatory for MFC evaluation of BM in a patient with cytopenia. A myeloid precursor cell (CD34+ CD19- ) count >3% should be considered immunophenotypically indicative of myelodysplasia. However, MFC results should always be evaluated as part of an integrated hematopathology work-up. Looking forward, several machine-learning-based analytical tools of interest should be applied in parallel to conventional analytical methods to investigate their usefulness in integrated diagnostics, risk stratification, and potentially even in the evaluation of response to therapy, based on MFC data. In addition, compiling large uniform datasets is desirable, as most of the machine-learning-based methods tend to perform better with larger numbers of investigated samples, especially in such a heterogeneous disease as MDS.

Levofloxacin prophylaxis vs no prophylaxis in patients with neutropenia within an endemic country for carbapenem-resistant GNB.

Fluoroquinolone prophylaxis's (FQ-P) usefulness in patients with neutropenia is controversial. In recent decades, Italian epidemiological data has shown worrisome rates of FQ resistance. A single-center cohort study on 136 autologous stem cell transplantations (ASCTs) and 223 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) was performed from January 2018 to December 2020. Piperacillin/tazobactam was the first-line therapy for febrile neutropenia (FN). Since February 2019, FQ-P has been omitted. We evaluated the day +30 posttransplant cumulative incidence function (CIF) of gram-negative bacteria pre-engraftment bloodstream infections (PE-BSIs) and any changes in antimicrobial resistance, FN, and infection-related mortality (IRM). In ASCTs, ≥1 FN episode occurred in 74.3% of transplants, without differences among groups (P = .66). CIF of gram-negative bacteria PE-BSI was 10.1%, with a significant difference according to FQ-P (0% [LEVO-group] vs 14.1% [NO-LEVO-group], P = .016). CIF of IRM was 0% in both groups. In allo-HSCTs, ≥1 FN episode occurred in 96.4% of transplants, without differences among groups (P = .72). CIF of gram-negative bacteria PE-BSI was 28%, significantly higher without FQ-P (14.7% [LEVO-group] vs 34.4% [NO-LEVO-group], P = .003). CIF of IRM was 5%, superimposable in both groups (P = .62). Comparing antimicrobial resistance among gram-negative bacteria of allo-HSCT setting, in the group without FQ-P, a significantly higher proportion of pathogens was susceptible to piperacillin/tazobactam (71% vs 30%, P = .026), FQ (49% vs 10%, P = .03), and carbapenems (95% vs 50%, P = .001). FQ-P discontinuation increased gram-negative bacteria PE-BSI but did not impact IRM, both in the ASCT and allo-HSCT settings; importantly, it concurred to significantly decrease antimicrobial resistance in gram-negative bacteria.

Use of steroids in the management of low-risk myelodysplastic syndromes with autoimmune features.

BACKGROUND: The boundaries between myelodysplastic syndromes (MDS) and immune-mediated cytopenias are often difficult to establish and both conditions may benefit from immunosuppressive therapy. The optimal timing and doses of immunosuppressants are largely unknown. MATERIALS AND METHODS: We systematically evaluated a retrospective cohort of 79 patients with low-risk MDS tested for anti-erythrocyte or anti-platelet autoantibodies to assess their frequency and the efficacy of immunosuppression, particularly with steroids. RESULTS: We found autoantibody positivity in 43% of cases and overt autoimmune diseases in 18%, including autoimmune hemolytic anemia, immune thromboctyopenia, and Evans syndrome. Steroid treatment improved cytopenia in about half of patients, with 26% achieving a complete recovery lasting for a median of 12 months. Better responses were observed in anemic patients with anti-erythrocyte autoantibodies than in those with anti-platelet autoantibodies, and the combination with recombinant erythropoietin (7/10) had a possible synergistic effect. Steroid doses were heterogeneous depending on the clinical intent (i.e., anti-inflammatory, immunosuppressive, anabolizing). Patients treated with a dose of 1 mg/kg day of prednisone for overt autoimmune cytopenia showed high rates of complete responses (60%). DISCUSSION: This observation suggests a trial with a short course (2-3 weeks) of standard steroid doses to ascertain efficacy and properly silence the autoimmune pathogenic mechanism. Steroid-related adverse events (16% of cases) should be monitored carefully in this elderly, frail population. In conclusion, features of autoimmunity are present in more than two-thirds of low-risk MDS patients and a trial with prednisone 0.5-1 mg/kg day for 2-3 weeks, with proper monitoring of adverse events, may be useful to improve cytopenias in selected cases.

Flow cytometric analysis of myelodysplasia: Pre-analytical and technical issues-Recommendations from the European LeukemiaNet.

BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.

Clinical application of flow cytometry in patients with unexplained cytopenia and suspected myelodysplastic syndrome: A report of the European LeukemiaNet International MDS-Flow Cytometry Working Group.

This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.

Psychiatric symptoms in adult patients with cerebral palsy: A cohort study.

Background: Patients with cerebral palsy (CP) have an increased risk of developing mental health disorders. Aims: This paper is aimed to investigate the occurrence of psychiatric symptoms in adults with CP and to explore the relation between clinical and psychosocial variables. Methods and procedures: We included 199 adults with a diagnosis of CP. The chi-square and the Mann-Whitney U tests were used to compare clinical and psychosocial variables, the level of perceived disability, and the type of observed parental style in patients with and without psychiatric symptoms. Logistic regression analysis was used to identify variables that could predict the occurrence of mental health disorders. Outcome and results: Anxiety and psychosis were the most represented disorders. Age, living status, assumption of drugs, motor, manual, and global impairment were significantly different between patients with and without psychiatric symptoms. Similarly, a different parental style was observed between the two groups. Logistic regression indicated that living status, prescribed drugs, parental style, and the perceived disability in getting along with others predicted the occurrence of psychiatric symptoms. Conclusions and implications: Results suggest that patients with and without psychiatric symptoms have different clinical and psychosocial characteristics. Some variables should be considered as potentially affecting the mental health of patients with CP.

Perturbed graphs achieve unit transport efficiency without environmental noise.

Coherent transport of an excitation through a network corresponds to continuous-time quantum walk on a graph, and the transport properties of the system may be radically different depending on the graph and on the initial state. The transport efficiency, i.e., the integrated probability of trapping at a certain vertex, is a measure of the success rate of the transfer process. Purely coherent quantum transport is known to be less efficient than the observed excitation transport, e.g., in biological systems, and there is evidence that environmental noise is indeed crucial for excitation transport. At variance with this picture, we here address purely coherent transport on highly symmetric graphs, and show analytically that it is possible to enhance the transport efficiency without environmental noise, i.e., using only a minimal perturbation of the graph. In particular, we show that adding an extra weight to one or two edges, depending on whether the initial state is localized or in a superposition of two vertex states, breaks the inherent symmetries of the graph and may be sufficient to achieve unit transport efficiency. We also briefly discuss the conditions to obtain a null transport efficiency, i.e., to avoid trapping.

Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients.

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.