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We evaluated response to VEN/HMA in 46 patients with acute myeloid leukemia (AML) characterized by extramedullary disease (EMD). Median age was 65 (range, 19-81) years. Patients had a median of two EMD sites (range, 1-5) and 35 (76%) patients had concurrent bone marrow involvement. Twenty (43%) patients had highrisk genetic features according to the European Leukemia Net 2022 classification. Twenty-nine (63%) were relapsed or refractory after intensive chemotherapy (CTX) including 13 (28%) with prior allogeneic hematopoietic cell transplantation (allo-HCT). Patients received a median of 2 cycles of VEN/HMA (range, 1-31). Twenty (43%) patients achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) after VEN/HMA and five (11%) achieved a partial remission (PR). Six patients were subsequently consolidated with allo-HCT (CR/CRi, n=4; PR, n=2). Median follow-up was 49.1 months (95%-CI, 26.1 months - not reached) and median overall survival (OS) 6.4 months (95%-CI, 5.1-11 months). One-year and 2-years OS rates were 29.3% (95%-CI, 18.6-46.2%) and 12.3% (95%-CI, 5.5-27.6%), respectively. Age with a cut-off of 60 years had no impact on OS (P=0.90). Relapse occurred in 12 of 20 (60%) patients who achieved CR/CRi after VEN/HMA treatment. Of those, all except one succumbed to their disease. Six (30%) patients were in CR/CRi at last follow-up and 2 (10%) died in CR. In our cohort of patients with AML with EMD with high-risk features, treatment with VEN/HMA resulted in an encouraging ORR of 54% with a CR/CRi rate of 43.5%. However, VEN/HMA alone may not be effective in maintaining disease control.

This systematic review examines the available clinical data on CD34+ cell mobilization, collection, and engraftment in multiple myeloma patients treated with the anti-CD38 monoclonal antibodies daratumumab and isatuximab in clinical trials and in real life. Twenty-six clinical reports were published between 2019 and February 2024. Most studies documented lower circulating CD34+ cells after mobilization compared to controls, leading to higher plerixafor requirements. Although collection yields were significantly lower in approximately half of the studies, the collection target was achieved in similar proportions of daratumumab- and isatuximab-treated and nontreated patients, and access to autologous stem cell transplant (ASCT) was comparable. This could be explained by the retained efficacy of plerixafor in anti-CD38 monoclonal antibody-treated patients, while no chemotherapy-based or sparing mobilization protocol proved superior. Half of the studies reported slower hematopoietic reconstitution after ASCT in daratumumab- and isatuximab-treated patients, without an excess of infectious complications. While no direct effect on stem cells was observed in vitro, emerging evidence suggests possible dysregulation of CD34+ cell adhesion after daratumumab treatment. Overall, anti-CD38 monoclonal antibodies appear to interfere with CD34+ cell mobilization, without consistently leading to significant clinical consequences. Further research is needed to elucidate the underlying mechanisms and define optimal mobilization strategies in this patient population.

The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5-6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2-63) after Allo-SCT ( p = 0.01). The median starting dose of PONA was 30 mg/day (range 15-45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7-118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2-100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank p = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE.

Competing Interests: We declare no competing interests.

We evaluated 58 patients with relapsed or refractory (r/r) acute B-lymphoblastic leukemia (B-ALL; median age 42.5 years; range, 16-69 years), treated with inotuzumab ozogamicin (INO) between 2016-2022 and who received an allogeneic hematopoietic stem cell transplantation (allo-HCT) consecutively. Forty-seven (81%) of the 58 patients were heavily pretreated receiving intensive chemotherapy +/- tyrosine kinase inhibitor, blinatumomab in 24 (41%) and allo-HCT at first-line in 11 (19%) patients. Complete remission rate prior to allo-HCT was 84%. Median follow-up was 30.5 months and median overall survival (OS) measured from start of INO was 11.2 months. One- and 2-year OS rates were 50% (95% confidence interval [CI]: 38.4-56.1) and 36.7% (95% CI: 25.5-52.9), respectively. Sinusoidal obstruction syndrome/venous occlusive disease (SOS/ VOD) after allo-HCT occurred in 17 (29%) patients. Of those, nine (53%) patients died due to SOS/VOD and multi-organ failure. Two had received >2 INO cycles (3 cycles, 5 cycles, N=1, each), all others ≤2 INO cycles prior to allo-HCT. Logistic regression analysis revealed conditioning with double alkylators (P=0.038) and allo-HCT during first-line therapy (P=0.050) as significant risk factors for SOS/VOD and in trend allo-HCT ≤60 days from last INO application (P=0.07), whereas number of INO cycles before allo-HCT and time between last INO application and allo-HCT were not significant. Relapse/progressive disease occurred in 20 (34%) patients. Of those, five (25%) patients are still alive, whereas 15 succumbed of their disease. Treatment with INO seems to be an effective approach with successful bridge-to-transplant. However, risk of SOS/VOD is high, necessitating continuous monitoring and recognition of SOS/VOD risk factors.

Competing Interests: BD received grants for speeches and advisory boards from Angelini, Astrazeneca, GSK, Novartis, Sanofi and Zambon. BL received fees from Astrazeneca, GSK, Novartis and Sanofi. BC received fees from GSK, Novartis and Sanofi. CL received fees for lectures from Alk Abellò, Astrazeneca, GSK, Novartis and Sanofi. DCE received fees for consultation, lectures and advisory board from Astrazeneca, GSK, Novartis, Regeneron and Sanofi. LMI reveived fees from Chiesi, DMG Firma, GSK, Novartis and Sanofi. MG has received fees from GSK, Novartis and Sanofi. MA received fee for advisory board and speaker for Astra Zeneca, Chiesi, CSL Boerhing, GSK, Novartis, Sanofi, and Takeda. SV partecipated in advisory boards and scientific meetings on behalf of Astrazeneca, Firma, GSK, Novartis and Sanofi. VA received fees for lectures and advisory boards from Astrazeneca, GSK, Novartis, and Sanofi. PP received grants for speeches and expert opinion from GSK, LeoPharma, and Novartis. CFRM received fees from GSK, Novartis and Sanofi. RM and SC are GSK full time employes. Macchi A, ML, NS, PG and PL declare to have no conflicts of interest.

Background: Alterations in vibration perception among children and adolescents with Charcot-Marie-Tooth disease might explain observed changes in foot posture. Therefore, this cross-sectional study compared the vibration perception of the lower limbs in youths with and without Charcot-Marie-Tooth disease and verified the cut-off value of the distal vibration perception for the Charcot-Marie-Tooth group. In addition, associations between dynamic plantar pressure, vibration perception and isometric muscle strength were investigated., Methods: Participants aged 9-18 (Charcot-Marie-Tooth group n = 32; Typical group n = 32) had vibration perception measured by a 128-Hz graduated tuning fork. The static and dynamic foot posture were evaluated by the Foot Posture Index and pressure distribution measuring system, respectively. For the Charcot-Marie-Tooth group, a hand-held dynamometer evaluated the isometric muscle strength of the lower limbs., Findings: Children with Charcot-Marie-Tooth disease presented impaired vibration perception at the distal phalanx of the hallux and head of the first metatarsal compared to their typically developing peers, while adolescents with Charcot-Marie-Tooth disease showed impairment in all the tested regions compared to their typically developing peers. The cut-off value for vibration perception for participants with Charcot-Marie-Tooth disease was 5.7, considering the original grade of the tuning-fork 128 Hz. Among the associations established for the Charcot-Marie-Tooth group, a greater vibration perception at the distal phalanx of the hallux was associated with a longer rearfoot contact time (β = 31.02, p = 0.04)., Interpretation: These new findings may guide the clinical evaluation and rehabilitation treatment for children and adolescents with Charcot-Marie-Tooth disease., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (InO) has improved the outcome of relapsed/refractory B-lymphoblastic leukemia (R/R B-ALL). However, little is known about the outcome after recurrence and re-treatment with immunotherapy., Methods: We describe 71 R/R B-ALL patients treated for different relapses with Blina and InO. Blina was the first treatment in 57 patients and InO in 14. Twenty-seven patients had a previous allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Results: In the Blina/InO group, after Blina, 36 patients (63%) achieved a complete remission (CR), with 42% of negative minimal residual disease (MRD-); after InO, a CR was achieved in 47 patients (82%, 34 MRD-). In the InO/Blina group, after InO, 13 cases (93%) reached a CR (6 MRD-); after Blina, a CR was re-achieved in 6 cases (43%, 3 MRD-). Twenty-six patients proceeded to allo-HSCT. In the Blina/InO group, the median overall survival (OS) was 19 months; the disease-free survival (DFS) after Blina was 7.4 months (11.6 vs. 2.7 months in MRD- vs. MRD+, p = 0.03) and after InO, 5.4 months. In the InO/Blina group, the median OS was 9.4 months; the median DFS after InO was 5.1 months and 1.5 months after Blina (8.7 vs. 2.5 months in MRD- vs. MRD+, p = 0.02). With a median follow-up of 16.5 months from the start of immunotherapy, 24 patients (34%) are alive and 16 (22%) are alive in CR., Conclusion: In our series of R/R B-ALL, Blina and InO treatment demonstrate efficacy for subsequent relapses in terms of MRD response, OS and DFS, and as a bridge to allo-HSCT.

There is no disputing the current established global consensus that people with lived experience of a mental health condition ("people with lived experience") play an integral role in influencing policy and processes in global mental health. Specifically, the role they hold as agents of change through which they can lead and co-lead projects on mental health, alongside a multidisciplinary team, as recommended in the findings of the report of Lancet Commission on ending stigma and discrimination (Thornicroft et al. [2022], "The Lancet Commission on ending stigma and discrimination in mental health", Lancet , 400, 1438-1480). Immense value is associated with their unique expertise not learned through theoretical concept but based on real-life experience. Appreciating their involvement in processes is a human right, supported by international human rights instruments such as the United Nations Convention on the Rights of Persons with Psychosocial Disabilities (2006). However, there remains an expectation that people with lived experience are expected to be involved in processes and service delivery without receiving remuneration for their expertise. This article will provide the basis for which processes must follow the principle of equity; that lived experience expertise ought to be equally compensated for based on equal pay for equal work. In closing, it will provide a recommendation for stakeholders on how to improve upon effective engagement with people with lived experience, leading to meaningful and authentic contributions., Competing Interests: The author declares no competing interests exist., (© The Author(s) 2023.)

Background: In older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question., Methods: In the present study, we tested the impact on survival of disease- and patient-related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs)., Results: In 131 patients with a median age of 76 years, we confirmed that early response (<0.001) and biology-based risk classification (p = 0.003) can select patients with better-predicted survival. However, a full disease-oriented model had limitations in stratifying our patients, prompting us to investigate the impact of baseline comorbidities on overall survival basing on a comorbidity score. The albumin level (p = 0.001) and the presence of lung disease (p = 0.013) had a single-variable impact on prognosis. The baseline comorbidity burden was a powerful predictor of patients' frailty, correlating with increased incidence of adverse events, especially infections, and predicted overall survival (p < 0.001)., Conclusion: The comorbidity burden may contribute to impact prognosis in addition to disease biology. While the therapeutic armamentarium of elderly AML is improving, a comprehensive approach that combines AML biology with tailored interventions to patients' frailty is likely to fully exploit the anti-leukemia potential of novel drugs., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The SETD2 tumor suppressor gene encodes a histone methyltransferase that safeguards transcription fidelity and genomic integrity via trimethylation of histone H3 lysine 36 (H3K36Me3). SETD2 loss of function has been observed in solid and hematologic malignancies. We have recently reported that most patients with advanced systemic mastocytosis (AdvSM) and some with indolent or smoldering SM display H3K36Me3 deficiency as a result of a reversible loss of SETD2 due to reduced protein stability., Methods: Experiments were conducted in SETD2-proficient (ROSA KIT D816V ) and -deficient (HMC-1.2) cell lines and in primary cells from patients with various SM subtypes. A short interfering RNA approach was used to silence SETD2 (in ROSA KIT D816V cells), MDM2 and AURKA (in HMC-1.2 cells). Protein expression and post-translational modifications were assessed by WB and immunoblotting. Protein interactions were tested by using co-immunoprecipitation. Apoptotic cell death was evaluated by flow cytometry after annexin V and propidium iodide staining, respectively. Drug cytotoxicity in in vitro experiments was evaluated by clonogenic assays., Results: Here, we show that the proteasome inhibitors suppress cell growth and induce apoptosis in neoplastic mast cells by promoting SETD2/H3K36Me3 re-expression. Moreover, we found that Aurora kinase A and MDM2 are implicated in SETD2 loss of function in AdvSM. In line with this observation, direct or indirect targeting of Aurora kinase A with alisertib or volasertib induced reduction of clonogenic potential and apoptosis in human mast cell lines and primary neoplastic cells from patients with AdvSM. Efficacy of Aurora A or proteasome inhibitors was comparable to that of the KIT inhibitor avapritinib. Moreover, combination of alisertib (Aurora A inhibitor) or bortezomib (proteasome inhibitor) with avapritinib allowed to use lower doses of each drug to achieve comparable cytotoxic effects., Conclusions: Our mechanistic insights into SETD2 non-genomic loss of function in AdvSM highlight the potential value of novel therapeutic targets and agents for the treatment of patients who fail or do not tolerate midostaurin or avapritinib., (© 2023. The Author(s).)

Purpose: Effective intervention, policy, and research in mental health and well-being (MHWB) require young people to be understood not only as beneficiaries, but also as active agents in codesigning and implementing initiatives. To identify pathways for young people's participation in promoting MHWB in low- and middle-income countries (LMICs), this study surveyed young people's aspirations for engagement, their spheres of influence, capacity building needs, and key barriers to participation., Methods: Using U-Report, United Nations Children's Emergency Fund's social messaging tool and data collection platform, we distributed a short quantitative survey to a nonrepresentative, but large sample of young people aged 15-29 across five LMICs: Nigeria, Brazil, Jamaica, South Africa, and Burundi., Results: A total of 42,689 young people responded, with representation from most or all provinces within each country. Participants' average age was 23.8 years (SD = 3.77). Young people's core aspirations were to join a mental health awareness project and to support their peers. Participants considered schools and community settings to be the most important spheres for engagement. Lack of information about mental health was the main perceived barrier to participation, and mental health classes the main training need., Discussion: In many countries, MHWB is not taught or discussed in schools and youth-led mental health interventions are rare. Findings from this study reveal clear aspirations for participatory engagement to promote MHWB among young people in LMICs. To support meaningful participation, policymakers and youth service providers must ensure that young people have access to mental health literacy training and opportunities to raise awareness in schools or community settings., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative atrial fibrillation (POAF) is one of the most common complications following cardiac surgery and is associated with increased morbidity. Intraoperative topical amiodarone application on epicardial tissue has been shown to reduce systemic concentrations while maintaining therapeutic myocardial concentrations, thereby, lowering the risk of extracardiac adverse effects associated with oral and intravenous amiodarone therapy. However, the efficacy and safety of topical amiodarone in preventing POAF is unclear., Objectives: This study summarizes the clinical studies to-date that have investigated the efficacy and safety of topical amiodarone administration in preventing POAF following cardiac surgery., Methods: A database search was conducted using Medline, Embase, and Cochrane Library to identify relevant studies. Abstracts were screened and data were extracted from relevant full-text articles that met the inclusion and exclusion criteria., Results: The search returned four studies with variable findings on the effect of topical amiodarone therapy on the incidence of POAF, cardiac effects, extracardiac effects, and hospital length of stay., Conclusion: Prophylactic topical application of amiodarone may be effective and safe for preventing post-operative new-onset atrial fibrillation. Further investigation is required to evaluate the efficacy and safety of topical amiodadrone therapy before it can be widely integrated into current practice., (© 2022 Wiley Periodicals LLC.)

Background: Population-level statistics on pandemic-related change in substance use can obscure patterns of use (e.g., polysubstance use) within individuals. This longitudinal study used a person-centered approach to identify subgroups with respect to patterns of substance use prior to and during the COVID-19 pandemic, and to examine profile correlates (e.g., socio-demographic characteristics), which can inform tailored intervention., Methods: The two youngest age cohorts of the Pittsburgh Girls Study (n = 938; 59.1 % Black, 40.9 % White; mean age= 26.2 (SD= 0.8)), a longitudinal community sample, provided data on past year frequency of cigarette/e-cigarette use, binge drinking (>4 drinks per occasion), and cannabis use prior to and during the pandemic, and perceived change in use. Latent profile analysis identified subgroups. Profile correlates were examined (e.g., sociodemographics, COVID-19 infection status and reported exposure, COVID-19 impacts on psychological health and finances)., Results: Seven profiles were identified: "Low use", "Occasional binge drinking", "Cannabis use", "Cigarette/e-cigarette & binge drinking", "Occasional binge drinking & cannabis", "Binge drinking & cannabis", and "Polysubstance use". Black women were overrepresented in "Low use", which was associated with fewer pandemic effects on health. Profiles associated with more frequent binge drinking were more likely to report COVID-19 infection, whereas "Cannabis use" had lower reported infection prevalence. "Polysubstance use" had more COVID-related depression and income loss, on average, than "Low use"., Conclusions: Distinct subgroups representing single substance use, co-use, and polysubstance use prior to and during the pandemic were identified. The profiles show differential response to COVID-19 impacts, ranging from relative hardiness to specific needs to guide personalized treatment., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: EM is the founder of the non-profit Mentally Unsilenced and a country committee member of the Global Mental Health Peer Network (GMHPN) representing Kenya. CS is Deputy Chief Executive Officer of the GMHPN; the GMHPN is a non-profit international lived experience advocacy organisation whose objectives are to influence policy and practice to promote human rights and overall wellbeing; Charlene Sunkel, a Co-Chair of the Lancet Commission on ending stigma and discrimination in mental health, is the founder and Chief Executive Officer of the GMHPN. We declare no other competing interests.

Introduction: Minimal residual disease (MRD) is commonly assessed in bone marrow (BM) aspirate. However, sample quality can impair the MRD measurement, leading to underestimated residual cells and to false negative results. To define a reliable and reproducible method for the assessment of BM hemodilution, several flow cytometry (FC) strategies for hemodilution evaluation have been compared., Methods: For each BM sample, cells populations with a well-known distribution in BM and peripheral blood - e.g., mast cells (MC), immature (IG) and mature granulocytes (N) - have been studied by FC and quantified alongside the BM differential count., Results: The frequencies of cells' populations were correlated to the IG/N ratio, highlighting a mild correlation with MCs and erythroblasts (R=0.25 and R=0.38 respectively, with p-value=0.0006 and 0.0000052), whereas no significant correlation was found with B or T-cells. The mild correlation between IG/N, erythroblasts and MCs supported the combined use of these parameters to evaluate BM hemodilution, hence the optimization of the ALLgorithMM . Once validated, the ALLgorithMM was employed to evaluate the dilution status of BM samples in the context of MRD assessment. Overall, we found that 32% of FC and 52% of Next Generation Sequencing (NGS) analyses were MRD negative in samples resulted hemodiluted (HD) or at least mildly hemodiluted (mHD)., Conclusions: The high frequency of MRD-negative results in both HD and mHD samples implies the presence of possible false negative MRD measurements, impairing the correct assessment of patients' response to therapy and highlighs the importance to evaluate BM hemodilution., 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 Vigliotta, Armuzzi, Barone, Solli, Pistis, Borsi, Taurisano, Mazzocchetti, Martello, Poletti, Sartor, Rizzello, Pantani, Tacchetti, Papayannidis, Mancuso, Rocchi, Zamagni, Curti, Arpinati, Cavo and Terragna.)

Antigen-directed target therapy for B-cell acute lymphoblastic leukemia (B-ALL) is now the standard of care for relapsed/refractory (R/R) disease. A comprehensive determination of the target itself is mandatory to aid physician's choice. We determined baseline Cluster of differentiation 22 (CD22) expression percentage and fluorescent intensity on lymphoblasts of 30 patients with R/R B-ALL treated with anti-CD22 immunoconjugate drug Inotuzumab Ozogamicin (INO) and analyzed the impact of both parameters on patient outcome. Most patients (24/30, 80%) had a high leukemic blast CD22-positivity defined as ≥90%. We did not observe a benefit in terms of complete remission, overall survival (OS) and duration of response (DoR) for patients with CD22 ≥ 90% versus CD22 < 90%. Concerning CD22-FI quartile analysis we appreciated a trend for superior response rates in higher quartiles (Q 2 -Q 4 ) compared to Q 1 and a significant benefit in terms of OS and DoR for patients with higher CD22-FI. INO demonstrates to be effective also in patients with lower CD22 expression, but therapeutical benefits are more evident in patients with higher CD22-FI. The evaluation of both CD22 percentage and CD22-FI of the leukemic blast may help physicians in therapeutic choices for R/R B-ALL patients when multiple treatment options are available, although no CD22 expression threshold can currently be identified below which INO should be considered not effective., (© 2022 John Wiley & Sons Ltd.)

Acute lymphoblastic leukemia (ALL) can relapse in the extramedullary compartment, with or without medullary involvement. Response to treatment may be individual. We evaluated response to inotuzumab ozogamicin in 31 patients with relapsed/refractory B-ALL with extramedullary disease. Median age was 31 years (range, 19-81). All patients were heavily pretreated, including allogeneic hematopoietic stem cell transplantation (HSCT; n=18). Overall response rate after two cycles of inotuzumab ozogamicin was 84% (complete remission, 55%; partial remission, 29%; resistant disease, 13%; early death, 3%). The median follow-up was 29 months and median overall survival was 12.8 months. One-year and 2-year overall survival rates were 53% (95% CI: 37-76%) and 18% (95% CI: 8-43%), respectively. Age had no impact on overall survival when assessed as a continuous variable or dichotomized at 60 years. Twelve patients proceeded to allogeneic HSCT (complete remission, n=6; partial remission, n=3; resistant disease, n=3). Prior to allogeneic HSCT, eight patients received two or fewer cycles and four patients received three or four cycles of inotuzumab ozogamicin. Sinusoidal obstruction syndrome was reported in three patients, including one after transplantation. Allogeneic HSCT, evaluated as a time-dependent variable, had no impact on overall survival. Inotuzumab ozogamicin seems to be effective as a debulking strategy in relapsed/refractory ALL with extramedullary disease. However, inotuzumab ozogamicin followed by allogeneic HSCT seems not to be effective in maintaining long-term disease control.

Globally, there has been an emphasis on the importance and value of involving people with lived experience of mental health conditions in service delivery, development and leadership. Such individuals have taken on various roles, from peer support specialists and other specialised professions to leadership in mainstream industries. There are, however, still obstacles to overcome before it is possible to fully include people with lived experience at all levels in the mental health and related sectors. This article discusses the benefits, both to the individual and to the public, of involving persons with lived experience in service delivery, development and leadership.

Venetoclax (VEN) and hypomethylating agent (HMAs) regimens are emerging as the standard of care for unfit for chemotherapy acute myeloid leukemia (AML) patients, but the safety and feasibility of a total outpatient management have not been fully investigated. Fifty-nine AML patients with active disease received VEN and HMAs. Nineteen out of 59 (32.2%) patients received the first cycle as inpatients, whereas 40/59 (67.8%) patients were treated in the outpatient setting. No significant differences were observed with regard to incidence of adverse events (AEs), including tumor lysis syndrome (TLS), and the 30-day and 60-day mortality was comparable. Notably, an infectious prophylaxis inspired to that adopted during intensive chemotherapy resulted in a low infection rate with a reduced bacterial infections incidence in out- versus hospitalized patients (p < .0001). The overall time of hospitalization was significantly shorter in patients who received a total outpatient treatment as compared to those who received the first cycle as inpatients (5.9 vs. 39.7 days, p < .0001). Despite the adopted differences in treatment management, the efficacy was similar. These data indicate that a total outpatient management of VEN and HMAs is feasible in AML patients without negatively impacting on treatment efficacy and may yield pharmacoeconomic and quality-of-life benefits., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In adult patients, acute lymphoblastic leukemia (ALL) is a rare hematological cancer with a cure rate below 50% and frequent relapses. With traditional therapies, patients with relapsed or refractory (R/R) ALL have a survival that may be measured in months; in these patients, inotuzumab ozogamicin (IO) is an effective therapy. IO was linked to increased risk of veno-occlusive disease/sinusoid obstruction syndrome (VOD/SOS), liver injury, and various grade of liver-related complications during clinical trials and real-life settings; however, hepatologic monitoring protocol is not established in this population. In our institution, 21 patients who received IO (median of 6 doses of IO administered) for R/R ALL were prospectively followed for hepatologic surveillance, including clinical evaluation, ultrasonography, and liver stiffness measurement (LSM) biochemistry. After a median follow-up of 17.2 months, two SOS events were reported (both after allogeneic transplant) as IO potentially related clinically relevant adverse event. Mild alterations were reported in almost the totality of patients and moderate-severe liver biochemical alterations in a quarter of patients. Within biochemicals value, AST and ALP showed an augment related to IO administration. LSM linearly augmented for each IO course administered. Baseline LSM was related to liver-related changes, especially with the severity of portal hypertension (PH)-related complications. Pre-transplant LSM was higher in patients receiving IO when compared with a control cohort. PH-related complications were discovered in nearly 77% of patients, with clinically significant PH occurrence and development of ascites in 38% and 14%, respectively. This prospective experience constitutes the rationale to design a hepatologic monitoring program in patients receiving IO. LSM may be of pivotal importance in this program, constituting a rapid and effective screening that quantitatively correlates with liver alterations., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Recently, many reports were published supporting the clinical use of adoptively transferred natural killer (NK) cells as a therapeutic tool against cancer, including acute myeloid leukemia (AML). Our group demonstrated promising clinical response using adoptive immunotherapy with donor-derived alloreactive KIR-ligand-mismatched NK cells in AML patients. Moreover, the antileukemic effect was correlated with the dose of infused alloreactive NK cells ("functional NK cell dose"). Herein, we update the results of our previous study on a cohort of adult AML patients (median age at enrollment 64) in first morphological complete remission (CR), not eligible for allogeneic stem cell transplantation. After an extended median follow-up of 55.5 months, 8/16 evaluable patients (50%) are still off-therapy and alive disease-free. Overall survival (OS) and disease-free survival (DFS) are related with the dose of infused alloreactive NK cells (≥2 × 10 5 /kg)., 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 Parisi, Ruggeri, Dan, Rizzi, Sinigaglia, Ocadlikova, Bontadini, Giudice, Urbani, Ciardelli, Sartor, Cristiano, Nanni, Zannoni, Chirumbolo, Arpinati, Lewis, Bonifazi, Marconi, Martinelli, Papayannidis, Paolini, Velardi, Cavo, Lemoli and Curti.)

Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.

The contribution of the bone marrow (BM) immune microenvironment to acute myeloid leukemia (AML) development is well-known, but its prognostic significance is still elusive. Indoleamine 2,3-dioxygenase 1 (IDO1), which is negatively regulated by the BIN1 proto-oncogene, is an interferon-γ-inducible mediator of immune tolerance. With the aim to develop a prognostic IDO1-based immune gene signature, biological and clinical data of 982 patients with newly diagnosed, nonpromyelocytic AML were retrieved from public datasets and analyzed using established computational pipelines. Targeted transcriptomic profiles of 24 diagnostic BM samples were analyzed using the NanoString's nCounter platform. BIN1 and IDO1 were inversely correlated and individually predicted overall survival. PLXNC1, a semaphorin receptor involved in inflammation and immune response, was the IDO1-interacting gene retaining the strongest prognostic value. The incorporation of PLXNC1 into the 2-gene IDO1-BIN1 score gave rise to a powerful immune gene signature predicting survival, especially in patients receiving chemotherapy. The top differentially expressed genes between IDO1lowand IDO-1high and between PLXNC1lowand PLXNC1high cases further improved the prognostic value of IDO1 providing a 7- and 10-gene immune signature, highly predictive of survival and correlating with AML mutational status at diagnosis. Taken together, our data indicate that IDO1 is pivotal for the construction of an immune gene signature predictive of survival in AML patients. Given the emerging role of immunotherapies for AML, our findings support the incorporation of immune biomarkers into current AML classification and prognostication algorithms., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

As global ocean temperatures continue to rise, severe declines in coral reef health and diversity are reported on a global scale. Recovery of coral reefs relies on reproduction and increased rates of successful recruitment, which can vary tremendously across coral species. We investigated the effects of increased temperatures in the environment of parental colonies on larval production, size, settlement and survival, in the heat-resistant coral Leptastrea purpurea in Guam . Thanks to two tank experiments (eleven and four weeks, respectively) conducted over two consecutive years we found that larvae released by heat-treated parents (30 °C) were significantly smaller in size but greater in number, had normal settlement behavior and increased post-settlement survival rates compared to those released by control parent colonies (28 °C). We conclude that changes in the environment of parental L. purpurea colonies trigger an anticipatory maternal effect which leads to the release of preconditioned larvae with an increased chance of survival., Supplementary Information: The online version contains supplementary material available at 10.1007/s00338-022-02241-y., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022.)

Background: Substance use is linked to increases in young women's risk for intimate partner violence (IPV). Increased understanding of the magnitude of and changes in the associations between substance use and risk for IPV in the transition to emerging adulthood, and differences between Black and White women, could inform efforts to protect women from substance use-related harm., Methods: Young women (N = 1,852; 59% Black, 41% White) in the Pittsburgh Girls Study completed yearly assessments at ages 17-21 on frequency of alcohol and cannabis use, and experiences of IPV (minor physical assault). Time-varying effect models (TVEMs) were used to examine changes in the strength of the association between frequency of alcohol and cannabis use with IPV across ages 17-21, controlling for time-invariant covariates (socioeconomic status, conduct problems, and depression)., Results: Across ages 17 to 21, White, relative to Black, women reported more frequent alcohol use and less frequent cannabis use, and lower rates of IPV. Alcohol use was not significantly associated with IPV at ages 17-21 among White women, but among Black women, alcohol use was associated with increased likelihood of IPV at ages 17-20. Cannabis use was associated with increased likelihood of IPV at ages 19-21 among Black women, and at ages 20-21 among White women., Conclusions: Associations between IPV (specifically minor assault) in the context of a romantic relationship differed for alcohol and cannabis across ages 17-21, and by race, among White and Black women. Results highlight the importance of substance-specific prevention efforts that are timed and tailored to subgroups., (Copyright © 2021 Elsevier Ltd. All rights reserved.)