Hôpital Maisonneuve-Rosemont is a hospital in Montreal, Quebec, Canada, located in the boroughs of Rosemont–La Petite-Patrie and Mercier-Hochelaga-Maisonneuve. It serves the eastern part of the city and offers 800 beds. It employs 5,000 people and 3,000 students annually..
BACKGROUND:Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel. METHODS:In this phase 2, single-arm, multicohort study, patients from 30 sites in the USA, Canada, Europe, and Japan with relapsed or refractory MZL who had at least two previous lines of systemic therapy were eligible to receive lisocabtagene maraleucel (100 × 106 CAR+ T cells). Bridging therapy was allowed. The primary endpoint was overall response rate per independent review committee by CT by use of Lugano 2014 criteria (null hypothesis ≤50%). This study is registered with ClinicalTrials.gov, NCT04245839, and is ongoing. FINDINGS:Of 77 leukapheresed patients recruited between November 11, 2020, and August 24, 2023, 67 received lisocabtagene maraleucel and 66 were efficacy evaluable. MZL subtypes included nodal (n=32 [48%]), splenic (n=18 [27%]), and extranodal-mucosa-associated lymphoid tissue (n=17 [25%]). Median (IQR) previous lines of systemic therapy was 3 (2-4). Median on-study follow-up was 24·1 months. The primary endpoint was met, with an overall response rate of 95% (n=63; 95% CI, 87·3-99·1; one-sided p<0·0001). All patients experienced a treatment-related adverse event. Grade 3 cytokine release syndrome or neurological events occurred in three (4%) patients each (no grade 4-5 events). 11 (16%) patients had grade ≥3 infections: six (9%) patients during the 90-day treatment-emergent period and seven (10%) during the post-treatment-emergent period. INTERPRETATION:In patients with relapsed or refractory MZL, lisocabtagene maraleucel showed high rates of durable responses. The safety profile was manageable, with no new safety signals. These results support lisocabtagene maraleucel as a new treatment option for patients with relapsed or refractory MZL. FUNDING:Celgene, a Bristol-Myers Squibb Company.
Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.
Background: Solid organ transplant (SOT) recipients in Canada are particularly vulnerable to adverse hospital outcomes, especially during admissions involving a COVID-19 diagnosis. Limited evidence exists regarding how risks vary across different organ types and the extent to which a COVID-19 diagnosis influences hospital outcomes. This study aims to examine the association of organ subtypes on hospital morbidity and mortality, both in the presence and absence of a COVID-19 diagnosis in a large, nationally representative Canadian cohort. Methods: We used data from the Canadian Organ Replacement Register and the Discharge Abstract Database to examine hospitalization rates and in-hospital outcomes among all available adult SOT recipients with functioning grafts in Canada (excluding Quebec and Manitoba) from January 2021 to December 2022. In-hospital outcomes included transfer to a special care unit (SCU) and hospital mortality. Comparisons between organ subtypes (kidney, liver, heart, lung, and other/multi-organ) were conducted separately for admissions with and without a diagnosis of COVID-19, using kidney transplant (KT) recipients as the reference group. We included all admissions with a COVID-19 diagnosis irrespective of whether it was the primary reason for admission or not. Rates of hospitalization, SCU transfer, and mortality were analyzed using negative binomial or Poisson regression models (adjusted for age and sex) and reported using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Results: Among 23 497 SOT recipients, the majority (14 628, 62%) were KT recipients. Within this cohort, 2428 individuals (10.3%) experienced a total of 2925 hospitalizations with a COVID-19 diagnosis. In comparison, 7808 (33.2%) individuals experienced 17 656 hospitalizations without a COVID-19 diagnosis. Lung transplant recipients were more likely to be hospitalized (IRR = 1.65, 95% confidence interval CI: 1.52-1.80) and die in hospital (IRR = 1.2, 95% CI: 1.05-1.34) than KT recipients during admissions involving a COVID-19 diagnosis. In contrast, heart and liver transplant recipients were less likely to be hospitalized or experience a poor outcome. For hospitalizations without a COVID-19 diagnosis, lung and other/multi-organ transplant recipients were more likely than KT recipients to be hospitalized (IRR = 1.94, 95% CI: 1.76-2.15; IRR = 1.81, 95% CI: 1.45-2.26, respectively), transferred to an SCU (IRR = 1.89, 95% CI: 1.58-2.27; IRR = 1.81, 95% CI: 1.45-2.26, respectively), and die in hospital (IRR = 2.04, 95% CI: 1.84-2.27; IRR = 1.57, 95% CI: 1.33-1.85; respectively). Conclusion: SOT recipients in Canada, especially lung transplant recipients, experience high rates of hospitalization, SCU admission, and in-hospital mortality. Notable differences observed between organ subtypes for admissions with and without a COVID-19 diagnosis may reflect differences in immunosuppressive medication regimens, informing areas for future research.
ABSTRACT:Myeloproliferative neoplasms (MPN) are associated with a high symptom burden and impaired quality of life (QoL), often unaided by available treatments. Physical activity has demonstrated benefits in other cancers; however, its potential has yet to be explored in MPN. This randomized controlled trial aimed to evaluate the feasibility, acceptability, and efficacy of a supervised exercise program for patients with MPN based on longitudinal assessment of symptom burden, QoL, and clinical/inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, ferritin, lactate dehydrogenase [LDH], and serum cytokines). Patients with MPN (n = 55) were randomized 3:2 to a 12-week home-based exercise intervention (flexibility/resistance/aerobics) supervised by a kinesiologist vs waitlist control. Measures included patient-reported outcome questionnaires, peripheral blood sampling, and postintervention interviews with participants. Forty-seven patients completed the trial (FIT group, n = 26; control group, n = 21). Median age was 66 years (range, 27-86), and 60% were female. All feasibility benchmarks were met, with 88% of participants satisfied and 92% with intent to continue an exercise program on a regular basis. A significant reduction in LDH was observed in FIT patients compared with controls (-14.5 U/L vs +4.0 U/L; P = .03). Patients interviewed described positive effects of the intervention on symptoms and would unanimously recommend the program to others with MPN. In this pilot study, supervised exercise was feasible, acceptable, and showed potential benefits on inflammatory/disease markers.
