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BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Inibidores de Proteínas Quinases , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Hemorragia/induzido quimicamente , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidoresRESUMO
Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial (NCT03740529). Prior covalent BTKi therapy was allowed, but not prior venetoclax. Patients were assigned to receive PV (n=15) or PVR (n=10) for 25 cycles. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4), and 17 (68%) patients had received prior covalent BTKi. At the data-cutoff date (May 5, 2023), median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% CI:68.1-99.8%) for PV and 100% (95% CI:69.2-100.0%) for PVR, with 10 complete responses (PV:7; PVR:3). After 12 cycles of treatment, 85.7% (95% CI:57.2-98.2%) of PV and 90.0% (95% CI:55.5-99.7%) of PVR patients achieved undetectable minimal residual disease assessed in peripheral blood by clonoSEQ® assay at a sensitivity of <1x10-4. Progression-free survival at 18 months was 92.9% (95% CI: 59.1-99.0) for PV patients and 80.0% (95% CI: 40.9-94.6) for PVR patients. No DLTs were observed in either treatment combination during the 5-week assessment period. The most common grade ≥3 adverse events for all patients included neutropenia (52%) and anemia (16%). Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.
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ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.
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Anticorpos Biespecíficos , Humanos , Anticorpos Biespecíficos/uso terapêutico , Consenso , Imunoterapia Adotiva/efeitos adversos , Ativação LinfocitáriaRESUMO
Chimeric antigen receptor (CAR) modified T cell therapy has transformed the management of relapsed/refractory B cell malignancies. Despite high overall response rates, relapse post CAR T treatment remains a clinical challenge. Loss of target antigen, specifically CD19, is one well-defined mechanism of disease relapse. The mechanism of CD19 loss and which patients are at higher risk of CD19 loss remain poorly understood. To overcome CD19 loss, CARs targeting multiple antigens are being tested in clinical trials. CD19/20 and CD19/22 bispecific CARs demonstrate cytotoxicity against CD19-negative cells in preclinical studies. These CARs have also shown efficacy, safety, and a relatively low rate of CD19-negative relapse in phase I trials. These small studies suggest that multispecific CAR T cells can deprive lymphomas of escape via antigen loss. However, the selection of an ideal target, the right CAR construct, and whether these multispecific CARs can induce long-term remissions are still under investigation.
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Linfoma , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T , Imunoterapia Adotiva , Recidiva Local de NeoplasiaRESUMO
We analyzed whether there is an interaction between the Kidney Donor Profile Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KTs). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into 3 KDPI groups (≤20%, 21%-85%, >85%) and 4 CIT strata (<12, 12-17.9, 18-23.9, ≥24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft nonfunction (PGNF), delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 6 and 12 months, patient survival, graft survival, and death-censored graft survival (DCGS). A total of 69,490 recipients were analyzed: 18,241 (26.3%) received a graft with KDPI ≤20%, 46,953 (67.6%) with KDPI 21%-85%, and 4,296 (6.2%) with KDPI >85%. Increasing KDPI and CIT were associated with worse post-KT outcomes. Contrary to our hypothesis, howerver, the interaction between KDPI and CIT was statistically significant only for PGNF and DGF and eGFR at 6 months. Paradoxically, the negative coefficient of the interaction suggested that increasing duration of CIT was more detrimental for low and intermediate-KDPI organs relative to high-KDPI grafts. Conversely, for mortality, graft survival, and DCGS, we found that the interaction between CIT and KDPI was not statistically significant. We conclude that, high KDPI and prolonged CIT are independent risk factors for inferior outcomes after KT. Their interaction, however, is statistically significant only for the short-term outcomes and more pronounced on low and intermediate-KDPI grafts than high-KDPI kidneys.
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Isquemia Fria , Função Retardada do Enxerto , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Transplante de Rim , Doadores de Tecidos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doadores de Tecidos/provisão & distribuição , Fatores de Risco , Adulto , Seguimentos , Função Retardada do Enxerto/etiologia , Prognóstico , Taxa de Sobrevida , Estudos Retrospectivos , Falência Renal Crônica/cirurgia , Rejeição de Enxerto/etiologia , Testes de Função Renal , Obtenção de Tecidos e Órgãos , Complicações Pós-OperatóriasRESUMO
Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii. Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.
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Amicacina , Pneumonia , Humanos , Animais , Camundongos , Amicacina/farmacocinética , Antibacterianos/farmacocinética , Pulmão , Pneumonia/tratamento farmacológico , Peso CorporalRESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.
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Mieloma Múltiplo , Neoplasias de Plasmócitos , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva , Transplante HomólogoRESUMO
BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50â×â106 (dose level 1) or 100â×â106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.
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Leucemia Linfocítica Crônica de Células B , Idoso , Feminino , Humanos , Masculino , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Indução de Remissão , Sulfonamidas/uso terapêuticoRESUMO
In 2023, approximately 650,000 people experienced homelessness (PEH) nightly in the United States, the highest number recorded in the country's history. This alarming statistic has made homelessness a key issue in the 2024 elections, especially with the White House's goal to reduce homelessness by 25% by 2025. Despite efforts and investments, homelessness remains a persistent public health challenge. The recent inclusion of street medicine services in Center for Medicare and Medicaid Services (CMS) billing codes represents a significant step forward. Street medicine, defined by CMS as healthcare provided in non-permanent locations to unsheltered individuals, now qualifies for Medicare reimbursement. This policy change, alongside state-level initiatives, aims to improve healthcare access for the unhoused, particularly older adults. However, challenges remain in establishing adequate fee schedules and integrating care management. Despite these obstacles, the integration of healthcare and housing services is crucial for addressing homelessness effectively, promoting stability, and improving health outcomes for PEH. This manuscript explores the history, practical guidance, and potential impacts of these developments on homelessness and public health.
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BACKGROUND: With recent advancements in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), healthcare specialists may face challenges making treatment and management decisions based on latest evidence for the optimal care of patients with these conditions. This study aimed to identify specific knowledge, skills, and confidence gaps impacting the treatment of CLL and MCL, to inform future educational activities. METHODS: Hematologists and hemato-oncologists (HCPs, n = 224) from France (academic settings), Germany, and the United States (academic and community settings) responded to a 15-minute quantitative needs assessment survey that measured perceived knowledge, skills, and confidence levels regarding different aspects of treatment and management of CLL and MCL patients, as well as clinical case questions. Descriptive statistics (cross tabulations) and Chi-square tests were conducted. RESULTS: Four areas of educational need were identified: (1) sub-optimal knowledge of treatment guidelines; (2) sub-optimal knowledge of molecular testing to inform CLL/MCL treatment decisions; (3) sub-optimal skills when making treatment decisions according to patient profile (co-morbidities, molecular testing results); and (4) challenges balancing the risk of toxicities with benefits of treatment. Over one-third of the respondents reported skill gaps when selecting suitable treatment options and prescribing therapies and reported a lack in confidence to initiate and manage treatment. Larger gaps in knowledge of guidelines and skills in patient assessment were identified in MCL, compared to CLL. CONCLUSIONS: This study suggests the need for continuing medical education specifically to improve knowledge of treatment guidelines, and to assist clinicians in developing skills and confidence when faced with clinical decision-making scenarios of patients with specific comorbidities and/or molecular test results, for example, through case-based learning activities.
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Competência Clínica , Conhecimentos, Atitudes e Prática em Saúde , Leucemia Linfocítica Crônica de Células B , Linfoma de Célula do Manto , Humanos , Linfoma de Célula do Manto/terapia , Linfoma de Célula do Manto/patologia , França , Alemanha , Leucemia Linfocítica Crônica de Células B/terapia , Estados Unidos , Inquéritos e Questionários , Masculino , Feminino , Tomada de Decisão Clínica , Pessoa de Meia-Idade , Tomada de DecisõesRESUMO
INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.
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A chromosome 14 inversion was found in a patient who developed bone marrow aplasia following treatment with allogeneic chimeric antigen receptor (CAR) Tcells containing gene edits made with transcription activator-like effector nucleases (TALEN). TALEN editing sites were not involved at either breakpoint. Recombination signal sequences (RSSs) were found suggesting recombination-activating gene (RAG)-mediated activity. The inversion represented a dominant clone detected in the context of decreasing absolute CAR Tcell and overall lymphocyte counts. The inversion was not associated with clinical consequences and wasnot detected in the drug product administered to this patient or in any drug product used in this or other trials using the same manufacturing processes. Neither was the inversion detected in this patient at earlier time points or in any other patient enrolled in this or other trials treated with this or other product lots. This case illustrates that spontaneous, possibly RAG-mediated, recombination events unrelated to gene editing can occur in adoptive cell therapy studies, emphasizes the need for ruling out off-target gene editing sites, and illustrates that other processes, such as spontaneous V(D)J recombination, can lead to chromosomal alterations in infused cells independent of gene editing.
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Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos Quiméricos , Humanos , Edição de Genes , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Linfócitos T , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva/efeitos adversosRESUMO
Smads are nuclear-shuttling transcriptional mediators of transforming growth factor-ß (TGF-ß) signaling. Although their essential nuclear roles in gene regulation during development and carcinogenesis are well established, whether they have important cytoplasmic functions remains unclear. Here we report that Smad2 is a critical determinant of mitochondrial dynamics. We identified mitofusin2 (MFN2) and Rab and Ras Interactor 1 (RIN1) as new Smad2 binding partners required for mitochondrial fusion. Unlike TGF-ß-induced Smad2/3 transcriptional responses underlying mitochondrial fragmentation and apoptosis, inactive cytoplasmic Smad2 rapidly promotes mitochondrial fusion by recruiting RIN1 into a complex with MFN2. We demonstrate that Smad2 is a key scaffold, allowing RIN1 to act as a GTP exchange factor for MFN2-GTPase activation to promote mitochondrial ATP synthesis and suppress superoxide production. These results reveal functional implications between Smads and mitochondrial dysfunction in cancer and metabolic and neurodegenerative disorders.
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GTP Fosfo-Hidrolases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/enzimologia , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Proteína Smad2/metabolismo , Células A549 , Trifosfato de Adenosina/metabolismo , Animais , Células COS , Chlorocebus aethiops , Metabolismo Energético , GTP Fosfo-Hidrolases/genética , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Mitocondriais/genética , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Interferência de RNA , Transdução de Sinais , Proteína Smad2/genética , Superóxidos/metabolismo , TransfecçãoRESUMO
IMPORTANCE: The burden of caring for children with complex medical problems such as major congenital anomalies falls principally on mothers, who in turn suffer a variety of potentially severe economic consequences. As well, health consequences of caregiving often further impact the social and economic prospects of mothers of children with major congenital anomalies (MCMCAs). Evaluating the long-term economic consequences of extensive in-home caregiving among MCMCAs can inform strategies to mitigate these effects. OBJECTIVE: To assess whether MCMCAs face reduced employment and increased need for disability benefits over a 20-year period. DESIGN: A population-based matched cohort study. SETTING: Denmark. PARTICIPANTS: All women who gave birth to a singleton child with a major congenital anomaly in Denmark between January 1, 1997 and December 31, 2017 (n = 23,637) and a comparison cohort of mothers matched by maternal age, parity, and infant's year of birth (n = 234,586). EXPOSURES: Liveborn infant with a major congenital anomaly. MAIN OUTCOMES AND MEASURES: The primary outcome was mothers' employment status, stratified by their child's age. Employment status was categorized as employed, outside the workforce (on temporary leave, holding a flexible job, or pursuing education), or unemployed; the number of weeks in each category was measured over time. The secondary outcome was time to receipt of a disability pension, which in Denmark implies permanent exit from the labor market. We used a negative binomial regression model to estimate the number of weeks in each employment category, stratified by the child's age (i.e., 0-1 year, > 1-6 years, 7-13 years, 14-18 years). A Cox proportional hazards regression model was used to compute hazard ratios as a measure of the relative risk of receiving a disability pension. Rate ratios and hazard ratios were adjusted for maternal demographics, pregnancy history, health, and infant's year of birth. RESULTS: During 1-6 years after delivery, MCMCAs were outside the workforce for a median of 50 weeks (IQR, 6-107 weeks), while members of the comparison cohort were outside the workforce for a median of 48 weeks (IQR, 4-98 weeks), corresponding to an adjusted rate ratio [ARR] of 1.05 (95% confidence interval [CI], 1.04-1.07). During the first year after delivery, MCMCAs were more likely to be employed than mothers in the comparison cohort (ARR, 1.08; 95% CI, 1.06-1.10). At all timepoints thereafter, MCMCAs had a lower rate of workforce participation. The rate of being outside the workforce was 5% higher than mothers in the comparison cohort during 1-6 years after delivery (ARR, 1.05; 95% CI, 1.04-1.07), 9% higher during 7-13 years after delivery (ARR, 1.09; 95% CI, 1.06-1.12), and 12% higher during 14-18 years after delivery (ARR, 1.12; 95% CI, 1.07-1.18). Overall, MCMCAs had a 20% increased risk of receiving a disability pension during follow-up than mothers in the matched comparison cohort [incidence rates 3.10 per 1000 person-years (95% CI, 2.89-3.32) vs. 2.34 per 1000 person-years (95% CI, 2.29-2.40), adjusted hazard ratio, 1.20; 95% CI, 1.11-1.29]. CONCLUSION AND RELEVANCE: MCMCAs were less likely to participate in the Danish workforce, less likely to be employed, and more likely to receive disability pensions than mothers of unaffected children. The rate of leaving the workforce intensified as their affected children grew older. The high demands of caregiving among MCMCAs may have long-term employment consequences even in nations with comprehensive and heavily tax-supported childcare systems, such as Denmark.
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Mães , Desemprego , Criança , Lactente , Gravidez , Humanos , Feminino , Recém-Nascido , Estudos de Coortes , Escolaridade , Dinamarca/epidemiologiaRESUMO
PURPOSE: Intraoperative hypoglycemia is presumed to be rare, but generalizable multicentre incidence and risk factor data for adult patients are lacking. We used a multicentre registry to characterize adults with intraoperative hypoglycemia and hypothesized that intraoperative insulin administration would be associated with hypoglycemia. METHODS: We conducted a cross-sectional retrospective multicentre cohort study. We searched the Multicenter Perioperative Outcomes Group registry to identify adult patients with intraoperative hypoglycemia (glucose < 3.3 mmol·L-1 [< 60 mg·dL-1]) from 1 January 2015 to 31 December 2019. We evaluated characteristics of patients with intraoperative glucose measurements and with intraoperative hypoglycemia. RESULTS: Of 516,045 patients with intraoperative glucose measurements, 3,900 (0.76%) had intraoperative hypoglycemia. Diabetes mellitus and chronic kidney disease were more common in the cohort with intraoperative hypoglycemia. The odds of intraoperative hypoglycemia were higher for the youngest age category (18-30 yr) compared with the odds for every age category above 40 yr (odds ratio [OR], 1.57-3.18; P < 0.001), and were higher for underweight or normal weight patients compared with patients with obesity (OR, 1.48-2.53; P < 0.001). Parenteral nutrition was associated with lower odds of hypoglycemia (OR, 0.23; 95% confidence interval [CI], 0.11 to 0.47; P < 0.001). Intraoperative insulin use was not associated with hypoglycemia (OR, 0.996; 95% CI, 0.91 to 1.09; P = 0.93). CONCLUSION: In this large cross-sectional retrospective multicentre cohort study, intraoperative hypoglycemia was a rare event. Intraoperative insulin use was not associated with hypoglycemia.
RéSUMé: OBJECTIF: L'hypoglycémie peropératoire est présumée rare, mais il n'existe pas de données généralisables sur l'incidence multicentrique et les facteurs de risque chez la patientèle adulte. Nous avons utilisé un registre multicentrique pour caractériser les personnes adultes atteintes d'hypoglycémie peropératoire et émis l'hypothèse que l'administration peropératoire d'insuline serait associée à l'hypoglycémie. MéTHODE: Nous avons réalisé une étude de cohorte multicentrique rétrospective transversale. Nous avons effectué des recherches dans le registre du Multicenter Perioperative Outcomes Group afin d'identifier les patient·es adultes atteint·es d'hypoglycémie peropératoire (glucose < 3,3 mmol· L−1 [< 60 mg·dL−1]) du 1er janvier 2015 au 31 décembre 2019. Nous avons évalué les caractéristiques des patient·es présentant des mesures de glucose et une hypoglycémie peropératoires. RéSULTATS: Sur 516 045 patient·es ayant des mesures de glucose peropératoires, 3900 (0,76 %) ont présenté une hypoglycémie peropératoire. Le diabète sucré et l'insuffisance rénale chronique étaient plus fréquents dans la cohorte présentant une hypoglycémie peropératoire. Les risques d'hypoglycémie peropératoire étaient plus élevés pour la catégorie d'âge la plus jeune (18-30 ans) par rapport aux catégories d'âge au-dessus de 40 ans (rapport des cotes [RC], 1,57-3,18; P < 0,001), et étaient plus élevés chez les patient·es de poids insuffisant ou de poids normal par rapport aux patient·es obèses (RC, 1,48-2,53; P < 0,001). La nutrition parentérale était associée à une probabilité plus faible d'hypoglycémie (RC, 0,23; intervalle de confiance [IC] à 95 %, 0,11 à 0,47; P < 0,001). L'utilisation peropératoire d'insuline n'était pas associée à l'hypoglycémie (RC, 0,996; IC 95 %, 0,91 à 1,09; P = 0,93). CONCLUSION: Dans cette vaste étude de cohorte multicentrique rétrospective transversale, l'hypoglycémie peropératoire était un événement rare. L'utilisation peropératoire d'insuline n'était pas associée à l'hypoglycémie.
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Despite significantly improving outcomes in patients with B-cell malignancies, covalent Bruton tyrosine kinase (BTK) inhibitors are limited by toxicities and the development of resistance. Some toxicities can be life-threatening, such as cardiotoxicity. These toxicities result from off-target effects of covalent BTK inhibitors and frequently lead to dose reductions and discontinuations of the drug. Noncovalent BTK inhibitors bind BTK in a unique fashion and, to date, have demonstrated an excellent safety profile as well as efficacy against a variety of B-cell malignancies. In addition, noncovalent BTK inhibitors have, for the first time, demonstrated efficacy in patients who progressed on other BTK inhibitors. Long-term data and comparative studies are needed to further investigate their efficacy and role in the landscape covalent BTK Inhibitors.
Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVES: Total knee arthroplasty (TKA) is an effective surgery for end-stage knee osteoarthritis, but chronic postoperative pain and reduced function affect up to 20% of patients who undergo such surgery. There are limited treatment options, but percutaneous peripheral nerve stimulation (PNS) is a promising nonopioid treatment option for chronic, persistent postoperative pain. The objective of the present study was to evaluate the effect of a 60-day percutaneous PNS treatment in a multicenter, randomized, double-blind, placebo-controlled trial for treating persistent postoperative pain after TKA. MATERIALS AND METHODS: Patients with postoperative pain after knee replacement were screened for this postmarket, institutional review board-approved, prospectively registered (NCT04341948) trial. Subjects were randomized to receive either active PNS or placebo (sham) stimulation. Subjects and a designated evaluator were blinded to group assignments. Subjects in both groups underwent ultrasound-guided placement of percutaneous fine-wire coiled leads targeting the femoral and sciatic nerves on the leg with postoperative pain. Leads were indwelling for eight weeks, and the primary efficacy outcome compared the proportion of subjects in each group reporting ≥50% reduction in average pain relative to baseline during weeks five to eight. Functional outcomes (6-minute walk test; 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index) and quality of life (Patient Global Impression of Change) also were evaluated at end of treatment (EOT). RESULTS: A greater proportion of subjects in the PNS groups (60%; 12/20) than in the placebo (sham) group (24%; 5/21) responded with ≥50% pain relief relative to baseline (p = 0.028) during the primary endpoint (weeks 5-8). Subjects in the PNS group also walked a significantly greater distance at EOT than did those in the placebo (sham) group (6MWT; +47% vs -9% change from baseline; p = 0.048, n = 18 vs n = 20 completed the test, respectively). Prospective follow-up to 12 months is ongoing. CONCLUSIONS: This study provides evidence that percutaneous PNS decreases persistent pain, which leads to improved functional outcomes after TKA at EOT.
Assuntos
Artroplastia do Joelho , Dor Pós-Operatória , Estimulação Elétrica Nervosa Transcutânea , Humanos , Masculino , Feminino , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Método Duplo-Cego , Idoso , Dor Pós-Operatória/terapia , Dor Pós-Operatória/etiologia , Pessoa de Meia-Idade , Estimulação Elétrica Nervosa Transcutânea/métodos , Resultado do Tratamento , Medição da Dor/métodos , Recuperação de Função Fisiológica/fisiologiaRESUMO
For relapsed chemosensitive diffuse large B-cell lymphoma (DLBCL), consolidation with autologous hematopoietic cell transplantation (auto-HCT) is a standard option. With the approval of anti-CD19 chimeric antigen receptor T cells in 2017, the Center for International Blood and Marrow Transplant Research (CIBMTR) reported a 45% decrease in the number of auto-HCTs for DLBCL in the United States. Using the CIBMTR database, we identified 249 relapsed DLBCL patients undergoing auto-HCT from 2003 to 2013 with a positive positron emission tomography/computed tomography (PET/CT)+ partial response prior to transplant were identified. The study cohort was divided into 2 groups: early chemoimmunotherapy failure (ECF), defined as patients with primary refractory disease (PRefD) or relapse within 12 months of diagnosis and late chemoimmunotherapy failure, defined as patients relapsing after ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. A total of 182 patients had ECF, whereas 67 did not. Among ECF cohort, 79% had PRefD. The adjusted 5-year probabilities for PFS and OS (ECF vs no ECF) were not different: 41% vs 41% (P = .93) and 51% vs 63% (P = .09), respectively. On multivariate analysis, ECF patients had an increased risk for death (hazard ratio, 1.61; 95% confidence interval, 1.05-2.46; P = .03) but not for PFS or relapse. In conclusion, for relapsed chemosensitive DLBCL patients with residual PET/CT+ disease prior to auto-HCT, the adjusted 5-year PFS (41%) was comparable, irrespective of time to relapse. These data support ongoing application of auto-HCT in chemosensitive DLBCL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Feminino , Humanos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
Assuntos
Acetamidas/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento , Adulto Jovem , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.