Homozygosity for a Rare FASTKD2 Variant Resulting in an Adult Onset Autosomal Recessive Mitochondrial Podocytopathy.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with sub-nephrotic proteinuria, who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 mutations. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy, which are, instead, pathogenically related to adenosine triphosphate deficiency.

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Diversity of gastrointestinal parasites and molecular characterization of Giardia duodenalis in free-living and captive howler monkeys (Alouatta guariba clamitans) in southern Brazil.

Non-human primates (NHPs) are the group that most share infectious agents with humans due to their close taxonomic relationship. The southern brown howler monkeys (Alouatta guariba clamitans) are endemic primates from Brazil and Argentina's Atlantic Forest. This study aimed to investigate the presence of intestinal parasites in free-living (FL) and captive (CA) southern brown howler monkeys. Thirty-nine stool samples were collected in two areas in southern Brazil, 15 FL and 24 CA. Stool sediments obtained by centrifugal sedimentation technique were used for microscopic analysis and direct immunofluorescence assay and evaluated by molecular analysis through amplification and sequencing of TPI fragments. Intestinal parasites Giardia duodenalis, Cryptosporidium spp., and Trypanoxyuris minutus were detected at coproparasitological analysis. This is the first report of the presence of Cryptosporidium spp. in free-living howlers. The molecular characterization of G. duodenalis isolates indicated assemblage B for the first time found in free-living A. guariba clamitans. The high prevalence of G. duodenalis transmission in CA howler monkeys can be explained by direct contact with humans and frequent soil contact. The presence of a potentially zoonotic assemblage in these animals indicates that the process of fragmentation and cohabitation with humans and livestock affects the wildlife, thus indicating a need for eco-health measures.

5-Year Real-World Outcomes With Frontline Pembrolizumab Monotherapy in PD-L1 Expression ≥ 50% Advanced NSCLC.

BACKGROUND: In clinical trials, frontline pembrolizumab for advanced NSCLC has demonstrated durable, clinically meaningful, long-term survival benefits over chemotherapy. Our objective was to evaluate 5-year survival rates outside the idealized setting of clinical trials for advanced/metastatic NSCLC treated with frontline pembrolizumab monotherapy. METHODS: Using a nationwide, electronic health record-derived, deidentified database in the United States, we studied adult patients with advanced/metastatic NSCLC (unresectable stage IIIB/IIIC, or stage IV), with PD-L1 expression ≥ 50%, no documented EGFR, ALK, or ROS1 genomic alteration, and ECOG performance status of 0-1 initiating frontline pembrolizumab monotherapy from November 1, 2016, through March 31, 2020, excluding those in clinical trials. Kaplan-Meier was used to determine overall survival (OS). Data cutoff was May 31, 2023. RESULTS: A total of 804 patients were eligible for the study, including 404 women (50%); median age was 72 years (range, 38-85 years), with 310 patients (39%) ≥ 75 years old. Median follow-up time from pembrolizumab initiation to data cutoff was 60.5 months (range, 38.0-78.7). At data cutoff, 549 patients (68%) had died. Median OS was 19.2 months (95% CI, 16.6-21.4), and survival rate at 5 years was 25.1% (95% CI, 21.7-28.7). Overall, 266 patients (33%) received 1 or more subsequent regimens, most commonly an anti-PD-(L)1 agent (as monotherapy or combination therapy) or platinum-based chemotherapy. CONCLUSIONS: With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness, with survival outcomes consistent with those of pivotal clinical trials, for treating patients with advanced NSCLC with PD-L1 expression of ≥ 50% and no EGFR, ALK, or ROS1 genomic alteration.

TIME UNTIL THE START OF ANTIBIOTIC PROPHYLAXIS AND THE RISK OF OPEN FRACTURE INFECTION: A SYSTEMATIC REVIEW.

Open fractures are highly incident injuries closely related to the modern life, in which accidents caused by motor vehicles or other machines impart high energy to bone tissue. Individual morbidity is represented by the functional impairment resultant of infection, nonunion, or vicious healing. In terms of public health, there are huge costs involved with the treatment of these fractures, particularly with their complications. One of the critical issues in managing open fractures is the use of antibiotics (ATB), including decisions about which specific agents to administer, duration of use, and ideal timing of the first prophylactic dose. Although recent guidelines have recommended starting antibiotic prophylaxis as soon as possible, such a recommendation appears to stem from insufficient evidence. In light of this, we conducted a systematic review, including studies that addressed the impact of the time to first antibiotic and the risk of infectious outcomes. Fourteen studies were selected, of which only four found that the early initiation of treatment with antibiotics is able to prevent infection. All studies had important risks of bias. The results indicate that this question remains open, and further prospective and methodologically sound studies are necessary in order to guide practices and health policies related to this matter. Level of Evidence II; Therapeutic Studies Investigating the Results Level of Treatment.

As fraturas expostas são lesões altamente incidentes, intimamente relacionadas à vida moderna, na qual os acidentes causados por veículos automotores ou outros aparatos transmitem alta energia ao tecido ósseo. A morbidade individual é representada pelo comprometimento funcional resultante de infecção, não-união ou cicatrização viciosa. Há enormes custos envolvidos no tratamento dessas fraturas em termos de saúde pública, principalmente quanto as complicações. Uma das questões críticas no tratamento de fraturas expostas é o uso de antibióticos, incluindo as decisões sobre quais agentes específicos devem ser administrados, a duração e o momento ideal para a primeira dose profilática. Embora as diretrizes recentes tenham recomendado o início da profilaxia antibiótica o mais rápido possível, essa recomendação parece se basear em evidências insuficientes. Em vista disso, realizamos uma revisão sistemática, incluindo estudos que abordaram o impacto do tempo até o primeiro antibiótico e o risco de resultados infecciosos. Foram selecionados 14 estudos, dos quais apenas quatro concluíram que o início precoce do tratamento com antibióticos é capaz de prevenir infecções. Todos os estudos tinham riscos importantes de viés. Os resultados indicam que essa questão permanece em aberto, sendo necessários mais estudos prospectivos e metodologicamente sólidos para orientar as práticas e políticas de saúde relacionadas a esse assunto. Nível de Evidência II; Estudos Terapêuticos que Investigam o Nível de Resultados do Tratamento.

Low and High-Normal FMR1 Triplet Cytosine, Guanine Guanine Repeats Affect Ovarian Reserve and Fertility in Women Who Underwent In Vitro Fertilization Treatment? Results from a Cross-Sectional Study.

Dynamic mutations in the 5' untranslated region of FMR1 are associated with infertility. Premutation alleles interfere with prenatal development and increase infertility risks. The number of CGG repeats that causes the highest decrease in ovarian reserves remains unclear. We evaluated the effect of FMR1 CGG repeat lengths on ovarian reserves and in vitro fertilization (IVF) treatment outcomes in 272 women with alleles within the normal range. FMR1 CGG repeat length was investigated via PCR and capillary electrophoresis. Alleles were classified as low-normal, normal, and high-normal. Serum levels of follicle-stimulating hormone and anti-Mullerian hormone (AMH) in the follicular phase of the menstrual cycle were measured, and antral follicles (AFC) were counted. IVF outcomes were collected from medical records. Regarding FMR1 CGG repeat length alleles, 63.2% of women presented at least one low-normal allele. Those carrying low-normal alleles had significantly lower AMH levels than women carrying normal or high-normal alleles. Low-normal/low-normal genotype was the most frequent, followed by low-normal/normal and normal/normal. A comparison of ovarian reserve markers and reproductive outcomes of the three most frequent genotypes revealed that AFC in the low-normal/normal genotype was significantly lower than the low-normal/low-normal genotype. The low number of FMR1 CGG repeats affected AMH levels and AFC but not IVF outcomes per cycle of treatment.

Açaí (Euterpe oleracea Mart.) Seed Oil and Its Nanoemulsion: Chemical Characterisation, Toxicity Evaluation, Antioxidant and Anticancer Activities.

This study explores a nanoemulsion formulated with açaí seed oil, known for its rich fatty acid composition and diverse biological activities. This study aimed to characterise a nanoemulsion formulated with açaí seed oil and explore its cytotoxic effects on HeLa and SiHa cervical cancer cell lines, alongside assessing its antioxidant and toxicity properties both in vitro and in vivo. Extracted from fruits sourced in Brazil, the oil underwent thorough chemical characterization using gas chromatography-mass spectrometry. The resulting nanoemulsion was prepared and evaluated for stability, particle size, and antioxidant properties. The nanoemulsion exhibited translucency, fluidity, and stability post centrifugation and temperature tests, with a droplet size of 238.37, PDI -9.59, pH 7, and turbidity 0.267. In vitro assessments on cervical cancer cell lines revealed antitumour effects, including inhibition of cell proliferation, migration, and colony formation. Toxicity tests conducted in cell cultures and female Swiss mice demonstrated no adverse effects of both açaí seed oil and nanoemulsion. Overall, açaí seed oil, particularly when formulated into a nanoemulsion, presents potential for cancer treatment due to its bioactive properties and safety profile.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.

Repeated human leukocyte antigens eplets, importance of typing the partner.

INTRODUCTION: Antibody-mediated rejection (AMR) is the most common cause of immune-mediated allograft failure after kidney transplant and impacts allograft survival. Previous sensitization is a major risk factor for development of donor specific antibodies (DSA). AMR can have a wide range of clinical features such as impaired kidney function, proteinuria/hypertension or can be subclinical. HLA molecules have specific regions of antigens binding antibodies called epitopes and eplets are considered essential components responsible for immune recognition. We present a patient with subclinical AMR 1 week post transplantation. CASE REPORT: A 48-year-old, caucasian woman with end-stage kidney disease (ESKD) secondary to autosomal dominant polycystic kidney disease (ADPKD) on peritoneal dialysis was registered in deceased donor waitlist. She was a hypersensitized patient from 3 prior pregnancies with a calculated panel reactive antibody of 93,48%. She was transplanted through kidney paired exchange donation with no evidence of DSA pre transplantation. Surgery and post-op were unremarkable with excellent and immediate graft function. Per protocol DSA levels on the 5th day was DR1 of 3300 MFI, with an increase in MFI by day 13 with 7820 MFI and a new B41 1979MFI. Allograft kidney biopsy findings were diagnostic of AMR and she was treated with immunoglobulin and plasmapheresis. As early onset AMR post transplantation was observed an anamnestic response was hypothesized from a previous exposure to allo-HLA. We decided to type her husband, her son's father, which was presented with DSA. Mismatch eplet analysis revealed a shared 41 T and 67LQ eplets between the donor and husband, responsible for the reactivity and new HLA class I B41 and HLA class II DR1 DSA, respectively. DISCUSSION: Shared eplets between the patient husband and donor was responsible for the alloimmune response and early development of DSAs. This case highlights the importance of early monitoring DSA levels in highly sensitized patients after transplant in order to promptly address and lower inflammatory damage. Mismatch eplet analysis can provide a thorough and precise evaluation of immune compatibility providing a useful technique to immune risk stratification, donor selection and post-transplant immunosuppressive therapy and monitoring.

Compressed fluid-based technology for downstream isolation of bluish anthocyanin-derived pigments obtained from blueberry surplus.

A dynamic compressed fluid-based separation process combining carbon dioxide and ethanol was explored to isolate portisins previously hemi-synthesized from blueberry surplus anthocyanins. The influence of process parameters such as pressure (100-500 bar), temperature (40-60 °C), and ethanol content in the compressed fluid mixture (20-50 wt%) on extraction yield, portisins yield, and portisins content in the extract was investigated. The two-step isolation process includes (1) a first step at 100 bar, 60 °C, and 20 wt% ethanol content in the compressed fluid mixture to remove the low polarity compounds; and (2) a second step at 500 bar, 40 °C, and 100 wt% ethanol to recover portisins, resulting in a 1.5-fold increase in portisins content. The performance of the two-step separation process was compared to centrifugal partitional chromatography and conventional reverse phase liquid chromatography already reported in terms of portisins content in the extract, process throughput, process efficiency, and total solvent used. The two-step separation process decreased the total solvent used, although with a decrease in the throughput and efficiency. Nevertheless, the choice of the best separation technology depends on the application, as these techniques result in different portisins purities. Overall, this study contributed to a scalable and more sustainable process for natural colorant production, specifically focusing on blue pigments, with several industrial applications.

Trend in the Prevalence of Overweight and Obese Adults in São Paulo, Brazil: Analysis between the Years 2006 and 2019.

The aim of this study was to investigate the trend in the prevalence of overweight and obese adults in São Paulo, Brazil, between 2006 and 2019 across chronic diseases and the domains of physical activity. A descriptive retrospective study was carried out on the trend in the prevalence of 26.612 overweight and obese adults (10.150 men and 16.462 women). All data analyzed were based on information from the national system for monitoring risk factors called Protective and Risk Factors for Chronic Diseases by Telephone Survey-VIGITEL. The variables obese and overweight were analyzed in general and stratified by sex, age group, education level, each type of physical activity domain (yes or no), presence of hypertension and diabetes (yes or no), and smoking (yes or no). The prevalence of obesity significantly increased from 11.1% in 2006 to 19.8% in 2019, regardless of age, sex, physical activity practice, and presence of diabetes or hypertension, except for people aged 55-64 y, working people, and smokers. The total prevalence of overweight adults significantly increased overall (from 30.5% in 2006 to 33.4% in 2019) but it significantly increased only in females, in people aged 18-24 y, those who are non-white, those with an education level of 9-11 y, those who are not working, those who are non-smokers, those who did not have diabetes or hypertension, and those who were not physically active during leisure time but physically active at work and at home. There was a significant increase in the prevalence of overweight adults and especially of obese adults living in the city of São Paulo (Brazil) between 2006 and 2019, the latter being observed in nearly every analyzed sub-category, regardless of age, sex, physical activity practice, and presence of diabetes or hypertension.

Psychological factors show limited association with the severity of Achilles tendinopathy.

BACKGROUND: This study aimed to investigate the association between psychosocial factors and the severity of Achilles tendinopathy, along with exploring their potential link to the pain's duration. METHODS: A cross-sectional study involving 111 individuals with Achilles tendon pain was conducted. METHODS: A cross-sectional study involving 111 individuals with Achilles tendon pain was conducted. Various psychological factors were assessed using the Pain Catastrophizing Scale, Chronic Pain Self-Efficacy Scale (CPSS), Tampa Scale for Kinesiophobia, and Hospital Anxiety and Depression Scale (HAD). Additionally, the severity of Achilles tendon pain was evaluated using the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A-Br). Regression analyses were employed to determine the association of these psychosocial factors with pain severity and duration. RESULTS: Self-efficacy for chronic pain showed a slight association with Achilles tendon pain severity (ß = 0.42 [95% CI: 0.06 to 0.16], p = 0.001), explaining only 19% of the dependent variable. The other variables, including anxiety, depression, pain catastrophizing, and fear of movement, did not exhibit significant associations. CONCLUSION: The study suggests that psychological factors demonstrate limited association with the severity of Achilles tendinopathy. While self-efficacy for chronic pain was weakly associated, its clinical relevance remains uncertain. Future research, particularly longitudinal studies, should explore the influence of psychosocial factors on treatment adherence and response to enhance management strategies for Achilles tendon pain.

Resilience: conceptualisations and challenges for effective heatwave public health planning.

OBJECTIVES: This article examines diverse perspectives on heatwave resilience in public health planning, interviewing stakeholders from various sectors. It identifies challenges, including operational, political, economic, and cultural aspects, hindering effective strategies. The study advocates for a holistic approach to heatwave resilience, emphasising interdisciplinary research and collaboration for targeted interventions. Enhancing resilience is crucial to mitigating adverse health impacts and safeguarding vulnerable populations during heatwaves. Conceptualisations of resilience related to heatwave public health planning and heatwave resilience vary significantly. There is a need to unveil the multifaceted nature of resilience in the context of heatwaves and identify key challenges that hinder effective public health planning efforts. STUDY DESIGN: Qualitative study to explore key stakeholders' conceptualisations of resilience and highlight challenges and opportunities needed for greater heatwave resilience and public health planning. METHODS: Interviews were conducted with a diverse group of key stakeholders involved in local, regional, and national heatwave planning, academics, civil sector and private sector representatives. RESULTS: The findings of this study highlight diverse conceptualisations of resilience. Conceptualisations of resilience mainly differ on the following: 'whom'; 'what'; 'how'; 'when'; and 'why'. This analysis shows that the concept of resilience is well understood but has different functions. The analysis of challenges revealed several key problems, such as operational and technical; political and governance; organisational and institutional; economic; linguistic; cultural, social, and behavioural; and communication, information, and awareness. These significantly hinder effective heatwave public health planning strategies. CONCLUSIONS: The study emphasises the need for a holistic and integrated approach to heatwave resilience. Addressing these challenges is crucial for enhancing heatwave public health planning. This study provides valuable insights into the complexities of heatwave resilience, offering guidance for different sectors of society to develop targeted interventions and strategies. The development of new resilience interdisciplinary and intersectoral research, practice, and governance will prove crucial to ongoing efforts to strengthen national heatwave resilience public health planning. By fostering resilience, societies can mitigate the adverse impacts of heatwaves and safeguard the health and well-being of vulnerable populations.

Racial iniquity in mortality from cervical cancer in Brazil: a time trend study from 2002 to 2021. / Iniquidade racial na mortalidade por câncer de colo de útero no Brasil: estudo de séries temporais de 2002 a 2021.

This ecological study examined time series, from 2002 to 20121, of age-adjusted coefficients of cervical cancer mortality, in Brazil, in women aged 20 years or more, by race. The information sources were Brazil's mortality information system (Sistema de Informação sobre Mortalidade - SIM) and the official bureau of statistics (Instituto Brasileiro de Geografia e Estatística - IBGE). Annual changes in age-adjusted mortality rates were calculated using the Prais-Winsten linear regression method. Black women die more and the rate is decreasing less. Racial inequality has increased over the years. In 2002, there were 0.08 more deaths per 100,000 women in the black population than among white women; in 2021, the number was one death. Health policymaking should consider racial differences in the implementation of strategies and goals.

O objetivo desse artigo é analisar séries temporais da mortalidade por câncer de colo do útero segundo raça/cor no Brasil de 2002 a 2021. Estudo ecológico de séries temporais com dados do Sistema de Informação sobre Mortalidade e informações populacionais do IBGE. Variações anuais das taxas de mortalidade ajustadas por idade de mulheres de 20 anos ou mais foram estimadas pelo modelo de regressão linear simples com correção de Prais-Winsten. Foram registrados 133.429 óbitos por câncer de colo de útero, destes, 51,2% foram de mulheres negras. As mulheres negras morrem mais e têm menor queda do coeficiente. Houve aumento da desigualdade racial ao longo dos anos. Em 2002, ocorriam 0,08 óbitos/100 mil mulheres a mais na população negra comparada com a população branca; em 2021 esse número é de aproximadamente 1 óbito. Para a elaboração de políticas de saúde da mulher devem ser consideradas as diferenças raciais na implementação de estratégias e metas.

Primary Health Care nurses' role in treating Lower Urinary Tract Dysfunction.

OBJECTIVE: To understand Primary Health Care nurses' role in treating Lower Urinary Tract Dysfunction. METHOD: Cross-sectional multi-methodological research, composed of quantitative and qualitative steps, independently and sequentially. Data collected remotely, through a questionnaire and focus group, analyzed using descriptive statistics and thematic analysis by Braun and Clarke, respectively. The project was approved under Opinion 22691119.0.0000.0030. RESULTS: A total of 145 nurses participated in the study in the quantitative step and 20 in the qualitative step, working in Primary Health Care in Brazil. Of the 93.1% nurses who reported having already cared for people with Urinary Tract Dysfunction, only 54.4% provided guidance, mainly for training the pelvic floor muscles. CONCLUSION: Even though they have legal support and access to demand, nurses do not have the knowledge to offer conservative treatment for Lower Urinary Tract Dysfunction. Despite this, they were motivated to do so as long as they received specific training.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor.

INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.