Ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.
The disappearance of large vertebrates in the tropical belt may be the next biological insult of the global extinction crisis. Large predators and their prey are at particular risk in Asia, where they are threatened by poaching and habitat loss. To facilitate the best use of limited conservation resources, we created an objective, ecology-based method for identifying priority areas for conservation that incorporates both habitat representation and landscape-level features. Using tigers as an example, our method captures the range of ecological habitats where they occur, accounting for ecological, demographic, genetic, and behavioral differences. Our analysis is hierarchical. We divided the tiger range into distinct bioregions and identified tiger habitat types within each. We then delineated tiger conservation units throughout the bioregions and ranked the units based on habitat integrity, poaching pressure, and tiger population trends. To maintain representation of tiger populations and their ecology in the different tiger habitats, we made comparisons only among tiger conservation units from the same tiger habitat types nested within the same bioregion. We identified 159 tiger conservation units in three bioregions-the Indian subcontinent, Indochina, and Southeast Asia. We ranked the units in three categories that reflect the probability of long-term persistence of tiger populations ( highest in level I units). Twenty-five tiger conservation units were classified as level I, 21 as level II, and 97 as level III. An additional 16 tiger conservation units for which little information is available were identified for immediate surveys. Levels I , II, and those identified for immediate surveys are the priority areas for immediate funding and for a regional tiger conservation strategy. One feature emerging from the study showed that protected areas cover only small areas of tiger conservation units. If the long-term prospects for tiger conservation are to improve, poaching must be stopped and protected areas increased in number, linked, and buffered by natural habitats. To enhance landscape integrity, the priority tiger conservation units that straddle international borders should be managed as transboundary reserves, giving tiger conservation a stronger regional structure. Like tigers, populations of other wide-ranging mammalian carnivores and large herbivores also are declining due to poaching and loss of habitat. The method we present for tigers can be adapted readily to improve conservation strategies for these species as well. Método con Bases Ecológicas para Definir Prioridades para la Conservación de Mamíferos Mayores: El Tigre como Caso de EstudioResumen: La desaparición de vertebrados grandes en el cinturón tropical podría ser el siguiente insulto biológico de la crisis de exteinción global. Los depredadores grandes y sus presas se encuentran en un riesgo particular en Asia donde la caza furtiva y la pérdida de hábitats los amenaza. Para facilitar el mejor uso de § Address correspondence to E. Dinerstein, lo...
Environmental carcinogenic exposures are major contributors to global disease burden yet how they promote cancer is unclear. Over 70 years ago, the concept of tumour promoting agents driving latent clones to expand was rst proposed. In support of this model, recent evidence suggests that human tissue contains a patchwork of mutant clones, some of which harbour oncogenic mutations, and many environmental carcinogens lack a clear mutational signature. We hypothesised that the environmental carcinogen, <2.5μm particulate matter (PM2.5), might promote lung cancer promotion through nonmutagenic mechanisms by acting on pre-existing mutant clones within normal tissues in patients with lung cancer who have never smoked, a disease with a high frequency of EGFR activating mutations. We analysed PM2.5 levels and cancer incidence reported by UK Biobank, Public Health England, Taiwan Chang Gung Memorial Hospital (CGMH) and Korean Samsung Medical Centre (SMC) from a total of 463,679 individuals between 2006-2018. We report associations between PM2.5 levels and the incidence of several cancers, including EGFR mutant lung cancer. We nd that pollution on a background of EGFR mutant lung epithelium promotes a progenitor-like cell state and demonstrate that PM accelerates lung cancer progression in EGFR and Kras mutant mouse lung cancer models. Through parallel exposure studies in mouse and human participants, we nd evidence that in ammatory mediators, such as interleukin-1 , may act upon EGFR mutant clones to drive expansion of progenitor cells. Ultradeep mutational pro ling of histologically normal lung tissue from 247 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 33% of normal tissue samples, respectively. These results support a tumour-promoting role for PM acting on latent mutant clones in normal lung tissue and add to evidence providing an urgent mandate to address air pollution in urban areas.
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.