Introduction
Despite recent advances in treatment for a number of cancers with immune checkpoint blockade (ICB), immunotherapy has had limited efficacy in glioblastoma (GBM). The recent ...multi-centered CheckMate 143 trial in first time recurrent GBM and the Checkmate 498 trial in newly diagnosed unmethylated GBM showed that antibodies against programmed cell death protein 1 (PD-1) failed to improve overall survival in patients with GBM. Recent preclinical and clinical studies have explored combining ICB with several other therapies including additional ICB against alternative checkpoint molecules, activation of costimulatory checkpoint molecules such as 4-1BB, radiation-induced tumor cell lysis and immunogenic recruitment, local chemotherapy, neoadjuvant ICB therapy, and myeloid cell reactivation.
Methods
We have reviewed the literature on ICB seminal to the progression of several preclinical studies and clinical trials in order to provide a compendium of the current state of combination immunotherapy for GBM. For ongoing clinical trials without associated publications, we searched
clinicaltrials.gov
for ongoing studies using the keywords, “GBM” and “glioblastoma”, as well as names of checkpoint molecules.
Results
Recent trends from clinical trials demonstrate that despite a variety of different combination strategies involving ICB, GBM remains largely elusive to current immunotherapies. There is a discordance of survival outcomes between GBM pre-clinical models and clinical trials, likely due to the heterogeneity of GBM in patients as well as other adaptive immune mechanisms not otherwise represented in murine models. However, in clinical studies, neoadjuvant ICB in GBM was found to diversify the T cell receptor (TCR) repertoire and increase chemokine mRNA transcripts when comparing pre- and post- surgical time points. Moreover, an increase in peripheral and tumor-infiltrating lymphocyte (TIL) clonotypes were also observed when comparing adjuvant and neoadjuvant cohorts.
Discussion
Despite the lack of clinical survival benefit, immune modulation was observed in multiple different combination strategies for GBM in both preclinical and clinical studies, indicating that ICB combination therapy results in a significant immunological impact on the tumor microenvironment.
Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in ...response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the "cold tumor" phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor.
Managing peri-mitral flutter Lim, Michael W; Kistler, Peter M
Journal of cardiovascular electrophysiology,
10/2023, Letnik:
34, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The exponential rise in the incidence of peri-mitral flutter has paralleled the increasing use of more extensive atrial substrate ablation for atrial fibrillation (AF). Given the relative paucity of ...randomized evidence to support its role in AF management, mitral isthmus ablation should largely be reserved for patients with peri-mitral flutter. Catheter ablation for peri-mitral flutter is challenging due to complex anatomic relationships. The aim of this report is to review the anatomic considerations and approaches to catheter ablation for peri-mitral flutter.
We present a game-theoretic model to analyze the role of two major biofuel policies in the U.S., namely mandates and subsidies, and their implications to biofuel industry development. By ...characterizing the farmers' land use decision (land allocation among food, energy, and reservation) and biofuel firm's mandate compliance strategy (whether to comply with the mandate or not), we identify the complementarity roles of mandate and subsidy. We further illustrate the impact of coordination in the two policy instruments; lack of coordination may result in excessive biofuel mandate in the early stage of industry development, while it may lead to insufficient mandate during the matured stage. With a case study based on the U.S. Midwest, we address recent trends in the U.S. biofuel industry and further discuss related policy insights.
•Biofuel policy impacts on land use competition and triple bottom line performances.•Complementarity roles of mandate and subsidy in biofuel industry development.•Lack of coordination and industry overestimation lead to low mandate and subsidy.•Discussion and insights on recent mandate adjustment in the U.S. biofuel industry
Ecological management problems often involve navigating from an initial to a desired community state. We ask whether navigation without brute‐force additions and deletions of species is possible via: ...adding/deleting a small number of individuals of a species, changing the environment, and waiting. Navigation can yield direct paths (single sequence of actions) or shortcut paths (multiple sequences of actions with lower cost than a direct path). We ask (1) when is non‐brute‐force navigation possible?; (2) do shortcuts exist and what are their properties?; and (3) what heuristics predict shortcut existence? Using a state diagram framework applied to several empirical datasets, we show that (1) non‐brute‐force navigation is only possible between some state pairs, (2) shortcuts exist between many state pairs; and (3) changes in abundance and richness are the strongest predictors of shortcut existence, independent of dataset and algorithm choices. State diagrams thus unveil hidden strategies for manipulating species coexistence and efficiently navigating between states.
It is often unclear what actions could be taken to efficiently shift between community states. We introduce an approach that uses low‐effort actions to hop between states, similar to the game Snakes and Ladders. The approach works well in many empirical cases and may offer new ways to work with, rather than against, nature in ecological management and control problems.
To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain ...metastases (BMs).
We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs.
A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio HR, 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64).
Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.
Background: Osteochondritis dissecans (OCD) of the capitellum is a rare yet debilitating injury seen in young athletes. This is the first report in the literature describing fresh osteochondral ...allograft transplantation (FOCAT) to treat OCD of the capitellum. Methods Nine male baseball players (mean age, 15.3; range, 14-18 years), with OCD of the capitellum were treated with FOCAT. There were 6 pitchers and 3 position players. A ligament-sparing, mini-open approach was used. A fresh femoral hemicondyle was used as a donor source. Of the 9 patients, 7 required 1 plug and 2 required 2 plugs. The average plug diameter was 11 mm (range, 8-18 mm). Five plugs were press fit, and 4 required additional fixation. Clinical outcomes were evaluated at a mean follow-up of 48.4 months (range, 11-90 months). Preoperative and postoperative outcome scores were calculated using the paired t test. Results The Mayo Elbow Performance score improved from an average 57.8 to 98.9 ( P < .01). The Oxford Elbow Score improved from 22.4 to 44.8 ( P < .01). The Disabilities of the Arm, Shoulder and Hand score improved from 35.2 to 5.4 ( P < .01). The visual analog scale score improved from 7.8 to 0.5 ( P < .01). The Kerlan-Jobe Orthopaedic Clinic Shoulder and Elbow score improved from 32.6 to 82.5 ( P < .01). All patients returned to throwing and were still active in their sport or played at least 2 years of baseball before leaving the sport unrelated to the elbow. Conclusions FOCAT for OCD of the capitellum in properly selected cases is a viable treatment with significant functional improvement and pain reduction in throwers.
