Engineering potent chimeric antigen receptor T cells by programming signaling during T-cell activation.

Programming cell signaling during T-cell activation represents a simple strategy for improving the potency of therapeutic T-cell products. Stim-R technology (Lyell Immunopharma) is a customizable, degradable synthetic cell biomimetic that emulates physiologic, cell-like presentation of signal molecules to control T-cell activation. A breadth of Stim-R formulations with different anti-CD3/anti-CD28 (αCD3/αCD28) antibody densities and stoichiometries were screened for their effects on multiple metrics of T-cell function.

Trends in the corpus of literature on endoscopic third ventriculostomy: a bibliometric analysis spanning 3 decades.

Objective: The objective of this study was to report the results of a bibliometric analysis on the modern corpus of literature pertaining to endoscopic third ventriculostomy (ETV). Prior bibliometrics studies on ETV have focused on highly cited articles, but an advanced bibliometric analysis has not yet been conducted.

Methods: The authors queried the Web of Science (WoS) for (ALL = (endoscopic third ventriculostomy)) OR (ALL = (ETV) AND ALL = (neurosurgery)).

Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer.

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC.

Association between structural rib autograft and the rate of arthrodesis in children undergoing occiput-C2 instrumentation and fusion.

Objective: The purpose of this study was to identify factors associated with fusion success among pediatric patients undergoing occiput-C2 rigid instrumentation and fusion.

Methods: The Pediatric Spine Study Group registry was queried to identify patients ≤ 21 years of age who underwent occiput-C2 posterior spinal rigid instrumentation and fusion and had a 2-year minimum clinical and radiographic (postoperative lateral cervical radiograph or CT scan) follow-up. Fusion failure was defined clinically if a patient underwent hardware revision surgery > 30 days after the index procedure or radiographically by the presence of hardware failure or screw haloing on the most recent follow-up imaging study.

Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer.

Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity.

Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer.

Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial.

Single-dose Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

Background: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [Lu]-prostate-specific membrane antigen (PSMA)-617 (Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit.

Methods: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA).

A Century of Evolution in Spine Surgery Publications: A Bibliometric Analysis of the Field From 1900 to 2023.

Background And Objectives: Spine surgery has advanced in concert with our deeper understanding of its elements. Narrowly focused bibliometric analyses have been conducted previously, but never on the entire corpus of the field. Using big data and bibliometrics, we appraised the entire corpus of spine surgery publications to study the evolution of the specialty as a scholarly field since 1900.

Developing an Automated Registry (Autoregistry) of Spine Surgery Using Natural Language Processing and Health System Scale Databases.

Background And Objectives: Clinical registries are critical for modern surgery and underpin outcomes research, device monitoring, and trial development. However, existing approaches to registry construction are labor-intensive, costly, and prone to manual error. Natural language processing techniques combined with electronic health record (EHR) data sets can theoretically automate the construction and maintenance of registries.

Dynamic CD8 T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.

CD8 T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8 T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging.

Racial and ethnic disparities in a real-world precision oncology data registry.

Biorepositories enable precision oncology research by sharing clinically annotated genomic data, but it remains unknown whether these data registries reflect the true distribution of cancers in racial and ethnic minorities. Our analysis of Project Genomics Evidence Neoplasia Information Exchange (GENIE), a real-world cancer data registry designed to accelerate precision oncology discovery, indicates that minorities do not have sufficient representation, which may impact the validity of studies directly comparing mutational profiles between racial/ethnic groups and limit generalizability of biomarker discoveries to all populations.

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.

Background: In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.

Methods: Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.

Methods and Impact for Using Federated Learning to Collaborate on Clinical Research.

Background: The development of accurate machine learning algorithms requires sufficient quantities of diverse data. This poses a challenge in health care because of the sensitive and siloed nature of biomedical information. Decentralized algorithms through federated learning (FL) avoid data aggregation by instead distributing algorithms to the data before centrally updating one global model.

A patient-driven clinicogenomic partnership for metastatic prostate cancer.

Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research.

Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis.

Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n = 9) and matched healthy donors (n = 8). Following anti-PD-1 treatment, CD14 monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14) increase in the circulation of patients with BTC tumors that are CPI resistant.

CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies.

Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART.

Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer.

Background: Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.

Methods: A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.