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Identification and validation of a T cell receptor targeting KRAS G12V in HLA-A*11:01 pancreatic cancer patients.
No full textT cells targeting a KRAS mutation can induce durable tumor regression in some patients with metastatic epithelial cancer. It is unknown whether T cells targeting mutant KRAS that are capable of killing tumor cells can be identified from peripheral blood of patients with pancreatic cancer. We developed an in vitro stimulation approach and identified HLA-A*11:01-restricted KRAS G12V-reactive CD8+ T cells and HLA-DRB1*15:01-restricted KRAS G12V-reactive CD4+ T cells from peripheral blood of 2 out of 6 HLA-A*11:01-positive patients with pancreatic cancer whose tumors expressed KRAS G12V. The HLA-A*11:01-restricted KRAS G12V-reactive T cell receptor (TCR) was isolated and validated to specifically recognize the KRAS G12V8-16 neoepitope. While T cells engineered to express this TCR specifically recognized all 5 tested human HLA-A*11:01+ and KRAS G12V+ pancreatic cancer organoids, the recognition was often modest, and tumor cell killing was observed in only 2 out of 5 organoids. IFN-γ priming of the organoids enhanced the recognition and killing by the TCR-engineered T cells. The TCR-engineered T cells could significantly slow the growth of an established organoid-derived xenograft in immunodeficient mice. Our data suggest that this TCR has potential for use in TCR-gene therapy, but additional strategies that enhance tumor recognition by the TCR-engineered T cells likely will be required to increase clinical activity
Classification of non-TCGA cancer samples to TCGA molecular subtypes using compact feature sets.
No full textMolecular subtypes, such as defined by The Cancer Genome Atlas (TCGA), delineate a cancer\u27s underlying biology, bringing hope to inform a patient\u27s prognosis and treatment plan. However, most approaches used in the discovery of subtypes are not suitable for assigning subtype labels to new cancer specimens from other studies or clinical trials. Here, we address this barrier by applying five different machine learning approaches to multi-omic data from 8,791 TCGA tumor samples comprising 106 subtypes from 26 different cancer cohorts to build models based upon small numbers of features that can classify new samples into previously defined TCGA molecular subtypes-a step toward molecular subtype application in the clinic. We validate select classifiers using external datasets. Predictive performance and classifier-selected features yield insight into the different machine-learning approaches and genomic data platforms. For each cancer and data type we provide containerized versions of the top-performing models as a public resource
Amivantamab Plus Lazertinib in Patients With EGFR-Mutant NSCLC After Progression on Osimertinib and Platinum-Based Chemotherapy: Results From CHRYSALIS-2 Cohort A.
No full textINTRODUCTION: Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited.
METHODS: CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib.
RESULTS: In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22-36). The blinded independent central review-assessed ORR was 35% (95% CI: 27-42), with a median duration of response of 8.3 months (95% CI: 6.7-10.9) and a clinical benefit rate of 58% (95% CI: 50-66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1-5.8); median overall survival was 14.8 months (95% CI: 12.2-18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).
CONCLUSIONS: For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable
Age-Related Ventricular Tachycardia Substrate Characteristics for Repaired Tetralogy of Fallot Before Transcatheter Pulmonary Valve Placement.
No full textBACKGROUND: Ventricular tachycardia (VT) substrate characteristics before transcatheter pulmonary valve replacement (TPVR) in repaired tetralogy of Fallot (rTOF) are unknown.
OBJECTIVES: In this study, the authors sought to evaluate substrates for sustained monomorphic VT before TPVR in rTOF.
METHODS: Retrospective (2017 to 2021) and prospective (commencing 2021) rTOF patients with native right ventricular outflow tract referred for electrophysiology study (EPS) before TPVR were included. Electrophysiologic findings and outcomes of VT ablation were determined.
RESULTS: One-hundred eighty patients (mean age 39 ± 14 years, 54% male, 71 retrospective, 109 prospective) were identified. At EPS, monomorphic VT was induced in 45 (25%), and a slowly conducting anatomic isthmus alone was observed in 40 (22%). VT isthmus conduction velocity decreased (-0.08 m/s per decade; P = 0.008) and VT inducibility (P \u3c 0.001 for trend) and cycle length (CL) (+15 ms per decade, P = 0.005) increased with age. Multivariable factors associated with shorter VT CL included preserved isthmus conduction velocity (-50 ms per m/s; P = 0.02), absence of atrial flutter (-18 ms; P = 0.007), and improved RV ejection fraction (-16 ms per 10% increase; P = 0.007). Catheter ablation was acutely successful in 80/83 (96%). At repeated EPS after a median of 5 months, previously ablated substrates were evident in 3/24 (13%) and new VT substrates in 3/33 (9%).
CONCLUSIONS: Pre-TPVR VT substrates in rTOF demonstrate age-related degeneration that was associated with VT inducibility and VT CL. Both recovery of VT isthmus conduction and new VT substrates were observed after TPVR despite successful catheter ablation
Induced pluripotent stem-cell-derived CD19-directed chimeric antigen receptor natural killer cells in B-cell lymphoma: a phase 1, first-in-human trial.
No full textBACKGROUND: FT596 is an induced pluripotent stem-cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cell therapy with three antitumour modalities: a CD19 CAR; a high-affinity, non-cleavable CD16 Fc receptor; and interleukin-15-interleukin-15 receptor fusion. In this study, we aimed to determine the recommended phase 2 dose (RP2D) and evaluate the safety and tolerability of FT596 as monotherapy and in combination with rituximab. We also aimed to evaluate the antitumour activity and characterise the pharmacokinetics of FT596 as monotherapy and in combination with rituximab.
METHODS: In this phase 1, first-in-human trial, we evaluated FT596 in patients with relapsed or refractory B-cell lymphoma at nine sites in the USA. Patients who had received at least one previous systemic therapy and had no curative treatment options were eligible for inclusion. FT596 was administered after conditioning chemotherapy without rituximab (regimen A) or combined with rituximab (regimen B). The study consisted of a dose-escalation phase using a 3 + 3 design, with dose escalation commencing at 3 × 10
FINDINGS: Between March 19, 2020, and Jan 12, 2023, 86 patients with B-cell lymphoma received FT596 on regimen A (n=18) or regimen B (n=68). 22 (26%) of 86 patients were female and 72 (84%) of 86 patients were White. Patients had received a median of four previous lines of therapy (range 1-11) and 33 (38%) of 86 patients had received previous CAR T-cell therapy. The maximum tolerated dose was not reached. Cytokine release syndrome was reported in one (6%) of 18 patients (maximum grade 1) on regimen A and nine (13%) of 68 patients on regimen B (six with maximum grade 1 and three with grade 2). Neurotoxicity was not observed.
INTERPRETATION: FT596 was well tolerated as monotherapy or with rituximab and induced deep and durable responses in patients with indolent and aggressive lymphomas and the RP2D was preliminarily identified to be 1·8 × 10
FUNDING: Fate Therapeutics
Ego networks associated with e-cigarette use among college fraternity students: a cross-sectional study.
No full textOBJECTIVE: To use egocentric network analysis (ENA) to identify how the role of social networks relates to e-cigarette use among college fraternity members.
PARTICIPANTS: 212 fraternity members participated in this study.
METHODS: Hierarchical logistic regression analyses assessed the relationship between egocentric network variables and ever use and current use of e-cigarettes. Network variables were created based on two relational networks of important and communicative networks.
RESULTS: Seventy-three percent (155/212) of our sample have used an e-cigarette at least once in their lifetime, and 41% (89/212) of our sample currently use e-cigarettes. Important people networks were significantly associated with ever use and current use while communicative networks were not significantly associated with ever use or current use of e-cigarettes among our sample population.
CONCLUSION: Perceived positive reactions to e-cigarette use by important relationships may be an important factor associated with ever use and e-cigarette use for fraternity members
American Association of Neurological Surgeons/Congress of the Neurological Surgeons Section on Tumors Guidelines: Assessing Their Impact on Brain Tumor Clinical Practice.
No full textClinical guidelines direct healthcare professionals toward evidence-based practices. Evaluating guideline impact can elucidate information penetration, relevance, effectiveness, and alignment with evolving medical knowledge and technological advancements. As the American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Tumors marks its 40th anniversary in 2024, this article reflects on the tumor guidelines established by the Section over the past decade and explores their impact on other publications, patents, and information dissemination. Six tumor guideline categories were reviewed: low-grade glioma, newly diagnosed glioblastoma, progressive glioblastoma, metastatic brain tumors, vestibular schwannoma, and pituitary adenomas. Citation data were collected from Google Scholar and PubMed. Further online statistics, such as social media reach, and features in policy, news, and patents were sourced from Altmetric. Online engagement was assessed through website and CNS+ mobile application visits. Data were normalized to time since publication. Metastatic Tumor guidelines (2019) had the highest PubMed citation rate at 26.1 per year and webpage visits (29 100 page views 1/1/2019-9/30/2023). Notably, this guideline had two endorsement publications by partner societies, the Society of Neuro-Oncology and American Society of Clinical Oncology, concerning antiepileptic prophylaxis and steroid use, and the greatest reach on X (19.7 mentions/y). Citation rates on Google Scholar were led by Vestibular Schwannoma (2018). Non-Functioning Pituitary Adenoma led Mendeley reads. News, patent, or policy publications were led by low-grade glioma at 1.5/year. Our study shows that the American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Tumors guidelines go beyond citations in peer-reviewed publications to include patents, online engagement, and information dissemination to the public
The Impact of Hypoalbuminemia on Outcomes in Non-Surgically Treated Patients With Central Cord Injury.
No full textSTUDY DESIGN: Database study.
OBJECTIVES: Acute traumatic central cord syndrome (atCCS) is the most common incomplete spinal cord injury in the US, characterized by motor weakness of the upper extremities with relative sparing of the lower extremities and varying degrees of bladder dysfunction and sensory changes caudal to the lesion. Hypoalbuminemia (HA) has previously been associated with poorer outcomes following acute spinal cord injury. We hypothesized that patients with atCCS and HA treated non-surgically experienced worse outcomes than those without HA.
METHODS: Data was collected using the Pearldiver
RESULTS: HA in conjunction with non-surgical care of atCCS was associated with an increased risk of development of renal failure and pressure ulcers as well as longer length of stay and two-year mortality. There was no significant increase in odds ratios for 90-day hospital readmission, pneumonia, UTI, respiratory failure, or sepsis.
CONCLUSIONS: Patients with hypoalbuminemia after atCCS treated non-surgically are at an increased risk of developing complications such as renal failure, pressure ulcers, longer lengths of stay and increased mortality. Surprisingly, respiratory failure, pneumonia, and sepsis were not found to be statistically different between patients with atCCS with and without HA. Inherent to a database study there are predictable limitations, however a large-scale analysis could help further delineate physiologic factors affecting outcomes of atCCS patients