Publications

s: Ninth International Congress of Therapeutic Drug Monitoring and Clinical Toxicology: Louisville, Kentucky April 23-28, 2005

Loss functions, which govern a deep learning-based optimization process, have been widely investigated to handle the class imbalanced data issue in crack segmentation. However, their performance varies according to models and datasets, making it challenging to choose the most appropriate ones. To address this issue, the paper conducts a large-scale performance comparison of twelve commonly used loss functions on four benchmark datasets. Various aspects are considered using a statistical test-based ranking scheme, which integrates accuracy, sensitivity to threshold change, and varying degrees of imbalance severity for a comprehensive comparison. The results show that most loss functions achieve relatively similar accuracy on mildly imbalanced datasets, while weighted binary cross-entropy loss, Focal loss, Dice-based loss, and compound loss functions significantly outperform others as imbalance severity increases. In general, Focal Tversky loss function exhibits excellent performance in handling the imbalanced data issue.

Cancer represents a challenging medical problem worldwide. Several exploratory studies have been conducted to overcome these limitations. RNA vaccines play an important role in cancer prevention and treatment. Recent studies have shown that RNA vaccines play an important role in cancer prevention. However, there are currently no relevant bibliometric studies. This study aimed to apply bibliometrics to summarize the knowledge structure and research hotspots regarding the role of RNA vaccines in cancer. Publications related to RNA vaccines in cancer were searched on the web of science core collection (WoSCC) database. VOSviewers, CiteSpace and R package "bibliometrix" were used to conduct this bibliometric analysis. A total of 1399 articles were included, comprising 803 original articles and 596 reviews. The number of studies on RNA vaccines against cancer has been increasing annually. China and the United States were the principal countries of origin of publications. Johannes Gutenberg University Mainz, NCI, and Duke University were the main organizations. Frontiers in Immunology is the leading journal in the field. Hot keywords included tumor antigens, lipid nanoparticles, emerging roles, and dendritic cells. This is the bibliometric study to summarize the research trends and development of RNA vaccines for cancer. This information will provide a reference for researchers studying RNA vaccines against cancer.

PURPOSE Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983 ) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma. METHODS Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses. RESULTS In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02. CONCLUSION The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

5005 Background: 177 Lu-PSMA-617, a PSMA-directed, radionuclide therapy improves progression free survival (PFS) and overall survival (OS) in patients (pts) with mCRPC. Although many pts benefit from treatment, approximately a third have primary resistance, median PFS is 5.1 months and all pts inevitably relapse. Poly (ADP-ribose) polymerase (PARP) is implicated in repairing radiation-induced DNA single-strand breaks (SSBs). The potent PARP inhibitor (PARPi) olaparib results in the conversion of DNA SSBs to lethal double-strand breaks. Multiple preclinical studies have shown enhanced anti-tumor activity from combined PARPi and radiotherapy. LuPARP aims to evaluate the safety and efficacy of the combination of 177 Lu-PSMA-617 and olaparib. Methods: 48 pts with mCRPC and high PSMA expression (SUVmax 15 at a site of disease, and SUVmax ≥ 10 at other measurable sites) without discordant FDG positive/PSMA negative disease will be enrolled in two stages: dose-escalation (standard 3+3 design) and dose-expansion at the recommended phase 2 dose (RP2D). 177 Lu-PSMA-617 is administered at 7.4 GBq IV on day 1, every 6 weeks for up to 6 cycles in conjunction with 9 prespecified dose schedules of olaparib. The dose-limiting toxicity (DLT) period is 6 weeks. The primary objectives are establishing the DLTs and RP2D. Secondary objectives are toxicity, radiological PFS (rPFS), PSA response rate (PSA50-RR), PSA-PFS, objective response rate (ORR) and OS. Responses are assessed by 3-weekly PSA and conventional and PSMA PET/CT imaging every 12 weeks. Results: 29 pts (median age 70 years: range: 52-84; prior docetaxel: 97%; prior androgen receptor pathway inhibitor: 100%) received 177 Lu-PSMA-617 on day 1 with escalating doses of olaparib (cohorts 1-6: 50mg - 300 mg BD days 2-15) or alternate olaparib schedules (cohort 7: 200 BD days - 4 to 14; cohort 8: 300 BD days - 4 to 14; cohort 9: 300 mg BD days -4 to 18) for up to 6 cycles. No DLTs were reported. Common treatment related adverse events (TRAE) (≥10%) were Grade (G) 1-2 and included xerostomia (83%), nausea (62%), fatigue (34%), constipation (31%), anorexia (17%), vomiting (14%) and diarrhea (10%). Hematologic TRAE included anemia (G1: 14%; G2: 7%; G3: 7%), thrombocytopenia (G1: 14%; G2: 7%; G3: 3%) and neutropenia (G1: 3%; G3: 7%) that were transient and without clinical sequelae. Across cohorts 1-9, the PSA50-RR was 62% (18/29) and PSA90-RR was 48% (14/29). Five of the 7 pts (71%) with RECIST measurable disease had a partial response. Conclusions: The combination of 177 Lu-PSMA-617 and olaparib is well tolerated and has promising activity. Three further patients are being enrolled to cohort 9 to confirm the RP2D ahead of dose-expansion. Clinical trial information: NCT03874884 . [Table: see text]