Robotic Central Pancreatectomy: Patient Selection and Surgical Approach.

Central pancreatectomy (CP) is one of the parenchyma-sparing approaches proposed for low-grade tumors. CP has a lower incidence of diabetes compared with distal pancreatectomy, but may harbor risks of positive distal pancreatic margin, inadequate lymph node (LN) removal, and pancreatic fistula from the pancreaticojejunal anastomosis. Given the reported oncologic safety, we selectively perform CP for small pancreatic neuroendocrine tumors (pNETs) that are localized to the pancreatic neck.

Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with Deletion.

The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10-15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets -deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in -deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for -deleted cancers and is currently in Phase I/II clinical trials.

MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design.

Deletion of the gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target -deleted cancer cells.

Delivery of Timely Adjuvant Radiation Among Veterans With Head and Neck Cancer.

Objective: The objective of this study was to determine the rate at which veterans with head and neck squamous cell carcinoma (HNSCC) received care adhering to National Comprehensive Care Network (NCCN) guidelines for postoperative radiation and to identify factors associated with non-adherence. The guidelines recommend initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery.

Study Design: This was a retrospective cohort analysis of a pre-existing database.

Characterization of TNG348: a selective, allosteric USP1 inhibitor that synergizes with PARP inhibitors in tumors with homologous recombination deficiency.

Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for the treatment of BRCA1/2 mutant cancers, potentially including patients whose tumors have primary or acquired resistance to PARP inhibitors (PARPi). Here, we present a comprehensive characterization of TNG348, an allosteric, selective, and reversible inhibitor of USP1 (USP1i). TNG348 induces dose-dependent accumulation of ubiquitinated protein substrates both in vitro and in vivo.