PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.

Background & Aims: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease.

Methods: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD.

Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial.

Background: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST.

Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour.

Purpose: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor α kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a ≥fourth-line therapy.

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study.

Background: Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.

Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.

Background: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours.

Methods: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries.

A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.

Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B).

A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation.

Objectives: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C).

Methods: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μ g oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period.

Elongation of simulated whipstitch post anterior cruciate ligament reconstruction tibial fixation after cyclic loading.

Whipstitch-post (WSP) tibial fixation is one of the most widely used and clinically successful methods of soft tissue graft fixation for anterior cruciate ligament reconstruction (ACLR). However, some consider the method prone to laxity. We hypothesized that WSP would have low elongation rates after experimental cyclic loading.

Magnetic resonance imaging measurement of the contralateral normal meniscus is a more accurate method of determining meniscal allograft size than radiographic measurement of the recipient tibial plateau.

Purpose: The purpose of this study was to develop and validate magnetic resonance imaging (MRI) scanning of the contralateral meniscus as a more accurate method of determining the needed size of a meniscal allograft than the traditional method of inferring meniscal size from radiographic measurement of the ipsilateral tibial plateau.

Methods: Tissue bank meniscal size records from the left and right knees of 500 meniscal donors were analyzed for symmetry. The menisci of 10 cadaveric knees were then sized indirectly via the radiographic tibial plateau method and directly via MRI and actual physical measurement.

A meta-analysis of stability of autografts compared to allografts after anterior cruciate ligament reconstruction.

Allografts have recently become increasingly popular for anterior cruciate ligament reconstruction (ACLR) in the United States even though many studies have shown high allograft failure rates (Gorschewsky et al. in Am J Sports Med 33:1202, 2005; Pritchard et al. in Am J Sports Med 23:593, 2005; Roberts et al.

A meta-analysis of stability after anterior cruciate ligament reconstruction as a function of hamstring versus patellar tendon graft and fixation type.

Purpose: Four-strand hamstring graft (4HS) is stronger than 10-mm bone-patellar tendon-bone graft (BPTB) and has equal tunnel pullout strength, but is believed by some to produce lower rates of stability after anterior cruciate ligament reconstruction (ACLR). Our purpose was to test the hypothesis that 4HS ACLR with modern fixation would produce equal or greater stability than BPTB ACLR.

Type Of Study: Meta-analysis.