Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial

Antitumor activity; Monotherapy; Solid tumorsActividad antitumoral; Monoterapia; Tumores sólidosActivitat antitumoral; Monoteràpia; Tumors sòlidsImportance Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti–programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor. Objective To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors. Design, Setting, And Participants The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months. Interventions Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. Main Outcomes and Measures The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Results The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified. Conclusions And Relevance In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need. Trial Registration ClinicalTrials.gov Identifier: NCT02715284This study was funded by GSK

Tissue Engineering for Rotator Cuff Repair: An Evidence-Based Systematic Review

The purpose of this systematic review was to address the treatment of rotator cuff tears by applying tissue engineering approaches to improve tendon healing, specifically platelet rich plasma (PRP) augmentation, stem cells, and scaffolds. Our systematic search was performed using the combination of the following terms: “rotator cuff”, “shoulder”, “PRP”, “platelet rich plasma”, “stemcells”, “scaffold”, “growth factors”, and “tissue engineering”. No level I or II studies were found on the use of scaffolds and stem cells for rotator cuff repair. Three studies compared rotator cuff repair with or without PRP augmentation. All authors performed arthroscopic rotator cuff repair with different techniques of suture anchor fixation and different PRP augmentation. The three studies found no difference in clinical rating scales and functional outcomes between PRP and control groups. Only one study showed clinical statistically significant difference between the two groups at the 3-month follow up. Any statistically significant difference in the rates of tendon rerupture between the control group and the PRP group was found using the magnetic resonance imaging. The current literature on tissue engineering application for rotator cuff repair is scanty. Comparative studies included in this review suggest that PRP augmented repair of a rotator cuff does not yield improved functional and clinical outcome compared with non-augmented repair at a medium and long-term followup

Tissue Engineered Strategies for Skeletal Muscle Injury

Skeletal muscle injuries are common in athletes, occurring with direct and indirect mechanisms and marked residual effects, such as severe long-term pain and physical disability. Current therapy consists of conservative management including RICE protocol (rest, ice, compression and elevation), nonsteroidal anti-inflammatory drugs, and intramuscular corticosteroids. However, current management of muscle injuries often does not provide optimal restoration to preinjury status. New biological therapies, such as injection of platelet-rich plasma and stem-cell-based therapy, are appealing. Although some studies support PRP application in muscle-injury management, reasons for concern persist, and further research is required for a standardized and safe use of PRP in clinical practice. The role of stem cells needs to be confirmed, as studies are still limited and inconsistent. Further research is needed to identify mechanisms involved in muscle regeneration and in survival, proliferation, and differentiation of stem cells

Stem Cells and Gene Therapy for Cartilage Repair

Cartilage defects represent a common problem in orthopaedic practice. Predisposing factors include traumas, inflammatory conditions, and biomechanics alterations. Conservative management of cartilage defects often fails, and patients with this lesions may need surgical intervention. Several treatment strategies have been proposed, although only surgery has been proved to be predictably effective. Usually, in focal cartilage defects without a stable fibrocartilaginous repair tissue formed, surgeons try to promote a natural fibrocartilaginous response by using marrow stimulating techniques, such as microfracture, abrasion arthroplasty, and Pridie drilling, with the aim of reducing swelling and pain and improving joint function of the patients. These procedures have demonstrated to be clinically useful and are usually considered as first-line treatment for focal cartilage defects. However, fibrocartilage presents inferior mechanical and biochemical properties compared to normal hyaline articular cartilage, characterized by poor organization, significant amounts of collagen type I, and an increased susceptibility to injury, which ultimately leads to premature osteoarthritis (OA). Therefore, the aim of future therapeutic strategies for articular cartilage regeneration is to obtain a hyaline-like cartilage repair tissue by transplantation of tissues or cells. Further studies are required to clarify the role of gene therapy and mesenchimal stem cells for management of cartilage lesions

Imaging Accuracy in Preoperative Staging of T3-T4 Laryngeal Cancers

Preoperative imaging impacts treatment planning and prognosis in laryngeal cancers. We investigated the accuracy of standard computed tomography (CT) in evaluating tumor invasions at critical glottic areas

Triphenylene based metal-pyridine cages

C3-symmetric pyridine containing tris-benzyl-O-substituted hexahydroxytriphenylene derivatives were prepared and used in combination with square-planar Pd(II) and Pt(II) complexes for the self-assembly of molecular cages in solution. The formation of a trigonal bipyramid M3L2 cage was demonstrated by multinuclear NMR analyses and pseudo 2D DOSY experiments and supported by semi-empirical calculation