Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib.

Adagrasib (MRTX849) is a KRASG12C inhibitor with favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration. As of September 1, 2022, a total of 853 patients with KRASG12C-mutated solid tumors, including patients with CNS metastases, had received adagrasib (monotherapy or in combination). Adagrasib-related treatment-related adverse events (TRAEs) are generally mild to moderate in severity, start early in treatment, resolve quickly with appropriate intervention, and result in a low rate of treatment discontinuation. Common TRAEs seen in clinical trials included gastrointestinal-related toxicities (diarrhea, nausea, and vomiting); hepatic toxicities (increased alanine aminotransferase/aspartate aminotransferase) and fatigue, which can be managed through dose modifications, dietary modifications, concomitant medications (such as anti-diarrheals and anti-emetics/anti-nauseants) and the monitoring of liver enzymes and electrolytes. To manage common TRAEs effectively, it is imperative that clinicians are informed, and patients are fully counseled on management recommendations at treatment initiation. In this review, we provide practical guidance on the management of adagrasib TRAEs and discuss some best practices for patient and caregiver counseling to facilitate optimal outcomes for patients. Safety and tolerability data from the phase II cohort of the KRYSTAL-1 study will be reviewed and presented with practical management recommendations based on our experience as clinical investigators.

Evaluating the Effects of Platelet-Rich Plasma and Amniotic Viscous Fluid on Inflammatory Markers in a Human Coculture Model for Osteoarthritis.

PURPOSE: To assess the anti-inflammatory effects of platelet-rich plasma (PRP) and amniotic viscous fluid using a human coculture system of cartilage and synovial tissue from osteoarthritic patients. METHODS: A coculture system was created using cartilage and synovium from 3 patients undergoing total knee arthroplasty. To induce inflammation, interleukin-1ß was added to each coculture. Biologic agents tested included 2 PRP concentrations (PRPL and PRPH) and 2 different samples of amniotic viscous fluid (Amnion and Flograft). Amnion was also tested with PRP to check for any additive effects. Quantitative polymerase chain reaction was used to measure gene expression of factors involved in osteoarthritis, including disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), aggrecan, type 1 collagen, and nitric oxide, at 0, 24, 48, and 72 hours. A synthetic nonsteroidal medication, Ketorolac, was used for baseline comparison to the biologic agents. RESULTS: When comparing from time 0, both Amnion and Flograft resulted in significant decreases of ADAMTS-5 and TIMP-1 gene expression in cartilage and synovium for up to 72 hours. Both amniotic preparations increased collagen-1 gene expression in cartilage and decreased VEGF expression in synovium. Amnion was not found to have any effect on nitric oxide concentration at any time point (P > .05), as opposed to both PRP concentrations (P < .05). All biologic agents showed differences in gene expression similar to Ketorolac in ADAMTS-5, TIMP-1, and VEGF expression. CONCLUSION: This study found that amniotic fluid had anti-inflammatory effects mostly similar to those of both PRPH and PRPL; however, no significant additive effects in reducing inflammatory gene expression were found when combining biologic agents. CLINICAL RELEVANCE: PRP and amniotic fluid may provide alternative treatment options to delay the progression of the disease without the systemic and intra-articular side effects of corticosteroids.

Coated Sutures.

The addition of specific proteins or growth factors onto sutures would provide a direct application of exogenous factors to promote tissue repair. The higher levels of growth factors and cytokines may optimize the healing environment and promote tissue recovery. Despite this proposed benefit, the current orthopedic literature on the use of coated sutures is limited. Although several of the published studies investigating healing improvement by coated sutures have shown promising results, these data are only based on in vitro or small animal experiments. Recent meta-analyses have reported positive effects of triclosan-coated antimicrobial sutures in regards to reduction of surgical site complications. However, biologically coated sutures are not yet widely accepted due to several unanswered questions (concentration, release kinematics, tissue reactions, etc.) in addition to the high costs of such products. Further studies are needed to demonstrate the efficacy of coated sutures in orthopedic surgery.

Insulin-like growth factor II induces apoptosis in osteoblasts.

The ability of insulin-like growth factor II (IGF-II) to modulate apoptosis was studied in murine osteoblasts. At 72 h of culture, 0.01, 0.1, and 1.0 nM IGF-II produced a dose-dependent increase in apoptosis assayed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) and confirmed with acridine orange-ethidium bromide staining. A maximal increase of 5.0-fold above control was found with 1 nM IGF-II. A time course of treatment with 0.1 nM IGF-II demonstrated a significant increase in apoptosis compared to vehicle-treated cells by 48 h. IGF-II-induced apoptosis could not be inhibited by a blocking antibody to the IGF-I receptor. Human osteoblast cultures demonstrated a similar dose-dependent increase in apoptosis with IGF-II. No significant effect of IGF-II was found on proliferation in murine osteoblast cultures. Western blot analysis demonstrated that IGF-II decreased Bcl-2 protein levels, but not Bax, resulting in a significant reduction in the Bcl-2/Bax ratio. To determine if overexpression of Bcl-2 could block IGF-II-induced apoptosis, osteoblasts were isolated from a transgenic mouse that overexpresses human Bcl-2 in bone through a construct utilizing the 2.3 kb promoter region of the Type I collagen gene linked to a 1.8 kb region of human Bcl-2 (Col2.3Bcl-2). At 72 h, IGF-II significantly increased apoptosis in a dose-dependent manner in osteoblast cultures from the control littermates. In osteoblasts from Col2.3Bcl-2 mice, no significant effect on apoptosis was found with 0.01, 0.1, or 1.0 nM IGF-II. Western blot analysis of Bcl-2 and Bax levels demonstrated a transient decrease in the Bcl-2/Bax ratio at 24 h with no decrease in the ratio at 48 or 72 h. Thus, IGF-II appears to promote osteoblast apoptosis, and overexpression of Bcl-2 is able to block IGF-II-induced apoptosis.

Usefulness of multislice computed tomography angiography to evaluate intravascular stents and transcatheter occlusion devices in patients with d-transposition of the great arteries after mustard repair.

Percutaneous interventions can treat long-term complications after Mustard atrial switch operation in patients with d-transposition of the great arteries (d-TGA), but follow-up for these procedures has not been established. Four patients with d-TGA and previous Mustard operation underwent percutaneous placement of covered stents to relieve superior and inferior vena caval baffle obstructions and leaks. At 6 to 13 months, assessment with 16-slice spiral computed tomography identified stent patency as well as lead placement and visualization of additional devices.

Tendon structure, disease, and imaging.

Tendon imaging plays a critical role in evaluating tendon diseases and injuries including mechanical, degenerative, and overuse disease, inflammatory enthesitis, as well as partial and full thickness tears. Ultrasound and magnetic resonance imaging (MRI), each with unique benefits and limitations, are commonly utilized to assist in diagnosing these diseases and conditions. This review delineates important structural properties of tendon and biochemical changes occurring in tendon pathology. This review also examines commonly injured tendons including tendons of the elbow, tendons of the rotator cuff of the shoulder, hip abductor tendons, patellar tendons, and the Achilles tendon to help clinicians better recognize tendon disease. Finally, this paper introduces several emerging imaging techniques including T2 mapping, ultra-short echo time MRI, and sonoelastography as ways in which tendon imaging and evaluation may be improved.

Therapeutic touch affects DNA synthesis and mineralization of human osteoblasts in culture.

Complementary and alternative medicine (CAM) techniques are commonly used in hospitals and private medical facilities; however, the effectiveness of many of these practices has not been thoroughly studied in a scientific manner. Developed by Dr. Dolores Krieger and Dora Kunz, Therapeutic Touch is one of these CAM practices and is a highly disciplined five-step process by which a practitioner can generate energy through their hands to promote healing. There are numerous clinical studies on the effects of TT but few in vitro studies. Our purpose was to determine if Therapeutic Touch had any effect on osteoblast proliferation, differentiation, and mineralization in vitro. TT was performed twice a week for 10 min each on human osteoblasts (HOBs) and on an osteosarcoma-derived cell line, SaOs-2. No significant differences were found in DNA synthesis, assayed by [(3)H]-thymidine incorporation at 1 or 2 weeks for SaOs-2 or 1 week for HOBs. However, after four TT treatments in 2 weeks, TT significantly (p = 0.03) increased HOB DNA synthesis compared to controls. Immunocytochemistry for Proliferating Cell Nuclear Antigen (PCNA) confirmed these data. At 2 weeks in differentiation medium, TT significantly increased mineralization in HOBs (p = 0.016) and decreased mineralization in SaOs-2 (p = 0.0007), compared to controls. Additionally, Northern blot analysis indicated a TT-induced increase in mRNA expression for Type I collagen, bone sialoprotein, and alkaline phosphatase in HOBs and a decrease of these bone markers in SaOs-2 cells. In conclusion, Therapeutic Touch appears to increase human osteoblast DNA synthesis, differentiation and mineralization, and decrease differentiation and mineralization in a human osteosarcoma-derived cell line.