Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.

PURPOSE: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRASG12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRASG12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRASG12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Randomized controlled trial of postoperative belladonna and opium rectal suppositories in vaginal surgery.

BACKGROUND: After vaginal surgery, oral and parenteral narcotics are used commonly for pain relief, and their use may exacerbate the incidence of sedation, nausea, and vomiting, which ultimately delays convalescence. Previous studies have demonstrated that rectal analgesia after surgery results in lower pain scores and less intravenous morphine consumption. Belladonna and opium rectal suppositories may be used to relieve pain and minimize side effects; however, their efficacy has not been confirmed. OBJECTIVE: We aimed to evaluate the use of belladonna and opium suppositories for pain reduction in vaginal surgery. MATERIALS AND METHODS: A prospective, randomized, double-blind, placebo-controlled trial that used belladonna and opium suppositories after inpatient or outpatient vaginal surgery was conducted. Vaginal surgery was defined as (1) vaginal hysterectomy with uterosacral ligament suspension or (2) posthysterectomy prolapse repair that included uterosacral ligament suspension and/or colporrhaphy. Belladonna and opium 16A (16.2/60 mg) or placebo suppositories were administered rectally immediately after surgery and every 8 hours for a total of 3 doses. Patient-reported pain data were collected with the use of a visual analog scale (at 2, 4, 12, and 20 hours postoperatively. Opiate use was measured and converted into parenteral morphine equivalents. The primary outcome was pain, and secondary outcomes included pain medication, antiemetic medication, and a quality of recovery questionnaire. Adverse effects were surveyed at 24 hours and 7 days. Concomitant procedures for urinary incontinence or pelvic organ prolapse did not preclude enrollment. RESULTS: Ninety women were randomly assigned consecutively at a single institution under the care of a fellowship-trained surgeon group. Demographics did not differ among the groups with mean age of 55 years, procedure time of 97 minutes, and prolapse at 51%. Postoperative pain scores were equivalent among both groups at each time interval. The belladonna and opium group used a mean of 57 mg morphine compared with 66 mg for placebo (P=.43) in 24 hours. Patient satisfaction with recovery was similar (P=.59). Antiemetic and ketorolac use were comparable among groups. Subgroup analyses of patients with prolapse and patients <50 years old did not reveal differences in pain scores. The use of belladonna and opium suppositories was uncomplicated, and adverse effects, which included constipation and urinary retention, were similar among groups. CONCLUSION: Belladonna and opium suppositories are safe for use after vaginal surgery. Belladonna and opium suppositories did not reveal lower pain or substantially lower narcotic use. Further investigation may be warranted to identify a population that may benefit optimally from belladonna and opium use.

Metabolic syndrome: definition and therapeutic implications.

The collection of impaired glucose metabolism, central obesity, elevated blood pressure, and dyslipidemia is identified as metabolic syndrome (MetS). It is estimated that approximately 25% of the world's population has MetS. In the United States, MetS is more common in men and Hispanics, and its incidence increases with age. Metabolic syndrome increases the risk of developing cardiovascular disease and type 2 diabetes mellitus. The underlying risk factors include insulin resistance and abdominal obesity. Confusion about MetS exists in part due to the lack of a consensus definition and treatment protocol. Treatment of MetS begins with therapeutic lifestyle changes and then pharmacologic treatment of the syndrome's individual components. Effective interventions include diet modification, exercise, and use of pharmacologic agents to treat risk factors. Weight loss and increasing physical activity significantly improve all aspects of MetS. A diet that includes more fruits, vegetables, whole grains, monounsaturated fats, and low-fat dairy products will benefit most patients with MetS. Physicians can be most effective in advising patients by customizing specific lifestyle recommendations after assessing patients for the presence of risk factors.