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.

Assessment of the Impact of Mandated Postmarketing Pediatric-Focused Safety Reviews on Safety-Related Regulatory Actions 2013-2019.

The US Food and Drug Administration's (FDA's) routine postmarketing drug safety monitoring may lead to safety-related labeling changes for identified risks. Additionally, the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) require the FDA to conduct postmarket pediatric-focused safety reviews of adverse events. The purpose of these pediatric reviews is to identify risks associated with drug or biological products 18 months after the FDA approves a pediatric labeling change pursuant to studies conducted under the BPCA or PREA. These reviews are presented to the FDA Pediatric Advisory Committee (PAC) or publicly posted on FDA's website. The aim of this study was to evaluate the impact of pediatric reviews prompted by BPCA/PREA from October 1, 2013, to September 30, 2019. The impact was quantified by the number of new safety signals identified and the subsequent safety-related labeling changes resulting from pediatric reviews relative to safety-related labeling changes triggered by other data sources. Among 163 products with at least one pediatric review completed, a new safety signal that resulted in a safety-related labeling change was found for 5 of these products (representing 3 active ingredients); none described risks specific to the pediatric population. Between October 2013 and September 2021, there were 585 safety-related labeling changes implemented for products with at least one completed pediatric review. Less than 1% of 585 safety-related labeling changes were the result of a mandated pediatric review. Our study suggests that mandated pediatric reviews conducted 18 months after a pediatric labeling change provided minimal value over other postmarket safety surveillance activities.

Characteristics of Successful Transitions From Inpatient to Outpatient Electroconvulsive Therapy.

OBJECTIVES: The purpose of this study was to identify clinical and psychosocial factors involved in transitioning hospitalized patients receiving electroconvulsive therapy (ECT) from the inpatient to the outpatient setting and to propose an algorithm to guide clinicians with this process. METHODS: A retrospective chart review was completed for adult patients discharged from a psychiatric hospital from 2002 to 2012 who had an acute course of ECT that was initiated in the hospital and completed as an outpatient. We reviewed demographic and clinical information and outcomes, including ECT treatments. RESULTS: Among the 277 patients who were identified, the mean age was 52.2 years, 60% were women, and 66% were married. The mean length of hospital stay was 12.9 days, and the mean number of ECT treatments was 4.9 as an inpatient and 3.1 as an outpatient. The most frequent primary diagnosis was depression. Most patients (81%) had a responsible adult at home. Patients had good cognitive functioning at both baseline and discharge, and showed improved functional status at discharge (P<0.001 for change in scores on the Global Assessment of Functioning from admission to discharge). CONCLUSIONS: Factors such as improved cognitive and functional status from admission to discharge, a medically uncomplicated course, and a responsible adult at home were observed among patients transitioned from inpatient to outpatient ECT. On the basis of these study results, a review of the literature, and clinical experience, an algorithm to assist clinical decisions for ECT transitioning was developed.

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.

Building the right physician platform.

The challenges health systems often face in aligning physicians with organizational cost and quality goals related to the delivery of value-based care differ between employed and independent physicians. With employed physicians, the focus should be on right-sizing the service delivery network and employed medical group, building a sustainable compensation program, enhancing the revenue cycle, increasing use of midlevel providers, and implementing a common technology platform. With independent physicians, the focus should be on understanding available contracting models, participating in shared-savings arrangements, considering alternative payment distribution models, choosing the right metrics, and exploring shared branding options.

Navigating performance-based risk.

Numerous factors contribute to an organization's "risk tolerance" under performance-based risk arrangements, including its size, patient population, and the strength of its financial position. There are three types of risk inherent in value-based contracting: Financial risk. Actuarial risk. Strategic risk.

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.

Correlates of myalgia in electroconvulsive therapy.

Myalgias are common in patients treated with electroconvulsive therapy (ECT). The mechanism of this side effect is unknown. Two commonly postulated etiologies are the motor activity during the convulsion and the fasciculations induced by succinylcholine. If the former phenomenon accounts for most of themyalgias, then the appropriate strategy will be to increase the succinylcholine dose at subsequent treatments. If, on the other hand, the latter phenomenon is more important in inducing myalgias, then the appropriate strategy may be to decrease succinylcholine dosages (on the theory that lower doses result in less fasciculating). On the other hand, if neither of these factors accounts for myalgias, then succinylcholine dose adjustments may be irrelevant to myalgias in the ECT situation. In this study, we assessed the degree of convulsive movements during the seizure as well as strength of fasciculations caused by succinylcholine to see which, if either, correlates with ultimate complaints of myalgias. The results indicated that neither of these factors, nor dose of succinylcholine, correlated with myalgias. We conclude that dose adjustments to succinylcholine are unlikely to affect complaints of myalgias in ECT patients.

Electrode placement and ictal EEG indices in electroconvulsive therapy.

The authors determine whether quantitative electroencephalography (EEG) indices in electroconvulsive therapy (ECT) seizures correlate with stimulus electrode placement. The authors analyzed data from ECT seizures involving three electrode placements on 37 different quantitative EEG measures. Though there were a few statistically significant comparisons, no consistent pattern of differences was discerned among the three electrode placements. Though many different EEG analytical indices are available on modern ECT machines, the clinical or neurophysiologic relevance has yet to be established. These data provide a groundwork for future research on the neurophysiological aspects of ECT.

QTc dispersion on the baseline ECG predicts arrhythmias during electroconvulsive therapy.

OBJECTIVE: Our objective in this study was to test the hypothesis that prolonged QTc dispersion predisposes to arrhythmias in electroconvulsive therapy (ECT). METHODS AND RESULTS: We measured QTc dispersion on ECT patients' baseline ECG and also measured PVCs and PACs during and for two minutes after ECT seizures. Using Poisson regression analysis, we found that baseline QTc dispersion was positively associated with ictal and post ictal PVCs and with post ictal PACs. CONCLUSIONS: We conclude that QTc dispersion appears to be a valid predictor of arrhythmias.

Blood glucose before and after ECT treatments in Type 2 diabetic patients.

Electroconvulsive therapy (ECT) is often performed for patients with psychiatric disorders who also have diabetes mellitus. Some research has suggested that the course of ECT treatments does not have a consistent effect on blood glucose, but little data exist to inform the clinician about the effects of individual ECT treatments on blood glucose. In this study, 18 patients with type 2 diabetes mellitus were treated with ECT for severe depressive illness. For each patient, a fingerstick blood glucose was routinely obtained before and approximately 20 minutes after each ECT treatment. We found a mean rise of blood glucose after each treatment of approximately 9%, similar to the mean rise of blood glucose among nondiabetic patients undergoing ECT found in a previous study. There were no cases of clinically significant rise or fall in blood glucose. We provide recommendations for management of diabetics during ECT.

Nonconvulsive seizures in electroconvulsive therapy: further evidence of differential neurophysiological aspects of bitemporal versus bifrontal electrode placement.

In recent years, attention has been focused on the role of electrode placement in determining efficacy and cognitive side effects of electroconvulsive therapy (ECT). In particular, interest in bifrontal electrode placement has increased. Some evidence indicates differential therapeutic, cognitive, and neurophysiological aspects of bifrontal versus bitemporal ECT. Occasionally in ECT practice, electroencephalographic seizure activity is manifested in the absence of motor convulsive activity, a phenomenon termed nonconvulsive seizures. This probably indicates isolated prefrontal seizure activity in the absence of motor strip involvement. We reviewed our records and found that bifrontally treated patients had a significantly higher incidence of nonconvulsive seizures in ECT than did bitemporally treated patients. Seizure threshold was also higher among the bifrontal patients. We hypothesize that this provides further evidence of differential neurophysiology of seizures induced with these 2 electrode placements.

The effect of electroconvulsive therapy treatments on blood sugar in nondiabetic patients.

There are conflicting data in the literature about the effects of electroconvulsive therapy (ECT) on blood sugar. In general, glycemic control and insulin requirements show no changes over a course of treatments, although there is interindividual variation. What is understudied is the acute effect of single ECT treatments on blood sugar in the post-ictal time period. To shed more light on this issue, we conducted a simple study of blood sugar assessed by fingerstick before and 20 minutes after ECT treatments in 33 nondiabetic patients. There was a small though statistically significant rise of 9 mg/dL in blood glucose after ECT treatments, without effect of age or gender. We conclude that ECT does not have a clinically significant effect on blood sugar in non-diabetic patients.

Long-term maintenance ECT: a retrospective review of efficacy and cognitive outcome.

Continuation and maintenance electroconvulsive therapy (ECT) are used to prevent relapse of depression after a successful course of index ECT. Such a course of treatment is typically extended for as long as a year. However, some patients seem to require longer courses of maintenance ECT. Little is known about the outcomes of long-term use (> 1 year) of maintenance ECT. We reviewed our maintenance ECT practice for the year 2000 and found that 43 patients had been receiving maintenance ECT for more than a year. This retrospective study reviews the outcomes of these patients. All patients had depression associated with either unipolar or bipolar disorder or schizoaffective disorder. These patients had multiple medication or psychotherapy trials or both and multiple hospitalizations before receiving maintenance ECT. Effects on depressive symptoms, level of functioning, health care use, frequency of hospitalizations, and cognition are discussed. We conclude that extended maintenance ECT is efficacious and well tolerated and reduces hospital use for a population of chronically depressed patients refractory to medication.