Citations

IMPORTANCE: Meropenem dosing is typically guided by creatinine-based estimated glomerular filtration rate (eGFR), but creatinine is a suboptimal GFR marker in the critically ill. OBJECTIVES: This study aimed to develop and qualify a population pharmacokinetic model for meropenem in critically ill adults and to determine which eGFR equation based on creatinine, cystatin C, or both biomarkers best improves model performance. DESIGN, SETTING, AND PARTICIPANTS: This single-center study evaluated adults hospitalized in an ICU who received IV meropenem from 2018 to 2022. Patients were excluded if they had acute kidney injury, were on kidney replacement therapy, or were treated with extracorporeal membrane oxygenation. Two cohorts were used for population pharmacokinetic modeling: a richly sampled development cohort (n = 19) and an opportunistically sampled qualification cohort (n = 32). MAIN OUTCOMES AND MEASURES: A nonlinear mixed-effects model was developed using parametric methods to estimate meropenem serum concentrations. RESULTS: The best-fit structural model in the richly sampled development cohort was a two-compartment model with first-order elimination. The final model included time-dependent weight normalized to a 70-kg adult as a covariate for volume of distribution (Vd) and time-dependent eGFR for clearance. Among the eGFR equations evaluated, eGFR based on creatinine and cystatin C expressed in mL/min best-predicted meropenem clearance. The mean (se) Vd in the final model was 18.2 (3.5) liters and clearance was 11.5 (1.3) L/hr. Using the development cohort as the Bayesian prior, the opportunistically sampled cohort demonstrated good accuracy and low bias. CONCLUSIONS AND RELEVANCE: Contemporary eGFR equations that use both creatinine and cystatin C improved meropenem population pharmacokinetic model performance compared with creatinine-only or cystatin C-only eGFR equations in adult critically ill patients.

ImportancePostoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.ObjectiveTo evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins.Design, Setting, and ParticipantsThe American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023.Main Outcomes and MeasuresMain outcomes were risk factors for local recurrence.ResultsA total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group.Conclusions and RelevanceIn this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Abstract Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.

Evaluation of rapidly progressive dementia (RPD) is usually challenging. In most cases, patients progress to dementia in weeks to months, and the differential diagnosis is broad. In this case, a woman in her 60s presented with a 1-month history of episodic vertigo, cognitive decline, ataxia and myoclonus. Cerebrospinal fluid total tau was markedly elevated, which was helpful in establishing the diagnosis and discussing prognosis/end-of-life measures with the patient’s family. This case summarises a stepwise diagnostic approach for patients with RPD and highlights recent literature on biomarkers of Creutzfeldt-Jakob disease and autoimmune encephalitis.