Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy. We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement. Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; < 0.001). A ctDNA response was associated with superior progression-free survival [hazard ratio (HR), 0.29; 95% CI, 0.09-0.89; = 0.03], and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62; = 0.007). A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC. .

Background. The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children.Methods. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine.Results. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations.Conclusions. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.

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Objective: This study aimed to answer 2 questions: first, to what degree does hospital operative volume affect mortality for adult patients undergoing 1 of 10 common emergency general surgery (EGS) operations? Second, at what hospital operative volume threshold will nearly all patients undergoing an emergency operation realize the average mortality risk? Background: Nontrauma surgical emergencies are an underappreciated public health crisis in the United States; redefining where such emergencies are managed may improve outcomes. The field of trauma surgery established regionalized systems of care in part because studies demonstrated a clear relationship between hospital volume and survival for traumatic emergencies. Such a relationship has not been well-studied for nontrauma surgical emergencies. Methods: Retrospective cohort study of all acute care hospitals in California performing nontrauma surgical emergencies. We employed a novel use of an ecological analysis with beta regression to investigate the relationship between hospital operative volume and mortality. Results: A total of 425 acute care hospitals in California performed 165,123 EGS operations. Risk-adjusted mortality significantly decreased as volume increased for all 10 EGS operations (P < 0.001 for each); the relative magnitude of this inverse relationship differed substantially by procedure. Hospital operative volume thresholds were defined and varied by operation: from 75 cases over 2 years for cholecystectomy to 7 cases for umbilical hernia repair. Conclusions: Survival rates for nontrauma surgical emergencies were improved when operations were performed at higher-volume hospitals. The use of ecological analysis is widely applicable to the field of surgical outcomes research.

Whereas the definition of sepsis moves away from SIRS, SIRS-based criteria may still have clinical benefit as an easy-to-automate detection tool for all-cause clinical deterioration among medical inpatients.