A Real-world Toxicity Atlas Shows that Adverse Events of Combination Therapies Commonly Result in Additive Interactions.

PURPOSE: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting. EXPERIMENTAL DESIGN: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heat maps. In addition, statistical synergy analyses were performed on the basis of BLISS independence or χ2 testing. RESULTS: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug-associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. CONCLUSIONS: Our study provides a framework for analyzing adverse events and suggests that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

Surgical outcome of a double versus a single pancreatoduodenectomy per operating day.

BACKGROUND: For logistical reasons, some high-volume centers have developed surgical programs wherein 1 surgical team performs 2 pancreatoduodenectomies on a single day. It is unclear whether this practice has a negative impact on surgical outcome. METHODS: We conuducted a retrospective analysis including all consecutive open pancreatoduodenectomies in a single high-volume center (2014-2021). Pancreatoduodenectomies were grouped as the first (pancreatoduodenectomy-1) or second (pancreatoduodenectomy-2) pancreatoduodenectomy on a single day (ie, paired pancreatoduodenectomies) and as pancreatoduodenectomy-3 whenever 1 pancreatoduodenectomy was performed per day (ie, unpaired). Patients undergoing minimally invasive procedures were excluded. The primary outcomes were major morbidity (ie, Clavien-Dindo grade ≥IIIa) and mortality. RESULTS: Among 689 patients, 151 patients had undergone minimally invasive pancreatoduodenectomy, leaving 538 patients after open pancreatoduodenectomy for inclusion. The overall rate of major morbidity was 37.4% (n = 200/538) and in-hospital/30-day mortality 1.7% (n = 9/538). Overall, 136 (25.3%) patients were operated in 68 pancreatoduodenectomy-1/ pancreatoduodenectomy-2 pairs and 402 (74.7%) patients as unpaired pancreatoduodenectomy (pancreatoduodenectomy-3). No differences were found between pancreatoduodenectomy-1 and pancreatoduodenectomy-2 regarding the rates of major morbidity (35.3% vs 26.5%; P = .265) and mortality (1.5% vs 0%; P = .999). Between the 68 pancreatoduodenectomy-1/ pancreatoduodenectomy-2 pairs and the 402 unpaired pancreatoduodenectomies, the rates of major morbidity (30.9% vs 39.6%; P = .071) and mortality (0.7% vs 2.0%; P = .461) did not differ significantly. In multivariable logistic regression analysis, pancreatoduodenectomy-1 was not associated with major morbidity (odds ratio = 0.913 [95% confidence interval 0.515-1.620]; P = .756), whereas pancreatoduodenectomy-2 was associated with less major morbidity (odds ratio = 0.522 [95% confidence interval 0.277-0.983]; P = .045). CONCLUSION: In a high-volume setting, performing 2 consecutive open pancreatoduodenectomies on a single operating day appears to be safe. This approach may be an option when logistically required.

Cost-effectiveness of direct discharge from the emergency department of patients with simple stable injuries in the Netherlands.

BACKGROUND: Approximately one-third of musculoskeletal injuries are simple stable injuries (SSIs). Direct discharge (DD) from the emergency department (ED) of patients with SSIs reduces healthcare utilization, without compromising patient outcome and experience, when compared with "traditional" care with routine follow-up. This study aimed to determine the cost-effectiveness of DD compared with traditional care from a societal perspective. METHODS: Societal costs, including healthcare, work absenteeism, and travel costs, were calculated for patients with an SSI, 6 months before (pre-DD cohort) and after implementation of DD (DD cohort). The pre-DD cohort was treated according to local protocols. The DD cohort was treated using orthoses, discharge leaflet, smartphone application, and telephone helpline, without scheduling routine follow-up. Effect measures included generic health-related quality of life (HR-QoL; EuroQol Five-Dimensional Questionnaire); disease-specific HR-QoL (functional outcome, different validated questionnaires, converted to 0-100 scale); treatment satisfaction (Visual Analog Scale (VAS), 1-10); and pain (VAS, 1-10). All data were assessed using a 3-month postinjury survey and electronic patient records. Incremental cost-effectiveness ratios were calculated and uncertainty was assessed using bootstrapping techniques. RESULTS: Before DD, 144 of 348 participants completed the survey versus 153 of 371 patients thereafter. There were no statistically significant differences between the pre-DD cohort and the DD cohort for generic HR-QoL (0.03; 95% CI -0.01 to 0.08), disease-specific HR-QoL (4.4; 95% CI -1.1 to 9.9), pain (0.08; 95% CI -0.37 to 0.52) and treatment satisfaction (-0.16; 95% CI -0.53 to 0.21). Total societal costs were lowest in the DD cohort (-€822; 95% CI -€1719 to -€67), including healthcare costs (-€168; 95% CI -€205 to -€131) and absenteeism costs (-€645; 95% CI -€1535 to €100). The probability of DD being cost-effective was 0.98 at a willingness-to-pay of €0 for all effect measures, remaining high with increasing willingness-to-pay for generic HR-QoL, disease-specific HR-QoL, and pain, and decreasing with increasing willingness-to-pay for treatment satisfaction. DISCUSSION: DD from the ED of patients with SSI seems cost-effective from a societal perspective. Future studies should test generalizability in other healthcare systems and strengthen findings in larger injury-specific cohorts. LEVEL OF EVIDENCE: II.