Duke Medical Center

The current AJCC medullary thyroid cancer (MTC) staging system anatomically stratifies lymph node (LN) status but does not incorporate quantitative assessment of LN metastases. Our past work identified ≥ 8 positive LNs and LN ratio (LNR) ≥ 14% as associated with significantly increased MTC-specific mortality. In this study, we 1) validate these thresholds using the NCDB and 2) compare them to the current AJCC staging system. In this retrospective cohort study, patients with MTC were abstracted from NCDB (2004-2020). Chi-square and Fisher's exact tests compared categorical variables, and t-tests continuous variables. Overall survival (OS) was estimated with Kaplan-Meier and log-rank testing. Cox Proportional hazards models estimated the association of LN thresholds with OS after adjusting for covariates. There were 5685 patients (median age: 55years; 56.4% female; 74.3% non-Hispanic White). The 5-year OS was 78.2% (95% confidence interval [CI] 76.4-79.9) for LNR ≥ 14% and 93.9% (95% CI 92.9-94.8) for LNR < 14%. For ≥ 8 positive LNs, 5-year OS was 77.2% (95% CI 74.8-79.4) versus 90.4% (95% CI 89.4-91.4) for < 8. After adjustment, LNR ≥ 14% was associated with a 44% increased mortality risk (hazard ratio [HR] 1.44, 95% CI 1.10-1.88, p = 0.008); ≥ 8 positive LNs conferred a 37% increased hazard (HR 1.37, 95% CI 1.13-1.66, p = 0.001). Neither AJCC N-stage nor nodal status was associated with a significant adjusted hazard difference. Previously identified prognostic LN thresholds for MTC were valid in the NCDB. A LNR ≥ 14% and ≥ 8 positive LNs provide better prognostic discrimination than the current AJCC system and aid refinement of the current MTC staging system.

Venetoclax plus azacitidine or decitabine is approved in the US for treatment of newly diagnosed patients with acute myeloid leukemia (AML) aged ≥ 75years or who have comorbidities precluding use of intensive chemotherapy. As novel targeted regimens expand treatment options for AML, this study evaluated the budget impact of adopting venetoclax combinations for this population from a US third-party payer perspective to inform affordability and access at the health plan level. The model estimated the 3-year budget impact of adopting venetoclax combinations in a hypothetical US health plan with 1 million members (60% commercial, 40% Medicare). Eligible patients were estimated using public data. Market share projections assumed venetoclax + azacitidine or decitabine captured a 53% and 15% share, respectively, from existing treatments (azacitidine, low-dose cytarabine [LDAC], decitabine, ivosidenib, gemtuzumab ozogamicin, glasdegib + LDAC, and ivosidenib + azacitidine). The model considered costs associated with drug acquisition/administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management (2024 USD). Clinical inputs for venetoclax combinations were informed by final VIALE-A and M14-358 data, respectively. Incremental budget impact was calculated as per-member-per-month (PMPM), with one-way sensitivity analyses performed. In a 1-million-member health plan, 48 patients were eligible for venetoclax combinations. Annual costs of venetoclax + azacitidine ($258,498) or decitabine ($259,921) were lower than those of the highest-cost comparators, ivosidenib + azacitidine ($477,520) and ivosidenib ($404,869). Drug acquisition costs of adopting venetoclax combinations were offset by lower subsequent AML management costs, resulting in savings of $0.0476 PMPM in years 1-3. Results remained robust in sensitivity analyses. In a 100% Medicare scenario, 117 patients were eligible for venetoclax combinations, with savings of $0.1137 PMPM over years 1-3. Inclusion of venetoclax combinations for newly diagnosed patients with AML aged ≥ 75years or with comorbidities precluding intensive chemotherapy reduced the budget impact, providing potential financial benefits for US payers.

Although validated prognostic models exist for men with metastatic castration-resistant prostate cancer (mCRPC), current tools do not incorporate genomic biomarkers such as circulating tumor DNA (ctDNA) aneuploidy or pathogenic genetic alterations (PGAs). This study aimed to estimate the prevalence of PGAs in ctDNA, assess their correlation with ctDNA aneuploidy fraction, and evaluate their association with overall survival (OS). Additionally, we developed and validated a clinical-genetic (CG) model to predict OS. We analyzed ctDNA from 776 patients enrolled in the Alliance phase 3 trial (A031201). PGAs were derived using the AR-ctDETECT assay. The net reclassification improvement (NRI) evaluated the added value of the CG model, and the time-dependent area under the receiver operating characteristic curve (tAUC) assessed the accuracy of the OS model. Feature selection using random survival forest identified gains in androgen receptor (AR), AR enhancer, MYC, RSPO2, CCND1, BRAF, and MET; losses or pathogenic variants in ZBTB16, PTEN, MSH6, PPP2R2A, NKX3-1, ZFHX3, TP53, ZNFR3, RB1, FANCA, CHECK1, APC, and CHD1; and a pathogenic AR variant. The CG model significantly outperformed the clinical model, with an average tAUC of 0.77 (95% confidence interval [CI]: 0.73-0.79) for the CG model compared with the tAUC of 0.72 (95% CI: 0.69-0.75, p=0.01) for the clinical model, and NRI of 0.29 between the models. Patients were categorized by the predicted risk scores into poor-, intermediate-, and low-risk groups with median OS of 19.6, 33.6, and 60.8mo, respectively. Incorporation of PGAs from ctDNA into a CG model improved OS prediction by nearly 30% over a clinical model. This model can classify patients into risk groups and is useful for selecting patients in future mCRPC trials.

To perform a systematic review and meta-analysis evaluating the efficacy and safety of preoperative silodosin in improving ureteroscopy (URS) outcomes for ureterolithiasis. PubMed, EMBASE and Cochrane Central were systematically searched for studies comparing preoperative silodosin with placebo or 'no preoperative silodosin' in patients undergoing URS for ureteral stones. Primary outcomes included ureteral wall injury, analgesia use, fever, haematuria, stone-free rate (SFR), operative time, and complications. Statistical analysis was performed using Review Manager 5.1.7. Study quality and risk of bias were assessed per Cochrane guidelines. Nine studies, including eight randomized clinical trials, including 960 patients were analysed; 450 (46.8%) received silodosin. Compared to controls, silodosin significantly reduced ureteral injuries (RR 0.30; 95% CI: 0.18-0.49; p < 0.00001) and operative time (MD -17.72 minutes; 95% CI: -24.72 to -10.72; p < 0.00001). It also lowered analgesia needs (RR 0.35; 95% CI: 0.16-0.75; p = 0.007), with trends toward reduced fever (RR 0.67; 95% CI: 0.36-1.22; p = 0.19) and haematuria (RR 0.57; 95% CI: 0.32-1.02; p = 0.06). In studies with ≥10 days of preoperative use, silodosin significantly improved SFR (RR 1.17; 95% CI: 1.10-1.26; p < 0.00001). Preoperative silodosin reduces ureteral injuries, operative time, and complications, supporting its use to improve safety and efficiency of URS for ureterolithiasis.