Krithika Suresh

Background: Prostate‐specific antigen (PSA) screening prevents prostate cancer death but also leads to overdiagnosis—diagnosis that would not occur during a man’s lifetime without screening—particularly in older men and those with life‐limiting comorbidities. Modern screening approaches attempt to mitigate overdiagnosis in older men by using a higher PSA threshold for further evaluation using magnetic resonance imaging (MRI), and discontinuing screening in men with low PSA levels. However, long‐term harms and benefits have not been estimated. Methods: Two microsimulation models estimated lifetime harms and benefits of modern screening approaches in men who were screened biennially at ages 50–70 years, remained undiagnosed with prostate cancer at age 72 years, and faced varying risks of competing mortality based on previously estimated comorbidity‐adjusted life tables. Results: By using a PSA threshold of 6.5 ng/mL for evaluation with MRI and MRI‐targeted biopsy, estimated ratios of overdiagnoses to cancer deaths prevented were similar when all men aged 70 years or older continued screening versus when only in men with PSA levels ≥ 3.0 ng/mL continued screening. For men with no comorbidities, this ratio increased from 2.7–3.1 at age 72 years to 4.5–5.1 at age 76 years. For men with severe comorbidities, this ratio increased from 9.6–10.2 at ages 72 to 11.3–12.6 at 76 years. Conclusions: Even using modern approaches, the ratio of overdiagnoses per cancer death prevented increases with age and is at least double in men with severe life‐limiting comorbidities compared with age‐matched men with no comorbidities. The current results can help inform patients and providers about when to stop PSA screening.

In resource-limited or time-sensitive care settings, there is interest in assessing the impact of time to treatment (TTT) on mortality. Traditional Cox proportional hazards models, which specify the effect of TTT as an unrestricted term in the log hazard ratio, can produce counterintuitive results where the survival probability may not decrease monotonically with longer delays. Moreover, hazard ratios from such models quantify the effect of TTT conditional on surviving until treatment, rather than the effect of delayed treatment at baseline. We propose a class of bounded hazard ratio (BHR) Cox models that constrain the hazard ratio for TTT to attenuate towards the null with increasing treatment delay, such that hazard for death after treatment cannot exceed the hazard without treatment. Estimation can be performed using direct optimization of the partial log-likelihood or with an iterative linearized estimation procedure for large sample sizes. From BHR models, the estimated hazard ratio curve describes how treatment benefit diminishes with delay. Additionally, we propose a survival probability difference that provides an absolute measure for comparing survival under different treatment delays. We evaluate model performance in simulations and apply the method to examine treatment delays for colon cancer with data from the National Cancer Database.

Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC), but clinical trials are lacking. This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The co-primary endpoints are determination of dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy +/- carboplatin. Secondary endpoints include safety, survival, and RR by tumor histology. After enrollment of 4 patients to combination therapy, the trial was modified to a single arm study of alrizomadlin monotherapy due to excess toxicity. 1 DLT was seen in the combination arm, all patients had ≥ G3 treatment related adverse events (TRAE). 37 patients were enrolled to alrizomadlin monotherapy. 3 DLTs were encountered, 67% of patients had ≥ G3 TRAE. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC.

Background: More young women than men experience first‐time strokes. This may be from improved detection of milder severity strokes in young women, as they are more likely to present with nondebilitating neurologic symptoms than men. Methods: The objective was to examine sex differences in stroke severity among young adults. Young adults (18–55) with index stroke (January 1, 2012–April 3, 2019) were identified, using Colorado All Payer's Claims Database and linked to the GWTG (Get With The Guidelines)‐Stroke Registry. Records were reviewed based on 5/5 linked identifiers (±1 day for admission/discharge dates, date of birth, sex, and hospital), then on 4/5 linked identifiers. Stroke severity based on National Institutes of Health Stroke Scale score was extracted from GWTG‐stroke. Logistic regression models were used to calculate odds ratios (OR) of having a mild severity stroke (National Institutes of Health Stroke Scale score ≤5) by sex in ages 18 to 45 and 46 to 55 years. Results: Colorado All Payer's Claims Database captured 3029 stroke cases; 2732 from hospitals that reported to GWTG‐Stroke; 1597 (58.7%) linked at least 4/5 identifiers; 1311 with National Institutes of Health Stroke Scale score (50.2% women, 80% ischemic). Women were younger (mean age 45.4 years, men 46.9 years, P =0.001), had lower blood pressure (median 143/85, men 150/91, P P P =0.02) but not in 46–55 (OR, 1.02 [95% CI, 0.5–2.08]). There was no difference in ischemic stroke severity by sex in either age group. Conclusions: Young women with index strokes did not present with more milder severity strokes compared with men.

Purpose: Prostate cancer treatment with ¹⁷⁷ Lu-PSMA-617 depends on specific binding to the PSMA protein. If receptors become saturated by the radioligand, the uptake of the drug may be affected. Our goal was to measure the pharmacological effect of standard 7.4 GBq (200 mCi) administration of ¹⁷⁷ Lu-PSMA-617 based on the uptake of ⁶⁸ Ga-PSMA-11 on subsequent PET. Patients and Methods: We performed ⁶⁸ Ga-PSMA-11 PET/CT within 0.5–75 hours after cycle 1 of therapy administration in 6 patients with metastatic castrate-resistant prostate cancer who volunteered for imaging. SUV _mean of tumors (N=27) and organs, stratified by early (mean for tumor, kidney, parotid gland, and liver among patients imaged early after therapy, with an average change in tumor SUV of −45% (95% CI: −66% to −25%; P P =0.42). Conclusions: There are measurable decreases in PSMA binding following ¹⁷⁷ Lu-PSMA-617 that resolve over time. As trials consider alternative therapeutic strategies, increasing dosage per cycle alone may not proportionally increase tumor uptake. Our findings warrant validation with a larger number of subjects, standardized post-therapy scan timing, and advanced pharmacokinetic analyses.

Data Supplement -FDG Calculation Methods