Citations

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

AbstractBackgroundClinical picture and outcome of incidental pulmonary embolism (iPE) compared to symptomatic pulmonary embolism (sPE) remain unclear.MethodsDemographics, recurrent venous thromboembolism (VTE), mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) were compared between iPE and sPE patients who were followed prospectively at Mayo Thrombophilia Clinic (March 1, 2013 to August 1, 2020).ResultsOut of 3576 VTE patients, 1417 (39.6%) had PE: 562 (39.7%) iPE and 855 sPE. Patients with cancer were more likely to have iPE (400 iPE vs. 314 sPE) compared to those without cancer (162 iPE vs. 541 sPE). VTE recurrence rate (all per 100 person‐years) was similar in all iPE and sPE patients (3.34 vs. 3.68, p = .50), with cancer (4.16 vs. 4.89, p = .370), and without cancer patients (0.89 vs. 2.80, p = .25). Higher mortality observed in all patients with iPE compared to sPE (46.45 vs. 23.47, p < .001) and with cancer (56.41 vs. 45.77, p = .03) became not significant after adjustment for age, antiplatelet therapy, metastases, and cancer location. Noncancer iPE patients had higher mortality (15.95 vs. 7.18, p = .006) even after adjustment (p = .05). The major bleeding rate was also higher in all patients iPE compared to sPE (7.10 vs. 3.68, p = .03), but not after adjustment (p = .974); higher major bleeding rate in noncancer patients (6.49 vs. 1.25, p = .007) remained significant after adjustment (.02). CRNMB rate was similar to iPE and sPE patients.ConclusioniPE represents a more serious clinical condition compared to sPE as indicated by the higher mortality and major bleeding but these differences reflect underlying comorbidities rather than the seriousness of the embolic event.

Purpose: Erdafitinib is a fibroblast growth factor receptor inhibitor indicated for the treatment of cancer. A case of fibroblast growth factor receptor inhibitor–associated retinopathy that resulted in significant visual symptoms and chronic subretinal abnormalities is reported. Methods: A 73-year-old man with a history of relapsed multiple myeloma was treated with erdafitinib. Soon after his fourth treatment cycle, he developed blurred vision in both eyes. Therapy with erdafitinib was subsequently discontinued. Results: Funduscopic examination and optical coherence tomography of both eyes revealed multifocal subretinal fluid in the macula of both eyes. Eleven weeks after cessation of the erdafitinib, the visual acuity improved but the patient reported bilateral annular scotomas. Evaluation was notable for resolution of the subretinal fluid with the development irregular subfoveal thickening in both eyes. The patient's symptoms improved, but the subfoveal abnormalities were persistent at 14 months follow-up. Conclusion: Erdafitinib may be associated with permanent retinal pigment epithelium toxicity.

6589 Background: Real-world utilization and comparative effectiveness of direct oral anticoagulants (DOACs), low molecular weight heparin (LMWH) and warfarin for cancer-associated venous thromboembolism (VTE) treatment remains largely unexplored. Methods: De-identified administrative claims data (OptumLabs - Data Warehouse) for adult active cancer patients with acute VTE (1/1/2012-9/30/2019) were assessed for utilization patterns, recurrent VTE, and major bleeding differences between DOACs, LMWH, and warfarin. Patients were followed up till the end of treatment. Patients who crossed over to other anti-coagulants within the follow up period were excluded. Multinomial logistic regression was used to assess predictors of anticoagulant administration. Kaplan-Meier curves were used to evaluate the differences in time to medication discontinuation among the three groups. Propensity score (PS) and inverse probability of treatment weighting were used to balance baseline differences between groups. Standardized difference (SD) was used to assess the balance of covariates after weighting and SD < 10% was considered acceptable. Weighted Cox proportional hazards regression with a robust variance estimator was then used to assess outcomes in PS weighted groups. Results: A total of 5100 patients met the inclusion criteria; 49.3% filled DOACs (n = 2512), 29.2% LMWH (n = 1488), and 28.6% warfarin (n = 1460). Median treatment duration was around 3.2 months for DOACs and warfarin, and 1.8 months for LWMH ( P-value < 0.01). Multinomial regression analysis showed that younger patients were more likely to be prescribed LMWH (OR 0.97 95% CI: 0.97-0.98) as compared to DOACs. Patients with lung (OR 2.07 95% CI: 1.12-3.65; OR 1.87 95% CI: 1.04-3.37), urological (OR: 1.94 95% CI:1.08-3.49; OR: 2.04 95% CI: 1.12-3.73), gynecological (OR 4.25, 95% CI: 2.31-7.82; OR 2.31 95% CI: 1.22-4.39) and colorectal cancer (OR 2.26 95% CI: 1.20-4.32; OR 2.51; 95% CI: 1.32-4.79) were more likely to be prescribed LMWH or warfarin respectively, compared to DOACs. VTE recurrences were more frequent for patients receiving LMWH (HR: 1.47; 95% CI: 1.14-1.90) or warfarin (HR: 1.46; 95% CI: 1.13-1.87) compared to DOACs. LMWH, but not warfarin, was associated with greater major bleeding rates compared to DOACs (HR: 2.27; 95% CI: 1.62-3.20). All-cause mortality rates were also significantly higher for patients receiving LMWH, but not warfarin compared to DOACs (HR: 1.61; 95% CI: 1.15-2.25). Conclusions: Patients with cancer associated VTE remain on anti-coagulation for a remarkably short duration in real-world clinical practice. DOACs and warfarin may offer better compliance than LMWH. Patients receiving DOACs have a lower risk of VTE recurrence, less major bleeding, and improved mortality. Warfarin may still be considered for patients with contraindications to DOACs and non-compliant to LMWH.

An 88-year-old woman with a history of exudative age-related macular degeneration presents with persistent subretinal fluid and enlarging pigment epithelial detachments. What would you do next?

Background: Patients with peripheral artery disease (PAD) are at increased risk for major adverse limb and cardiac events including mortality. Developing screening tools capable of accurate PAD identification is a necessary first step for strategies of adverse outcome prevention. This study aimed to determine whether machine analysis of a resting Doppler waveform using deep neural networks can accurately identify patients with PAD. Methods: Consecutive patients (4/8/2015 – 12/31/2020) undergoing rest and postexercise ankle–brachial index (ABI) testing were included. Patients were randomly allocated to training, validation, and testing subsets (70%/15%/15%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict normal (> 0.9) or PAD (⩽ 0.9) using rest and postexercise ABI. A separate dataset of 151 patients who underwent testing during a period after the model had been created and validated (1/1/2021 – 3/31/2021) was used for secondary validation. Area under the receiver operating characteristic curves (AUC) were constructed to evaluate test performance. Results: Among 11,748 total patients, 3432 patients met study criteria: 1941 with PAD (mean age 69 ± 12 years) and 1491 without PAD (64 ± 14 years). The predictive model with highest performance identified PAD with an AUC 0.94 (CI = 0.92–0.96), sensitivity 0.83, specificity 0.88, accuracy 0.85, and positive predictive value (PPV) 0.90. Results were similar for the validation dataset: AUC 0.94 (CI = 0.91–0.98), sensitivity 0.91, specificity 0.85, accuracy 0.89, and PPV 0.89 (postexercise ABI comparison). Conclusion: An artificial intelligence-enabled analysis of a resting Doppler arterial waveform permits identification of PAD at a clinically relevant performance level.