Citations

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Abstract Background Anaplastic sarcoma of the kidney (ASK) is a DICER1 ‐related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1 ‐related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. Methods Individuals with known or suspected DICER1 ‐related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. Results Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two‐year event‐free survival (EFS) for stage I–II ASK was 81.8% (95% confidence interval [CI]: 67.2%–99.6%), compared with 46.6% EFS (95% CI: 24.7%–87.8%) for stage III–IV ( p = .07). Two‐year overall survival (OS) for stage I–II ASK was 88.9% (95% CI: 75.5%–100.0%), compared with 70.0% (95% CI: 46.7%–100.0%) for stage III–IV ( p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02–0.31) and 0.08 (95% CI: 0.02–0.42), respectively. Conclusion ASK is a rare DICER1 ‐related renal neoplasm. In the current report, we identify clinical and treatment‐related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Abstract VEXAS (vacuoles, E1-ubiquitin-like modifier activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described autoinflammatory disorder caused by acquired UBA1 mutations in hematopoietic precursor cells. The prevalence, clinical significance, and genomic landscape of UBA1variants in patients with hematologic malignancies (HM) remains unexplored. We analyzed the genomic profiles of 86 patients carrying 17 different UBA1variants amongst an unbiased cohort of 8,976 HM patients. Specific genetic and clinical features seen more frequently in patients with UBA1 pathogenic variants (PV) versus those with variants of uncertain significance (VUS) included: marked male predominance (98% versus 80%, P=0.002), macrocytic anemia (MCV 105 ± 1.4 fl versus 96 ± 1.4 fl, p=0.01), frequent dominant clones without concurrent somatic variants (53% versus 15%, p=0.004), and association with molecularly distinct low-risk myelodysplastic syndrome (MDS; 13%) with superior overall survival (OS). Interestingly, while the genetic profiles of UBA1 PV patients resemble patients with clonal cytopenia of unknown significance (CCUS), rapid UBA1 clonal expansion predispose patients to convert to low-grade MDS with a notably hastened progression compared to UBA1 wild-type CCUS. This “clone surge to clinical stability” (CS) is a mechanism that emphasizes the unique pathobiology of UBA1mutations in VEXAS and supports it as a distinct entity.

Abstract The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP‐NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP‐NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP‐NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP‐NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

Background: Arsenic is a well-known toxin which may contaminate household water. It is harmful when ingested over prolonged periods of time. As a result, public health experts recommend that water should be screened and treated to prevent arsenic ingestion. In the United States, the responsibility of testing and treatment of private wells falls on homeowners. Despite recommendations for routine screening, this is rarely done. Objectives: To assess the prevalence of well water use in a Midwestern patient population, how patients and clinicians perceive the risks of arsenic in well water, and whether additional resources on well water testing are desired. These findings will be used to influence tools for clinicians regarding symptom and examination findings of chronic arsenic exposure and potentiate the distribution of informational resources on well water testing. Methods: Surveys were sent via email to all actively practicing primary care clinicians at the Mayo Clinic in the United States Midwest, and all active adult patients at the Mayo Clinic in the same region. Our team analyzed survey data to determine whether both patients and clinicians are aware of the health effects of chronic arsenic toxicity from well water, the need for routine well water testing and whether each group wants more information on the associated risks. Results: Both patients and primary care clinicians worry about arsenic exposure. Patients with well water are concerned about their water safety yet feel uninformed about testing options. Clinicians do not know how prevalent well water use is among their patients, feel uninformed about the chronic risks of arsenic exposure and the physical examination associated with it. Both groups unanimously want more information on testing options. Conclusions: Our findings show a significant reliance on well water use in the American Midwest, and unanimous support for the need for further well water testing information and resources for patients and their clinicians.

Abstract Purpose Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non‐RCR). Patients and methods This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi‐square tests were conducted for differences among groups. Kaplan–Meier curves were generated for OS and pulmonary relapse. Results Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five‐year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR ( p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17–0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16–0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non‐RCR groups ( p = .14). Five‐year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non‐RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). Discussion Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Introduction: Atrial Fibrillation (AF) is an important contributor to insufficient left ventricular pacing and mortality in patients undergoing cardiac resynchronization therapy (CRT). The incidence and prevalence of AF post-CRT implant, in patients with and without previous history of AF, has not previously been described. Hypothesis: AF prevalence in CRT patients, despite history of AF, is higher than previously understood. Methods: Subjects implanted with a CRT-Defibrillator (CRT-D) enrolled in the PainFree SST study and with device data collection were analyzed. Subjects who exited within 30 days of implant, had < 27 days of available daily AT/AF burden data, or had ≥ 10% of daily AT/AF data missing were excluded. We defined incidence and prevalence of clinically meaningful device documented AF using previously published criteria (≥1 day with AF > 6 hours). History of AF at enrollment was documented based on clinical history. Results: The analysis included 944 patients (68±11 years; 78% male, EF 28±9%, QRS 152±29 ms; 59% NYHA III/IV). The duration from implant to study exit or death was 2.0 ± 0.8 years (IQR 1.5-2.5). History of AT/AF was documented in 37% of patients at baseline. Overall, any AT/AF was found in 85.2 % of subjects during follow-up. Clinically meaningful AT/AF was found in 30.3% of subjects. Of the 345 subjects with history of AF at baseline, 51.9% had clinically meaningful AT/AF during follow-up vs.17.9% for subjects without known AF (p<0.0001). 24.8% of subjects experienced at least one day of ≥ 23h of AT/AF. 6.9% of subjects had ≥ 23h of AT/AF for > 95% of days with data. Conclusions: AF occurs in a substantial proportion of CRT-D patients and clinically documented history of AF prior to CRT-D implant corresponds poorly with device documented AT/AF during follow-up. Device documented AF should be evaluated in CRT-D patients with and without previous history of AF to individualize strategies to maximize left ventricular pacing and minimize disruption due to AF.

Device infection is associated with increased mortality in cardiovascular implantable electronic device (CIED) recipients. However, published data regarding clinical predictors of mortality in patients with CIED infection are limited. In current investigation, we sought to identify patient and device-related factors associated with mortality in CIED infection cases. We performed a retrospective review of all cases of CIED infection admitted to Mayo Clinic Rochester from 1991 to 2008. Survival data were obtained from hospital medical records and United Sates Social Security Index. Key data regarding patient demographics, device features, comorbid conditions, clinical presentation, echocardiographic findings and management strategies were abstracted. Potential risk factors for short (30-day) and long-term mortality were analyzed using univariate and multivariable logistic and Cox proportional hazards regression models, respectively. 415 cases of CIED infection were identified from the institutional database. The mean duration of follow-up for the 243 patients who were alive at last follow-up was 6.9 years. In multivariable model, congestive heart failure (CHF, Odds ratio 9.31, 95% CI 2.08-41.67), chronic corticosteroid use (OR 4.04, 1.40-11.60) and presentation with CIED-related infective endocarditis (CIED-IE), (OR 5.6, 2.25-13.92) were associated with increased odds of short-term mortality. Independent predictors of long-term mortality on multivariable model included patients' age (hazard ratio for 10-year increase 1.2, 95% CI 1.06-1.36), CHF (HR 2.01, 1.42-2.86), metastatic malignancy (HR 5.99, 1.67-21.53), corticosteroid use (HR 1.97, 1.22-3.18), renal failure (HR 1.94, 1.37-2.74) and CIED-IE (HR 1.68, 1.17-2.41). Our investigation provides some novel insights into predictors of short- and long-term mortality in CIED infection cases. While comorbid conditions and immunocompromised host status were primary determinants of both short- and long-term mortality, complicated device infection (CIED-IE) is the only predictor that presents an opportunity for intervention where mortality may be reduced by early diagnosis and expedited device removal.