Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.

Importance: In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. Objective: To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. Design, Setting, and Participants: In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Main Outcomes and Measures: Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Results: Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. Conclusions and Relevance: In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma.

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.

Impact of an Emergency Department Observation Unit Management Algorithm for Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a common, growing, and costly medical condition. We aimed to evaluate the impact of a management algorithm for symptomatic AF that used an emergency department observation unit on hospital admission rates and patient outcomes. METHODS AND RESULTS: This retrospective cohort study compared 563 patients who presented consecutively in the year after implementation of the algorithm, from July 2013 through June 2014 (intervention group), with 627 patients in a historical cohort (preintervention group) who presented consecutively from July 2011 through June 2012. All patients who consented to have their records used for chart review were included if they had a primary final emergency department diagnosis of AF. We observed no significant differences in age, sex, vital signs, body mass index, or CHADS2 (congestive heart failure, hypertension, age, diabetes mellitus, and prior stroke or transient ischemic attack) score between the preintervention and intervention groups. The rate of inpatient admission was significantly lower in the intervention group (from 45% to 36%; P<0.001). The groups were not significantly different with regard to rates of return emergency department visits (19% versus 17%; P=0.48), hospitalization (18% versus 16%; P=0.22), or adverse events (2% versus 2%; P=0.95) within 30 days. Emergency department observation unit admissions were 40% (P<0.001) less costly than inpatient hospital admissions of ≤1 day's duration. CONCLUSIONS: Implementation of an emergency department observation unit AF algorithm was associated with significantly decreased hospital admissions without increasing the rates of return emergency department visits, hospitalization, or adverse events within 30 days.

Evaluation of the National Comprehensive Cancer Network and American Urological Association renal cell carcinoma surveillance guidelines.

PURPOSE: The National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) provide guidelines for surveillance after surgery for renal cell carcinoma (RCC). Herein, we assess the ability of the guidelines to capture RCC recurrences and determine the duration of surveillance required to capture 90%, 95%, and 100% of recurrences. PATIENTS AND METHODS: We evaluated 3,651 patients who underwent surgery for M0 RCC between 1970 and 2008. Patients were stratified as AUA low risk (pT1Nx-0) after partial (LR-partial) or radical nephrectomy (LR-radical) or as moderate/high risk (M/HR; pT2-4Nx-0/pTanyN1). Guidelines were assessed by calculating the percentage of recurrences detected when following the 2013 and 2014 NCCN and AUA recommendations, and associated Medicare costs were compared. RESULTS: At a median follow-up of 9.0 years (interquartile range, 5.7 to 14.4 years), a total of 1,088 patients (29.8%) experienced a recurrence. Of these, 390 recurrences (35.9%) were detected using 2013 NCCN recommendations, 742 recurrences (68.2%) were detected using 2014 NCCN recommendations, and 728 recurrences (66.9%) were detected using AUA recommendations. All protocols missed the greatest amount of recurrences in the abdomen and among pT1Nx-0 patients. To capture 95% of recurrences, surveillance was required for 15 years for LR-partial, 21 years for LR-radical, and 14 years for M/HR patients. Medicare surveillance costs for one LR-partial patient were $1,228.79 using 2013 NCCN, $2,131.52 using 2014 NCCN, and $1,738.31 using AUA guidelines. However, if 95% of LR-partial recurrences were captured, costs would total $9,856.82. CONCLUSION: If strictly followed, the 2014 NCCN and AUA guidelines will miss approximately one third of RCC recurrences. Improved surveillance algorithms, which balance patient benefits and health care costs, are needed.

Practice-based clinical evaluation of ceramic single crowns after at least five years.

STATEMENT OF PROBLEM: Long-term practice-based clinical evaluations of various contemporary ceramic crown restorations from multiple practitioners are limited. PURPOSE: The aims of this study were to evaluate the clinical performance of ceramic single crowns and to identify factors that influence their clinical performance. MATERIAL AND METHODS: Ceramic single crowns that had been placed at the Mayo Clinic and in function since 2005 were identified and included in the study. The restorations were examined clinically, radiographically, and with photographs. Modified United States Public Health Services criteria were used for the clinical evaluation. The ceramic systems evaluated were bilayer and monolayer. RESULTS: Fifty-nine patients (41 women, 18 men) with 226 single teeth and implants restored with single ceramic crowns were identified. The mean duration from insertion date to study examination date was 6.1 years. Thirteen restorations (6%) were replaced at a mean 3.3 years after insertion date (range, 0.1-6.1 years). Estimated replacement-free survival rates (95% confidence interval [CI]; number of teeth/implants still at risk) at 5 years after insertion date were 95.1% (95% CI, 92.2-98.1; 153) and at 10 years were 92.8% (95% CI, 89.1-96.8; 8). The most common reason for replacement was fracture to the core of posterior layered ceramic crowns. The most commonly used luting agent was resin-modified ionomer cement. Most restorations exhibited clinically acceptable marginal integrity, shade, no caries recurrence, and no periapical pathology. CONCLUSIONS: The clinical performance of ceramic single crowns at 5 and 10 years supports their application in all areas of the mouth. With the majority of fractures to the core occurring early in the lifetime of layered ceramic posterior crowns, consideration of other monolithic ceramic systems for posterior crowns is advised.