Citations

Context.— Detecting copy number variations (CNVs) at certain loci can aid in the diagnosis of histologically ambiguous melanocytic neoplasms. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and inexpensive method for CNV detection in other cancers, but not yet melanoma. Objective.— To evaluate the performance of a 4-gene ddPCR panel that simultaneously tests for ras responsive binding element protein 1 (RREB1) gain; cyclin-dependent kinase inhibitor 2A (CDKN2A) loss; MYC proto-oncogene, bHLH transcription factor (MYC) gain; and MYB proto-oncogene, transcription factor (MYB) loss in melanocytic neoplasms. Design.— One hundred sixty-four formalin-fixed, paraffin-embedded skin samples were used to develop the assay, of which 65 were used to evaluate its performance. Chromosomal microarray analysis (CMA) data were used as the gold standard. Results.— ddPCR demonstrated high concordance with CMA in detecting RREB1 gain (sensitivity, 86.7%; specificity, 88.9%), CDKN2A loss (sensitivity, 80%; specificity, 100%), MYC gain (sensitivity, 70%; specificity, 100%), and MYB loss (sensitivity, 71.4%; specificity, 100%). When one CNV was required to designate the test as positive, the 4-gene ddPCR panel distinguished nevi from melanomas with a sensitivity of 78.4% and a specificity of 71.4%. For reference, CMA had a sensitivity of 86.2% and a specificity of 78.6%. Our data also revealed interesting relationships with histology, namely (1) a positive correlation between RREB1 ddPCR copy number and degree of tumor progression; (2) a statistically significant correlation between MYC gain and nodular growth; and (3) a statistically significant correlation between MYB loss and a sheetlike pattern of growth. Conclusions.— With further validation, ddPCR may aid both in our understanding of melanomagenesis and in the diagnosis of challenging melanocytic neoplasms.

Background: Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials. Methods: A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale. Results: Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood’s lamp, dermatoscope, and negative tissue controls was established in Round 2. Conclusions: This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.

Importance Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration–approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs. Observations This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males. Conclusions and Relevance Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.

Strategic projects in large healthcare organisations are often highly complex and dynamic, and they require a team of skilled business professionals to execute them. Examples of difficult, costly and extended project executions have been shared in the literature. Successful project execution involves many critical facets. One facet that continues to be of marked interest is effective resourcing of strategic projects. This paper focuses on describing a staffing approach used at Mayo Clinic (Rochester, Minnesota) to facilitate successful, agile and sustainable execution, with desired outcomes. In 2016, Management Engineering & Consulting (ME&C) began exploring a collaborative staffing model that partnered management engineers with project managers (PMs) to drive strategic, multisite projects. This ongoing collaboration model was evaluated from multiple perspectives, including project outcomes, timeliness, client and staff satisfaction and opportunities for innovation. Data and feedback on the model were collected with historical reports, surveys and focus groups with stakeholders, leaders, PMs and management engineers. The feedback and data indicated that the collaborative staffing strategy and model have further optimised service delivery, enabled professional staff to work at the highest level of their competency and dynamically blended knowledge, expertise and skills to achieve better and more sustainable overall project outcomes.

In 2018, Mayo Clinic completed the largest transformational project in its 150-year history. Mayo Clinic was prepared to take on the implementation of new software systems (Epic Systems Corp) as an integrated electronic health record (EHR) and revenue cycle management (RCM) system across all sites of the enterprise. Three foundational teams were launched for this project: leadership, project management and change management. In a project such as this, a common pitfall is to focus completely on the system and lose sight of the end users. For Mayo Clinic, the people side of change was at the forefront of the project. A robust change management team was budgeted, staffed and engaged with an experienced outside consulting partner. A goal for the change management team centred on the best way to measure the change management impact and the degree to which it was making a positive contribution in driving successful adoption of the new EHR and RCM system. With literature lacking in this area, the team moved forward with courage and quickly learned that the easy part was the development of a survey with questions mapped to the six components of the change management strategy and the phases of the awareness, desire, knowledge, ability, reinforcement (ADKAR) Model (Prosci Inc). The hard part was building the infrastructure to visually display millions of rows of data that needed to be positioned, filtered and analysed for all affected locations. The authors share the methods to measure change and explain the importance of developing a comprehensive and robust means of gathering and displaying large volumes of change management data at the project onset. This paper prepares the reader to confidently develop an organisational framework to measure and report the effectiveness of a change management strategy.

As project leaders plan large, transformational initiatives, impacted departmental leaders are often forgotten. Operational leaders are in need of a practical, concise guide to prepare for project activities and allocate resources. The Plummer Project change management team of Mayo Clinic created a single source of timelines and tasks with links to more detailed information, termed a ‘playbook’ for operational leaders. The tool was dynamic and provided the operations-relevant project timeline, required preparedness activities and essential references. This paper analyses the format and content of this playbook to assist other organisations with the execution of complex projects. The playbook provided clarity, efficiency and cohesiveness with deep benefits to the project team and organisation.

Abstract This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.

Background Pulmonary atresia with ventricular septal defect without major aortopulmonary collateral arteries (MAPCAs) is an uncommon form of congenital heart disease. As more patients with congenital heart disease live to adulthood, the objective of this article was to review the long-term results of this specific population. Methods A review of the PubMed database was performed using pertinent key words (pulmonary atresia, tetralogy of Fallot, conduit, right ventricle-pulmonary artery) concentrating on studies from 1990-present and published in English. Most studies of pulmonary atresia-ventricular septal defect patients included those with and without MAPCAs. Analysis included examination of the entire cohort, consideration of the proportion of patients with MAPCAs, and any subgroup analysis of the patients without MAPCAs. Results Survival is approximately 80% at ten years and is improved with complete repair and larger pulmonary arteries. Some studies have found genetic syndromes and extracardiac anomalies to impact survival, while others have not. Incomplete repair has been shown to be associated with worse survival. Independent of initial management strategy, patients with pulmonary atresia and ventricular septal defects without MAPCAs require repeat intervention on the right ventricular outflow tract. Hypoplastic pulmonary arteries have been shown to be a risk factor for reintervention, and decreased conduit durability has been shown with younger age at implantation of conduit. Conclusions Long-term outcomes have improved for patients with pulmonary atresia-ventricular septal defect without MAPCAs, with complete repair and adequate pulmonary arteries favorable for survival. Long-term outcomes include reinterventions, both catheter-based and surgical, predominantly on the right ventricular outflow tract.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135