Citations

Importance Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2 -positive (formerly HER2 -positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures The primary outcome was ipsilateral breast tumor recurrence. Results Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2 -positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02945579

Objectives/Goals: Identifying and indexing rare disease studies is labor intensive, especially in research centers with a large number of trials. To address this gap, we applied natural language processing (NLP) and visualization techniques to develop an efficient pipeline and user-friendly web interface. Our goal is to offer the rare disease study identification (RDSI) tool for adoption by other sites. Methods/Study Population: The RDSI retrieves study information (short and long titles, study abstract) from the IRB system. These descriptive fields are then processed by the MetaMap Lite NLP program for identifying disease terms and standardizing them to UMLS concepts. By terminology identifier mapping, the diseases intersecting with concepts in rare disease databases (Genetic and Rare Disease program and Orphanet) are further scored to pinpoint studies that focus on a rare disease. The web interface displays a scatter bubble chart as an overview of all the rare diseases, with each bubble size proportional to the number of studies for that disease. In addition to the visual navigation, users can search studies by disease name, PI, or IRB number. Search results contain detailed study information as well as the evidence used by algorithms of the pipeline. Results/Anticipated Results: The RDSI identification results and functions were verified manually and spot-checked by several study investigators. The web interface is a self-contained solution available to our staff for various use cases like reporting or environment scan. We have built in a versioning mechanism that logs the date of each major result in the process. Therefore, even as the rare disease data sources evolve over time, we will be able to preserve any historical context or perform updates as needed. The RDSI outputs are replicated to Mayo Clinic’s enterprise data warehouse daily, allowing tech-savvy users to leverage any useful intermediate results at the backend. We anticipate the performance of the rare disease identification to be further enhanced by employing the advancements in AI technology. Discussion/Significance of Impact: The RDSI represents an informatics solution that offers efficiency in identifying and navigating rare disease clinical studies. It features the use of public databases and open-source tools, manifesting return on investment from the broad translational science ecosystem. These considerations are informative and adoptable by other institutions.

Objectives/Goals: The operation of a clinical trials unit involves multifaceted tasks and stakeholders. A competent information system is critical to daily operations while ensuring smooth conduct of clinical research. We share 15 years of experience in the design and implementation of such a system at Mayo Clinic to inform other institutions with similar interests. Methods/Study Population: The Informatics team collaborated closely with nurse leaders and elicited input from additional stakeholders including nurse unit coordinators, lab managers, schedulers, investigators, study coordinators, and regulatory specialists throughout the phases of system design, development and continuous enhancements, and expansion. The stakeholders offered insights on the corresponding requirements throughout the study life cycle, from engaging with the study sponsor, operational review for protocol execution, development of study budgets, human subject protection and risk mitigation, data management and integration, to outcome monitoring, and regulatory reporting. The activities were then translated into functional components and implemented as a seamless and effective solution. Results/Anticipated Results: Patient safety, scientific rigor, operation automation, efficiency, and regulatory requirements were all considered in developing an integrated system, or the clinical research trials unit (CRTU) Tools. Our institution has leveraged the system for essential tasks from the study start-up, visit scheduling and execution, specimen collection and tracking, to individual protocol metrics and billing. We adopted a measure-as-we-go methodology so that data such as visit census, resource usage, and protocol deviation are tracked and collected during routine use of the system. Specifically, an issues/concerns/exceptions (ICE) tool is used for quality control and patient safety. Moreover, data quality greatly benefits from a task dictionary, standardizing the study activities that can be ordered and executed. Discussion/Significance of Impact: The implementation of a well-rounded clinical trials unit information system not only improves the operation efficiency and team productivity but also ensures scientific rigor and contributes to patient safety. We believe the experience can be informative to other institutions. More details will be shared in the poster.

PURPOSE Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various malignancies. However, the high cost of these therapies limits access for much of the global population. This systematic review aims to evaluate the efficacy of low-dose ICIs compared with standard doses in different malignancies, addressing financial and access barriers in global cancer care. METHODS We conducted a systematic review of studies comparing the efficacy of low-dose versus standard-dose ICI regimens in advanced solid tumors. A comprehensive search was performed across multiple electronic databases, including retrospective and prospective studies. Excluded were animal studies, editorials, conference papers, book chapters, and other immunotherapy modalities. Outcomes assessed included overall survival (OS), progression-free survival, and objective response rate. Results were summarized descriptively due to study heterogeneity. RESULTS From 1,010 screened articles, four studies with 435 Asian patients were included, covering a variety of solid tumors. All included studies were with a low quality of evidence and a high risk of bias due to retrospective design. Two studies used weight-based dosing (pembrolizumab <2 mg/kg and nivolumab <2.15 mg/kg), showing similar OS to standard dosing in non–small cell lung cancer (NSCLC) and renal cell carcinoma, respectively. Flat dose regimens in two studies (nivolumab 20 mg or 100 mg once every 3 weeks and pembrolizumab 100 mg once every 3 weeks) also demonstrated comparable OS in NSCLC. CONCLUSION Low-dose ICIs may offer equivalent clinical benefits to standard dosing, potentially reducing costs and expanding access in developing countries. Although awaiting more representative randomized clinical trials, weight-based ICI regimens could be a viable alternative in low- and middle-income countries.

Abstract Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare PPM1M mutation in patients with Parkinson’s disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson’s disease. Teaser Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.

Abstract Pancreatic neuroendocrine tumors (PanNETs) have an age-adjusted incidence of 1.5 per 100,000 people, with a notable rise in the incidence of small (≤2 cm) non-functional PanNETs (NF-PanNETs) in recent decades. While surgery is traditionally the preferred treatment for localized NF-PanNETs, active surveillance is now an accepted management strategy for tumors smaller than 2 cm due to their relatively benign behavior. However, this approach has not yet been fully integrated into routine clinical practice. There is considerable histopathological heterogeneity observed in NF-PanNETs, which results in significant variability in clinical presentation, behavior and treatment outcomes. Hence, tumor size alone does not provide sufficient certainty regarding a benign clinical course for decision-making. Although studies advocate for incorporating WHO grade into clinical prognostic assessments, this marker also has limitations. Several established tissue-based markers, such as ATRX and DAXX alterations, alternative lengthening of telomeres, and copy number variations, can be used for PanNET subtyping and correlate with metastatic risk. Combining these markers with traditional histopathological parameters may yield a more comprehensive and accurate prognostic assessment. This review discusses the advantages and limitations of current prognostication methods for small NF-PanNETs and highlights recently established prognostic markers, along with the requirements for their implementation into routine clinical practice. It also proposes practical solutions to address the challenges associated with the immediate integration of these biomarkers into routine care.

Précis: 240-degree and 360-degree goniotomy (GT) demonstrated similar efficacy in intraocular pressure (IOP) reduction, both outperforming 120-degree GT in patients with juvenile open angle glaucoma (JOAG) at postoperative 6-month follow-up. Objective: To compare the surgical efficacy and safety of 120-degree, 240-degree, and 360-degree GT for patients with JOAG. Patients and Methods: This multicenter retrospective study included 102 eyes of 102 patients with JOAG, who underwent GT with a follow-up of at least 6 months. Patients were categorized into 3 groups: (1) 120-degree GT, (2) 240-degree GT, and (3) 360-degree GT. IOP, glaucoma medications, and complications were recorded at baseline and the final visit. Complete success and qualified success were defined as a postoperative IOP ≤21 mm Hg without and with medications, respectively. Results: Mean age of the participants was 24.4 ± 7.9 years. After a mean follow-up of 8.1 ± 2.7 months, complete success rates were similar between the 240-degree GT (45.2%) and the 360-degree GT (63.2%; P = 0.135), and both were superior to 120-degree GT (18.2%; P < 0.05). Qualified success rates among patients in the 120-degree, 240-degree, and 360-degree GT groups were 93.9%, 96.8%, and 100%, respectively, and showed no statistically significant difference (P = 0.292). 360-degree GT required fewer medications than 240-degree GT and 120-degree GT (P < 0.05), with no significant difference in medications between 120-degree GT and 240-degree GT (P > 0.05). Hyphema was the most common postoperative complication, with a significantly higher incidence in the 360-degree GT (68.4%) compared with the 240-degree GT (41.9%) and 120-degree GT (33.3%; P < 0.05). Conclusions: 240-degree and 360-degree GT showed similar efficacy in IOP reduction and were superior to 120-degree GT. More extensive GT may provide better outcomes in JOAG.