Citations

Abstract Background: Estrogen receptor (ER) positive breast cancer is commonly treated with endocrine therapy, yet resistance to estrogen deprivation remains a significant clinical challenge. Using custom FISH probes designed to detect tumor-specific genomic alterations, we identified circulating tumor cells (CTCs) of true tumor origin in early-stage luminal breast cancer patients. Longitudinal analysis revealed that 80% of patients had FISH-positive CTCs after completing therapy and while on antiestrogen treatment, despite no clinical evidence of disease. This finding suggests that standard endocrine therapy is insufficient to eradicate all malignant clones, indicating the persistence of therapy-resistant tumor cells. Methods: Primary tumor DNA was analyzed using the Oncoscan microarray platform to identify somatic copy-number alterations (SCNAs). Custom FISH probes targeting these alterations were applied to peripheral blood samples before and after therapy. Immunofluorescence characterization of CTCs was performed to assess epithelial and mesenchymal phenotypes as well as ER expression status. Genomic profiling focused on identifying drivers of proliferation, known ER resistance genes, and ER transcriptional regulators. Results: Immunofluorescence revealed that CTCs were highly heterogeneous, displaying both epithelial and mesenchymal phenotypes. ER expression among CTCs was variable: while some CTCs were ER-positive, a significant proportion showed reduced or absent ER staining. This heterogeneity suggests that loss or downregulation of ER is a key mechanism of resistance, allowing tumor cells to persist despite antiestrogen therapy. Genomic profiling of parent tumors demonstrated multiple, overlapping mechanisms supporting both proliferation and endocrine resistance. All tumors harbored several genomic alterations known to drive proliferation, most commonly involving MCL1, NTRK1, SDHC, SDHD, CHEK1, ATM, and BCL6. Every tumor exhibited at least one established mechanism of ER resistance, with frequent alterations in ATM and PIK3CA, and additional recurrent changes in AKT3, MTOR, and ARID1A. Several tumors also had alterations in genes directly involved in ER transcriptional regulation, notably ARID1A and SPEN. Conclusions: The persistence of FISH-positive CTCs in the majority of patients after therapy—despite no clinical evidence of disease—highlights the insufficiency of current endocrine regimens. The underlying genomic complexity, characterized by multiple drivers of proliferation, redundant ER resistance mechanisms, and disruption of ER regulatory pathways, underpins the survival and persistence of CTCs. These findings underscore the need for therapeutic strategies that address the multifaceted and overlapping nature of endocrine resistance in luminal breast cancer. Citation Format: K. Baldwin, K. von Maltzan, A. Zulli, M. Richard, J. Abdulsattar, D. Maroni, P. T. Greipp, R. Knudson, Mayo Cytogenetics Core, S. P. Thayer. Fish-positive circulating tumor cells persist after effective therapy in estrogen receptor positive breast cancer: insights into genomic mechanisms of endocrine resistance [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-03.

INTRODUCTION: High-quality colonoscopy requires accurate risk stratification for surveillance per the 2020 US Multi-Society Task Force guidelines and adherence to 2024 American College of Gastroenterology/American Society for Gastrointestinal Endoscopy quality benchmarks. Both are operationally challenging in clinical practice. We developed and validated Colon-Pilot, a large language model—powered clinical decision support system using GPT-4o to automate and standardize both functions. METHODS: The system was evaluated in 2 operational modes: (i) a human-in-the-loop clinical decision support validation of surveillance recommendations for 596 colonoscopies, comparing concordance with 2020 US Multi-Society Task Force guidelines against expert consensus, and (ii) an automated administrative audit applying Colon-Pilot to 42,632 colonoscopies across the Mayo Clinic Health System to calculate 2024 American College of Gastroenterology/American Society for Gastrointestinal Endoscopy priority quality indicators. Recommendations were autogenerated unless predefined safety criteria triggered manual review. RESULTS: Colon-Pilot issued recommendations for 522 of 596 cases (87.6%) and flagged 12.4% for manual review. For automated cases, guideline-concordant accuracy was 97.5% (Cohen κ = 0.970) versus 69.7% (κ = 0.781) for original endoscopist recommendations. Discordant artificial intelligence (AI) cases (n = 13) most often recommended longer-than-appropriate intervals (62%). Applied to the enterprise data set, Colon-Pilot calculated performance exceeding 2024 targets: adenoma detection rate 49.8% (≥35%), sessile serrated lesion detection rate 17.7% (≥6%), bowel preparation adequacy 91.8% (≥90%), and cecal intubation rate 97.4% (≥95%). DISCUSSION: Colon-Pilot demonstrated high fidelity in applying surveillance guidelines and automated quality benchmarking, outperforming unassisted endoscopists in guideline adherence. By combining safety protocols with large-scale automated reporting, it offers a scalable solution for improving both efficiency and quality in colorectal cancer prevention.

AbstractBackgroundRetinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival.ResultsRbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers. Transgenic rescue of rbbp4 mutant embryos shows Rbbp4 is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ‐H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. rbbp4; rb1 mutants show an additive effect on the number of M phase cells. In rbbp4 mutants, Tp53 acetylation is detected; however, Rbbp4 overexpression did not rescue DNA damage‐induced apoptosis.ConclusionRbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0 independent of Rb. Tp53‐dependent apoptosis in the absence of Rbpb4 correlates with Tp53 acetylation. Together these results suggest that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival through the regulation of Tp53 acetylation.

Background Recent studies have shown improved outcomes in cardiogenic shock through protocols directed toward early identification and initiation of mechanical circulatory support. However, objective therapeutic targets—based on clinical and/or laboratory data—to guide real‐time clinical decision making are lacking. Lactate clearance has been suggested as a potential treatment target because of its independent association with mortality. Methods and Results In a post hoc analysis of the DOREMI (Dobutamine Compared to Milrinone in the Treatment of Cardiogenic Shock) trial—a randomized, double‐blind, controlled trial comparing milrinone to dobutamine in the treatment of cardiogenic shock—we used prospectively collected lactate data to evaluate lactate clearance as a surrogate marker for in‐hospital mortality. In total, 82 (57.7%) patients survived to hospital discharge (survivors). In multivariate logistic regression analysis, complete lactate clearance, percentage lactate clearance, and percentage lactate clearance per hour were independently associated with survival beginning as early as 8 hours after enrollment. Complete lactate clearance was the strongest predictor of survival at all time points, with odds ratios ranging between 2.46 (95% CI, 1.09–5.55; P =0.03) at 8 hours to 5.44 (95% CI, 2.14–13.8; P <0.01) at 24 hours. Conclusions Complete lactate clearance is a strong and independent predictor of in‐hospital survival in patients with cardiogenic shock. Together with previously published data, these results further support the validity of lactate clearance as an appropriate surrogate for mortality and as a potential therapeutic target in future cardiogenic shock trials. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03207165.

Introduction Although neurotization has the potential to improve sensory outcomes after autologous breast reconstruction, this technique remains controversial. There is debate regarding the clinical outcomes and the recipient nerve of choice. This histoanatomical study aims to quantitatively compare the sensory components of the recipient nerves involved in neurotization of the deep inferior epigastric perforator flap. Methods Subjects undergoing bilateral autologous breast reconstruction were enrolled. Transected nerve specimens underwent immunohistochemical staining with antibodies against neurofilament 1 and choline acetyltransferase for total and motor neurons within the axons, respectively. Photomicrographs were captured, and axons were analyzed using ImageJ. Sensory axons were calculated as equal to the difference between the total and cholinergic axonal counts. Results Thirty-eight nerves from 19 subjects were included. The overall mean sensory axon count was 1246.3 (±1171.9) in the lateral cutaneous branch (LCB) of the fourth intercostal nerve and 1123.8 (±1213.0) in the anterior cutaneous branch (ACB) of the third intercostal nerve. The fourth LCB presented with an additional 10.9% sensory axonal count (P > 0.05). On average, sensory fibers constituted 36.7% and 31.7% of all fibers in the third ACBs and fourth LCBs, respectively. Conclusions This study provides anatomic and histological evidence that the fourth LCB and third ACB contain comparable mean numbers of sensory axons. Both constitute adequate recipient nerves for coaptation in deep inferior epigastric perforator reinnervation to achieve optimal sensory return after breast reconstruction. The fourth LCB should be preferable when the third ACB remains intact to preserve any native breast flap sensation.

Aims Wear of the polyethylene (PE) tibial insert of total knee arthroplasty (TKA) increases the risk of revision surgery with a significant cost burden on the healthcare system. This study quantifies wear performance of tibial inserts in a large and diverse series of retrieved TKAs to evaluate the effect of factors related to the patient, knee design, and bearing material on tibial insert wear performance. Methods An institutional review board-approved retrieval archive was surveyed for modular PE tibial inserts over a range of in vivo duration (mean 58 months (0 to 290)). Five knee designs, totalling 1,585 devices, were studied. Insert wear was estimated from measured thickness change using a previously published method. Linear regression statistical analyses were used to test association of 12 patient and implant design variables with calculated wear rate. Results Five patient-specific variables and seven implant-specific variables were evaluated for significant association with lower insert wear rate. Six were significant when controlling for other factors: greater patient age, female sex, shorter duration in vivo, polished tray, highly cross-linked PE (HXLPE), and constrained knee design. Conclusion This study confirmed that knee wear rate increased with duration in vivo. Older patients and females had significantly lower wear rates. Polished modular tibial tray surfaces, HXLPE, and constrained TKA designs were device design factors associated with significantly reduced wear rate. Cite this article: Bone Joint J 2021;103-B(11):1695–1701.

AbstractBackgroundPeripheral nerve damage resulting in pain, loss of sensation, or motor function may necessitate a reconstruction with a bridging material. The RANGER® Registry was designed to evaluate outcomes following nerve repair with processed nerve allograft (Avance® Nerve Graft; Axogen; Alachua, FL). Here we report on the results from the largest peripheral nerve registry to‐date.MethodsThis multicenter IRB‐approved registry study collected data from patients repaired with processed nerve allograft (PNA). Sites followed their own standard of care for patient treatment and follow‐up. Data were assessed for meaningful recovery, defined as ≥S3/M3 to remain consistent with previously published results, and comparisons were made to reference literature.ResultsThe study included 385 subjects and 624 nerve repairs. Overall, 82% meaningful recovery (MR) was achieved across sensory, mixed, and motor nerve repairs up to gaps of 70 mm. No related adverse events were reported. There were no significant differences in MR across the nerve type, age, time‐to‐repair, and smoking status subgroups in the upper extremity (p > .05). Significant differences were noted by the mechanism of injury subgroups between complex injures (74%) as compared to lacerations (85%) or neuroma resections (94%) (p = .03) and by gap length between the <15 mm and 50–70 mm gap subgroups, 91 and 69% MR, respectively (p = .01). Results were comparable to historical literature for nerve autograft and exceed that of conduit.ConclusionsThese findings provide clinical evidence to support the continued use of PNA up to 70 mm in sensory, mixed and motor nerve repair throughout the body and across a broad patient population.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

Abstract Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259–70. ©2016 AACR.