Citations

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.

As plastic surgery has grown, leaders within the field have advocated transforming plastic surgery divisions into independent departments. This shift raises critical questions regarding departmental identity, resource allocation, and potential administrative conflicts. The purpose of this study was to explore the potential implications of these institutional hierarchies from the perspective of plastic surgery program chairs. An anonymous online survey was distributed to chairs of accredited plastic surgery programs. Thirty-five of 103 (34.0%) individuals responded to the online questionnaire. Twenty-eight of 33 (84.8%) programs were classified as divisions of surgery, whereas 5 of 33 (15.2%) were independent departments. Nine of 28 (32.1%) respondents believed their division had lost patients to other surgical specialties because their program was not an independent department. Eighteen of 33 (54.5%) respondents believed that plastic surgery is negatively impacted when institutional programs are not independent departments. Respondents who indicated losing patients to other specialties, compared with those who did not, were 22.4 times more likely to be critical of institutional hierarchies ( P =0.004). Respondents from independent departments were 12.6 times more likely to also express a negative view ( P =0.049). Our findings provide a nuanced understanding of the institutional structures within plastic surgery programs. The extent to which institutional hierarchies negatively impact plastic surgery remains unclear. The significant association between patient loss and negative perceptions implies that direct clinical or financial repercussions strongly shape opinions. Moreover, chairs from independent departments may be more critical of institutional hierarchies because they have a deeper appreciation for the advantages that come with departmental status.

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Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

Abstract IBC Clear: A decentralized multi-center MRD Registry for Inflammatory Breast CancerInflammatory breast cancer is an aggressive subtype of breast cancer with distinct clinical phenotypes, including early recurrence post-tri-modal care (neoadjuvant systemic therapy, surgery, adjuvant radiation). Preliminary data from MDACC have shown a high rate of baseline and serial MRD positivity in IBC patients (35-40% at 6-12 months post-surgery), suggesting that newly diagnosed IBC is an ideal population to test MRD as a standard of care and design adjuvant interventional trials. However, to date, our understanding of the optimal monitoring cadence and interventions following MRD positivity remains limited. IBC Clear is a decentralized protocol developed to collect real-world data from patients treated amongst our IBC Connect network of 19 US-based and three international institutions (7 of whom have expressed interest in participating). Patients who have had, or plan to have Signatera® ordered at the post-chemo/pre-surgery timepoint can self-enroll from the community by emailing IBCClear@mdanderson.org for information on the consent process. Study Design: Eligibility criteria include English-speaking patients > 18 years of age with a clinical diagnosis of IBC, with Signatera testing ordered or planned. The post-chemo/pre-surgery timepoint is the only study-mandated timepoint; however, any additional serial testing conducted before or after this timepoint will also be collected. Patients who have at least one Signatera test ordered and plan to have a pre-surgery/post-chemo collection as standard of care will be enrolled in a central REDCap database. Physicians enrolling patients may act on the results according to their clinical judgment, including imaging assessments and treatment changes. These interventions will be captured in the database. An electronic EORTC QLQ C30 survey will also be administered prior to and after receiving Signatera results to gather information about the impact of testing on the patient's quality of life. A total of 200 patients from all sites will be enrolled over a period of two years. Patients will be followed remotely for up to 2 years from the first Signatera test or until clinical recurrence, whichever comes first. Endpoints: Data collected will include the feasibility of decentralized data collection studies, as well as Signatera and recurrence information. The goals are to gather real-world data regarding the association of MRD positivity with pathologic response in IBC, patient-reported QOL for worry about recurrence, median lead time between the first MRD-positive result and clinical recurrence, and, if possible, whether the adjuvant therapies decrease the amount of MRD in IBC patients (pending optional longitudinal testing). Status of the study: The study was activated in June 2025. As of abstract submission, 2 patients have been enrolled at the lead site. Collaborating sites are being added. Sponsor: The University of Texas MD Anderson Cancer Center Clinicaltrials.gov Accession number: NCT06966050 Citation Format: A. Alexander, M. Kai, K. A. Abou-Hussein, S. Ali, C. Anderson, S. W. Bahadur, Y. C. Cheng, N. T. Ueno, X. Wang, A. Lucci, W. A. Woodward, S. Saleem, MDACC Inflammatory Breast Cancer Team. PS2-02-05: Ibc clear: a decentralized multi-center mrd registry for inflammatory breast cancer [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 PS2-02-05.

OBJECTIVE: To evaluate the effect of joint preparation and patient factors on outcomes and complications in patients treated acutely with hindfoot fusion nails for ankle and pilon fractures. METHODS: Design: Retrospective chart review. Setting: Thirteen US trauma centers and 2 UK trauma centers. Patient Selection Criteria: Ankle and pilon fractures (AO-OTA types A-C) from 2010 to 2020 acutely treated definitively with hindfoot fusion nail were reviewed. Patients at least 18 years old and with minimum 6 months follow-up or earlier diagnosis of complication were included. Exclusion criteria included nonambulatory at baseline, prior internal fixation that failed and underwent revision, and prior tibiotalar or subtalar arthrodesis. Outcome Measurements and Comparisons: The primary outcome was final postoperative ambulatory status. Secondary outcomes were infectious and fracture-related complications. RESULTS: One hundred forty-nine patients (75 men; 74 women; age 20–99; median 63 years) were treated for ankle (104) or pilon (45; 8A, 13B, 24C) fractures. Eighty-five patients (44%) had open fractures and 55 (37%) had diabetes. Thirty-six patients (24%) had joint preparation at the time of surgery. Forty-five (30%) were made weight bearing as tolerated postoperatively; the median time to mobilize was 1.5 days (0–210) and to full weight bearing was 35 days (0–1462). Fifty-seven patients (85%) returned to their preinjury ambulatory status, which was not affected by joint preparation (50% vs. 59%, P = 0.327). Joint preparation led to higher articular fusion rates (94% vs. 24%; P = 0.001) and fewer hardware removals (19% vs. 42%, P = 0.013), but trended toward a higher fracture nonunion rate (19% vs. 8%, P = 0.053). Forty-five patients (30%) had infectious complications, 60 (40%) had a fracture-related complication, and 67 (45%) had additional procedures. Open fractures did not lead to any differences in superficial or deep infection. Insulin-dependent diabetes was associated with higher rates of infectious complications (31% vs. 15%, P = 0.028) and amputation (17% vs. 4%, P = 0.029). CONCLUSIONS: Hindfoot fusion nails for acute ankle and pilon injuries had high complication rates. More complications occurred in patients with insulin-dependent diabetes. While 95% regained ambulation, only 57% returned to preoperative status. Joint preparation led to higher rates of articular fusion (94% vs. 24%, P < 0.001) but not fracture union (81% vs. 66%, P = 0.106). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Abstract INTRODUCTION The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD. METHODS Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series. RESULTS Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non‐amnestic compared to amnestic AD cases. DISCUSSION These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young‐onset, and non‐amnestic presentations.

Importance Patients with recurrent prostate cancer after previous radiotherapy typically have poor survival. Those with recurrences prostate confined might be suitable for salvage focal therapy (sFT) or salvage radical prostatectomy (sRP). sFT may offer good cancer control with comparatively less toxic effects, but outcomes beyond 5 years have not been reported, and no study has compared sFT to sRP. Objective To compare cancer control and perioperative complications among patients after sFT vs sRP. Design, Setting, and Participants In this international, multicenter cohort study of matched comparison data, patients undergoing sFT were derived from the prospective UK HIFU (high-intensity focused ultrasound) Evaluation and Treatment and International Cryotherapy Evaluation registries (9 centers; 2006-2024) and the prospective UK Focal Recurrent Assessment and Salvage Treatment cohort study (6 centers; 2014-2018). Patients undergoing sRP were derived from an international retrospective registry (12 centers in 8 countries; 2000-2021). Patients with biopsy-confirmed, localized recurrent prostate cancer postradiotherapy, either external beam radiotherapy, brachytherapy, or both, were included. Data were analyzed from March to July 2025. Exposures sFT using HIFU or cryotherapy vs sRP. Main Outcomes and Measures The primary outcome was cancer-specific survival up to 10 years. Secondary outcomes were overall survival, any perioperative complications (Clavien-Dindo grades 1-5), and major perioperative complications (Clavien-Dindo grades 3-5). Comparisons were made on matched patients following 1:1 cardinality matching within individual multiply-imputed datasets. Matching variables used were radiotherapeutic treatment, years between primary and salvage treatments, European Association of Urology recurrence risk group, and presalvage age, prostate-specific antigen, prostate volume, grade group, T stage, and androgen-deprivation therapy use. Results A total of 923 patients were eligible for matching (419 undergoing sFT and 504 undergoing sRP). Of the patients undergoing sFT, 325 (77.6%) underwent HIFU and the remainder cryotherapy, with 241 (57.5%) treated with quadrant ablation. Of patients treated with sRP, 376 (74.6%) underwent open surgery and the remainder robot-assisted surgery. For sFT vs sRP, 10-year cancer-specific survival was 92% (95% CI, 86%-98%) vs 99% (95% CI, 97%-100%), with no statistically significant difference (restricted mean time lost, −0.09 years; 95% CI, −0.22 to 0.03 years; P = .15; subdistribution hazard ratio, 0.45; 95% CI, 0.05-4.00; P = .47). There was no statistically significant difference in 10-year overall survival (restricted mean survival time, −0.13 years; 95% CI, −0.86 to 0.60 years; P = .72). Undergoing sRP was associated with statistically significant higher odds of any complication (adjusted odds ratio, 24.20; 95% CI, 12.94-45.27; P &amp;lt; .001) and major complication (adjusted odds ratio, 9.31; 95% CI, 3.42-25.36; P &amp;lt; .001). Conclusions and Relevance In this cohort study, sFT and sRP were effective for treating localized radiorecurrent prostate cancer, while sFT was associated with fewer perioperative complications. sFT may provide a favorable therapeutic ratio for many patients with localized radiorecurrent prostate cancer.