Astha Rohit, Adam Holtzman, James Bates, Scott Lester, Roi Dagan, Barbara Vischioni, Ester Orlandi, Maria Bonora, Amy Tien Yee Chang, Rohan Deraniyagala, Martin Bues, Steven Frank, Samir H. Patel, Atsushi Musha, Tatsuya Ohno, Nancy Lee, Lisa McGee
Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by indolent growth, frequent perineural invasion, and a propensity for locally advanced disease involving the skull base. High-dose radiation to complex target volumes must be balanced with minimizing exposure to adjacent organs at risk, making particle therapy attractive. Proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) provide favorable dose distributions compared with photon-based radiotherapy, while CIRT offers additional theoretical radiobiologic advantages through its higher linear energy transfer and relative biological effectiveness. However, whether these properties translate into superior clinical outcomes remains uncertain. This perspective reviews physical and radiobiologic characteristics of PBT and CIRT and evaluates contemporary clinical evidence supporting their use in ACC. Available studies demonstrate favorable local control, overall survival, and toxicity outcomes with both modalities but have not established a clear clinical advantage of CIRT over modern PBT. Interpretation is limited by heterogeneous patient populations, treatment techniques, fractionation schedules, institutional practices, follow-up, and the absence of prospective data. Additionally, differences in infrastructure, cost, geographic availability, and reimbursement influence treatment selection and patient access. Current evidence supports PBT as an efficacious and broadly applicable treatment option for ACC, particularly for complex skull base and perineural target volumes. Future research should prioritize comparative dosimetry, refinement of biologic dose modeling, multicenter clinical outcomes, contemporary cost-effectiveness analyses, and patient selection. Expanding equitable access to particle therapy should remain a parallel objective. Current literature supports PBT in the treatment of ACC. Reported treatment outcomes are comparable to CIRT.
To develop and externally validate a ridge logistic regression model containing only pre-procedural predictors to estimate the individual probability of requiring chest drainage after CT-guided percutaneous core-needle lung biopsy. This multicenter retrospective study included 2,492 patients. All 2,092 patients who underwent biopsy at Institution 1 from 2015 to 2025 were used for model development, and 400 patients treated at Institution 2 in 2025 formed the external-validation cohort. Nine variables available before needle entry were prespecified: age, sex, planned position, emphysema, lesion short-axis diameter, longitudinal lesion location, anatomical lobe, planned fissure traversal, and visceral-pleural adjacency. A ridge-penalized logistic model was fitted; the penalty was selected by stratified 10-fold cross-validation using the one-standard-error rule, and the complete modeling process was internally validated with 1,000 bootstrap resamples. The frozen model was applied directly to Institution 2 without refitting, recalibration, or threshold optimization. Development and external-validation sample sizes were formally assessed retrospectively using the Riley frameworks. Chest drainage was required in 127/2,092 patients (6.1%) at Institution 1 and 34/400 (8.5%) at Institution 2. At Institution 1, the apparent AUC was 0.786 (95% CI, 0.745-0.827) and the optimism-corrected AUC was 0.766. For the frozen model at Institution 2, the AUC was 0.683 (95% CI, 0.579-0.779) and the Brier score was 0.0755 (95% CI, 0.0550-0.0982). The external calibration intercept was 0.41 (95% CI, 0.00-0.72), calibration slope was 1.13 (95% CI, 0.52-1.85), and observed-to-expected ratio was 1.44 (95% CI, 1.00-1.89), indicating systematic underprediction. The development sample was slightly smaller than required under conservative assumptions. Under the prespecified stringent precision targets, external validation would require approximately 17,397 patients and 1,479 events, whereas the available cohort contained 400 patients and 34 events. External validation should therefore be interpreted as independent but preliminary. The pre-procedural model showed moderate discrimination in an independent external institutional cohort but underestimated absolute risk. Prospective multicenter validation, with local recalibration where appropriate, is required before routine clinical use.
Treatment resistance is usually attributed to genetic or adaptive changes within tumor cells. Here, we propose that, in some tumors, resistance also depends on specific interactions between malignant and non-malignant cells. We define relational resistance as a resistant phenotype that requires the functional organization of particular intercellular relationships. This concept is narrower than microenvironment-mediated resistance: the presence of stromal, immune, or vascular cells is not sufficient to establish relational resistance; a defined interaction must contribute functionally to treatment failure. We organize evidence along a five-step sequence: predicted edge, spatial support, functional edge, relational dependency, and therapeutic vulnerability. Genitourinary cancers illustrate different positions along this sequence: bladder cancer provides a predicted CD6–ALCAM edge with independent clinical association but without targeted perturbation; prostate cancer provides myeloid circuits with preclinical causal support and phase 1 proof-of-concept targetability; and renal cell carcinoma provides spatially organized multicellular programs with functional and preclinical perturbation support. We further propose relational memory as the hypothesis that a treatment-induced or treatment-selected interaction persists after therapy and influences response to a subsequent treatment. The framework therefore shifts the therapeutic question from which resistant cells are present to which relationships are required for resistance to persist.
Yan Lin, Shao-hong Yu, Chai-Ming Zeng, Shuang-long Cai, Lei Han
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, especially in postmenopausal women who are routinely treated with anthracycline/taxane-based chemotherapy. However, wide inter-individual variation in disease-free survival (DFS) underscores an urgent need for reliable predictive markers and practical prognostic tools. We aimed to develop and validate a real-world nomogram that integrates clinically accessible predictive markers for individualised DFS prediction in this specific population. In this two-centre real-world study, we enrolled 479 postmenopausal TNBC patients who received initial adjuvant anthracycline/taxane-based chemotherapy (sequential or concurrent). Patients were randomly assigned 7:3 to a training cohort (n=335) and a validation cohort (n=144). We used univariate and multivariate Cox regression with stepwise bidirectional selection to identify independent predictors, which were then incorporated into a nomogram. Model performance was assessed using Harrell’s C-index, time-dependent receiver operating characteristic curves, and calibration plots. Baseline characteristics did not differ significantly between the two cohorts (all P>0.05). Multivariate Cox analysis identified four independent predictors: postoperative pathological T stage (T2+T3 vs T1: hazard ratio [HR]=2.607, 95% CI 1.347-5.047, P = 0.004); N stage (N2 vs N0: HR = 4.077, 2.049-8.112, P<0.001; N3 vs N0: HR = 4.479, 2.561-7.835, P<0.001); high stromal tumour-infiltrating lymphocyte (sTIL) expression (vs low: HR = 0.025, 0.008-0.081, P<0.001); and Ki67 >20% (vs ≤20%: HR = 2.060, 1.082-3.919, P = 0.028). The nomogram achieved excellent discrimination: training cohort C-index=0.899; validation cohort C-index=0.861. Time-dependent AUCs for 1-, 3-, and 5-year DFS were 0.915, 0.945, and 0.959 in the training cohort, and 0.895, 0.943, and 0.900 in the validation cohort, respectively. Calibration curves showed good agreement between predicted and observed outcomes. We developed and validated a real-world nomogram integrating four readily available predictive markers-T stage, N stage, sTIL, and Ki67-that accurately predicts 1-, 3-, and 5-year DFS in postmenopausal TNBC patients receiving standard anthracycline/taxane chemotherapy. This practical tool supports personalised risk stratification and clinical decision-making, directly addressing the need for predictive markers in advancing breast cancer chemotherapy.
Sarah Stewart, Karen Thomas, Jenni Parmar, Alison Claire Tree, Chris Parker, Helen McNair, Sophie Alexander, Julia Henderson, James Talbot, Christopher Scrase, Chee Goh, Reena Davda, Emma Gray, Peter Hoskin, Sarah Needleman, Jenny Nobes, Kamalram Thippu Jayaprakash, Yvonne Rimmer, Ranachandran Venkitaraman, Anna Wilkins, Vincent Khoo, Julia Murray, David Paul Dearnaley
The introduction of volumetric modulated arc therapy (VMAT) has enabled dosimetric improvements during prostate bed (PB) radiotherapy; however, the planning target volume (PTV) margins remain substantially greater than for prostate radiotherapy. New approaches are required to further optimise rectal dose and minimise target and organ motion. ProSpare ® , a self-inserted rectal obturator designed to facilitate daily image guidance, may enhance radiotherapy accuracy and reduce treatment-related morbidity. Patients scheduled to receive adjuvant or salvage PB radiotherapy after radical prostatectomy were randomised to either standard-of-care (SOC) PB-IMRT using centre-standard PTV margins and verification protocol (SOC) or PB-IMRT with daily ProSpare ® -guided radiotherapy using a reduced 5-mm posterior margin. Dose and fractionation schedules were selected by each centre according to protocol recommendations. The primary endpoint is patient-reported EPIC bowel function and bother at 2 years. Secondary endpoints include acute Radiation Therapy Oncology Group (RTOG) and CTCAE toxicity, patient-reported outcomes, device tolerability, and anorectal dosimetry. We report the results from the prespecified analysis of these secondary endpoints. Between 2017 and 2023, 162 patients were recruited; 158 began radiotherapy and were evaluable at 18 weeks. Acute toxicity data were available for 146 patients (SOC 76/81, ProSpare 70/77). Compared with SOC, ProSpare ® was associated with lower 18-week RTOG ≥grade 1 gastrointestinal (GI) and genitourinary (GU) toxicity (39% vs. 31% and 37% vs. 29%, respectively). The incidence of worst CTCAE grade 2 GI and GU toxicity was <6%. Of 51 responders, 50 found ProSpare ® tolerable and would recommend its use. Use of ProSpare ® resulted in consistently lower ano-rectal dose–volume parameters. ProSpare ® -guided prostate bed radiotherapy (PBRT) resulted in lower acute RTOG bowel toxicity at all time points. Patient-reported tolerability was very favourable. Use of ProSpare ® improved rectal and anal canal dosimetry. ClinicalTrials.gov , identifier NCT02978014.
