Citations

Abstract Background Accurate and efficient dose calculation is essential for online adaptive planning in proton therapy. Deep learning (DL) has shown promising dose prediction results for pencil beam scanning proton therapy (PBSPT) in recent years, but existing DL‐based dose prediction methods still suffer from limited generalizability and an inability to effectively handle outlier clinical cases. This may lead to inaccurate dose delivery to targets or excessive irradiation to organs at risk (OARs), thereby compromising the safety and efficacy of online adaptive proton therapy. Purpose To design a physics‐aware and generalizable AI‐based PBSPT dose prediction method that incorporates underlying physics to enhance generalizability, particularly in handling outlier clinical cases. Methods This study analyzed PBSPT plans of 103 prostate (93 for training and 10 for testing) and 78 lung cancer patients (68 for training and 10 for testing) from our institution, with each case comprising CT images and structure sets. Using the doses generated by our Monte Carlo‐based dose engine as the reference standard, we compared three methods: the region of interest (ROI)‐based method, the beam mask and sliding window method, and the proposed noisy probing dose method, which rapidly generates a low‐statistics dose via uniformly weighted spots on an expanded spot‐placement target volume without optimization. To evaluate the generalizability of these methods to rare treatment planning scenarios, 12 cases with uncommon beam angles or prescription doses were used to assess their performance, which was evaluated using dose‐volume histogram (DVH) indices, 3D Gamma passing rates (3%/2 mm/10%), and Dice coefficients for dose agreement, while prediction times were measured to gauge model efficiency. Results The proposed noisy probing dose method consistently outperformed the ROI‐based and beam mask baselines across all evaluated metrics, with more accurate dose agreement and superior generalizability. For DVH indices, the noisy probing dose method achieved the smallest deviation in clinical target volume (CTV) dose coverage: in prostate cancer, CTV D98 deviation was reduced by 45% (from 0.53 ± 0.22 Gy [RBE] for ROI‐based) and 29% (from 0.41 ± 0.28 Gy [RBE] for beam mask) to 0.29 ± 0.06 Gy [RBE]; in lung cancer, similar improvements were observed, with CTV D98 deviations reduced to 0.34 ± 0.12 Gy [RBE]. The 3D Gamma passing rates improved to 99.65% ± 1.15% for prostate targets and 97.04% ± 1.17% for lung targets. The dice coefficients of the 90% iso‐dose lines were also the highest with the noisy probing dose method (prostate: 0.983 ± 0.005; lung: 0.967 ± 0.01). For the 12 outlier cases, the noisy probing dose method maintained superior generalizability, yielding higher 3D Gamma passing rates (prostate targets: 96.79% ± 0.83%, OARs: 94.29% ± 1.01%; lung targets: 93.38% ± 1.34%, OARs: 93.95% ± 1.32%), demonstrating robust generalizability to rare clinical scenarios. The dose predictions for all testing cases were completed within 0.3 seconds. Conclusions A novel noisy probing dose method was proposed for PBSPT dose prediction in prostate and lung cancer patients. By embedding more proton‐specific physics, this method demonstrated an improvement in the generalizability of dose prediction.

ABSTRACT Interferon-γ (IFNγ) signaling is prominent in inflammatory CNS microenvironments across many neurological disorders, but the neuronal peptides presented on HLA class I under these conditions and their functional consequences for CD8 + T cells remain incompletely defined. Here we combine human iPSC-derived human neural aggregates (HNAs), HLA class I immunoprecipitation coupled to LC-MS/MS immunopeptidomics, and microfluidic co-culture assays to map IFNγ-induced neuronal antigen presentation and test antigen-specific cytotoxicity. IFNγ stimulation induced robust HLA class I expression in HNAs and enabled recovery of a canonical 8-12-mer class I ligandome enriched for 9-mers. Neuron-restricted expression of a synapsin-driven polyepitope cassette yielded presentation of defined neoantigen 9-mer peptides on donor HLA class I molecules and, in the presence of IFNγ, elicited activation of autologous antigen-specific CD8 + T cells and consequent antigen-dependent neurite injury. Across four donors, comparative immunopeptidomics identified large IFNγ-unique neural peptide repertoires distinct from matched fibroblasts and revealed a consistent enrichment of predicted high-affinity binders on HLA-B allotypes. Finally, β2-microglobulin deletion ablated peptide recovery, and neuron-restricted β2-microglobulin reconstitution enabled identification of neuron-derived peptides, including peptides derived from neurofilament light (NEFL) that were shared across donors and presented on multiple HLA allotypes. Together, these data provide an integrated platform for neuronal autoantigen discovery and functional validation and support a model in which IFNγ-driven neuronal HLA class I presentation creates an HLA-B-weighted epitope landscape that can be recognized by autoreactive cytotoxic CD8 + T cells.

Noncirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology—such as idiopathic portal hypertension (IPH), noncirrhotic portal fibrosis (NCPF), obliterative portal venopathy, and nodular regenerative hyperplasia—leading to substantial variability in diagnosis, reporting, and international research collaboration. Differences in guideline definitions from major societies (AASLD, EASL, and APASL), together with the presence of characteristic histologic lesions in patients without clinically overt portal hypertension, have further complicated disease classification. To address these challenges, a large, multisociety, international initiative was convened to harmonize nomenclature and diagnostic criteria. Representatives from liver, pathology, and pediatric hepatology societies across the Americas, Europe, and Asia participated in a structured consensus process that included specialized working groups and external Delphi validation. The initiative produced a globally harmonized and implementable diagnostic framework. Consensus was reached that the terms porto-sinusoidal vascular disorder (PSVD) and NCPF may be used interchangeably when identical diagnostic criteria are applied, and that they should be written as PSVD or NCPF . The diagnosis was defined as fundamentally clinicopathological, requiring integrated assessment. Core principles include the need for a high-quality liver biopsy (≥10 mm), mandatory exclusion of cirrhosis, and systematic exclusion of specific alternative conditions. Importantly, the consensus recognizes that PSVD or NCPF may be diagnosed even without clinical portal hypertension and may coexist with other liver diseases, provided cirrhosis is excluded. Standardized major and minor histologic criteria were developed collaboratively by expert pathologists and externally validated. Features of portal hypertension were harmonized into specific and nonspecific categories applicable to routine clinical practice. An integrated diagnostic scoring system incorporating histology, clinical features, associated conditions, and concommitant etiologies was developed and validated using the Delphi method. This consensus provides the first internationally endorsed, unified framework for the diagnosis of PSVD or NCPF. Its global implementation is expected to reduce diagnostic variability, improve comparability across regions, and facilitate the development of robust, internationally harmonized clinical and translational research cohorts.

OBJECTIVE Historically, craniopharyngioma (CP) was divided into adamantinomatous CP (ACP) and papillary CP (PCP) subtypes based on histopathological features. However, each harbors a unique genetic profile and progressively differing treatment paradigms, leading to their reclassification by the WHO in 2016 as two distinct entities. Descriptive in nature, this large multi-institutional study aimed to establish current differences between the presentation, treatment patterns, and clinical course of these pathologies to serve as a baseline for future studies as new treatment paradigms emerge. METHODS The authors queried the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, which encompassed patients from 14 participating institutions across the United States between 2000 and 2024. The database was screened for adult patients who underwent initial CP treatment with a confirmed histopathological diagnosis of ACP or PCP. Patient demographic characteristics, clinical course, tumor treatment, and outcomes data were collected and compared by CP type. RESULTS The final analysis included 273 ACP and 99 PCP adult patients who underwent initial surgical treatment. ACP patients presented younger on average (mean 48.3 vs 52.8 years, p = 0.034). PCP patients were more likely to present with hypothyroidism (33.3% vs 20.5%, p = 0.010), hyperlipidemia (25.3% vs 15.8%, p = 0.036), fatigue (28.3% vs 17.6%, p = 0.024), temperature intolerance (9.1% vs 1.5%, p < 0.001), and cardiac arrhythmia (6.1% vs 1.1%, p = 0.006). The groups demonstrated similar postsurgical and neuroendocrinological outcomes. Postoperative median (IQR) progression-free survival did not significantly differ between groups (19.0 [7.0–37.0] for ACP vs 5.0 [3.5–7.5] months for PCP, p = 0.972). ACP patients were more likely to receive radiation after surgery (27.8% vs 15.2%, p = 0.012). CONCLUSIONS This large multicenter descriptive study aimed to characterize similarities and differences between the clinical courses of molecularly distinct ACP and PCP, which has not previously been described. The findings should serve as a baseline to inform future studies, particularly with the recent introduction of targeted therapy for PCP.

OBJECTIVE Craniopharyngiomas are challenging lesions, and aggressive resections may cause significant postoperative morbidity and mortality. To mitigate morbidity, a potential strategy of subtotal resection (STR) and adjuvant radiation therapy (RT) has been used, but its impact on survival when compared to gross-total resection (GTR) has been under-investigated. Thus, the objective of this study was to analyze short-term mortality between patients undergoing STR ± RT and GTR, and differences in overall survival (OS) between patients undergoing STR, STR + RT, and GTR in a large, nationally representative database. METHODS The authors queried the National Cancer Database for patients diagnosed with craniopharyngioma between 2004 and 2017. Tumor characteristics, treatment strategies, and extent of resection were analyzed. Endpoints were 3-month mortality rate and OS, which were compared between treatment modalities. Firth’s logistic regression was used to analyze 3-month mortality and was adjusted for age, sex, Charlson Comorbidity Index score, histopathological diagnosis, income quartile, insurance payor, and maximal tumor diameter. Differences in survival between treatment modalities were compared with log time-to-event analyses after excluding deaths occurring within 3 months to control for immortal time bias. RESULTS A total of 1460 adult and 390 pediatric patients were included. Adults undergoing STR ± RT had a lower rate of 3-month mortality compared to those undergoing GTR in adjusted analysis (2.8% vs 4.6%, odds ratio 0.42; p = 0.03). Survival curves for the STR + RT and GTR cohorts did not significantly differ (p = 0.198). A strategy of STR alone showed worse OS compared with GTR and STR + RT (p < 0.01). The average follow-up length for adults was 65.5 months. For pediatric patients, 3-month mortality for those undergoing GTR and STR ± RT was similar (0% vs 1%, respectively; p = 0.33). Additionally, compared to GTR, there were no significant differences in OS between STR + RT (p = 0.41) and STR alone (p = 0.44). The average follow-up length for the pediatric cohort was 79 months. CONCLUSIONS STR + RT was associated with a favorable perioperative mortality profile when compared with GTR and provided similar long-term survival outcomes. Therefore, STR + RT may be considered when GTR carries significant risks.

OBJECTIVE Frailty is a known predictor of adverse outcomes in pituitary surgery, yet its impact regarding craniopharyngioma remains unclear. The authors assessed preoperative frailty, measured by the 11-factor modified frailty index (mFI-11), and its association with perioperative morbidity among adult patients undergoing craniopharyngioma surgery. METHODS Using the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, the authors performed a retrospective cohort study of the records of patients ≥ 18 years of age who underwent craniopharyngioma surgery between June 2007 and November 2024. Patients were stratified into the following categories according to their numeric mFI-11 score: fit (scores 0 and 1), managing well (scores 2 and 3), and mildly frail (scores 4–6). Primary outcomes included hospital length of stay (LOS) and discharge disposition. Secondary outcomes included 90-day readmission, surgical outcomes, and complications. Multivariable analyses were performed to identify independent predictors of hospital LOS and non-home discharge, adjusting for age, surgeon experience, American Society of Anesthesiologists class, complications, and surgical approach. RESULTS Among 278 patients (221 fit, 43 managing well, 14 mildly frail), higher-frailty patients were older (mean age 47.8 ± 16.1 years in fit vs 60.1 ± 12.5 years in managing well vs 67.6 ± 8 years in mildly frail, p < 0.001) and more likely to present urgently (24.2% vs 36.4% vs 78.6%, p = 0.001). Gross-total resection was achieved less frequently in frail patients (44.8% vs 24.3% vs 23.1%, p = 0.030). Overall complication rates were similar; however, increasing frailty was associated with higher rates of postoperative mortality (0% vs 2.8% [1/36] vs 7.7% [1/13], p = 0.018), pneumonia (0.5% [1/195] vs 2.8% [1/36] vs 15.4% [2/13], p = 0.006), and reintubation (2.6% [5/195] vs 2.8% [1/36] vs 30.8% [4/13], p = 0.002). Higher frailty was associated with a stepwise rise in median [IQR] LOS (5 [3–8] days vs 7 [4–12] days vs 13 [6.5–21.8] days, p < 0.001) and remained an independent predictor of extended LOS on multivariable analysis (β = 1.729 per point, p = 0.006). Rates of non-home discharge showed a similar pattern (9.2% vs 30.0% vs 64.3%, p < 0.001), with frailty independently predicting non-home discharge (OR 2.352, 95% CI 1.527–3.822). Unplanned 90-day readmission rates were significantly higher in the mildly frail cohorts (22.5% vs 45.7% vs 53.8%, p = 0.002). CONCLUSIONS The mFI-11 scores independently predicted perioperative morbidity following craniopharyngioma resection. Incorporating frailty screening into preoperative screening may improve risk stratification, family and patient counseling, and discharge planning.

OBJECTIVE Craniopharyngiomas are benign intracranial tumors that can be difficult to manage operatively and often result in postoperative complications and prolonged recovery. Understanding the factors that influence length of stay (LOS), discharge disposition, and readmission can guide perioperative planning and patient counseling. The authors examined the clinical, radiographic, and surgical predictors of extended LOS (eLOS), nonhome discharge, 90-day readmission, and hospitalization ratio (HR) after craniopharyngioma resection using a large, multicenter cohort. METHODS A retrospective analysis was conducted using the Registry of Adenomas of the Pituitary and Related Disorders database, encompassing 469 patients who underwent craniopharyngioma resection at 14 US academic centers from 2011 to 2025. Patients were stratified by 4 outcomes: eLOS (> 75th percentile), discharge to home versus skilled nursing facility/rehabilitation, 90-day hospital readmission, and hospitalization ratio (i.e., integration of initial and readmission LOS). Multivariable logistic regression models identified independent predictors for each outcome among patient and surgical variables. RESULTS An eLOS (> 10 days) was independently associated with preoperative memory loss (OR 3.75, 95% CI 1.95–7.21), gait imbalance (OR 5.90, 95% CI 1.53–22.70), and postoperative complications (OR 4.07, 95% CI 2.34–7.06). The use of a nasoseptal flap was protective against an eLOS (OR 0.52, 95% CI 0.28–0.93). Discharge to home was predicted by an endoscopic approach (OR 3.87, 95% CI 1.78–8.44) and postoperative intact thirst (OR 2.22, 95% CI 1.05–4.66) and negatively predicted by preoperative diabetes mellitus (OR 0.21, 95% CI 0.09–0.50), LOS (OR 0.87, 95% CI 0.84–0.91), and postoperative cognitive dysfunction (OR 0.30, 95% CI 0.13–0.72). Among 385 patients with follow-up data, a 90-day readmission was independently associated with postoperative complications (OR 5.62, 95% CI 3.12–10.13), preexisting coronary artery disease (OR 4.30, 95% CI 1.46–12.69), and postoperative cognitive dysfunction (OR 3.33, 95% CI 1.76–6.44). A higher HR was associated with diabetes mellitus (unstandardized B 0.059, 95% CI 0.010–0.108, p = 0.02), postoperative complications (unstandardized B 0.054, 95% CI 0.021–0.086, p = 0.001), and postoperative cognitive dysfunction (unstandardized B 0.049, 95% CI 0.006–0.092, p = 0.02). Tumor pathologic subtype and size, prior treatment, extent of resection, and surgeon experience were not directly predictive of outcomes. CONCLUSIONS Cognitive and functional status, systemic comorbidities, and postoperative complications, in addition to surgical approach, are important predictors of the early clinical course after craniopharyngioma surgery. Early identification of high-risk patients may help to guide treatment decisions, improve discharge planning, and reduce healthcare utilization.

Abstract Background Three-dimensional visualization and quantitative analysis of cerebral arteries on 3DRA are central to endovascular treatment planning, device selection, and cerebrovascular research. Manual segmentation is time-consuming and operator-dependent, yet no open-source deep learning model has been prospectively validated for this task on 3DRA. Methods A nnUNet v2 model was trained for binary cerebral artery segmentation on 400 consecutive 3DRA acquisitions from three angiographic systems, comparing four configurations across architectures and loss functions. The best-performing configurations were prospectively validated on 40 patients using a dual approach: quantitative metrics (DSC, clDice, HD95, ASD, Precision, Recall), and blinded expert qualitative evaluation by two interventional neuroradiologists assessing 12 arterial segments, a global quality score, and clinical usability across 40 test cases. Results The ensemble model achieved median DSC 0.917, clDice 0.932, and HD95 1.494 mm. Global quality scores were significantly lower for nnUNet v2 than for expert segmentations (median 4 vs 5, p<0.001), but nnUNet v2 segmentations were rated clinically usable in 88–90% of cases versus 95–98% for expert segmentations, without significant difference on the binary usability criterion. A consistent proximal-to-distal quality gradient was identified, with comparable scores at proximal arteries and the largest differences at distal arterial segments. Conclusion nnUNet v2 with topology-aware training provides clinically usable cerebral artery segmentations on 3DRA, prospectively validated through both quantitative metrics and structured expert qualitative assessment, and represents a reproducible open-source foundation for endovascular and research applications.