Citations

Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies ranging from relatively indolent well-differentiated neuroendocrine tumors (NETs) to more aggressive poorly differentiated neuroendocrine carcinomas (NECs). The advent of somatostatin receptor (SSTR)–targeting therapies, particularly radioligand therapy (RLT), has transformed the therapeutic landscape of NETs. Ongoing efforts are aimed at maximizing the therapeutic benefit of RLT and include retreatment and combination strategies as well as novel α-emitter–based radiopharmaceuticals. The increasing use of molecular profiling has led to the identification of recurrent canonical alterations in pancreatic NETs, including in MEN1 , ATRX / DAXX , PI3K/Akt/mTOR, and angiogenic signaling pathways, facilitating the development of effective targeted therapies. However, despite the addition of newer targeted therapies to the therapeutic armamentarium, resistance remains inevitable and highlights the need for improved predictive markers to inform therapy sequencing and novel biomarker-selected therapies. In addition, the development of novel therapeutic strategies including SSTR antagonists, nonpeptide drug conjugates, and novel radiopharmaceutical constructs highlights the potential of biomarker-informed therapies in this space. By contrast, treatment options for NECs remain limited, with modest therapeutic benefit of platinum-based chemotherapy. The identification of delta-like ligand 3 (DLL3) as a therapeutic target in high-grade NENs has led to the development of novel targeted therapies such as T-cell engagers, which have demonstrated promising activity in early phase clinical trials. In addition, other DLL3-targeting agents such as antibody-drug conjugates, trispecific engagers, and cellular therapies remain under investigation. Collectively, these advances underscore the potential of biomarker-informed treatment approaches to personalize treatment decisions and improve long-term outcomes across the NEN spectrum.

Abstract Citation-prediction studies often estimate citation counts using information unavailable at publication. We evaluated whether citation-risk outcomes can be predicted using only publication-time information: metadata, references, author history, and text available on or before publication. We assembled 9,424 original-research articles published from 2017 to 2022 across seven clinical gastroenterology journals using OpenAlex and PubMed. The primary reference-observed cohort included 8,409 articles with a parsed reference list. The primary outcome was ≤ 3 citations within 2 years; secondary outcomes were 0 citations within 3 years, ≤ 3 citations within 3 years, and > 20 citations within 2 years. Models compared a nonsemantic citation/reference/context baseline, author-history variables, whole-document title/abstract embeddings, role-segmented source-text embeddings, and reference-context distributional features. Evaluation used two held-out publication-year folds with PR-AUC, or area under the precision-recall curve, F1, and precision among the top-ranked 10% of predictions. For the primary outcome, the nonsemantic baseline achieved PR-AUC 0.818, F1 0.722, and precision@10% 0.935. Adding whole-document embeddings improved performance to 0.828, 0.735, and 0.962, respectively. Structure-aware features did not improve the primary outcome but provided endpoint-specific gains for secondary outcomes. Author-history features showed standalone signal but did not improve the baseline. Pooled performance exceeded journal-local performance, indicating that citation-risk signal operated at the corpus level. These findings support publication-time-valid citation-risk modeling as a reproducible framework for studying evidence visibility within bounded literatures and motivate replication across other journal sets, specialties, and publication eras.

Abstract Background Approximately 12,000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA and adult). Results The cohort of 21,099 CNS tumors included 5139 tumors from AYAs (24%), which showed a mixed pattern, with tumors typical of childhood (e.g. medulloblastoma) as well as those common in older adults (e.g. glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Abstract Background & Objectives Cholangiocarcinoma (CCA) is a rare and aggressive malignancy of the bile ducts characterized by complex imaging patterns, high inter-reader variability, and limited subspecialty expertise. Despite the critical importance of early detection for improving patient outcomes, most artificial intelligence (AI) tools developed for radiology have focused on other organ systems, leaving CCA largely underserved. Furthermore, clinicians with relevant domain expertise frequently lack the programming background required to participate meaningfully in AI development. This work aimed to create an accessible, educational AI framework “AI Starter” designed to empower radiologists and clinicians to initiate medical image analysis projects for CCA without requiring extensive coding knowledge. Methods A structured, end-to-end AI pipeline was introduced covering the key stages of image acquisition, preprocessing, segmentation, feature extraction, and predictive modeling. Open-source frameworks, specifically MONAI and PyTorch, were employed to ensure reproducibility and accessibility. Transfer learning strategies were incorporated to address the challenge of limited CCA-specific training datasets. The pipeline was designed with modular components to reduce technical barriers and accommodate users across varying levels of computational experience. Results Radiologists and clinicians were able to successfully engage with and deploy AI tools for CCA imaging analysis using this framework. Transfer learning demonstrably improved model performance under data-limited conditions, and the open-source implementation supported reproducible research workflows. Key challenges identified included scanner variability, segmentation instability, feature instability, and model overfitting, all of which were transparently mapped within the pipeline. Conclusion The AI Starter framework offers a practical and educational entry point for the CCA community including basic scientists and clinicians to meaningfully engage with and understand AI-driven imaging analysis.

Background: Hepatic stellate cells (HSCs) play a pivotal role in driving fibrosis during chronic liver injury. HSCs produce vast amounts of fibrotic proteins, causing endoplasmic reticulum (ER) stress and initiating the unfolded protein response (UPR). While the UPR is important for fibrogenesis, how signaling through UPR transducer Protein Kinase R-like ER Kinase (PERK) and its effectors impact HSC activation and fibrogenesis is unclear. Here, we sought to uncover the role of PERK and its effector GADD45A in liver fibrosis. Methods: PERK–GADD45A signaling was assessed in primary and immortalized HSCs treated with TGFβ, and mouse models of fibrosis. Genetic and pharmacological disruption of PERK or GADD45A was used to assess the role of PERK or GADD45A in HSC activation, proliferation, and fibrogenesis. HSC-specific Gadd45a -null mice were utilized to investigate the role of GADD45A on CCl 4 -induced fibrosis. Results: We found that TGFβ-induction of collagen I drives activation of PERK signaling in HSCs. Furthermore, loss or inhibition of PERK limits long-term HSC activation as illustrated by reduced levels of collagen I and fibronectin, impaired collagen I deposition, and reduced cell proliferation in vitro. Next, we show that PERK signaling induces expression of GADD45A during HSC activation, and loss of GADD45A disrupts HSC activation and expression of proliferation and cell-cycle-associated genes in immortalized and primary HSCs. Finally, HSC-specific GADD4Aa loss limits CCl 4 -driven fibrogenesis in vivo. Conclusion: PERK signaling is critical for HSC activation, and loss of the PERK downstream effector GADD45A limits fibrosis progression. Disruption of HSC activation and proliferation, coupled with dysregulation of cell-cycle-associated genes upon PERK or GADD45A loss, suggests that PERK–GADD45A signaling impacts multiple facets of HSC pathophysiology.

ABSTRACT Prior surveys of chronic automated red blood cell exchange (RCE) for patients with sickle cell disease (SCD) have identified considerable procedural variability, especially with the use of isovolemic hemodilution red blood cell exchange (IHD‐RCE). We conducted a survey of chronic RCE practices among American Society for Apheresis (ASFA) members to identify opportunities for practice harmonization and future studies. The ASFA SCD Research Subcommittee developed a 72‐item survey of chronic RCE practices, with a focus on IHD‐RCE. The survey was validated internally and distributed by email to all ASFA members from September 2024 to February 2025. One survey response from each institution was retained for data analysis. Descriptive statistics were performed. Sixty‐two survey responses, including three from international institutions, were retained for analysis. Sixty‐one percent of respondents (38/62) reported using at least one fixed RCE target, with end hematocrit being the most common fixed parameter (40%, 25/62), followed by fraction of cells remaining (31%, 19/62) and hemoglobin S% (27%, 17/62). Most respondents (60%, 37/61) performed IHD‐RCE at their institution, though other details such as the minimum hematocrit, exclusion criteria, and response to adverse effects were variable. Consistent pre‐ and post‐RCE laboratory monitoring practices were reported. Consistent with earlier surveys, procedural variability in chronic RCE practices for patients with SCD is observed. This highlights opportunities to compare outcomes where practice variability exists. Consensus guidelines based on institutional practices with optimal outcomes should be developed.

Abstract Introduction Despite regulatory mandates for advanced therapy (AT) washout periods of up to 5 drug half-lives before enrolling patients in inflammatory bowel disease (IBD) trials, the evidence base for these requirements is largely empirical, and whether shorter intervals independently increase the risk of serious infections in real-world practice remains unknown. Methods Using the OptumLabs Data Warehouse, we identified adult patients with IBD who initiated a new AT (tumor necrosis factor antagonists, vedolizumab, interleukin (IL)-12/23 or IL-23 antagonists, or Janus kinase inhibitors) between 2018 and 2023 using a class-specific new-user design. We examined whether exposure to AT within the preceding 12 months (vs no exposure to AT within that window) and timing of discontinuation (≤1 month, 1-<3 months, or 3-12 months) were associated with risk of serious infections using multivariable Cox proportional hazards regression. Results Among 21 564 AT initiators (47 ± 18 years; 52% female; 57% Crohn’s disease), 7490 (34.7%) had AT exposure within the preceding 12 months. Over a mean follow-up of 1.6 ± 0.9 y, 1955 (9.1%) experienced a serious infection. Prior AT exposure was associated with higher infection risk (hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.07-1.33), consistent in inverse probability of treatment-weighted analyses (HR, 1.20 [1.06-1.37]). Among patients with prior exposure, timing of discontinuation was not associated with infection risk (HR, 1.17 [0.95-1.43] for ≤1 month vs 3-12 months; HR, 1.01 [0.83-1.22] for 1-<3 months), with no dose–response relationship on continuous modeling. Discussion AT exposure within the preceding 12 months is associated with modestly higher risk of serious infection after initiating a new AT in IBD, but timing of discontinuation does not independently influence this risk.

BACKGROUND AND OBJECTIVES: Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS: A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm 3 . Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS: A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm 3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION: VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm 3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

The NCCN Guidelines for Melanoma: Cutaneous provide strategies for the diagnosis, treatment, and follow-up of patients with cutaneous melanoma, which is among the most common cancers in the United States. The outcome of cutaneous melanoma is significantly influenced by stage at initial presentation. Generally, localized disease and smaller primary tumors have been associated with more favorable prognosis. Thus, the select content featured in this issue focuses on risk factors associated with cutaneous melanoma development and which should be considered during an initial assessment. These include (1) phenotypic predispositions, (2) personal medical history or comorbidities, (3) genetic predispositions, and (4) environmental factors.