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The WHO guidelines for classifying central nervous system (CNS) tumours are changing considerably with each release. The classification of CNS tumours is uniquely complex among most other solid tumours as it incorporates not just morphology, but also genetic and epigenetic features. Keeping current with these changes across medical fields can be challenging, even for clinical specialists. Large language models (LLMs) have demonstrated their ability to parse and process complex medical text, but their utility in neuro‐oncology has not been systematically tested. We hypothesised that LLMs can effectively diagnose neuro‐oncology cases from free‐text histopathology reports according to the latest WHO guidelines. To test this hypothesis, we evaluated the performance of ChatGPT‐4o, Claude‐3.5‐sonnet, and Llama3 across 30 challenging neuropathology cases, which each presented a complex mix of morphological and genetic information relevant to the diagnosis. Furthermore, we integrated these models with the latest WHO guidelines through Retrieval‐Augmented Generation (RAG) and again assessed their diagnostic accuracy. Our data show that LLMs equipped with RAG, but not without RAG, can accurately diagnose the neuropathological tumour subtype in 90% of the tested cases. This study lays the groundwork for a new generation of computational tools that can assist neuropathologists in their daily reporting practice.

Purpose We aimed to expand and refine the experimental models for pediatric-type diffuse high grade gliomas (pHGG) and the methods to follow up disease progression in mouse pHGG xenografts. Methods Using whole exome sequencing and immunoassays we characterized pHGG primary cultures and xenografts established at hospital SJD Barcelona. We obtained tumor samples and serial CSF samples from mouse xenografts. To assess tumor progression, we evaluated: (1) mouse weight, (2) human cell counts in brain paraffin sections, and (3) tumor DNA amount, quantified through droplet digital polymerase chain reaction (ddPCR) in paraffin sections and cerebrospinal fluid (CSF). Results We established 15 experimental models of three pHGG subclasses, four of which engrafted in mice. Xenografts HSJD-DIPG-007 and HSJD-DMG-005 are diffuse midline glioma (DMG) H3 K27-altered, HSJD-GBM-002 is an H3 G34-mutant diffuse hemispheric glioma, and HSJD-GBM-001 is an H3-wildtype and IDH-wildtype pHGG. ddPCR quantification of human H3F3A K27M, H3F3A G34R, and ACVR1 R206H in paraffin samples is linear and sufficiently sensitive. We required a preamplification step to detect H3F3A K27M in CSF. In HSJD-DIPG-007 xenografts, human cell counts correlated with H3F3A amounts in paraffin for the whole engraftment period. Weight loss correlated with human cell counts and H3F3A amounts in paraffin. Serial collection of CSF was feasible, but H3F3A amounts in the CSF correlated only with weight loss. Conclusion The developed methods contribute to the preclinical field of pHGG and introduce for the first time the concept of liquid biopsy in mice, which still needs improvement regarding its use as a preclinical biomarker.

Diffuse-type gastric cancer, also known as scirrhous gastric cancer, is characterized by a larger number of stromal cells, referred to as cancer-associated fibroblasts (CAFs), than the number of cancer cells in the tissue. The present study focused on CAFs in gastric cancer and examined their potential as a blood biomarker. A total of 46 and 84 patients with gastric cancer were respectively included in a development and an independent validation cohort to assess the clinicopathological characteristics of plasma podoplanin (PDPN) levels. The prognostic impact of plasma PDPN was also investigated in the validation cohort. The cut-off value of the plasma-PDPN concentration was set to the median plasma PDPN concentration in the development cohort that was then divided into the high-PDPN and low-PDPN groups. The high-PDPN group tended to have more diffuse-type disease (P=0.079), which was further confirmed through logistic regression analysis (P=0.008). Kaplan-Meier survival estimates indicated that the recurrence-free survival rate was significantly lower in the high-PDPN group (P=0.029). In conclusion, plasma soluble PDPN was demonstrated to be a marker for diffuse gastric cancer and may reflect the prognosis of this disease.

The primary treatment for fatal pediatric‐type diffuse high‐grade glioma (PED‐DHGG) which harbor the H3K27M or H3G34R/V mutation is radiation, but it provides only short‐term relief. Inhibitors of phosphorylated eIF2α (PeIF2α) phosphatase—namely raphin‐1 and salubrinal—decrease survival of PED‐DHGG cell lines and sensitize them to radiation. However, although both drugs increase PeIF2α, they have different effects on common targets and different targets altogether. Here, we aimed to identify PeIF2α‐phosphatase‐dependent and PeIF2α‐phosphatase‐independent molecular targets. Raphin‐1 but not salubrinal, decreased the level of BiP and CReP and increased that of DR5, in an ISRIB‐independent manner. Raphin‐1 induced similar changes in MEFS51A cells and in irradiated PED‐DHGG, suggesting a PeIF2α‐independent contribution to raphin‐1's radiosensitizing effect. Importantly, while the expression of [S51D] eIF2α decreased the survival of PED‐DHGG and both raphin‐1 and salubrinal decreased the survival of MEFWT cells, only raphin‐1 decreased the survival of mutant MEFS51A cells. Our results suggest that the sensitivity of PED‐DHGG to raphin‐1 is mediated by both PeIF2α‐dependent and PeIF2α‐independent processes. Elucidating these processes could reveal targets for the development of drugs to overcome radiotherapy resistance of PED‐DHGG. Raphin‐1 reduces the survival of PED‐DHGG cells and enhances their radiation sensitivity through both PeIF2α‐dependent and PeIF2α‐independent mechanisms. Raphin‐1 sustains elevated levels of PeIF2α, contributing to its PeIF2α‐dependent effects. Additionally, raphin‐1 interacts with CReP to mediate a separate radiosensitizing pathway that operates independently of PeIF2α. This mechanism involves: Downregulation of BiP, upregulation of DR5 and activation of caspase‐8.

Objective Diffuse‐type tenosynovial giant cell tumors (Dt‐TGCTs) commonly occur in the knee joint and tend to recur postoperatively. However, limited clinical data are available on ankle joint involvement especially associated multiportal arthroscopic treatment outcomes. The purpose of this study was to report the clinical results of multiportal arthroscopy‐assisted resection of Dt‐TGCTs of the ankle. Methods We retrospectively reviewed the clinical data of 33 patients with Dt‐TGCT of the ankle who underwent multiportal arthroscopic treatment between August 2011 and December 2020. Clinical follow‐up included the visual analogue scale (VAS) score, American Orthopedic Foot and Ankle Society (AOFAS) score, Kofoed score, and recurrence rate to assess surgical outcomes. The number of patients who achieved the patient acceptable symptom state (PASS) based on the AOFAS score was also examined. Additionally, the patients were categorized into two groups based on the final surgical approach: Group A who underwent multiportal arthroscopic synovectomy and Group AO who underwent combined arthroscopic and open surgical excision. Intergroup comparisons were conducted. Intraoperative characteristics, such as the number of patients with involvement of the tarsal tunnel and fibularis tendon and the Outerbridge grading of cartilage damage, were recorded to assess the selection of surgical procedures. Results Among the 33 patients, 15 were assigned to Group A, and 18 were in Group AO. The median follow‐up duration for the 33 patients was 77 months (range, 28–142 months). The median VAS score was 1 (range, 0–4), the AOFAS score was 96 (range, 65–100), and the Kofoed score was 96 (range, 67–100). A total of 27 patients (82%) achieved PASS based on AOFAS scores, while five patients (15%) had recurrence. No statistically significant difference was observed between the two groups in recurrence rate, follow‐up VAS score, AOFAS score, Kofoed score, or number of patients who reached the PASS (p > 0.05). In the AO group, 16 cases of Dt‐TGCT involved the tarsal tunnel, and 11 cases involved the fibularis tendon. All these patients exhibited extension beyond the joint. In contrast, only one patient in Group A had involvement of the tarsal tunnel. Statistically significant differences were observed between the groups (p < 0.001). Conclusion This study demonstrated that, with the assistance of a multiportal arthroscopic approach, surgical excision of Dt‐TGCT in the ankle resulted in favorable clinical outcomes with a relatively low recurrence rate. Additionally, patients with extra‐articular involvement were more likely to require concomitant open surgery. Ankle arthroscopy is characterized by its short duration, minimal trauma, and rapid recovery. Moreover, it enables clear visualization of lesions, and with the use of multiportal approaches, complete excision of diffuse‐type tenosynovial giant cell tumors (Dt‐TGCTs) within the ankle joint cavity is feasible. Follow‐up assessments have demonstrated favorable clinical outcomes.

Background The 2021 WHO Classification of Central Nervous System Tumors introduces more molecular markers for glioma reclassification, including TERT promoter (TERTp) mutation as a key feature in glioblastoma diagnosis. Aims Given the changes in the entities included in each subtype under the new classification, this research investigated the distribution, prognostic value, and correlations with other molecular alterations of TERTp mutation in different subgroups under this latest classification. Methods All glioma patients admitted to Peking Union Medical College Hospital for surgical resection or biopsy from 2011 to 2022 were included. Samples were analyzed for TERTp mutation and 59 other gene alterations and chromosome copy number variations. Results A total of 207 patients were included. The occurrence of TERTp mutations varied with percentages of 4.55%, 100%, and 77.92% in astrocytoma, oligodendroglioma, and glioblastoma, respectively. 65% of all adult‐type glioma patients and 42.6% of IDH‐wildtype histology grade 2 or 3 patients were TERTp‐mutant. Survival analysis showed that TERTp mutation was a predictor of better prognosis in IDH‐mutant grade 2 gliomas (median OS (mOS): not reached (NA) (95% CI: NA–NA) vs. 75.9 (95% CI: 55.4–NA) months, HR = 0.077 (95% CI: 0.01–0.64), p = 0.003), while poor OS was associated with all Grade 4 gliomas (mOS: 17.5 (95% CI: 12.6–24.2) vs. 40.5 (95% CI: 24.4–83.8) months, HR = 2.014 (95% CI: 1.17–3.47), p = 0.01) and all IDH‐wildtype histology grade 2 or 3 gliomas (median OS: 12.6 (95% CI: 11–24.2) vs. 83.8 (95% CI: 35.2–NA) months, HR = 3.768 (95% CI: 1.83–7.78), p < 0.001). Moreover, TERTp mutation tended to co‐occur with EGFR, KRAS, and MET in glioblastoma. In the IDH‐mutant subgroup, it tended to co‐occur with CIC and FUBP1 alterations, while being mutually exclusive with ATRX and TP53 alterations. These correlations may further refine prognostic predictions. Given the big changes in the entities included in each subtype under the 2021 CNS tumor classification, the effect of TERTp mutation on prognosis and the relationship between TERTp mutation and other molecular alterations in different subgroups should be reevaluated. In this research, we investigated the distribution, prognostic value, and molecular correlation of TERTp mutation under this latest classification. Survival analysis showed that TERTp mutation was a predictor of better prognosis in IDH‐mutant grade 2 gliomas, while poor OS was associated with all Grade 4 gliomas and all IDH‐wildtype histology grade 2 or 3 gliomas. The correlation between TERTp mutation and other molecular alterations was multiform in different subgroups, which needs to be investigated further.

The Consortium to Inform Molecular and Practical Approaches to Central Nervous System Tumor Taxonomy (cIMPACT‐NOW) updates provide guidelines for the diagnosis of central nervous system (CNS) tumors and suggestions for future World Health Organization (WHO) classification. Following publication of the fifth edition WHO Classification of CNS Tumors (WHO CNS5) in 2021, the cIMPACT‐NOW working group “Clarification” reviewed WHO CNS5 and prioritized two topics for further elucidation: (a) distinction of Glioblastoma, IDH‐wildtype from Diffuse pediatric‐type high‐grade glioma, H3‐wildtype, and IDH‐wildtype and (b) clarification of subgroups of posterior fossa (PF) ependymal tumors. Recommendations regarding the IDH‐ and H3‐wildtype diffuse high‐grade gliomas include: (1) use caution assigning CNS WHO grade 4 (diagnosis of Glioblastoma, IDH‐wildtype) to a “TERT promoter only”, histologically low‐grade, IDH‐wildtype tumor; (2) EGFR gene amplification and +7/−10 chromosome copy number alterations should not be used as solitary defining features for diagnosing high‐grade gliomas as Glioblastoma, IDH‐wildtype in patients <40 years of age; (3) Diffuse pediatric‐type high‐grade glioma, H3‐wildtype, and IDH‐wildtype should be considered in the differential diagnosis in adults, especially those <40 years of age; (4) PDGFRA alteration, EGFR alteration, or MYCN amplification count as key molecular features of Diffuse pediatric‐type high‐grade glioma, H3‐wildtype, and IDH‐wildtype only in patients <25 years. Guidelines for improved diagnosis of posterior fossa ependymal tumors include: (1) immunohistochemical demonstration of nuclear EZHIP supports classification as PF group A ependymoma; (2) a PF ependymoma with retained nuclear H3 K27me3 expression and no nuclear EZHIP overexpression for which DNA methylation profiling is not performed should be considered as PF ependymoma, “not otherwise specified”; (3) for emerging tumors not included in WHO CNS5, “not elsewhere classified” (NEC) can be added to the diagnosis. Of note, these recommendations are not formal changes to the WHO definitions and diagnostic criteria but are intended to provide diagnostic guidance in advance of WHO CNS6.

Signet ring cell adenocarcinomas (SRCCs) are a rare histological subtype of adenocarcinomas with a poor prognosis, typically due to advanced disease at diagnosis. A signet ring cell, mimicking its moniker, contains abundant intracytoplasmic mucin that pushes the nucleus to the periphery. In these cancers, this cell feature comprises more than 50% of the tumor. Despite predilection for the gastrointestinal tract, and in particular the stomach, primary SRCCs are also described in other sites, typically in case reports. This literature, however, lacks a standardized overview of the SRCC disease entity. Using a retrospective cohort approach, we summarize the clinicodemographic and mortality outcomes of SRCCs in thirteen primary sites, comprising 95% of all SRCCs in the Surveillance, Epidemiology, and End Results Program (SEER), a population-level cancer database covering nearly one-third of the United States population. SRCCs general trends compared to matching nonvariant adenocarcinomas are earlier age of onset, with initial presentation favoring higher rates of regional or distant disease presentation and poor tumor differentiation. After multivariable analysis, SRCCs typically have worse overall survivals, but substantial variances exist depending on tumor location. Identifying SRCCs at earlier disease stages is likely the single most important intervention to improving outcomes for these patients.