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BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Background: It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location. Methods: We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis. Results: In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94). Conclusion: Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status. Contexte : Selon un récent rapport, le statut du système de réparation des mésappa-riements (MMR, pour mismatch repair) et de l'instabilité microsatellitaire (MSI, pour microsatellite instability) dans le cancer gastro-oesophagien permet de prédire l'issue des traitements (chirurgie, chimiothérapie et immunothérapie); or, on observe une importante variabilité quant à l'incidence rapportée et quant aux répercussions cliniques du statut MMR/MSI dans les adénocarcinomes gastro-oesophagiens. Auprès d'une cohorte de patients canadiens qui ont été opérés, nous avons recueilli le statut MMR, les corrélats clinicopathologiques et la localisation de la tumeur. Méthodes : Nous avons établi le statut MMR et BRAF V600E des adénocarcinomes gastro-oesophagiens chez des personnes ayant subi une gastrectomie ou une oesophagectomie avec lymphadénectomie étendue (D2) dans 1 seul centre entre 2011 et 2019. Nous avons établi la corrélation entre les modes d'expression du MMR dans la cohorte entière et dans des sous-groupes définis selon la localisation de la lésion, la réponse au traitement et la survie globale, à l'aide d'analyses multivariées. Résultats : En tout, nous avons inclus 226 cas d'adénocarcinomes gastro-oesophagiens (63 de l'oesophage, 98 de la jonction gastro-oesophagienne et 65 de l'estomac). L'immunophénotype MMR-déficient (dMMR) a été observé dans 28 tumeurs (12,3 %) (15 de la jonction [15,3 %], 13 de l'estomac [20,0 %] et aucun de l'oesophage). La majorité (25 [89 %]) des cas dMMR étaient négatifs pour MLH1/PMS2, sans mutation BRAF V600E concomitante. Deux tumeurs gastriques négatives pour MSH2/MSH6 et 1 tumeur de la jonction négative pour MSH6 ont été détectées. La réponse anatomo-pathologique à la chimiothérapie préopératoire a été comparable dans les cohortes dMMR et MMR-compétentes (pMMR). Toutefois, le statut dMMR a été associé à une survie médiane globale significativement plus longue que le statut pMMR (5,8 ans c. 2,4 ans, risque relatif [RR] 1,91, intervalle de confiance [IC] de 95 % 1,06-3,46), particulièrement pour les tumeurs de la jonction (4,6 ans c. 1,9 an, RR 2,97, IC de 95 % 1,27-6,94). Conclusion : Selon notre étude, le statut MMR a la moins grande valeur pronostique, ce qui appuie le recours à un dosage des biomarqueurs pour les adénocarcinomes gastro-oesophagiens, y compris les adénocarcinomes de la jonction gastrooesophagienne. Cela rappelle l'importance au plan clinique de déterminer le statut MMR dans tous cas d'adénocarcinome des voies digestives hautes. La réponse à la chimiothérapie d'induction n'a toutefois subi aucune influence du statut MMR., Upper gastrointestinal malignant diseases represent close to 9% of all new cancer cases and 14% of all cancer deaths worldwide. (1) Of their 2 main histologic subtypes, squamous cell carcinoma [...]

Of the over 250 Aspergillus species, Aspergillus fumigatus accounts for up to 80% of invasive human infections. A. fumigatus produces galactosaminogalactan (GAG), an exopolysaccharide composed of galactose and N-acetyl-galactosamine (GalNAc) that mediates adherence and is required for full virulence. Less pathogenic Aspergillus species were found to produce GAG with a lower GalNAc content than A. fumigatus and expressed minimal amounts of cell wall-bound GAG. Increasing the GalNAc content of GAG of the minimally pathogenic A. nidulans, either through overexpression of the A. nidulans epimerase UgeB or by heterologous expression of the A. fumigatus epimerase Uge3 increased the amount of cell wall bound GAG, augmented adherence in vitro and enhanced virulence in corticosteroid-treated mice to levels similar to A. fumigatus. The enhanced virulence of the overexpression strain of A. nidulans was associated with increased resistance to NADPH oxidase-dependent neutrophil extracellular traps (NETs) in vitro, and was not observed in neutropenic mice or mice deficient in NADPH-oxidase that are unable to form NETs. Collectively, these data suggest that cell wall-bound GAG enhances virulence through mediating resistance to NETs.

Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme [B.sup.+][CD8.sup.+] T cells (Gzm[B.sup.+][CD8.sup.+] T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An 'immune-cold' microenvironment with an absence of tumoral [CD8.sup.+] T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of [CD8.sup.+] T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC., Introduction Triple-negative breast cancer (TNBC) lacks targeted therapies, has high rates of distant recurrence, and poor overall survival for patients. Large-scale gene expression and sequencing studies have revealed high heterogeneity [...]