Association of hospital volume with survival but not with postoperative mortality in glioblastoma patients in Belgium.

OBJECTIVES: Standard of care treatment for glioblastoma (GBM) involves surgical resection followed by chemoradiotherapy. However, variations in treatment decisions and outcomes exist across hospitals and physicians. In Belgium, where oncological care is dispersed, the impact of hospital volume on GBM outcomes remains unexplored. This nationwide study aims to analyse interhospital variability in 30-day postoperative mortality and 1-/2-year survival for GBM patients. METHODS: Data collected from the Belgian Cancer Registry, identified GBM patients diagnosed between 2016 and 2019. Surgical resection and biopsy cases were identified, and hospital case load was determined. Associations between hospital volume and mortality and survival probabilities were analysed, considering patient characteristics. Statistical analysis included logistic regression for mortality and Cox proportional hazard models for survival. RESULTS: A total of 2269 GBM patients were identified (1665 underwent resection, 662 underwent only biopsy). Thirty-day mortality rates post-resection/post-biopsy were 5.1%/11.9% (target < 3%/<5%). Rates were higher in elderly patients and those with worse WHO-performance scores. No significant difference was found based on hospital case load. Survival probabilities at 1/2 years were 48.6% and 21.3% post-resection; 22.4% and 8.3% post-biopsy. Hazard ratio for all-cause death for low vs. high volume centres was 1.618 in first 0.7 year post-resection (p < 0.0001) and 1.411 in first 0.8 year post-biopsy (p = 0.0046). CONCLUSION: While 30-day postoperative mortality rates were above predefined targets, no association between hospital volume and mortality was found. However, survival probabilities demonstrated benefits from treatment in higher volume centres, particularly in the initial months post-surgery. These variations highlight the need for continuous improvement in neuro-oncological practice and should stimulate reflection on the neuro-oncological care organisation in Belgium.

Epigenetic landscape reorganization and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma.

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is however difficult and, apart from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. Experimental Design: RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n=138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. We used the DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) that is based on classification scores derived from a CNS-tumor classifier. We found that the CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with i) an upregulation of cell cycling genes; ii) a downregulation of glial differentiation genes; iii) an upregulation of embryonic development genes (e.g. HOX, PAX and TBX) and iv) an upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes.

Molecular analysis using SalvGlandDx improves risk of malignancy estimation and diagnosis of salivary gland cytopathology: An exploratory multicenter study.

BACKGROUND: Diagnosis of salivary gland neoplasms is challenging, especially on cytological specimens acquired by fine-needle aspiration. The recently implemented standardized Milan system for reporting salivary gland cytopathology provides an estimated risk of malignancy (ROM); yet, for two of the categories, the diagnosis of the lesion remains unclear. However, a precise diagnosis is desirable for optimal patient management, including planning of surgery and imaging procedures. METHODS: Cytological specimens (n = 106) were subjected to molecular analysis using the SalvGlandDx panel. The risk of malignancy was calculated for each detected alteration based on the diagnosis of the resection specimen. By taking into account the molecular alterations, their associated ROM, the clinical and cytological features, and the current literature, the Milan category was evaluated. RESULTS: Of n = 63 technically valid cases, 76% revealed a molecular alteration. A total of 94% of these molecularly altered cases could be assigned to a different Milan category when additionally taking molecular results into account. In only 2% of the salivary gland neoplasms of uncertain malignant potential, in which a molecular alteration was detected, the classification remained salivary gland neoplasms of uncertain malignant potential. CONCLUSION: Molecular analysis of cytological specimens provides a benefit in classifying salivary gland neoplasms on fine-needle aspiration. It can improve the ROM estimation and thus help to assign cases of formerly unknown malignant potential to clearly benign or malignant categories.

CD4+ T cell activation distinguishes response to anti-PD-L1+anti-CTLA4 therapy from anti-PD-L1 monotherapy.

Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.

The prognostic effect of radiological extranodal extension in HPV-positive oropharyngeal squamous cell carcinomas: a retrospective cohort analysis.

PURPOSE: Radiological extranodal extension (rENE) is a well-known negative prognosticator in head and neck squamous cell carcinoma (HNSCC). However, controversy remains regarding the prognostic effect of rENE in HPV-positive oropharyngeal SCCs (OPSCC). This single-center retrospective cohort analysis assessed the prognostic role of rENE in an HPV + OPSCC population and tried to validate a recently proposed modification of the TNM8 N-classification. METHODS: 129 patients with HPV + OPSCC, of whom 106 cN + patients, were included. Radiological imaging (CT, MRI or both) was reanalyzed by a senior head and neck radiologist. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRFS), and disease-specific survival (DSS) were evaluated. Cox proportional hazard models were used for estimating hazard ratios (HR). RESULTS: A non-significant trend towards better outcomes in the rENE- group, as compared to the rENE + population, was observed for 5 year OS [80.99% vs 68.70%, HR: 2.05, p = 0.160], 5 year RFS [78.81% vs 67.87%, HR: 1.91, p = 0.165], 5 year DFS [77.06% vs 60.16%, HR: 2.12, p = 0.0824] and 5 year DSS [88.83% vs 81.93%, HR: 2.09, p = 0.195]. OS declined with ascending levels of rENE (p = 0.020). Multivariate analysis identified cT-classification and smoking as independent negative predictors for OS/DFS. The proposed modification of the TNM8 N-classification could not be validated. CONCLUSIONS: Although rENE could not be identified as an independent negative prognosticator for outcome in our HPV + OPSCC population, outcomes tend to deteriorate with increasing rENE.

Exploring long-term responses to immune checkpoint inhibitors in recurrent and metastatic head and neck squamous cell carcinoma.

OBJECTIVES: Immune checkpoint inhibitors (ICI) have introduced a new era in the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Optimal duration for ICI therapy is still unclear and the long-term outcomes and toxicity in patients responding to these therapies warrant further exploration. This study attempts to identify the clinical and biological determinants of a durable response and evaluate outcomes following ICI treatment discontinuation. MATERIALS AND METHODS: A retrospective review of 181 patients treated with ICI for R/M HNSCC was conducted. Long-term responders were defined as patients who sustained disease control at least two years after initiating ICI therapy. We compared clinical and biological characteristics associated with these long-term responders against the broader treatment population. RESULTS: 10 % of R/M HNSCC patients treated with ICIs demonstrated a durable long-term response. Only three relapses (16 %) occurred after discontinuing ICI treatment in this subset, with a median follow-up of 52 months. Upon retreatment with ICI, two attained a documented response. Extended ICI response was observed even with < 2 years of treatment. 74 % of long-term responders experienced immune-related adverse events (irAEs), 37 % of which severe irAEs. Hypothyroidism was the most frequently reported irAEs. The predictive potential of systemic inflammation indices for clinical response appears to be limited. CONCLUSIONS: ICI present an optimistic avenue for HNSCC patients, offering substantial long-term responses. The study suggests that a two-year treatment could be optimal and irAEs, although common, are typically mild.