Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1α, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9–100.0] vs. 16.7% [95% CI: 0.0–44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis.

To analyze the presence of cancer stem cells markers in consecutive patients with locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) and establish their suitability as a prognostic biomarker in samples from routine practice. Retrospective study of 104 consecutive patients with locally advanced HNSCC treated with definitive surgery and adjuvant chemoradiotherapy. Immunohistochemical expression of CD44, HLA-I, pan-cytokeratin, and phosphorylated Epidermal Growth Factor Receptor (p-EGFR) were evaluated in surgical specimens. Overall Survival (OS) and Disease-Free Survival (DFS) rates were calculated based on clinical characteristics and the total positive score (for tumor marker expression). Hazard ratios were calculated by Cox multivariate analysis. After a median follow-up of 50-months, higher OS rates were observed for patients without cervical node pathological involvement (p < 0.001), patients with HLA-I overexpression and a total positive score ≥ 15% (p = 0.017), and patients with low CD44 expression and a total positive score ≤ 60% (p = 0.022). Grouping by p-EGFR (p = 0.648) or pan-cytokeratin (p = 0.477) expression did not show statistical differences in OS. None of the biomarkers were associated with different DFS rates. Cox multivariate analysis revealed that positive cervical nodes (HR = 1.294; 95% CI 1.025-1.634; p = 0.030) and the expressions of HLA (HR = 0.373; 95% CI 0.168‒0.829; p = 0.015) and CD44 (HR = 2.170; 95% CI 1.031-4.569; p = 0.041) were independently associated with OS. Nodal involvement, HLA-I overexpression, and decreased CD44 expression are independent prognostic factors of survival in patients with locally advanced HNSCC. III.

The aim of our study is to evaluate the correlation between gynecological examination and magnetic resonance (MRI) findings for the assessment of local response in cervical cancer patients treated with radiotherapy/chemotherapy (RT/ChT). This study is a retrospective review of 75 consecutive cervical cancer patients from April 2004 to November 2009 treated with RT/ChT. Clinical and radiological data were subsequently analyzed. Patient's median age was 51 with a FIGO stage from Ib to IVb. Individualized RT/ChT was administered with a median dose of 45 Gy. Sixty-three patients received a complementary brachytherapy. Seventy-one patients received chemotherapy on a weekly basis. Gynecological exam was performed 3 months and 6 months after treatment and these findings were compared to MRI results at the same time. We used the Spearman's Rho test to determine the correlation level between the clinical and radiological methods. A correlation of 0.68 (60%) was observed between the clinical and MRI findings at 3 months with a further increase of up to 0.86 (82.6%) at 6 months. In the few cases with a poor correlation, the subsequent assessment and the natural history of the disease showed a greater value of the clinical exam as compared with the MRI findings. Physical exam remains an essential tool to evaluate the local response to RT/ChT for cervical cancer. The optimal clinical radiological correlation found at 6 months after treatment suggests that the combination of gynecological examination and MRI are probably adequate in patient monitoring.

Purpose: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials. Experimental Design: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes. Results: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype–negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes. Conclusions: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.