Andrea Bianchi

Evidence is conflicting on the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in head and neck squamous cell carcinoma. The aim of our study was to determine the impact of semiquantitative and qualitative metabolic parameters on the outcome in patients managed with standard treatment for locally advanced disease. A systematic review of the literature was conducted. A meta-analysis was performed of studies providing estimates of relative risk (RR) for the association between semiquantitative metabolic parameters and efficacy outcome measures. The analysis included 25 studies, for a total of 2,223 subjects. The most frequent primary tumour site was the oropharynx (1,150/2,223 patients, 51.7%). According to the available data, the majority of patients had stage III/IV disease (1,709/1,799, 94.9%; no information available in four studies) and were treated with standard concurrent chemoradiotherapy (1,562/2,009 patients, 77.7%; only one study without available information). A total of 11, 8 and 4 independent studies provided RR estimates for the association between baseline FDG PET metrics and overall survival (OS), progression-free survival (PFS) and locoregional control (LRC), respectively. High pretreatment metabolic tumour volume (MTV) was significantly associated with a worse OS (summary RR 1.86, 95% CI 1.08–3.21), PFS (summary RR 1.81, 95% CI 1.14–2.89) and LRC (summary RR 3.49, 95% CI 1.65–7.35). Given the large heterogeneity (I2 > 50%) affecting the summary measures, no cumulative threshold for an unfavourable prognosis could be defined. No statistically significant association was found between SUVmax and any of the outcome measures. FDG PET has prognostic relevance in the context of locally advanced head and neck squamous cell carcinoma. Pretreatment MTV is the only metabolic variable with a significant impact on patient outcome. Because of the heterogeneity and the lack of standardized methodology, no definitive conclusions on optimal cut-off values can be drawn.

OBJECTIVE: The purpose of the study was to explore the usefulness of fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET-CT) in the preoperative assessment of isolated anterior mediastinal lesions, especially in the planning of operative strategy (biopsy or upfront resection). METHODS: During the last 36 months, 19 consecutive patients (10 males, mean age 54+/-16 years) underwent PET-CT in the preoperative work-up of isolated anterior mediastinal diseases. Maximal transverse diameter at CT and the postoperative histology and Masaoka staging for thymomas were collected and related to the maximum standardised uptake values (SUVs). Thymomas were divided into low-risk thymoma (LRT=A, AB and B1) and high-risk thymoma (HRT=B2, B3 and C). RESULTS: There were 13 thymomas (six LRT and seven HRT), three lymphomas and three other primitive thymic tumours (one paraganglioma, two non-seminomatous germ cell tumours). In LRT, the mean SUV was 3.3+/-0.5 resulting significantly lower than HRT, 13.5+/-7 (p=0.009). The SUV in LRT was also significantly lower with respect to lymphoma, 12.4+/-4 (p=0.001), and the other primitive anterior mediastinal tumours, 8+/-0.8 (p=0.001). Between thymomas we found a significant correlation between Masaoka stage and SUV, r=0.718, p=0.006. No correlation was found between transverse diameters and SUV, r=0.141, p=0.6. CONCLUSIONS: In our experience, low SUV (<5) is associated with LRT and minimal invasive thymoma (Masaoka stages I-II) and, therefore, susceptible to upfront surgery. For lesions with an infiltrative aspect on CT scan associated with a higher SUV (>5), an open biopsy is mandatory to exclude mediastinal lymphomas or, in case of HRT, to address a neoadjuvant treatment.

Lamin A is a component of the inner nuclear membrane that, together with epigenetic factors, organizes the genome in higher order structures required for transcriptional control. Mutations in the lamin A/C gene cause several diseases belonging to the class of laminopathies, including muscular dystrophies. Nevertheless, molecular mechanisms involved in the pathogenesis of lamin A-dependent dystrophies are still largely unknown. The polycomb group (PcG) of proteins are epigenetic repressors and lamin A interactors, primarily involved in the maintenance of cell identity. Using a murine model of Emery-Dreifuss muscular dystrophy (EDMD), we show here that lamin A loss deregulated PcG positioning in muscle satellite stem cells, leading to derepression of non-muscle-specific genes and p16INK4a, a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional program caused impairment in self-renewal, loss of cell identity, and premature exhaustion of the quiescent satellite cell pool. Genetic ablation of the Cdkn2a locus restored muscle stem cell properties in lamin A/C-null dystrophic mice. Our findings establish a direct link between lamin A and PcG epigenetic silencing and indicate that lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells.

Hutchinson-Gilford progeria syndrome is a genetic disease caused by an aberrant form of Lamin A resulting in chromatin structure disruption, in particular by interfering with lamina associated domains. Early molecular alterations involved in chromatin remodeling have not been identified thus far. Here, we present SAMMY-seq, a high-throughput sequencing-based method for genome-wide characterization of heterochromatin dynamics. Using SAMMY-seq, we detect early stage alterations of heterochromatin structure in progeria primary fibroblasts. These structural changes do not disrupt the distribution of H3K9me3 in early passage cells, thus suggesting that chromatin rearrangements precede H3K9me3 alterations described at later passages. On the other hand, we observe an interplay between changes in chromatin accessibility and Polycomb regulation, with site-specific H3K27me3 variations and transcriptional dysregulation of bivalent genes. We conclude that the correct assembly of lamina associated domains is functionally connected to the Polycomb repression and rapidly lost in early molecular events of progeria pathogenesis.