The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis.

BACKGROUND: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR. METHODS: To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets. RESULTS: The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of 'classical' subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3' end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. CONCLUSIONS: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours

Array-CGH and breast cancer

The introduction of comparative genomic hybridization (CGH) in 1992 opened new avenues in genomic investigation; in particular, it advanced analysis of solid tumours, including breast cancer, because it obviated the need to culture cells before their chromosomes could be analyzed. The current generation of CGH analysis uses ordered arrays of genomic DNA sequences and is therefore referred to as array-CGH or matrix-CGH. It was introduced in 1998, and further increased the potential of CGH to provide insight into the fundamental processes of chromosomal instability and cancer. This review provides a critical evaluation of the data published on array-CGH and breast cancer, and discusses some of its expected future value and developments

Toward a higher accuracy in orthognathic surgery by using intraoperative computer navigation, 3D surgical guides, and/or customized osteosynthesis plates: A systematic review

The aim of this study was to systematically review the accuracy of intraoperative computer navigation, three-dimensional surgical guides and customized osteosynthesis plates for the transfer of the virtual surgical plan to the patient in orthognathic surgery. A systematic review of the currently available publications was performed in databases MEDLINE, Embase, and Cochrane Library, using a PICOS search strategy, and reported according to PRISMA. The initial search yielded 3050 articles. In total, 16 studies were included for final quantitative analyses. The results of individual studies demonstrated a comparable accuracy in the transfer of planned surgical displacement of the jaws. A large variability was found with regard to the method of accuracy assessment and reported outcomes. The findings of this review show that these modern techniques have the potential to replace interocclusal splints in routine clinical practice in the future. We recommend that authors presenting new data on the accuracy of a technique should choose the method of accuracy assessment meticulously, acquiring postoperative imaging as soon as possible after surgery. They should report as much as possible, summarizing values or, ideally, even the raw data of the accuracy assessment in order to allow comparison with other techniques in a meta-analysis

The role of muscular traction in the occurrence of skeletal relapse after advancement bilateral sagittal split osteotomy (BSSO): A systematic review

The aim of this systematic review was (i) to determine the role of muscular traction in the occurrence of skeletal relapse after advancement BSSO and (ii) to investigate the effect of advancement BSSO on the perimandibular muscles. This systematic review reports in accordance with the recommendations proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Electronic database searches were performed in the databases MEDLINE, Embase and Cochrane Library. Inclusion criteria were as follows: assessment of relapse after advancement BSSO; assessment of morphological and functional change of the muscles after advancement BSSO; and clinical studies on human subjects. Exclusion criteria were as follows: surgery other than advancement BSSO; studies in which muscle activity/traction was not investigated; and case reports with a sample of five cases or fewer, review articles, meta-analyses, letters, congress abstracts or commentaries. Of the initial 1006 unique articles, 11 studies were finally included. In four studies, an intervention involving the musculature was performed with subsequent assessment of skeletal relapse. The changes in the morphological and functional properties of the muscles after BSSO were studied in seven studies. The findings of this review demonstrate that the perimandibular musculature plays a role in skeletal relapse after advancement BSSO and may serve as a target for preventive strategies to reduce this complication. However, further research is necessary to (i) develop a better understanding of the role of each muscle group, (ii) to develop new therapeutic strategies and (iii) to define criteria that allow identification of patients at risk

EWSR1::POU2AF3(COLCA2) sarcoma: an aggressive, polyphenotypic sarcoma with a head and neck predilection

EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of neuroendocrine-appearing round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiatio

Mutation analysis of genes in the EGFR pathway in Head and Neck cancer patients : implications for anti-EGFR treatment response

BACKGROUND: Targeted therapy against the Epidermal Growth Factor Receptor (EGFR) is among the most promising molecular therapeutics for Head and Neck Squamous Cell Carcinoma (HNSCC). However, drug resistance limits the clinical efficacy of anti-EGFR monoclonal antibodies and no predictive biomarker has entered the clinic yet. METHODS: A retrospective clinical study was performed utilizing pathological specimens from 52 newly diagnosed HNSCC patients. These patients were screened for mutations in EGFR and KRAS. Tyrosine kinase mutations in EGFR and KRAS mutations were evaluated by high resolution melting analysis (HRMA), whereas EGFRvIII was determined using one-step real-time PCR. Finally, patient samples were screened for HPV-DNA by GP5+/6+ PCR. Survival analysis was performed using Kaplan-Meier analysis and significance was calculated using log-rank statistic. RESULTS: In our study population no EGFRvIII mutations were present. However, two silent mutations were found; T785T in exon 20 and R836R in exon 21 of the EGFR gene. Additionally, HRMA revealed an abnormal KRAS melting pattern in 7.0% of the samples. However, the KRAS StripAssay could confirm only one sample with a G12S mutation and none of these samples could be confirmed by direct sequencing. HPV DNA was present in 3/25 larynx and 9/27 oropharynx tumors. CONCLUSION: The low rate of EGFR and KRAS mutations in this Belgian HNSCC population suggests that these genes will probably not play a major role in predicting response to anti-EGFR therapy in HNSCC. Hence, other predictive markers need to be discovered in order to optimize EGFR targeting therapy

Molecular test algorithms for breast tumours

In order to advise the Federal Government on all matters related to personalised medicine in oncology, including the reimbursement of molecular tests, the Commission of Personalized Medicine (ComPerMed) has applied, for the breast tumours, the same methodology as previously applied for the digestive tumours. Meaning, the different molecular tests, represented in the shape of algorithms, are annotated with test levels — which aim to reflect their relevance based on current available data and to define the reimbursement — and are documented with recent literature, guidelines and a brief technical&nbsp;description.</p