The NHS England 100,000 Genomes Project: feasibility and utility of centralised genome sequencing for children with cancer

Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally.Methods Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value.Results Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36).Conclusion Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.Subject terms: Cancer genomics, Cancer genomics     

Negative prognostic effect of low nuclear GLI1 expression in glioblastomas

This is preliminary study assessing the efficacy and safety of concurrent use of radiation therapy (RT) and T-DM1 for the treatment of brain metastases (BM) in patients with HER2-positive metastatic breast cancer (BC). We retrospectively studied 12 patients treated for BM at the Institut Curie in 2014–2015 with T-DM1 and concurrent (4) or sequential (8) radiosurgery with or without whole brain irradiation. The following variables were studied: local control, clinical and radiological response as well as early and late side effects. The mean age of the population was 38 years at the time of diagnosis of BC and 46 years at of BM. All patients were with good PS. The response rate of the concurrent treatment group was 75?% with 1 complete response, 1 partial response, one stable disease and 1 progression. Comparatively, the response rate in the sequential group was as follows: two complete responses, two partial responses, six cases of stable disease and two cases of local progression. No patient experienced interruption of irradiation because of side effects. About 50?% of patients were asymptomatic after treatment. Radiation necrosis was observed in 50?% of patients in the concurrent group and 28.6?% of patients in the sequential group with a similar rate of oedema in the two groups. We found that the combination of T-DM1 and radiosurgery was feasible but can increase the incidence of radiation necrosis. Larger prospective studies with longer follow-up are needed to more clearly evaluate this association.     

Dendritic cell based vaccination strategy: an evolving paradigm

The basement membrane collagen IV-degrading matrix metalloproteinases -2 and -9 (MMPs) are most often linked to the malignant phenotype of tumor cells by playing a critical role in invasion, metastasis, angiogenesis, and vasculogenesis. We verified the activity of these two MMPs in the sera of patients affected by brain tumors (20 gliomas, 28 meningiomas and 20 metastasis) by zymography. The sera of 25 healthy volunteers with no concomitant illnesses were used for controls. Zymography showed four dominant gelatinolytic bands of 240, 130, 92 (MMP-9) and 72 (MMP-2) kDa. No statistically significant variations of MMP-2 proteolytic activity between patients and healthy individuals were observed. On the contrary, MMP-9 (both monomeric and multimeric forms) lytic activities were significantly higher in tumors specimens compared to healthy controls (p?<?0.001). Moreover, MMP-9 immunohistochemistry revealed: (1) a strong reactivity in neoplastic vessels of high-grade gliomas showing an inverse correlation with serum multimeric gelatinolytic activity; (2) a cytoplasmatic reactivity in meningiomas with a significantly increase in atypical meningioma compared with low-grade ones (p?=?0.036); (3) a positive correlation between MMP-9 and Ki-67 (Sperman Rho coefficient r?=?0.418 and p?=?0.034). Our results suggest that serum and tissue MMP-9 might provide clinicians additional objective information in intracranial neoplasms. Finally, it should be possible to use MMP-9 as a target for new forms of therapy. Nevertheless, due to the small number of patients included in the study, the conclusion may not be transferable to the general population and therefore further evaluations are needed.     

Impact of interim progression during the surgery-to-radiotherapy interval and its predictors in glioblastoma treated with temozolomide-based radiochemotherapy

This study was designed to investigate the impact of interim progression of disease (PD) during the surgery-to-radiotherapy interval (SRI) and its predictors in glioblastoma based on MRIs. A total of 222 patients were planned for radiotherapy (RT) and 166 of them were evaluable for the presence of interim PD by 2 separate MRIs. The size criteria from the updated Response Assessment in Neuro-Oncology criteria was adopted to determine interim PD. 32 (19.3%) patients experienced interim PD, and their median survival (MS) was shorter than patients without PD in univariate (11.3 vs. 19.6 months, p?<?0.001) and multivariate analysis (HR 2.237, 95% CI 1.367–3.660, p?=?0.002). The volume of residual enhancing tumor (p?=?0.003) and prolongation of the SRI (p?=?0.004) were significant predictors of interim PD. Every 1-cc increase in residual enhancing tumor and every 1-day prolongation of the SRI significantly increased the risk of interim PD by 3.9% (p?=?0.003) and 8.1% (p?=?0.004), respectively. A significant portion of patients demonstrate interim PD during SRI and these patients have poor prognosis. The presence of interim PD should be concerned as a significant confounding factor for stratification in future clinical trials. A baseline pre-RT MRI is essential for accurate disease evaluation and RT-target delineation, especially in patients with larger residual disease after surgery and prolonged SRI due to the high risk of interim PD.     

Platelet “first responders” in wound response,cancer, and metastasis

Platelets serve as “first responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity, and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation, and wound biology that leads to sterilization, tissue repair, and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression, and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation, and metastasis. This process, along with the hypercoagulable states associated with malignancy, is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “first responder” role of platelets during diverse physiologic stresses provide a useful therapeutic target that deserves further exploration.