Improving on whole-brain radiotherapy in patients with large brain metastases: a planning study to support the AROMA clinical trial

PURPOSE: To develop a novel dose-escalated volumetric modulated arc therapy (VMAT) strategy for patients with single or multiple large brain metastases which can deliver a higher dose to individual lesions for better local control (LC), and to compare dosimetry between whole brain radiotherapy (WBRT), hippocampal-sparing whole brain radiotherapy (HS-WBRT) and different VMAT-based focal radiotherapy approaches. METHODS AND MATERIALS: We identified 20 patients with one to ten brain metastases and at least one lesion larger than 15 cm3 who had received WBRT as part of routine care. For each patient, we designed and evaluated five radiotherapy treatment plans, including WBRT, HS-WBRT and three VMAT dosing models. A dose of 20 Gy in 5 fractions was prescribed to the whole brain or target volumes depending on the plan, with higher doses to smaller lesions and dose-escalated inner planning target volumes (DE-iPTV) in VMAT plans, respectively. Treatment plans were evaluated using the efficiency index, mean dose and D0.1cc to the target volumes and organs at risk. RESULTS: Compared with WBRT, VMAT plans achieved a significantly more efficient dose distribution in brain lesions, especially with our DE-iPTV model, while minimising the dose to the normal brain and other organs at risks (OARs) (p < 0.05). CONCLUSIONS: VMAT plans obtained higher doses to brain metastases and minimised doses to OARs. Dose-escalated VMAT for larger lesions allows higher radiotherapy doses to be delivered to larger lesions while maintaining safe doses to OARs

An integrated inspection of the somatic mutations in a lung squamous cell carcinoma using next-generation sequencing

Squamous cell carcinoma (SCC) of the lung kills over 350,000 people annually worldwide, and is the main lung cancer histotype with no targeted treatments. High-coverage whole-genome sequencing of the other main subtypes, small-cell and adenocarcinoma, gave insights into carcinogenic mechanisms and disease etiology. The genomic complexity within the lung SCC subtype, as revealed by The Cancer Genome Atlas, means this subtype is likely to benefit from a more integrated approach in which the transcriptional consequences of somatic mutations are simultaneously inspected. Here we present such an approach: the integrated analysis of deep sequencing data from both the whole genome and whole transcriptome (coding and non-coding) of LUDLU-1, a SCC lung cell line. Our results show that LUDLU-1 lacks the mutational signature that has been previously associated with tobacco exposure in other lung cancer subtypes, and suggests that DNA-repair efficiency is adversely affected; LUDLU-1 contains somatic mutations in TP53 and BRCA2, allelic imbalance in the expression of two cancer-associated BRCA1 germline polymorphisms and reduced transcription of a potentially endogenous PARP2 inhibitor. Functional assays were performed and compared with a control lung cancer cell line. LUDLU-1 did not exhibit radiosensitisation or an increase in sensitivity to PARP inhibitors. However, LUDLU-1 did exhibit small but significant differences with respect to cisplatin sensitivity. Our research shows how integrated analyses of high-throughput data can generate hypotheses to be tested in the lab

Ecological succession reveals potential signatures of marine-terrestrial transition in salt marsh fungal communities

Marine-to-terrestrial transition represents one of the most fundamental shifts in microbial life. Understanding the distribution and drivers of soil microbial communities across coastal ecosystems is critical given the roles of microbes in soil biogeochemistry and their multifaceted influence on landscape succession. Here, we studied the fungal community dynamics in a well-established salt marsh chronosequence that spans over a century of ecosystem development. We focussed on providing high-resolution assessments of community composition, diversity and ecophysiological shifts that yielded patterns of ecological succession through soil formation. Notably, despite containing 10- to 100-fold lower fungal internal transcribed spacer abundances, early-successional sites revealed fungal richnesses comparable to those of more mature soils. These newly formed sites also exhibited significant temporal variations in beta-diversity that may be attributed to the highly dynamic nature of the system imposed by the tidal regime. The fungal community compositions and ecophysiological assignments changed substantially along the successional gradient, revealing a clear signature of ecological replacement and gradually transforming the environment from a marine into a terrestrial system. Moreover, distance-based linear modelling revealed soil physical structure and organic matter to be the best predictors of the shifts in fungal beta-diversity along the chronosequence. Taken together, our study lays the basis for a better understanding of the spatiotemporally determined fungal community dynamics in salt marshes and highlights their ecophysiological traits and adaptation in an evolving ecosystem