Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes.

BACKGROUND: Intratumoral heterogeneity may help drive resistance to targeted therapies in cancer. In breast cancer, the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of breast cancer by whole genome next generation sequencing (NGS) of a primary breast tumor, a matched locally-involved axillary lymph node and healthy normal DNA from blood. METHODS: Whole genome NGS was performed on 12 µg (range 11.1-13.3 µg) of DNA isolated from fresh-frozen primary breast tumor, axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with tumor metastasis. RESULTS: Whole genome sequencing revealed overlapping variants between the tumor and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, TGIF2 and CCNB2, which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in PDS5B, which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from tumor to node, including SNVs in TP53 and ARAP3, which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferation and can segregate breast cancers by outcome. CONCLUSION: This case study provides preliminary evidence that primary tumor and early nodal metastasis have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of patient samples

Hemispherectomy - a Further Modification Using Omentum Vascularized Free Flaps

This report describes the authors' technique designed to further prevent the late complications of hemispherectomy. A vascularized omental free flap is used to fill the extradural dead space left following the procedure advocated by Adams. This procedure may provide further stability to the residual brain and reduce infective complications

A clinically oriented computer model for radiofrequency ablation of hepatic tissue with internally cooled wet electrode

PURPOSE: To improve the computer modelling of radiofrequency ablation (RFA) by internally cooled wet (ICW) electrodes with added clinically oriented features. METHODS: An improved RFA computer model by ICW electrode included: (1) a realistic spatial distribution of the infused saline, and (2) different domains to distinguish between healthy tissue, saline-infused tumour, and non-infused tumour, under the assumption that infused saline is retained within the tumour boundary. A realistic saline spatial distribution was obtained from an in vivo pig liver study. The computer results were analysed in terms of impedance evolution and coagulation zone (CZ) size, and were compared to the results of clinical trials conducted on 17 patients with the same ICW electrode. RESULTS: The new features added to the model provided computer results that matched well with the clinical results. No roll-offs occurred during the 4-min ablation. CZ transversal diameter (4.10 ± 0.19 cm) was similar to the computed diameter (4.16 cm). Including the tumour and saline infusion in the model involved (1) a reduction of the initial impedance by 10 - 20 Ω, (2) a delay in roll-off of 20 s and 70 - 100 s, respectively, and (3) 18 - 31% and 22 - 36% larger CZ size, respectively. The saline spatial distribution geometry was also seen to affect roll-off delay and CZ size. CONCLUSIONS: Using a three-compartment model and a realistic saline spatial distribution notably improves the match with the outcome of the clinical trials