Circulating Tumor Cell Transcriptomics as Biopsy Surrogates in Metastatic Breast Cancer

BACKGROUND Metastatic breast cancer (MBC) and the circulating tumor cells (CTCs) leading to macrometastases are inherently different than primary breast cancer. We evaluated whether whole transcriptome RNA-Seq of CTCs isolated via an epitope-independent approach may serve as a surrogate for biopsies of macrometastases. METHODS We performed RNA-Seq on fresh metastatic tumor biopsies, CTCs, and peripheral blood (PB) from 19 newly diagnosed MBC patients. CTCs were harvested using the ANGLE Parsortix microfluidics system to isolate cells based on size and deformability, independent of a priori knowledge of cell surface marker expression. RESULTS Gene expression separated CTCs, metastatic biopsies, and PB into distinct groups despite heterogeneity between patients and sample types. CTCs showed higher expression of immune oncology targets compared with corresponding metastases and PB. Predictive biomarker (n = 64) expression was highly concordant for CTCs and metastases. Repeat observation data post-treatment demonstrated changes in the activation of different biological pathways. Somatic single nucleotide variant analysis showed increasing mutational complexity over time. CONCLUSION We demonstrate that RNA-Seq of CTCs could serve as a surrogate biomarker for breast cancer macrometastasis and yield clinically relevant insights into disease biology and clinically actionable targets

The Associations between Socioeconomic Status, Allostatic Load, and Measures of Health in Older Taiwanese Persons: Taiwan Social Environment and Biomarkers of Aging Study.

Data from a national representative sample of 1023 elderly and near-elderly Taiwanese were used to explore whether allostatic load is associated with health outcomes and mediates the association between socioeconomic status and health in a non-Western population. The information collected included: demographic characteristics; allostatic load scores; socioeconomic status, measured by education and income; health behaviours; health-related variables, including self-rated health, basic activities of daily living difficulties, instrumental activities of daily living difficulties, and physical activity difficulties. The adjusted prevalent odds ratios of higher allostatic load level were 1·25 (95% CI: 1·00, 1·56) for reporting one level worse in self-rated health and 1·43 (95% CI: 1·14, 1·82) for reporting one more physical activity difficulty. There were significant associations of lower education or less income with worse self-rated health and more difficulties with physical functioning. The associations between education, income and health status are not mediated by the conventional ten-point measure of allostatic load in older Taiwanese adults

The Associations between Socioeconomic Status, Allostatic Load, and Measures of Health in Older Taiwanese Persons: Taiwan Social Environment and Biomarkers of Aging Study.

Data from a national representative sample of 1023 elderly and near-elderly Taiwanese were used to explore whether allostatic load is associated with health outcomes and mediates the association between socioeconomic status and health in a non-Western population. The information collected included: demographic characteristics; allostatic load scores; socioeconomic status, measured by education and income; health behaviours; health-related variables, including self-rated health, basic activities of daily living difficulties, instrumental activities of daily living difficulties, and physical activity difficulties. The adjusted prevalent odds ratios of higher allostatic load level were 1·25 (95% CI: 1·00, 1·56) for reporting one level worse in self-rated health and 1·43 (95% CI: 1·14, 1·82) for reporting one more physical activity difficulty. There were significant associations of lower education or less income with worse self-rated health and more difficulties with physical functioning. The associations between education, income and health status are not mediated by the conventional ten-point measure of allostatic load in older Taiwanese adults

Characterization of molecular pathways for targeting therapy in glioblastoma.

Glioblastoma remains the most common malignant brain neoplasm in adults. The available therapies for treatment have only modestly extended survival. Traditional chemotherapy agents have shown only slight effectiveness in controlling this disease. The use of molecular profiling has allowed personalized medicine options to be explored for the care of these individuals. Targeted therapies have shown significant benefit in numerous other cancer types with survival being extended significantly. In glioblastoma, several promising markers have been identified including vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). These targets have been shown to play a critical role in glioblastoma formation and proliferation. The pathways of these receptors have been elucidated in detail. This level of understanding has led to the a more robust understanding of possible mechanism of pathway modification. The targeting of these specific markers has led to the development of several selective therapies with additional therapies being evaluated. The clinical trials validating these markers have been promising but have yet to show a clear benefit in brain tumors. This identification of alternative methods to address these markers or identify additional targets may be the key to the fight against this disease. The molecular targeting of glioblastoma pathways may have significant impact on disease control and patient survival

Update and developments in the treatment of glioblastoma multiforme - focus on bevacizumab.

Glioblastoma is the most common primary brain tumor with a relatively poor prognosis. This article reviews the current standard therapy and discusses new developments in treatment of this disease. Surgical resection followed by radiation and chemotherapy has proven to be the most effective initial therapy. Recent advancement in molecular targeted therapies has led to the Food and Drug Administration (FDA) approval of bevacizumab in the setting of recurrent glioblastoma. The molecular pathways of glioblastoma growth are highlighted in this review. While numerous molecular targets are currently being intensely investigated, vascular endothelial growth factor (VEGF) receptor targeted therapy has been the only one to have shown clinical effect. The role of bevacizumab in this context provides a dynamic breakthrough in cancer therapy. Clinical trials have demonstrated significantly increased overall survival and six month progression free survival (PFS) in recurrent glioblastoma treated with bevacizumab alone or in combination with irinotecan. The use of this agent has also dramatically changed the imaging characteristics of glioblastoma. The anti-angiogenesis effects of bevacizumab have complicated the criterion for determining tumor growth. This may lead to redefinition of progressive disease based on non-invasive monitoring

NCMP-07. CASE SERIES OF REGULARLY SCHEDULED MANNITOL INFUSIONS SHOWING WITH PROLONGED CLINICAL BENEFIT FOR MANAGEMENT OF CEREBRAL EDEMA IN GLIOMAS

Gliomas account for the vast majority of malignant primary tumors arising in the central nervous system. Elevated intracranial pressure (ICP) may be a potentially devastating complication of brain tumors and hydrocephalus. Brain tumors may occupy significant space causing displacement and compression of delicate structures within a finite intracranial compartment. The compliance relationship is nonlinear and decreases as the combined volume of the intracranial contents increases. When these compensatory mechanisms have been exhausted, significant increases in pressure develop with relatively small increases in volume. The diagnosis of elevated ICP is generally based on clinical findings and corroborated by imaging studies and the patient\u27s medical history. The best therapy for intracranial hypertension (ICH) is the resolution of the proximate cause of elevated ICP such as the evacuation of a blood clot, resection of a tumor, or cerebrospinal fluid (CSF) diversion in the setting of hydrocephalus. If these modalities have been exhausted or unavailable, osmotic diuretics such as mannitol can be utilized. This medication reduces brain volume by drawing free water out of the tissue and into the circulation, where it is excreted by the kidneys, thus dehydrating brain parenchyma. The common belief is that effects are usually present within minutes, peak at approximately one hour, and last 4 to 24 hours. We report a series of 33 patients treated for a minimum of 1 month of regularly scheduled maintenance infusions of Mannitol 1g/kg every two weeks, 64% showed improved clinical outcomes or stabilization of edema clinical symptoms. Patients expressed improvements in headaches, dizziness, and cognitive ability. This supports the bi-weekly maintenance use of Mannitol in glioma patients with symptomatic cerebral edema. A controlled trial should be supported. This series also suggest a mechanism of action with a more durable response than osmotic diuresis

Molecularly targeted treatment of recurrent anaplastic astrocytoma - a case report.

High-grade astrocytomas are malignant and aggressive, with limited treatment options. Treatment is geared not only toward increasing patient\u27s overall survival but also in delaying or preventing neurological disability, a cause of significant morbidity. Increasingly, targeted and customized treatment approaches, especially for recurrent disease, are being explored. Here we present a successful outcome in a young patient with rapidly progressive disease who responded to targeted treatment based on genetic sequencing and circulating tumor DNA markers, given the inaccessibility of the tissue to biopsy. Molecular testing on tissue, serum or CSF may be helpful in identifying unique targets in these complex patients