The burden of symptomatic skeletal events in castrate-resistant prostate cancer patients with bone metastases at three Canadian uro-oncology centres.

INTRODUCTION: Metastatic bone disease in castrate-resistant prostate cancer risks significant morbidity, including symptomatic skeletal events. We estimated the healthcare resource costs of managing skeletal events. METHODS: A retrospective chart review was conducted for patients who died from or were treated palliatively for metastatic castrate-resistant prostate cancer from 2006-2013 at Centre Hospitalier de l'Université de Montréal (Montreal), Princess Margaret Cancer Centre (Toronto), or Vancouver General Hospital (Vancouver). RESULTS: Of 393 patients, 275 (70%) experienced 833 events (85 per 100 patient-years), with a median (95% confidence interval) time (months) to first event of 17.6 (15.3, 21.7). The mean metastatic bone disease-related healthcare resource use cost (2014 Canadian dollars) estimate for patients without symptomatic skeletal events was $9550 and between $22 101 (observed) and $34 615 (adjusted) for patients with at least one event. Fewer patients in Montreal (55%) experienced events compared to Toronto (79%) or Vancouver (76%). Median time (months) to first event was longer in Montreal (25.0 [18.5, 32.6]) than in Toronto (14.6 [9.7, 16.8] or Vancouver (17.3 [14.8, 24.0]). More patients received bone-targeted therapy in Montreal (64%) and Toronto (60%) than in Vancouver (24%). Bone-targeted therapy was mostly administered every 3-4 weeks in Montréal and every 3-4 months in Toronto. CONCLUSIONS: Metastatic bone disease-related healthcare resource use costs for Canadian castrate-resistant prostate cancer patients are high. Symptomatic skeletal events occurred frequently, with the incremental cost of one or more events estimated between $12 641 and $25 120. Symptomatic skeletal event incidence and bone-targeted therapy use varied considerably between three Canadian uro-oncology centres. An important limitation is that only patients who died from prostate cancer were included, potentially overestimating costs.

Somatic reactivation of expression of the silent maternal Mest allele and acquisition of normal reproductive behaviour in a colony of Peg1/Mest mutant mice.

Genomic imprinting confers allele-specific expression in less than 1% of genes, in a parent-of-origin specific fashion. In humans and mice the Peg1/Mest gene (Mest) is maternally repressed, and paternally expressed. Mest is expressed in embryogenic mesoderm-derived tissues and in adult brain, and paternal mutations in Mest lead to growth retardation and defective maternal behaviour. Despite our current understanding of mechanisms associated with the establishment of imprinting of Mest and other imprinted genes, it is unclear to what extent Mest imprinting needs to be maintained in adult tissues. Aberrations of imprinting are known to occur in certain rare syndromes, and involve either inherited mutations, or constitutive epigenetic alterations occurring soon after fertilization. Imprinting abnormalities may also occur in the aging somatic tissues of adult individuals. Here we report an occurrence of post-embryonic somatic variability of Mest allelic expression in a colony of mice where heterozygotes at the imprinted Mest locus for a mutation inherited from the father spontaneously expressed the normally silenced allele from the mother. In addition, a newly acquired ability to overcome the deficit in maternal reproductive behaviour had occurred in the mutant mice, but this appeared not to be directly linked to the Mest mutation. Our results suggest that at least one allele of Mest expression is required in the somatic tissues of adult individuals and that under certain conditions (such as in the presence of a Mest insertional mutation or in an altered genetic background), somatically acquired alterations of allelic expression at the Mest locus may occur.

AMG 386: profile of a novel angiopoietin antagonist in patients with ovarian cancer.

INTRODUCTION: ovarian cancer is the second most common gynecologic malignancy in the world with the majority of women presenting with advanced disease; whilst chemotherapeutic advances have improved progression-free survival, the increases in overall survival have been marginal. Novel biologic agents, including those designed to disrupt tumor angiogenesis, have demonstrated promising antitumor activity. AREAS COVERED: this review evaluates AMG 386, a novel investigational angiopoietin antagonist peptide-Fc fusion protein (peptibody), which potently and selectively inhibits angiopoietin-1 and angiopoietin-2 binding to the Tie2 tyrosine kinase receptor. Preclinical and clinical studies for AMG 386 are summarized, highlighting data pertaining to ovarian cancer. The role of angiopoietins in regulating physiologic and tumorigenic angiogenesis is addressed, as well as a brief discussion of non-angiopoietin anti-angiogenic strategies, followed by a review of preclinical, Phase I and II data and ongoing clinical studies for AMG 386, all in the context of ovarian cancer. EXPERT OPINION: AMG 386 has clinical activity and an acceptable safety profile both as monotherapy and in combination with chemotherapy. Of note, as the toxicity profiles of AMG 386 and inhibitors of the VEGF axis do not substantially overlap, AMG 386 could potentially be combined with other anti-angiogenic compounds to maximize disruption of malignant vascularization in ovarian cancer and other solid tumors.

Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines.

Epithelial-to-mesenchymal transition (EMT) is an essential embryogenic and developmental process, characterized by altered cellular morphology, loss of cell adhesion, and gain of migratory ability. Dysregulation of this process has been implicated in tumorigenesis, mediating the acquisition of migratory and invasive phenotypes by tumor cells. Mammary epithelial cells provide an excellent model in which to study the process, being derived from mammary gland tissue that utilizes EMT to facilitate branching morphogenesis through which the developing gland migrates into and invades the fat pad. Inappropriate EMT has been heavily implicated in the progression of ductal hyperplasia and mammary tumor metastasis. We examined the morphological and molecular changes of three murine mammary epithelial cell lines following EMT induction. EMT was induced in the EpH-4 and NMuMG cell lines by transforming growth factor (TGF)-beta1 but not by ethanol, while the KIM-2 cell line was partially resistant to TGF-beta1 but responded fully to ethanol. The response to EMT-inducing reagent was shown to be critically dependent on the time of treatment, with confluent cells failing to respond. Timelapse photography identified increased motility during wound healing in cells pre-treated with EMT-inducing reagent compared with untreated controls. Furthermore, EMT conferred resistance to UV-induced apoptosis. Our data indicate that evaluation of characteristics other than loss and gain of phenotypic markers may be of benefit when assessing EMT, and contribute to the evidence suggesting that inappropriate EMT facilitates the acquisition of resistance to apoptosis, a key characteristic required for tumor survival.

A PANorama of PAX genes in cancer and development.

Populations of self-renewing cells that arise during normal embryonic development harbour the potential for rapid proliferation, migration or transdifferentiation and, therefore, tumour generation. So, control mechanisms are essential to prevent rapidly expanding populations from malignant growth. Transcription factors have crucial roles in ensuring establishment of such regulation, with the Pax gene family prominent amongst these. This review examines the role of Pax family members during embryogenesis, and their contribution to tumorigenesis when subverted.