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Tabaries S.,McGill University | Dupuy F.,McGill University | Dong Z.,McGill University | Monast A.,McGill University | And 9 more authors.
Molecular and Cellular Biology | Year: 2012

We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes. © 2012, American Society for Microbiology.

Bismar T.A.,University of Calgary | Bismar T.A.,Segal Cancer Center | Bismar T.A.,Duke University | Yoshimoto M.,Queens University | And 5 more authors.
BJU International | Year: 2011

OBJECTIVE To investigate the interaction between, and significance of, ERG gene rearrangements and PTEN genomic deletions in relation to the development and progression of prostate cancer (PCA). PATIENTS AND METHODS We interrogated an initial cohort of 220 men with localized PCA using fluorescence in situ hybridization for ERG rearrangements and PTEN genomic deletions. RESULTS The incidences of ERG rearrangements and PTEN deletions in PCA were significantly higher than in high-grade prostatic intra-epithelial neoplasia (HGPIN) and benign prostate tissue (P < 0.001). ERG rearrangements and PTEN deletions were detected in 41.9 and 42.6% of patients' tumours, respectively. ERG rearrangements were never detected in benign prostate tissue, while PTEN aberrations were present at a basal level of 4.6%. PTEN hemizygous deletions showed higher frequency than homozygous deletions within each diagnostic category from benign prostate tissue to HGPIN and PCA (P â 0.001). Furthermore, in 29 patients where all three tissues were available, PTEN genomic aberrations in PCA were significantly different from those in benign tissue (P = 0.005) and HGPIN (P = 0.02), reflecting the accumulation of genomic aberrations in the early stages of disease progression. Within this cohort, 71.4% of homozygous and 44.2% of hemizygous PTEN deletions occurred simultaneously with ERG rearrangements (P a;circ; 0). Stratified according to Gleason score (GS), hemizygous PTEN deletions across various GS groups were observed at a higher frequency than homozygous deletions. However, PTEN homozygous deletions showed positive trends with higher GS, increasing in poorly differentiated PCA (GS 8-10) in comparison to moderately and well differentiated tumours (GS 6 and 7). CONCLUSION We show significant association between ERG gene rearrangements and PTEN genomic aberrations in subset of PCA. Our analysis also provides further support for the observation that homozygous PTEN deletions can occur within the subset of HGPIN lesions, and shows accumulating genetic aberrations with disease progression, evidenced by higher detection in PCA than in HGPIN and more PTEN homozygous deletions in GS 8-10 than in 6-7. © 2010 BJU International.

Lapi F.,Lady Davis Institute for Medical Research | Lapi F.,McGill University | Lapi F.,University of Florence | Azoulay L.,Lady Davis Institute for Medical Research | And 6 more authors.
JAMA - Journal of the American Medical Association | Year: 2013

IMPORTANCE: The use of androgen deprivation therapy (ADT) in the treatment of advanced prostate cancer has been shown to delay the clinical progression of the disease. However, the testosterone suppression associated with this therapymay lead to a hypogonadal condition that can have detrimental effects on renal function, thus raising the hypothesis that ADT-induced hypogonadism could potentially lead to acute kidney injury (AKI). OBJECTIVE: To determine whether the use of ADT is associated with an increased risk of AKI in patients newly diagnosed with prostate cancer. DESIGN AND SETTING: A nested case-control analysis using medical information extracted from the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database. PARTICIPANTS: Men newly diagnosed with nonmetastatic prostate cancer between January 1, 1997, and December 31, 2008, were selected and followed up until December 31, 2009. Cases were patients with incident AKI during follow-up who were randomly matched with up to 20 controls on age, calendar year of prostate cancer diagnosis, and duration of follow-up. MAIN OUTCOMES AND MEASURES: Conditional logistic regressionwas used to estimate odds ratios (ORs) with 95%CIs of AKI associated with the use of ADT. ADT was categorized into 1 of 6 mutually exclusive groups: gonadotropin-releasing hormone agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, estrogens, and combination of the above. RESULTS: A total of 10 250 patients met the study inclusion criteria. During a mean follow-up of 4.1 (SD, 2.9) years, 232 incident cases of AKI were identified (rate, 5.5/1000 person-years). Overall, current use of any ADT was associated with an increased risk of AKI when compared with never use (OR, 2.48 [95%CI, 1.61-3.82]), generating a rate difference of 4.43/1000 persons per year (95%CI, 1.54-7.33). This association was mainly driven by a combined androgen blockade consisting of gonadotropin-releasing hormone agonists with oral antiandrogens (OR, 4.50 [95%CI, 2.61-7.78]), estrogens (OR, 4.00 [95%CI, 1.06-15.03]), other combination therapies (OR, 4.04 [95%CI, 1.88-8.69]), and gonadotropin-releasing hormone agonists (OR, 1.93 [95%CI, 1.20-3.10]). CONCLUSIONS AND RELEVANCE: In a cohort of patients with newly diagnosed nonmetastatic prostate cancer, the use of ADT was significantly associated with an increased risk of AKI. These findings require replication in other well-designed studies as well as further investigation of their clinical importance.

Arnaout A.,Ottawa Hospital Research Institute | Boileau J.-F.,Segal Cancer Center | Brackstone M.,London Health Sciences Center
Current Opinion in Supportive and Palliative Care | Year: 2014

Purpose of review The definition of locally advanced breast cancer (LABC) includes patients with large tumors, extensive regional lymph node involvement, or direct involvement of the skin or underlying chest wall. Neoadjuvant chemotherapy followed by surgery has become the standard of care and a valuable strategy in the multimodality management of LABC. Variations in practice exist and the purpose of this article is to explore the surgical considerations in the management of LABC. Recent findings There exist various diagnostic and treatment considerations in LABC patients that help guiding clinicians in the optimal management of LABC. The evolving concepts of breast conservation, immediate breast reconstruction and optimal management of the axilla are addressed. Summary LABC represents a heterogenous cohort of patients for whom a multidisciplinary care team is critical. A more detailed understanding of the surgical considerations will facilitate the optimal diagnostic evaluation and management of these patients. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Tan T.C.,Harvard University | Bouras S.,Harvard University | Sawaya H.,Harvard University | Sebag I.A.,McGill University | And 6 more authors.
Journal of the American Society of Echocardiography | Year: 2015

Background Trastuzumab, a HER2 monoclonal antibody, has transformed the prognosis of patients with the aggressive HER2-positive breast cancer type. Trastuzumab augments the cardiotoxic effects of anthracyclines, but its effect is thought to be at least partially reversible. The objective of this study was to examine the time trends of left ventricular (LV) size and function in a cohort of women treated with anthracyclines and trastuzumab. Methods Twenty-nine patients >18 years of age with first-time breast cancer treated with anthracyclines and trastuzumab were monitored using echocardiography before, at the completion of, and at a median follow-up of 24.7 months (interquartile range, 15.9-34 months) after the end of their cancer treatment. LV volume, LV ejection fraction, and global peak systolic longitudinal strain and strain rate were measured in the apical four- and two-chamber views. Left ventricular ejection fraction was measured using a modified Simpson's biplane method. Results LV end-diastolic and end-systolic volumes increased at the end of treatment compared with baseline and did not recover during follow-up. Left ventricular ejection fraction, strain, and strain rate decreased at the end of treatment compared with baseline (from 64 ± 6% to 59 ± 8%, from -20.0 ± 2.5% to -17.6 ± 2.6%, and from -1.26 ± 0.23 to -1.13 ± 0.16 sec<-1<, respectively; P <.05 for all parameters) and remained decreased at follow-up. Conclusions LV dilation and subclinical impairment in cardiac function persists >2 years after the end of anthracycline and trastuzumab treatment, without significant recovery after trastuzumab cessation, suggestive of long-term underlying cardiac damage and remodeling. © 2015 American Society of Echocardiography.

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