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Kefah Mokbel

Publications and source records attributed to Kefah Mokbel.

18 recordsLinked to original sources
PubMed2003

Is telomerase reactivation associated with the down-regulation of TGF beta receptor-II expression in human breast cancer?

BACKGROUND: Telomerase is a ribonucleoprotein that synthesizes telomeres and plays an important role in chromosomal stability and cellular immortalisation. Telomerase activity is detectable in most human cancers but not in normal somatic cells. TGF beta (transforming growth factor beta) is a member of a family of cytokines that are essential for cell survival and seems to be down-regulated in human cancer. Recent in vitro work using human breast cancer cell lines has suggested that TGF beta down-regulates the expression of hTERT (human telomerase reverse transcriptase) : the catalytic subunit of telomerase. We have therefore hypothesised that telomerase reactivation is associated with reduced immunohisto-chemical expression of TGF beta type II receptor (RII) in human breast cancer. METHODS: TGF beta RII immunohistochemical expression was determined in 24 infiltrating breast carcinomas with known telomerase activity (17 telomerase-positive and 7 telomerase-negative). Immunohistochemical expression of TGF beta RII was determined by a breast pathologist who was blinded to telomerase data. RESULTS: TGF beta RII was detected in all lesions. The percentage of stained cells ranged from 1-100%. The difference in TGF beta RII expression between telomerase positive and negative tumours was not statistically significant (p = 1.0). CONCLUSION: The results of this pilot study suggest that there is no significant association between telomerase reactivation and TGF-beta RII down-regulation in human breast cancer.

Journal Article↗
PubMed2003

Current management of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of all screen-detected breast cancers. Total mastectomy can achieve a 98% cure rate in patients with DCIS, but its impact on quality of life should be weighed against the risk of local recurrence. Skin-sparing mastectomy with immediate reconstruction using autologous tissue can achieve excellent cosmesis and therefore should be considered when mastectomy is indicated. Nevertheless, mastectomy is considered an over-treatment for localized DCIS, and breast conservation is the goal of modern treatment. Three recent randomized controlled trials have demonstrated that adjuvant radiotherapy (RT) after adequate local excision of localized DCIS significantly reduces the incidence of local recurrence. Non-randomized studies suggest that patients with adequately excised small (<15 mm), non-high-grade DCIS not associated with necrosis can be safely spared adjuvant RT. However, this issue requires further evaluation in randomized controlled trials. The role of adjuvant tamoxifen is not well established, especially in relation to the hormone receptor status. Formal axillary dissection is not appropriate for DCIS; however, the potential role of the sentinel node biopsy (SNB) in selected high-risk cases requires further evaluation. The potential role of new selective estrogen receptor (ER) modulators and third-generation aromatase inhibitors in postmenopausal women with ER-positive DCIS, gene and protein expression profiling, and mammary ductoscopy will be the focus of future research.

Breast Neoplasms↗
PubMed2003

Towards optimal management of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) represents a spectrum of heterogenous disease that accounts for approximately one fifth of all screen-detected breast cancers and is considered as a precursor of invasive breast cancer if left untreated (35-50% risk). DCIS can be treated by total mastectomy with or without immediate breast reconstruction, local excision (LE) plus adjuvant radiotherapy (RT) or LE alone. Total mastectomy is associated with low rates of local recurrence (1.4%) and breast cancer-specific mortality (0.59%). Three recent randomized controlled trials (RCTs) have demonstrated that adjuvant RT after LE of localized DCIS significantly reduces the incidence of local recurrence. However these trials did not identify any subgroups of patients where RT could be safely omitted. Retrospective studies suggest that RT can be safely omitted after adequate LE (margin width > or =1 cm) of small (< 15 mm), non-high grade DCIS not associated with necrosis. Further RCTs are required to validate these retrospective findings, with an emphasis on standardized and meticulous tissue processing and pathological evaluation. The role of adjuvant tamoxifen in the management of DCIS continues to evolve. Formal axillary dissection is not appropriate for DCIS, however, the potential role of the sentinel node biopsy (SNB) in selected high risk cases requires further evaluation. The International Breast Cancer Intervention Study (IBIS-II) trial aims to evaluate the potential role of third generation aromatase inhibitors in postmenopausal women with hormone-sensitive DCIS.Future research will focus on the relevance of gene expression profiling, proteomics, Laser therapy and mammary ductoscopy to the management of DCIS.

Antineoplastic Agents, Hormonal↗
PubMed2003

Recent advances in breast cancer: the 25th Annual San Antonio Breast Cancer Symposium.

Some of the important developments in breast cancer treatment and biology are highlighted from presentations made at the 25th San Antonio Breast Cancer Symposium 2002 (San Antonio, Texas, 11-14 December 2002). These include an updated analysis of the ATAC trial, new data demonstrating the superiority of dose-dense adjuvant chemotherapy over conventional scheduling, and recent developments in the field of proteomics.

Breast Neoplasms↗
PubMed2003

The evolving role of telomerase inhibitors in the treatment of cancer.

Telomerase is a ribonucleoprotein that maintains telomeres and is essential for cellular immortality and tumour growth. The differential expression of telomerase in cancer cells makes it an attractive therapeutic target. Anti-sense oligonucleotides directed against the RNA template of hTR and small molecules that can interact and stabilise the G-quadruplex represent promising therapeutic strategies. Human trials investigating the potential role of the catalytic subunit hTERT as a universal cancer vaccine have already commenced. Alternative lengthening of telomeres (ALT) and efficacy delay remain important limitations to anti-telomerase therapy.

Animals↗
PubMed2003

Recent advances in breast cancer: the 27th ESMO Congress 2002.

Breast cancer was the focus of several presentations during the 27th European Society of Medical Oncology (ESMO) Congress held in Nice. Fulvestrant seems to be equally effective to tamoxifen as a first-line therapy in hormone-sensitive advanced breast cancer in postmenopausal women. However, it may be more effective than tamoxifen in ER- and PgR-positive disease. The addition of tamoxifen to epirubicin containing regimens was found to significantly increase PFS and OS in patients with MBC according to a multivariate analysis of 640 patients. BRCA-1 linked breast cancer was reported to be more sensitive to anthracycline-based CT than sporadic and BRCA-2 linked disease. VEGF was found to be an independent prognostic factor in patients with node-negative breast cancer. The implications and limitations of these findings are discussed.

Breast Neoplasms↗
PubMed2002

The evolving role of aromatase inhibitors in breast cancer.

Anti-aromatase agents inhibit the cytochrome p-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues. These drugs can be classified into first-generation (e.g., aminoglutethimide), second-generation (e.g., formestane and fadrazole), and third-generation (e.g., anastrozole, letrozole, and exemestane) agents. Anti-aromatase agents can also be divided into type I and type II inhibitors. Type I inhibitors have a steroidal structure similar to androgens and inactivate the enzyme irreversibly by blocking the substrate-binding site, and are therefore known as aromatase inactivators. Type II inhibitors are nonsteroidal and their action is reversible. This article reviews the recent evidence regarding the role of third-generation aromatase inhibitors in the management of breast cancer. Relevant PubMed listed articles and presentations at recent international symposia were reviewed. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) as first-line and second-line therapy for estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor-positive invasive breast cancer unsuitable for breast-conserving surgery. Furthermore, the preliminary results of the ATAC (Arimidex, Tamoxifen, Alone and in Combination) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), adverse effects, and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. However, longer follow-up is required to assess the long-term effects of these agents on bone mineral density, cognitive function, and overall survival prior to considering their routine use in the adjuvant setting instead of tamoxifen. The potential role of these drugs in the management of ductal carcinoma in situ (DCIS), premenopausal breast cancer, and breast cancer prevention is worth investigating.

Anastrozole↗
PubMed2002

The evolving role of mammary ductoscopy.

Mammary ductoscopy (MD) is an emerging technique that allows direct visualisation of the mammary duct system, and that produces sharp and clear video images and ductal washings for cytological analysis. There is a growing body of evidence that MD may have a role in the management of women with pathological nipple discharge, the guiding of breast conserving surgery for cancer, and the screening of high risk women. Further research is required to confirm these potential applications and the feasibility of its use in the rapid intervention and outpatient setting under local anaesthesia. Furthermore, the addition of molecular and genetic analysis of cells obtained by MD and the emergence of newer generations of microendoscopes are likely to enhance the use of this technique.

Breast Neoplasms↗
PubMed2002

The mRNA expression of cyclo-oxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in human breast cancer.

AIMS: There is a growing body of evidence that cyclo-oxygenase 2 (COX-2) plays an important role in carcinogenesis and angiogenesis of human tumours. The present study aims to compare COX-2 expression in human breast cancer and adjacent non-cancerous tissue (ANCT), and to identify any correlation between COX-2 and VEGF expression. METHODS: Total cellular RNA was extracted from frozen breast tissue samples according to standard methodology. The mRNA copy numbers for COX-2 and vascular endothelial growth factor 189 (VEGF-189) were determined 40 infiltrating carcinomas and 40 matched ANCT specimens using quantitative RT-PCR and TaqMan methodology. RESULTS: The COX-2 mRNA copy number per microg of RNA was two-fold higher in ANCT compared with the cancerous tissue (p = 0.01). Median mRNA copy number was 5.44 x 10(6) for ANCT and 2.30 x 10(6) for tumour, (ANCT range: 1 x 10(6) to 4.12x 10(7)) (tumour range: 1.29 x 10(5) to 1.07 x 10(7)). There was a significant correlation between COX-2 and VEGF-189 mRNA copy numbers in the cancer specimens (correlation coefficient = 0.5528, p = 0.0076). CONCLUSIONS: COX-2 mRNA is overexpressed in both human breast cancer and ANCT. We found higher levels in the matched ANCT which suggests that paracrine effects may be important in the role of COX-2 in mammary carcinogenesis. Furthermore, our results indicate that in human breast cancers COX-2 overexpression is linked to VEGF-189 overexpression and therefore tumour angiogenesis.

Breast Neoplasms↗
PubMedDate not supplied

Treatment of ductal carcinoma in situ of the breast: review of recent advances and future prospects.

Ductal carcinoma in situ (DCIS) is a heterogeneous disease characterized by noninvasive clonal proliferation of malignant epithelial cells arising from the mammary ducts and terminal ductal-lobular units. Its reported incidence is rising due to the wide adoption of screening mammography. The combination of nuclear grade and presence of necrosis is currently the best predictor of biological behavior. Approximately 25-50% of DCIS lesions progress to invasive disease if left untreated. The treatment options for DCIS include total mastectomy with or without immediate breast reconstruction (IBR), local excision (LE) plus adjuvant radiotherapy (RT), and LE alone. Total mastectomy is associated with lowest rates of local recurrence and breast cancer-specific mortality. If IBR is considered, then skin-sparing mastectomy (SSM) combined with autologous myocutaneous flap reconstruction can achieve excellent cosmesis without compromising local control. The role of adjuvant radiotherapy (RT) after LE remains controversial. Three recent randomized controlled trials have demonstrated that adjuvant RT after LE of localized DCIS significantly reduces the incidence of local recurrence. However, these trials did not identify any subgroups of patients where RT could be safely omitted and were criticized for lack of emphasis on standardized and meticulous tissue processing and pathological evaluation. Retrospective studies indicate that RT can be safely omitted after adequate LE (margin width > or = 1 cm) of small (< 15 mm), non-high grade DCIS not associated with necrosis. The role of tamoxifen in the treatment of DCIS continues to evolve. Formal axillary dissection is not appropriate for DCIS; however, the potential role of the sentinel node biopsy (SNB) in selected high-risk cases requires further evaluation. Areas of ongoing and future research include the potential role of third-generation aromatase inhibitors and third- and fourth-generation selective estrogen receptor modulators in women with hormone-sensitive DCIS; the potential role of cyclo-oxygenase type 2 inhibitors in DCIS treatment and prevention; the value of magnetic resonance and nuclear medicine imaging; and the clinical relevance of gene expression profiling, proteomics, radiofrequency or LASER ablation and mammary ductoscopy in the management of DCIS.

Breast Neoplasms↗