- Email: [email protected]
Detection of premalignant and malignant breast cells by ductal lavage
Monday
April 30, 2001 Cytokine-Mediated Modulation of Cisplatin Sensitivity in Ovarian Cancer Cells Niloofar Eskandari, MD University of California, Los Angeles, Center for Health Sciences, Los Angeles, CA
Julia Gage, PhD, Michael T. Johnson, MD, and Otoniel Martinez-Maza, PhD Background: Epithelial ovarian cancer cells are known to produce interleukin-6 (IL-6) and are known to express IL-6 receptors. Serum and peritoneal fluid concentrations of IL-6 are elevated in patients with epithelial ovarian cancers. Metallothioneins are a group of proteins with high affinity for heavy metal ions, including platinum; they are inducible by IL-6 and may confer resistance of ovarian cancer cells to cisplatin chemotherapy. Objective: To determine whether IL-6 induces cisplatin resistance in ovarian cancer cells and to assess whether it does so by increasing intracellular metallothionein. Methods: Two ovarian cancer cell lines (SKOV3, OC194) were incubated with either recombinant IL-6, anti-IL-6 antibody, anti-IL-6 receptor antibody, or IL-10 for 24 hours. Cisplatin was then added, and an MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) cytotoxicity assay was performed after 48 hours. Western blot probing for metallothionein was performed after a 24-hour incubation of SKOV3 cells with IL-6. Results: Pretreatment of ovarian cancer cells with IL-6 before adding cisplatin resulted in a significant reduction in cytotoxicity. Reversal of this IL-6 effect with anti-IL-6 antibody, anti-IL-6 receptor antibody, and IL-10 was demonstrated. Western blot analysis of IL-6 –treated cells revealed a positive correlation between IL-6 exposure and cellular metallothionein content. Conclusion: These results demonstrate that expression of IL-6 by ovarian cancer cells confers resistance to cisplatin cytotoxicity by upregulation of metallothione. In addition, inhibition of IL-6 effect reverses this cisplatin resistance. Clinically, suppression of IL-6 effect may be exploited to potentiate cisplatin chemotherapy, leading to better survival rates in ovarian cancer patients.
2S Monday Papers
FIRST PRIZE PAPER Detection of Premalignant and Malignant Breast Cells by Ductal Lavage William C. Dooley, MD Johns Hopkins School of Medicine, Baltimore, MD
U. Veronesi, R. Elledge, J. O’Shaughnessy, B-M Ljung, and R. Arias All ductal and lobular breast cancers originate in the single layer of epithelial cells that line the ductal/lobular systems of all milk ducts. Ductal lavage (DL) enables the retrieval of these cells using a microcatheter. The microcatheter is inserted into the milk ducts through the nipple surface orifices, and saline is flushed through the ducts to wash out cells for cytological evaluation. Methods: High-risk women (Gail index ⬎ 1.7, previous breast cancer or BRCA1/BRCA2–positive) with nonsuspicious mammograms and physical exams were aspirated to identify fluid-yielding ducts for subsequent lavage. Cytological diagnoses were rendered as either insufficient cellular material for diagnosis (ICMD), benign (B), mild atypia/premalignant cells (A/P), or suspicious for malignancy/unequivocally malignant cells (ASM/M). Results: DL was performed on 426 high-risk women (551 breasts). Cytological analysis of 470 eligible breasts has been completed. Of lavaged breasts, 15.1% and 5.1% yielded a cytological diagnosis of A/P and ASM/M, respectively, for a combined atypia prevalence of 20.2%. In two cases of ASM/M cytology, a 1.8-cm high-grade ductal carcinoma in situ (DCIS) and a 6-cm intermediate-grade DCIS were confirmed and resected with clear margins following exploration and partial resection of the afflicted ducts. In a third case, extensive papillomas with a small focus of cells resembling DCIS were confirmed following prophylactic mastectomy. Workup of two more cases with repeat mammograms, MRI, ultrasonography, and ductoscopy revealed papillomas but no high-grade intraductal lesions correlating with the lavage cytology, although ductoscopy is obviously limited in its ability to access and sample all ductal branches. The other ASM/M cases are still undergoing workup. Conclusions: Ductal lavage is a safe, well-tolerated, and relatively noninvasive procedure for collecting breast ductal epithelial cells to allow for the determination and differentiation of normal, premalignant, and malignant cytology. Ductal lavage may be a useful adjunct to mammography and other currently available imaging modalities for the early detection of intraductal breast pathology.
Obstetrics & Gynecology
April 30, 2001 Cytokine-Mediated Modulation of Cisplatin Sensitivity in Ovarian Cancer Cells Niloofar Eskandari, MD University of California, Los Angeles, Center for Health Sciences, Los Angeles, CA
Julia Gage, PhD, Michael T. Johnson, MD, and Otoniel Martinez-Maza, PhD Background: Epithelial ovarian cancer cells are known to produce interleukin-6 (IL-6) and are known to express IL-6 receptors. Serum and peritoneal fluid concentrations of IL-6 are elevated in patients with epithelial ovarian cancers. Metallothioneins are a group of proteins with high affinity for heavy metal ions, including platinum; they are inducible by IL-6 and may confer resistance of ovarian cancer cells to cisplatin chemotherapy. Objective: To determine whether IL-6 induces cisplatin resistance in ovarian cancer cells and to assess whether it does so by increasing intracellular metallothionein. Methods: Two ovarian cancer cell lines (SKOV3, OC194) were incubated with either recombinant IL-6, anti-IL-6 antibody, anti-IL-6 receptor antibody, or IL-10 for 24 hours. Cisplatin was then added, and an MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) cytotoxicity assay was performed after 48 hours. Western blot probing for metallothionein was performed after a 24-hour incubation of SKOV3 cells with IL-6. Results: Pretreatment of ovarian cancer cells with IL-6 before adding cisplatin resulted in a significant reduction in cytotoxicity. Reversal of this IL-6 effect with anti-IL-6 antibody, anti-IL-6 receptor antibody, and IL-10 was demonstrated. Western blot analysis of IL-6 –treated cells revealed a positive correlation between IL-6 exposure and cellular metallothionein content. Conclusion: These results demonstrate that expression of IL-6 by ovarian cancer cells confers resistance to cisplatin cytotoxicity by upregulation of metallothione. In addition, inhibition of IL-6 effect reverses this cisplatin resistance. Clinically, suppression of IL-6 effect may be exploited to potentiate cisplatin chemotherapy, leading to better survival rates in ovarian cancer patients.
2S Monday Papers
FIRST PRIZE PAPER Detection of Premalignant and Malignant Breast Cells by Ductal Lavage William C. Dooley, MD Johns Hopkins School of Medicine, Baltimore, MD
U. Veronesi, R. Elledge, J. O’Shaughnessy, B-M Ljung, and R. Arias All ductal and lobular breast cancers originate in the single layer of epithelial cells that line the ductal/lobular systems of all milk ducts. Ductal lavage (DL) enables the retrieval of these cells using a microcatheter. The microcatheter is inserted into the milk ducts through the nipple surface orifices, and saline is flushed through the ducts to wash out cells for cytological evaluation. Methods: High-risk women (Gail index ⬎ 1.7, previous breast cancer or BRCA1/BRCA2–positive) with nonsuspicious mammograms and physical exams were aspirated to identify fluid-yielding ducts for subsequent lavage. Cytological diagnoses were rendered as either insufficient cellular material for diagnosis (ICMD), benign (B), mild atypia/premalignant cells (A/P), or suspicious for malignancy/unequivocally malignant cells (ASM/M). Results: DL was performed on 426 high-risk women (551 breasts). Cytological analysis of 470 eligible breasts has been completed. Of lavaged breasts, 15.1% and 5.1% yielded a cytological diagnosis of A/P and ASM/M, respectively, for a combined atypia prevalence of 20.2%. In two cases of ASM/M cytology, a 1.8-cm high-grade ductal carcinoma in situ (DCIS) and a 6-cm intermediate-grade DCIS were confirmed and resected with clear margins following exploration and partial resection of the afflicted ducts. In a third case, extensive papillomas with a small focus of cells resembling DCIS were confirmed following prophylactic mastectomy. Workup of two more cases with repeat mammograms, MRI, ultrasonography, and ductoscopy revealed papillomas but no high-grade intraductal lesions correlating with the lavage cytology, although ductoscopy is obviously limited in its ability to access and sample all ductal branches. The other ASM/M cases are still undergoing workup. Conclusions: Ductal lavage is a safe, well-tolerated, and relatively noninvasive procedure for collecting breast ductal epithelial cells to allow for the determination and differentiation of normal, premalignant, and malignant cytology. Ductal lavage may be a useful adjunct to mammography and other currently available imaging modalities for the early detection of intraductal breast pathology.
Obstetrics & Gynecology