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Cohen J.G.,Cedars Sinai Womens Cancer Research Institute | Chan J.K.,University of California at San Francisco | Kapp D.S.,Stanford University
Current Opinion in Oncology | Year: 2012

Purpose of Review: Small-cell carcinomas of the gynecologic tract are aggressive malignancies that can be misdiagnosed or inappropriately managed. This review provides a summary of current literature that will help the clinician to correctly diagnose and treat patients with small-cell carcinomas of the cervix, ovary, uterus, vagina, and vulva. Recent Findings: Small-cell carcinomas of gynecologic sites are rare and carry a poor prognosis. Stage is an important prognostic factor in small-cell carcinoma of the cervix, uterus, and ovary. Early stage disease has varied treatment approaches based on the site of malignancy, but systemic chemotherapy with or without radiation plays a role in the adjuvant setting to mitigate the risk of recurrence. Advanced stage patients require treatment with chemotherapy and possibly radiation, usually in a manner analogous to small-cell lung cancer. The preferred chemotherapy regimen contains a platinum agent and etoposide. For small-cell ovarian carcinomas, it is important to differentiate those of the hypercalcemic type from those of the pulmonary type. The small-cell carcinomas of the vagina and vulva need to be distinguished from Merkel cell cancers. Summary: The majority of small-cell tumors of the gynecologic tract will require systemic chemotherapy with a platinum agent and etoposide, both in the setting of early and advanced stage disease. Prospective trials with new chemotherapy or targeted agents are needed to improve the treatment of this aggressive cancer. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Chien W.,Cedars Sinai Medical Center | Chien W.,National University of Singapore | O'Kelly J.,Cedars Sinai Medical Center | Lu D.,Cedars Sinai Medical Center | And 8 more authors.
International Journal of Oncology | Year: 2011

Connective tissue growth factor (CTGF/CCN2) belongs to the CCN family of matricellular proteins, comprising Cyr61, CTGF, NovH and WISP1-3. The CCN proteins contain an N-terminal signal peptide followed by four conserved domains sharing sequence similarities with the insulin-like growth factor binding proteins, von Willebrand factor type C repeat, thrombospondin type 1 repeat, and a C-terminal growth factor cysteine knot domain. To investigate the role of CCN2 in breast cancer, we transfected MCF-7 cells with full-length CCN2, and with four mutant constructs in which one of the domains had been deleted. MCF-7 cells stably expressing full-length CCN2 demonstrated reduced cell proliferation, increased migration in Boyden chamber assays and promoted angiogenesis in chorioallantoic membrane assays compared to control cells. Deletion of the C-terminal cysteine knot domain, but not of any other domain-deleted mutants, abolished activities mediated by full-length CCN2. We have dissected the role of CCN2 in breast tumorigenesis on a structural basis. Copyright © 2011 Spandidos Publications Ltd. All rights reserved.

Fleming N.D.,Cedars Sinai Womens Cancer Research Institute | Cass I.,Cedars Sinai Womens Cancer Research Institute | Walsh C.S.,Cedars Sinai Womens Cancer Research Institute | Karlan B.Y.,Cedars Sinai Womens Cancer Research Institute | And 2 more authors.
Gynecologic Oncology | Year: 2011

Objective: Recent data suggest that serial CA125 surveillance following remission in asymptomatic patients with epithelial ovarian cancer (EOC) does not impact overall survival. However, earlier detection of recurrence may influence resectability at secondary cytoreductive surgery (SCS). We hypothesized that a shorter time interval between CA125 elevation and SCS correlates with a higher likelihood of optimal resection among eligible patients. Methods: We identified patients with recurrent epithelial ovarian cancer who underwent SCS from 1995 to 2009 at our institution. All patients initially underwent primary cytoreductive surgery followed by platinum-based chemotherapy. CA125 elevation was considered the first value two-times the patient's nadir level. Our "study interval" was the time between CA125 elevation and SCS. Optimal SCS was defined as microscopic residual disease (≤ 0.5 cm). Our analysis compared patients who underwent optimal vs. suboptimal SCS. Results: Seventy-four patients who underwent SCS for recurrent EOC met inclusion criteria. Median disease-free interval prior to SCS was 19 vs. 12 months for the optimal and suboptimal SCS groups. More patients undergoing suboptimal SCS had ascites (21% vs. 2%, p = 0.01) and carcinomatosis (42% vs. 5%, p < 0.0001). Patients who underwent optimal SCS went to the operating room 5.3 vs. 16.4 weeks (HR 1.03, 95% CI 1.01-1.06, p = 0.04) from the time of their CA125 elevation. Optimal SCS was associated with a longer overall survival (47 vs. 23 months, p < 0.0001). Conclusions: Each week delay after first CA125 elevation correlated with a 3% increased chance of suboptimal resection at SCS. Serial CA125 surveillance for early detection of recurrence may increase rates of optimal SCS and potentially influence overall survival. © 2011 Elsevier Inc. All rights reserved.

Norquist B.,University of Washington | Wurz K.A.,University of Washington | Pennil C.C.,University of Washington | Garcia R.,University of Washington | And 5 more authors.
Journal of Clinical Oncology | Year: 2011

Purpose: Secondary somatic BRCA1/2 mutations may restore BRCA1/2 protein in hereditary ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary and recurrent BRCA1/2-mutated ovarian carcinomas to define the frequency of secondary mutations and correlate these changes with clinical outcomes. Methods: Neoplastic cells were isolated with laser capture microdissection, and DNA was sequenced at the site of the known germline BRCA1/2 mutation. When secondary mutations were found that restored wild-type sequence, haplotyping was performed using single nucleotide polymorphisms in tumor and paired lymphocyte DNA to rule out retention of the wild-type allele. Results: There were 64 primary and 46 recurrent ovarian carcinomas assessed. Thirteen (28.3%) of 46 (95% CI, 17.3% to 42.6%) recurrent carcinomas had a secondary mutation compared with two (3.1%) of 64 (95% CI, 1.0% to 10.7%) primary carcinomas (P = .0003, Fisher's exact test). Twelve (46.2%) of 26 (95% CI, 28.7% to 64.7%) platinum-resistant recurrences had secondary mutations restoring BRCA1/2, compared with one (5.3%) of 19 (95% CI, 1.2% to 24.8%) platinum-sensitive recurrences (P = .003, Fisher's exact test). Six (66.7%) of nine (95% CI, 34.8% to 87.8%) women with prior breast carcinoma had a recurrent carcinoma with a secondary mutation, compared with six (17.1%) of 35 (95% CI, 8.2% to 32.8%) with no history of breast carcinoma (P = .007, Fisher's exact test). Conclusion: Secondary somatic mutations that restore BRCA1/2 in carcinomas from women with germline BRCA1/2 mutations predict resistance to platinum chemotherapy and may also predict resistance to PARP inhibitors. These mutations were detectable only in ovarian carcinomas of women whom have had previous chemotherapy, either for ovarian or breast carcinoma. © 2011 by American Society of Clinical Oncology.

Fleming N.D.,Cedars Sinai Womens Cancer Research Institute | Lentz S.E.,Kaiser Permanente | Cass I.,Cedars Sinai Womens Cancer Research Institute | Li A.J.,Cedars Sinai Womens Cancer Research Institute | And 2 more authors.
Gynecologic Oncology | Year: 2011

Objective: Prior studies have shown that age ≥ 70 years is associated with more aggressive non-endometrioid histology and worse survival in endometrial cancer. The purpose of this study is to assess if age is an independent poor prognostic factor in endometrioid histologies. Methods: Under an IRB-approved protocol, we identified patients with surgical stage I to II endometrioid endometrial adenocarcinoma from 1995 to 2008 at two institutions. Patients were divided into two groups based on age at diagnosis: Group A (age 50-69 years) and Group B (age ≥ 70 years). All patients underwent hysterectomy, bilateral salpingoophorectomy, +/-pelvic/aortic lymphadenectomy and adjuvant therapy. Prognostic factors were evaluated by univariate and multivariate analyses. Results: We identified 338 patients with stage IA to IIB endometrioid endometrial adenocarcinoma. The median age in Group A was 59 years (range 50-69) and Group B was 75 years (range 70-92). Patients in Group B were more likely to have hypertension (51% vs. 68%, p = 0.006) and coronary artery disease (9% vs. 18%, p = 0.03). There were no differences in progression-free or disease-specific survival, however, Group B had a worse overall survival (OS) (50.1 vs. 62.6 months, p = 0.03). On univariate analysis, age (p = 0.04), grade (p = 0.006), and coronary artery disease (p = 0.01) were associated with worse OS. After adjusting for grade and coronary artery disease, age was no longer a significant variable for OS (p = 0.17). Conclusions: After adjusting for other poor prognostic factors, age ≥ 70 years alone may not be a significant variable affecting overall survival in patients with early stage endometrioid endometrial adenocarcinoma. © 2010 Elsevier Inc. All rights reserved.

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