Nonna Kolomeyevskaya

A small-molecule inhibitor targeting the mitotic spindle checkpoint impairs the growth of uterine leiomyosarcoma.

Purpose: Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies. Experimental Design: Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo. Results: We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts. Conclusions: Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease. Clin Cancer Res; 18(12); 3352–65. ©2012 AACR.

Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-α and interleukin-6 in predicting reduced progression-free survival in epithelial ovarian cancer

OBJECTIVES Epithelial ovarian cancer (EOC) typically presents with advanced disease. Even with optimal debulking and response to adjuvant chemotherapy, the majority of patients will have disease relapse. We evaluated cytokine and chemokine profiles in ascites at primary surgery as biomarkers for progression-free survival (PFS) and overall survival (OS) in patients with advanced EOC. METHODS Retrospective analysis of patients (n =70) who underwent surgery at Roswell Park Cancer Institute between 2002 and 2012, followed by platinum-based chemotherapy. RESULTS The mean age at diagnosis was 61.8 years, 85.3% had serous EOC, and 95.7% had stage IIIB, IIIC, or IV disease. Univariate analysis showed that ascites levels of tumor necrosis factor (TNF)-α were associated with reduced PFS after primary surgery. Although the ascites concentration of interleukin (IL)-6 was not by itself predictive of PFS, we found that stratifying patients by high TNF-α and high IL-6 levels identified a sub-group of patients at high risk for rapid disease relapse. This effect was largely independent of clinical prognostic variables. CONCLUSIONS The combination of high TNF-α and high IL-6 ascites levels at primary surgery predicts worse PFS in patients with advanced EOC. These results suggest an interaction between ascites TNF-α and IL-6 in driving tumor progression and resistance to chemotherapy in advanced EOC, and raise the potential for pre-treatment ascites levels of these cytokines as prognostic biomarkers. This study involved a small sample of patients and was an exploratory analysis; therefore, findings require validation in a larger independent cohort.

Aspirin and Acetaminophen Use and the Risk of Cervical Cancer.

Objective In this study, we investigated whether regular use of aspirin or acetaminophen was associated with risk of cervical cancer in women treated at an American cancer hospital. Methods This case-control study included 328 patients with cervical cancer and 1,312 controls matched on age and decade enrolled. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Analgesic use was defined as regular (at least once per week for ≥6 months), frequent (≥7 tablets/week), very long term (≥11 years), or frequent, long term (≥7 tablets per week for ≥5 years). Results Compared to nonusers, frequent aspirin use was associated with decreased odds of cervical cancer (odds ratio, 0.53; 95% confidence interval, 0.29-0.97). A slightly larger association was observed with frequent, long-term use of aspirin (odds ratio, 0.46; 95% confidence interval, 0.22-0.95). Acetaminophen use was not associated with the risk of cervical cancer. Conclusions Our findings suggest that frequent and frequent, long-term use of aspirin is associated with decreased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the widespread use of nonsteroidal anti-inflammatory drugs and acetaminophen worldwide, further investigations of the possible role of analgesics in cervical cancer, using a larger sample size with better-defined dosing regimens, are warranted.

Myeloid-derived suppressor cells modulate immune responses independently of NADPH oxidase in the ovarian tumor microenvironment in mice.

The phagocyte NADPH oxidase generates superoxide anion and downstream reactive oxidant intermediates in response to infectious threat, and is a critical mediator of antimicrobial host defense and inflammatory responses. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are recruited by cancer cells, accumulate locally and systemically in advanced cancer, and can abrogate anti-tumor immunity. Prior studies have implicated the phagocyte NADPH oxidase as being an important component promoting MDSC accumulation and immunosuppression in cancer. We therefore used engineered NADPH oxidase-deficient (p47phox−/−) mice to delineate the role of this enzyme complex in MDSC accumulation and function in a syngeneic mouse model of epithelial ovarian cancer. We found that the presence of NADPH oxidase did not affect tumor progression. The accumulation of MDSCs locally and systemically was similar in tumor-bearing wild-type (WT) and p47phox−/− mice. Although MDSCs from tumor-bearing WT mice had functional NADPH oxidase, the suppressive effect of MDSCs on ex vivo stimulated T cell proliferation was NADPH oxidase-independent. In contrast to other tumor-bearing mouse models, our results show that MDSC accumulation and immunosuppression in syngeneic epithelial ovarian cancer is NADPH oxidase-independent. We speculate that factors inherent to the tumor, tumor microenvironment, or both determine the specific requirement for NADPH oxidase in MDSC accumulation and function.

Oxaliplatin is a safe alternative option for patients with recurrent gynecologic cancers after hypersensitivity reaction to Carboplatin.

Objective The aim of this study was to determine the tolerability and efficacy of oxaliplatin in patients with recurrent gynecologic malignancies after carboplatin hypersensitivity reactions in comparison with conventionally used cisplatin. Methods Forty-six patients were treated with platinum-based chemotherapy from 2006 to 2011 and developed hypersensitivity reactions to carboplatin. Oxaliplatin was administered to 27 patients; 19 patients received cisplatin. Clinicopathologic variables, toxicity, and time-to-failure were analyzed retrospectively using descriptive statistics, Fisher exact, and independent sample permutation t tests. Results The median number of carboplatin cycles and cumulative dose before reaction were similar in the oxaliplatin and cisplatin groups, respectively (6 vs 7.5 cycles, P = 0.93; 980 [662] mg vs 686 [579.6] mg, P = 0.49). Non–life-threatening hypersensitivity reaction to oxaliplatin developed in 2 of 27 patients. No reactions to cisplatin occurred. The median number of oxaliplatin/cisplatin cycles was 6 in both groups. Complete response to therapy was 34.6% (oxaliplatin) and 31.6% (cisplatin); stable disease was seen in 50.0% and 36.8% of oxaliplatin- and cisplatin-treated patients, respectively (P = 0.46). Exposure to oxaliplatin resulted in less neurotoxicity than cisplatin (25.9% vs 68.4%, P = 0.01). The median number of prior chemotherapy lines in both groups was 2. The median time-to-failure was 10.8 months in oxaliplatin group and 9.8 months in cisplatin group (P = 0.86). Conclusions Salvage therapy with oxaliplatin after hypersensitivity reaction to carboplatin is associated with excellent tolerability and time-to-failure comparable to cisplatin. When further administration of carboplatin is precluded, oxaliplatin represents a safe and effective treatment strategy in the platinum-sensitive relapse setting. The significantly lower neurotoxicity profile makes it an attractive alternative to cisplatin.

Balloon tamponade of hemorrhage after uterine curettage for gestational trophoblastic disease.

BACKGROUND: Uterine bleeding frequently complicates gestational trophoblastic disease, particularly after uterine evacuation. Hysterectomy and other procedures used to control this bleeding incur significant risk and can limit fertility. CASE: We present a case of massive hemorrhage complicating uterine curettage performed for metastatic gestational trophoblastic disease. The patient’s bleeding was controlled successfully by intrauterine tamponade performed using a balloon catheter. After catheter removal, she achieved complete disease remission. CONCLUSION: Intrauterine balloon catheterization appears to be a promising alternative to control uterine hemorrhage and preserve fertility for young women undergoing treatment for gestational trophoblastic disease. Its use may help avoid invasive interventions, such as hysterectomy and embolization, currently used to control hemorrhage after uterine evacuation.

Oral Contraceptive Use and Reproductive Characteristics Affect Survival in Patients With Epithelial Ovarian Cancer: A Cohort Study.

Objectives Prognostic risk factors influencing survival in patients with epithelial ovarian cancer (EOC) include tumor stage, grade, histologic subtype, debulking, and platinum status. Little is known about the impact of hormonal milieu and reproductive factors before cancer diagnosis on clinical outcome. We sought to evaluate whether oral contraceptive (OC) use carries any prognostic significance on overall survival (OS) in patients with EOC. Methods Newly diagnosed patients with EOC, fallopian tube, and primary peritoneal cancers between 1982 and 1998 were prospectively evaluated with a comprehensive epidemiologic questionnaire. A retrospective chart review was performed to abstract clinicopathologic data, including OS. A Kaplan-Meier analysis was performed to compare survival across various exposures. A Cox regression model was used to compute adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs). Results We identified 387 newly diagnosed cancers with evaluable information in this cohort. Decreased risk of death was observed in women who reported prior use of OC (aHR, 0.79; 95% CI, 0.58–1.09), previous pregnancy (aHR, 0.77; 95% CI, 0.57–1.04), or a live birth (aHR, 0.81; 95% CI, 0.60–1.08) after adjusting for age at diagnosis, stage, and histologic subtype. Oral contraceptive use was associated with a crude reduced risk of death (HR, 0.55; 95% CI, 0.42–0.72), with reported median OS of 81 months in OC users versus 46 months in nonusers. Patients who reported a single live birth experienced the largest potential survival advantage (aHR, 0.61; 95% CI, 0.39–0.94). Oral contraceptive use and prior pregnancy were associated with improved survival across all strata. Conclusions Oral contraceptive use may have lasting effects on epithelial ovarian tumor characteristics conferring favorable prognosis. Putative mechanisms that affect tumor biology include complex interactions between ovarian cells, host immune cells, and hormonal microenvironment during carcinogenesis. Future efforts should be directed to determine the role of reproductive factors in antitumor immunity.

Phyllodes tumor of the breast metastasizing to the vulva.

Phyllodes tumors of the breast are rare breast tumors that resemble fibroadenoma. They are composed of two types of tissues: stromal and glandular tissues. Unlike fibroadenoma, they are commonly found in the third decade of life and they tend to grow more rapidly. Depending on the relative components of the cells and mitotic activity, they are classified into benign, borderline, and malignant. They are usually present as a lump in the breast. Phyllodes tumors are usually managed by wide excision. The excision should be wide enough to ensure a tumor-free margin. Recurrence rate is very high and most recurrences are usually local. Metastasis to the vulva has not been reported.

MicroRNAs and Recent Insights into Pediatric Ovarian Cancers

Ovarian cancer is the most common pediatric gynecologic malignancy. When diagnosed in children, ovarian cancers present unique challenges that differ dramatically from those faced by adults. Here, we review the spectrum of ovarian cancers found in young women and girls and discuss the biology of these diseases. A number of advances have recently shed significant new understanding on the potential causes of ovarian cancer in this unique population. Particular emphasis is placed on understanding how altered expression of non-coding RNA transcripts known as microRNAs play a key role in the etiology of ovarian germ cell and sex cord-stromal tumors. Emerging transgenic models for these diseases are also reviewed. Lastly, future challenges and opportunities for understanding pediatric ovarian cancers, delineating clinically useful biomarkers, and developing targeted therapies are discussed.