Melina Shoni

Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix.

Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma.

Changes in serum CA-125 can predict optimal cytoreduction to no gross residual disease in patients with advanced stage ovarian cancer treated with neoadjuvant chemotherapy.

OBJECTIVE To evaluate the predictive power of serum CA-125 changes in the management of patients undergoing neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) for a new diagnosis of epithelial ovarian carcinoma (EOC). METHODS Using the Cancer Registry databases from our institutions, a retrospective review of patients with FIGO stage IIIC and IV EOC who were treated with platinum-based NACT-IDS between January 2006 and December 2009 was conducted. Demographic data, CA-125 levels, radiographic data, chemotherapy, and surgical-pathologic information were obtained. Continuous variables were evaluated by Students t test or Wilcoxon-Mann-Whitney test. RESULTS One hundred-three patients with stage IIIC or IV EOC met study criteria. Median number of neoadjuvant cycles was 3. Ninety-nine patients (96.1%) were optimally cytoreduced. Forty-seven patients (47.5%) had resection to no residual disease (NRD). The median CA-125 at diagnosis and before interval debulking was 1749U/mL and 161U/mL, respectively. Comparing patients with NRD v. optimal macroscopic disease (OMD), there was no statistical difference in the mean CA-125 at diagnosis (1566U/mL v. 2077U/mL, p=0.1). There was a significant difference in the mean CA-125 prior to interval debulking, 92 v. 233U/mL (p=0.001). In the NRD group, 38 patients (80%) had preoperative CA-125≤100U/mL compared to 33 patients (63.4%) in the OMD group (p=0.04). CONCLUSIONS Patients who undergo NACT-IDS achieve a high rate of optimal cytoreduction. In our series, after treatment with taxane and platinum-based chemotherapy, patients with a preoperative CA-125 of ≤100U/mL were highly likely to be cytoreduced to no residual disease.

Benign Metastasizing Leiomyomas to the Lungs: An Institutional Case Series and a Review of the Recent Literature

BACKGROUND Benign metastasizing leiomyomas (BMLs) represent the extrauterine spread of a benign uterine process. Pulmonary BMLs are the most common example of distant spread of uterine leiomyomas and are usually found incidentally in premenopausal women. The rarity of BMLs accounts for the limited literature that currently exists regarding their underlying pathophysiology, disease course, and management. METHODS A retrospective analysis was performed of all BML cases diagnosed and managed at Brigham and Womens Hospital during a 22-year period. The demographic and clinical characteristics of these patients were compared with a PubMed-derived cohort of BML cases reported since 2006. RESULTS Benign metastasizing leiomyoma tumors were identified in 10 Brigham and Womens Hospital patients, whereas 57 cases were reported in the literature. The average age at diagnosis was 54.1 and 46.7 years, respectively. Mean interval time from a pertinent gynecologic procedure to BML diagnosis was 23 years at Brigham and Womens Hospital. All patients demonstrated positivity for actin, desmin, and estrogen/progesterone receptors, confirming the diagnosis of uterine leiomyomas. Management primarily consisted of diagnostic resection with subsequent observation with or without hormonal suppression for residual pulmonary nodules. Progression of residual BMLs was noticed in 30% and 8.3% of Brigham and Womens Hospital and literature patients, respectively, when follow-up was reported. One patient in our series required further surgical management. CONCLUSIONS Benign metastasizing leiomyomas are a rare cause of pulmonary nodules. They likely represent a clonal spread of uterine leiomyomas to the lungs. Management includes pathologic diagnosis with long-term surveillance with or without hormonal manipulation.

The significance of preoperative leukocytosis in endometrial carcinoma

OBJECTIVE To evaluate the impact of preoperative leukocytosis among patients with endometrial carcinoma. METHODS The medical records of all patients that underwent surgical treatment for endometrial carcinoma between January 2005 and December 2010 were retrospectively reviewed. Patients were separated into two groups based on the presence or absence of preoperative leukocytosis (WBC ≥ 10,000 cells per μl). The groups were then compared with respect to pathologic findings, progression-free survival and overall survival. RESULTS 1144 patients were identified, 156 (13.6%) with preoperative leukocytosis and 988 (86.4%) without leukocytosis. The leukocytosis group had a greater percentage of patients with stage 3 (15.4% vs. 9.8%, crude p=0.02) and 4 (7.1% vs. 3.0%, crude p=0.007) disease. Leukocytosis was associated with a greater mean tumor size (4.4 vs. 3.4 cm, p=0.0002) and a greater percentage of patients with cervical stromal involvement (14.8% vs. 8.7%, crude p=0.02), adnexal involvement (14.1% vs. 7.5%, crude p=0.007) and lymphvascular space invasion (24% vs. 16.3%, crude p=0.02). On multivariate analysis, mean tumor size (OR, 95% CI; 1.10, 1.02-1.18) remained significantly associated with preoperative leukocytosis. There was no difference between groups, with respect to time to recurrence. However, leukocytosis was independently associated with an increased risk of death (HR, 95% CI; 1.69, 1.07-2.68). CONCLUSIONS Preoperative leukocytosis, among endometrial cancer patients, was independently associated with increasing tumor size and independently imposed an increased risk of death.

Low-grade and high-grade serous Mullerian carcinoma: Review and analysis of publicly available gene expression profiles

OBJECTIVE Mullerian low grade serous carcinoma (LGSC) and high grade serous carcinoma (HGSC) have distinct molecular profiles, clinical behavior and treatment response. Our objective was to study the biological profiles of these carcinomas. METHODS This study examines publicly available gene expression profiles of LGSC and HGSC to identify differentially expressed genes and key pathways involved in carcinogenesis and chemotherapy response. RESULTS Our analysis supports the hypothesis that serous mullerian carcinoma develop through two different pathways yielding two distinct malignancies, namely LGSC and HGSC. Furthermore, genes potentially involved in chemotherapeutic resistance of LGSC were identified. Suppressing the levels of these genes/proteins may increase clinical response to standard chemotherapy in patients with LGSC. CONCLUSION In summary, this review shows the molecular profile of LGSC and HGSC through multi-center analysis of gene expression profiles of these tumors. The gene signatures of these neoplasms may potentially be used to develop disease-specific, targeted therapy for LGSC and HGSC.

The Role of Para-Aortic Lymphadenectomy in the Surgical Staging of Women with Intermediate and High-Risk Endometrial Adenocarcinomas

Objectives. To characterize clinical outcomes in patients with intermediate or high-risk endometrial carcinoma who underwent surgical staging with or without para-aortic lymphadenectomy. Methods. This is a retrospective cohort study of patients with intermediate or high-risk endometrial adenocarcinoma who underwent surgical staging with (PPALN group) or without (PLN) para-aortic lymphadenectomy. Data were collected, Kaplan-Meier curves were generated, and univariate and multivariate analyses performed to compare differences in adjuvant therapy, disease recurrence, disease-free survival (DFS), and overall survival (OS). Results. 118 patients were included in the PPALN group and 139 in the PLN group. Patients in the PPALN group were more likely to receive adjuvant vaginal brachytherapy (25.4% versus 11.5%, OR = 2.5, P = 0.03) and less likely to receive adjuvant multimodal combination therapy (17.81% versus 28.8%, OR = 0.28, P = 0.002). DFS was improved in the PLN group as compared to PPALN (80% versus 62%, P = 0.02). OS was equivalent (P = 0.93). Patients in the PPALN group who had less than 10 para-aortic nodes removed were twice as likely to recur than patients who had 10 or more para-aortic nodes or patients in the PLN group (HR 2.08, CI 1.20–3.60, P = 0.009). Conclusions. Patients in the PLN group were more likely to receive multimodal adjuvant therapy and had better DFS than the PPALN group. Pelvic lymphadenectomy followed by adjuvant radiation and chemotherapy may represent an effective treatment option for patients with intermediate or high-risk disease. If systematic para-aortic lymphadenectomy is performed and less than 10 para-aortic lymph nodes are obtained, multimodality adjuvant therapy should be considered to improve DFS.

Preoperative leukocytosis imposes an increased risk of recurrence and death among patients with nonendometrioid endometrial carcinoma.

Objective To evaluate the impact of preoperative leukocytosis among patients with nonendometrioid endometrial carcinoma. Methods The medical records of all patients with nonendometrioid endometrial carcinoma who underwent surgical treatment between January 2005 and December 2010 were retrospectively reviewed. The patients were separated into 2 groups based on the presence or absence of preoperative leukocytosis (white blood cell count ≥10,000/&mgr;L). The groups were then compared with respect to pathologic findings, progression-free survival, and overall survival. Results A total of 222 patients were identified, and preoperative leukocytosis was observed in 33 patients (14.9%). The leukocytosis group was associated with a larger mean size of the primary tumor (6.8 vs 4.6 cm, P = 0.016) and a greater percentage of patients with cervical stromal involvement (36.4% vs 20.1%, P = 0.039), adnexal involvement (42.4% vs. 22.8%, P = 0.017), and pelvic/para-aortic lymph node involvement (50% vs 27.4%, P = 0.025). On multivariate analysis, preoperative leukocytosis was independently associated with an increased risk of recurrence (hazard ratio, 2.07; 95% confidence interval, 1.12–3.84) and an increased risk of death (hazard ratio, 3.33; 95% confidence interval, 2.01–5.53). Conclusions Among patients with nonendometrioid endometrial carcinoma, preoperative leukocytosis is independently associated with an increased risk of recurrence and death.

Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

Protein kinases (PKs) mediate the reversible conversion of substrate proteins to phosphorylated forms, a key process in controlling intracellular signaling transduction cascades. Pluripotency is, among others, characterized by specifically expressed PKs forming a highly interconnected regulatory network that culminates in a finely-balanced molecular switch. Current high-throughput phosphoproteomic approaches have shed light on the specific regulatory PKs and their function in controlling pluripotent states. Pluripotent cell-derived endothelial and hematopoietic developments represent an example of the importance of pluripotency in cancer therapeutics and organ regeneration. This review attempts to provide the hitherto known kinome profile and the individual characterization of PK-related pathways that regulate pluripotency. Elucidating the underlying intrinsic and extrinsic signals may improve our understanding of the different pluripotent states, the maintenance or induction of pluripotency, and the ability to tailor lineage differentiation, with a particular focus on endothelial cell differentiation for anti-cancer treatment, cell-based tissue engineering, and regenerative medicine strategies.

p-21-Activated kinase-1, -4 and -6 and estrogen receptor expression pattern in normal placenta and gestational trophoblastic diseases

OBJECTIVES To delineate the potential role of p21-activated kinases (PAKs) in the pathogenesis of gestational trophoblastic diseases (GTD) by defining the expression pattern of PAK-1, -4 and -6 and their potential implication in estrogen receptor (ER) regulation of normal placental tissue and GTD. METHODS We evaluated immunohistochemically 10 normal first-trimester placentas (NP), 10 partial moles (PM), 15 complete moles (CM) and 3 choriocarcinomas (CCA) for PAK-1, PAK-4, PAK-6 and ER expression intensity and localization. Staining outcomes were assessed utilizing non-parametric Kruskal-Wallis one-way analysis of variance test followed by pairwise Wilcoxon Rank Sum tests. Statistical significance was determined by two-sided p-value of <0.05. RESULTS In NP, PAK-6 immunoreactivity was predominantly cytoplasmic. Compared to NP, PM and CM demonstrated significant increase of cytoplasmic PAK-6 in cytotrophoblast (p=0.012, p=0.033 respectively), accompanied by significantly increased nuclear immunoreactivity in cytotrophoblast (p=0.008, p=0.045 respectively) and intermediate trophoblast (p=0.003, p=0.015 respectively). PAK-4 was found significantly upregulated in both cytoplasmic and nuclear compartments of cytotrophoblast and syncytiotrophoblast in PM (p=0.004 and p=0.002 for cytotrophoblast; p=0.018 and p=0.002 for syncytiotrophoblast, respectively) and CM (p=0.001 and p=0.001 for cytotrophoblast; p=0.002 and p=0.001 for syncytiotrophoblast, respectively) when compared to NP, whereas PAK-1 expression was significantly reduced in the syncytiotrophoblast of PM (p=0.025 for cytoplasm and p=0.008 for nucleus). Nuclear expression of ER was undetectable in all stained samples. CONCLUSION Our results reveal PAK-6 upregulation in GTD compared to NP. The absence of nuclear expression of ER might stem in part from the repressive effect of PAK-6 in trophoblastic tissue.

Ovarian Cancer Relapse: Experimental Therapies

Epithe ovarian cancer has the highest mortality of all gynecologic cancers with an estimated 22,280 cases diagnosed in 2012 in the United States and 15,500 deaths [1]. For women between the ages of 60 and 79 years of age, ovarian cancer is the fifth leading cause of cancer death following lung, breast, colorectal, and pancreatic cancer [2]. Survival improvements for newly diagnosed ovarian cancer have reached a plateau using upfront surgery followed by platinum- and taxane-based chemotherapy. Thus, investigational efforts with new therapeutic agents are underway in an effort to overcome platinum- and chemotherapy-resistant cancer and ultimately improve survival. Insights into the molecular biology of ovarian cancer through mechanisms such as The Cancer Genome Atlas Project have identified potential therapeutic targets [2]. Efficacy, toxicities, and drug metabolism related to targeted therapies in the elderly patient with ovarian cancer are not available, and thus, data on the risk-benefit ratio of targeted therapies in this age group are mainly derived from studies in non-gynecologic cancers. This chapter reviews the available targeted therapies for the management of ovarian cancer and outlines the application of newer biologic agents in elderly patients with recurrent ovarian cancer.