Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin.

HER2/neu positive breast tumors predict a high mortality and comprise 25%-30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl2, BclX/L, XIAP, and survivin. FKA also downregulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to an enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through downregulation of Myt1, Wee1, Skp2, survivin, and XIAP. Our results suggest FKA as a promising and novel apoptosis inducer and G2 blocking agent that, in combination with Herceptin, enhances for the treatment of HER2-overexpressing breast cancer.

Flavokawain B, a kava chalcone, inhibits growth of human osteosarcoma cells through G2/M cell cycle arrest and apoptosis.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Limited by the severe toxicity of conventional agents, the therapeutic bottleneck of osteosarcoma still remains unconquered. Flavokawain B (FKB), a kava extract, has been reported to have significant anti-tumor effects on several carcinoma cell lines both in vitro and in vivo. Its efficacy and low toxicity profile make FKB a promising agent for use as a novel chemotherapeutic agent. RESULTS: In the current study, we investigated the anti-proliferative and apoptotic effects of FKB against human osteosarcomas. Exposure of OS cells to FKB resulted in apoptosis, evidenced by loss of cell viability, morphological changes and the externalization of phosphatidylserine. Apoptosis induced by FKB resulted in activation of Caspase-3/7, -8 and -9 in OS cell lines, 143B and Saos-2. FKB also down-regulated inhibitory apoptotic markers, including Bcl-2 and Survivin and led to concomitant increases in apoptotic proteins, Bax, Puma and Fas. Therefore, the induction of apoptosis by FKB involved both extrinsic and intrinsic pathways. FKB also caused G2/M phase cell cycle arrest, which was observed through reductions in the levels of cyclin B1, cdc2 and cdc25c and increases in Myt1 levels. Furthermore, migration and invasion ability was decreased by FKB in a dose-dependent manner. The cytotoxicity profile showed FKB had significant lower side effects on bone marrow cells and small intestinal epithelial cells compared with Adriamycin. CONCLUSIONS: Taken together, our evidence of apoptosis and cell cycle arrest by FKB treatment with less toxicity than the standard treatments provides an innovative argument for the use of FKB as a chemotherapeutic and chemopreventive compound. In vivo experiments utilizing FKB to reduce tumorigenesis and metastatic potential will be crucial to further justify clinical application.

Analysis of postoperative complications associated with the use of anti-adhesion sodium hyaluronate-carboxymethylcellulose (HA-CMC) barrier after cytoreductive surgery for ovarian, fallopian tube and peritoneal cancers.

OBJECTIVE: To evaluate the risk of postoperative complications related to HA-CMC use in patients undergoing optimal cytoreductive surgery for primary and recurrent ovarian, fallopian tube, and peritoneal cancers. METHODS: A single institution retrospective review identified all patients undergoing optimal (≤1 cm) cytoreductive surgery for primary or recurrent ovarian, fallopian tube, and peritoneal cancers between 1/95 and 12/08. Operative details and post-operative complications (<30 days) were extracted from the medical record. Fisher's exact test, Mann-Whitney-U, and multiple regression analyses were performed to identify factors, including HA-CMC use, associated with post-operative complications. RESULTS: Three hundred seventy-five cases were analyzed: HA-CMC was utilized in 168 debulking procedures. There was no difference in the incidence of overall morbidity for patients with HA-CMC compared to those without HA-CMC (OR 1.07; 95% CI: 0.68-1.67). On univariate analysis, application of HA-CMC increased the risk of pelvic abscess (OR 2.66; 95% CI: 1.21-5.86), particularly in the primary surgery setting (OR 4.65; 95% CI: 1.67-12.98) and in patients undergoing hysterectomy (OR 3.36; 95% CI: 1.18-9.53). After controlling for confounding factors using multiple linear regression, HA-CMC use approached statistical significance in predicting an increased risk of pelvic abscess but not major postoperative morbidity. CONCLUSIONS: HA-CMC adhesion barrier placement at the time of optimal cytoreductive surgery for ovarian, fallopian tube, and peritoneal cancer is not associated with major postoperative complications but may be associated with increased risk of pelvic abscess.

A case of ovarian endometrioid adenocarcinoma with yolk sac differentiation and Lynch syndrome.

Ovarian endometrioid adenocarcinoma with yolk sac component has been reported in fewer than twenty cases in the literature. A majority of the diagnoses are described in postmenopausal women without specific reference to germline genetic testing. We describe, to our knowledge, the first case in the English literature of a premenopausal woman that presented with an ovarian endometrioid adenocarcinoma with focal yolk sac component and was subsequently found to have a germline MSH2 mutation confirming a diagnosis of Lynch syndrome. Concurrent diagnosis of ovarian endometrioid adenocarcinoma with yolk sac tumor and Lynch syndrome is an extremely rare finding in a young patient and requires careful follow-up. Genetics evaluation and testing may be reasonable for individuals with this rare or mixed tumor pathology at young age of onset and can have clinical utility in guiding future cancer treatment or surveillance.

Integration of bevacizumab with chemotherapy doublets for advanced cervical cancer.

INTRODUCTION: Historically, treatment options were limited for women diagnosed with late-stage or recurrent cervical cancer until recently. The publication of the results of GOG240 marks the beginning of the anti-angiogenesis era in cervical cancer. This randomized controlled trial showed significant improvements in response rates, progression-free survival and overall survival when bevacizumab was added to conventional chemotherapy in patients with metastatic, recurrent, or persistent cervical cancer. Bevacizumab is the first new drug to be approved in this disease in over 8 years. It is also the first biologic agent to be approved for use in patients with a gynecologic malignancy. AREAS COVERED: This review will highlight the evolution of combination chemotherapy for advanced cervical carcinoma, with particular emphasis on the recent ground-breaking research on the anti-angiogenesis therapy. EXPERT OPINION: Experts believe that the discoveries surrounding angiogenesis inhibitors have changed the standard of practice for women with incurable invasive cervical cancer. We will explore the advantages and disadvantages of anti-angiogenesis therapies. Ultimately, we hope that the research summarized here will one day alter the face of this disease by offering this high-risk population a rare commodity: survivorship.

Exploring the therapeutic rationale for angiogenesis blockade in cervical cancer.

PURPOSE: This review highlights the molecular and pathologic evidence that cervical cancer is driven by angiogenesis and presents a summary of the recent clinical research in antiangiogenesis therapy for advanced cervical cancer with a focus on the use of bevacizumab. METHODS: The articles chosen for this review reveal the rationale for antiangiogenesis agents in cervical cancer from 3 perspectives: pathologic, molecular, and clinical data. FINDINGS: Several translational investigations have revealed that proangiogenic signaling cascades are active in cervical carcinogenesis and can be used to improve patient outcomes in advanced disease. For example, in a recently published study of patients with recurrent and metastatic cervical cancer, bevacizumab was the first targeted agent to improve overall survival in a gynecologic cancer when successfully combined with 2 different chemotherapy regimens. IMPLICATIONS: Because of recent advances in screening, aggressive management of cervical intraepithelial neoplasia, and human papillomavirus vaccination, cervical cancer is preventable and curable with radical surgery plus lymphadenectomy surgery or chemoradiation plus brachytherapy if detected early. Unfortunately, for patients with metastatic or recurrent disease, effective therapeutic options are limited for this aggressive life-threatening condition. However, molecularly targeted agents have provided a critical opportunity to improve patient outcomes beyond optimizing cytotoxic chemotherapy regimens so that they may benefit from other agents or emergent therapies in the future.

Molecular targeted approaches to cancer therapy and prevention using chalcones.

There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, ß-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, ß-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and ß-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.

Robotic surgery: gynecologic oncology.

In the field of gynecologic oncology, robotic-assisted surgery has emerged as an invaluable minimally invasive approach to comprehensive surgical staging and the treatment of cervical and endometrial cancer. This review focuses on operative indications for robotic surgery in several gynecologic disease sites and summarizes the available literature on perioperative outcomes for robotics compared with conventional methods and evolving common practice patterns among gynecologic oncologists. Areas of controversy surrounding this technology and justification of widespread use are also discussed, including the paucity of randomized controlled trials, long-term efficacy data, and cost-effectiveness research.

Disparities in human papillomavirus vaccine completion among vaccine initiators.

OBJECTIVE: To estimate rates of completing the full three-dose prophylactic human papillomavirus (HPV) vaccination regimen in patients who initiated the series and to identify variables associated with not completing vaccination. METHODS: This single-institution review identified all patients initiating HPV vaccination at one of four affiliated clinics between January 2007 and June 2008. Vaccination "completers" were defined as patients who had completed all three vaccinations within 12 months of initiating the vaccination series. Logistic regression was used to identify factors associated with vaccine completion. Variables analyzed included age, type of insurance (private compared with public), practice location (urban compared with suburban), practice type (pediatrics, gynecology, or family practice), and race or ethnicity (white or African American and Hispanic). RESULTS: Of the 1,413 girls and young women who initiated HPV vaccination, 469 (33.2%) completed the vaccine series. Overall, private insurances (odds ratio 1.87, 95% confidence interval 1.26-2.76) and suburban practice locations (odds ratio 1.44, 95% confidence interval 1.04-1.98) were associated with higher vaccine completion rates. African American race was associated with lower completion rates (odds ratio 0.50, 95% confidence interval 0.38-0.65). In multivariable analyses, the combination of younger age (11-17 years) and urban practice location was associated with very low likelihood of completing HPV vaccination (22%; P=.023). CONCLUSION: The HPV vaccine completion rate is low. When resources are limited, disparities in HPV vaccine completion should be considered when developing programs to improve vaccine utilization. Urban girls and young women should be targeted as an at-risk population.

Value of intraoperative examination of axillary sentinel nodes in carcinoma of the breast.

BACKGROUND: The value of frozen sections in the intraoperative examination of sentinel nodes (SN) remains controversial. Accurate frozen sections will spare those patients with node metastasis from a second procedure to complete the axillary dissection. We examined our own experience with intraoperative examination of SN. STUDY DESIGN: Between January 1, 2006, and December 31, 2006, we performed 236 sentinel lymph node biopsy procedures that were read as "frozen-section-negative." An additional 47 sentinel lymph node biopsy patients were frozen-section-positive for metastatic disease and underwent immediate completion axillary dissection. At least 1 SN was found in all 283 women (100%). The number of patients with false-negative frozen sections was tallied; patient data were reviewed for a number of variables to see which factors might be associated with a false-negative result. RESULTS: Eleven patients had positive nodes on subsequent examination of the formalin-fixed, hematoxylin and eosin-stained slides; the false-negative rate of intraoperative frozen section was 4.7%. The sensitivity of the negative frozen section was > 95%. The following variables were compared for significance: pathologist, nuclear grade, histologic grade, margins, lymphovascular invasion, tumor type (ductal versus lobular), and estrogen receptor and progesterone receptor values. The only significant variables were lymphovascular invasion (p = 0.019) and presence of in situ ductal carcinoma (p = 0.001). CONCLUSIONS: Our data confirm the value of intraoperative examination of SN: > 95% sensitivity. Presence of in situ ductal carcinoma or lymphovascular invasion makes these tumors more likely than others to have micrometastases to SN overlooked.