Lauren S. Krill

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

BackgroundOsteosarcoma (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.ResultsIn 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.ConclusionsTaken 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.

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, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-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 β-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.

AbstractIn 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.

Does adjuvant chemotherapy improve survival for women with early-stage uterine leiomyosarcoma?

OBJECTIVES To examine whether adjuvant therapy after primary surgery for treatment of early-stage uterine leiomyosarcoma (LMS) improves recurrence and survival rates. METHODS A multisite, retrospective study of women diagnosed with stage I-II high grade LMS from 1990-2010 was performed. All patients (pts) underwent primary surgery followed by observation (OBS), radiotherapy (RT), or chemotherapy (CT) postoperatively. RESULTS One hundred eight patients were identified with long-term follow-up; 94 pts (87.0%) had stage I and 14 (13.0%) had stage II disease. The mean patient age was 55.4 years and mean BMI was 28.0. Thirty-four (31.5%) patients underwent OBS, 35 (32.4%) received RT, and 39 (36.1%) received chemotherapy. After a median follow-up of 41.8 months, a recurrence was diagnosed in 70.8%. Recurrence was evident in 25/34 (73.5%) OBS, 23/35 (65.7%) RT, and 28/39 (71.8%) of CT cohorts and was not different based on treatment (p=0.413). However, extra-pelvic recurrences were significantly higher in the RT (95.2%) than in the OBS (60%) or CT (64.3%) cohorts (p=0.012). Additionally, recurrences were more likely to be successfully treated or palliated in those who initially received CT (p=0.031). On multivariate analysis, stage (p<0.001) and chemotherapy (p=0.045) were associated with overall survival. CONCLUSIONS Women with early-stage, high grade uterine LMS experience high recurrence rates and poor survival outcomes, irrespective of adjuvant therapy. These rates are higher than previously reported in the literature. Although women treated with CT had similar recurrence rates as those treated with OBS or RT, treatment with adjuvant chemotherapy may decrease the risk of extra-pelvic recurrence and improve survival.

Assessment of palliative care training in gynecologic oncology: A gynecologic oncology fellow research network study

OBJECTIVE Palliative care is recognized as an important component of oncologic care. We sought to assess the quality/quantity of palliative care education in gynecologic oncology fellowship. METHODS A self-administered on-line questionnaire was distributed to current gynecologic oncology fellow and candidate members during the 2013 academic year. Descriptive statistics, bivariate and multivariate analyses were performed. RESULTS Of 201 fellow and candidate members, 74.1% (n=149) responded. Respondents were primarily women (75%) and white (76%). Only 11% of respondents participated in a palliative care rotation. Respondents rated the overall quality of teaching received on management of ovarian cancer significantly higher than management of patients at end of life (EOL), independent of level of training (8.25 vs. 6.23; p<0.0005). Forty-six percent reported never being observed discussing transition of care from curative to palliative with a patient, and 56% never received feedback about technique regarding discussions on EOL care. When asked to recall their most recent patient who had died, 83% reported enrollment in hospice within 4 weeks of death. Fellows reporting higher quality EOL education were significantly more likely to feel prepared to care for patients at EOL (p<0.0005). Mean ranking of preparedness increased with the number of times a fellow reported discussing changing goals from curative to palliative and the number of times he/she received feedback from an attending (p<0.0005). CONCLUSIONS Gynecologic oncology fellow/candidate members reported insufficient palliative care education. Those respondents reporting higher quality EOL training felt more prepared to care for dying patients and to address complications commonly encountered in this setting.

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.

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.

Clinical commentary: Medical ethics and the ramifications of equipoise in clinical research. Is a confirmatory trial using a non-bevacizumab containing arm feasible in patients with recurrent cervical cancer?

controlled trials (RCTs) represent the gold standard of methodology in clinical research and maximize the validity of scientific data through eliminating systematic biases. However, for clinical investigators one of the major ethical weaknesses is the act of randomization itself [1]. Clinical-researchers face the dilemma of reconciling their duty as physicians to provide the best care for their patients with the preeminent scientific process of assigning research participants to competing therapies by chance alone. The concept of ‘clinical equipoise’has been utilized by ethicists and researchers to overcome this crisis of professional responsibility. The reigning definition was described by Freedman as “an ethically necessary condition in all cases of clinical research... [that exists when] there is no consensus within the expert clinical community about the comparative merits of the alternatives to be tested” [2]. Since the 1970s equipoise has been challenged, deconstructed, and reformulated in the ethics literature, and it remains open for interpretation. Contemporary ethicists caution against relying on equi-

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. Fishers 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.

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.