Ramez N. Eskander

Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta

BACKGROUND: The incidence of placenta accreta has increased dramatically over the last three decades, in concert with the increase in the cesarean delivery rate. Optimal management requires accurate prenatal diagnosis. The purpose of this study was to determine the precision and reliability of ultrasonography and magnetic resonance imaging (MRI) in diagnosing placenta accreta. METHODS: A historical cohort study was performed with information gathered from our obstetric, radiologic, and pathology databases. Records from January 2000 to June 2005 were reviewed to identify patients with a diagnosis of placenta previa, low-lying placenta with a prior cesarean delivery, or history of a myomectomy to determine the accuracy of pelvic ultrasonography in the diagnosis of placenta accreta. The records of those considered to be suspicious for placenta accreta and subsequently referred for additional confirmation by MRI were also analyzed. The sonographic and MRI diagnoses were compared with the final pathologic or operative findings or with both. RESULTS: Of the 453 women with placenta previa, previous cesarean delivery and low-lying anterior placenta, or previous myomectomy, 39 had placenta accreta confirmed by pathological examination. Ultrasonography accurately predicted placenta accreta in 30 of 39 of women and correctly ruled out placenta accreta in 398 of 414 without placenta accreta (sensitivity 0.77, specificity 0.96). Forty-two women underwent MRI evaluation because of findings suspicious or inconclusive of placenta accreta by ultrasonography. Magnetic resonance imaging accurately predicted placenta accreta in 23 of 26 cases with placenta accreta and correctly ruled out placenta accreta in 14 of 14 (sensitivity 0.88, specificity 1.0). CONCLUSION: A two-stage protocol for evaluating women at high risk for placenta accreta, which uses ultrasonography first, and then MRI for cases with inconclusive ultrasound features, will optimize diagnostic accuracy. LEVEL OF EVIDENCE: II-3

Effect of predelivery diagnosis in 99 consecutive cases of placenta accreta.

OBJECTIVE: To estimate the effects of prenatal diagnosis and delivery planning on outcomes in patients with placenta accreta. METHODS: A review was performed of all patients with pathologically confirmed placenta accreta at the University of California, San Diego Medical Center from January 1990 to April 2008. Cases were divided into those with and without predelivery diagnosis of placenta accreta. Patients with prenatal diagnosis of placenta accreta were scheduled for planned en bloc hysterectomy without removal of the placenta at 34–35 weeks of gestation after betamethasone administration. Maternal and neonatal outcomes were assessed. RESULTS: Ninety-nine women with placenta accreta were identified, of whom 62 were diagnosed before delivery and 37 were diagnosed intrapartum. Comparing women with predelivery diagnosis with those diagnosed at the time of delivery, there were fewer units of packed red blood cells transfused (4.7±2.2 compared with 6.9±1.8 units, P=.02) and a lower estimated blood loss (2,344±1.7 compared with 2,951±1.8 mL, P=.053), although this trend did not reach statistical significance. Comparison of neonatal outcomes demonstrated a higher rate of steroid administration (65% compared with 16%, P≤.001), neonatal admission to the neonatal intensive care unit (NICU) (86% compared with 60%, P=.005), and longer neonatal hospital stays (10.7±1.9 compared with 6.9±2.1 days, P=.006). Length of NICU stay, rates of respiratory distress syndrome, and surfactant administration did not differ between the groups. CONCLUSION: Predelivery diagnosis of placenta accreta is associated with decreased maternal hemorrhagic morbidity. Planned delivery at 34–35 weeks of gestation in this cohort did not significantly increase neonatal morbidity. LEVEL OF EVIDENCE: II

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

Despite survival gains achieved nearly two decades ago with combination platinum- and taxane-based intravenous chemotherapy, overall survival curves have remained relatively unchanged during the 21st century using newer cytotoxic agents. Although combined intravenous-intraperitoneal (IV-IP) chemotherapy is promising, tolerability remains a significant issue. An emphasis has been placed on exploring dose dense schedules and targeted agents. Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in several solid tumors including ovarian carcinoma. The monoclonal antibody, bevacizumab, binds VEGF, thus preventing activation of the VEGF receptor (VEGFR) leading to inhibition of tumor angiogenesis. To date eight phase 3 randomized controlled trials incorporating anti-angiogenesis therapy in the treatment of newly diagnosed and recurrent ovarian carcinoma have met their primary endpoints. Four of these trials included bevacizumab and were reported from 2010 to 2012. During 2013, the other four studies were reported, each studying one of the following novel anti-angiogenesis agents: pazopanib, cediranib, trebananib, and nintedanib. Importantly, none of these drugs have been approved by the United States Food and Drug Administration (US FDA) for the treatment of ovarian cancer. The purpose of this review will be to highlight both VEGF-dependent and non-VEGF dependent angiogenic pathways in ovarian cancer and discuss the phase 3 experiences and regulatory implications of targeting the tumor microenviroment with anti-angiogenesis therapy.

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.

Flavokawain B, a Kava Chalcone, Induces Apoptosis in Synovial Sarcoma Cell Lines

Synovial sarcomas (SS) are soft tissue sarcomas with poor prognosis, displaying a lack of response to conventional cytotoxic chemotherapy. Although SS cell lines have moderate chemosensitivity to isofamide and doxorubicin therapy, the clinical prognosis is still poor. In this article, we showed that flavokawain B (FKB), a novel chalcone from kava extract, potently inhibits the growth of SS cell lines SYO‐I and HS‐SY‐II through induction of apoptosis. Treatment with FKB increased caspase 8, 9, and 3/7 activity compared to vehicle‐treated controls, indicating that both extrinsic and intrinsic apoptotic pathways were activated. Furthermore, FKB treatment of both cell lines resulted in increased mRNA and protein expression of death receptor‐5 and the mitochondrial pro‐apoptotic proteins Bim and Puma, while down‐regulating the expression of an inhibitor of apoptosis, survivin in a dose‐dependent manner. Our results suggest the natural compound FKB has a pro‐apoptotic effect on SS cell lines. FKB may be a new chemotherapeutic strategy for patients with SS and deserves further investigation as a potential agent in the treatment of this malignancy.

Comparison of computed tomography and magnetic resonance imaging in cervical cancer brachytherapy target and normal tissue contouring.

Objective: To evaluate the differences between target and normal tissue delineation between magnetic resonance imaging (MRI) and computed tomography (CT) in cervical cancer patients and to explore the differences in dosimetry after brachytherapy planning. Methods: High-dose-rate brachytherapy was performed on 11 patients. Planning CT and MRI were performed with tandem and ring in place. The radiation oncologist contoured the rectum, the bladder, the sigmoid, and the high-risk clinical target volume (HR-CTV) on CT and MRI. The values compared between CT and MRI included D90 and D100 to HR-CTV; coronal, sagittal, and axial measurements of HR-CTV; and minimum dose to most irradiated 0.1-, 0.5-, 1.0-, and 2.0-cm3volumes for the organs at risk (OAR). Doses were converted to the equivalent dose in 2 Gy by applying the linear quadratic model. Volume optimization was also performed, and the above parameters were evaluated. Results: Magnetic resonance imaging showed a significantly greater HR-CTV length in the sagittal plane (P = 0.006), with CT showing a greater length in the coronal plane (P = 0.004). The equivalent dose in 2 Gy to 2.0 cm3 for the bladder was greater on CT than MRI (P = 0.041). The remainder of the dose volume histogram values for the OAR were similar between CT and MRI. With volume optimization, no significant differences were seen between HR-CTV dose parameters or doses to OAR. Conclusions: The CT- and MRI-based brachytherapy tissue delineation seems adequate for evaluation of OAR and target tissues, although the shapes of HR-CTV and OAR do differ. When adopting volume-based prescription, these differences may lead to altered target dosing. The clinical impact of these differences seems to be small and may demonstrate that planning with CT, if combined with one MRI, may be sufficient.

Inhibition of enhancer of zeste homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration, and invasion in endometrial cancer cell lines.

Objective To investigate the impact of enhancer of zeste homolog 2 (EZH2) expression on endometrial cancer cell line behavior. Materials and Methods Enhancer of zeste homolog 2 expression levels were compared between the nonmalignant endometrial cell line T-HESC and 3 endometrial cancer cell lines, ECC-1, RL95-2, and HEC1-A. Stable EZH2 knockdown cell lines were created, and the impact on cellular proliferation, migration, and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. Enhancer of zeste homolog 2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and short-hairpin EZH2 cell lines was performed using the Student t test and the Fischer exact test. Results Enhancer of zeste homolog 2 protein expression was increased in all 3 cancer cell lines and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration, and invasion. Down-regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in the G2/M phase. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3 and a concomitant decrease in &bgr;-catenin. Enhancer of zeste homolog 2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion, and nodal metastasis. Conclusions Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation, migration, and invasion in 3 endometrial cancer cell lines as well as with increased stage, grade, depth of invasion, and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted.

Bevacizumab in the treatment of ovarian cancer.

Despite advances in surgical cytoreduction and cytotoxic chemotherapy, ovarian cancer continues to be the leading cause of death in women with gynecologic malignancy. Our understanding of the treatment of ovarian cancer was revolutionized with the discovery of platinum- and taxane-based adjuvant chemotherapy regimens. Since that time however, overall survival has been stable. Given the above, an emphasis has been placed on exploring alternative therapeutics. Recent research efforts have improved our understanding of the molecular biology of ovarian cancer and novel targeted treatment strategies have emerged. The most studied of these agents has been the monoclonal anti-vascular endothelial growth factor antibody bevacizumab. The purpose of this review is to discuss management issues related to the treatment of ovarian cancer, with a focus on the utilization of bevacizumab, summarizing applicable clinical trials, its potential benefits, and reported adverse events.

Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Using in vivo and in vitro studies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector. In vitro experiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.

Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study

BACKGROUND To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER NCT00262847.