Matthew A Powell

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (149)618.74 Total impact

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    ABSTRACT: Residency training in obstetrics and gynecology is being challenged by increasingly stringent regulations and decreased operative experience. We sought to determine the perception of preparedness of incoming gynecologic oncology fellows for advanced surgical training in gynecologic oncology. An online survey was sent to gynecologic oncologists involved in fellowship training in the United States. They were asked to evaluate their most recent incoming clinical fellows in the domains of professionalism, level of independence/graduated responsibility, psychomotor ability, clinical evaluation and management, and academia and scholarship using a standard Likert-style scale. The response rate among attending physicians was 40% (n = 105/260) and 61% (n = 28/46) for program directors. Of those who participated, 49% reported that their incoming fellows could not independently perform a hysterectomy, 59% reported that they could not independently perform 30 min of a major procedure, 40% reported that they could not control bleeding, 40% reported that they could not recognize anatomy and tissue planes, and 58% reported that they could not dissect tissue planes. Fellows lacked an understanding of pathophysiology, treatment recommendations, and the ability to identify and treat critically ill patients. In the academic domain, respondents agreed that fellows were deficient in the areas of protocol design (54%), statistical analysis (54%), and manuscript writing (65%). These results suggest that general Ob/Gyn residency is ineffective in preparing fellows for advanced training in gynecologic oncology and should prompt a revision of the goals and objectives of resident education to correct these deficiencies.
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    ABSTRACT: Objectives: The aim of this study is to evaluate knowledge of obesity-related peri-operative risks in women newly diagnosed with complex atypical hyperplasia and endometrial cancer. Methods: A cross sectional study of patients newly diagnosed with complex atypical hyperplasia or endometrial cancer who underwent preoperative counseling between 2011 and 2014 was conducted, using a 17-item questionnaire. Obesity was defined as body mass index (BMI) of 30 kg/m2 or greater. Bivariate analysis was conducted using Pearson's Chi-Square or Fisher's Exact tests where appropriate and Mann–Whitney U for continuous variables. Results: Of 98 patients recruited, mean age was 58 years, 87% were obese, 83% white, and 51% had grade 1 endometrioid adenocarcinomas. Sixty-four percent of obese women reported that their physicians had discussed surgical risks related to obesity. However, 17% of obese and 42% of non-obese patients responded that they were unsure of the peri-operative risks associated with obesity. There was a substantial lack of understanding among obese patients regarding their increased risks of respiratory problems (29%), thrombo embolism (29%), heart attack (35%), or longer operating time (35%) and hospital stay (47%). However, obese patients were more aware of wound infection risks associated with obesity compared to their non-obese counterparts (72% vs. 28 31%, p = 0.004). Conclusions: Pre-operative counseling for obese women with newly diagnosed endometrial cancer should incorporate more focused education about obesity-related risks. They report being knowledgeable about the risks associated with their surgery; however, more than a quarter are unaware of the impact obesity has on respiratory problems, thrombo embolism, wound infection, heart attack or longer operating time and hospital stay.
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    ABSTRACT: Evaluate effects of a Lynch syndrome universal screening protocol in newly diagnosed endometrial cancers on subsequent genetic counseling (GC) and germline testing (GT) referral and acceptance rates.
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    ABSTRACT: Clinical validation of a chemoresponse assay was recently published, demonstrating a significant increase in overall survival in recurrent ovarian cancer patients treated with therapies to which their tumor was sensitive in the assay. The current study investigates the cost effectiveness of using the assay at the time of ovarian cancer recurrence from the payer’s perspective.Methods Using a Markov state transition model, patient characteristics and survival data from the recent clinical study, the cumulative costs over the study horizon (71 months) for both the baseline (no assay) and intervention (assay consistent, hypothetical) cohorts were evaluated.ResultsThe assay consistent cohort had an incremental cost effectiveness ratio (ICER) of $6,206 per life year saved (LYS), as compared to the baseline cohort. Cost-effectiveness was further demonstrated in platinum-sensitive and platinum-resistant populations treated with assay-sensitive therapies, with ICERs of $2,773 per LYS and $2,736 per LYS, respectively.Conclusions Use of a chemoresponse assay to inform treatment decisions in recurrent ovarian cancer patients has the potential to be cost-effective, in both platinum-sensitive and platinum-resistant patients.
    Gynecologic Oncology 11/2014; 136(1). DOI:10.1016/j.ygyno.2014.11.019 · 3.69 Impact Factor
  • Gynecologic Oncology 11/2014; 135(2). DOI:10.1016/j.ygyno.2014.07.010 · 3.69 Impact Factor
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    ABSTRACT: Objective: This study compares surgical and survival outcomes of women with stage IV uterine serous carcinoma (USC) treated with neoadjuvant chemotherapy (NAC) and interval cytoreduction to women treated with primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy. Methods: This retrospective dual cohort study included women diagnosed with stage IV USC at a single academic institution. Kruskal-Wallis and Fisher exact tests were used to compare demographics and surgical outcomes. Progression-free survival (PFS) and overall survival (OS) were estimated by using Kaplan-Meier methods. Comparison between study groups was tested by log-rank statistics. Results: Ten women with stage IV USC who received NAC and 34 who underwent PCS met inclusion criteria. Neoadjuvant chemotherapy patients had a lower mean body mass index and were more often African American. Compared with PCS, the NAC cohort had shorter mean operative times (137 +/- 66 vs 203 +/- 80 minutes, P = 0.025) and were discharged from the hospital earlier (median length of stay, 3 vs 5 days; P = 0.002). Rates of debulking to no gross residual disease (70% NAC vs 32.3% PCS) or less than 1 cm of disease (30% NAC vs 50% PCS) did not differ (P=0.10). Median follow-up time was 17.5 months. There was no difference in median PFS (10.4 vs 12 months, P = 0.29) or OS (17.3 vs 20.7 months, P = 0.23) for NAC and PCS cohorts. Conclusions: Women receiving NAC for stage IV USC had shorter surgeries and hospital stays than did those receiving PCS. There was no difference in PFS or OS, although our sample size was small. Neoadjuvant chemotherapy may be an appropriate therapy for select patients with advanced-stage USC.
    International Journal of Gynecological Cancer 10/2014; 25(1). DOI:10.1097/IGC.0000000000000321 · 1.95 Impact Factor
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    ABSTRACT: Background. Ovarian cancer (OC) requires complex multidisciplinary care with wide variations in outcome. We sought to determine the impact of institutional and process of care factors on overall survival (OS) and delivery of guideline care nationally. Methods. This was a retrospective cohort study of primary OC diagnosed from 1998 to 2007 using the National Cancer Data Base (NCDB) capturing 80% of all U.S. cases. Patient- (demographics, comorbidities, stage/grade), process of care (adherence to guidelines) and institutional- (facility type, case volume) factors were evaluated. Primary outcomes were OS and delivery of guideline therapy. Multivariable logistic regression and Cox proportional hazards models were used for analysis. Results. We analyzed 96,802 consecutive cases. Five-year OS was 84%, 66.3%, 32% and 15.7% for stages I, II, III and IV, respectively. The annual mean facility case volumes varied by cancer center type (range: 5.7 to 26.7), with 25% of cases spread over 65% of centers - all treating fewer than 8 cases. Overall, 56% of cases received nonguideline care. Low facility case volume and higher comorbidity index independently predicted non-guideline care; high volume centers were less likely to deliver non-guideline care (OR: 0.44, 95% CI: 0.41-0.47). Delivery of non-guideline care (OR: 1.4, 95% Cl: 1.36-1.44), and higher facility case volume (OR: 0.91, 95% CI: 0.86-0.96) were both independent predictors of OS. Conclusions. Delivery of guideline care and facility case volume are important drivers of overall survival. Most cancer centers treat very few women with OC. National efforts should focus on improved access to centers with expertise in OC and ensuring delivery of guideline care.
    Gynecologic Oncology 10/2014; 136(1). DOI:10.1016/j.ygyno.2014.10.023 · 3.69 Impact Factor
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    ABSTRACT: Background Sarcopenia or loss of skeletal muscle mass is an objective measure of frailty associated with functional impairment and disability. This study aimed to examine the impact of sarcopenia on surgical complications and survival outcomes in patients with endometrial cancer. Methods A retrospective review of endometrial cancer patients who underwent surgery between 2005 and 2009 was performed. Sarcopenia was assessed on preoperative computed tomography (CT) scan by measurement of the lumbar psoas muscle cross-sectional area and defined as any value below the median (2). Sarcopenic obesity was defined as sarcopenia plus a body mass index (BMI) of 30 kg/m2 or higher. Microsatellite instability (MSI) was analyzed using the National Cancer Institute (NCI) consensus markers and tumor from hysterectomy specimens. Results Of 122 patients, 27 (22 %) met the criteria for sarcopenic obesity. Sarcopenic patients were older than patients with normal muscle mass (mean age, 69.7 vs. 62.1 years; p 2; p p = 0.048). Sarcopenia was not associated with tumor MSI, hospital stay, 90-day readmission rate, or early/late complications. Patients with sarcopenia had a shorter recurrence-free survival than nonsarcopenic patients (median 23.5 vs. 32.1 months; log-rank p = 0.02), but did not differ in terms of overall survival (log-rank p = 0.25). After adjustment for race, BMI, lymphocyte count, and tumor histology, sarcopenia was associated with a fourfold shorter recurrence-free survival (adjusted hazard ratio [HRadj], 3.99; 95 % confidence interval [CI], 1.42-11.3). Conclusions Sarcopenia has an impact on recurrence-free survival, but does not appear to have a negative impact on surgical outcomes or overall survival among endometrial cancer patients who undergo preoperative CT scan.
    Annals of Surgical Oncology 09/2014; 22(3). DOI:10.1245/s10434-014-4040-8 · 3.94 Impact Factor
  • Sara S Lange, Akiva P Novetsky, Matthew A Powell
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    ABSTRACT: Uterine sarcomas are a heterologous group of rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognoses. Management of uterine sarcomas including leiomyosarcoma and endometrial stromal sarcoma are reviewed here, with additional discussions regarding high-grade undifferentiated sarcoma and adenosarcoma. Uterine carcinosarcomas are currently staged and treated similar to high-grade epithelial endometrial carcinomas, thus will not be discussed in this review. Gemcitabine/docetaxel with adriamycin holds promise for the treatment of leiomyosarcoma, but currently, limited advancements have been made in discovering targeted therapies to these tumors. Continued translational research in both medical oncology and gynecologic oncology is necessary to forward the development of novel and targeted therapeutic agents in the treatment of sarcoma. Enrollment of these patients in clinical trials is encouraged, and will allow for the development of safer and more effective therapies.
    Discovery medicine 09/2014; 18(98):133-40. · 3.50 Impact Factor
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    ABSTRACT: Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). Patients and Methods Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed.
    Gynecologic Oncology 07/2014; 135(1). DOI:10.1016/j.ygyno.2014.07.083 · 3.69 Impact Factor
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    ABSTRACT: Background:Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well.Methods:Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch).Results:Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50-0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66-0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies.Conclusions:These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives.British Journal of Cancer advance online publication, 8 July 2014; doi:10.1038/bjc.2014.375 www.bjcancer.com.
    British Journal of Cancer 07/2014; DOI:10.1038/bjc.2014.375 · 4.82 Impact Factor
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    ABSTRACT: Objectives. Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. Methods. Women with a body mass index (BMI) >= 30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Camper's fascia, closure of Camper's fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound,complications. Patients were compared using a multivariable model to a historical grdup of obese patients to assess the efficacy of the care pathway. Results. 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p < 0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). Conclusion. This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2).
    Gynecologic Oncology 06/2014; 134(2). DOI:10.1016/j.ygyno.2014.06.012 · 3.69 Impact Factor
  • Gynecologic Oncology 06/2014; 133:161. DOI:10.1016/j.ygyno.2014.03.424 · 3.69 Impact Factor
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    ABSTRACT: Objective To examine the patterns of care, predictors, and impact of chemotherapy on survival in elderly women diagnosed with early-stage uterine carcinosarcoma. Methods The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify women 65 years or older diagnosed with stage I-II uterine carcinosarcoma from 1991 through 2007. Multivariable logistic regression and Cox-proportional hazards models were used for statistical analysis. Results A total of 462 women met the eligibility criteria; 374 had stage I, and 88 had stage II uterine carcinosarcoma. There were no appreciable differences over time in the percentages of women administered chemotherapy for early stage uterine carcinosarcoma (14.7% in 1991–1995, 14.9% in 1996–2000, and 17.9% in 2001–2007, P = 0.67). On multivariable analysis, the factors positively associated with receipt of chemotherapy were younger age at diagnosis, higher disease stage, residence in the eastern part of the United States, and lack of administration of external beam radiation (P < 0.05). In the adjusted Cox-proportional hazards regression models, administration of three or more cycles of chemotherapy did not reduce the risk of death in stage I patients (HR: 1.45, 95% CI: 0.83-2.39) but was associated with non-significant decreased mortality in stage II patients (HR: 0.83, 95% CI: 0.32-1.95). Conclusions Approximately 15-18% of elderly patients diagnosed with early-stage uterine carcinosarcoma were treated with chemotherapy. This trend remained stable over time, and chemotherapy was not associated with any significant survival benefit in this patient population.
    Gynecologic Oncology 06/2014; DOI:10.1016/j.ygyno.2014.02.021 · 3.69 Impact Factor
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    ABSTRACT: Combination chemotherapy and radiation are used for adjuvant treatment of stage III-IV endometrial cancer. The goal of this study was to review the treatment duration, toxicity, and survival for patients treated with concomitant chemotherapy and radiation. Women with stage III-IV endometrial cancer treated with concurrent chemotherapy and radiation between 2006 and 2013 were included. Toxicities were classified per CTCAE v3.0 and RTOG/EORTC late radiation morbidity scoring. Descriptive statistics were used to quantify treatment and toxicities. Kaplan-Meier method was used to estimate survival. Fifty-one patients met our inclusion criteria. Median age was 60 (range 33-85). Thirty-six patients (70.6%) had endometrioid histology, 13 patients (25.5%) had serous, clear cell, or mixed histology, and two women (3.9%) had carcinosarcoma. Forty-eight patients had stage III disease and three patients were stage IVB. Mean treatment duration was 107±19days. Forty-two patients received all planned chemotherapy, and sixteen patients required a dose reduction. Thirty-four patients (66.7%) experienced grade 3-4 toxicities, the majority of which were hematologic. There were no deaths related to therapy. Eighty-six percent of patients received leukocyte growth factors, and 25% of patients received a blood transfusion. Seven late grade 3-4 complications occured: four gastrointestinal, two genitourinary, and one patient had ongoing neuropathy. Median progression-free survival was 42.8months (range 4.4-81.5months) and median overall survival was 44.9months (range 5.1-82.6months). Three-year overall survival was 80%. Concomitant chemotherapy and radiation is an adequately tolerated treatment modality that allows for shorter treatment duration.
    Gynecologic Oncology 05/2014; 134(1). DOI:10.1016/j.ygyno.2014.05.002 · 3.69 Impact Factor
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    ABSTRACT: The objectives of this study are to identify the characteristics of febrile gynecologic oncology patients and to evaluate the utility of common diagnostic procedures used to assess the etiologies of their fevers. Retrospective data were collected for 200 consecutive patients admitted to the gynecologic oncology service at 1 institution between January 2008 and December 2012 for a diagnosis of fever. Data were collected using contingency tables, and the χ test was used as appropriate. Of the patients admitted for evaluation of fever, 142 (71%) of 200 had a documented fever during hospitalization. The most common etiologies of fever in this population were urinary tract infections (28%) and bloodstream infections (27%), whereas 24% of those admitted for fever did not have a source identified. Abdominal/pelvic computed tomography (CT) scans established the etiology of fever in 53 (60%) of the 89 patients tested, whereas chest x-ray and chest CT were diagnostic for 6% and 21%, respectively. Blood and urine cultures were diagnostic in 29% and 32% of cases, respectively. Patients admitted within 30 days of surgery had a higher percentage of wound infections (38% vs 10%, P < 0.001) as compared with those admitted for more than 30 days after surgery. The initial evaluation of the febrile gynecologic oncology patient without obvious source by history and examination should include urinalysis with reflex culture and blood cultures. Abdominopelvic and chest CT may be useful when fever persists and initial assessment is unrevealing. Chest x-ray is commonly done but infrequently diagnostic. Wound exploration may be important in patients with fevers for more than 30 days after surgery.
    International Journal of Gynecological Cancer 05/2014; DOI:10.1097/IGC.0000000000000129 · 1.94 Impact Factor
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    ABSTRACT: Intensity-modulated radiation therapy (IMRT) is frequently utilized in the treatment of cervical cancer. Our study compared instances of pelvic fractures, osteonecrosis, and osteomyelitis posttreatment with conventional radiation therapy (RT) versus IMRT in patients with cervical carcinomas. Eighty-three patients primarily treated with IMRT were case matched with 83 historical control subjects treated with conventional RT. Pretreatment and posttreatment computed tomography scans were reviewed. Logistic regression analysis was utilized to examine the effects of treatment type (conventional RT vs IMRT) on the occurrence of posttreatment pelvic bony structure complications while adjusting for confounders. In the IMRT group, 3 (4%) of 83 patients developed posttreatment sacral fractures (median follow-up, 51 months). In the conventional RT group, there were 14 pelvic girdle complications (17%): 9 fractures, 2 cases of osteonecrosis, and 3 cases of osteomyelitis (median follow-up, 43.5 months; odds ratio, 4.49 for conventional vs IMRT groups, P = 0.01; 95% confidence interval, 1.4-14.1). In addition, there were 4 cases of posttreatment osteoporosis in the conventional RT group. All patients with complications in the IMRT group and 11 of 13 in the conventional RT group were symptomatic. Intensity-modulated radiation therapy is associated with a lower risk for pelvic girdle complications than conventional RT.
    International Journal of Gynecological Cancer 03/2014; DOI:10.1097/IGC.0000000000000117 · 1.94 Impact Factor
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    ABSTRACT: Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy. In the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo. We have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-[cyrillic small letter ka with descender]B activation and TNFalpha-dependent cell death. Our findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.
    Molecular Cancer 03/2014; 13(1):50. DOI:10.1186/1476-4598-13-50 · 5.40 Impact Factor
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    ABSTRACT: The targeted delivery of cancer therapeutics represents an ongoing challenge in the field of drug development. TRAIL is a promising cancer drug but its activity profile could benefit from a cancer-selective delivery mechanism, which would reduce potential side effects and increase treatment efficiencies. We recently developed the novel TRAIL-based drug platform TR3, a genetically fused trimer with the capacity for further molecular modifications such as the addition of tumor-directed targeting moieties. MUC16 (CA125) is a well characterized biomarker in several human malignancies including ovarian, pancreatic and breast cancer. Mesothelin is known to interact with MUC16 with high affinity. In order to deliver TR3 selectively to MUC16-expressing cancers, we investigated the possibility of targeted TR3 delivery employing the high affinity mesothelin/MUC16 ligand/receptor interaction. Using genetic engineering, we designed the novel cancer drug Meso-TR3, a fusion protein between native mesothelin and TR3. The recombinant proteins were produced with mammalian HEK293T cells. Meso-TR3 was characterized for binding selectivity and killing efficacy against MUC16-positive cancer cells and controls that lack MUC16 expression. Drug efficacy experiments were performed in vitro and in vivo employing an intraperitoneal xenograft mouse model of ovarian cancer. Similar to soluble mesothelin itself, the strong MUC16 binding property was retained in the Meso-TR3 fusion protein. The high affinity ligand/receptor interaction was associated with a selective accumulation of the cancer drug on MUC16-expressing cancer targets and directly correlated with increased killing activity in vitro and in a xenograft mouse model of ovarian cancer. The relevance of the mesothelin/MUC16 interaction for attaching Meso-TR3 to the cancer cells was verified by competitive blocking experiments using soluble mesothelin. Mechanistic studies using soluble DR5-Fc and caspase blocking assays confirmed engagement of the extrinsic death receptor pathway. Compared to non-targeted TR3, Meso-TR3 displayed a much reduced killing potency on cells that lack MUC16. Soluble Meso-TR3 targets the cancer biomarker MUC16 in vitro and in vivo. Following attachment to the tumor via surface bound MUC16, Meso-TR3 acquires full activation with superior killing profiles compared to non-targeted TR3, while its bioactivity is substantially reduced on cells that lack the tumor marker. This prodrug phenomenon represents a highly desirable property because it has the potential to enhance cancer killing with fewer side-effects than non-targeted TRAIL-based therapeutics. Thus, further exploration of this novel fusion protein is warranted as a possible therapeutic for patients with MUC16-positive malignancies.
    BMC Cancer 01/2014; 14(1):35. DOI:10.1186/1471-2407-14-35 · 3.32 Impact Factor
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    ABSTRACT: Recent reports have suggested that uterine manipulators can induce lymphovascular space involvement (LVSI) by endometrial cancer in laparoscopic hysterectomy specimens. The prognostic significance of this phenomenon known as "vascular pseudo invasion" remains elusive. The authors conducted a retrospective, single institution study of patients who underwent initial surgery for grade 1 and grade 2 endometrioid endometrial cancers with LVSI. Cases were stratified by surgical approach (laparoscopy vs laparotomy). Clinicopathologic and procedure characteristics as well as outcome data were analyzed. Univariate and multivariate analyses were performed. Disease-free survival (DFS) was analyzed using the Kaplan-Meier product limit method. A total of 104 cases (20 laparoscopic, 84 laparotomy) were analyzed. Mean age (65 vs 64 years, respectively), stage distribution, mean number of lymph nodes sampled (18 vs 21, respectively) and use of adjuvant therapy was similar for both groups (p > 0.05). Mean body mass index (BMI) was 30 vs 35 kg/m2, respectively (p = 0.002). Mean follow up was 24 months (range 0.1-102). Univariate analysis demonstrated that LVSI in the laparoscopic setting was associated with worse DFS (p = 0.002). After adjusting for grade the risk of recurrence remained higher for laparoscopic cases (HR: 15.7, 95% CI 1.7-140.0, p = 0.014). Adjusted risk of recurrence associated with LVSI is higher in cases approached laparoscopically arguing against the concept of "vascular pseudo invasion" associated with the use of uterine manipulators and balloons. LVSI should be regarded as a serious risk factor and taken into account for triage to adjuvant therapies, even in laparoscopically treated early-stage endometrial cancer.
    European journal of gynaecological oncology 01/2014; 35(1):7-10. DOI:10.1016/j.ygyno.2010.12.229 · 0.60 Impact Factor

Publication Stats

3k Citations
618.74 Total Impact Points

Institutions

  • 2002–2015
    • Washington University in St. Louis
      • Department of Obstetrics and Gynecology
      San Luis, Missouri, United States
  • 2012
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
  • 2005–2009
    • Barnes Jewish Hospital
      • Department of Obstetrics and Gynecology
      San Luis, Missouri, United States
    • Baylor University
      Waco, Texas, United States
  • 2007
    • Temple University
      • Department of Obstetrics, Gynecology and Reproductive Sciences
      Filadelfia, Pennsylvania, United States
  • 2006
    • University of Alabama at Birmingham
      • Department of Obstetrics and Gynecology
      Birmingham, Alabama, United States