Geographic disparities in the distribution of the U.S. gynecologic oncology workforce: A Society of Gynecologic Oncology study.

A recent ASCO workforce study projects a significant shortage of oncologists in the U.S. by 2020, especially in rural/underserved (R/US) areas. The current study aim was to determine the patterns of distribution of U.S. gynecologic oncologists (GO) and to identify provider-based attitudes and barriers that may prevent GOs from practicing in R/US regions. U.S. GOs (n = 743) were electronically solicited to participate in an on-line survey regarding geographic distribution and participation in outreach care. A total of 320 GOs (43%) responded; median age range was 35-45 years and 57% were male. Most practiced in an urban setting (72%) at a university hospital (43%). Only 13% of GOs practiced in an area with a population < 50,000. A desire to remain in academics and exposure to senior-level mentorship were the factors most influencing initial practice location. Approximately 50% believed geographic disparities exist in GO workforce distribution that pose access barriers to care; however, 39% "strongly agreed" that cancer patients who live in R/US regions should travel to urban cancer centers to receive care within a center of excellence model. GOs who practice within 50 miles of only 0-5 other GOs were more likely to provide R/US care compared to those practicing within 50 miles of ≥ 10 GOs (p < 0.0001). Most (39%) believed the major barriers to providing cancer care in R/US areas were volume and systems-based. Most also believed the best solution was a hybrid approach, with coordination of local and centralized cancer care services. Among GOs, a self-reported rural-urban disparity exists in the density of gynecologic oncologists. These study findings may help address barriers to providing cancer care in R/US practice environments.

Is age a prognostic biomarker for survival among women with locally advanced cervical cancer treated with chemoradiation? An NRG Oncology/Gynecologic Oncology Group ancillary data analysis.

OBJECTIVE: To determine the effect of age on completion of and toxicities following treatment of local regionally advanced cervical cancer (LACC) on Gynecologic Oncology Group (GOG) Phase I-III trials. METHODS: An ancillary data analysis of GOG protocols 113, 120, 165, 219 data was performed. Wilcoxon, Pearson, and Kruskal-Wallis tests were used for univariate and multivariate analysis. Log rank tests were used to compare survival lengths. RESULTS: One-thousand-three-hundred-nineteen women were included; 60.7% were Caucasian, 15% were age 60-70years and an additional 5% were >70; 87% had squamous histology, 55% had stage IIB disease and 34% had IIIB disease. Performance status declined with age (p=0.006). Histology and tumor stage did not significantly differ. Number of cycles of chemotherapy received, radiation treatment time, nor dose modifications varied with age. Notably, radiation protocol deviations and failure to complete brachytherapy (BT) did increase with age (p=0.022 and p<0.001 respectively). Only all grade lymphatic (p=0.006) and grade≥3 cardiovascular toxicities (p=0.019) were found to vary with age. A 2% increase in the risk of death for every year increase >50 for all-cause mortality (HR 1.02; 95% CI, 1.01-1.04) was found, but no association between age and disease specific mortality was found. CONCLUSION: This represents a large analysis of patients treated for LACC with chemo/radiation, approximately 20% of whom were >60years of age. Older patients, had higher rates of incomplete brachytherapy which is not explained by collected toxicity data. Age did not adversely impact completion of chemotherapy and radiation or toxicities.

Primary and acquired platinum-resistance among women with high grade serous ovarian cancer.

OBJECTIVE: Women with primary platinum resistant (PPR) high grade serous ovarian cancer (HGSOC) are known to have a poor prognosis. Less is known regarding outcomes in patients with acquired platinum resistance (APR). The goal of this study was to evaluate survival in both PPR and APR patients. METHODS: A retrospective review of HGSOC patients diagnosed between 2000 and 2010 was performed. Descriptive statistics summarized clinical characteristics and demographics. The Kaplan-Meier method estimated progression free survival (PFS) and overall survival (OS). The association of OS and clinical factors was modeled using Cox proportional-hazards. RESULTS: Of the 330 patients identified, 81 (25%) had PPR. Of the remaining women, 55 (22%) developed APR. Median PFS of PPR patients was 4.2months and median OS was 17.8months. On multivariate analysis, the number of biologic agents received was the only predictor of OS. Patients with APR had a median PFS of 14.2months and a median OS of 56months. OS from the date of platinum resistance was 21.9months, though this was not different than PPR patients (p=0.19). Multivariate analysis found cancer stage and clinical trial participation to be associated with OS. CONCLUSIONS: Platinum resistance confers a poor prognosis in the APR and PPR setting. The number of biologic agents received is the strongest predictor of OS among women with PPR. Cancer stage and clinical trial participation predicts OS in patients with APR. Providing opportunities to participate in clinical trials, especially those involving targeted therapy, should be a priority in these populations.

Role of TGF-ß signaling in uterine carcinosarcoma.

Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGFß) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGFß at 19q13.1 prompted us to investigate the role of TGFß signaling in UCS.Here we demonstrated the components of TGFß pathway are expressed and functional in UCS. TGFß-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGFß receptor I (TGFßR-I) or TGFß receptor I/II (TGFßR-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGFß-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGFß-I. Inhibition of NFAT-1 or TGFßR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGFß the TGFßR-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGFßR-I could be efficacious in treatment of UCS.

Central nervous system metastasis in gynecologic cancer: symptom management, prognosis and palliative management strategies.

INTRODUCTION: CNS metastasis (CNSmet) with gynecologic malignancy (GM) is associated with poor prognosis and symptom burden. Two prognostic indices, the recursive partitioning analysis (RPA) and graded prognostic assessment (GPA), used in other solid tumors to guide intervention options were evaluated among GM patients. METHODS: Retrospective chart review was performed to identify patients with primary GM diagnosed with CNSmet from 2005-2014. RPA and GPA were applied and evaluated for goodness of fit. Long-term survivors (LTS) were those with survival time from CNSmet ≥9 months. RESULTS: 35 patients were identified with median age of 62 years (range, 41-78). The majority had ovarian cancer (54%). Median survival was 4.5 months (0.1-25.9), and median time from initial diagnosis was 2.6 years (0-19.6). Presenting symptoms varied but headache (57%) and altered mental status (23%) were most common. 37% had a solitary CNS lesion, 31% had 2-8, and 31% >8. 57% were treated with WBRT, 14% with stereotactic radiosurgery (SRS), and 20% with combinations of treatments, and 2 elected for hospice. 27% (9/33) of the patients were LTS. The GPA was not significantly associated with patient outcome (p=0.46). The RPA predicted time to death (p=.0010). CONCLUSION: Prognostic indices used to guide therapeutic interventions perform poorly in GM. Detection and aggressive symptom management are critical in maintaining QOL. Multidisciplinary consultation is critical to optimize outcomes and symptom control.

Anti-angiogenic therapy versus dose-dense paclitaxel therapy for frontline treatment of epithelial ovarian cancer: review of phase III randomized clinical trials.

The investigation of anti-angiogenic agents and dose-dense paclitaxel therapy in epithelial ovarian cancer is an active area of research. To date several phase III trials have shown both approaches to be effective strategies for the frontline treatment of ovarian cancer over standard every 21 day chemotherapy alone. However, most of the improvement is seen only in progression-free survival, with added toxicity (e.g., hypertension, diarrhea, sensory neuropathy, fatigue). Subset analyses based on clinical predictors (e.g., residual disease) have been able to identify patients more likely to benefit from anti-angiogenic agents. And more recently, molecular profiling of tumor genetics has shown similar promising results. Ongoing research will help enhance our ability to match patients to therapeutic strategies most likely to optimize outcomes and minimize risk.

Minimally invasive surgery for endometrial cancer: does operative start time impact surgical and oncologic outcomes?

OBJECTIVE: Recent literature in ovarian cancer suggests differences in surgical outcomes depending on operative start time. We sought to examine the effects of operative start time on surgical outcomes for patients undergoing minimally invasive surgery for endometrial cancer. METHODS: A retrospective review was conducted of patients undergoing minimally invasive surgery for endometrial cancer at a single institution between 2000 and 2011. Surgical and oncologic outcomes were compared between patients with an operative start time before noon and those with a surgical start time after noon. RESULTS: A total of 380 patients were included in the study (245 with start times before noon and 135 with start times after noon). There was no difference in age (p=0.57), number of prior surgeries (p=0.28), medical comorbidities (p=0.19), or surgical complexity of the case (p=0.43). Patients with surgery starting before noon had lower median BMI than those beginning after noon, 31.2 vs. 35.3 respectively (p=0.01). No significant differences were observed for intraoperative complications (4.4% of patients after noon vs. 3.7% of patients before noon, p=0.79), estimated blood loss (median 100 cc vs. 100 cc, p=0.75), blood transfusion rates (7.4% vs. 8.2%, p=0.85), and conversion to laparotomy (12.6% vs. 7.4%, p=0.10). There was no difference in operative times between the two groups (198 min vs. 216.5 min, p=0.10). There was no association between operative start time and postoperative non-infectious complications (11.9% vs. 11.0%, p=0.87), or postoperative infections (17.8% vs. 12.3%, p=0.78). Length of hospital stay was longer for surgeries starting after noon (median 2 days vs. 1 day, p=0.005). No differences were observed in rates of cancer recurrence (12.6% vs. 8.8%, p=0.39), recurrence-free survival (p=0.97), or overall survival (p=0.94). CONCLUSION: Our results indicate equivalent surgical outcomes and no increased risk of postoperative complications regardless of operative start time in minimally invasive endometrial cancer staging, despite longer length of hospital stay for surgeries beginning after noon.

The survival detriment of venous thromboembolism with epithelial ovarian cancer.

OBJECTIVE: The aim of this study is to evaluate the effect of venous thromboembolism (VTE) chronology with respect to surgery on survival with epithelial ovarian cancer (EOC). METHODS: An IRB approved, retrospective review was performed of patients treated for Stage I-IV EOC from 1996 to 2011. Cox proportional hazards model was used to assess associations between VTE and the primary outcomes of progression free survival (PFS) and overall survival (OS). SAS 9.3 was used for statistical analyses. RESULTS: 586 patients met study criteria. Median age was 63 years (range, 17-94); median BMI was 27.1 kg/m(2) (range, 13.7-67.0). Most tumors were high grade serous (68.3%) and advanced stage (III/IV, 75.4%). 3.7% had a preoperative VTE; 13.2% had a postoperative VTE. Upon multivariate analysis adjusting for age, stage, histology, performance status, and residual disease, preoperative VTE was predictive of OS (HR 3.1, 95% CI: 1.6-6.1, p=0.001) but not PFS (p=0.55). Postoperative VTE was associated with shorter PFS (HR 1.45, 95% CI: 1.04-2.02, p=0.03) and OS (HR 1.8, 95% CI: 1.3-2.6, p=0.001). When VTE timing was modeled, preoperative VTE (HR 3.5, 95% CI: 1.8-6.9, p<0.001) and postoperative VTE after primary therapy (HR 2.3, 95% CI: 1.4-3.6, p=0.001) were predictive of OS. CONCLUSION: Preoperative and postoperative VTE appear to have a detrimental effect on OS with EOC. When modeled as a binary variable, postoperative VTE attenuated PFS; however, when VTE timing was modeled, postoperative VTE was not associated with PFS. It is unclear whether VTE is an inherent poor prognostic marker or if improved VTE prophylaxis and treatment may enable similar survival to patients without these events.

Measurements of adiposity as clinical biomarkers for first-line bevacizumab-based chemotherapy in epithelial ovarian cancer.

OBJECTIVE: There is a lack of reliable indicators to predict who will benefit most from anti-angiogenic therapy, such as bevacizumab. Recognizing obesity is associated with increased levels of VEGF, the main target of bevacizumab, we sought to assess if adiposity, measured in terms of BMI, subcutaneous fat area (SFA), and visceral fat area (VFA) was prognostic. METHODS: Reviewed 46 patients with advanced EOC who received primary treatment with bevacizumab-based chemotherapy (N=21) or chemotherapy alone (N=25) for whom complete records, CT prior to the first cycle of chemo, and serum were available. CT was used to measure SFA and VFA by radiologists blinded to outcomes. ELISA was used to measure serum levels of VEGF and angiopoietin-2 in the bevacizumab group. RESULTS: BMI, SFA, and VFA were dichotomized using the median and categorized as "high" or "low". In the bevacizumab group median PFS was shorter for patients with high BMI (9.8 vs. 24.7months, p=0.03), while in the chemotherapy group median PFS was similar between high and low BMI (17.6 vs. 11.9months, p=0.19). In the bevacizumab group patients with a high BMI had higher median levels of VEGF and angiopoietin-2, 371.9 vs. 191.4pg/ml (p=0.05) and 45.9 vs. 16.6pg/ml (p=0.09) respectively. On multivariate analysis neither BMI, SFA, nor VFA were associated with PFS (p=0.13, p=0.86, p=0.16 respectively) or OS (p=0.14, p=0.93, p=0.28 respectively) in the chemotherapy group. However, in the bevacizumab group BMI was significantly associated with PFS (p=0.02); accounting for confounders adjusted HR for high vs. low BMI was 5.16 (95% CI 1.31-20.24). Additionally in the bevacizumab group SFA was significantly associated with OS (p=0.03); accounting for confounders adjusted HR for high vs. low SFA was 3.58 (95% CI 1.12-11.43). CONCLUSION: Results provide the first evidence in EOC that patients with high levels of adiposity may not derive benefit from bevacizumab and that measurements of adiposity are likely to be a useful biomarker.

Referrals to phase I clinical trials in a gynecologic oncology unit.

OBJECTIVES: Previous reviews of phase I clinical trials report limited response rates. Development of novel biologic agents and trials designs have increased these rates. A contemporary appraisal of phase I clinical trials in gynecologic malignancies could help validate these findings. METHODS: Retrospectively reviewed records for 410 patients with gynecologic malignancies treated in a phase I unit, January 1999 to October 2012. Patient characteristics and treatment outcomes were abstracted and analyzed. RESULTS: Patients enrolled in 43 different phase I trials, 17 phase Ia, 17 phase Ib dose escalation and 9 dose expansion. 9 trials (21%) investigated unique cytotoxic delivery methods, 15 (35%) conventional cytotoxic plus novel agents and 19 (44%) novel agents alone. For patients treated in the first-line setting, 90 (74.4%) achieved CR, 20 (16.5%) PR, 9 (7.4%) SD and 2 (1.7%) PD, yielding an overall response rate of 90.9%. In patients treated for recurrent disease, 2 (1.6%) achieved CR, 11 (8.9%) PR, 57 (46.0%) SD and 54 (43.5%) PD, yielding a response rate of 11% and an overall clinical benefit rate of 57%. Response rate for molecular targeted therapies was 11.5% with an overall clinical benefit rate of 46.2%. Patients with prior anti-angiogenic exposure had comparable median PFS to those who had not been previously exposed (3.5 vs. 4.0 months, p = 0.29). CONCLUSIONS: Results support referral of gynecologic cancer patients for phase I clinical trials. Patients with advanced, heavily pretreated disease fare at least as well as they do on phase II trials and a proportion of them can attain an objective response or stabilization of their disease.

Endometriosis for the colorectal surgeon.

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. Although the exact pathophysiology is unclear, endometriosis is a well-known cause of pelvic pain and infertility in reproductive-aged women. Endometriosis can have extrapelvic manifestations relevant for colorectal surgeons to appreciate, such as cyclic constipation, diarrhea, hematochezia, and dyschezia. The treatment of endometriosis involves a combination of medical and surgical interventions where close collaboration between the gynecologist and colorectal surgeon can help achieve prolonged periods of symptom remission.

Neuromuscular organization of the superior longitudinalis muscle in the human tongue. 1. Motor endplate morphology and muscle fiber architecture.

Proper tongue function is essential for respiration and mastication, yet we lack basic information on the anatomical organization underlying human tongue movement. Here we use microdissection, acetylcholinesterase histochemistry, silver staining of nerves, alpha bungarotoxin binding and immunohistochemistry to describe muscle fiber architecture and motor endplate (MEP) distribution of the human superior longitudinalis muscle (SL). The human SL extends from tongue base to tongue tip and is composed of fiber bundles that range from 2.8 to 15.7 mm in length. Individual muscle fibers of the SL range from 1.2 to 17.3 mm in length (1.3-18.2% of muscle length). Seventy-one percent of SL fibers have blunt-blunt terminations; the remainder have blunt-taper terminations. Multiple MEPs are present along SL length and dual MEPs are present on some muscle fibers. These data demonstrate that the human SL is a muscle of "in-series" design. We suggest that SL motor units are organized to innervate specific regions of the tongue body and that activation of SL motor units according to anteroposterior location is one strategy employed by the nervous system to control tongue shape and tongue movement.