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Figure S6 shows the association of circulating cytokine levels with objective clinical response.

Purpose:A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment.Patients and Methods:Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot.Results:Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival.Conclusions:Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Low anterior rectosigmoid resection for a gynecologic disease is usually performed in concert with other procedures and can result in significant morbidity should anastomotic complication occur. This study examined surgical outcomes of side-to-end reanastomosis after low anterior resection (STELAR) performed by gynecologic oncology service.This is a case series examining consecutive patients who underwent STELAR for gynecologic indications by a single gynecologic oncology group from 2009 to 2018. Prospectively collected institutional surgical database was searched for STELAR, and standard descriptive statistics were used to describe intraoperative and postoperative complications specific to reanastomosis.A total of 69 women underwent STELAR, with median age and body mass index of 54 years and 24 kg/mSide-to-end reanastomosis may be a safe and feasible procedure to accomplish low rectosigmoid anastomosis in women with gynecologic disease.

To examine population-level trends, characteristics, and outcomes of patients with stage IVB endometrial cancer who received neoadjuvant chemotherapy (NACT) prior to surgery.The National Cancer Institute's Surveillance, Epidemiology, and End Results Program was retrospectively queried by examining 5505 patients with stage IVB endometrial cancer from 2010 to 2018. Exposure allocation was per treatment: primary surgery followed by chemotherapy (n = 3052, 55.4%), NACT followed by surgery (n = 930, 16.9%), and chemotherapy alone (n = 1523, 27.7%). Main outcomes measured were (i) the trend of utilization of NACT and patient characteristics related to NACT assessed with multinomial regression analysis and (ii) overall survival (OS) assessed with multivariable Cox proportional hazards regression model.The number of patients receiving NACT prior to surgery increased from 11.6% to 21.7% whereas those undergoing primary surgery followed by chemotherapy decreased from 62.7% to 48.3% (P0.001). Increasing utilization of NACT remained independent in multivariable analysis (adjusted-odds ratio per one-year increments 1.11, 95% confidence interval [CI] 1.08-1.15). Increasing utilization of NACT was observed in several sub-cohorts including patients aged65 years, ≥65 years, White, non-White, endometrioid, non-endometrioid, and cases with non-distant organ metastasis (P0.05). In a multivariable analysis, NACT followed by surgery and primary surgery followed by chemotherapy had comparable OS (median 25 versus 26 months, adjusted-hazard ratio [HR] 1.03, 95%CI 0.93-1.15). When examined for metastatic extent, NACT followed by surgery was associated with decreased OS compared to primary surgery followed by chemotherapy in the non-distant organ metastasis group (adjusted-HR 1.20, 95%CI 1.05-1.36) whereas it was associated with improved OS in the distant organ metastasis group (adjusted-HR 0.79, 95%CI 0.66-0.95).The treatment of stage IVB endometrial cancer is shifting from primary surgery to NACT in the United States.

Open spina bifida is the most common congenital anomaly of the central nervous system compatible with life. Prenatal repair of open spina bifida via open maternal-fetal surgery has been shown to improve postnatal neurologic outcomes, including reducing the need for ventriculoperitoneal shunting and improving lower neuromotor function. Fetoscopic repair of open spina bifida minimizes the maternal risks while providing similar neurosurgical outcomes to the fetus. The following 2 fetoscopic techniques are currently in use: (1) the laparotomy-assisted approach, and (2) the percutaneous approach. The laparotomy-assisted fetoscopic technique appears to be associated with a lesser risk of preterm birth than the percutaneous approach. However, the percutaneous approach avoids laparotomy and uterine exteriorization and is associated with lesser anesthesia risk and improved maternal postsurgical recovery. The purpose of this article was to describe our experience with a modified surgical approach, which we call percutaneous/mini-laparotomy fetoscopy, in which access to the uterus for one of the ports is done via a mini-laparotomy, whereas the other ports are inserted percutaneously. This technique draws on the benefits of both the laparotomy-assisted and the percutaneous techniques while minimizing their drawbacks. This surgical approach may prove invaluable in the prenatal repair of open spina bifida and other complex fetal surgical procedures.

Background Adjuvant hysterectomy following chemoradiation for bulky, early stage cervical cancer has been shown to decrease local relapse rate. The objective of this study is to compare complications and recurrences between minimally invasive and open adjuvant hysterectomy for early stage cervical cancer. Methods Patients were identified who had undergone adjuvant hysterectomy following chemoradiation for 2009 FIGO stage IB2 and IIA2 cervical cancer from August 2006 to June 2018. Demographic information, treatment course, complications, recurrence data were retrospectively extracted from the medical record. Frequency of complications was compared with Fisher exact test or chi-square test as appropriate and inverse probability of treatment propensity score weighting was used to calculate the disease-free survival. Results Fifty-four patients met inclusion criteria with a median follow up time of 60.4 months (interquartile range 28.0–98.1 months). There were 24 (44%) open versus 30 (56%) minimally invasive hysterectomies performed. The overall grade 2 or worse complication rate was 43%. There were 8 (27%) patients with complications in the minimally invasive group compared to 4 (17%) in the open group (OR 1.82 (95% CI 0.5–7.0)). There were 9 vaginal cuff defects, dehiscences and/or fistulas in the minimally invasive group compared to 3 in the open group (OR 3.0 (95% CI 0.8–11.2)). There was no statistically significant difference between disease free survival and overall survival among the two groups, however there was a trend towards decreased disease-free survival in the minimally invasive group. Conclusions Among women undergoing adjuvant hysterectomy following chemoradiation for bulky, early stage cervical cancer, there was no difference in complication rates between an open or minimally invasive surgical approach. However, the overall complication rate was high, including a high rate of vaginal cuff defect, dehiscence and/or fistulas. Our findings suggest that an adjuvant hysterectomy should be reserved for patients in which chemoradiation is not anticipated to successfully treat the primary tumor and, if performed, an open approach should be considered.

Objectives: Eribulin (E), a Halichondrin B analog from the marine sponge H. okadai has clinical efficacy in pretreated metastatic breast cancer and liposarcoma as well as preclinical antitumor activity in squamous cell carcinoma (SCC). We conducted a 2-stage Phase 2 study of E in patients (pts) with advanced/recurrent cervical cancer (CC) to examine its clinical activity and evaluate potential biomarkers for predictors of response. Methods: Pts with advanced/recurrent CC after ≤1 prior chemotherapy (CT) regimen, measurable disease and ECOG performance status ≤2 were treated with E (1.4mg/m2 IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival PFS6; secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS); and exploratory were associations of tumor biomarkers involved in apoptosis/proliferation, the unfolded protein response and tubulin subtypes with clinical activity. A total of 30 evaluable pts would ensure 80% power when the true PFS6= 26% with a 1-sided α ≤0.1 (Ho: PFS6= 10%). A prespecified futility analysis gating stage 2 was set if 0/15pts showed at least SD at 6 months (mos). Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores are ≥2. Results: A total of 32 pts were enrolled, median age 51 years (range 29-76), 22 had SCC, the median number of cycles was 4 (range 1-77). A total of 29 pts had received prior CT with cisplatin/gemcitabine (12) and cisplatin/paclitaxel/bevacizumab (12) as the most common regimens. A total of 14 pts had received prior paclitaxel (PTX). A total of 6/32 pts (19%) achieved > PFS6; median PFS is 2.5 mos (95% CI: 1.2, 4.2). Median OS is 6.5 mos (95% CI: 4.5, 12.7). A total of 2 pts were inevaluable for response having received less than 2 cycles. Among the 30 evaluable pts, 1 (3%) had a complete response, 5 (17%) had a partial response and 13 (43%) had stable disease (clinical benefit rate 63%). Grade 3/4 adverse events occurring in > 10 % of pts are anemia (12pts), neutropenia (7pts) and leukopenia (6pts). A total of 2 pts were removed from study due to paresthesia. Pts who received prior PTX responded less favorably than those who did not (p=.002) and had a significantly shorter PFS at 1.2 mos (95% CI: 1.1, 2.0) compared to 3.5 mos (95% CI: 2.6, 5.4) for those who did not (p=.008). Analysis of correlative predictors of response revealed significant associations between βII and βIII tubulin subtypes as well as BAX. Patients who did not overexpress βII and BAX were more likely to respond to E (p=.040, p=.002, respectively). On univariate analysis, PFS was shorter in patients with BAX overexpression 1.2 mos (95% CI: 1.1, 2.6) vs 4.6 mos (95% CI: 2.7, 7.8, p=.006) in those without. This was also observed in OS with 4.3 mos (95% CI: 2.7, 6.5) in those who overexpressed BAX vs 1.3 mos (7.7, 28.3, p=.006) in those who did not overexpress. In multivariate analyses, prior PTX (HR 4.80, 95% CI: 1.12, 20.7), βIII tubulin overexpression (HR 5.22, 95% CI: 1.52, 17.93), and BAX overexpression (HR 3.61, 95% CI 1.11, 11.73) remained significant factors in PFS. Similar results were observed for OS. Conclusions: Eribulin shows some limited activity in patients with recurrent/advanced CC with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased E response. bII, bIII tubulin subtypes and BAX are predictors of response and survival. While the primary end point was not met, Eribulin may be an option for women with paclitaxel-naive recurrent/advanced CC.

OBJECTIVE. To examine trends of adjuvant radiotherapy choice and to examine associations between pelvic lymphadenectomy and radiotherapy choice for women with early-stage endometrial cancer. METHODS. The Surveillance, Epidemiology, and End Results Program was used to identify surgically treated stage I-II endometrial cancer between 1983 and 2012 (type 1 n = 79,474, and type 2 n = 25,020). Piecewise linear regression models were used to examine temporal trends of intracavitary brachytherapy (ICBT) and whole pelvic radiotherapy (WPRT) use, pelvic lymphadenectomy rate, and sampled node counts. Multivariable binary logistic regression models were used to identify independent predictors for ICBT use. RESULTS. There was a significant increase in ICBT use and decrease in WPRT use during the study period. ICBT use exceeded WPRT use in 2003 for type 1 stage IA, and in 2007 for type 1 stage IB and type 2 stage IA diseases. In addition, number of sampled pelvic nodes significantly increased over time in type 1–2 stage I-II diseases (mean, 7.0–12.7 in 1988 to 15.2–17.6 in 2012, all P < 0.001). On multivariable analysis, extent of sampled pelvic nodes was significantly associated with ICBT use for type 1 cancer: adjusted-odds ratios for 1–10 and > 10 nodes versus no lymphadenectomy in stage IA (1.38/2.40), IB (2.75/6.32), and II (1.36/2.91) diseases. Similar trends were observed for type 2 cancer: adjusted-odds ratios for stage IA (1.69/3.73), IB (2.25/5.65), and II (1.36/2.19) diseases. CONCLUSION. Our results suggest that surgeons and radiation oncologists are evaluating the extent of pelvic lymphadenectomy when counseling women with early-stage endometrial cancer for adjuvant radiotherapy.

Glucose-regulated protein (GRP)-78, the key regulator of endoplasmic reticulum (ER) stress, is associated with endometrial cancer (EC) development and progression. However, its role in the continuum from complex atypical hyperplasia (CAH) to EC is unknown and the focus of this study. Methods 252 formalin-fixed, paraffin-embedded endometrial biopsies from patients with CAH diagnosed between 2003 and 2011 were evaluated for GRP78 expression by immunohistochemistry. Expression was also evaluated in subsequent biopsies from those patients treated with progestins. Differences in GRP78 expression were assessed using standard statistical methods. Results GRP78 expression was undetectable in 45(18%) patients with CAH, while 120(48%) CAH cases showed moderate/strong expression. Among women who ultimately underwent hysterectomy for CAH ( n =134), 54(40%) had occult EC while 57(43%) had persistent CAH. Those with occult EC upon hysterectomy had significantly stronger GRP78 expression than those who did not have occult EC ( p =0.007). Greater GRP78 expression within CAH remained independently associated with the presence of an occult EC ( p =0.017). Thirty-four of 54 (63%) patients with occult EC had moderate/strong GRP78 expression compared to 36 of 80 (45%) patients with persistent CAH, benign or non-atypical hyperplastic endometrium. In those treated with progestins, samples with persistent CAH and EC were more likely to have high levels of GRP78 expression in the initial biopsies than those who responded ( p =0.014). Conclusions Increased GRP78 expression in untreated CAH correlates with the presence of an occult EC. In addition, CAH specimens with greater GRP78 expression may identify patients who are less likely to respond to progestin therapy.

Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8(+) T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting that s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection. (C) 2015 Elsevier Inc. All rights reserved.

We are reporting 3 cases of the uterine corpus with collision of endometrioid adenocarcinoma (EAC) with endometrial stromal sarcoma (ESS). The patients' ages ranged from 36 to 59 years old. The major clinical presentation was abnormal uterine bleeding. Microscopically, all 3 cases presented with 2 separate components, EAC Grade 1 and ESS (one low grade and two high grades). The EAC component ranged from 10% to 70%, and the ESS component ranged from 30% to 70% of total tumor volume. The EAC component was stage 1A in two cases and stage II in one case. The ESS component was stages IA, IIB, and IIIB. Adjuvant hormonal therapy was administrated to one patient while a second patient was treated with chemo/radiation therapy. Two patients were still alive with no evidence of disease at 4 years post-therapy. One patient was lost for follow-up. Collision tumor should be distinguished from carcinosarcoma due to its different treatment modality, outcome and, prognosis., Highlights • Endometrioid adenocarcinoma and endometrial stromal sarcoma should be classified as collision tumors. • They should be differentiated from carcinosarcoma due to their different behavior and treatment.

AimsTo evaluate an immunohistochemical panel differentiating endometrial stromal sarcoma (ESS) from uterine leiomyosarcoma (ULMS) and leiomyoma (LM).Methods94 cases (28 ESS, 41 ULMS, 25 LM) were retrieved and arrayed. 10 immunomarkers (estrogen receptor (ER), progesterone receptor (PR), CD10, smooth muscle actin, desmin, h-caldesmon, transgelin, GEM, ASC1, stathmin1) were used. A predictive model was constructed and examined by receiver operating characteristics curve analysis to determine area under the curve (AUC).ResultsThe combination of ER+/PR+/CD10+/GEM−/h-caldesmon−/transgelin−can predict ESS versus ULMS with AUC predictive value of 0.872 (95% CI 0.784 to 0.961, p+/PR+/CD10+/h-caldesmon−/transgelin−can predict low grade (LG) ESS from ‘LG’ ULMS with AUC predictive value of 0.914 (95% CI 0.832 to 0.995, p+than LM.ConclusionsDue to the different clinical course and management, adding novel antibodies (GEM, transgelin) to the well established immunohistochemistry panel seemed to be useful in distinguishing ESS from ULMS and LG ESS from ‘LG’ ULMS. Finally, stathmin1 expression could be of value in differentiating LM from uterine sarcomas.

OBJECTIVE: Unmarried status including single marital status is associated with increased mortality in women bearing malignancy. Infectious disease weights a significant proportion of mortality in patients with malignancy. Here, we examined an association of single marital status and infectious mortality in cervical cancer. METHODS: This is a retrospective observational study examining 86,555 women with invasive cervical cancer identified in the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Characteristics of 18,324 single women were compared with 38,713 married women in multivariable binary logistic regression models. Propensity score matching was performed to examine cumulative risk of all-cause and infectious mortality between the 2 groups. RESULTS: Single marital status was significantly associated with young age, black/Hispanic ethnicity, Western US residents, uninsured status, high-grade tumor, squamous histology, and advanced-stage disease on multivariable analysis (all, P < 0.05). In a prematched model, single marital status was significantly associated with increased cumulative risk of all-cause mortality (5-year rate: 32.9% vs 29.7%, P < 0.001) and infectious mortality (0.5% vs 0.3%, P < 0.001) compared with the married status. After propensity score matching, single marital status remained an independent prognostic factor for increased cumulative risk of all-cause mortality (adjusted hazards ratio [HR], 1.15; 95% confidence interval [CI], 1.11–1.20; P < 0.001) and those of infectious mortality on multivariable analysis (adjusted HR, 1.71; 95% CI, 1.27–2.32; P < 0.001). In a sensitivity analysis for stage I disease, single marital status remained significantly increased risk of infectious mortality after propensity score matching (adjusted HR, 2.24; 95% CI, 1.34–3.73; P = 0.002). CONCLUSIONS: Single marital status was associated with increased infectious mortality in women with invasive cervical cancer.

To determine the maximal tolerated dose (MTD) of the combination of weekly temsirolimus and every other week vinorelbine in patients with advanced or refractory solid tumors. Patients were treated with intravenous temsirolimus on days 1, 8, 15, and 22 and intravenous vinorelbine on days 1 and 15. Cycles were repeated every 28 days. Nineteen patients were enrolled in the study. Tumor types included lung (5), prostate (2), neuroendocrine of pancreas (1), bladder (2), uterus (3), cervix (4), and vagina (2). All patients had received prior chemotherapy. Four patients were enrolled to dose level I, nine to dose level II, and six to dose level III. Six patients were inevaluable and replaced. Fifty-seven total cycles were administered. There was 1 dose-limiting toxicity at level II (grade 3 anorexia/dehydration) and 2 at level III (grade 3 hypokalemia; grade 4 neutropenia). Two patients died at dose level III; one was study-related with grade 4 neutropenia. Grade 3/4 toxicities observed during the first cycle included neutropenia (2), anemia (1), anorexia (1), dehydration (1), hyperglycemia (1), hypertriglyceridemia (1), and hypokalemia (1). Best response included two patients (prostate and non-small cell lung cancer) with partial response and eight patients with stable disease with median duration of best response of 3.2 months. Temsirolimus 25 mg given days 1, 8, 15, and 22 in combination with vinorelbine 20 mg/m2 given days 1 and 15 every 4 weeks was found to be the MTD. This dose combination is considered feasible in phase II trials.

To profile characteristics and survival of endometrial cancer patients who develop venous thromboembolism (VTE) and to establish a predictive model of VTE in endometrial cancer.Cases were identified using an institutional database between 2000 and 2011. VTE was correlated to clinico-pathological information and survival outcomes. Frequency and odds ratio (OR) of VTE were examined in a predictive model based on combination patterns of independent risk factors for VTE.VTE was seen in 42 (8.1%, 95% CI 5.8-10.5) out of 516 cases subsequent to the diagnosis of endometrial cancer. Multivariate analysis identified 4 independent risk factors for VTE: elevated CA-125 (hazard ratio [HR] 5.38, p0.001), extrauterine disease (HR 2.87, p=0.019), thrombocytosis (HR 2.11, p=0.04), and high risk histology (serous and clear cell, HR 2.09, p=0.049). VTE was the strongest variable for decreased progression-free survival (HR 4.28) and the second strongest variable for decreased overall survival (HR 5.65) in multivariate analysis. In a predictive model of VTE, the presence of multiple risk factors was associated with significantly increased risk of VTE: frequency of VTE, 1.4% if no risk factors, 0-9.3% (OR 1.0-4.2) if a single risk factor, 11.1-25.0% (OR 9.0-24.0) if two risk factors, and 42.9-46.2% (OR 54.0-61.7) if ≥3 risk factors.VTE represents a surrogate for aggressive disease in endometrial cancer. Multiple risk factors of VTE in our predictive model demonstrated exceedingly high risk of VTE, suggesting that there may be a certain population of endometrial cancer patients who would benefit from long-term anti-coagulant prophylaxis to improve survival outcome.

This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1–7) for reduction in Grade 3–4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1–7) in platelet production and retention of scheduled dose intensity were also determined. Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg (n = 11), 300 mcg/kg (n = 13), or placebo (n = 10) following chemotherapy for up to six cycles. Hematologic variables were obtained throughout each treatment cycle. There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo (p = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1–7) compared to placebo (p = 0.02). This increase was accompanied by a reduction in the nadir absolute neutrophil count (p = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1–7) compared to placebo (p = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo. A 100 mcg/kg dose of A(1–7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3–4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1–7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.

Background Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. Methods 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state. Results The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period. Conclusion Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting. Trial registration NCT00936364, registered propectively on July 9, 2009. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2370-6) contains supplementary material, which is available to authorized users.

5526Background: Eribulin (E), a Halichondrin B analog from the marine sponge H. okadai has clinical efficacy in pretreated metastatic breast cancer patients (pts) and preclinical antitumor activity...

A 36-yr-old woman presented with abdominal discomfort. A computed tomography scan revealed a large left cystic and solid pelvic mass without evidence of metastatic disease. Total hysterectomy with bilateral salpingo-oophorectomy and tumor staging was performed. Grossly, the ovarian mass measured 20×18 cm and the cut surface was multiloculated with 1 single mural nodule measuring 2×1.5 cm. The histologic diagnosis of ovarian mucinous borderline tumor with a microfocus of anaplastic carcinoma arising in sarcoma-like mural nodule, FIGO Stage IA was rendered. After 3 mo, the patient returned with symptomatic anemia. A computed tomography scan showed enlarged retroperitoneal and pelvic lymph nodes. Image-guided biopsy of the pelvic lymph node showed a metastatic anaplastic carcinoma from her primary ovarian carcinoma. Chemotherapy was initiated, but the patient developed fulminant disseminated intravascular coagulation within

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.

Objective. The objective of this study was to determine the efficacy and sensitivity of laparoscopic photodynamic diagnosis to detect 5-aminolevulinic acid (ALA)-induced fluorescent tumors in an animal model. Methods. Cancer cells were injected into the peritoneum of rats to induce peritoneal carcinomatosis. After 3–4 weeks, ALA was administered to establish fluorescence in tumor nodules. All intraperitoneal surfaces were inspected using fluorescence and white light laparoscopy. Suspicious lesions were then biopsied in vivo under either fluorescence or white light laparoscopic guidance. Fluorescence intensities of the cancerous lesions compared to normal tissues were determined. A pathologist blinded to our clinical impression analyzed all biopsied specimens. We compared the sensitivity of fluorescence and white light laparoscopic-guided detection of cancerous lesions and determined the clinical utility of fluorescent photodynamic diagnosis in detecting metastatic ovarian cancer. Results. Forty-three biopsies were performed in vivo under laparoscopic fluorescent guidance and 42 biopsies were taken using white light in various regions of the peritoneal surface from nine rats. Ten biopsies were also removed from nonfluorescent regions as nontumor controls. Cancerous lesions showed significantly higher fluorescent intensity compared to noncancerous lesions. Cancerous lesions that were difficult to differentiate from normal surrounding tissue under white light conditions were clearly detected by ALA-induced fluorescence. The average size of these metastatic lesions biopsied under fluorescent light was 1.0 mm (range: 0.3–2.5) compared to 1.5 mm (range: 0.5–2.9) with white light illumination ( P Conclusions. Fluorescent laparoscopic detection of micrometastatic ovarian cancer using ALA is significantly more sensitive than white-light laparoscopy in detecting smaller cancerous lesions in an ovarian cancer rat model. Human trials are indicated.

5526 Background: The outcome of lymph node positive (LN) cervical cancer (CC) with chemoradiation (CRT) is dismal, especially with involved para-aortic nodes (PAN). The anti-CTLA-4 immune checkpoint inhibitor ipilimumab (ipi) holds promise. We report the safety, tolerability, and efficacy in this GOG phase I study examining sequential ipi after CRT for CC. Methods: Patients (pts) with LN CC were treated with 6 weekly doses of cisplatin (40 mg/m2) and extended field radiation (RT). 2-6 weeks after RT, if there was no progression of disease, sequential ipi was given at the following dose levels: dose level 1: 3mg/kg, level 2: 10mg/kg, and an expansion cohort of 10mg/kg. The primary endpoints (endpts) were the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of adjuvant ipi. Secondary endpt included the 1-yr disease free survival (DFS). Translational endpts included the effect of CRT on enumeration and subsets of T-cells, and CTLA4, PD-1 and ICOS expression. Results: 34 pts were enrolled, and 19 pts are evaluable for the endpts: 14 pts went off study to reasons unrelated to the study drug, 1 pt continues in her DLT evaluable period. Of the evaluable pts, all had pelvic LN, with 25% PAN. All pts completed CRT, 90% had 4 cycles of ipi, and the other 10% had 2 cycles of ipi. The ipi MTD was 10 mg/kg. There were 3 pts (16%) with acute grade 3 toxicity (lipase, ↓ANC, rash) which self-resolved. Most of the acute toxicities were grade 1-2 GI distress, rash, endocrinopathies. There were no minor or major RT quality deviations. With a median follow up of 12 months, there were no major late toxicities reported, with a 1-year DFS of 74%. There was no difference in CD4+- and CD8+- T cell levels nor CTLA-4 expression with sequential ipi. CRT itself increased ICOS and PD-1 expression. Conclusions: This study is the first to describe the safety of immunotherapy sequencing with definitive CRT in CC. Our data suggests that immunotherapy is tolerable and shows possible activity in this population with a historical dismal prognosis with standard therapy. CRT increased ICOS and PD-1 expression which was sustained with ipi, illustrative of immune modulation targets for future clinical trials and radioimmunotherapy combinations. Clinical trial information: NCT01711515.

Purpose To estimate the antitumor activity of pemetrexed and cisplatin with objective tumor response (partial and complete) in patients with advanced, persistent, or recurrent carcinoma of the cervix and to determine the nature and degree of toxicity of this regimen. Secondarily, this study will determine the effects of this regimen on progression-free survival and overall survival. Patients and Methods Eligible, consenting patients received pemetrexed 500 mg/m2 and cisplatin 50 mg/m2 intravenously repeated every 21 days until disease progression or adverse events prohibited further therapy. Patients received no prior therapeutic chemotherapy, except when administered concurrently with primary radiation therapy. Subsequent doses were adjusted according to observed toxicity and protocol guidelines. Adverse events were assessed with Common Terminology Criteria for Adverse Events v 3.0. The primary measure of efficacy was tumor response according to Response Evaluation Criteria in Solid Tumors. The study was stratified by prior radiation therapy. Results From September 2008 to November 2011, 55 patients were enrolled by five Gynecologic Oncology Group member institutions; of those, 54 patients were eligible and assessable. The regimen was well tolerated with 26% receiving more than nine cycles. The most common greater than grade 2 toxicities were neutropenia 35%, leukopenia 28%, and metabolic 28%. The overall response rate was 31% (one complete and 16 partial). The median progression-free survival was 5.7 months, and overall survival was 12.3 months. Conclusion Pemetrexed in combination with cisplatin demonstrates activity in the treatment of advanced, persistent, or recurrent carcinoma of the cervix.

To evaluate the activity of gemcitabine and docetaxel in patients with recurrent ovarian cancer. Methods: Patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with docetaxel on day 1 and gemcitabine on days 1 and 8, repeated every three weeks. Results: Twenty patients, with a platinum-free interval of three months, were enrolled. Overall response rate was 25%. Treatment was associated with significant myelosuppression. Conclusions: In chemotherapy-resistant patients, this regimen exhibited encouraging activity. Excessive myelosuppression led to early closure. This was prevented by administering docetaxel on day 8 (instead of day 1) and prophylactic use of G-CSF.

TPS5617 Background: Eribulin (E), a Halichondrin B analog from the marine sponge H. okadai shows anticancer effects via G2/M cell cycle arrest, mitotic spindle disruption, and apoptosis. E has effi...

To determine the importance of margin status and other prognostic factors associated with the recurrence and survival of patients with squamous cell vulvar carcinoma.Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. All slides were re-reviewed by two gynecologic pathologists.Ninety patients (median age: 69) were treated for vulvar carcinoma from 1984 to 2002, including 28 FIGO stage I, 20 stage II, 26 stage III and 16 with stage IV disease. Sixty-three (70%) patients underwent complete radical vulvectomies and 27 (30%) had modified radical vulvectomies. Nineteen (20%) patients received adjuvant radiotherapy. Five-year disease-specific survival rates were 100%, 100%, 86% and 29% for stages I-IV, respectively. None of the 30 patients with a pathologic margin distance8 mm had local recurrence. Of the 53 women with tumor-free pathologic margin of8 mm, 12 (23%) had a local recurrence. Moreover, women with2 positive groin nodes had significantly higher recurrence risk compared to those with2 metastatic groin nodes (p0.001). On multivariate analysis, positive groin nodes and margin distance were important prognostic factors for recurrence. Moreover, stage, tumor size, margin distance, and depth of invasion were significant independent predictors for disease-specific survival. The median follow-up was 58 months (range: 2-188).Pathologic margin distance is an important predictor of local vulvar recurrence. Our data suggest that aor =8-mm pathologic margin clearance leads to a high rate of loco-regional control.

9632 Background: Fasting confers dramatic protection against chemotherapy toxicity in mice (PNAS 2008). We studied safety and feasibility of escalated fasting duration prior to platinum doublet chemotherapy in cancer patients (pts). Insulin, glucose, ketones and insulin-like growth factor (IGF) were measured as potential biomarkers of the fasting state. Methods: 3 fasting cohorts were evaluated: 24, 48 and 72 hours (hr) (48 pre/24 post chemotherapy). Subjects recorded all calories consumed during the fast period. Feasibility was defined as 4/6 subjects in each cohort consuming < 200 kCal/24 hr without excess fasting toxicity (using CTCAE v4.0). Results: Primary cancer: Urothelial 5, breast 5, ovarian 7, uterine 1, NSCLC 1. Regimens: gemcitabine+ cisplatin 6, docetaxel + carboplatin (C) + trastuzumab 5, C + paclitaxel 8. Median age: 61y (31-73). 4/6 pts, 5/7 pts and 4/6 pts in the 24, 48 and 72 hr groups were fasting compliant

5527 Background: To estimate the antitumor activity of Pemetrexed and cisplatin with objective tumor response (partial and complete) in patients with advanced, persistent, or recurrent carcinoma of the cervix and to determine the nature and degree of toxicity of this regimen. Secondarily, to determine the effects of this regimen on progression-free survival and overall survival. Methods: Eligible, consenting patients received pemetrexed 500mg/m2 and cisplatin 50 mg/m2 IV repeated every 21 days until disease progression or adverse effects prohibited further therapy. Patients had received no prior therapeutic chemotherapy, except when administered concurrent with primary radiation therapy. Subsequent doses were adjusted according to observed toxicity and protocol guidelines. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST. The study was stratified by prior radiation therapy. Results: From September 2008 to November 2011, 55 patients were enrolled by 5 GOG member institutions. Of those, 49 patients were eligible and assessable. The regimen was well tolerated with 14 (29%) receiving >9 cycles. Common grade >2 toxicities were neutropenia 35%, leukopenia 28%, and metabolic 28%. The overall response rate was 31% (one complete and 16 partial responses). The median response duration was 7 months and survival 12 months. Conclusions: Pemetrexed in combination with cisplatin has demonstrated activity in the treatment of advanced, persistent, or recurrent carcinoma of the cervix. Additional study of this regimen in a phase III setting is justified in this patient population. Clinical trial information: NCT00691301.

e15500 Background: Although the majority of patients with uterine leiomyosarcoma (ULMS) present with early stage disease, the risk of recurrence is high. Because ULMS is a rare disease, standardized adjuvant treatment options do not exist. Therefore, the goal of this study is to determine the role of adjuvant chemotherapy in patients with stages I-II high grade ULMS. Methods: Women with stages I-II ULMS treated at our institution from 1988-2008 were retrospectively identified and included in this study (N=44). Data was collected on patient age, stage of disease, surgical procedure, adjuvant treatment, recurrence, and survival. Results: In this population, 24 (55%) patients received cytotoxic chemotherapy, 3 (7%) received concurrent chemoradiation, 2 (4.5%) patients received radiation alone, and 15 (34%) received no further treatment. Median follow up for survivors was 71 months. In the no treatment and radiation alone groups, 71% of patients recurred and 29% were alive at last follow up. In the chemothera...