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Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma
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Abstracts / Gynecologic Oncology 133 (2014) 2–207
animals were further trained to not respond to the aromas of multiple benign fresh ovarian tissues. Once imprinting was complete, the animals were exposed to urine from either affected or benign women. Results: The dogs were able to imprint on a scent specific to ovarian cancer within 3 h of training, the time to produce imprinting fell dramatically with each animal. Once the animals could discriminate the aroma produced by serous ovarian cancers and benign ovarian tissue, they were exposed to urine. The animals were 100% accurate in determining benign or malignant scent in the urine, which included specimens from patients to whom the dogs were not previously (i.e., had not previously smelled the patients' tumors). Conclusions: This study illustrated the ability to train SAR dogs to detect a scent specific to ovarian cancer and to detect this aroma in urine. This work is been expanded to a large prospective study to determine the sensitivity and specificity of this method as a screening. It is hoped that this will ultimately result in a reduction in mortality from ovarian cancer by early detection. doi:10.1016/j.ygyno.2014.03.275
256 - Poster Session A Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma J.P. Diaz1, J. Kreafle2, K. Angel1, R.A. Estape1, E.D. Schroeder3, R.E. Estape4. 1South Miami Gynecologic Oncology Group, Miami, FL, USA, 2 University of Miami School of Medicine, Miami, FL, USA, 3University of Miami-Jackson Memorial Hospital, Miami, FL, USA, 4South Miami Hospital, Miami, FL, USA. Objectives: To evaluate the feasibility and tolerability of hyperthermic intraperitoneal chemotherapy (HIPEC) following robotic or open cytoreduction for recurrent ovarian cancer. Methods: In a single-institution pilot study, patients underwent optimal cytoreductive surgery in combination with HIPEC followed by consolidation chemotherapy from September 2011 to May 2013. Optimal cytoreduction was defined as no lesion N1 cm. Adverse and oncologic outcomes were measured. Standard statistical analysis was used. Results: Thirteen patients with a median age of 52 years (range 20–86 years) were identified. The median number of chemotherapy regimens prior to HIPEC was 3 (range, 1–12 regimens). A median of 2 platinumcontaining regimens were administered prior to HIPEC (range, 0–5 regimens). Median CA-125 at the time of HIPEC was 256 U/mL (range, 13–8,543 U/mL). Seven (54%) patients were platinum-sensitive at the time of HIPEC. Six (46%) patients underwent robotic optimal cytoreductive surgery. The following cytotoxic agents were used during HIPEC: mitomycin in 6 patients (46%), cisplatin and paclitaxel in 4 (31%), carboplatin in 2 (15%), and paclitaxel in 1 (8%). There were no intraoperative complications or adverse events attributable to HIPEC therapy. Median hospital stay was 8 days (range, 1 25 days). All patients received consolidation chemotherapy following their cytoreduction and HIPEC. At a median follow-up of 4 months (range, 1 7 months), the progression-free survival free and overall survivals have not been reached. Conclusions: In select patients, robotic and open cytoreductive surgery in combination with HIPEC is feasible and safe. The optimal candidate and chemotherapy regimen have yet to be defined. Preliminary survival data suggest efficacy. Further investigation for the role of robotic cytoreduction and HIPEC is warranted. doi:10.1016/j.ygyno.2014.03.276
257 - Poster Session A Development of flow cytometric predictive biomarker assay for response to PARP inhibitor (PARPi) therapy in high-grade serous ovarian cancer (HGSOC) J.M. Lee, N. Gordon, M.J. Lee, J. Trepel, M. Yu, E.C. Kohn. National Cancer Institute, Bethesda, MD, USA. Objectives: Approximately 50% of HGSOC are deficient in homologous recombination (HRD). Understanding which HGSOC have HRD is of therapeutic importance to triage women to PARPi-based therapy. γH2AX and RAD51 have been employed individually as surrogate measures of DNA double strand break (DSB) damage and repair, respectively, but neither alone has been proven a predictive biomarker. Quantification of both γH2AX and RAD51 using a high throughput measure, such as a flow cytometric method, can allow determination of homologous recombination (HR) competence (low γH2AX/RAD51 ratio) and incompetence (high γH2AX/RAD51 ratio). We hypothesized HRD, described by a high ratio, will predict susceptibility to PARPi in HGSOC. Methods: A sensitive and reproducible flow cytometry method was developed and validated using dual-color immunofluorescence (IF). Phorbol myristate acetate and ionomycin were used to stimulate peripheral blood mononuclear cells (PBMCs) for 4 h before an up to 48-hour treatment with carboplatin 50 μM/olaparib 10 μM. PBMC samples from healthy blood donors were obtained from the National Institutes of Health Clinical Center Blood Bank. Changes in RAD51, γH2AX, and MRE11, a protein involved in the initial process of HR, were examined over time. Cycloheximide treatment during stimulation was performed to test if there was de novo production of MRE11 in response to injury. Results: Flow cytometry measures of HRD demonstrated that changes in γH2AX and MRE11 can be assessed reliably in the setting of DNA damage and repair. γH2AX expression increased over the first 36 h of treatment, and MRE11 increase in expression was delayed, starting at 36 h. Cycloheximide treatment significantly decreased MRE11 induction but not γH2AX induction (P = 0.003), indicating de novo production of MRE11 in response to DNA injury. Preliminary IF results support the findings of the flow cytometry. Further validation studies using IF are ongoing. PBMC samples from patients in an olaparib/carboplatin study (NCT01445418) will be examined and correlated to outcome and toxicity. Conclusions: Dual-label flow cytometry to measure the γH2AX/MRE11 intensity ratio is a promising tool with which to predict DSB repair competence (high ratio) and incompetence (low ratio). Validation using PBMCs from olaparib/carboplatin patients is pending. Prospective confirmation will be needed. Funded in part by the 2011-2012 Caring Together, NY Ovarian Cancer Research Grant. doi:10.1016/j.ygyno.2014.03.277
258 - Poster Session A Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: Implications for immune-mediated cancer therapy I. Wilkinson-Ryan1, J. Kim2, S. Kim1, M.A. Powell1, D.G. Mutch1, D. Spitzer1, T. Hansen1, S.P. Goedebeuure1, D.T. Curiel1, W. Hawkins1. 1 Washington University School of Medicine, St. Louis, MO, USA, 2University of Chicago, Chicago, IL, USA. Objectives: Dendritic cells (DCs) loaded with tumor antigen are capable of eliciting a T-cell-mediated antitumor immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery and antigen loading but has limited infection in DCs, which lack the proper receptors. Addition of the
Abstracts / Gynecologic Oncology 133 (2014) 2–207
animals were further trained to not respond to the aromas of multiple benign fresh ovarian tissues. Once imprinting was complete, the animals were exposed to urine from either affected or benign women. Results: The dogs were able to imprint on a scent specific to ovarian cancer within 3 h of training, the time to produce imprinting fell dramatically with each animal. Once the animals could discriminate the aroma produced by serous ovarian cancers and benign ovarian tissue, they were exposed to urine. The animals were 100% accurate in determining benign or malignant scent in the urine, which included specimens from patients to whom the dogs were not previously (i.e., had not previously smelled the patients' tumors). Conclusions: This study illustrated the ability to train SAR dogs to detect a scent specific to ovarian cancer and to detect this aroma in urine. This work is been expanded to a large prospective study to determine the sensitivity and specificity of this method as a screening. It is hoped that this will ultimately result in a reduction in mortality from ovarian cancer by early detection. doi:10.1016/j.ygyno.2014.03.275
256 - Poster Session A Robotic and open cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of recurrent ovarian carcinoma J.P. Diaz1, J. Kreafle2, K. Angel1, R.A. Estape1, E.D. Schroeder3, R.E. Estape4. 1South Miami Gynecologic Oncology Group, Miami, FL, USA, 2 University of Miami School of Medicine, Miami, FL, USA, 3University of Miami-Jackson Memorial Hospital, Miami, FL, USA, 4South Miami Hospital, Miami, FL, USA. Objectives: To evaluate the feasibility and tolerability of hyperthermic intraperitoneal chemotherapy (HIPEC) following robotic or open cytoreduction for recurrent ovarian cancer. Methods: In a single-institution pilot study, patients underwent optimal cytoreductive surgery in combination with HIPEC followed by consolidation chemotherapy from September 2011 to May 2013. Optimal cytoreduction was defined as no lesion N1 cm. Adverse and oncologic outcomes were measured. Standard statistical analysis was used. Results: Thirteen patients with a median age of 52 years (range 20–86 years) were identified. The median number of chemotherapy regimens prior to HIPEC was 3 (range, 1–12 regimens). A median of 2 platinumcontaining regimens were administered prior to HIPEC (range, 0–5 regimens). Median CA-125 at the time of HIPEC was 256 U/mL (range, 13–8,543 U/mL). Seven (54%) patients were platinum-sensitive at the time of HIPEC. Six (46%) patients underwent robotic optimal cytoreductive surgery. The following cytotoxic agents were used during HIPEC: mitomycin in 6 patients (46%), cisplatin and paclitaxel in 4 (31%), carboplatin in 2 (15%), and paclitaxel in 1 (8%). There were no intraoperative complications or adverse events attributable to HIPEC therapy. Median hospital stay was 8 days (range, 1 25 days). All patients received consolidation chemotherapy following their cytoreduction and HIPEC. At a median follow-up of 4 months (range, 1 7 months), the progression-free survival free and overall survivals have not been reached. Conclusions: In select patients, robotic and open cytoreductive surgery in combination with HIPEC is feasible and safe. The optimal candidate and chemotherapy regimen have yet to be defined. Preliminary survival data suggest efficacy. Further investigation for the role of robotic cytoreduction and HIPEC is warranted. doi:10.1016/j.ygyno.2014.03.276
257 - Poster Session A Development of flow cytometric predictive biomarker assay for response to PARP inhibitor (PARPi) therapy in high-grade serous ovarian cancer (HGSOC) J.M. Lee, N. Gordon, M.J. Lee, J. Trepel, M. Yu, E.C. Kohn. National Cancer Institute, Bethesda, MD, USA. Objectives: Approximately 50% of HGSOC are deficient in homologous recombination (HRD). Understanding which HGSOC have HRD is of therapeutic importance to triage women to PARPi-based therapy. γH2AX and RAD51 have been employed individually as surrogate measures of DNA double strand break (DSB) damage and repair, respectively, but neither alone has been proven a predictive biomarker. Quantification of both γH2AX and RAD51 using a high throughput measure, such as a flow cytometric method, can allow determination of homologous recombination (HR) competence (low γH2AX/RAD51 ratio) and incompetence (high γH2AX/RAD51 ratio). We hypothesized HRD, described by a high ratio, will predict susceptibility to PARPi in HGSOC. Methods: A sensitive and reproducible flow cytometry method was developed and validated using dual-color immunofluorescence (IF). Phorbol myristate acetate and ionomycin were used to stimulate peripheral blood mononuclear cells (PBMCs) for 4 h before an up to 48-hour treatment with carboplatin 50 μM/olaparib 10 μM. PBMC samples from healthy blood donors were obtained from the National Institutes of Health Clinical Center Blood Bank. Changes in RAD51, γH2AX, and MRE11, a protein involved in the initial process of HR, were examined over time. Cycloheximide treatment during stimulation was performed to test if there was de novo production of MRE11 in response to injury. Results: Flow cytometry measures of HRD demonstrated that changes in γH2AX and MRE11 can be assessed reliably in the setting of DNA damage and repair. γH2AX expression increased over the first 36 h of treatment, and MRE11 increase in expression was delayed, starting at 36 h. Cycloheximide treatment significantly decreased MRE11 induction but not γH2AX induction (P = 0.003), indicating de novo production of MRE11 in response to DNA injury. Preliminary IF results support the findings of the flow cytometry. Further validation studies using IF are ongoing. PBMC samples from patients in an olaparib/carboplatin study (NCT01445418) will be examined and correlated to outcome and toxicity. Conclusions: Dual-label flow cytometry to measure the γH2AX/MRE11 intensity ratio is a promising tool with which to predict DSB repair competence (high ratio) and incompetence (low ratio). Validation using PBMCs from olaparib/carboplatin patients is pending. Prospective confirmation will be needed. Funded in part by the 2011-2012 Caring Together, NY Ovarian Cancer Research Grant. doi:10.1016/j.ygyno.2014.03.277
258 - Poster Session A Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: Implications for immune-mediated cancer therapy I. Wilkinson-Ryan1, J. Kim2, S. Kim1, M.A. Powell1, D.G. Mutch1, D. Spitzer1, T. Hansen1, S.P. Goedebeuure1, D.T. Curiel1, W. Hawkins1. 1 Washington University School of Medicine, St. Louis, MO, USA, 2University of Chicago, Chicago, IL, USA. Objectives: Dendritic cells (DCs) loaded with tumor antigen are capable of eliciting a T-cell-mediated antitumor immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery and antigen loading but has limited infection in DCs, which lack the proper receptors. Addition of the