Barbara M. Buttin

The impact of robotics on practice management of endometrial cancer: transitioning from traditional surgery

Evaluation of the impact of a new robotic surgery programme on perioperative outcomes for endometrial cancer

Robotic surgery in gynecologic oncology: Impact on fellowship training

OBJECTIVES To report the impact of a new robotic surgery program on the surgical training of gynecologic oncology fellows over a 12 month period of time. METHODS A robotic surgery program was introduced into the gynecologic oncology fellowship program at Northwestern University Feinberg School of Medicine in June 2007. A database of patients undergoing surgical management of endometrial and cervical cancer between July 2007 and July 2008 was collected and analyzed. Changes in fellow surgical training were measured and analyzed. RESULTS Fellow surgical training for endometrial and cervical cancer underwent a dramatic transition in 12 months. The proportion of patients undergoing minimally invasive surgery increased from 3.3% (4/110 patients) to 43.5% (47/108 patients). Fellow training transitioned from primarily an open approach (94.4%) to a minimally invasive approach (11% laparoscopic, 49% robotic, 40% open) for endometrial cancer stagings, and from an open approach (100%) to an open (50%) and robotic (50%) approach for radical hysterectomies. Fellow participation in robotic procedures increased from 45% in the first 3 months to 72% within 6 months, and 92% by 12 months. The role of the fellow in robotic cases transitioned from bedside assistant to console operator within 3 months. CONCLUSIONS Fellow surgical training underwent a dramatic change with the introduction of a robotic surgery program. The management of endometrial and cervical cancer was impacted the most by robotics. Robotic surgery broadened fellowship surgical training, but balanced surgical training and standardized fellow training modules remain challenges for fellowship programs.

Chemosensitization of endometrial cancer cells through AKT inhibition involves FOXO1

OBJECTIVE Endometrial cancer is the most common type of gynecologic cancer in the United States. In this study, we propose that inhibition of the AKT pathway sensitizes cells to chemotherapeutic agents by increasing FOXO1 expression. METHODS Ishikawa and RL95 cells were treated with the AKT inhibitor (API-59CJ-OMe) alone and in combination with carboplatin or paclitaxel. Cells were counted using a hemocytometer and cell cycle analysis done with flow cytometry. Apoptosis was measured with TUNEL and Annexin V/DAPI staining. FOXO1 protein expression and localization was done using immunofluorescent staining of cells. Finally, the adenovirus containing triple mutant FOXO1 was used to overexpress the constitutively active FOXO1 in Ishikawa cells and its effects on cell viability were studied. RESULTS Treatment with 6 microM API-59CJ-OME resulted in preferential cell death in Ishikawa and RL95 cells compared to another endometrial cancer cell line, ECC1 after 48 h of treatment. API-59CJ-OME treatment of Ishikawa cells resulted in cell cycle arrest in the G2/M phase. The addition of API-59CJ-OME to carboplatin resulted in a synergistic increase in cell death by apoptosis compared to the responses to each agent separately. Treatment with API-59CJ-OME, carboplatin, paclitaxel or the combinations for 24 h increased nuclear expression of FOXO1 in Ishikawa cells. Overexpression of FOXO1 caused 37% of the cells to die within 24 h. Addition of carboplatin to the AD-FOXO1 expressing cells further increased cell death to 71%. CONCLUSIONS Inhibition of AKT signaling potentiates cell death in Ishikawa and RL95 cells when combined with carboplatin through mechanisms involving FOXO1 activation.

Synuclein-γ (SNCG) may be a novel prognostic biomarker in uterine papillary serous carcinoma

OBJECTIVES SNCG in breast cancer is a marker for advanced and aggressive disease thereby correlating with a poor prognosis in patients. We set out to determine if SNCG expression in UPSC correlates with aggressive cellular properties, poor prognosis, and chemoresistance, and if silencing SNCG can reverse these attributes in vitro. METHODS A focused, real time PCR array was performed comparing a papillary serous (SPEC2) and an endometrioid (Ishikawa) endometrial cancer cell line. SNCG was the most differentially expressed gene. SNCG expression was confirmed by real time PCR, Western blot, and immunohistochemistry (IHC) and correlated with outcomes in a pilot set of 20 UPSC patients. A stably transfected SPEC2 cell line was created using shSNCG oligonucleotides. The effect of SNCG knockdown in SPEC2 cells on cell proliferation and sensitivity to paclitaxel-induced apoptosis was measured using a cell viability assay, BrdU incorporation assay, as well as cleaved PARP analyses. RESULTS SNCG mRNA as well as protein was highly expressed in SPEC2 cells while minimally to undetectable in several endometrioid endometrial cancer and normal endometrial cell lines. IHC also confirmed unique SNCG expression in UPSC tumors compared to low grade endometrial cancers. In UPSC patients, SNCG expression by IHC correlated with advanced stage and decreased progression-free survival. Knockdown of SNCG in SPEC2 cells caused a significant decrease in cell proliferation and increased sensitivity to paclitaxel-induced apoptosis. CONCLUSIONS SNCG is a novel biomarker for aggressive disease and chemoresistance in UPSC and merits further investigation both as a prognostic tool and as a therapeutic target.

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

BRCA1/BRCA2 mutations are common and the hallmarks of high-grade serous ovarian carcinoma. We found that MIR182, a negative BRCA1 regulator, is significantly overexpressed in high-grade serous ovarian carcinoma. To examine whether overexpression of MIR182 and its target genes, including BRCA1, HMGA2 (high-mobility group A2), FOXO3 and MTSS1, are associated with high-grade serous ovarian carcinoma tumor types and clinical outcome, we studied MIR182 by in situ hybridization and its target gene expression by immunohistochemistry in 117 cases of advanced ovarian cancer. We found that high-grade serous ovarian carcinoma had significantly higher MIR182 (P=0.0003) and HMGA2 (P=0.04) expression, and significantly lower BRCA1 (P<0.0001) and FOXO3 (P<0.001) expression than normal controls. MIR182 is significantly correlated with MTSS1 expression (r=0.31; P<0.001), whereas other target genes did not show a significant correlation with MIR182, indicating a complicated regulatory mechanisms of these genes in high-grade serous ovarian carcinoma. Among the examined MIR182 target genes, only HMGA2 was significantly associated with serous type carcinomas (P<0.01), ascites (P<0.01) and high death rate (P=0.02). FOXO3 expression was associated with lower-stage disease (P=0.04) and solid growth pattern (P=0.03). MIR182 expression is significantly higher in high-grade serous ovarian carcinoma than in fallopian tubes.

An outpatient intraperitoneal chemotherapy regimen for advanced ovarian cancer

OBJECTIVES To assess the feasibility, associated toxicities, and reasons for early cessation of an outpatient intraperitoneal (IP) chemotherapy regimen for treatment of advanced ovarian cancer following optimal cytoreductive surgery. METHODS Between January 2006 and December 2007, 42 patients with stages IIC-IV epithelial ovarian, tubal, or primary peritoneal cancer who had residual disease <1 cm after cytoreductive surgery were treated with an outpatient IP chemotherapy protocol. Patients received intravenous (IV) docetaxel 75 mg/m(2) and IP cisplatin 75-100 mg/m(2) on day 1, followed by IP paclitaxel 60 mg/m(2) on day 8, with the intent to treat patients every 21 days for 6 cycles of chemotherapy. Charts were abstracted for demographic, chemotherapy, and toxicity-related data. RESULTS The median age of the 42 patients was 59 years (range 33-70) and the majority of patients had epithelial ovarian cancer (80%), FIGO stage IIIC (83%), and papillary serous histology (74%). Of an intended 252 IP chemotherapy cycles, 172 (68%) were administered. Twenty-nine patients (69%) completed >or=4 cycles and 12 (29%) received all 6 IP cycles. Common grade 3/4 toxicities by patient included neutropenia (43%), infection (21.5%), and gastrointestinal effects (14%). There was one treatment-related death. Reasons for discontinuation were largely chemotherapy (43%) or port (37%) related. CONCLUSIONS With supportive measures, such as scheduled hydration and granulocyte colony-stimulating factors, outpatient administration of IP chemotherapy was feasible. This regimen resulted in few hospitalizations or treatment delays and demonstrated less toxicity than previously reported IP chemotherapy regimens. Port-related complications were a leading cause of IP chemotherapy discontinuation.

Thalidomide-induced reversible interstitial pneumonitis in a patient with recurrent ovarian cancer

BACKGROUND Thalidomide is an oral immunomodulatory agent with antiangiogenic properties and activity in ovarian cancer. Pulmonary toxicity unrelated to venous thromboembolism is rare and its etiology is poorly understood. CASE We present the first reported case of reversible drug-induced interstitial lung disease in a patient with recurrent ovarian cancer treated with weekly topotecan and thalidomide. The patients symptoms and radiographic findings completely resolved upon discontinuing thalidomide while continuing on topotecan. CONCLUSION Due to its antiangiogenic properties and good tolerance, thalidomide is an attractive agent for the treatment of recurrent ovarian cancer. Gynecologic oncologists and pulmonologists should be aware that acute interstitial lung disease is a possible side effect that appears easily reversible when the drug is stopped.

Synuclein-γ in uterine serous carcinoma impacts survival: An NRG Oncology/Gynecologic Oncology Group study

Synuclein‐γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG‐8023).

Abstract 3548: Role of synuclein-gamma (SNCG) in paclitaxel resistance and mitogen activated protein kinase activation in uterine papillary serous carcinoma(UPSC)

Objectives: SNCG is a novel prognostic biomarker in UPSC. We have shown that its overexpression correlates with aggressive cellular properties and resistance to paclitaxel in a UPSC cell line (SPEC2) as well as poor prognosis in a pilot set of UPSC patients. The goal of this study was to determine the mechanism of SNCG-associated taxane resistance by evaluating the effect of SNCG on the mitotic checkpoint and its propensity to modulate extracellular signal-regulated protein kinase 1/2 (ERK 1/2) signaling pathways. Methods: A stably transfected SPEC2 cell line was created using shSNCG versus shControl oligonucleotides. Similarly, Ishikawa cells were transiently transfected with an SNCG expression vector versus empty vector. Differences in cell proliferation were measured using a cell viability assay and BrdU incorporation assay after treatment with paclitaxel. Cell cycle analysis was used to study the effect of SNCG on the mitotic checkpoint. Differences in expression of the checkpoint kinase BubR1 due to SNCG were studied using real time PCR, Western blot, 26S ubiquitin-proteasome inhibition, and siRNA to BubR1. ERK and phospho-ERK levels were measured in SPEC2 cells with and without SNCG expression by Western blot. SPEC2 cells were treated with paclitaxel with and without the MEK inhibitor UO126 and apoptosis was measured using cleaved PARP analysis. Results: SNCG overexpression lead to acquired, reversible paclitaxel resistance in endometrial cancer cell lines. SNCG was noted to interfere with mitotic checkpoint function by causing degradation of the critical checkpoint protein BubR1 thereby allowing cells to escape paclitaxel-induced mitotic arrest. SPEC2 cells exhibited sustained activation of ERK which was attenuated by silencing SNCG. When SPEC2 cells were exposed to paclitaxel combined with the MEK inhibitor UO126, decreased cell viability and increased apoptosis was noted compared to either agent alone. SNCG knockdown further enhanced paclitaxel and UO126 sensitivity. Cell cycle analysis revealed that silencing SNCG in SPEC2 cells and adding UO126 acted synergistically in overcoming paclitaxel resistance. Conclusions: SNCG overexpression in UPSC leads to taxane resistance by interacting with the mitotic checkpoint kinase BubR1 causing its degradation. SNCG is also associated with sustained ERK activation. Targeting SNCG in conjunction with MEK inhibition may represent a novel therapeutic strategy to overcome taxane resistance in these cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3548.