Nicole M. Stavitzski

Sentinel lymph node mapping with staging lymphadenectomy for patients with endometrial cancer increases the detection of metastasis

OBJECTIVES To compare the performance of sentinel lymph node (SLN) mapping with staging lymphadenectomy versus staging lymphadenectomy alone for the detection of metastasis and the use of adjuvant therapies in patients with endometrial cancer. METHODS All patients with apparent early-stage endometrial cancer (n=780) who underwent robotic-assisted hysterectomy with pelvic±aortic lymphadenectomy from July-2006 to June-2013 were compared [pelvic±aortic lymphadenectomy (n=661) versus SLN-mapped cases with pelvic±aortic lymphadenectomy (n=119)]. Isosulfan-blue and indocyanine-green with near-infrared imaging were used for SLN mapping. Clinico-pathological data, FIGO stage, GOG risk category, and adjuvant therapies were compared. RESULTS Non-mapped and mapped cases were comparable with respect to BMI, histology, depth-of-invasion, and lympho-vascular space invasion. The mapped group had more pelvic lymph node (LN) harvested compared to non-mapped group (26.4±10.5 vs. 18.8±8.5, p<0.001). Aortic LN yields were identical for both groups (9.0±5.6 vs. 9.0±6.0). The mapped group had more LN metastasis detected (30.3% vs. 14.7%, p<0.001), more stage IIIC (30.2% vs. 14.5%, p<0.001), more GOG high-risk cases (32.8% vs. 21.8%, p=0.013), and received more chemotherapy+radiation (28.6% vs. 16.3%, p<0.003). The SLN was the only metastasis in 18 (50%) mapped cases with positive nodes. The SLN false negative rate was 1/36 (2.8%). Micrometastases or isolated tumor cells were identified in 22/35 (62.9%) SLN metastases. Multivariate analysis demonstrated that SLN mapping imparted a significant effect on the detection of metastatic disease [adjusted OR=3.29, p<0.001]. CONCLUSIONS The performance of SLN mapping with staging lymphadenectomy increased the detection of lymph node metastasis and was associated with more use of adjuvant therapies.

Robotic transperitoneal infra-renal aortic lymphadenectomy in early-stage endometrial cancer ☆

OBJECTIVES To assess the clinical performance of robotic-assisted infra-renal aortic lymphadenectomy (IRL) using a single center-docked approach for patients with endometrial cancer. METHODS Robotic-assisted hysterectomy with pelvic and aortic lymphadenectomy was performed in 97 clinical stage I endometrial cancer (EC) patients with the intent to remove infra-renal aortic lymph nodes. Peri-operative data was contemporaneously accessioned and a retrospective database analysis was performed to examine clinical outcomes. RESULTS IRL versus infra-mesenteric artery (IMA) dissections were accomplished in 88 (90.7%) and nine (9.3%) cases, respectively. There were no laparotomy conversions. Histology included 20.6% G1, 41.2% G2, and 38.1% G3 (endometrioid and Type II histologies). Forty-four (45.4%) cases had >50% depth-of-invasion and 43 (44.3%) cases had lymphovascular space invasion. Lymph node metastases were detected in 39 (40.2%) cases [37 (38.1%) pelvic, 16 (16.5%) pelvic+aortic, two (2.1%) isolated aortic lymph nodes]. Aortic metastasis was identified in 16/37 (43.2%) pelvic node positive cases, and 6/34 (17.7%) IRL cases with positive pelvic nodes had infra-renal metastasis, yet normal aortic nodes below the IMA. Harvested aortic lymph nodes for IRL exceeded IMA cases (15.9±6.3 vs. 8.9±4.6; p<0.01). Mean BMI for IMA cases exceeded IRL cases (37.4±3.3 vs. 31.4±7.1kg/m(2); p<0.001). Twenty-five (81%) patients with BMI >35kg/m(2) underwent successful IRL (range 36-47kg/m(2)) compared to 95% of cases <35kg/m(2) (p=0.03). CONCLUSIONS IRL was accomplished in 95% of EC patients with BMI <35kg/m(2) and 81% with BMI >35kg/m(2) using a single center-docked approach. A strict 35kg/m(2) BMI cut-off for avoiding IRL is therefore not advised.

Abstract 2159: Expression of Sp1 and survivin in ovarian cancer specimens: potential novel therapeutic targets in disease treatment.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Ovarian cancer (OC) is one of the most common female cancers and is the leading cause of death from gynecologic malignancies. Although, cisplatin is the front-line chemotherapeutic option for OC, its success is compromised due to dose-limiting toxicity and acquired resistance by tumor cells. Specificity protein 1 (Sp1) is a transcription factor that is over-expressed in several cancers and is inversely associated with survival. Survivin, a member of IAP family, is known to cause resistance to chemo- and radiation therapy. Studies from our laboratories have shown that the NSAID, tolfenamic acid (TA), targets Sp1 protein and inhibits expression of survivin in various cancer models. Our primary objective was to evaluate the expression of Sp1 and survivin in OC patients’ specimens and target these candidates using TA for enhancing the cisplatin response. Expression of Sp1 and survivin in clinical specimens was determined by qPCR and Western blots. qPCR showed increased expression of survivin (∼5-fold) and Sp1 (∼2-fold) in tumor samples. Western blot also revealed over-expression of both Sp1 (>2.6-fold) and survivin (>100-fold). OC cell lines (ES2, OVCAR-3) were used to determine the anti-proliferative response to cisplatin and TA. TA and cisplatin showed a dose- and time-dependent inhibition of cell viability in OC cell lines [TA (50 ÂμM) caused 50% (ES2) and 40% (OVCAR-3) growth inhibition and cisplatin (5 ÂμM) caused 60% and 40% inhibition at 48 h post-treatment]. Combination treatment using optimized doses of TA (50 ÂμM) and cisplatin (5 ÂμM) resulted in a synergistic response and caused stronger inhibition (ES2: ∼80%, OVCAR-3: >60) compared to single-agent. Increased inhibition of proliferation by the combination of TA and cisplatin was accompanied by cell-cycle arrest, predominantly in the G2/M phase. A significant increase in apoptosis, as determined by Caspase 3/7 activity, annexin-V staining, and PARP cleavage, was also observed in the combination treatment. Cell invasion and migration was assessed using matrigel coated transwell chambers. Compared to TA or cisplatin treatment alone, their combination significantly inhibited ES2 cell invasion. Analysis of ES2 cells by global proteomic profiling indicated that the combination treatment upregulated proteins associated with oxidative phosphorylation, apoptosis, and electron transport chain; and down-regulated cytoplasmic ribosomal proteins, translational factors, and proteins involved in DNA damage response, and cell cycle. In conclusion, elevated expression of Sp1 and survivin confirmed their association in OC and demonstrated the relevance of targeting these candidates, which may render the OC cells more sensitive to chemotherapy and offer therapeutic potential. Further studies to delineate underlying mechanism(s) of action possibly involving signaling pathways and reactive oxygen species are currently underway. Citation Format: Umesh T. Sankpal, Susan B. Ingersoll, Mohammed I. Shukoor, Chris M. Lee, Nicole M. Stavitzski, Vadiraja B. Bhat, Sarfraz Ahmad, Robert W. Holloway, Liz Abraham, Riyaz Basha. Expression of Sp1 and survivin in ovarian cancer specimens: potential novel therapeutic targets in disease treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2159. doi:10.1158/1538-7445.AM2013-2159

Prognostic Significance of the Standardized Uptake Value of Pretherapeutic 18F-Labeled 2-Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography in Patients With Locally Advanced Cervical Cancer

Objectives To determine the prognostic significance of the pretreatment and posttreatment maximum standardized uptake value (SUVmax) of 18F-labeled 2-fluoro-2-deoxyglucose positron emission tomography (PET)/computed tomography imaging in patients with stage IB2–IVA cervical cancer. Methods This was a retrospective review of cervical cancer patients with International Federation of Gynecology and Obstetrics stages IB2–IVA, from March 2008 to April 2014. All patients had pretreatment and posttreatment PET imaging and received primary whole pelvic radiation therapy with concurrent radiosensitizing chemotherapy, followed by intracavitary brachytherapy. Of the 58 patients who met the inclusion criteria, 31 patients (group A) showed no evidence of disease at last follow-up, and 27 patients (group B) presented with recurrence/persistence of disease. Results The mean pretreatment SUVmax in group A was 17.65 ± 7.82 versus 18.8 ± 7.77 in group B (P = 0.577). The mean posttreatment SUVmax between the groups was 0.85 ± 1.83 versus 6.05 ± 3.01 (P < 0.001), respectively. The mean difference between pretreatment and posttreatment SUVmax was 17.73 ± 7.50 in group A versus 13.29 ± 7.15 in group B (P = 0.045). In group A, 80.7% of patients demonstrated no posttreatment hypermetabolic activity on PET imaging versus 11.1% in group B. Of the patients who experienced treatment failure, the site of failure was pelvic in 25.9%, distant in 44.4%, and both pelvic and distant in 29.6%. Conclusions No threshold was identified for the pretreatment SUVmax relative to the risk of recurrence. However, distinct correlations were found between the risk of recurrence, percent reduction in SUVmax, and the observation of residual hypermetabolic activity. This finding may help identify candidates for sequential chemotherapy.