Association between Obesity, Surgical Route, and Perioperative Outcomes in Patients with Uterine Cancer.

OBJECTIVE: To study temporal trends of hysterectomy routes performed for uterine cancer and their associations with body mass index (BMI) and perioperative morbidity. METHODS: A retrospective review of the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) 2005-2013 databases was conducted. All patients who were 18 years old and older with a diagnosis of uterine cancer and underwent hysterectomy were identified using ICD-9-CM and CPT codes. Surgical route was classified into four groups: total abdominal hysterectomy (TAH), total vaginal hysterectomy (TVH), laparoscopic assisted vaginal hysterectomy (LAVH), and total laparoscopic hysterectomy (TLH) including both conventional and robotically assisted. Patients were then stratified according to BMI. RESULTS: 7199 records were included in the study. TLH was the most commonly performed route of hysterectomy regardless of BMI, with proportions of 50.9%, 48.9%, 50.4%, and 51.2% in ideal, overweight, obese, and morbidly obese patients, respectively. The median operative time for TAH was 2.2 hours compared to 2.7 hours for TLH (p < 0.01). The median length of stay for TAH was 3 days compared to 1 day for TLH (p < 0.01). The percentage of patients with an adverse outcome (composite indicator including transfusion, deep venous thrombosis, and infection) was 17.1 versus 3.7 for TAH and TLH, respectively (p < 0.01). CONCLUSION: During the last decade, TLH has been increasingly performed in women with uterine cancer. The increased adoption of TLH was seen in all BMI subgroups.

Total Laparoscopic Hysterectomy in the Setting of Prior Bilateral Renal Transplant, a Case Report and Review of the Literature.

In recent years, more women are undergoing renal transplantation as a treatment for end-stage renal disease. Women with kidney transplants are prone to certain gynecologic issues which might necessitate hysterectomy. Laparoscopic hysterectomy can safely be performed in patients with prior unilateral or bilateral renal transplantation. Laparoscopy offers magnification of anatomy, decreased wound-related problems, and continuation of immunosuppression therapy. We present a case report and review of the literature for total laparoscopic hysterectomy and bilateral salpingectomy for a patient with prior bilateral renal transplant.

Laparoscopic Hemi-hysterectomy and Trachelectomy in a Case of Herlyn-Werner-Wunderlich Syndrome.

BACKGROUND: Herlyn-Werner-Wunderlich Syndrome (HWWS) is a rare Müllerian anomaly characterized by uterus didelphys coexisting with an obstructed hemivagina and ipsilateral renal agenesis. CASE: A 13-year-old female presented one-year after menarche with severe dysmenorrhea and a right-sided pelvic mass. Imaging identified a right uterus with hematometra, hematocolpos, absent right kidney, normal left kidney, ureter, left uterus, and vagina compressed to the left by right hematocolpos. We performed laparoscopic hemi-hysterectomy of the non-communicating hemi-uterus, and laparoscopic trachelectomy. CONCLUSION: Laparoscopic hemi-hysterectomy and trachelecotmy is a minimally invasive surgical option for patients with Herlyn-Werner-Wunderlich Syndrome.

BAD-mediated apoptotic pathway is associated with human cancer development.

The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

The Chinese herb polyphyllin D sensitizes ovarian cancer cells to cisplatin-induced growth arrest.

PURPOSE: We evaluated the effects of polyphyllin D (PD), a natural compound with anti-neoplastic activity and a major component of the Chinese herb Paris polyphylla, on ovarian cancer (OVCA) cell line proliferation and platinum sensitivity. METHODS: A panel of 20 OVCA cell lines was subjected to PD treatment, MTS proliferation assays, and determination of IC50. Pre-treatment, baseline genome-wide Affymetrix expression analysis was performed on each cell line, and Pearson's correlation was performed to identify genes associated with OVCA PD sensitivity. Twelve cell lines were treated with PD with and without cisplatin, and the effects of PD on cisplatin IC50 were quantified. Genes associated with OVCA PD sensitivity were evaluated for associations with survival in a publically available clinico-genomic dataset of 218 patients with OVCA. RESULTS: Our results showed that PD exhibited anti-proliferative effects against all OVCA cell lines tested, with IC50 values ranging from 0.2 to 1.4 µm. Furthermore, in all cell lines, PD treatment significantly decreased cisplatin IC50 (mean IC50 reduction of 2.1 µm; P < 0.02). Pearson's correlation test identified 25 probe sets, representing 18 unique genes to be associated with PD sensitivity (FDR = 0). We found that one of these genes was associated with overall survival in women with OVCA: CLDN4 (P = 0.014). CONCLUSION: Our findings highlight the value of PD as a natural product with anti-cancer properties, which may also enhance the activity of existing therapeutic agents.

Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer.

OBJECTIVE: The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival. STUDY DESIGN: Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied. RESULTS: Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration. CONCLUSION: Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.

Perifosine, an AKT inhibitor, modulates ovarian cancer cell line sensitivity to cisplatin-induced growth arrest.

OBJECTIVES: AKT, a key regulator of diverse tumor signaling, is associated with progression of many cancers. Here, we investigated 1) the influence of AKT on survival from ovarian cancer (OVCA), 2) the activity of the AKT inhibitor perifosine ± cisplatin, and 3) the molecular determinants of perifosine-response. Phospho-AKT expression values and Affymetrix U133a expression data were downloaded from The Cancer Genome Atlas. METHODS: Pearson correlation was used to determine associations between overall survival from OVCA and therapy response. Genes and represented signaling pathways associated with perifosine-response were explored in OVCA cells (n=10) and the NCI60 cancer cell panel. Pathway expressions, modeled by PCA, were evaluated for influences on survival using publically available clinico-genomic datasets. RESULTS: Phospho-AKT (serine473) expression correlated with survival from OVCA (P<0.05) and platinum-response (P=0.004). In vitro, perifosine showed anti-proliferative effects against OVCA cells and potentiated cisplatin-induced growth arrest. Perifosine-response was associated with the expression (FDR<0.05) of 7 signaling pathways in OVCA cells and 64 signaling pathways in the NCI60 cell panel. Three pathways were found in common: 1) Cytoskeleton remodeling/cytoskeleton remodeling (cyto), 2) cell adhesion/chemokines and adhesion (chemokines), and 3) cytoskeleton remodeling/TGF-WNT (TGF-WNT). The TGF-WNT was associated with survival from OVCA (P=0.0055). CONCLUSIONS: AKT signaling is an important determinant of OVCA response to chemotherapy and overall patient survival. Our data provide insight into the molecular basis to perifosine activity and identifies pathways associated with perifosine sensitivity and patient clinical outcome.

A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth.

Elevated serum levels of hepatocyte growth factor (HGF) and high tumor expression of c-Met are both indicators of poor overall survival from ovarian cancer (OVCA). In the present study, we evaluated the role of the HGF signaling pathway in OVCA cell line chemoresistance and OVCA patient overall survival as well as the influence of HGF/c-Met signaling inhibition on the sensitivity of OVCA cells to combinational carboplatin plus paclitaxel therapy. The prevalence of the HGF receptor, c-Met, was determined by immunohistochemistry in primary OVCA samples (n=79) and OVCA cell lines (n=41). The influence of the c-Met-specific inhibitor MK8033 on OVCA cell sensitivity to combinations of carboplatin plus paclitaxel was examined in a subset of OVCA cells (n=8) by CellTiter-Blue cell viability assays. Correlation tests were used to identify genes associated with response to MK8033 and carboplatin plus paclitaxel. Identified genes were evaluated for influence on overall survival from OVCA using principal component analysis (PCA) modeling in an independent clinical OVCA dataset (n=218). Immunohistochemistry analysis indicated that 83% of OVCA cells and 92% of primary OVCA expressed the HGF receptor, c-Met. MK8033 exhibited significant anti-proliferative effects against a panel of human OVCA cell lines. Combination index values determined by the Chou-Talalay isobologram equation indicated synergistic activity in combinations of MK8033 and carboplatin plus paclitaxel. Pearson's correlation identified a 47-gene signature to be associated with MK8033-carboplatin plus paclitaxel response. PCA modeling indicated an association of this 47-gene response signature with overall survival from OVCA (P=0.013). These data indicate that HGF/c-Met pathway signaling may influence OVCA chemosensitivity and overall patient survival. Furthermore, HGF/c-Met inhibition by MK8033 represents a promising new therapeutic avenue to increase OVCA sensitivity to carboplatin plus paclitaxel.

Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity.

OBJECTIVE: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists. METHODS: In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level. RESULTS: We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate < 0.2) representing 27 biologic pathways (P < 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity. CONCLUSIONS: Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE's effect on human cancer cells.