Vaginal Recurrence More than 17 Years after Hysterectomy and Adjuvant Treatment for Uterine Carcinoma with Successful Salvage Brachytherapy: A Case Report

Purpose: Although the majority of recurrences occur within the first 3 years of hysterectomy for endometrioid carcinoma, we report herein a successful salvage vaginal brachytherapy in a patient with endometrioid uterine carcinoma which recurred more than 17 years after initial treatment. Materials and Methods: A 61-year-old female was diagnosed with endometrioid adenocarcinoma of the uterus and treated with TAH-BSO, followed by adjuvant external beam radiation therapy (EBRT) to the whole pelvis. After remaining free of any recurrent or metastatic disease for more than 17 years, she was diagnosed with isolated vaginal cuff recurrence and successfully treated with a salvage high-dose-rate intracavitary vaginal brachytherapy. Results: The patient remained disease free until her death from unrelated causes 7 years later. Conclusion: To the best of our knowledge, this case represents the longest time to recurrence of endometrial cancer in someone who had been treated with TAH-BSO and adjuvant pelvic EBRT. This case highlights that even with adjuvant therapy, late recurrences may occur, and successful salvage brachytherapy is very effective

Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB

<p>Abstract</p> <p>Background</p> <p>Platinum-resistance (PR) continues to be a major problem in the management of epithelial ovarian cancer (EOC). Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells <it>in vitro </it>and <it>in vivo </it>by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS) and resistant EOC cells.</p> <p>Methods</p> <p>The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA) was used to evaluate NF-κB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP.</p> <p>Results</p> <p>Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-κB DNA binding activity were all found to be down-regulated in the combination groups.</p> <p>Conclusion</p> <p>This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.</p

Bioenergetic Adaptations in Chemoresistant Ovarian Cancer Cells.

Earlier investigations have revealed that tumor cells undergo metabolic reprogramming and mainly derive their cellular energy from aerobic glycolysis rather than oxidative phosphorylation even in the presence of oxygen. However, recent studies have shown that certain cancer cells display increased oxidative phosphorylation or high metabolically active phenotype. Cellular bioenergetic profiling of 13 established and 12 patient derived ovarian cancer cell lines revealed significant bioenergetics diversity. The bioenergetics phenotype of ovarian cancer cell lines correlated with functional phenotypes of doubling time and oxidative stress. Interestingly, chemosensitive cancer cell lines (A2780 and PEO1) displayed a glycolytic phenotype while their chemoresistant counterparts (C200 and PEO4) exhibited a high metabolically active phenotype with the ability to switch between oxidative phosphorylation or glycolysis. The chemosensitive cancer cells could not survive glucose deprivation, while the chemoresistant cells displayed adaptability. In the patient derived ovarian cancer cells, a similar correlation was observed between a high metabolically active phenotype and chemoresistance. Thus, ovarian cancer cells seem to display heterogeneity in using glycolysis or oxidative phosphorylation as an energy source. The flexibility in using different energy pathways may indicate a survival adaptation to achieve a higher \u27cellular fitness\u27 that may be also associated with chemoresistance

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary

Background:The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT).Methods:Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Student's t-test, Kaplan–Meier and Cox proportional hazard methods.Results:In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND−1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND−1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62–2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67–10.96, P=0.16).Conclusion:Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan–Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III–IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I–II (74, 82, and 86%; P<0.0001) and stage III–IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients

Analysis of the expression of human tumor antigens in ovarian cancer tissues

Biomarkers for early detection of cancer have great clinical diagnostic potential. Numerous reports have documented the generation of humoral immune responses that are triggered in response to changes in protein expression patterns in tumor tissues and these biomarkers are referred to as tumor associated antigens (TAAs). Using a high-throughput technology, we previously identified 65 proteins as diagnostically useful TAAs by profiling the humoral immune responses in ovarian cancer (OVCA) patients. Here we determined the expression status of some of those TAAs in tissues from OVCA patients. The protein expression patterns of 4 of those 65 antigens, namely NASP, RCAS1, Nijmegen breakage syndrome1 (NBS1) and eIF5A, along with p53 and Her2 (known molecular prognosticators) and two proteins that interact with NBS1, MRE11 and RAD50, were assessed by immunohistochemistry (IHC). NASP and RCAS1 proteins were more frequently expressed in ovarian cancer tissues than with normal ovarian tissue and serous cystadenomas and MRE11 was less frequently expressed. When evaluated simultaneously, only NASP and MRE11 remained statistically significant with sensitivity of 66% and specificity of 89%. None of these proteins’ expression levels were prognostic for survival. Together, our results indicate that occurrence of humoral immune responses against some of these TAAs in OVCA patients is triggered by antigen protein overexpression

Secondary cytoreductive surgery for recurrent epithelial ovarian carcinoma: proposal for patients selection

The value of secondary cytoreductive surgery (SCS) for recurrent ovarian cancer is still controversial. The aim of this study was to clarify candidates for SCS. Between January 1987 and September 2000, we performed SCS in 44 patients with recurrent ovarian cancer, according to our selection criteria, disease-free interval (DFI) >6 months, performance status <3, no apparent multiple diseases, age <75years and no progressive disease during preoperative chemotherapy, if undertaken. The variables were investigated by univariate and multivariate analyses. Of 44 patients, 26 (59.1%) achieved complete removal of all visible tumours at SCS. Secondary cytoreductive surgery outcome, complete or incomplete resection, was significantly related to overall survival (P=0.0019). As for variables determined before SCS, DFI >12 months, no liver metastasis, solitary tumour and tumour size <6 cm were independently associated with favourable overall survival after recurrence in the multivariate analysis. Patients with three or all four variables (n=31) had significantly better survival compared with the other patients (n=13) (47 vs 20 months in median survival, P<0.0001). In these patients, fairly good median survival (40 months) was obtained even in patients with incomplete resection. Secondary cytoreductive surgery had a large impact on survival of patients with recurrent ovarian cancer when they had three or all of the above-mentioned four factors at recurrence. These patients should be considered as ideal candidates for SCS

Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model

INTRODUCTION: The purpose of the present study was to determine whether cytotoxic chemotherapeutic agents administered prior to immunotherapy with gene vaccines could augment the efficacy of the vaccines. METHODS: Mice were injected in the mammary fat pad with an aggressive breast tumor cell line that expresses HER2/neu. The mice were treated 3 days later with a noncurative dose of either doxorubicin or paclitaxel, and the following day with a gene vaccine to HER2/neu. Two more doses of vaccine were given 14 days apart. Two types of gene vaccines were tested: a plasmid vaccine encoding a self-replicating RNA (replicon) of Sindbis virus (SINCP), in which the viral structural proteins were replaced by the gene for neu; and a viral replicon particle derived from an attenuated strain of Venezuelan equine encephalitis virus, containing a replicon RNA in which the Venezuelan equine encephalitis virus structural proteins were replaced by the gene for neu. RESULTS: Neither vaccination alone nor chemotherapy alone significantly reduced the growth of the mammary carcinoma. In contrast, chemotherapy followed by vaccination reduced tumor growth by a small, but significant amount. Antigen-specific CD8(+ )T lymphocytes were induced by the combined treatment, indicating that the control of tumor growth was most probably due to an immunological mechanism. The results demonstrated that doxorubicin and paclitaxel, commonly used chemotherapeutic agents for the treatment of breast cancer, when used at immunomodulating doses augmented the antitumor efficacy of gene vaccines directed against HER2/neu. CONCLUSIONS: The combination of chemotherapeutic agents plus vaccine immunotherapy may induce a tumor-specific immune response that could be beneficial for the adjuvant treatment of patients with minimal residual disease. The regimen warrants further evaluation in a clinical setting

Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

INTRODUCTION: Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. METHODS: MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. RESULTS: The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E(2 )secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G(0)/G(1 )checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E(2 )in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. CONCLUSION: The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor