Heidi Godoy

Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients

Recombinant poxviruses (vaccinia and fowlpox) expressing tumor-associated antigens are currently being evaluated in clinical trials as cancer vaccines to induce tumor-specific immune responses that will improve clinical outcome. To test whether a diversified prime and boost regimen targeting NY-ESO-1 will result in clinical benefit, we conducted two parallel phase II clinical trials of recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1), followed by booster vaccinations with recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in 25 melanoma and 22 epithelial ovarian cancer (EOC) patients with advanced disease who were at high risk for recurrence/progression. Integrated NY-ESO-1-specific antibody and CD4+ and CD8+ T cells were induced in a high proportion of melanoma and EOC patients. In melanoma patients, objective response rate [complete and partial response (CR+PR)] was 14%, mixed response was 5%, and disease stabilization was 52%, amounting to a clinical benefit rate (CBR) of 72% in melanoma patients. The median PFS in the melanoma patients was 9 mo (range, 0–84 mo) and the median OS was 48 mo (range, 3–106 mo). In EOC patients, the median PFS was 21 mo (95% CI, 16–29 mo), and median OS was 48 mo (CI, not estimable). CD8+ T cells derived from vaccinated patients were shown to lyse NY-ESO-1-expressing tumor targets. These data provide preliminary evidence of clinically meaningful benefit for diversified prime and boost recombinant pox-viral-based vaccines in melanoma and ovarian cancer and support further evaluation of this approach in these patient populations.

Synuclein-γ (SNCG) protein expression is associated with poor outcome in endometrial adenocarcinoma

OBJECTIVE Synuclein-γ (SNCG) is a marker for adverse and aggressive disease in breast cancer. In previous study, we found SNCG mRNA to be overexpressed in uterine serous carcinoma compared to uterine endometrioid adenocarcinoma. The aim of this study is to explore the prognostic value of SNCG in patients with endometrial cancer. METHODS 279 endometrial cancer patients were retrieved from the archives. The tissue paraffin blocks were stained for SNCG antibody and its expression was correlated with clinicopathological prognostic factors. RESULTS There was a positive association between SNCG(+) immunoexpression and tumor grade, tumor stage, type II carcinomas, deep myometrial invasion and lymphovascular invasion. A correlation between SNCG(+) and adverse outcomes, such as shorter overall survival (OS) and disease free survival (DFS), was also detected. Following adjuvant therapy (radiation and chemotherapy or chemotherapy alone), we observed a difference in 5years DFS rate between SNCG(+) (41.6%) and SNCG(-) patients (59.5%). CONCLUSION Overexpression of SNCG seemed to be a predictor biomarker for aggressive tumor behavior and adverse outcome in patients with endometrial cancer. Future exploration of SNCG as a potential therapeutic target for selected patients could be of interest.

Expression of poly (adenosine diphosphate-ribose) polymerase and p53 in epithelial ovarian cancer and their role in prognosis and disease outcome.

PARP, poly (adenosine diphosphate-ribose) polymerase, is a damage-sensing protein, which is essential for the repair of DNA single-strand breaks. PARP and p53 function synergistically in repairing DNA damage and suppressing chromosomal rearrangements. The aim of this study was to determine the expression of PARP and p53 in epithelial ovarian cancer (EOC) and to correlate their expression with clinicopathologic characteristics. PARP and p53 were evaluated using immunohistochemistry applied on a tissue microarray of 189 EOC and their expressions were correlated to clinicopathologic variables, including the age of diagnosis, stage, grade, histologic type, optimal debulking, progression-free survival, and overall survival (OS). PARP and p53 expressions were shown in 61% and 54% of cases, respectively. PARP-positive tumors are more likely to have higher grade (P=0.03) and complete response to initial first-line chemotherapy (P=0.009). Patients with positive p53 staining are more likely to be at the advanced stage disease (P=0.004). Finally, there were no significant associations between PARP and p53 expression and no differences in progression-free survival and OS for PARP or p53 expressions. The overexpression of PARP and p53 in high grade, and advanced stage tumors indicated that these 2 markers might serve as an indicator of aggressive disease behavior. Additional studies are warranted to evaluate the role of PARP and PARP inhibitors in the setting of adjuvant chemotherapy.

Tumor lysis syndrome associated with carboplatin and paclitaxel in a woman with recurrent endometrial cancer.

⁎ Corresponding author. Division of Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Tel.: +1 716 845 5776; fax: +1 716 845 7608. E-mail address: Shashi.Lele@roswellpark.org (S. Lele). Tumor lysis syndrome (TLS) consists of a constellation of metabolic derangements including hyperuricemia, hyperkalemia, hyperphosphatemia, uremia, and hypocalcemia, usually triggered by cytotoxic chemotherapy. It results from the lysis of malignant cells with a resultant immense and rapid release of cellular contents from lysed neoplastic cells. TLS is rare in solid tumors [1]. Here we describe a patient who developed TLS after carboplatin and paclitaxel for recurrent endometrial cancer. A 60-year-old woman with a history of FIGO stage IIB uterine cancer receiving carboplatin and paclitaxel for recurrent endometrial cancer presented to the emergency room with shortness of breath. The patient had received carboplatin and paclitaxel 4 days previously. She admitted to a several day history of shortness of breath, weakness, and fatigue. Upon arrival she was hypotensive and tachycardic. Physical examination showed that the woman was in discomfort with decreased breath sounds at the lung bases and a diffusely tender abdomen. Laboratory evaluation revealed several abnormalities (Table 1). A CT scan showed bilateral atelectasis with consolidation at the lung bases and multiple mesenteric and peritoneal implants. The patient was given empiric antibiotics and intravenous hydration for suspected septicemia. Repeat lab values revealed worsening metabolic abnormalities consistent with TLS (Table 1). Despite aggressive interventions including dialysis and attempted correction of her metabolic and electrolyte derangements, her condition deteriorated and she died on hospital day 2. TLS is exceedingly rare in solid malignancies. In a review by Baeksgaard and Sørensen [1], they noted only 45 cases of TLS had been reported in patients with solid tumors. We are aware of only 5 reported cases occurring in gynecologic malignancies [1–3]. TLS results from the lysis of tumor cells with the release of their intracellular contents into the bloodstream. This leads to metabolic derangements including hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and elevated lactate dehydrogenase (LDH). These electrolyte abnormalities, if uncorrected, can lead to cardiovascular, renal, and neuromuscular compromise. Clinically, patients may present with acute renal failure, nausea, vomiting, diarrhea, anorexia, hematuria, cardiac arrhythmias, seizures, hypotension, and neuromuscular symptoms, including muscle cramps and paresthesia [4]. Our patient presented with shortness of breath, fatigue, and malaise. Laboratory evaluation revealed profound electrolyte disturbances. She required hemodialysis secondary to renal failure and metabolic derangements. Unfortunately, this patients condition deteriorated rapidly and she died 2 days after presentation and aggressive management. The mortality rate of TLS associated with solid tumors is 1 in 3 [1]. The optimal management of TLS is its prevention. Effective prevention involves recognition of those at risk with close monitoring and frequent assessment for electrolyte abnormalities. Patients at risk should receive aggressive hydration and diuresis with administration of an antihyperuricemic agent (e.g. allopurinol, rasburicase) [4]. We report a case of TLS in a patient receiving carboplatin and paclitaxel for recurrent endometrial cancer. Despite the infrequency of its occurrence in the gynecologic oncology setting, clinicians need to be aware of those at risk, its clinical and laboratory presentation, treatment, and prophylaxis because of its potential lethality.

Pair Box 8 (PAX8) protein expression in high grade, late stage (stages III and IV) ovarian serous carcinoma

OBJECTIVES Pair-Box 8 (PAX8) is a transcription factor which has been found to be overexpressed in ovarian serous carcinoma (OSC). Silencing PAX8 by using shRNA led to a drop in cell viability in ovarian cancer cell lines, suggesting its use as a targeted therapeutic agent. The prognostic value of PAX8 in OSC is still widely unknown. The aim of this study was to evaluate PAX8 as a prognostic biomarker in patients with advanced stage OSC. METHODS PAX8 was evaluated using immunohistochemistry on a tissue microarray of 148 OSC and the expression was correlated to the following clinico-pathologic variables; age of diagnosis, tumor stage, optimal debulking, recurrence free survival (RFS) and overall survival (OS). RESULTS We found that PAX8 was expressed in 61% of cases. There was no association between PAX8 and tumor stage, optimal debulking and disease recurrence. In addition, PAX8 failed to have a predictive value in disease outcome. CONCLUSION Despite showing that PAX8 protein is not a useful predictive marker in patients with high grade, advanced stage OSC, its overexpression in a large number of these cases makes the inhibition of PAX8 a very attractive targeted therapy.

Pair-Box (PAX8) protein-positive expression is associated with poor disease outcome in women with endometrial cancer

Background:The Pax8 transcription factor genes have a role in cell differentiation and cell growth, and silencing of Pax8 in cell cultures results in cell death. The aims of this study were to determine the expression and correlation of Pax8 protein with several clinicopathological variables in patients with endometrial cancer.Methods:The following clinical parameters from 229 patients were used for correlation with Pax8 expression; age, histological subtype, myometrial depth of invasion, lymphovascular invasion (LVI), the International Federation of Gynecology and Obstetrics grade, lymph nodes status, and disease status.Results:A positive association of Pax8+ expression was found with high tumour grade (P=0.002), LVI+(P=0.0186), and type II tumour subtype (P<0.0001) in univariate analysis. Survival analysis showed an association of Pax8 and 5-year overall survival probability (P=0.01486), 80.04% for patients with Pax8− and 55.59% for patients with Pax8+. There was also an association of Pax8 and 5-year disease-free survival probability (P=0.02028), 72.12% for patients with Pax8− vs 49.88% for patients with Pax8+. Finally, an association of Pax8+ and shorter recurrence-free survival was also found (P=0.00203), with 74.36% for Pax8− and 52.11% for Pax8+.Conclusion:Overexpression of Pax8 protein by endometrial cancer is associated with poor disease outcomes. Inhibition of Pax8 may be a very attractive targeted therapy for selective patients.

Myeloid-derived suppressor cells modulate immune responses independently of NADPH oxidase in the ovarian tumor microenvironment in mice.

The phagocyte NADPH oxidase generates superoxide anion and downstream reactive oxidant intermediates in response to infectious threat, and is a critical mediator of antimicrobial host defense and inflammatory responses. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are recruited by cancer cells, accumulate locally and systemically in advanced cancer, and can abrogate anti-tumor immunity. Prior studies have implicated the phagocyte NADPH oxidase as being an important component promoting MDSC accumulation and immunosuppression in cancer. We therefore used engineered NADPH oxidase-deficient (p47phox−/−) mice to delineate the role of this enzyme complex in MDSC accumulation and function in a syngeneic mouse model of epithelial ovarian cancer. We found that the presence of NADPH oxidase did not affect tumor progression. The accumulation of MDSCs locally and systemically was similar in tumor-bearing wild-type (WT) and p47phox−/− mice. Although MDSCs from tumor-bearing WT mice had functional NADPH oxidase, the suppressive effect of MDSCs on ex vivo stimulated T cell proliferation was NADPH oxidase-independent. In contrast to other tumor-bearing mouse models, our results show that MDSC accumulation and immunosuppression in syngeneic epithelial ovarian cancer is NADPH oxidase-independent. We speculate that factors inherent to the tumor, tumor microenvironment, or both determine the specific requirement for NADPH oxidase in MDSC accumulation and function.

Malignant melanoma arising in mature cystic teratoma of the ovary

► Teratomas are composed of elements of all three germ layers, all potentially capable of undergoing malignant transformation. ► A case of malignant melanoma arising in a mature teratoma is presented.

Developmentally restricted differentiation antigens are targets for immunotherapy in epithelial ovarian carcinoma.

Developmentally restricted differentiation antigens or cancer-placental antigens, tastin and bystin, are components of an adhesion molecule that plays a critical role in the implantation of the embryo to the uterus. Cell adhesion molecules have been implicated in the metastasis of carcinomas and could be critical targets for immunotherapy in epithelial ovarian carcinomas (EOCs). Our objectives were to define the expression of tastin and bystin proteins in EOCs. Expression of tastin and bystin mRNA in a panel of human tissues and 70 EOC specimens was investigated using qualitative polymerase chain reaction. Amplification products were confirmed by sequencing. Validation of results was performed using immunohistochemical analysis of tastin and bystin applied on a tissue microarray of 202 EOC tissues. The distribution of tastin and bystin expression and clinicopathologic variables were analyzed. Survival probabilities were estimated using the Kaplan–Meier method and statistical significance was determined by performing the logrank test. Expression of tastin and bystin was restricted to placental and testis tissue by qualitative polymerase chain reaction. Of the 70 EOC specimens tested with polymerase chain reaction, 89% and 94% expressed tastin and bystin, respectively. Immunoexpressions of tastin and bystin protein were observed in 69% and 80 % of the ovarian tumors, respectively. Tastin and bystin expression in Stage I/II disease were 66% and 67% compared with 69% and 81% in Stage III/IV disease, respectively. The tissue-restricted expression of tastin and bystin and their abundant expression in EOCs and advanced-stage disease make these developmentally restricted antigens attractive targets for antigen-specific immunotherapy in EOCs.

Pyrimidine base damage is increased in women with BRCA mutations

Oxidatively-induced DNA damage was measured in the DNA of WBC from two groups of women: carriers of a BRCA mutation, but asymptomatic for disease, and healthy controls. Two oxidatively induced lesions were measured: a formamide remnant of pyrimidine base and the glycol modification of thymine. These lesions, employed previously in studies of the effects of smoking, antioxidant usage and ovarian cancer, are proving valuable indicators of oxidative stress. The BRCA carriers of mutations, with no overt sign of cancer, nevertheless had significantly higher levels of DNA damage than the controls. The level measured for the formamide lesion was 5.9 ± 1.0 (femtomoles/μg of DNA ± SEM) compared with 2.4 ± 0.3 in controls. The level of the glycol lesion was 2.9 ± 0.4 compared with 1.8 ± 0.2 in controls. The experimental design utilized DNA from WBC and employed LC-MS/MS to detect the lesions.