Eirini Pectasides

Germ cell tumors of the ovary

PURPOSE Malignant ovarian germ cell tumors (MOGCTS) are rare but curable at all stages of disease. This review gives an outline of the management of this disease. METHODS We performed a literature search in the PubMed of almost all relevant articles concerning MOGCTs on pathology, prognostic factors, surgery, post-operative therapy and late effects of therapy. The available literature is mainly composed of retrospective reviews and articles. RESULTS Prognostic factors include stage, amount of residual tumor, histologic type and raised tumor markers. For patients with early stage disease, cure rates approach 100%, while for those with advanced-stage disease are at least 75%. Appropriate surgical treatment for patients where fertility needs to be preserved consists in laparotomy with unilateral salpingo-oophorectomy (USO) and resection of all visible disease. For patients with advanced-stage disease, the role and the extent of debulking surgery remain controversial despite its routine use. However, it is suggested a benefit from minimal residual disease at completion of primary surgical cytoreduction with both non-platinum and platinum-based chemotherapy regimens. Second-look surgery clearly is not indicated in patients with early stage non-dysgerminoma or in all patients with dysgerminoma. However, teratoma patients may benefit from secondary cytoreduction. Three courses of bleomycin, etoposide and cisplatin (BEP) is the current standard adjuvant chemotherapy and four courses of BEP are recommended in case of bulky residual tumor after surgery. More evidence is required to show that surveillance is a safe option. There is a hint that high-dose chemotherapy may play a role in relapsed patients. The majority of MOGCTs patients who undergo fertility-sparing surgery and chemotherapy retain their gonadal and reproductive function. There is an increasing concern about life-threatening long-term effects of treatment. CONCLUSION MOGCTs are rare neoplasms that affect girls and young women and have excellent prognosis at all stages of disease with optimal therapy. The majority of MOGCTs patients retain their reproductive function.

Activation of Wnt Signaling Pathway by Human Papillomavirus E6 and E7 Oncogenes in HPV16-Positive Oropharyngeal Squamous Carcinoma Cells

We sought to determine the role of human papillomavirus (HPV) E6 and E7 oncogenes in nuclear β-catenin accumulation, a hallmark of activated canonical Wnt signaling pathway. We used HPV16-positive oropharyngeal cancer cell lines 147T and 090, HPV-negative cell line 040T, and cervical cell lines SiHa (bearing integrated HPV16) and HeLa (bearing integrated HPV18) to measure the cytoplasmic and nuclear β-catenin levels and the β-catenin/Tcf transcriptional activity before and after E6/E7 gene silencing. Repression of HPV E6 and E7 genes induced a substantial reduction in nuclear β-catenin levels. Luciferase assay showed that transcriptional activation of Tcf promoter by β-catenin was lower after silencing. The protein levels of β-catenin are tightly regulated by the ubiquitin/proteasome system. We therefore performed expression analysis of regulators of β-catenin degradation and nuclear transport and showed that seven in absentia homologue (Siah-1) mRNA and protein levels were substantially upregulated after E6/E7 repression. Siah-1 protein promotes the degradation of β-catenin through the ubiquitin/proteasome system. To determine whether Siah-1 is important for the proteasomal degradation of β-catenin in HPV16-positive oropharyngeal cancer cells, we introduced a Siah-1 expression vector into 147T and 090 cells and found substantial reduction of endogenous β-catenin in these cells. Thus, E6 and E7 are involved in β-catenin nuclear accumulation and activation of Wnt signaling in HPV-induced cancers. In addition, we show the significance of the endogenous Siah-1–dependent ubiquitin/proteasome pathway for β-catenin degradation and its regulation by E6/E7 viral oncoproteins in HPV16-positive oropharyngeal cancer cells. Mol Cancer Res; 8(3); 433–43

Chemotherapy for recurrent cervical cancer

PURPOSE Cervical cancer is the second most common cancer of women worldwide and one of the leading cause of death in relative young women. This review gives an outline of chemotherapy of advanced, persistent or recurrent cervical cancer. METHODS We performed a literature search in the PubMed of almost all relevant articles concerning chemotherapy of advanced, persistent or recurrent cervical cancer. RESULTS The available data from the literature is mainly composed of most recent reviews, phase II and randomized phase III clinical trials. CONCLUSION Single-agent cisplatin remains the current standard therapy for advanced, persistent or recurrent cervical cancer. Several single-agents have been tested, but none has been found to be superior compared to cisplatin. Both topotecan and paclitaxel in combination with cisplatin, have yielded superior response rates and progression-free survival without diminishing patient quality of life. However, only the combination of cisplatin and topotecan has improved overall survival. It is important to identify clinical and tumor-related factors predictive of response to cisplatin-based chemotherapy. Future trials are necessary, not only to compare combinations of existing agents, but to incorporate biological agents (monoclonal antibodies or small molecules) to chemotherapy in order to improve the treatment results of advanced, persistent or recurrent cervix cancer.

Carboplatin and paclitaxel in advanced or metastatic endometrial cancer

OBJECTIVES The purpose of this study was to evaluate the activity and toxicity of carboplatin and paclitaxel combination in advanced or recurrent endometrial carcinoma. METHODS Forty-seven eligible patients with measurable advanced or recurrent endometrial carcinoma were treated with carboplatin [area under the curve (AUC) 5] and paclitaxel 175 mg/m(2) every 3 weeks for 6-9 cycles or until disease progression or unacceptable toxicity. RESULTS There were 10 complete responses (CRs) (21%) and 19 partial responses (PRs) (41%) for an overall response rate (RR) of 62% (29 patients) (95% confidence interval [CI], 47-76%). The median progression-free survival (PFS) was 15 months (95% CI, 7.3-22.7 months) and the median overall survival (OS) was 25 months (95% CI, 19.0-31.0 months). No difference was found in RR and OS in patients with primary advanced disease and those with recurrent tumors. Similarly, no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 36% of patients and 6% experienced febrile neutropenia. One patient each developed grade 4 thrombocytopenia and anemia. Grade 3 sensory neuropathy was recorded in 6% of patients. CONCLUSION The combination of carboplatin and paclitaxel appears to have activity in advanced or recurrent endometrial carcinoma with an acceptable toxicity profile.

Quantitative assessment shows loss of antigenic epitopes as a function of pre-analytic variables.

Pre-analytic variables, specifically cold ischemic time, have been implicated as key variables in the measurement of proteins by immunohistochemistry. To determine the significance and magnitude of antigenic loss due to pre-analytic variables, we have compared protein antigenicity in core needle biopsies, with essentially no cold ischemic time, with that in routinely processed tumor resection specimens. Two cohorts of matched core needle biopsies and tumor resections were collected with 20 matched pairs and 14 matched pairs, respectively. Both series were analyzed by quantitative immunofluorescence using the AQUA® method. Epitopes phospho-ERK, total ERK, phospho-AKT, total AKT, phospho-S6K1, total S6K1, estrogen receptor (ER), Ki67, cytokeratin and GAPDH were assessed. Detection levels for all phospho-epitopes were significantly decreased in tumor resections compared with biopsies while no significant change was seen in the corresponding total proteins. Of the other four proteins examined, ER and cytokeratin showed significant loss of antigenicity. This data suggest that measurement of phospho-protein antigenicity in formalin-fixed tissue by immunological methods is dramatically affected by pre-analytic variables. This study suggests that core needle biopsies are more accurate for assessment of tissue biomarkers.

Comparative Prognostic Value of Epidermal Growth Factor Quantitative Protein Expression Compared with FISH for Head and Neck Squamous Cell Carcinoma

Purpose: Epidermal growth factor receptor (EGFR) overexpression correlates with recurrence and with treatment resistance in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the relationship of EGFR gene copy number utilizing FISH and protein expression with automated quantitative analysis (AQUA) and to correlate those with patient outcome. Experimental Design: A tissue microarray composed of 102 HNSCC treated with (chemo)radiation was constructed and analyzed for EGFR copy number by FISH (Vysis; Abbott Laboratories) and EGFR protein expression using AQUA analysis of EGFR staining scored on a scale of 0 to 255. We evaluated associations of EGFR FISH status and AQUA score with clinicopathologic parameters and survival prognosis. Results: Eleven (17.2%) of 64 tumors with FISH results showed EGFR high polysomy and/or gene amplification (FISH positive). Protein levels assessed by AQUA in FISH-positive cases were significantly higher (P = 0.04) than in FISH-negative cases. Using the continuous AQUA scores for EGFR expression, AQUA and FISH showed significant agreement (Pearsons ρ = 0.353, P = 0.04). Patients with high tumor EGFR protein expression had inferior 5-year overall survival (27.7%) compared with those with low tumor EGFR expression (54%; P = 0.029). There was no significant association between EGFR FISH status and overall survival (P = 0.201). In the multivariate model, high tumor EGFR protein expression status remained an independent prognostic factor for overall survival (P = 0.047). Conclusions: EGFR protein content correlates with gene copy number if protein content is quantitated and automatically analyzed, as with AQUA. EGFR protein levels assessed by AQUA strongly predict for patient outcome in HNSCC, whereas EGFR FISH status does not provide prognostic information. Clin Cancer Res; 17(9); 2947–54. ©2011 AACR.

Cisplatin-based chemotherapy for merkel cell carcinoma of the skin.

Purpose: Merkel cell carcinoma (MCC), a rare tumor of the skin with aggressive behavior, is usually fatal when advanced disease is present. The role of chemotherapy (CT) in the treatment of patients with MCC is unclear. Methods: Over 15 years, 9 patients with locally advanced or metastatic disease were treated with carboplatin (CBDCA) (300 mg/m2 of AUC 5 on Day 1) and etoposide (VP-16) (100 mg/m2 on Days 1–3) every 3 weeks. As second-line CT, cisplatin (CDDP) (60–100 mg/m2), ifosfamide (IFO) (3–5 g/m2) and epirubicin (EPI) (30–50 mg/m2) were utilized. Results: Of the 3 patients who received adjuvant therapy, one achieved complete response after 108+ months with second-line chemotherapy and radiotherapy, despite a brief relapse; 2 patients remain disease-free after 84+ and 108+ months. Of the 6 patients with locally advanced or metastatic disease who were treated with first-line chemotherapy, one (16.6 percent) achieved a complete response and 3 (50 percent) achieved partial response, for an overall response rate of 66.6 percent. Two patients (one with complete and one with partial response) received subsequent radiotherapy, following which complete response was achieved. Of the 2 complete responders, one patient remains disease-free after 56+ months. The median overall survival from the time of initial diagnosis for the whole group was 56 months (range 15–114 months); the median overall survival from the initiation of chemotherapy was 18 months (range 6–108+). Local recurrences and soft tissue metastases responded better than visceral metastases. Patients with partial response and no response had rapid disease progression and fatality, despite second-line chemotherapy and/or radiotherapy. Conclusion: MCC appears to be chemosensitive but can progress rapidly with fatal outcomes. Although the rarity of these tumors precludes randomized trials, a common treatment plan should be utilized by those treating MCC. This may allow some conclusions regarding the optimum treatment of patients with MCC to be drawn in the future.

Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma

Patients with gastric and esophageal (GE) adenocarcinoma tumors in which the oncogene ERBB2 has been amplified are routinely treated with a combination of cytotoxic chemotherapy and the ERBB2-directed antibody trastuzumab; however, the addition of trastuzumab, even when tested in a selected biomarker-positive patient population, provides only modest survival gains. To investigate the potential reasons for the modest impact of ERBB2-directed therapies, we explored the hypothesis that secondary molecular features of ERBB2-amplified GE adenocarcinomas attenuate the impact of ERBB2 blockade. We analyzed genomic profiles of ERBB2-amplified GE adenocarcinomas and determined that the majority of ERBB2-amplified tumors harbor secondary oncogenic alterations that have the potential to be therapeutically targeted. These secondary events spanned genes involved in cell-cycle regulation as well as phosphatidylinositol-3 kinase and receptor tyrosine kinase signaling. Using ERBB2-amplified cell lines, we demonstrated that secondary oncogenic events could confer resistance to ERBB2-directed therapies. Moreover, this resistance could be overcome by targeting the secondary oncogene in conjunction with ERBB2-directed therapy. EGFR is commonly coamplified with ERBB2, and in the setting of ERBB2 amplification, higher EGFR expression appears to mark tumors with greater sensitivity to dual EGFR/ERBB2 kinase inhibitors. These data suggest that combination inhibitor strategies, guided by secondary events in ERBB2-amplified GE adenocarcinomas, should be evaluated in clinical trials.

Nuclear Localization of Signal Transducer and Activator of Transcription 3 in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis

Purpose: A high frequency of head and neck squamous cell cancers (HNSCC) contain constitutively activated signal transducer and activator of transcription 3 (STAT3). To further elucidate the prognostic role of STAT3 in HNSCC, the expression pattern of STAT3 was correlated with outcome in two independent data sets. Experimental Design: STAT3 protein expression analysis was done on a test cohort of 102 patients with HNSCC recruited between 1992 and 2005. Automated quantitative analysis was used to assess STAT3 protein expression. We evaluated associations with clinicopathologic parameters and survival prognosis. Associations were validated in a second, independent cohort of 58 patients with confirmed HNSCC enrolled in the Early Detection Research Network–sponsored study who underwent surgical resection with curative intent at the University of Pittsburgh Medical Center between 2000 and 2004. Results: STAT3 displayed mixed nuclear and cytoplasmic staining. Survival analysis showed that high nuclear STAT3 expression (top tertile versus the rest) was associated with longer progression-free survival (n = 70, mean survival of 88.9 versus 46.7 months, P = 0.012 for the first cohort; n = 37, mean survival of 60.3 versus 33.0 months, P = 0.009 for the second cohort). After best model selection in the multivariable analysis context, only STAT3 was significant, revealing a lower risk of progression and death for patients with high nuclear STAT3-expressing tumors (hazard ratio, 0.28; 95% confidence interval, 0.10-0.82; P = 0.019; and hazard ratio, 0.23; 95% confidence interval, 0.07-0.76; P = 0.016, respectively). Conclusions: Our results indicate that high nuclear STAT3 expression levels by automated quantitative analysis are associated with favorable outcome in HNSCC. Clin Cancer Res; 16(8); 2427–34. ©2010 AACR.

Primary fallopian tube carcinoma: results of a retrospective analysis of 64 patients.

OBJECTIVE The objective of this retrospective study was to determine the clinical outcomes of patients with primary fallopian tube carcinoma (PFTC) treated with paclitaxel and platinum analogue-based combination chemotherapy following primary cytoreductive surgery. METHODS Sixty-four patients with the diagnosis of PFTC were identified through the gynecology service database and the tumor registry of 4 different institutions. The majority of patients (48/64, 75%) were treated with carboplatin AUC (area under curve) 6 and paclitaxel 175 mg/m(2) as a 3 h infusion. RESULTS Among 28 patients with measurable disease, we observed 19 (68%) complete clinical and 7 (25%) partial responses for an overall response rate of 93%. After a median follow-up of 40 months (3+-134+ months), the 5-year survival rate of the entire population was 70% (median overall survival [mOS] not reached) and the median time to tumor progression (mTTP) was 81 months (95% CI: 53-109). Stage and residual disease were of prognostic significance. The mTTP was not reached in patients with stage I/II and was 38 months for patients with stage III/IV (p=0.004). The mOS for patients with stage I/II was not reached, whereas it was 62 months for those with stage III/IV (p=0.057). The mTTP was 86 and 23 months for patients with residual disease <2 cm and >2 cm, respectively (p<0.001). The mOS was not reached for patients with residual disease <2 cm, while it was 36 months for residual disease >2 cm (p<0.001). CONCLUSION Optimally cytoreduced patients with PFTC treated with platinum and paclitaxel-based chemotherapy regimen have an excellent possibility of survival.