In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival.

BACKGROUND: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. METHODS: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX). For each cell line, IC(50) levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC(50) correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. RESULTS: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway ('Transcription/CREB pathway') was associated with OVCA overall survival. CONCLUSION: The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.

Radiation therapy with concomitant and adjuvant cisplatin and paclitaxel in high-risk cervical cancer: long-term follow-up.

INTRODUCTION: Chemo-potentiation of radiation improves survival in women with cervical cancer. Our group has previously demonstrated the tolerability of weekly paclitaxel combined with cisplatin during radiation therapy. We sought to determine the efficacy of this regimen in patients with "high risk" cervical cancer, and to determine the short- and long-term toxicity of this approach. METHODS: We prospectively enrolled surgically staged patients with positive peritoneal cytology, resectable nodal metastases, or primary tumor > 6 cm. Patients were treated using external beam radiation with concomitant cisplatin (50 mg/m2) during weeks 1, 4, and 7, and weekly paclitaxel (50 mg/m2), followed by four courses of adjuvant cisplatin (50 mg/m2) and paclitaxel (135 mg/m2). Toxicity, overall, and disease-free survival were evaluated. RESULTS: Twenty-three patients were enrolled, and 21 were evaluable. Patient allotment by FIGO stage was: IB1 - seven, IB2 - five, IIA - two, IIB - four, IIIB - two, IV - three. Twenty patients (95%) completed radiation treatment (median dose to point A was 8278 cGy). Seventeen patients (81%) completed all chemotherapy. At a median follow-up of 58 months the overall survival was 68%. Overall survival for patients with clinical Stage I and II disease was 82% at a median of 64 months. Hematologic toxicity was common but rarely resulted in treatment delays. Late complications requiring intervention (obstruction, fistula, significant lymphocyst) occurred in 11 patients (52%). CONCLUSION: The combination of paclitaxel and cisplatin appears efficacious in "high-risk" cervical cancer patients. Hematologic toxicity was common but tolerable. Long-term survival was common in these patients, however late toxicity was significant. This regimen should be investigated in collaborative phase III trials.

Vaginal adenosarcoma arising from endometriosis.

OBJECTIVE: Malignant transformation of endometriosis has been well documented. Endometrioid adenocarcinoma is the most common malignancy to occur in this setting, although other carcinomas and rarely stromal tumors can be seen. We present the first case in the literature of adenosarcoma, a rare mixed mullerian or mesodermal tumor, arising in extrauterine vaginal endometriosis. CASE: A 42-year-old woman underwent multiple medical therapies and surgeries for aggressive endometriosis. A pelvic exenteration was abandoned secondary to severe fibrosis, and low-dose radiotherapy was used to control bleeding from vaginal endometriosis. The pathologic diagnosis of recurrent endometriosis was confirmed multiple times over her 4-year course. Excision of a recurrent vaginal mass revealed adenosarcoma with heterologous elements. CONCLUSION: It is important to biopsy or excise recurrent endometriosis, as malignant transformation can occur, giving rise to epithelial, stromal, or mixed epithelial-mesenchymal tumors.

Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma.

BACKGROUND: Focal adhesion kinase (FAK) is a tyrosine kinase that is important to such key functions such as cell adhesion, motility, and invasion. A MEDLINE search of the years 1980-1998 found no previous reports of FAK expression in human ovarian carcinoma. The authors performed experiments to determine whether FAK expression is elevated in this disease. METHODS: Ten normal human ovarian tissue samples and 26 cancer samples from patients with Stage I-IV ovarian carcinoma were obtained. Two ovarian carcinoma cell lines were also analyzed. FAK expression was determined by Western blot analysis with the V39 anti-human FAK polyclonal antibody. The level of FAK protein expression was determined using densitometric scanning of the 125 kD band on autoradiographs of Western immunoblots. RESULTS: Serous cancers expressed fourfold-increased values of FAK relative to normal ovarian tissue (P < 0.0001), and nonserous adenocarcinomas expressed threefold- to fourfold-increased values of FAK (P < 0. 0006). Ovarian carcinoma cell lines also expressed increased values of FAK. With a cutoff of 40, an elevated FAK level was associated with a sensitivity of 93% and specificity of 100%. There was no significant difference in FAK expression with regard to grade or stage of tumor. CONCLUSIONS: FAK is significantly overexpressed in ovarian carcinoma, implying that FAK may play an important role in ovarian carcinogenesis. FAK expression may be useful as a screening tool to identify newly developed disease or as a tumor marker in confirmed cases of epithelial ovarian carcinoma. FAK may also serve as a potential target for therapeutic disruption of ovarian carcinoma progression.

Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: possible explanation for failure of combination therapy.

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown significant efficacy over previous drug combinations in ovarian cancer, 20-30% of patients fail to respond to this combination. These patients are deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available to ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we assessed the efficacy of combination drug therapy on cisplatin-resistant (cisplatinR) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatinR cells as well as in the cisplatin-sensitive parental cell lines. In cisplatinR C-13 cells, the concomitant addition of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel-induced multimininucleation was also inhibited when the cells were exposed sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel-induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 expression in cisplatinR cells. Conversely, paclitaxel did not inhibit p53 protein accumulation by cisplatin. These results suggest that cisplatin blocks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cisplatin can inhibit the effectiveness of paclitaxel in cispatinR cell lines. Therefore, the establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.

Importance of atypical glandular cells of uncertain significance in cervical cytologic smears.

OBJECTIVE: To determine the clinical implications of atypical glandular cells of uncertain significance (AGCUS) in cervical cytologic smears. STUDY DESIGN: Retrospective analysis. RESULTS: Eighty-eight of 32,181 (0.27%) cervical smears obtained during the study period contained AGCUS. Of the 47 women with AGCUS, 16 had intraepithelial or invasive neoplasms (34%; 95% confidence interval, 21-49%), including 9 low or high grade squamous intraepithelial lesions, 1 adenocarcinoma in situ of the cervix, 3 adenocarcinomas of the cervix, 2 adenocarcinomas of the endometrium and 1 adenoid basal cell carcinoma of the cervix. CONCLUSION: The high prevalence of cervical and endometrial neoplasia among women with the isolated finding of AGCUS on cervical cytologic smears warrants a thorough diagnostic evaluation.

Two-dimensional echocardiograms of a transvenous left ventricular pacing catheter.

A permanent transvenous pacemaker lead was placed across the atrial septum and retained in the left ventricle for eight years. M-mode echocardiograms showed a linear echocardiographic density in the left atrium and mitral valve. Cross-sectional echocardiograms further defined the location and course of the pacing lead.