Optimal modeling for phase I design of a two drug combination-results of a phase I study of cisplatin with 9-nitrocamptothecin.

Combination of platinum with topoisomerase-I inhibitors are synergistic. The objectives of this study were to determine MTD range and toxicity profile of combinations of oral 9-nitrocamptothecin (9NC) and intravenous cisplatin in patients with refractory solid tumors. Each course was 28 days starting on day 1 with cisplatin, and then 9NC daily for 5 days/week for three weeks. A new two arm crossing design was created: patients in arm 1 were treated with at the single agent recommended dose of cisplatin (50 mg/m(2)), and increasing doses of 9NC and in arm 2 with the single agent recommended dose of 9NC (1.5 mg/day) and increasing dose of cisplatin. Once a dose limiting toxicity was observed, the dose of the escalated drug was decreased by one level, and the fixed-dose drug was then escalated. A 3 + 3 design was used. Eligibility criteria were standard for a phase I trial. Pharmacokinetics was performed. Eighteen patients were treated on Arm 1, 3 at the crossing level, and 33 on Arm 2. Dose limiting toxicities were gastrointestinal at the crossing dose level. After crossing, prolonged grade 3 thrombocytopenia was the DLT in arm 1, and grade 4 neutropenia in Arm 2. Only one patient with ovarian cancer had a partial remission, and 12 patients had disease stabilization (24% of clinical benefit). A Bayesian optimal dose finding was tested post-facto. The recommended doses for phase II studies by the 3 + 3 design are cisplatin 60 mg/m(2) and 9NC 1.25 mg/day and cisplatin 40 mg/m(2) and 9NC 2.0 mg/day. The Bayesian optimal dose finding suggested a different solution, closest to that of the latter dosing which may be less toxic.

Retrospective review: re-treatment of patients with ovarian cancer with carboplatin after platinum resistance.

The objective of the analysis was to determine the effectiveness of re-treating patients with ovarian cancer, primary peritoneal cancer, and fallopian tube cancer with carboplatin after being deemed platinum resistant. From a database period January 1, 1996, to December 12, 2002, 34 patients were identified who received nonplatinum agents before resuming treatment with carboplatin. The median age was 65 years, and a median of two nonplatinum chemotherapy (range 1-5) prior to re-treatment with carboplatin was received. The median platinum-free interval from the time platinum was last received to re-treatment with carboplatin was 15.2 months (95% confidence interval [CI] 12.6-17.9; range 6.2-47.0). A median number of four cycles of carboplatin (range 1-11) was received. Two patients (5.9%) achieved partial response, while 21 patients (61.7%) achieved stable disease. The median time to progression for these 23 patients after re-treatment with carboplatin was 5.7 months (95% CI 5.2-6.3; range 1.8-15.3). Twenty-seven patients have died, and all patients have progressed. Seven patients are still receiving salvage therapy. The median overall survival from the time deemed to be platinum resistant is 23.2 months (95% CI 20.1-26.4). Patients who have been deemed platinum resistant may still benefit from platinum re-treatment after an interval of treatment with nonplatinum agents.

Thiotepa in combination with cisplatin for primary epithelial ovarian cancer: a phase II study.

The objectives of this phase II protocol were: 1) to determine the clinical activity of thiotepa combined with cisplatin in suboptimally debulked advanced epithelial ovarian carcinoma as first-line chemotherapy, 2) to determine by surgery the response after 6 courses of chemotherapy, and 3) to identify the regimen's qualitative and quantitative toxicities. Patients with FIGO stage IIIC or IV epithelial ovarian cancer were eligible to receive cisplatin (50 mg/m2) followed by thiotepa (40 mg/m2) on an every 4-week schedule. Patients showing no evidence of disease after six cycles of chemotherapy underwent surgical reassessment. Thirty-one patients were evaluable for toxicity and response. Myelosuppression was the major toxicity and hematologic toxicities prompted all dose reductions. No growth factor support was given in this trial. Thirty-nine percent of patients (12/31) had a clinical complete response. Of these, 16% (5/31) had complete pathologic response and 19% (6/31) had partial pathologic response. One long-term survivor declined reassessment laparotomy. Including the 16% of patients with a partial response, the overall response rate was 55% (17/31). Five patients are currently alive 8 years after enrollment. Median survival was 16.8 months for all patients, 21.5 months for patients with partial response, and 60.8 months for patients with complete pathologic response. A normalization or >50% decrease in CA125 level occurred in 93% of patients. This study indicates that first-line treatment with thiotepa and cisplatin produces significant long-term responses when tumors are sensitive. Such treatment is a reasonable option when paclitaxel is not available.

Phase II study of carboplatin and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix.

BACKGROUND: The activity of the combination of carboplatin and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma.

Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy.

BACKGROUND: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy. METHODS: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy. RESULTS: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia. CONCLUSIONS: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

Vulvar melanoma at the M. D. Anderson Cancer Center: 25 years later.

The purpose of this study was to review the clinical course of patients diagnosed with vulvar melanoma. Charts of patients diagnosed between 1970 and 1997 were reviewed for demographics, lesion characteristics, disease duration and extent, and treatments. Actuarial survival curves were computed by the Kaplan Meier method and compared by Cox proportional hazards regressions. Fifty-one patients (median age 54) with vulvar melanoma presented with a vulvar mass (39%), pain (30%), bleeding (24%), and itching (20%). Anatomical distribution was mucosa of the vulva (65%), vulvar epidermal site (21%), or unspecified vulva (14%), with 20% having multifocal disease at diagnosis. Histologic types were superficial spreading or nodular (50% each). Median lesion characteristics were diameter 2 cm, Breslow index 4.4 mm, and Clark level IV. Distribution of patients per American Joint Committee on Cancer (AJCC) stage was 29%, 50%, 16%, and 7% for stages I, II, III and IV, respectively. Inguinal node metastases were unilateral in 16% and bilateral in 7%. Despite complete surgical resection, 32 patients (63%) recurred. Median survival for all patients was 41 months (range, 5-324), with 91% 5-year survival for patients with stage I and 31% for stage >or= IIA (P = 0.0002). As with cutaneous melanoma, the AJCC classification, Breslow's thickness, and Clark's levels are the major predictors of overall survival (P = 0.0001 each) and disease-free survival (P

Breaking bad news about cancer: patients' preferences for communication.

PURPOSE: The goal of this study was to assess patients' preferences regarding the way in which physicians deliver news about their cancer diagnosis and management. PATIENTS AND METHODS: A sample of 351 patients with a variety of cancers completed a measure assessing their preferences for how they would like to be told news about their cancer. Patients rated characteristics of the context and content of the conversation as well as physician characteristics. RESULTS: Factor analysis indicated that patients' preferences for how they would like to be told news regarding their cancer can be grouped into the following three categories: (1) content (what and how much information is told); (2) facilitation (setting and context variables); and (3) support (emotional support during the interaction). Women (P =.02) and patients with higher education (P =.05) had significantly higher scores on the Content scale, women (P =.02) had higher scores on the Support scale, and younger patients (P =.001) and those with more education (P =.02) had higher scores on the Message Facilitation scale. Medical variables were not associated with patients' ratings of the importance of the three subscales. CONCLUSION: Patients rated items addressing the message content as most important, though the supportive and facilitative dimensions were also rated highly. Understanding what is important to patients when told news about their cancer provides valuable information that may help refine how this challenging task is best performed.

Diffuse large B-cell non-Hodgkin's lymphoma presenting as a vaginal mass in a patient with a history of intestinal mucosa-associated lymphoid tissue (MALT) lymphoma.

Vaginal involvement in non-Hodgkin's lymphoma is uncommon and is often secondary to disseminated disease. Primary disease at this site is quite rare. We present here an unusual case of a patient who developed a diffuse large B-cell lymphoma presenting as a vaginal mass after having been treated for primary intestinal mucosa-associated lymphoid tissue (MALT) lymphoma 4 years earlier. Combined chemotherapy and radiation therapy for the intestinal MALT lymphoma produced complete remission that lasted for 2 years. Chemotherapy given for the diffuse large B-cell lymphoma with secondary vaginal involvement produced a second complete remission. The second remission was consolidated with high-dose chemotherapy and autologous bone marrow transplantation. Although the patient died from complications related to the transplant procedure, the disease was in complete remission at the time of her death. Given the rarity of primary intestinal MALT lymphoma and primary vaginal lymphoma, no standard treatment has been established. Treatment options have included chemotherapy, radiation therapy, or surgery, given alone or in combination.

Accelerated HER-2 degradation enhances ovarian tumor recognition by CTL. Implications for tumor immunogenicity.

We investigated the ubiquitination and degradation of a tumor antigen, the HER-2/neu (HER-2) protooncogene product which is overexpressed in epithelial cancers. HER-2 degradation was investigated in the ovarian tumor line, SKOV3.A2, that constitutively overexpressed long-life HER-2. We used as agonist geldanamycin (GA), which initiated downmodulation of HER-2 from the cell surface. HER-2 was polyubiquitinated and degraded faster in the presence than in the absence of GA. GA did not decrease HLA-A2 expression. Presentation of the immunodominant cytotoxic T lymphocyte (CTL) epitope, E75 (369-377) from SKOV.A2 was inhibited by proteasome inhibitors, such as LLnL but was enhanced by cysteine protease inhibitors such as E64, indicating that both the proteasome and cysteine proteases are involved in epitope formation but have different effects. Enhanced tumor recognition was not an immediate or early effect of GA treatment, but was evident after 20 h of GA treatment. In contrast, 20 h GA treatment did not increase tumor sensitivity to LAK cell lysis. Twenty hour GA-treated SKOV3.A2 cells expressed an unstable HER-2 protein synthesized in the presence of GA, of faster electrophoretic mobility than control HER-2. This suggested that the newly synthesized HER-2 in the presence of GA was the main source of epitopes recognized by CTL. Twenty hour GA-treated SKOV3.A2 cells were better inducers of CTL activity directed to a number of HER-2 CTL epitopes, in peripheral blood mononuclear cells compared with control untreated SKOV3.A2 cells. Thus, induction of HER-2 protein instability enhanced the sensitivity of tumor for CTL lysis. Increased HER-2 CTL epitopes presentation may have implications for overcoming the poor immuno-genicity of human tumors, and design of epitope precursors for cancer vaccination.

Limitations of size as a criterion in the evaluation of adrenal tumors.

BACKGROUND: Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that have been identified incidentally. However, small adrenal cortical cancers have been reported from multiple centers. METHODS: We retrospectively evaluated the value of tumor size and other clinical parameters in the prediction of the presence of adrenal malignancy. RESULTS: The records of 117 patients who underwent evaluation for tumors of the adrenal gland were reviewed. The median tumor size of the adrenal cortical carcinomas (n = 38 carcinomas) was 9.2 cm (range, 1.7-30 cm); 5 cancers (13.5%) were smaller than 5.0 cm. The median overall size of the benign tumors, excluding pheochromocytomas, was 4.0 cm (n = 38 carcinomas); 10 benign tumors (26%) were larger than 5.0 cm. The imaging features of 4 of 5 small adrenal cancers predicted malignancy; the remaining patients had hormonally functioning tumors. The imaging features of 7 of 10 large benign adrenal tumors predicted benign histologic features, including 5 of 5 myelolipomas. CONCLUSIONS: Although size remains a good predictor of the histologic features and clinical behavior of adrenal neoplasms, both small adrenal cortical cancers and large benign tumors occur with measurable frequency. High-quality imaging studies may be helpful in the identification of relatively small adrenal cancers and of characteristic benign lesions that may be selectively followed.

Induction of determinant spreading and of Th1 responses by in vitro stimulation with HER-2 peptides.

Immunization with tumor antigens induces cellular and humoral immune responses. These responses by T cells are specific for defined epitopes (determinants) in the molecule of the immunizing tumor antigen. Extension of such responses to self-antigens requires induction of autoimmunity to the tumor. As with systems of autoimmune disease, expression of T cell autoimmunity is charaterized by diversification of responses from the inducer determinant to other responder (cryptic) determinants. Since similar strategies may be useful for therapy of human cancers, we investigated whether the induction of response to a HER-2 peptide F7 (776-789) induces enhanced reactivity of other HER-2 peptides. We found that stimulation with F7 can expand a response to another epitope F13 (884-899) in both an ovarian cancer patient with progressive disease and a healthy donor who shared HLA-DR11. This response was characterized mainly by increased interferon gamma secretion, and proliferation, but was not observed with another donor who shared HLA-DR14 and HLA-DQ5 with the patient. Since repeated vaccination with the same epitope may lead to a decline of primary cell reactivity caused by apoptosis spreading the response to other epitopes, the tumor antigen may provide an approach for maintaining an inflammatory Th1 response during cancer vaccination.

Use of docetaxel (Taxotere) in patients with paclitaxel (Taxol) hypersensitivity.

Anaphylaxis or significant hypersensitivity reaction is one of the most catastrophic potential complications of chemotherapy. There is a 2-5% risk of hypersensitivity with paclitaxel, a commonly used chemotherapeutic agent for various cancers. Three patients, who developed hypersensitivity to paclitaxel infusion, received docetaxel without allergic reactions. Docetaxel may therefore be an alternative treatment for patients with paclitaxel hypersensitivity.

Estrogen replacement therapy and ovarian cancer.

Estrogen replacement therapy (ERT) has been shown to be of benefit for menopausal women, especially in prevention of coronary heart disease and osteoporotic fractures. Cancer fear is an important obstacle to use of ERT. From our literature review, there is a weak or no association between ERT and ovarian cancer risk. Individual risk of cancer should be considered before ERT use. The second issue in this review is ERT in patients with ovarian cancer. The majority of patients with ovarian cancer are postmenopausal or become menopausal after surgery. ERT is considered by many physicians to be contraindicated in patients with cancer. However, there is evidence that ERT in selected cancer patients may be of benefit for survival and quality of life. After weighing the evidence from studies on ERT in patients with ovarian, breast or endometrial cancer, we propose the use of ERT in selected ovarian cancer patients who are suffering from or are at a high risk of debilitating menopausal symptoms, osteoporosis, and coronary heart disease. The benefit of ERT to selected patient's health and quality of life appears to outweigh the risk of cancer recurrence.

SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer.

We describe a protocol for disclosing unfavorable information-"breaking bad news"-to cancer patients about their illness. Straightforward and practical, the protocol meets the requirements defined by published research on this topic. The protocol (SPIKES) consists of six steps. The goal is to enable the clinician to fulfill the four most important objectives of the interview disclosing bad news: gathering information from the patient, transmitting the medical information, providing support to the patient, and eliciting the patient's collaboration in developing a strategy or treatment plan for the future. Oncologists, oncology trainees, and medical students who have been taught the protocol have reported increased confidence in their ability to disclose unfavorable medical information to patients. Directions for continuing assessment of the protocol are suggested.

Docetaxel for patients with paclitaxel-resistant Müllerian carcinoma.

PURPOSE: To determine the efficacy and toxicity of docetaxel in patients with müllerian carcinoma resistant to paclitaxel. PATIENTS AND METHODS: Thirty-two patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who failed paclitaxel-based chemotherapy received either 100 or 75 mg/m(2) of docetaxel every 3 weeks. Resistance to paclitaxel was defined as either progression of disease during treatment, failure to achieve regression of disease after at least four courses, or rapid recurrence (within 6 months) after completion of therapy. RESULTS: Eighteen patients were treated on a formal protocol and fourteen with the commercially available docetaxel. Thirty were assessable for response. Toxicities were thoroughly evaluated in the 18 patients on protocol. Twenty-seven patients (85%) had epithelial ovarian cancer. The overall response rate was 23% (one complete and six partial responses), with a median survival time of 44 weeks (9.5 months). Nine patients had stable disease and 14 progressive disease. Among 19 patients who progressed during prior paclitaxel treatment, two (11%) responded to docetaxel, compared with five (45%) of 11 patients in other paclitaxel-resistance categories. The responders had a median taxane-free interval (ie, the time between the last paclitaxel and first docetaxel treatment) of 73 weeks, compared with 19 weeks for the nonresponder group. Toxic effects were as expected. CONCLUSION: Docetaxel is an active chemotherapeutic agent in patients with müllerian carcinoma previously treated with paclitaxel-based chemotherapy, especially in the patients who had a long taxane-free interval after a previous short response to paclitaxel.

Clinical and biological effects of intraperitoneal injections of recombinant interferon-gamma and recombinant interleukin 2 with or without tumor-infiltrating lymphocytes in patients with ovarian or peritoneal carcinoma.

To identify strategies that enhance tumor-specific immunity in patients with ovarian carcinoma, 22 patients received four to six doses of i.p. recombinant IFN-gamma (rIFN-gamma), 200 microg/m2 on days 1, 3, 5, 8, 10, and 12, and i.p. recombinant interleukin 2 (rIL-2), either 6.0 x 10(5) IU/m2 (group A) or 1.0 x 10(5) IU/m2 (group B), on days 9, 10, and 11. Two patients in group A also received T-cell lines expanded from peritoneal tumor-infiltrating lymphocytes (TILs) obtained after i.p. rIFN-gamma/rIL-2 administration. Toxicity was manageable and included five nonhematological grade 3 or 4 events in 22 patients (23%). A patient had normalization of CA-125 values and a progression-free interval of 18 months, after receiving i.p. rIFN-gamma/rIL-2 without TILs. Another patient who received i.p. rIFN-gamma/rIL-2 plus TILs had stabilization of ascites and intra-abdominal tumors and >50% reduction in serum CA-125 values over 6 months. A third patient who received i.p. rIFN-gamma/rIL-2 had stabilization of intra-abdominal tumors and ascites accompanied by CA-125 values of 50 to 100 units over 6 months. T-cell lines for adoptive immunotherapy were developed for only 3 of 20 patients who were treated with rIFN-gamma/rIL-2. Large numbers of CD3- CD56+ adherent cells were expanded in rIL-2 in the remaining patients, precluding the development of T-cell lines. i.p. rIFN-gamma, either alone or followed by rIL-2, increased proportions of human leukocyte antigen (HLA) class I+ and class II+ tumor cells and increased HLA class I staining intensity on peritoneal carcinoma cells. i.p. rIFN-gamma plus rIL-2 also enhanced cytotoxic activity against Daudi and K562 cells and against allogeneic ovarian tumor cells. Increased cytotoxic activity was associated with an increase in the proportion of CD56+ cells. IFN-gamma and IL-2 transcripts were expressed more frequently after rIFN-gamma and rIL-2 treatment. In addition, the proportions of CD45RA+ (naive lymphocytes) were increased, and CD8+ DR+ lymphocytes were increased relative to CD8+ CD69+ cells, which were decreased. IL-10 concentrations in peritoneal fluids were increased after treatment with rIFN-gamma and the higher rIL-2 dosing (group A) but not in those treated with rIFN-gamma and the lower rIL-2 dosing (group B). These results demonstrated that patients with ovarian carcinoma can tolerate treatment with rIFN-gamma and rIL-2 and that rIFN-gamma alone or rIFN-gamma combined with rIL-2 enhances the expression of HLA class I and class II antigens on ovarian tumor cells, although immunosuppressive cytokines, such as transforming growth factor-beta and IL-10, may persist. Treatment with rIFN-gamma/rIL-2 i.p. did not facilitate the production of TIL-derived T-cell lines ex vivo.

Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer.

BACKGROUND: Thrombocytopenia is a significant problem in the treatment of cancer. OBJECTIVE: To assess the clinical safety of therapy with recombinant human thrombopoietin (rhTPO) and its ability to ameliorate chemotherapy-induced severe thrombocytopenia. DESIGN: Phase I/II clinical cohort study. SETTING: The University of Texas M.D. Anderson Cancer Center, Houston, Texas. PATIENTS: 29 patients with gynecologic cancer. INTERVENTION: Recombinant human thrombopoietin was given before chemotherapy and after a second cycle of carboplatin therapy. MEASUREMENTS: Peripheral blood counts and platelet transfusions. RESULTS: Administration of rhTPO after chemotherapy significantly reduced the degree and duration of thrombocytopenia and enhanced platelet recovery. In patients who received the optimal biological dose of rhTPO (1.2 microg/kg of body weight) in cycle 2 (carboplatin plus rhTPO), the mean platelet count nadir was higher (44x10(9) cells/L and 20x10(9) cells/L; P = 0.002) and the duration of thrombocytopenia was shorter (days with a platelet count <20x10(9) cells/L, 1 and 4 [P = 0.002]; days with a platelet count <50x10(9) cells/L, 4 and 7 [P = 0.006]) than in cycle 1 (carboplatin only). The need for platelet transfusion in this group was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = 0.013). CONCLUSIONS: Therapy with rhTPO seems to be safe and may attenuate chemotherapy-induced severe thrombocytopenia and reduce the need for platelet transfusions.

Synchronous primary cancers of the breast and cervix: planning multidisciplinary primary treatment [clinico-pathological conference].

Multiple metachronous primary malignancies are becoming increasingly frequent; however, multiple synchronous primary malignancies are still unusual. We report the case of a 61-year-old woman with synchronous stage IIIB ductal carcinoma of the left breast and FIGO stage IB2 squamous cell carcinoma of the cervix. The patient was treated initially every 4 weeks with a 24-h intravenous infusion of paclitaxel (175 mg/m2) followed by a 1-h infusion of carboplatin (area under the curve of 5 mg/ml x min) with concurrent irradiation of the pelvis. Significant toxic reactions including nausea, vomiting, and diarrhea required hospitalization or outpatient intravenous fluids and antiemetics. After four cycles of chemotherapy, the breast cancer was in complete clinical remission, and the patient underwent a modified radical mastectomy with axillary lymph node dissection. Pathologic findings revealed a few microscopic foci of residual infiltrating ductal carcinoma exhibiting a marked treatment effect; none of the 14 axillary lymph nodes removed showed evidence of metastatic tumor. A near-complete pathologic response of the breast cancer and a complete clinical response of the cervical cancer were obtained. Adjuvant chemotherapy for the breast cancer was then initiated, followed by radiation and hormonal therapy.

Increased expression of fascin, motility associated protein, in cell cultures derived from ovarian cancer and in borderline and carcinomatous ovarian tumors.

Fascin bundles actin microfilaments within dynamic cellular structures such as microspikes, stress fibers and membrane ruffles. Fascin overexpression induces membrane protrusions and increased cell motility, and is highly expressed in various transformed cells, and in specialized normal cells including neuronal, endothelial and dendritic cells. In breast cancer, fascin expression correlates with high-grade tumors. To investigate whether fascin might be a predictor factor for ovarian cancer progression, eighteen cell cultures derived from ovarian cancer, and thirty four archival paraffin-embedded material of normal versus borderline and carcinomatous ovaries were stained by immunocytochemistry and immunohistochemistry with fascin Mab 55K-2. Overall expression of the fascin protein was found in 50% (9/18) of cell cultures derived from original samples of ovarian tumors. Expression of fascin protein was found in 67% (6/9) of cell cultures derived from patients diagnosed with stage IV disease, and 33% (3/9) of cell cultures from patients diagnosed with stage II/III. There was no clear relationship between fascin expression and histologic types, tumor grade, or DNA ploidy. However, 75% of cell cultures, which developed into a xenograft after intraperitoneal inoculation, showed fascin expression, while 86% of non-tumorigenic cell cultures did not show fascin expression. Expression of fascin in these established ovarian tumor cell cultures was significantly associated with the ability for these cells to grow intraperitoneally (P < 0.05). Furthermore, fascin was never expressed in normal epithelial ovarian tissues, but was present in all pathologic ovaries. Both diffuse and focal patterns were observed in borderline ovarian tumors (67% and 33%), advanced primary ovarian cancer (67% and 33%) and metastatic ovarian cancer (89% and 11%). Therefore, our data suggest that fascin could serve as a prognostic factor for abnormal ovarian epithelial pathology and could be a novel target for the treatment of ovarian cancer.