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OBJECTIVES: The objective of this study was to examine whether the oncologic outcomes of BRCA1-associated and BRCA2-associated ovarian cancers correlate differently. METHODS: Genetic data and clinical characteristics were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: Data from 147 BRCA-mutated patients (119 BRCA1-positive and 28 BRCA2-positive) were analyzed. At a median follow-up of 69 months, the median PFS was 27.2 and 45.46 months for BRCA1 and BRCA2 patients, respectively (p = 0.03). Median OS was 77.23 and 111.47 months for BRCA1 and BRCA2 patients, respectively (p = 0.08). CONCLUSION: BRCA2 mutations confer PFS and a trend to OS advantage compared with the BRCA1 mutation in BRCA-mutated epithelial ovarian cancer patients.

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Because of the higher risk of developing breast cancer and the early onset of the disease in women proved or suspected to be carriers of a breast cancer susceptibility gene, a dedicated screening should be offered as a less invasive approach with respect to the otherwise suggested prophylactic mastectomy. This should be optimized in order to overcome the limitations of conventional breast imaging with the application of new technologies such as Breast Magnetic Resonance Imaging (BMRI). A diagnostic protocol for routine control in patients with high risk for developing breast cancer has been prepared. Within a 7 months period, 23 patients suspected or proved to carry a breast cancer susceptibility gene underwent BMRI. Four breast cancers were identified with BMRI. In these cases mammography was negative because of the density of the parenchyma or for its fibroglandular pattern. US was negative in two cases, not specific for malignancy in one case and considered as only possibly malignant but with biopsy recommendation on the basis of MR findings in the last one. Clinic analysis was positive for mass in two cases. The accuracy of BMRI is known to be higher than that of conventional imaging in the study of breast parenchyma. High spatial resolution and no breast density influence can give more detailed information about smaller lesions and the right extent of the disease.

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This report presents the preliminary results of the first phase (21 months) of a multi-centre, non-randomised, prospective study, aimed at evaluating the effectiveness of contrast-enhanced magnetic resonance imaging (MRI), X-ray mammography (XM) and ultrasound (US) in early diagnosis of breast cancer (BC) in subjects at high genetic risk. This Italian national trial (coordinated by the Istituto Superiore di Sanità, Rome) so far recruited 105 women (mean age 46.0 years; median age 51.0; age range 25-77 years), who were either proven BRCA1 or BRCA2 mutation carriers or had a 1 in 2 probability of being carriers (40/105 with a previous personal history of BC). Eight cases of breast carcinomas were detected in the trial (mean age 55.3 years, median age 52.5; age range 35-70 years; five with previous personal history of BC). All trial-detected BC cases (8/8) were identified by MRI, while XM and US correctly classified only one. MRI had one false positive case, XM and US none. Seven "MRI-only" detected cancers (4 invasive, 3 in situ) occurred in both pre- (n = 2) and post-menopausal (n = 5) women. With respect to the current XM screening programmes addressed to women in the age range 50-69 years, the global incidence of BC in the trial (7.6%) was over ten-fold higher. The cost per "MRI-only" detected cancer in this particular category of subjects at high genetic risk was substantially lower than that of an XM-detected cancer in the general women population. These preliminary results confirmed that MRI is a very useful tool to screen subjects at high genetic risk for breast carcinoma, not only in pre-, but also in post-menopausal age, with a low probability of false positive cases.

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Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m(2) cisplatin (i.e. 40 mg/m(2) daily for 3 consecutive days plus 600 mg/m(2) cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.

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AIMS AND BACKGROUND: Adult granulosa cell tumor has a low malignant potential but requires an extensive follow-up of more than 5 years to accurately assess tumor activity. The aim of the present study was to evaluate the clinical characteristics, the treatment and the outcome of this rare ovarian tumor. STUDY DESIGN: A retrospective review of 35 cases treated at primary onset of disease during a 23-year period from 1971 to 1993. RESULTS: The disease-free survival rate for stages IA-B-C at 5 and 10 years was 90% and 84%, respectively; for stages III-IV the 5-year freedom from progression rate was 16%. CONCLUSIONS: The most important prognostic factor appears to be the extent of tumor involvement outside of the ovary.

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Germline mutations in the BRCA1 and BRCA2 genes are associated with approximately 80% of families with a high incidence of breast and/or ovarian cancers (OMIM database reference numbers: 113705, 600185). Furthermore, constitutional mutations in the these genes have been reported in women with early-onset breast carcinoma and without family history of cancer. We analyzed by protein truncation test (PTT) and single strand conformation polymorphism (SSCP) followed by sequence analysis, BRCA1 exons 11 and 20 and BRCA2 exons 10 and 11 in 142 Italian cancer patients. These included six male breast cancer cases, 61 women with breast carcinoma diagnosed before 36 years old and selected independently of family history of breast cancer and 75 familial breast and/or ovarian cancer patients. In a previous report, we described 11 different BRCA1 mutations in a subset of 70 cases. Here, we report the characterization of 23 additional mutations, 14 in BRCA1 and 9 in BRCA2, subsequently identified. Ten mutations were not previously described, while the other 13 were recurrent. Of the 61 women with early-onset breast cancer, 11 carried a germline mutation in BRCA1 (18.0%) and four in BRCA2 (6.6%). These frequencies indicate that BRCA1/BRCA2 genetic tests should be advised to women with breast cancer diagnosed at early age, independently of family history of cancer.

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INTRODUCTION: We describe bilateral optic neuropathy in a patient affected by ovarian carcinoma treated with cis-platin 160 mg/m2 and carboplatin, 640 mg/m2. The patient was followed for 1 year, when recovery appeared. The few previous descriptions of CDDP optic nerve toxicity did not report recovery. METHODS: Computerized visual field, visual evoked potentials, pattern electroretinograms, full field flash electroretinograms were recorded during follow-up. RESULTS: Optic neuritis appeared 13 weeks after cis-platin discontinuation, with right eye central scotoma; 2 days later the patient became bilaterally blind. Visual evoked potentials were initially absent, reappeared, with delayed latencies to left eye stimuli at 6 months, in both eyes at 9 months. At 1 year delayed VEPs were recorded with right eye stimuli, normal VEPs were recorded for left eye. CONCLUSION: Cis-platin can induce delayed optic neuritis, that can recover in 1 year.

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The most common mutations in the familial breast and ovarian cancer susceptibility gene BRCA1 are frameshift and nonsense mutations, which lead to the synthesis of truncated proteins. On this ground, we have analysed BRCA1 exon 11, which includes about 61% of coding region, in germline DNA from 70 Italian breast and/or ovarian cancer patients, using the protein truncation test (PTT). BRCA1 mutations were identified in nine of 29 (approximately 31%) patients with a family history of cancer and in three of 41 (approximately 7%) women with early-onset breast carcinomas, and were subsequently characterized by sequence analysis. In addition, BRCA1 mutations were also detected in six affected relatives of two positive index cases. The observed frequencies of mutations were not significantly different from those expected on the basis of the phenotypic characteristics of patients and their families, indicating that PTT is a rapid and sensitive method that can be used for a first BRCA1 mutational screening. The histological findings in BRCA1 mutated cases showed that eight of nine (approximately 89%) breast carcinomas were of grade III and nine of 9 (100%) ovarian carcinomas were of the endometrioid type (eight of grade III and one of grade II). This suggests that specific histological characteristics may represent additional criteria for selection of cases eligible to BRCA1 mutational analysis.

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DNA topoisomerases, nuclear enzymes that regulate DNA topology, are recognized as the primary targets of effective anti-tumor drugs. These enzymes may also have a role in the repair of DNA damage induced by alkylating agents and platinum compounds; therefore, their expression may be a determinant of tumor response to chemotherapy. Our study was undertaken in an attempt to establish a correlation between the enzyme expression and response of ovarian cancer to cisplatin-based chemotherapy. The expression of topoisomerase I, II alpha and II beta genes was assessed by RNase protection assay in tumor specimens obtained from 37 untreated patients with advanced epithelial ovarian cancer at initial surgery and from 13 pre-treated patients at subsequent laparotomy. The expression levels were compared with those found in 5 specimens from benign ovarian tissue and 5 specimens from normal ovarian tissue. The expression levels in untreated patients were used to establish a correlation with response to high-dose cisplatin therapy. A significant intertumor variability of mRNA expression was noted for all the genes examined. However, a comparison of median values indicated a remarkable increase of expression in malignant tumors over benign or normal tissues only for topoisomerase II alpha. This change is not related to alterations or amplification of topoisomerase II alpha gene. Interestingly, a correlation was found between tumor response to chemotherapy and the expression level of the isoform alpha (but not of topoisomerase II beta and topoisomerase I). The observed correlation suggests a contribution of the enzyme in determining tumor sensitivity. Alternatively, increased expression levels of the alpha isoenzyme gene in responsive tumors might reflect higher fractions of proliferating tumor cells that may be more drug-sensitive than resting cells.

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The p53 protein is a multifunctional transcriptional regulator involved in cellular response to DNA damage and has been implicated as a putative determinant of sensitivity of tumor cells to cytotoxic agents. Since the p53 gene becomes inactivated in over one-half of advanced ovarian carcinoma, in this study we have examined the relationships between p53 gene alterations, p53 immunoreactivity, and response to cisplatin-based chemotherapy in ovarian cancer patients. All patients had advanced (FIGO stage III or IV) ovarian carcinoma and, with one exception, were untreated at the time of collection of tumor specimens. After initial debulking surgery, patients received high-dose cisplatin therapy. Tumor samples were analyzed for p53 gene mutations and for p53 protein accumulation, and the findings were correlated with tumor responsiveness. Of the 33 tumors examined, p53 gene mutations were found in 20 cases, including 15 missense mutations, 2 deletions, 2 nonsense mutations, and a base substitution at splice site. Twenty tumors showed positive immunostaining for p53. Only missense mutations were associated with positive immunostaining. In addition, p53 overexpression was detected in five tumors in the absence of mutations. Most (12 of 14) of the missense mutations associated with p53 protein stabilization were found refractory to therapy, as well as tumors overexpressing wild-type p53 (4 of 5). A significant correlation has been found between p53 accumulation, type of mutation (i.e., missense mutations), and pathological response to cisplatin-based therapy. In conclusion, the present results are consistent with a role of p53 as a determinant of chemosensitivity of ovarian carcinoma.

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Intraperitoneal hyperthermic perfusion (IPHP) with a solution that contains CDDP (25 mg/m(2)/l) and MMC (3.3 mg/m(2)/l) was clinically introduced in the treatment of peritoneal carcinomatosis. Twenty-six patients underwent surgical treatment and IPHP. Peritoneal carcinomatosis was classified at laparotomy using the Japanese classification: P1 (n=3), P2 (n=5), P3 (n=15), unclassifiable (n=3). In this series of patients only the creatinine and amylase values were significant in biological toxicity evaluation. The surgical complication rate (2 duodenal fistulas) does not differ from the general extensive abdominal surgery.

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AIMS AND BACKGROUND: Both mitoxantrone (DHAD) and ifosfamide (IFO) have given promising results when administered as single agents in advanced ovarian cancer pretreated with platinum compounds. The aim of this I.T.M.O. group pilot trial was to evaluate, in a selected population of ovarian cancer patients, the efficacy and tolerability of the following intensive second-line regimen: DHAD, 12 mg/m2 i.v., day 1; IFO, 4,000 mg/m2 i.v., days 1 and 2; Mesna, 800 mg/m2 i.v. t.i.d., days 1 and 2. Filgrastim (5 micrograms/kg/day i.m.) was given from day 6 to day 19 to reduce the expected neutropenia. Cycles were repeated every 21 days. METHODS: Nineteen platinum-pretreated patients were enrolled and 14 were evaluated for tumor response; the disease of 5 patients was not measurable clinically or radiologically. RESULTS: Seven responses were observed (3 CRs), with a median response duration of 5 months. The median time to treatment failure and overall survival for all 19 patients was respectively 8 and 13 months. Anemia was observed in all of the treated patients (grade 3-4 in 9 cases). Only 6 of the 19 patients ended the five planned cycles of chemotherapy without any delay. CONCLUSIONS: Although DHAD plus IFO induced a considerable number of objective responses, the limited response duration time to treatment failure, and overall survival as well as the reported side effects suggest that this is not a recommended regimen for the palliative treatment of ovarian cancer patients undergoing second-line chemotherapy.

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No published data are available concerning the activity and tolerability of intramuscularly administered granulocyte colony-stimulating factor (G-CSF) in humans. To fill this gap, 19 patients with advanced ovarian cancer previously treated with at least one first-line chemotherapy cycle received the following myelosuppressive regimen: mitoxantrone (DHAD) 12 mg m-2 i.v. on day 1; ifosfamide (IFO) 4 g m-2 i.v. on days 1 and 2; mesna 800 mg m-2 i.v. t.i.d. on days 1 and 2. G-CSF (Filgrastim) was given at a dose of 5 micrograms/kg/day i.m. from day 6 to day 19, its pharmacokinetics being assessed in five patients. The neutrophil nadir was observed after a mean period of 8 days, and the neutrophil count was < 1.0 x 10(3) mm-3 for a mean of 6 days during the cycle of chemotherapy. The neutrophil count fell after the withdrawal of G-CSF on the 19th day of treatment. The difference in absolute neutrophil count between day 19 and day 21 was statistically significant (P = 0.0001); nevertheless, at day 21 no WHO grade 3-4 neutropenia was reported. DHAD and IFO were respectively given at 95% and 93% of the planned dose. The pharmacokinetics of G-CSF i.m. seems to be similar to that of the drug given subcutaneously. No evidence of cumulative myelosuppression was observed. G-CSF was well tolerated and no complications were observed at the injection sites. In conclusion, if the results obtained in this pilot study regarding the activity of i.m. G-CSF are confirmed by a randomised trial, the intramuscular administration of G-CSF could become a valid alternative for patients who dislike the subcutaneous route and who are being treated with chemotherapy that does not induce profound thrombocytopenia.

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BACKGROUND AND AIMS: In the radiologic assessment of ovarian masses, the major difficulty consists in the late recognition and lack of parameters for a differential diagnosis between benign and malignant lesions, especially in the post-menopause when the incidence of cancer is higher. The use of a transvaginal probe and the color-Doppler examination have recently improved the study of the female pelvis. This study is aimed to verify the possibility of the color-Doppler imaging to differentiate between malignant and benign ovarian lesions during transvaginal echographies, on the basis of the qualitative and quantitative characteristics of the vascular pattern of the ovarian lesions. RESULTS: Twenty-six expansive ovarian lesions were studied: 8/26 showed no vascular signals and were considered benign as confirmed at histology. In the remaining lesions with some vascularization, the resistance index (RI) was evaluated: those with RI > 0.40 were considered benign, those with RI < 0.40 malignant. In 8/9 benign lesions and 7/9 malignant neoplasms, the results of color-Doppler were coherent with histology. The results showed a sensibility of 87.5% and a specificity of 88.8% for the transvaginal examination. CONCLUSIONS: The main advantages of the color-Doppler transvaginal examination are: the high frequency of visualization of the ovaries, even in postmenopausal patients; the definition of small lesions; the visualization of small parenchymal vessels, both physiologic and pathologic, and their quantitative analysis. The importance of the RI cutoff was critical for the differential diagnosis between benign and malignant lesions; we think that a cutoff of 0.50, instead of 0.40 proposed by other authors, would be far more appropriate.

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BACKGROUND: On the basis of preliminary results achieved with a high-dose cisplatin regimen including glutathione as chemoprotector, the efficacy and toxicity of the new regimen was further evaluated in a larger series of patients with advanced ovarian cancer (stage III and IV). PATIENTS AND METHODS: The study included patients with bulky or extensive residual disease after primary laparotomy or with bulky inoperable tumor masses. A total of 79 patients were treated with up to five courses of high-dose cisplatin (40 mg/m2 daily in normal saline, for four days) plus glutathione (2500 mg as a short-term infusion before cisplatin), together with cyclophosphamide (600 mg/m2 as an i.v. bolus on day 4). A standard i.v. hydration consisting of a total of 2000 ml of fluids without diuretics was employed. RESULTS: All eligible patients, who received a total of 345 courses, were assessed for response and toxicity and 52 received the planned five courses of the protocol. Forty-five patients (57%) achieved complete clinical responses and 20 (25%) had partial remissions for an overall response rate of 82%. The response rate was critically dependent on tumor size before chemotherapy. Thirty-eight of 45 patients who had complete clinical responses underwent second-look laparotomy, and 29 had pathological complete responses (37%). Seventeen of these 29 patients subsequently relapsed (median disease-free interval, 12 months; range, 6-45). With a median follow-up time of 44 months, the median survival for the 79 analyzed cases was 40 months. The toxicity of the regimen was moderate. Nausea/vomiting was the most severe acute toxicity. Myelotoxicity was acceptable, with severe leukopenia and thrombocytopenia (grade 4) occurring in 8% and 3% of patients, respectively. Nephrotoxicity was minimal with a transient increase (to < 2 mg/dL) in serum creatinine in only 6 patients (8%). Peripheral neurotoxicity and ototoxicity were the most significant long-term toxicities. The severity of these side effects (grade 3 WHO neurotoxicity occurred in only 4% of patients) was apparently less than has been reported with other high-dose cisplatin regimens. Neurotoxicity required discontinuation of therapy in three patients after four courses. Most affected patients had complete or partial recovery of symptoms with time. DISCUSSION: The efficacy and tolerability of the regimen confirm the feasibility of this new approach including glutathione in order to increase cisplatin dose intensity. The superiority of this regimen over standard induction therapy should be confirmed in randomized trials.

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Twenty-four consecutive patients with nondysgerminomatous germ cell tumor of the ovary were treated after surgery with cisplatin, vinblastine, and bleomycin (PVB regimen). The cycle was repeated every 3 weeks for three to five courses. Fourteen patients had endodermal sinus tumor, and 10 had mixed germ cell tumors. Stage of disease (FIGO, 1986) was as follows: stage I, 6; stage IIc-IV, 17; and recurrence, 1 patient. All patients were monitored by alpha-fetoprotein and human chorionic gonadotropin. Only 1 patient had received previous chemotherapy. All 5 patients without residual disease and with negative marker levels in which PVB was used as adjuvant treatment were free of disease for a median duration of 59 months from the start of PVB. Of the 19 patients with measurable disease (evident disease or positive marker levels), complete remission was obtained in 16 (84%), but 5 of these relapsed. Therefore, treatment with PVB failed in 8 out of 19 patients (42%) with measurable disease. Toxicity was evident, but no patient died of it. Menses were regular in 11 patients whose initial surgery was conservative. PVB regimen is an effective but not a satisfactory treatment. The considerable failure rate of PVB treatment suggests the investigation of other regimens.

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The use of high-dose cisplatin is limited by development of severe peripheral neurotoxicity and gradual worsening of renal function. In an ongoing study of high-dose cisplatin glutathione has been employed with the aim of preventing major cisplatin-induced toxicities. Neurotoxicity was examined in detail in 32 patients with ovarian cancer treated with cisplatin (160 mg/m2) and cyclophosphamide (600 mg/m2) every 3-4 weeks for five courses. In addition to serial complete neurological examination, sensory action potentials (SAPs) and motor conduction velocities (MCVs) were also assessed. We confirmed the development of a predominant sensory involvement, characterized by mild distal paresthesias and decrease in vibratory sensibility and in deep tendon reflexes, with a slight reduction of SAPs, observed after three courses of treatment. After five courses, distal paresthesias and disesthesias, decreased proprioception and loss of vibratory sensibility with ataxic signs, absence of deep tendon reflexes, unobtainable SAPs and only moderately reduced MCVs were seen. We did not observe any case of disabling neuropathy. There was a tendency to a more severe involvement of peripheral nerves in patients aged more than fifty. The 3 patients presenting the most serious neuropathy were the oldest in the whole group. Low degree of neurotoxicity observed in this study supports a glutathione protection against cisplatin-induced neurotoxicity. As the urinary excretion of platinum indicated no changes in the renal clearance of cisplatin following repeated courses, the lack of drug accumulation and high plasma peak due to preserved renal function might explain the reduced neurotoxicity observed.

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One course of preoperative chemotherapy including high-dose cisplatin (40 mg/m2 daily for 5 consecutive days) with glutathione protection and bleomycin (15 mg on days 2, 8 and 9) was administered to 27 patients with bulky operable cervical carcinoma (stage IB/II) in a pilot study. In all patients the tumor diameter was greater than 4 cm. Surgery (radical hysterectomy with pelvic and para-aortic lymphadenectomy) was planned within one month of chemotherapy. In 27 evaluable patients, nausea/vomiting was the most pronounced side effect. Significant (but transient) increases in serum transaminases were detected in 19 patients. Electrolyte imbalance (hypokalemia) was detected in 6 patients (one with hypocalcemia). These reversible effects were not associated with other signs of renal toxicity. Objective clinical responses were observed in 21 patients, 18 of them partial and 3 complete responders (pathologically confirmed in 2). Radical hysterectomy with pelvic and para-aortic lymphadenectomy was performed with no particular complications. The shrinking of bulky tumor made the operation easier, especially in parametrial resections. High-dose cisplatin chemotherapy prior to surgery is feasible with acceptable toxicity. The encouraging results of this study warrant further investigations to define the role of neoadjuvant therapy.

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Glutathione (GSH) is a sulfur-containing nucleophile that protects against cisplatin-induced renal toxicity without reducing the antitumor activity of the cytotoxic agent. To document further the clinical role of GSH in improving the outcome of cisplatin-containing regimens, the feasibility of the GSH/cisplatin combination using a low-volume hydration protocol was evaluated in untreated ovarian cancer patients. Twelve patients at stage III (minimal residual disease) and 23 with localized disease at high risk for recurrence were treated with cisplatin (90 mg/m2, i.v. in 250 ml of normal saline over 30 min) and cyclophosphamide (600 mg/m2 i.v.) every 3 weeks. GSH (5 g in 200 ml of normal saline) was administered by a short-term infusion (15 min) prior to cisplatin. The hydration protocol consisted of 1 liter of fluids without diuretics. The treatment was well tolerated; no nephrotoxic or neurotoxic manifestations were observed. The renal excretion of cisplatin (23%) at 24 hours following infusion was lower than expected using a standard i.v. hydration protocol. No reduction of renal elimination of cisplatin could be detected in subsequent courses, thus suggesting a minimal degree of impairment in renal function. In the series of evaluable patients (11) with stage III disease, 9 had complete pathological response. In the series of patients with no clinically detectable disease initially, all were disease-free at treatment completion. Taken together with previous observations, these results support the view that the use of GSH is a successful approach in the attempt to optimize cisplatin treatment, providing a new modality of drug administration for out-patient treatment.

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