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Human papillomaviruses (HPVs) are necessary, but not sufficient, for the development of cervical cancer (CC). Human β-herpesviruses (β-HHVs) have been suggested as possible cofactors in the oncogenesis of CC. In this cross-sectional study, the prevalence and possible association of cytomegalovirus (CMV), HHV-6 and -7 with HPV presence was investigated by quantitative real-time PCR assays in cervical samples obtained from 208 italian women. The two most common high-risk HPV types found were 31 and 16. Overall, the positive rates for CMV, HHV-6 and HHV-7 were 66%, 25%, and 6%, respectively. In particular, the prevalence of CMV was found to be extremely high irrespective of either the cytological category or HPV positivity. The prevalence of HHV-6 DNA was significantly higher in high-grade squamous intraepithelial lesions (HSIL) respect to normal women (P

Two independent and consecutive randomized clinical trials, conducted by the American Gynecological Oncology Group and by an European–Canadian Intergroup, have shown superiority, in clinical response rate, progression-free survival, and overall survival, of a cisplatin–paclitaxel regimen over cisplatin–cyclophosphamide given as first-line chemotherapy for women with advanced epithelial ovarian cancer. The results of these studies, published with a median follow-up of about 3 years, have been updated with a 6.5-year follow-up: In each case, an 11% absolute gain in survival favoring the paclitaxel arm is shown; this advantage remains both statistically and clinically significant and supports a role for paclitaxel in frontline chemotherapy for advanced ovarian cancer.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Objective: The standard treatment for stage IB-IIA cervical cancer over the past three decades has been the Piver-Rutledge type III radical hysterectomy. This surgery implies a high rate of urologic morbidity. The objective was to determine the role of class I radical hysterectomy compared to class III radical hysterectomy in terms of morbidity, overall survival, DFS and patterns of relapse in patients undergoing primary surgery. Materials and methods: 125 patients with stage IB1 and IIA cervical cancer ≤4 cm were randomized between type I and type III hysterectomy. Clinical, pathologic and follow-up data were prospectively collected. Adjuvant radiotherapy was administered when indicated. Univariate and multivariate analyses were carried out. Results: Sixty-two patients were randomized to class I surgery and 63 to class III. No significant differences were observed regarding pathologic findings and adjuvant treatment. Morbidity rates were higher after class III surgery (84% versus 45%). Pelvic recurrences were equal in both groups (8 cases each one). Fifteen-year overall survival rate was 90 and 74% respectively (p = 0.11) and 76 and 80% when cervical size is ≤3 cm (p = 0.88). Conclusions: There are no significant differences in terms of both recurrence rate and overall survival among patients with stage IB-IIA cervical cancer undergoing simple extrafascial hysterectomy (class I) or radical hysterectomy (class III). Morbidity is proportional to the extent of radicality. These data confirm the need of tailoring the extent of resection to the characteristics of the cervical neoplasia and open new interesting pathways to upcoming protocols for the conservative management of these tumors. © 2011 Elsevier Ltd. All rights reserved.

The aim of this study is to evaluate the effectiveness of radiation, concomitant chemoradiation and primary chemotherapy in the treatment of FIGO stage IIIB cervical carcinoma.Between January 1981 and December 2001 94 women with stage IIIB FIGO cervical carcinoma were observed. Exclusive radiotherapy was administered in 30 cases (32%), radiotherapy and radiosensitizing chemotherapy in 20 cases (21%) and primary chemotherapy in 44 cases (47%); among the latter patients 2 (4%) developed neoplastic progression, 28 (64%) underwent surgery and 14 (32%) underwent radiotherapy.After a median follow-up of 69 months, 5-year overall survival of the 3 groups is respectively 23%, 36% and 26% (p=0.7). Total dose to point A greater than 60 Gy and the use of brachyradiotherapy are suggestive for a better outcome among women treated with radiation therapy (5-year overall survival 31% versus 18%, p=0.8 and 33% versus 23%, p=0.4, respectively). Radiologically assessed nodal status is the only statistically significant risk factor (p=0.001). Although not statistically significant, vaginal involvement is a relevant factor influencing survival (p=0.1). Women treated with concomitant chemoradiation showed a better 5-year disease-free survival (45%) when compared to the other treatment groups (radiation alone 27%, primary chemotherapy 30%, p=0.4).Primary chemotherapy, although useful to allow subsequent surgery, does not yield a survival advantage with respect to the irradiated patients. Among these, concomitant radiosensitizing chemotherapy is likely to improve the disease-free survival.

Background: Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. Methods: Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. Findings: With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% CI 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% CI -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% CI 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% CI -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. Interpretation: Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemo therapy for ovarian cancer.

The medical treatment of squamous cell cervical carcinoma is receiving increasing attention. Cisplatin and ifosfamide are known effective drugs. Paclitaxel has been tested with interesting results in cervical cancer. We evaluated the toxic effects and the antitumor activity of a multiagent regimen that included paclitaxel, ifosfamide, and cisplatin (TIP) in two different settings: bulky and locally advanced cervical cancer and recurrent-persistent disease. Treatment consisted of paclitaxel 175 mg/m2 given over 3 hours on day 1, cisplatin 50 mg/m2 (75 mg/m2 in 24 patients), ifosfamide 5 g/m2 and mesna 5 g/m2 given on day 2, and mesna 3 g/m2 given on day 3. In the neoadjuvant setting, the course was repeated every 3 weeks for three courses. Unless there was progression of disease or reason to avoid surgery, all patients were scheduled for radical hysterectomy and pelvic lymphadenectomy. Thirty-eight patients with locally advanced cervical cancer were studied: 11 women achieved a clinical complete response, 21 had a partial response, five had stable disease, and one had disease progression. Among the 34 patients who underwent surgery, six had a pathologically documented complete response, seven had an optimal partial response (only microscopic residual disease), 19 had a suboptimal partial response, and two stable diseases. Grade 3-4 neutropenia was recorded in 71% of patients, grade 3-4 thrombocytopenia in 10.5%, and grade 2 peripheral neuropathy in 2.6%. With a median follow-up period of 22 months for the patients who remain alive, 28 women are alive without recurrence and five are alive with persistent/recurrent disease. Five patients have died of disease. In the salvage setting, 45 women with persistent-recurrent disease after primary treatment were treated; 31 of these women had received prior radiation. In the salvage setting we observed 15 clinical complete responses, 15 partial responses, nine stable diseases, and six disease progressions. The objective response rate was 66.6%. Ten complete responders underwent subsequent surgery and seven had pathologic complete response (two in radiated areas). The response rate was 52% in radiated areas and 75% in nonradiated areas. The median survival time is 6 months for the nonresponders, 9+ month for the partial responders, and 13+ months for the complete responders. The most relevant side effect was myelotoxicity, with 91% of patients experiencing grade 3-4 myelotoxicity. One woman had life-threatening toxicity. This regimen yields a high response rate with acceptable toxicity and should be prospectively compared with other regimens. The high rate of pathologic complete and optimal responses might impact positively on survival, but only a longer follow-up period will allow objective assessment of this impact. The specific roles of paclitaxel and ifosfamide in this regimen remain to be fully understood.

Several prognostic factors for stage I ovarian carcinoma have been analyzed. Some of them are biological and clinical in nature, but others such as the thoroughness of the staging procedure, the extent of the surgery and the philosophy of treatment, are defined by the human element.We reviewed the records of 351 patients with Stage I ovarian cancer who had been treated from 1981 to 1991. For all patients the following information was available: age, size of the tumor, FIGO sub-stage, tumor grade, histologic type, rupture of the tumor, cytology, extent of the staging and of the surgery (hysterectomy and bilateral salpingo-oophorectomy vs. fertility-conserving surgery) and use of adjuvant treatments. The thoroughness of the staging was defined as: optimal staging: total abdominal hysterectomy and bilateral salpingo-oophorectomy or fertility-conserving surgery, peritoneal cytology or washing, omentectomy, multiple peritoneal biopsies, sampling of the retroperitoneal nodes or formal lymphadenectomy, peritoneal staging: all the criteria described above were met with the exception of retroperitoneal sampling, incomplete staging: lack of any of the previously-cited criteria.An optimal staging was performed in 100 patients, a peritoneal staging in 107 and an incomplete staging in 144. Radical surgery was performed in 295 women and fertility-conserving surgery in 56. With a median follow-up of 108 months (range 14-184) 64 patients had recurrence of the tumor. Fifty-three died of the disease, two are currently alive with disease and nine were salvaged by surgery and/or chemotherapy. In a multivariate analysis only the tumor grade and the type of staging were significant independent prognostic factors for both disease-free and overall survival.As described by other authors, we confirm that tumor grade is the single most important biological prognostic factor in early ovarian carcinoma. The thoroughness of the staging impacts significantly on survival, particularly in poorly differentiated carcinomas. Fertility-sparing surgery is not associated with a worse outcome than standard radical surgery.

To report and evaluate a conservative and individualized treatment policy in a homogeneously selected series of patients affected by pure ovarian immature teratoma.This prospective trial, with specific treatment policies according to stage and grade, was planned and started in 1982. The study population consisted of 32 patients affected by pure immature teratoma, with the exclusion of mixed germ cell tumors. Fertility-sparing surgery was performed whenever possible. Surgery alone, with careful follow-up, was adopted for stage I or II according to the International Federation of Gynecology and Obstetrics (FIGO) and grade 1 or 2 tumors. The other patients, with stage III or with grade 3 stage I or II tumors, or those referred at relapse, were treated with platinum-based chemotherapy regimens.Thirty of 32 patients underwent fertility-sparing surgery. Ten of 32 patients received chemotherapy after surgery, either as adjuvant treatment or in the presence of visible tumor. All 32 patients are alive and disease-free, with a median follow-up from surgery of 47 months (range 11-138). In six patients, regardless of the administration of chemotherapy, the tumor either spontaneously differentiated toward mature glia or increased in volume, mimicking progression but still remaining completely mature. Five of six patients wishing to procreate had a total of seven normal pregnancies.Pure ovarian immature teratoma is a potentially curable disease with a unique natural history. Our data substantiate the hypothesis that low-grade and low-stage tumors do not require chemotherapy, and that a fertility-sparing surgical approach is warranted in all cases.

A case-control study was conducted on 91 cases with histologically-confirmed borderline ovarian tumours and 237 control subjects in hospital for acute non-gynaecological, hormonal or neoplastic disease. Women reporting three or more births, compared to nulliparae, had a relative risk (RR) estimate of 0.6, but this finding was not statistically significant (95% confidence interval (CI): 0.2-1.4). The risk of borderline tumours increased, although not significantly, with later age at first birth: compared to women reporting first birth at age 24 or before, the RRs were 1.3 and 1.7 in those reporting respectively their first birth at age 25-29 and 30 years or more. No significant relationship emerged between borderline ovarian cancer and age at menarche, menopausal status and lifelong menstrual pattern. Cases tended to report a later age at menopause than controls, but the trend in risk was not statistically significant. Nine cases (9.9%) and 68 controls (24.9%) reported oral contraceptive use: compared with never users the multivariate RR for ever users was 0.3, and the risk dropped with duration of use to 0.2 in users for two years or more (chi 2 (1) trend = 12.70, p less than 0.001). This study provides epidemiological evidence of a pathogenetic continuum between borderline and invasive ovarian tumours.Researchers compared 91 women with histologically confirmed borderline ovarian tumors at the University of Milan with 237 women (controls) admitted to Ospedale Maggiore in Milan, Italy for acute nongynecological, nonhormonal and nonneoplastic conditions to learn more about the epidemiology of borderline ovarian tumors. Oral contraceptives (OC) users had about a 70% lower risk of borderline ovarian tumors than nonOC users (relative risk ¿RR¿=0.3). In fact, the RR fell significantly to 0.2 for women who used OCs for at least 2 years (p.001). Further the risk of borderline ovarian tumors increased significantly as the age of women at the time of 1st birth increased (RR=1.8 for 25-29 year olds and RR=2.5 for =or 30 year olds; p=.02 [Mantel-Haenszel technique]). Women who experienced at least 1 induced abortion were less likely to have borderline ovarian tumors than those who had never experienced an induced abortion (RR=0.2). This may be because these women were of high fertility which agreed with the finding of lower risk in women of parity =or 3 (RR=0.7; p=0.23 insignificant). A higher risk was associated with late age at menopause, but the association was insignificant (RR=around 50 years old). Since the sample size was small due to the rarity of borderline ovarian tumors, one should interpret these results which caution. Nevertheless they supported the incessant ovulation hypothesis in ovarian carcinogenesis where the more exposure to ovulation or ovulatory cycles the greater the chance of ovarian neoplasms. Therefore they suggested an epidemiological continuum between various grades of malignancy of epithelial ovarian neoplasms.

Seven patients with advanced epithelial carcinoma and ascites, relapsing after two or more regimens of standard chemotherapy, have been treated with recombinant gamma-interferon (rIFN-gamma) i.p., via a permanent catheter. rIFN-gamma (Immuneron; Biogen; 0.5 mg = 10(7) IU in 2 liters of saline) was administered 3 times a week, on alternate weeks, for a total of nine courses. No major toxicities were observed: mild fever, malaise, and a flu-like syndrome occurred in all patients. The modulation of immunological parameters was studied. Cytotoxic activity of immunocompetent cells against tumor cell lines was measured both in the peritoneal compartment and in peripheral blood mononuclear cells. A significant increase of cytotoxicity of tumor-associated macrophages was observed in 5 of 7 patients and in 4 of 7 patients with tumor-associated peritoneal lymphocytes. Circulating effector cells were only occasionally stimulated. Tumor-associated macrophages isolated from the ascitic fluid and stimulated with lipopolysaccharide produced higher amounts of interleukin 1 in 5 of 6 patients tested, while interleukin 6 production by unstimulated tumor-associated macrophages was augmented in 2 of 2 patients after rIFN-gamma treatment. Freshly isolated ovarian carcinoma cells from the ascitic fluid has a variable, although usually low, expression of HLA-DR antigens. rIFN-gamma treatment caused a marked increase in HLA-DR expression in all patients tested. Expression of HLA class I antigens was negative in 2 of 5 patients and was strongly increased in 1 of the 2 after treatment. The observation that rIFN-gamma administered i.p. activates in situ effector cells and augments major histocompatibility antigen expression in tumor cells, with minimal toxicity, encourages further efforts to investigate its therapeutic potential in ovarian carcinoma.

The incidence of cervical intraepithelial neoplasias has increased in HIV - infected women, and invasive cervical ca is currently considered an AIDS defining condition. However the natural history of HIV - related cervical ca is still unknown. To better characterize cervical ca in HIV - infected women we evaluated 54 cases, including 35 (65%) carcinoma in situ (Cis) and 19 (35%) invasive ca, collected by the GICAT between January 1986 and June 1995. The median age was 28 years (range 19–38). The majority (70%) of patients (pts) were intravenous drug users and an history of sexual promiscuity and anogertital HPV-disease was reported by 55% and 88% of pts, respectively. At the diagnosis of cervical ca, 59% of pts had asymptomatic HIV - disease or PGL (category A), while 20% had sympotmatic HIV disease for diagnostic for AIDS (category B) and 15% had already a diagosis of AIDS (category C). Overall the mean CD4 cell count was 360 (± 230.8 SD), however the mean CD4 cell count was significantly lower in the Cis group than in the invasive ca group (279 ± 221.7 vs 455 ± 270.4, p = 0.03). All pts had squamous cell neoplasia. Among pts with invasive Ca, 63% had stage I acording to FIGO, 21% stage II and 16% stage III-IV. Pts with Cis received cone biopsy (85%) and cryotherapy or laser therapy (15%), whereas pts with invasive ca were treated with major surgery (S) (53%), radiotherapy (24%) or combination therapy (S-chemotherapy) (23%). Complete remission (CR) occurred in 97% of Cis pts and in 81% of invasive ca pts (p = 0.09); the recurrence rate was similar in the two groups (13% vs 20%, respectively), as well is the incidence of AIDS-associated infections during follow up (52% vs 57%, respectively). Median survival was 66 me for Cis pts and 101 mo for invasive ca pts (p = NS). In conclusion, invasive cervical ca is still occurring in at low rate in pts with HIV-infection in Italy, usually with a relatively good immune function. On the other hand there is a higher prevalence of Cis (65%) emphasizing the importance of integrating gynecological care into medical service for HIV-infected women. Supported by ISS grants.

The process and outcome of care for a group of patients with ovarian cancer treated over two years in two groups of Italian general hospitals were investigated. The quality of diagnostic and therapeutic measures did not substantially differ in specialised and non-specialised centres when selected indicators of quality of care were examined. Similarly, no differences in survival emerged for the two groups of hospitals. Overall results of the Italian series compared well with statistics of survival published by international centres for cancer, suggesting that when the yield of available treatments is limited both the process and outcome of care should be evaluated to obtain a reliable picture of quality of care. In the light of these results there are useful implications for planning future clinical trials and ways of caring.

Progestin therapy of ovarian carcinoma in the past has been reported to lead to varying response rates. A multicenter phase II study of high-dose MPA was conducted in 53 patients with epithelial ovarian cancer who had received adequate trials of conventional therapy with cytotoxic agents. Forty-one patients were included for response and toxicity evaluations. Only one partial response has been recorded with a duration of 20 weeks. Stabilization of disease was observed in 7 patients. The present investigation shows that MPA given at the present high dose is not effective in patients extensively pretreated with chemotherapy.

The aim of this multicenter randomized trial was to compare carboplatin (400 mg/m2) and cisplatin (100 mg/m2) in patients with untreated advanced epithelial ovarian cancer. Toxicity and treatment efficacy assessed by pathological response rate, progression-free survival, and survival were the endpoints of the study. One hundred seventy-three patients with advanced epithelial ovarian cancer, F.I.G.O. (International Federation of Gynecology and Obstetrics) stages III and IV were accrued in the trial. The median follow-up time was 15 months (maximum, 34); three patients in each treatment arm were not eligible (four, nonepithelial ovarian cancer type; one, no data, and one, stage II). Patient characteristics were similar in the two groups. In the carboplatin-treatment arm, the overall pathological response rate was 57.3% and the complete pathological response rate was 26.8%. In the cisplatin-treatment arm, the overall pathological response rate was 71.6% and the complete pathological response rate was 24.7%. There was no statistical difference in the two arms in survival or progression-free survival. Cisplatin was more nephrotoxic while carboplatin induced a higher degree of myelosuppression, especially thrombocytopenia; however, severe hematological toxicity was seldom observed. Carboplatin is a cisplatin analog with definite activity in ovarian cancer, but it is not more active than the parent compound. Because of less nonhematological toxicity, carboplatin is undoubtedly a useful substitute in patients who cannot be given cisplatin. Further experience is needed to indicate whether or not carboplatin should completely displace cisplatin in the clinical treatment of ovarian cancer. [J Natl Cancer Inst 81: 1464-1471, 1989]

Eleven previously untreated women with recurrent and/or metastatic granulosa cell tumor of the ovary were treated with cisplatin, vinblastine, and bleomycin in combination. All the six pathological complete responders but one are alive and free of disease at a median follow-up time of 14 months from the start of treatment. Of three partial responders, two died of drug-related toxicity while one, with only microscopic disease at second-look laparotomy, is alive and without evidence of disease at 34 months. Hematologic and nonhematologic toxicity were severe. These promising results require further examination of the activity and the best schedule of treatment with this combination.

Twenty patients with epithelian ovarian cancer treated with DDP (cis-diammine-dichloroplatinum II) 50 mg/m2 were followed for 24 weeks in order to assess the nephrotoxicity of the drug. Ten patients received the total dose in one day with heavy osmotic hydration (Group A), and for the other 10 the dose was subdivided over 3 consecutive days (Group B). The renal tubular toxicity of DDP treatment was evaluated over a total of 120 courses. After the first DDP administration, there was a prompt, reversable and dose-dependent increase in the urinary excretion of beta 2 microglobulin with no difference between the two groups: Group A from 405 to 990 and Group B from 109 to 585 ng/mg creatinine. An increase always occurred during subsequent courses, but it was significantly lower in Group B after the sixth course, from 125 to 331 ng/mg creatinine. A similar pattern was found for the urinary excretion of N-acetyl-glucosaminidase (NAG), a lysosomal enzyme of tubular origin. The percentage fraction of urinary sodium excretion (FeNa%) increased after each dose of DDP; Group A from 0.82 to 2.30 and Group B from 0.68 to 2.53. This effect was reversible and it occurred to the same extent during the subsequent courses. There was no impairment of the glomerular filtration rate. Thus, enzymuria and beta 2 microglobulin excretion are a sensitive tool to reveal minor tubular damage. Their use to predict serious renal dysfunction in longitudinal studies, however, seems questionable.

Out of 130 ovarian cancer patients the DNA index of cells from ovarian carcinoma was studied in 56 cases in which cytospin preparations showed the presence of atypical cells. In 24 patients the population had a diploid DNA index (1.0) and in the others the DNA index ranged from 1.2 to 2.0 (tetraploid). No hypodiploid or hypertetraploid populations were detected. Repeated samples from the same patients did not show any significant differences and primary culture did not alter the DNA index. In contrast, cell cycle phase distribution differed greatly from sample to sample, as also the ratio between DNA diploid and DNA aneuploid populations. Primary culture was successful in 57% of the tumours, with a higher percentage of success in DNA aneuploid tumours. After primary culture the ratio between DNA aneuploid cells and DNA diploid cells increased. In relation to the histological gradings of malignancy, DNA aneuploid cells clustered in the highest grade of malignancy. The mean S-phase for tumours with a DNA index of 1.0 was 3.5 and 14.1% for those with DNA index greater than 1. Ovarian carcinomas show a large difference in DNA index between patients even after primary culture.

A total of 155 samples from 101 patients with ovarian cancer were investigated using flow cytometry to evaluate the DNA index and the percentage of cells in the various cell cycle phases. Thirty-four samples were DNA diploid tumours, while the other 121 were DNA aneuploid tumours. The DNA index was very stable in different sites and over time in the same patient. Tumour stage and ploidy were significantly associated: stages III and IV tumour stage were more likely to be DNA aneuploid. Patients with residual tumour size at first surgery greater than 2 cm had a significantly larger number of DNA aneuploid than DNA diploid tumours. The DNA index was also related to the degree of differentiation of the tumours. The percentage of cells in the S phase of the cell cycle was significantly higher in DNA aneuploid and in poorly differentiated tumours than DNA diploid and well differentiated tumours. Multivariate analysis using the Cox model showed that the DNA index and the percentage of cells in S phase were not independent prognostic variables in this study. Prospectively collected data should be accumulated before assigning the DNA index an important role as a biological prognostic factor in ovarian cancer.

In a large percentage of ovarian cancer patients, primary surgical treatment leaves a situation of clinically non-followable tumor. The spread of ovarian cancer is, however, usually confined initially to the peritoneal cavity, but in view of the size and number of the sites, early diagnosis of relapse becomes even more difficult than primary diagnosis. Biochemical markers such as α fetoprotein, CEA, or βHCG, found to be specific for monitoring infrequent special tumors of the ovary [11, 14, 15], have not yet been shown to be of value in detecting the early phases of relapse in the epithelial types [3–10].

Biopsy of the left supraclavear area was performed on 20 patients affected by uterine cervical carcinoma at an advanced stage and showing positivity in the pelvic or para-aortic lymph nodes. The aim was revealing clinically occult metastasis to the prescalene lymph nodes. The histologic examination revealed no metastasis in the 98 lymph nodes that were examined. Despite the negligible morbility of this minor surgical intervention, the Authors believe it to be useless as a common practice examination at the beginning of a therapeutical program. In their opinion, it may be useful in cases of clear positivity in lombo-aortic lymph nodes, with no abdominal metastasis, for which radical pelvic surgic therapy is planned.

176 cases of cervical stump cancer have been reviewed. "Coincident cancer" and "True cancer" distinction has been made. Histological features, therapeutic plane and survival have been reported.

INTRODUCTION. Cisplatin is the most active single agent in the treatment of epithelial ovarian cancer. Si nce the fi rst report of its acti vity (1), several efforts have been made to try to identify the most effective schedule and to combine cisplatin in multiple drug regimens with hoped increased efficacy. No clear evidence exists that combination therapy is more effective than single agent cisp1atin in producing long term survival in patients with advanced epithelial ovarian cancer. Experimental and clinical data suggest a steep dose-response relationship for cisplatin in human ovarian cancer (2,3). Responses cou1 d be achi eved in pati ents res i stant to convent i ona 1 doses by increasing the dosage to 100-200 mg/mq. (4). Unfortunately, nephrotOXicity, neurotoxicity and otoxicity are important 1 imiting factors in reaching higher and more effective doses of cisplatin.The concept of dose-intensity has been recently introduced and seems to correlate with median survival times and tumor response rates. Dose intensity (=dosage of a therapeutic agent administered per unit time) may be increased by shortening the interval between courses, keeping the dosage low and thus avoiding undue toxicity.

This paper reports the results of lymphography in germinal and stromal tumors of the ovary. The group of patients is made up of 30 cases of germ cell tumors (70% dysgerminomas) and 29 cases of stromal tumors (62% granulosa cell tumors). The overall incidence of metastases was 29%; 37% in germ cell and 21% in stromal tumors. There was bilateral involvement in 41% of the patients with metastases. The para-aortic region alone was involved in 23%, the iliac alone in 18% and both the regions were simultaneously involved in 59%. In 17/30 operated patients (57%) retroperitoneal node biopsies were performed and diagnostic accuracy was 9/10 in the radiographically positive and 6/7 in the negative cases.

Mononuclear phagocytes were isolated from the peripheral blood (PB) and ascites tumors of 35 patients with epithelial ovarian tumors. After 48 hours of incubation with the TU5 tumor, tumor-associated macrophages (TAM) and PB monocytes from cancer patients showed lower cytolytic activity than did control cells, but by 72 hours there was little difference between control and ovarian cancer effector cells. Primary ovarian carcinoma cultures were heterogeneous in their susceptibility to macrophage cytotoxicity. Tumor cells from 7 patients were significantly lysed by monocytes and macrophages, whereas four ovarian cancer cell preparations were resistant to cytotoxicity. A "feeding" effect of mononuclear phagocytes on non-lysable tumor cells was detected in terms of both lower [3H]thymidine-release values in the cytolysis assay and increased proliferation in cytostasis assays. Thus patients with ovarian carcinomatous ascites PB monocytes and TAM had impaired cytotoxicity against a tumor cell line, and primary ovarian carcinoma cultures were heterogeneous in their interaction with mononuclear phagocytes.

A novel cell culture system is reported for the growth of ovarian tumors. Two approaches were developed to isolate tumor cells, one for ovarian carcinomas and the other for benign cystomas or borderline cystadenomas, which yield virtually pure tumor-cell clusters. The plating efficiency exceeded 10% in approximately 80% of the processed surgical specimens. Cells grown in a newly developed KOV medium (a modification of MCDB 151 supplemented with 6 defined growth factors and a moderate amount of FBS) had an average growth rate of 0.23 population doublings/day. Primary tumor-derived cultures, including those derived from cystomas, were analyzed by flow cytometry demonstrating a DNA heteroploid content in 55% of the cases. The neoplastic origin of the cells in culture was further confirmed by 3 monoclonal antibodies (OC125; MOv2; MOv19) with high specificity against epithelial ovarian malignancies. Cultures were tested with cis-DDP to determine their suitability for pharmacological studies. Exposure to the drug (from 10 to 80 microM for 1 hr) resulted in variable cell-killing responses, and the prominent effect on cell-cycle progression in primary cultures was a prolonged arrest in S phase. The formation and persistence of DNA-ISC caused by an exposure to 40 microM cis-DDP for 1 hr was studied by alkaline elution in 6 different tumor-derived cultures. DNA-ISC equivalents were highest between 9 and 24 hr after treatment and were repaired only to a limited extent within 48 hr of recovery time. The present study confirms the usefulness of this culture system for pharmacological studies of active chemotherapeutic agents against human ovarian tumors.

Tumor-associated lymphocytes (TAL) were isolated from ascites ovarian tumors by stepwise application of density and velocity sedimentation on discontinuous Ficoll-Hypaque gradients and fetal bovine serum. TAL had low levels of natural killer (NK) activity compared to levels of peripheral blood lymphocytes (PBL) from the same patients or control subjects. When TAL were mixed with PBL, significant inhibition of NK activity was observed in 7 of 27 patients tested, with the suppression levels ranging from 14 to 60%. Inhibition of PBL NK activity was observed at the ratio of TAL to PBL of 1:1 or 2:1. Suppression of NK activity was detected with effector-to-target cell ratios ranging from 6:1 to 25:1 and at incubation time from 4 to 20 hours in the cytolysis assay. Tumor-associated macrophages from 6 patients were tested for suppression of NK activity. Only with 1 donor was a 17% inhibition observed at a ratio of macrophages of PBL of 1:1. Thus suppression by mature plastic adherent macrophages does not play a major role in the determination of the low levels of NK in human ascites ovarian tumors and the inhibitory activity of suppressor TAL, which had a minor contamination (less than 5%) with mononuclear phagocytes. When TAL from 1 patient with suppressive activity were passed through nylon wool, inhibition of NK activity was observed with both adherent and nonadherent cells.

Peripheral blood lymphocytes (PBLs) and tumor-associated lymphocytes (TALs) were isolated from 36 patients with advanced ovarian adenocarcinoma and peritoneal effusions for study of lymphokine-activated killer activity. PBLs and TALs cultured in vitro for 3-5 days in the presence of interleukin-2 (IL-2, supernatant of the MLA 144 gibbon cell line, or human recombinant IL-2) expressed higher levels of cytotoxicity as compared to cells cultured in medium alone, against natural killer (NK)-susceptible (K562) or NK-resistant targets (Daudi and the human ovarian carcinoma cell line SW626). When ovarian tumor cells, freshly isolated from carcinomatous ascites or surgical specimens, were used as target cells in the cytotoxicity assay, 8 of 14 PBLs and 5 of 7 TAL preparations lysed the autologous tumor after treatment with IL-2, while no spontaneous reactivity was observed in any of the 14 patients tested. Although levels of lysis were usually relatively low, these data demonstrate that PBLs and TALs from ovarian cancer patients (TALs usually exhibiting low NK activity) when stimulated in vitro by IL-2 acquire some cytotoxic potential against the autologous tumor.

From 1982 to 1989 positive alpha-fetoprotein (AFP) levels were detected after surgery in 3 patients with pure immature teratoma, 7 patients with mixed germ cell tumors and 16 patients with pure endodermal sinus tumor (EST) of the ovary. In the three patients with pure immature teratoma, AFP serum levels became spontaneously undetectable in one month without chemotherapy. The marker was thereafter negative, despite the persistence of tumor in 2 patients, and a relapse in the third one. The serum levels of AFP did not correlate with the stage of EST and mixed germ cell tumors. The monitoring of AFP serum levels during treatment correlated with response to chemotherapy: of the 16 patients with pure EST, 14 achieved a serological complete response and did not undergo second look surgery; two patients had a serological partial response. One of them reached a serological complete response after further chemotherapy. The other patient with liver extragonadic tumor underwent liver lobectomy with negative histology. Among 7 patients with mixed germ cell tumor, 6 achieved a serological and pathologic complete response. The 7th patient had a serological complete response, but microscopic residual tumor at second look laparotomy. The decrement curve of AFP was not predictive for recurrence. However, AFP monitoring was useful for an early diagnosis of relapse in 4 patients. AFP is a reliable marker for the diagnosis, treatment evaluation and follow-up of patients with pure EST and a useful marker in the clinical management of mixed germ cell tumors of the ovary.

The Authors report survival data concerning 40 patients affected by cervicocarcinoma who, between 1970 and 1979, underwent exploratory laparotomy after pelvic radiotherapy, with detection of paraaortic lymphnode metastases. The patients subjected to laparotomy only (21 cases) have a 9-month average survival, which increases to 24 months in those with lymphadenectomy and complete pelvic surgery. While all the patients in the first group have died, in the second 3 survive at 5 years and 3 show no evidence of disease at 52,46 and 35 months from surgery. Hysterectomy with pelvic and lomboaortic lymphadenectomy, whether therapeutical or palliative, seems to be in patients with paraortic metastases provided surgery is feasable.