Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines.

The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmacokinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitro and in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin-DNA modifications in vivo and in vitro were studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin-DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin-DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum-DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3-5 mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.

Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix.

The aim of this study was to assess the expression of cytokine transcripts, reflecting the type of ongoing immune responses at the site of human papillomavirus (HPV) infection, in relation to the development of cervical neoplasia. To this end reverse transcription-polymerase chain reaction (RT-PCR) was performed for interferon (IFN) gamma, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12 (p35 and p40), and transforming growth factor (TGF beta 1) in snap-frozen cervical biopsies, which were tested for the presence of high risk HPV DNA and histologically classified from normal to invasive carcinoma (n = 40). IFN gamma, IL-10 and IL-12 (p35 and p40) transcripts were found to be expressed at significantly lower frequencies in invasive carcinoma as compared with premalignant biopsies (P = 0.006, P = 0.007 and P = 0.002, respectively). IFN gamma IL-10 mRNA were associated with the presence of the IL-12 p35 and p40 transcripts (P = 0.008 and P < 0.00001, respectively). These results are consistent with a locally reduced cellular (type 1) immunity correlating with HPV-induced invasive cervical carcinoma.

Antibodies against human papillomavirus type 16 and 18 E6 and E7 proteins in cervicovaginal washings and serum of patients with cervical neoplasia.

Serum antibodies against the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18 are associated with cervical cancer. The aim of this study was to investigate the presence of local antibodies against HPV in cervicovaginal washings (CWs). In this study antibodies against the native HPV16 and HPV18 E6/E7 proteins were detectable in CWs (48%) and sera (29%) from patients with cervical cancer (n = 21) utilizing a sandwich protein enzyme-linked immunosorbent assay (ELISA). In paired CWs and sera from patients with cervical intraepithelial neoplasia (n = 38) and from healthy women (n = 22) no antibodies against these proteins were found. In 10 of 11 patients, the antibody response corresponded with the HPV type in the cervical smear and/or tumor tissue, which indicates the HPV type specificity of the assay. In 7 of 11 patients with antibody reactivity against HPV16 or HPV18 E6 and/or E7 proteins a higher level of antibody reactivity in the CWs than in the paired serum samples was found at similar inputs of total IgG. This suggests that the antibodies in the CWs against the investigated HPV proteins in these patients were locally produced.

The prognosis of cervical cancer associated with pregnancy: a matched cohort study.

OBJECTIVE: To assess the effect of pregnancy on the prognosis of cervical cancer and the morbidity of standard treatment. METHODS: We analyzed 44 women with cervical carcinoma associated with pregnancy, who were matched with 44 controls. Matching criteria were age, stage of disease (according to the International Federation of Gynecology and Obstetrics classification), tumor type, treatment modality, and period of treatment. RESULTS: In 23 cases, cervical cancer was diagnosed during pregnancy and in the other 21 cases, within 6 months after delivery. Thirty-nine women had early-stage disease (eight IA, 25 IB, and six IIA), and five had advanced stages (four IIB and one IIIB). The overall 5-year survival rate was 80% among subjects and 82% among controls, whereas the relative risk (RR) of dying within 5 years was 1.12 (95% confidence interval [CI] 0.48-2.65). With regard to the 5-year survival rate (85% for both subjects and controls, the RR of dying was 1.00 [95% CI 0.35-2.83]); no differences were found between subjects and controls for early-stage cervical carcinoma. The size of the group with advanced-stage cervical carcinoma was too small to allow any statistical analysis. No statistically significant differences in survival were observed between cases diagnosed during pregnancy and cases diagnosed after delivery. In addition, the mode of delivery had no effect on survival. Early complications within 6 weeks after treatment were seen 33 times in 25 subjects and 29 times in 23 controls. No differences were observed in the prevalence and type of early complications in subjects versus controls. Late complications after 6 weeks of treatment were seen nine times in nine subjects and 11 times in ten controls. No significant differences were observed in the prevalence and type of late complications in subjects versus controls. CONCLUSION: The prognosis of early-stage cervical cancer is similar in pregnant and nonpregnant patients when standard treatment is given. Because of the limited number of patients, no conclusions can be drawn about advanced-stage cervical cancer. The goal should be standard oncologic treatment, which does not lead to increased morbidity in pregnant patients.

A mathematical evaluation of dose-dependent PpIX fluorescence kinetics in vivo.

The in vivo pharmacokinetics of protoporphyrin IX (PpIX) after administration of 5-aminolevulinic acid (ALA) cannot be described accurately by mathematical models using first-order rate processes. We have replaced first-order reaction rates by dose-dependent (Michaelis-Menten [MM]) reaction rates in a mathematical compartment model. Different combinations of first-order and dose-dependent reaction rates were evaluated to see which one would improve the goodness-of-fit to experimentally determined in vivo PpIX fluorescence kinetics as a function of concentration. The mathematical models that were evaluated are all based on a three-compartment model for drug distribution, conversion to PpIX and subsequent conversion to heme. Implementation of dose-dependent reaction rates improved the goodness-of-fit and enabled interpolation to other drug doses. For most data sets the time constant for delivery to the target cells turned out to be dose dependent. For all data sets the use of MM rates for the conversion of ALA to PpIX yielded better fits. The clearance of PpIX turned out to be a first-order process for all doses and types of administration. Fluorescence curves measured on a specific tissue type but obtained in different studies with different measurement techniques could be described with a single set of parameters.

Photodetection with 5-Aminolevulinic acid-induced protoporphyrin IX in the rat abdominal cavity: drug-dose-dependent fluorescence kinetics.

In 75% of cases, ovarian carcinoma has already metastasized in the abdominal cavity at the time of diagnosis. For determination of the necessity for a supplementary therapy, in addition to surgical resection, it is important to localize and stage microscopical intraperitoneal metastases of the tumor. Intraperitoneal photodetection of tumor metastases is based on preferential tumor distribution of a fluorescent tumor marker. The time-dependent differences in drug concentration between tumor and normal (T/N) tissues can be used to visualize small tumors. We performed fluorescence measurements on abdominal organs and tumor in the peritoneal cavity of rats. 5-Aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) was used as the fluorescent marker. Three different drug doses (100, 25 and 5 mg/kg) were used and PpIX fluorescence profiles were followed up to 24 h after intravenous administration. Maximum T/N ratios were found 2-3 h after administration of ALA with all drug doses. A significant T/N tissue contrast was obtained for all abdominal organs tested after administration of 5 mg/kg.

Extensive cytoreductive surgery combined with intra-operative intraperitoneal perfusion with cisplatin under hyperthermic conditions (OVHIPEC) in patients with recurrent ovarian cancer: a feasibility pilot.

AIMS: The feasibility, morbidity and toxicity of an intensified surgical treatment strategy consisting of aggressive cytoreductive surgery, intra-operative intraperitoneal perfusion of cisplatin and hyperthermia were evaluated in women with recurrent ovarian cancer. METHODS: Five heavily pre-treated patients with extensive abdominal tumour bulk entered this pilot study. In all cases aggressive cytoreduction leaving tumour remnants <5 mm in diameter could be performed. This was followed intra-operatively by perfusion of the abdominal cavity with hyperthermic cisplatin 50-70 mg/m(2)for 90 min. During perfusion the intra-abdominal temperature was maintained at 40 degrees C. The median duration of surgery was 10 hours (range 9-11 hours). RESULTS: No major intra- or post-operative complications emerged. Median post-operative ileus (resuming of soft diet) was 11 days (9-13 days). The mean period of hospitalization was 25 days (range 17-42). Toxicity due to i.p. cisplatin was mainly metabolic and of grade 1-2, while no nephrotoxicity was observed. The pharmacokinetics of cisplatin indicated that the maximum concentration of cisplatin measured in the perfusate was 15 times higher than in plasma. CONCLUSIONS: We conclude that aggressive cytoreduction combined with hyperthermic intra-operative intraperitoneal cisplatin was feasible in a small group of heavily pre-treated ovarian cancer patients with extensive tumour bulk with acceptable morbidity and toxicity. Further studies are required in larger groups of patients to further establish the feasibility of this intensified treatment strategy. We stress that OVHIPEC is not a treatment modality on its own for advanced ovarian cancer. The effectiveness of OVHIPEC is likely to be dependent on the effectiveness of post-operative adjuvant chemotherapeutic regimens.

Pharmacokinetics and pharmacodynamics of cisplatin after intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC).

BACKGROUND: HIPEC is a new treatment modality for abdominal cancers that combines cytoreductive surgery with Hyperthermic, Intraoperative Peritoneal Chemotherapy, followed by systemic chemotherapy. A significant survival benefit has been shown for HIPEC compared with systemic therapy alone. However, it is not clear what is the contribution of i.p. drug delivery and what influence the mild hyperthermia has on the uptake of cisplatin in abdominal tumors. MATERIALS AND METHODS: We used a peritoneal perfusion system in rats to compare the pharmacokinetics and pharmacodynamics of cisplatin, after normothermic (37 degrees C/90 minutes) and hyperthermic (40 degrees C/90 minutes) intra-peritoneal perfusion, with an i.p. bolus injection. RESULTS: Hyperthermic perfusion with 15 micrograms/ml (in 200 ml) cisplatin gave equivalent plasma drug levels to a maximum tolerated dose (MTD) i.p. bolus injection of 4 mg/kg (36 micrograms/ml in 20 ml). The drug concentration in small (1-5 mm) intra-peritoneal tumors was also comparable for both these treatments, and for normothermic perfusion. CONCLUSION: Mild hyperthermic perfusion with cisplatin (40 degrees C/90 minutes) did not improve drug uptake in small intra-peritoneal tumors, relative to normothermic perfusion or i.p. bolus injection.

Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone.

The effect of seven low-dose oral contraceptive preparations on sex hormone binding globulin (SHBG), cortisol binding globulin (CBG), total and absolute free testosterone were investigated in groups of 10 healthy volunteers. All preparations contained about the same amount of ethinylestradiol but they differed in type and/or dose of progestagen. The progestagens studied were: levonorgestrel (LNG; in mono- and triphasic preparations), norethisterone (NET; in monophasic preparation), desogestrel (DSG; in mono- and biphasic preparations) and gestodene (GSD; in triphasic preparation), all 19-nortestosterone derivatives, and the anti-androgen cyproterone acetate (CPA) in a monophasic preparation. Differences observed in SHBG level, which reflect the estrogen-androgen balance, can be attributed to the intrinsic androgenic (or anti-androgenic) properties of the progestagens, and were in agreement with the results of published receptor binding studies, performed in vitro. Based on our results the following ranking (high to low) can be made with respect to the androgenicity of the preparations: monophasic LNG greater than or equal to monophasic NET = triphasic LNG greater than or equal to triphasic GSD = biphasic DSG = monophasic DSG greater than monophasic CPA. An anti-estrogenic effect of the 19-nortestosterone derived progestagens can be excluded by the effect on CBG, a marker for estrogenic activity. All preparations containing a 19-nortestosterone derived progestagen, independent of their type and dose, induce a similar rise in CBG, whereas the preparation with cyproterone acetate induced an even higher CBG level. Irrespective of the effect on total testosterone, which varies between the preparations, the absolute free testosterone level decreased to a comparable degree for all preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of seven low-dose combined contraceptives on vitamin B6 status.

The effect of seven low-dose oral contraceptive preparations on vitamin B6 status was investigated in 55 women. All preparations contained about the same amount of ethinylestradiol but differed in the content and type of progestagen. The following preparations were investigated: monophasic and triphasic levonorgestrel, monophasic and biphasic desogestrel, monophasic norethisterone, monophasic cyproterone acetate and triphasic gestodene. The vitamin B6 status was evaluated by measuring erythrocyte glutamate oxaloacetate transaminase (EGOT) activity and its degree of in vitro stimulation. From these two variables the total EGOT activity was calculated. In addition plasma pyridoxal-5'-phosphate (PLP) levels were estimated. After six months' treatment, EGOT activity and the calculated total EGOT activity were increased, but no changes were observed in the degree of in vitro stimulation (which is a more reliable parameter). Plasma PLP levels initially decreased during the first three months of treatment but after six months a return to normal levels was observed. Differences between the seven preparations were not found. We conclude from these results that the low-dose preparations investigated in this study have no any adverse effects on vitamin B6 status.

IgG antibodies against human papillomavirus type 16 E7 proteins in cervicovaginal washing fluid from patients with cervical neoplasia.

Little information is available about the cervicovaginal mucosal antibodies against human papillomavirus (HPV) proteins. In this study specific IgG antibodies against HPV 16 E7 protein were determined in paired samples of cervicovaginal washing fluid and serum from patients with cervical cancer (n = 22), cervical intraepithelial neoplasia (CIN) (n = 38), healthy individuals (n = 22), and serum from children (n = 41) by a radioactive immunoprecipitation assay (RIPA). HPV 16 E7 specific IgG antibodies were found in cervicovaginal washings (n = 8) and in sera (n = 8) of the patients with cervical cancer. About 60% of the patients with HPV 16 positive cervical cancer had HPV 16 E7 specific IgG antibodies. Titration studies showed that the IgG antibody reactivity in cervicovaginal washings was higher than in the paired serum samples of six patients with cervical cancer (P < 0.001). In the CIN group we found no IgG reactivity in the serum, but in five patients we found a low IgG reactivity in the cervicovaginal washings. No IgG reactivity was found in cervicovaginal washings and sera from healthy individuals and sera from children. HPV 16 E7 specific IgG antibodies seem to be locally produced in a number of patients with HPV 16 positive (pre)malignant cervical lesions. For more definitive evidence for the local production of these antibodies immunostaining should be performed to demonstrate the presence of specific anti-HPV 16 E7 IgG producing plasma cells in the cervical epithelium.

Restricted surgical management of vulvar intraepithelial neoplasia 3: Focus on exclusion of invasion and on relief of symptoms.

van Beurden M, van der Vange N, ten Kate FJW, de Craen AJM, Schilthuis MS, Lammes FB. Restricted surgical management of vulvar intraepithelial neoplasia 3: Focus on exclusion of invasion and on relief of symptoms. Int J Gynecol Cancer 1998; 8: 73-77. A study was undertaken to determine the effectiveness of extensive and restricted surgery for vulvar intraepithelial neoplasia (VIN) 3. All consecutive patients with VIN 3 admitted to a tertiary referral hospital were included. The main outcome measures were relief and recurrence of symptoms and progression to invasive disease in patients with VIN 3 after extensive or restricted surgery. Of every vulvoscopic visible lesion a biopsy was taken to establish extent and grade of VIN and to rule out invasive carcinoma. Patients with unifocal VIN 3 underwent extensive surgery. Patients with multifocal VIN 3 underwent extensive or restricted surgery or an expectant management was adopted, depending on the existence of symptoms and the presence of invasive vulvar carcinoma. Forty-seven patients were evaluated. Eighty-three percent of patients had a long history of symptoms. Eight patients (17%) had unifocal VIN 3. In 9% of the patients a superficially invasive vulvar carcinoma was found, ie with a depth of invasion of 1 mm or less. Only 20% of the extensively operated patients had free surgical margins. There was recurrence of symptoms in all of the extensively operated patients, in contrast to a 26% persistence or recurrence rate of symptoms in the restrictedly operated patients. In patients with multifocal VIN 3 who underwent restricted surgery, young age of the patient (P = 0.02) and large extension of VIN 3 (P = 0.02) were significant factors in predicting persistence or recurrence of symptoms. Only once was a superficially invasive vulvar carcinoma diagnosed during follow-up, and this was in an extensively operated patient. Vulvoscopically directed biopsies in VIN 3 are a safe method to exclude invasive disease. Restricted surgery is effective in relieving symptoms in multifocal VIN 3.

Hydrops fetalis associated with inferior vena cava thrombosis.

A case of hydrops fetalis associated with inferior vena cava thrombosis is described. Although in the literature this association is always listed, this is the first report of a well-documented case.

[Hyperthermic intra-peritoneal chemotherapy (HIPEC) in patients with peritoneal pseudomyxoma or peritoneal metastases of colorectal carcinoma; good preliminary results from the Netherlands Cancer Institute]. / Hypertherme intraperitoneale chemotherapie (HIPEC) bij patiënten met pseudomyxoma peritonei of peritoneummetastasen van colorectaal carcinoom; gunstige eerste ervaringen in het Nederlands Kanker Instituut.

OBJECTIVE: To apply (HIPEC) using mitomycin in patients with peritoneal carcinomatosis. DESIGN: Descriptive. METHOD: The HIPEC treatment includes cytoreductive surgery and subsequent peritoneal lavage with exposure of the superficial tumour residues to a high concentration of a cytostatic drug at an intra-abdominal temperature of 40-42 degrees C. The HIPEC treatment was given to 24 patients with pseudomyxoma peritonei and to 29 patients with peritoneal carcinomatosis of colorectal origin. The adequate dose of mitomycin was determined in the Netherlands Cancer Institute in 26 patients: doses of 15 mg/m2 (n = 8), 25 mg/m2 (n = 3), 35 mg/m2 (n = 7) and 40 mg/m2 (n = 8) were administered. RESULTS: The maximal tolerable dose of mitomycin appeared to be 35 mg/m2, while unacceptable toxicity was recorded at a dose of 40 mg/m2. Therefore 35 mg/m2 was used in subsequent cases. Among the patients with pseudomyxoma peritonei 8 developed severe complications, two of which were fatal. After a median follow-up of 12 months, 21 patients were alive of whom 18 were free of disease. Among the patients with peritoneal carcinomatosis of colorectal origin one patient died from a treatment-related complication. After a median follow-up of 18 months, 18 patients were alive of whom 11 were free of disease. The actuarial 2 year survival was 59%. CONCLUSION: In the Netherlands Cancer Institute HIPEC treatment is considered the treatment of choice for pseudomyxoma peritonei. The results in cases of peritoneal carcinomatosis of colorectal origin are promising, but the results of a randomized trial are awaited.

Effects of seven low dose combined oral contraceptives on high density lipoprotein subfractions.

The effects on lipid metabolism of seven combined oral contraceptives were investigated, particularly the effects on high density lipoprotein (HDL) subfractions, which were separated by density gradient ultracentrifugation. There were no differences between the preparations in the effects on the LDL fraction, the so-called atherogenic particle, but there were marked differences in the effects on the anti-atherogenic HDL fraction, of which the effects on HDL-2 were most pronounced. After treatment with monophasic cyproterone acetate and biphasic desogestrel, the cholesterol and phospholipid contents of the HDL-2 fraction were significantly higher than those found after treatment with the other preparations. The lowest values were found after treatment with monophasic levonorgestrel, whereas monophasic desogestrel, triphasic levonorgestrel, monophasic norethisterone and triphasic gestoden induced intermediate values for these variables. The levels of HDL-2 reflect the intrinsic androgenicity of the various progestogens used in the preparations.

Effect of seven low-dose combined oral contraceptive preparations on carbohydrate metabolism.

The effect of seven low-dose oral contraceptive preparations on carbohydrate metabolism was investigated in groups of 10 healthy volunteers. All preparations contained a similar amount of ethinyl estradiol but differed in the content and type of progestogen. The following progestogens were used: levonorgestrel (monophasic and triphasic), norethisterone (monophasic), cyproterone acetate (monophasic), desogestrel (monophasic and biphasic) and gestodene (triphasic). An oral glucose tolerance test was performed before and after 6 months of treatment; glucose disappearance and insulin response curve were determined. Long-term glucose homeostasis was assessed by the estimation of the extent of glycosylation of plasma proteins and hemoglobin A1. The area under the curve for insulin and glucose did not change during treatment with any of the preparations. In addition the representative variables for long-term glucose control did not increase for any of the preparations during treatment. We conclude from these results that the low-dose pills investigated in this study do not have any adverse effects on glucose metabolism after treatment for 6 months.

PIP: 70 healthy female volunteers participated in a study designed to investigate the effect of 7 low-dose oral contraceptive (OC) preparations on carbohydrate metabolism. The study participants were divided randomly into 7 groups (10 volunteers per group), each receiving 1 of the preparations. Table 1 presents the composition and intake regimen of the various preparations. The treatment period lasted 6 cycles; each cycle consisted of 21 days of tablet intake followed by 7 tablet-free days. An oral glucose challenge test was performed. It was carried out during the luteal phase of the control cycle (days 19-24) and on day 15 or 19 of the 6th treatment cycle. Blood samples were taken after overnight fasting (12-15 hours) just before the glucose loading and 30, 60, 120, and 180 minutes after glucose intake. Glucose was determined with the glucose-oxidase method on a Beckman glucose analyzer, and insulin was assayed with a radio-immunoassay. Statistically significant differences between pretreatment and treatment values were calculated with the paired "t" test. Although treatment values were frequently higher than those before treatment, there were no significant differences between pretreatment and treatment values for glucose and insulin levels with the preparations, with the following exceptions after 6 treatment cycles: a lower fasting glucose level with monophasic desogestrel, a higher 30-minute glucose value with triphasic levonorgestrel, and a higher 180-minute insulin level with monophasic norethisterone. The area under the curve for insulin and glucose was not changed significantly for all prepartions during treatment. Total hemoglobin A and glycosylated proteins were not influenced by any of the preparations with the exception of a significant decrease with monophasic levonorgestrel during treatment. No significant difference was found between the different preparations except that monophasic levonorgestrel was associated with significantly lower hemoglobin Al values compared with those of the other 6 preparations and that monophasic cyproterone acetate had significantly lower hemoglobin Al values than monophasic norethisterone after treatment for 6 months. In sum, the low-dose OCs investigated did not have any adverse effects on glucose metabolism after treatment for 6 months.

Experience with hormonal therapy in advanced epithelial ovarian cancer.

The experience from using different hormonal trials in 33 ovarian cancer patients, who were beyond the stage of standard therapies and experimental cytotoxic therapies in a single institution, are reported. Agents used were progestins, an antiestrogen (tamoxifen), an antiandrogen (flutamide) and a GnRH-agonist (decapeptyl). Twenty-one patients completed at least 8 weeks of treatment. Two patients obtained an objective response (10%): one partial response on tamoxifen for 6 months and one complete response on decapeptyl for 38 + months. Two further patients achieved disease stabilizations on tamoxifen and flutamide for 6 and 8 months respectively. Although the objective response rate with hormonal therapies is limited in these circumstances the absence of important toxicities favor their use. It is suggested to further study this in patients who do not reach a complete response after standard induction chemotherapy, particularly in those with well-differentiated tumors.

Epidemiologic and mucosal immunologic aspects of HPV infection and HPV-related cervical neoplasia in the lower female genital tract: a review.

Human papillomavirus (HPV) infections are known to play an important role in the pathogenesis of cervical neoplasia. Considering the morbidity and mortality of cervical cancer, infection with HPV can be regarded as a worldwide problem, especially in developing countries. Currently, many studies focus on the development of both prophylactic and therapeutic HPV vaccines. Crucial for these vaccination protocols to be successful is that they will result in a long-lasting ability to generate an immune response that will eliminate the virus. HPV transmission and subsequent infection is a local event in the lower female genital tract and therefore the efficacy of vaccines against this locally transmitted infection can be best assessed by parameters of local immunity. In this review we describe both the epidemiology of HPV-related cervical neoplasia and the general aspects of mucosal immunity in the female genital tract while focusing on the local humoral immunity in HPV-related cervical neoplasia.