Palliative chemotherapy with trofosfamide in advanced prostate cancer.

BACKGROUND: A phase II study with trofosfamide in hormone-refractory prostate cancer was conducted to test the palliative efficacy. PATIENTS AND METHODS: Twenty patients suffering from advanced prostate cancer were treated with per os trofosfamide after progression on androgen ablation and/or estramustine. The mean age was 72 years. The patients were treated with 150 mg/day as continuous treatment. The treatment was continued until progressive disease or severe toxicity. RESULTS: A decline in the prostate specific antigen (PSA) level was observed in 5 patients (27%) with a 0-25% decline in 2 patients and a >50% decline in 3 patients (16%, 95% confidence interval 3.4-39.6). There were no clinical or radiological complete (CR) or partial (PR) responses in 19 evaluable patients. Some toxicity was observed: 15 patients developed anaemia and grade 2-4 adverse effects were observed in 16 patients. One patient died of cardiac event. CONCLUSION: Trofosfamide has some activity in hormone-refractory advanced prostate cancer. When used in fragile or heavily pre-treated patients, careful monitoring for haematological and cardiac effects is recommended.

Delayed diagnosis and large size of breast cancer after a false negative mammogram.

The aim of this prospective, multicentre study was to investigate the effects of a false negative mammogram on treatment delay and tumour size. Among 306 consecutive women with histologically diagnosed, invasive breast cancer, the frequency of a false negative mammogram was small (13%) among women aged over 50 years, but 35% among those aged 50 or younger (P < 0.0001). Forty-five per cent of the women with a false negative mammogram had a longer than 2-month and 29% a longer than 6-month interval from mammography to surgery as compared with only 2 and 0% of women, respectively, who had a true positive mammogram (P < 0.0001 for both). Women with a false negative mammogram and a longer than 2-month interval to surgery had larger primary tumour size (60 versus 26% pT2-4, P = 0.005) and more often positive axillary nodes (60% versus 32% pN+, P = 0.03) at the time of surgery than those with a shorter delay. We conclude that a false negative mammogram is common in women younger than 50, and may lead to treatment delay and advanced clinical stage.

Discordant levels of serum bioactive LH in man as measured in different in-vitro bioassay systems using rat and mouse interstitial cells and human granulosa-luteal cells.

Serum samples from healthy men (n = 6), perimenopausal women (n = 9) and patients with polycystic ovarian disease (n = 4) were analysed for LH bioactivity by the two widely used in-vitro bioassay systems: the mouse and rat interstitial cell testosterone-formation assays. The results were compared with an assay employing LH-stimulated cyclic AMP production by cultured human granulosa-luteal cells. Average bioactive LH levels in the mouse cell assay were 1.6-fold higher than those measured using the rat assay. A good correlation (r = 0.89, P less than 0.01) was observed between the bioactive LH levels measured by these two assays. No significant difference was found between the sensitivities of the two assays: 0.009 +/- 0.003 IU/l (mean +/- S.E.M., n = 10) with rat cells and 0.011 +/- 0.003 IU/l (n = 10) with mouse cells. The LH level resulting in half-maximal stimulation of testosterone production in the mouse model was twofold higher than that in the rat model (0.185 +/- 0.020 vs 0.083 +/- 0.022 IU/l, P less than 0.01). The bioactive LH levels measured by the human granulosa-luteal cell assay averaged 12% higher than those obtained with the rat assay (r = 0.84, P less than 0.01), but 58% lower than levels measured with the mouse assay (r = 0.86, P less than 0.01). The data indicate that the target cell model used in the in-vitro bioassay of LH contributes to the documented discrepancies in reports on serum levels of bioactive LH.(ABSTRACT TRUNCATED AT 250 WORDS)

Acinar cell carcinoma of the pancreas. Report of three cases.

Pancreatic acinar cell carcinoma is a rare neoplasm (comprising about 1% of pancreatic tumours). We studied three cases (61-year-old female; 42-year-old male; 57-year-old male), whose survival after diagnosis ranged from 1 year 2 months to 6 years 8 months. There were widespread metastases in each case. The tumours had acinar, trabecular and solid growth patterns. By immunohistochemistry, pancreatic acinar cell markers including carboxyl ester lipase, pancreatic secretory trypsin inhibitor and pancreatic phospholipase A2 (group I PLA2) gave a strong positive reaction in all three cases. By electron microscopy, zymogen granules were seen in the cytoplasm of the tumour cells. Immunostaining for prostate-specific antigen was positive in all three cases. Above-normal concentrations of pancreatic PLA2 were measured in the serum of one patient and the values decreased during chemotherapy concomitantly with the reduction in the size of the tumour mass. In conclusion, immunohistochemical demonstration of the secretory products of acinar cells including the new marker pancreatic PLA2 is useful in the differential diagnosis of pancreatic acinar cell carcinoma. Determination of the concentration of pancreatic group I PLA2 in serum may be helpful in the evaluation of therapy.

Carboplatin and etoposide in advanced lung cancer:--a phase I study.

This phase I study was carried out to determine the maximal tolerated dose of carboplatin (Car) together with a fixed dose of etoposide (E) and to recommend the optimal dose for a phase II study. The dose of E was 100 mg/m2 given i.v. on days 1-3, and the starting dose of Car was 200 mg/m2 given i.v. on day 1. The dose was escalated until WHO grade 4 toxicity developed after two treatment cycles in more than one-third of the patients. A total of 33 patients with advanced lung cancer entered the trial. The maximal tolerated toxicity of the combination was reached at a dose of 500 mg/m2 Car. Myelosuppression was moderate, and hematological toxicity of WHO grade 4 was encountered in one of five patients at 475 mg/m2 and in two out of five patients at 500 mg/m2. The main toxic effects were leucopenia and thrombocytopenia. The frequency of treatment-related infections was low and no deaths were caused by treatment. There was a significant overall correlation between the platelet nadir and creatinine clearance. One complete response and three partial responses were achieved after two treatment cycles. Based on the results of the present study, the dose of carboplatin (combined with 100 mg/m2 eposide given on days 1-3) recommended for phase II studies is 450 mg/m2.

Chlamydial serology in infertile women by immunofluorescence.

The chlamydial serum immunoglobulin G antibodies of 128 infertile women were determined by a single-antigen (L2) immunofluorescence test. The antibody titers were compared with those of female contacts of men with nonspecific urethritis and with those of "normal" pregnant women. Among infertile women, 43% lacked chlamydial antibodies (titer less than or equal to 8). The corresponding proportion for contacts of men with nonspecific urethritis was 14% and that for pregnant women 71%. A very high titer (greater than or equal to 256) was recorded in 25 infertile women and in 7% of pregnant women. Among women with positive chlamydial isolation, 46% had titers greater than or equal to 256. Bilateral tubal obstruction was demonstrated in 23 infertile women (18%). The geometric mean titer of these patients was higher than that of patients with normal hysterosalpingograms. In nine cases with bilateral tubal obstruction and very high chlamydial antibody titers, there was no history of pelvis infections. The operative findings were typical of previous salpingo-oophoritis.

Total renin after gonadotropin stimulation in polycystic ovarian disease.

OBJECTIVE: To examine the influence of polycystic ovarian disease (PCOD) on the levels of total renin in plasma and follicular fluid (FF) after stimulation with hMG. DESIGN: Comparative study of the plasma and FF concentrations of total renin in women with and without PCOD after stimulation with hMG. SETTING: In vitro fertilization-embryo transfer program at the Department of Obstetrics and Gynecology, the University Central Hospital of Turku, Finland. PATIENTS: Thirty-six women undergoing IVF-ET for infertility with (n = 10) or without (n = 26) ultrasonographically diagnosed PCOD. Of the latter group, 15 women had tubal infertility, and the rest suffered from an anovulatory infertility and reacted with PCO-like ovarian response to stimulation. MAIN OUTCOME MEASURES: The concentrations of total renin in plasma and FF, serum E2, and protein in FF. RESULTS: The concentrations of plasma total renin after the gonadotropin stimulation were significantly higher in the PCOD and PCO-like groups when compared with the tubal group. The concentration of total renin in FF and the ratio of total renin per protein in FF were higher in the PCOD and PCO-like groups than in the tubal group, but the differences did not reach statistical significance. Positive correlations were found between the plasma total renin and serum E2 concentrations in the PCO-like and in the tubal group and between plasma total renin concentrations and the number of mature follicles in all groups. Follicular fluid total renin did not correlate with FF protein in any group. All findings were independent of the total hMG dosage used and the body mass index of the patients. CONCLUSIONS: In the present study the concentrations of total renin in plasma were enhanced markedly after gonadotropin stimulation in women with PCOD compared with women having tubal infertility. The pattern of the hormonal secretions revealed a group of infertile patients reacting biochemically like women with PCOD.

Treatment results of osteogenic sarcoma. An evaluation of 36 patients treated during 30-year period in south-western Finland.

Histological re-evaluation revealed 36 osteogenic sarcoma (OS) patients for analysis in South-Western Finland treated between 1958 and 1987. In 21 cases (58%) the tumour was located in the knee region. The mean age at diagnosis was 28 years (range: 5-62 years) and the follow-up time of the patients was at least 5 years or until death. In 29 patients without metastases at the time of diagnosis, the extent of the primary tumour was T2 in 37% and T3 in 63% of the patients. There were no differences regarding the extent of the primary tumour, delay of the diagnosis, mean age of the patients, or duration of the symptoms while comparing the three decades of the study. Before the 1970s the treatment consisted of surgery with or without radiotherapy in most cases. Since the 1970s the combination of surgical treatment (amputation or wide excision) and adjuvant chemotherapy was the most common treatment modality. Since the late 1970s limb-salvage surgery has been applied in selected cases, and it seems to be justified. None of the patients treated before 1970 survived for 5 years. The 5- and 10-year survival of all 36 patients was 44.4% and 33.6%, respectively. In non-metastatic patients both the 5- and 10-year disease-free survival was 46.7%. A certain group exhibiting a good prognosis was found; the 10-year survival of the 10 patients with OS in extremities, treated with combined chemotherapy and surgery, was 70%. The median survival time was significantly longer for the patients with an intracompartmental tumour extent of T2 (112 months) compared with an extracompartmental extent of T3 (23 months), and for the patients with the primary tumour in the knee region (112 months) compared with other locations (18 months). The long-term survival of the OS patients has improved concomitantly with the multimodality of the treatment.

Effect of local epididymal levonorgestrel on the fertilizing ability of male rat, a model for post-testicular contraception.

A thin levonorgestrel-silicone layer was applied on the capsule of the cauda epididymis of male rats to study a model for post-testicular male contraception. The effect of different levonorgestrel doses on the fertility of males was tested with fertile females. The time-dependent influence of a standard dose of levonorgestrel on serum LH and on testicular histology was estimated. Among the males tested, there was a group of animals where successful contraception with local application of levonorgestrel-silicone membrane was obtained. Sexual behavior was normal and the spermatogenesis was functioning, but the sperm were infertile. Although further research is needed to estimate adequate dose and strength of levonorgestrel in silicone matrix, this study shows that post-testicular contraception is possible to achieve.

Flow cytometric analysis of tumor DNA profile related to response to treatment and survival in small-cell lung cancer.

Flow cytometric (FCM) analysis of tumor DNA ploidy and S-phase fraction (SPF) has been widely used to predict prognosis and treatment response in many malignant tumors, but rarely in small-cell lung cancer (SCLC). In the present study, tumor DNA ploidy and SPF were measured from paraffin-embedded tumor biopsy samples of 36 small-cell lung cancer patients treated with combination chemotherapy and radiotherapy. Aneuploidy was detected in 69% of the tumors. There was a statistically non-significant trend towards more aneuploidy among extensive disease (ED) patients as compared to patients with limited disease (LD): 80% versus 65%, respectively (p = 0.69). The mean SPF was 21.3% (+/-7.6) in patients with LD and 29.0% (+/-5.3) in patients with ED, the difference (7.6%) being statistically significant (p = 0.008, 95% CI for the difference 2.2-13.1). No significant differences was detected in the survival of aneuploid and diploid patients or patients with low (< or = 24.9%) and high (> 24.9%) SPF. Similarly, no significant difference was observed between aneuploid and diploid cases in relation to response to treatment or response duration. It is concluded that the difference detected in the SPF with LD and ED of SCLC may indicate the biological aggressiveness of extensive SCLC.

Problems and benefits in early diagnosis of ectopic pregnancy.

A 5-yr retrospective study is presented of 168 consecutive patients operated on for ectopic pregnancy during 1977-1981, showing the prevalent features and trends of this disorder and its diagnosis. The overall incidence was 1.48% of deliveries, with a range of 1.00-2.34%. The number of unruptured cases (52.1%) in the series reflects the low gestational age. Some of the problems (and benefits) commonly associated with early diagnosis are surveyed. The presenting symptoms at arrival are compared between patients with an IUD in situ (33.3%) and those without, and between patients with a delay in diagnosis (47.6%) and those without. The use and the results of the diagnostic procedures are also compared between the latter two groups. An absence of clear amenorrhoea was significantly more common (P less than 0.005) in IUD-users than in non-users. Spotting was almost significantly more common (P less than 0.025) among patients with a delayed diagnosis than in those who underwent an operation on the first day seen. It is shown that patients whose diagnosis was delayed had had significantly more often either curettage (P less than 0.001) or an ultrasound examination which (in spite of a positive pregnancy test) did not show an intrauterine pregnancy (P less than 0.005) than those whose diagnosis was not delayed. It is emphasized that the physician should be on the alert in excluding the possibility of ectopic pregnancy in IUD patients and suspected spontaneous and threatened abortions, especially. In such cases an active laparoscopy is again recommended.

Postmenopausal endometriosis.

The frequency of postmenopausal endometriosis (ovarian endometriosis and adenomyosis) was 2.2%. The mean of the menopausal ages in 11 patients with ovarian endometriosis was 50.3 yr and the average time elapsed since menopause, 7.3 yr. The corresponding values in 8 patients with adenomyosis were 52.1 and 8.8 yr. Carcinoma was a common associated finding in patients with ovarian endometriosis. Increased estrogen activity was observed more frequently in patients with adenomyosis than in those with ovarian endometriosis. Only one of the patients had received estrogen therapy. Hormone-producing tumors in the ovaries or adrenal glands were not confirmed. 70% of the patients were obese and the signs of increased estrogen activity could be explained by extraglandular estrogen formation.

Ovarian function during and after curative intracavitary high dose-rate irradiation: steroidal output and morphology.

The endocrinological function of the ovary during and after curative intracavitary high dose-rate irradiation has been studied by determining the peripheral plasma levels of P, E1, E2, FSH, LH and PROL in 8 patients aged 37 +/- 7 yr (+/- SD). In addition, the concentrations of E1 and E2 in ovarian venous blood during the estimated ovulatory phase after irradiation were determined. The functional structure of the ovary was studied histochemically using 3 beta-hydroxysteroid dehydrogenase (HSD) and ultrastructurally and histologically with routine methods. The results during and after irradiation were compared to those before irradiation. In addition, 28 postmenopausal patients were used as controls. At the end of the irradiation course, which lasted from the premenstrual to the ovulatory phase, 3 out of 4 patients with cervical carcinoma had normal plasma P levels; the menstrual cycles of these patients was previously ovulatory. The normal P levels as well as a rise in E1 and E2 concentrations indicate ovulation. During the next menstrual cycle these values and the E2/E1 ratio in peripheral venous blood decreased and the levels of FSH and LH rose to the postmenopausal values. In patients with endometrial carcinoma, the menstrual cycle was anovulatory both before and after radiotherapy; in estrogen and gonadotrophin levels, similar changes were observed as in patients having ovulatory cycles. In ovarian venous blood, the E2 plasma levels and the E2/E1 ratios were in both groups significantly higher at the time of the second potential ovulatory phase than the corresponding postmenopausal values. As in the postmenopausal women, both E1 and E2 levels in irradiated patients were higher in ovarian effluent blood than peripherally. The ovarian/cubital E1 ratios did not differ between these groups. For E2, this ratio was, however, significantly higher in irradiated patients than in postmenopausal controls. The morphological findings--both by light and electron microscopy--as well as the enzyme-histochemical studies support the chemical results reflecting a decreased yet significant estrogen production in the ovaries after irradiation.

Intrapleural endodermal sinus tumor arising from the diaphragm.

We report a primary endodermal sinus tumor (EST) of the right hemidiaphragm, presenting as a right-sided hemothorax in an 18-month-old female. Four operations were performed, the last three being indicated solely by an elevated level of serum alpha-fetoprotein (AFP). Cyclic chemotherapy with varying drug combinations together with irradiation therapy were not effective in controlling the disease. To our knowledge, this is the first instance of a primary EST arising from the diaphragm.

Uterine malignant degeneration after low- dose endometrial irradiation.

The effectiveness of low-dose intrauterine irradiation for benign diseases and its possible carcinogenic effect on the uterus was studied in 190 patients who were treated during the years 1952-1974. The indications for irradiation were premenopausal functional bleeding, leukemia, hemophilia, fibroids, endometriosis or other benign reason. Radiation was also performed on patients with severe neurologic diseases that contraindicated surgery and on some mentally retarded patients whose restlessness and epileptic seizures were aggravated premenstrually and during menstruation. The mean follow-up period was 15 years. Uterine bleeding recurred in 21% of the patients. No cases of uterine malignant degeneration were found.