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.

Combination of subcutaneous levonorgestrel implants and transdermal dihydrotestosterone gel for male hormonal contraception.

The primary aim of the present study was to determine the therapeutic dose of subcutaneous levonorgestrel (LNG) to induce azoospermia or severe oligozoospermia (<3 x 10(6)/mL) in normal men requiring contraception. Transdermal 5 alpha-dihydrotestosterone (DHT) was combined to the treatments to maintain peripheral androgen level. Forty-three 21-45-year-old healthy men were enrolled in this phase II randomised and comparative clinical performance study. The subjects were allocated to five groups to receive: (1) transdermal DHT (Andractim(R), Besins Iscovesco, Paris, France) and one subdermal LNG implant (Jadelle, Leiras, Turku, Finland); (2) transdermal DHT and two subdermal LNG implants; (3) transdermal DHT and four subdermal LNG implants; (4) transdermal DHT and oral LNG (Microluton, Schering, Germany); or (5) transdermal DHT only. A total of 27 men completed the suppression phase. None of them reached azoospermia. One subject with oral LNG and transdermal DHT reached <3 million/mL at 5 months of suppression, but not repeatedly. Together 2/27 (7%) subjects, one with oral LNG and DHT and the other with four subdermal LNG implants and DHT reached <5 million/mL temporarily. Altogether 9/27 (33%) subjects reached <20 million/mL. Serum testosterone concentrations (S-T) decreased significantly during the first 3 months of treatment with one, two and four LNG implants and DHT and during the next 3 months S-T remained significantly lower with two or four implants. Serum oestradiol concentrations (S-E(2)) decreased significantly during the first 3 months only with four implants, but at 6 months S-E(2) was lower also in the group with two implants. Serum luteinizing hormone (LH) decreased significantly only with two LNG implants and DHT gel at 5 and 6 months. Serum FSH did not decrease in any of the groups. None of the subjects filled the criteria to continue to the efficacy phase. A total of 16 men discontinued for various reasons. Of the 27 men completing the suppression phase, all have recovered to sperm levels >20 million/mL. There were no changes in blood count, lipid profile, liver function tests, prostate-specific antigen (PSA), sex hormone binding globulin (SHBG), prolactin or cortisol. The mixed antiglobulin reaction (MAR)-IgG, MAR-IgA or tray agglutination test (TAT) did not change during any of the treatments. The present study shows that the LNG implants themselves are well-tolerated by men and safe, and might be suitable for replacing part of the testosterone used as injections to reduce the androgen dose during male hormonal contraception. The DHT gel was considered as quite or very uncomfortable by 66% of the men because of feeling cold during the time it was on the skin, but noncompliance in using the gel was not reported by the men.

Feasibility of prolonged use of interferon-alpha in metastatic kidney carcinoma: a phase II study.

BACKGROUND: Interferon-alpha has proven effective in the treatment of metastatic renal cell carcinoma. However, the optimal schedule has not yet been determined. The authors have studied the efficacy and toxicity of prolonged use interferon-alpha2a (IFN-alpha) in metastatic renal cell carcinoma (RCC). Interferon-alpha was administered intermittently for outpatients. METHODS: Seventy-five patients with metastatic RCC without prior biochemotherapy were treated. During the first month, the IFN-alpha dose was increased from 4.5 to 18 million units (MU) 3 times a week to define the individual maximal tolerated dose for each patient. The treatment was continued at the maximal tolerated dose with a 1-week pause each month until either progression or intolerable toxicity was observed or up to 2 years. RESULTS: The overall response rate (5 complete response [CRs] and 8 partial responses [PRs]) was 17% (95% confidence interval, 10-28%). Stable disease was observed in 32 patients (43%). Three late objective responses (4%) occurred after 12 months treatment. The median progression free time of all patients was 12.3 months, and median survival time was 19.3 months. The median duration of response in CR/PR patients was 16 months. In multivariate analysis independent prognostic factors were poor performance status (P = 0.004), presence of bone metastases (P = 0.001), and time to metastases less than 24 months (P = 0.003), which predicted poor survival. Six patients (8%) discontinued the treatment because of fatigue, elevation of liver enzymes, or cardiac arrhythmias. No life-threatening side effects were observed. CONCLUSIONS: Prolonged and intermittently administered IFN-alpha2a three times per week in 3 weekly cycles in metastatic RCC is a feasible and effective therapy. A prolonged treatment duration of more than 12 months for stable and responding patients is beneficial and may improve the outcome of patients with RCC.

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.

Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy of the combination of vinorelbine and gemcitabine as a non-platinum chemotherapy regimen in patients with inoperable locally-advanced or metastatic non-small-cell lung cancer (NSCLC). Efficacy was assessed primarily in terms of response rate, and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Patients with cytologically- or histologically-proven stage IIIB-IV NSCLC, bi-dimensionally measurable lesions, adequate haematological, hepatic and renal function, WHO performance status < or = 2 and no previous chemotherapy or radiotherapy were eligible. The first 12 patients were entered in a pilot study and received vinorelbine (VNR) 30 mg/m2 on days 1, 8, 15 and 22, and gemcitabine (GEM) 1000 mg/m2 on days 1, 8 and 15, of a 28-day cycle. Subsequently, patients were entered in a phase II trial of VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle. Treatment consisted of three cycles of the chemotherapy, with a further three cycles for those patients who achieved stable disease or a complete or partial response (CR/PR) to the first three cycles. Patients who had achieved CR or PR after six cycles continued with the treatment until relapse. RESULTS: The dosage and scheduling of VNR and GEM in the pilot study resulted in neutropenia necessitating reductions or delays in treatment, and consequently low dose intensity. The schedule was thus modified to VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle for the phase II trial. Thirty-three patients were enrolled in the phase II trial, and 28 were evaluable for response. The overall intent-to-treat response rate of all 45 patients was 40% (18 of 45), comprising 4 CR (9%) and 14 PR (31%). For the 28 evaluable patients who received the fortnightly chemotherapy the response rate was 46% (13 of 28), CR 11% (3 of 28) and PR 36% (10 of 28). Seven patients (25%) had stable disease. The one-year cumulative survival rate for the 33 patients receiving the fortnightly chemotherapy was 24% and median time-to-progression 4 months (range 1-16 months). Median survival for these patients was eight months. Nine out of twelve patients in the pilot study (75%) suffered grade 3-4 neutropenia. There was one toxic death, attributed to neutropenic fever and sepsis, and two cases of pulmonary embolism. One patient suffered Grade 4 thrombocytopenia. Only eight patients (24%) on the fortnightly schedule suffered grade 3-4 neutropenia, resulting in dose reductions or delays for three of them (9%). None of the patients on the fortnightly schedule suffered thrombocytopenia or anaemia. CONCLUSIONS: The fortnightly schedule of gemcitabine and vinorelbine was a well-tolerated out-patient regimen, producing response and survival rates comparable to those of cisplatin combination regimens, but with a more favourable toxicity profile. Gemcitabine and vinorelbine should now be tested in a triplet combination with a taxane as the third drug, or against a platinum-containing regimen in a phase III study.

Percutaneous sclerotherapy for varicocele embolization.

Varicocele is a common cause of male infertility and can be treated surgically or by angiographic occlusion of the internal spermatic (testicular) vein. The treatment of clinical as well as subclinical varicoceles has been reported to improve sperm parameters. Varicocele also can cause scrotal pain and discomfort. We treated 89 patients using percutaneous sclerotherapy on an outpatient basis. Our technique proved to be simple and effective and was associated with low morbidity. At follow-up only three failures occurred.

[Vasectomy or male sterilization--still the most frequent solution to contraceptive problems]. / Vasektomia eli miehen sterilisaatio yhä useammin ratkaisu ehkäisyongelmaan.

In the Nordic countries, Finland leads the sterilization statistics, but the proportion of men is smaller than in the other countries. In 1995, a project was started where men are offered vasectomy as an option of contraception. Vasectomy is a short, typical outpatient, easy-to-do operation. Only topical anaesthesia and a short sick leave are needed. Vasectomy is an efficient and cheap contraceptive method. After the operation, the sexual functions remain unchanged. Since there is hidden need for increasing vasectomy, what we need is more publicity and information. Neither clients nor professionals have enough knowledge about this method.

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.

Palliative chemotherapy in non-Hodgkin's lymphoma.

GOALS OF WORK: There is a need for an effective and nontoxic chemotherapy for palliative indication in non-Hodgkin's lymphoma (NHL) patients who relapse after conventional or high-dose chemotherapy. The aim of this study was to investigate the feasibility and efficacy of peroral chemotherapy in the palliative treatment of NHL patients. PATIENTS AND METHODS: Seventeen NHL patients were treated with peroral trofosfamide (Ixoten) with an initial dose of 50 mg three times daily. The median age of the patients was 62 years (range: 45-78). Most of the patients had received multiple courses of combination chemotherapy. MAIN RESULTS: The overall response rate (complete remission and partial remission) was 53% (95% confidence interval 29-77), and median response duration was 7 months. Cross-resistance was not observed between trofosfamide and chlorambucil. Grade 1-3 hematological toxicity occurred in 16 patients. Other side effects, including mild or moderate nausea, neurotoxicity, alopecia and fatigue, did not require dose adjustments. No fatal complications occurred. CONCLUSION: Trofosfamide as a palliative regimen is feasible and effective in NHL patients even following previous heavy treatment.

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.

Free thyroid hormones and a third-generation TSH assay in the detection of hyperthyroidism during long-term thyroxine treatment in thyroid carcinoma patients.

We evaluated the value of serum-free thyroid hormone and thyrotropin (TSH) concentrations in the detection of peripheral hyperthyroidism during thyroxine suppression therapy. A total of 57 patients on a stable thyroxine dose and 70 controls participated in the study. Serum-free thyroxine (FT4), free triiodothyronine (FT3) and TSH were measured by immunoassays based on time-resolved fluorescence (Delfia). The assay for TSH was a modification of a third generation Delfia hTSH Ultra method. The patients were classified into euthyroid and hyperthyroid subgroups based on clinical signs and symptoms (Wayne index). Systolic time intervals (STI) were measured. The Wayne indices were higher among patients than controls (p < 0.0001). The STI results were similar in patients and controls. Only FT4 had the discriminatory power for classifying euthyroid and hyperthyroid patients according to discriminant analyses. The diagnostic value of FT4 was further assessed by calculating the area under the relative operating characteristic (ROC) curve. The area was 0.707 (SE 0.0918), which was significantly different from an area of 0.5, i.e. the area of a test of no value (p = 0.032). In conclusion, a high serum FT4 concentration indicates hyperthyroidism during long-term thyroxine treatment among thyroid carcinoma patients. Although the degree of TSH suppression can now be exactly monitored with new third generation TSH assays, hyperthyroidism cannot be defined using TSH concentration in thyroid carcinoma patients. Therefore, additional serum FT4 concentration assays are needed in the assessment of hyperthyroidism associated with TSH suppression therapy in thyroid carcinoma patients.

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.

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.

Accelerated bone degradation in thyroid carcinoma patients during thyroxine treatment, measured by determination of the carboxyterminal telopeptide region of type I collagen in serum.

We studied the effects of long-term suppressive thyroxine treatment on serum markers of bone collagen synthesis and degradation in thyroid carcinoma patients, and the relationship of these effects to the serum concentrations of thyrotropin, free thyroxine and free triiodothyronine were investigated. Thirty-seven thyroid carcinoma patients receiving a stable thyroxine dose, and thirty-five controls participated in a cross-sectional study. Bone collagen synthesis and degradation were measured by using specific radioimmunoassays to determine the serum concentrations of carboxyterminal propeptide of type I procollagen, and carboxyterminal telopeptide region of type I collagen, respectively. Serum thyrotropin, free T4 and free T3 were measured by time-resolved fluoroimmunoassays (Delfia). Serum carboxyterminal telopeptide region of type I collagen concentrations of thyroid carcinoma patients were significantly higher than those of the controls (p = 0.0012). Serum carboxyterminal propeptide of type I procollagen concentrations did not differ significantly between the patients and controls (p = 0.85). Significant associations between age or physical activity, and carboxyterminal propeptide of type I procollagen or carboxyterminal telopeptide region of type I collagen were found in the controls, but not in the patients. Thyrotropin, free T4 or free T3 were not significantly associated with carboxyterminal propeptide of type I procollagen or carboxyterminal telopeptide region of type I collagen in either the control or patient group. From these results it is concluded that long-term suppressive thyroxine treatment seems to accelerate bone degradation, but not bone formation, and therefore carries a risk for osteoporosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Incorporation and clinical results of large allografts of the extremities and pelvis.

The results of implantation of 37 large deep-frozen allografts with 29 osteoarticular grafts of the extremities and pelvis following the resection of malignant or aggressive benign bone tumors were evaluated at followup (mean, 6 years; range, 2.5-20 years). The patients had excellent or good results in 62% of all cases according to the Mankin-Waber functional rating score, and a corresponding rating of 81% in the Musculoskeletal Tumor Society Score. Benign versus malignant disease rated 83% and 76%, respectively, in the Musculoskeletal Tumor Society Score, and 67% and 46%, respectively, in the Mankin-Waber score. Radiological and nuclear medicine (single-photon emission computed tomography) studies and histological biopsies indicated that the incorporation, perfusion, and replacement with new bone was only partial and of a low degree. Late degenerative cartilage and sclerotic changes occurred in 20 of 29 cases with osteoarticular grafts. The best functional results were achieved with knee osteoarticular allografts (81%-88%) compared with modest results in the proximal humerus (69%) and hemipelvis (57%) according to the Musculoskeletal Tumor Society Score rating. Chemotherapy did not influence the union or infection rate of the allografts. In the 4 cases (11%) with infection, all grafts could be salvaged, but the functional results were only 63% in the Musculoskeletal Tumor Society Score. The overall complication rate was high (57%); graft-related complications occurred in 43%, including fatigue fractures in 27%. There were no cases of nonunion at the host graft junction. Clinical rejection did not occur. These clinical results may be improved in the future by new technology that uses bone substitutes, growth factors, and bone morphogenetic proteins.

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.

Disturbances of the endometrium in the luteal phase of cycles stimulated for in vitro fertilization and of normal cycles treated with vaginal progesterone.

Thirty-nine cycles of primarily (n = 32) and secondarily (n = 7) tubal infertile women were studied to evaluate the state of the luteal endometrium in women undergoing In Vitro Fertilization (IVF) without embryo transfer and in women in the normal unstimulated luteal phase with and without vaginal progesterone supplementation. One to four endometrial biopsies were performed in the luteal phase. Serum progesterone (P) and estradiol (E2) as well as the endometrial thickness were estimated on the same days. In groups stimulated for IVF, serum progesterone and estradiol levels were significantly higher (P < 0.01) compared to the control group. The endometrium was significantly thicker and grew more rapidly when cycles were stimulated, but the endometrial thickness did not correlate with endometrial maturation as assessed by histology. The endometrium was disturbed in a major part of the biopsies in all stimulated groups. Progesterone support had no beneficial effect. In women with unstimulated cycles, vaginal progesterone support caused mainly delayed gland maturation: the higher the dose of vaginal progesterone, the sooner the pathological changes in the endometrium were seen. With regard to endometrial histology, vaginal progesterone treatment in the luteal phase of IVF patients may not be advantageous.