Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy.

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m(-2) q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9-43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2-7.2), median progression-free survival was 3.7 months (95% CI: 2.8-4.2) and median overall survival was 14.3 months (95% CI: 9.2-19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.

A randomized study of radiotherapy alone versus radiotherapy plus 5-fluorouracil and platinum in patients with inoperable, locally advanced squamous cancer of the esophagus.

Squamous cell cancer of the esophagus is the most common cancer among black South African males, and 60% of patients present with localized inoperable disease. Combined chemoradiotherapy has been reported to be superior to radiotherapy alone for localized inoperable esophageal cancer in North American patients. A study was carried out to determine if this was also applicable to South African patients, who present with more advanced disease. From September 1991 through June 1995, 70 patients with locally advanced (T3N0-1M0) squamous cancer of the esophagus were prospectively randomized to receive radiotherapy alone or radiotherapy combined with cisplatin and 5-fluorouracil. There was no statistically significant survival difference between the two groups. The median survival was 144 days in the group receiving radiotherapy alone, and 170 days in the group receiving radiotherapy combined with chemotherapy (p = 0.42). The degree of weight loss before initiation of therapy had a significant effect on survival regardless of the treatment arm. Radiotherapy in combination with chemotherapy, as administered in this study for South African patients with locally advanced, inoperable squamous cancer of the esophagus, is no better than radiotherapy alone.

13-Cis-retinoic acid and interferon alpha-2a in patients with advanced esophageal cancer: a phase II trial.

The aim of this study was to investigate the possible therapeutic effect of 13-cis-retinoic acid plus interferon alpha-2a in patients with inoperable squamous cancer of the esophagus. Patients with advanced, measurable, histologically confirmed squamous carcinoma of the esophagus with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 who had adequate bone marrow, liver, and renal function were eligible for study. Patients were given cis-retinoic acid 1 mg/kg/day per mouth continuously and interferon alpha-2a 3 Mu/day for 3 days followed by 6 Mu subcutaneously daily thereafter. Seventeen patients were entered on study. Fifteen patients were evaluable for toxicity. The most common toxicities were grade 1 and 2 cheilitis, dry skin and flu-like symptoms which occurred in all patients. Two patients had grade 3 toxicity (1 anorexia and 1 fatigue). No grade 4 toxicity occurred. Fifteen patients were evaluable for response. No objective response was documented. The median survival time was 15 weeks. With no response seen it is unlikely that the combination of treatment as used in this study will be of benefit in patients with advanced squamous cancer of the esophagus.

The effect of seminal plasma on gonadotrophin secretion by sheep pituitary cells in culture.

We tested the effect of seminal plasma fractions of pooled normozoospermic and azoospermic seminal plasma on secretion of LH by sheep pituitary cells in culture. From these experiments we conclude that there is activity in seminal plasma (molecular mass 10.000-80.000) which inhibits LH secretion. This activity is not steroid-mediated and is absent in azoospermic seminal plasma. These data support our thesis that LH secretion is not only controlled by testosterone but also by spermatogenesis per se.

Second pregnancies among immunologically infertile women: a preliminary report.

Two females with sperm antibody activity in their blood serum and cervical mucus were treated with high dosages of methylprednisolone. Both patients became pregnant during therapy. Following the birth of their first offspring, one was treated with steroids and the other conceived without steroids in order to establish their second pregnancies. The sperm antibody activity showed a sharp decline in the blood serum and cervical mucus during therapy. The response of the females showed drastic modification in the antibody activity in that the females revealed a complete disappearance or a significant decrease in their initial sperm antibody reactions after treatment with high dosages of steroids.

The SCMC test: a screening test for spermatozoal antibodies.

The sperm cervical mucus contact test (SCMC-test) were performed on 62 couples on account of their post coital test results. Fifteen of the 17 couples (88%) who repeatedly demonstrated unexpected poor post coital tests, revealed a positive SCMC-test. In 10 cases the SCMC test results were confirmed by the tray-agglutination and mixed antiglobulin reaction. The SCMC-test is considered to be a reliable screening test for the detection of spermantibodies amongst infertile couples.

Inhibition of lymphocytes by seminal plasma fractions from azo-, oligo- and normozoospermic men.

Human seminal plasma specimens from 62 patients were collected and divided into three groups according to their fertility state. Five protein peaks, obtained by column chromatography, were used in lymphocyte transformation studies to measure their effect on blast transformation rates. The results expressed as percentage inhibition showed that the immunosuppressive activity of isolated seminal plasma fractions were more marked than whole seminal plasma. There was no statistical correlation between inhibition caused by each fraction and the fertility state of the patient groups. Inhibitory components do not seem to relate to the amount of sperm cells in the ejaculate.

The mixed antiglobulin reaction as a screening test for antispermatozoal antibodies.

The semen samples of 363 patients were investigated for the presence of antispermatozoal IgG antibodies on the spermatozoa during routine semen analyses. The results were obtained by means of the mixed antiglobulin reaction (MAR) test and the Friberg spermagglutination test. It was concluded that the MAR test should form a part of routine semen analysis on account of its reliability and the importance of the information it supplies to the clinician.

Evidence for the role of androgens in the feedback control of gonadotrophin secretion in the human female.

The effect of androgens on the luteinizing hormone (LH) response to LH-releasing hormone (LH-RH) is fairly well documented. However, the evidence concerning the effect on follicle-stimulating hormone (FSH) is less convincing and clear-cut. We administered LH-RH to a patient with an androgen-producing adrenal tumour both before and after removal of the tumour. Before operation, testosterone levels were elevated and oestradiol levels reduced. There was no response of either LH or FSH levels to LH-RH on two separate occasions. Postoperatively LH and FSH values rose sharply, to 404% and 170% above basal levels respectively. The data suggest that androgens do play a role in the feedback control of both LH and FSH secretion.

Corticosteroid therapy in case of immunologic infertility--a preliminary report.

Six couples with immunologic infertility were treated with corticosteroids. In five patients prednisone 5 mg three times daily were used and in one patient methylprednisolone 96 mg daily for seven days. The duration of therapy varied from two to eleven months before any positive results occurred. In five patients the serum antibody titre declined significantly and three pregnancies resulted. In the two cases where the serum antibody titre declined, but the SCMC test did not improve, pregnancy did not result. The follow-up SCMC test after completion of therapy may have more prognostic value than the serum sperm antibody estimations.

Reproductive immunology: 4. The effect of seminal plasma from immunologic infertile men on in vitro lymphocyte cultures.

The seminal plasma of 31 patients were examined for the presence of sperm antibodies and for inhibitory properties on the transformation rates of donor lymphocytes cultured in vitro. Twenty five (80%) of the men revealed apart from fertile semen, no sperm antibody activities while six (20%) patients showed high spermagglutinating antibody titres in their seminal plasma and blood serum. Following the routine semen analyses and sperm antibody estimations the seminal plasma were used in lymphocyte transformation studies in order to examine their inhibitory effect. The influence of the seminal plasmas on the lymphocytes were expressed as a percentage inhibition. The percentage inhibition of the normozoospermic men differed significantly from the immunologic infertile man (p less than 0,05). We concluded from the study that the inhibitory potential of the seminal plasma from immunologic infertile male with a normal sperm count are elevated compared with that of normozoospermic men without sperm antibodies. It also appears as if the sperm antibodies in the seminal fluid are able to bind with the inhibitory factor thus causing an enhanced inhibition effect on the lymphocytes.