Franz Porzsolt

Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials.

Whats known on the subject? and What does the study add?

Polymorphism of the tumour necrosis factor‐alpha and lymphotoxin‐alpha genes in chronic lymphocytic leukaemia

The neoplastic cells of CLL are able to produce TNF which is known to stimulate the proliferation of CLL cells in an autocrine and paracrine manner. Genetic polymorphism of molecules of the TNF ligand superfamily has been described and certain alleles were suspected to predispose to variant biological responses. Previously, the rare allele TNFB*1 of the TNF‐β/lymphotoxin (LT)‐α gene (NcoI, asparagine at amino acid position 26) was found to be associated with a stronger LT‐α response of PBMC in vitro.

Elevated plasma cortisol levels during interferon-γ treatment

Abstract We investigated plasma levels of cortisol and ACTH in 9 patients with advanced metastatic tumors before and during treatment with interferon-γ (IFN-γ). 2–4 h after administration of IFN-γ there was a sharp rise in plasma cortisol levels. The rise coincided with the onset of fever. Highest cortisol levels were reached 4–6 h after IFN-γ injections, whereas IFN-γ serum levels peaked 6–10 h after the IFN-γ injections. Elevated cortisol levels during IFN-γ treatment may be part of a homeostatic response of the neuroendocrine system to the immunological stimulus induced by IFN-γ. On the other hand, the increased plasma levels of cortisol in response to pharmacological doses of IFN-γ may dampen the in vivo effectiveness of IFN-γ.

Goals of palliative cancer therapy: scope of the problem

This article describes some of the problems of palliative cancer therapy and proposes possible solutions. The topics discussed include the reasons for death in cancer patients, the definition of intermediate and indirect as opposed to direct and measurable goals of treatment, the insufficient outcomes of palliative therapies and the problems associated with the separation of palliative treatment and palliative care. As a solution to these problems, a concept of Tumor versus Host Disease (TvHD) is discussed, and different end points for palliation are defined for daily oncology practice and oncology research. Finally, a way to collect data outside randomized trials is proposed, and the need for data collection is emphasized.

Reversible Keimzelltoxizität nach aggressiver Chemotherapie bei Patienten mit Hodentumoren: Ergebnisse einer prospektiven Studie

The impact of aggressive chemotherapy on reproductive and endocrine gonadal function was prospectively studied in 44 patients with germ cell tumors. Diagnostic procedures to determine gonadal toxicity consisted of hormone determinations, semen analyses, interviews with a standardized questionnaire, and gonadal histology. After chemotherapy all patients showed elevated serum levels of follicle-stimulating hormone (FSH) and azoospermia due to germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH levels and sperm density, occurred in 77% of the patients 25-60 months after cessation of chemotherapy. In all patients serum testosterone and luteinizing hormone (LH) values remained within normal limits after therapy indicating resistance of Leydig cells to cytotoxic drugs. Three patients fathered four healthy children after completion of chemotherapy. These data suggest significant reproductive dysfunction in all men treated for germ cell tumors. However, most patients showed late and complete recovery of spermatogenesis. In contrast, endocrine gonadal function was unaffected after chemotherapy in all patients. FSH and LH are feasible markers to assess drug-induced gonadal toxicity.SummaryThe impact of aggressive chemotherapy on reproductive and endocrine gonadal function was prospectively studied in 44 patients with germ cell tumors. Diagnostic procedures to determine gonadal toxicity consisted of hormone determinations, semen analyses, interviews with a standardized questionnaire, and gonadal histology. After chemotherapy all patients showed elevated serum levels of follicle-stimulating hormone (FSH) and azoospermia due to germ cell and stem cell loss. Recovery of spermatogenesis, as indicated by normalization of serum FSH levels and sperm density, occurred in 77% of the patients 25–60 months after cessation of chemotherapy. In all patients serum testosterone and luteinizing hormone (LH) values remained within normal limits after therapy indicating resistance of Leydig cells to cytotoxic drugs. Three patients fathered four healthy children after completion of chemotherapy. These data suggest significant reproductive dysfunction in all men treated for germ cell tumors. However, most patients showed late and complete recovery of spermatogenesis. In contrast, endocrine gonadal function was unaffected after chemotherapy in all patients. FSH and LH are feasible markers to assess drug-induced gonadal toxicity.

A phase I/II study of recombinant interferon alpha 2a and hydroxyurea for chronic myelocytic leukemia

SummaryNine previously untreated patients with Philadelphia chromosome-positive chronic myelocytic leukemia (CML) were treated with recombinant interferon alpha 2a (rIFN-alpha 2a) and hydroxyurea. Patients received 6×106 U rIFN-alpha 2a daily for the first week and 3×106 U rIFN-alpha 2a daily for the second week. As maintenance treatment starting on day 15, patients received 3×106 U rIFN-alpha 2 a 3 times a week. Simultaneously, hydroxyurea was given, starting at a dose of 40 mg/kg on day one. The maintenance dosage was adjusted to the white blood cell count. Two patients responded with complete hematological remissions but without cytogenetic and molecular-genetic improvements. Seven patients responded with partial hematological remissions. Response to therapy was rapid; normal white blood cell counts were reached after a median of 12 days. The doses of rIFN-alpha 2a and hydroxyurea needed to keep the leucocyte count in the normal range were low (3×106 U rIFN-alpha 2a 3 times per week, 0.5–1.5 g hydroxyurea/day). Acute toxicity of the combination therapy consisted of fever (9 of 9 patients), flulike symptoms (7 of 9 patients), pruritus and/or rash (3 of 9 patients) and evidence of a tumor cell lysis syndrome (1 of 9 patients). The side effects were not dose-limiting. Combination therapy with rIFN-alpha 2a and hydroxyurea for CML is well tolerated and allows quick and effective hematological control of the disease.

Capillary leak syndrome associated with elevated IL-2 serum levels after allogeneic bone marrow transplantation

SummaryThe pathophysiological mechanisms involved in the development of a spontaneous systemic capillary leak syndrome (CLS) are unknown. In contrast, CLS is a well-known side effect of high-dose interleukin-2 (IL-2) therapy in solid tumors. We report on a patient who developed CLS with high serum levels of endogenous IL-2 under immunosuppressive therapy for chronic graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation (BMT). Generalized edema persisted for 10 weeks. The condition resolved after antibiotic therapy of a septic shock withβ hemolyzing streptococci group A. Thus, a latent infection may alter cytokine homeostasis and may cause CLS in BMT patients.

Practical aspects of quality-of-life measurement: design and feasibility study of the quality-of-life recorder and the standardized measurement of quality of life in an outpatient clinic.

Although ‘Quality of Life’ (QL) has gained importance in recent years, few articles on this subject have been reviewed, showing that there is no broad consensus about the interpretation of the term nor about the methods applied for QL measurement. The present work reports practical experiences made with the QL recorder developed by the authors. This instrument makes validated QL tests available for use as an everyday standardized routine measure. This work aims to support QL measurement as a common element in research and practice for investigation and documentation of the success of these measures. The development of the QL recorder included four phases: construction and acceptance test of the QL recorder; investigation of acceptance and additional personnel and management requirements; collection of representative data from a large patient sample in a standardized procedure; and statistical analysis of the data obtained. As a report on the whole project can be found elsewhere (I), this article will focus on Phases III and IV of the project. Theoretical aspects of QL measurement are discussed elsewhere (2-6).

Spontaneous interferon-α antibodies in a patient with pure red cell aplasia and recurrent cutaneous carcinomas

SummaryHigh-titered spontaneous interferon (IFN) antibodies were detected in a patient with pure red cell aplasia (PRCA), a benign mediastinal tumor, and recurrent cutaneous carcinomas. The circulating IFN antibodies reacted broadly with various human IFN-α subtypes (20–140×103 neutralizing units/ml serum) but not with IFN-β or IFN-γ, and they neutralized the antiviral activity of the patients endogenous IFN-α. The IFN-αbinding activity was restricted to the IgG1 subclass in a nonmonoclonal manner. Whereas the PRCA repeatedly responded to immunosuppression with high-dose cyclosporin A (CSA) and CSA plus plasmapheresis, IFN antibody production continued during treatment with cyclophosphamide and CSA. Serological analysis revealed past infection with parvovirus B19 and persistent B19 IgM titers. Antibody-mediated impairment of the IFN-α system might have favored the development of both PRCA and the various cutaneous carcinomas in this patient.

Endocrine effects of recombinant interleukin 6 in man.

In a phase II study, 5 male patients with a good performance status, who had metastatic renal cell carcinoma, received interleukin 6 (IL-6) to evaluate a possible antitumor effect of the cytokine. This offered the opportunity to investigate endocrine effects of IL-6 in man. The patients were studied the day before (day-1), and on days +1 and +21 of the IL-6 therapy (150 micrograms administered subcutaneously every day at 09.00 h). Blood was sampled at 09.00, 11.00, 13.00, 16.00, and 20.00 h. Compared with day -1, on days +1 and +21 serum levels of IL-6 were substantially elevated between 11.00 and 20.00 h. IL-6 significantly decreased serum thyrotropin (TSH) levels on day +1 (p < 0.05). The decrease was even more pronounced on day +21 when TSH concentrations were persistently below the respective values of day +1, suggesting, in addition to the acute action of IL-6, an effect developing with repeated IL-6 administrations. Total serum T3 and T4 levels were significantly lower on day +21 than on days -1 and +1. In contrast, free T3 and free T4 values did not differ among days -1, +1 and +21. Acutely, IL-6 had no effect on serum luteinizing hormone (LH) concentrations. However, on day +21, averaged serum LH levels (between 11.00 and 20.00 h) were significantly higher (8.4 +/- 1.1 IU/l) than on days -1 (6.5 +/- 0.2 IU/l) and +1 (6.4 +/- 0.4 IU/l). Average serum testosterone levels were slightly but not significantly enhanced on day +21. IL-6 did not influence follicle-stimulating hormone, growth hormone, or prolactin levels, neither acutely nor after 3 weeks of daily administration. The data indicate a modulating effect of IL-6 on secretory activity of different endocrine axes in man.