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Biomedical subjects

C Bokemeyer

Publications and source records attributed to C Bokemeyer.

At least 163 records · Page 9Linked to original sources
PubMed1996

Hematopoietic growth factors and treatment of testicular cancer: biological interactions, routine use and dose-intensive chemotherapy.

With the use of aggressive cis-platinum-based combination chemotherapy the majority of patients with metastatic testicular cancer will be cured. Hematopoietic growth factors (HGFs), particularly G- and GM-CSF, have been investigated for the treatment of testicular cancer in order to (a) ameliorate chemotherapy-induced myelosuppression, (b) increase the dose intensity of treatment, or (c) generate peripheral blood stem cells (PBSC) as hematopoietic support for mega-dose chemotherapy. Results from in vitro and animal models have excluded a significant influence of both factors, G-CSF and GM-CSF, on tumor growth and response to cytotoxic treatment. For the group of 'good-risk' patients with metastatic testicular cancer, 85-90% of whom will reach long-term survival, the incidence of granulocytopenic infections after standard chemotherapy regimens appears to be lower than 20%. The prophylactic use of HGFs for these patients is not routinely recommended but may be considered in case of an increased risk for infections. For 'poor risk' patients, who will achieve 50% survival following standard chemotherapy, different attempts of treatment intensification have been investigated. The use of aggressive multidrug regimens is associated with granulocytopenic infections in 20-70% of patients. A randomized trial has demonstrated that the prophylactic use of G-CSF significantly reduces granulocytopenia, the number of septic infections, and the infection-related death rate. For 'poor risk' patients the prophylactic use of HGFs, particularly G-CSF due to its favorable side effect profile, is recommended. The availability of G- and GM-CSF has made it possible to develop dose-intensified chemotherapy regimens. Demonstrated particularly for GM-CSF, a 1.5 fold dose increase can be achieved by the use of a myeloid growth factor alone, and thrombocytopenia and other organ toxicity will become dose limiting. Mobilization of PBSC, either after stimulation with HGFs alone or with HGFs, following chemotherapy has been successfully used in patients with testicular cancer. For the treatment of patients with relapsed disease PBSC support followed by HGFs has allowed the use of mega-dose therapy in multiple phase-II studies. This has prompted the investigation of high-dose therapy as first-line treatment for 'poor-risk' patients. In these patients sequential high-dose treatment with cis-platinum, etoposide, and ifosfamide for four consecutive cycles, each supported by G- or GM-CSF and PBSC, is currently being investigated by the German Testicular Cancer Study Group. HGFs have substantially reduced treatment-associated morbidity and mortality in patients receiving chemotherapy for testicular cancer. They make it possible for the first time to clinically explore the true value of dose-intensified chemotherapy regimens in testis cancer, serving as a model of a highly chemotherapy sensitive disease. Enrollment of patients in prospective clinical trials evaluating the role of high-dose therapy is strongly recommended.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Treatment of clinical stage I testicular cancer and a possible role for new biological prognostic parameters.

Three different treatment strategies for patients with stage I non-seminomatous testicular cancer are available that will all result in long-term survival in more than 98% of the patients: a "wait and see" strategy with follow-up and chemotherapy in cases of tumour progression, retroperitoneal lymphadenectomy, with or without application of systemic chemotherapy, in cases of retroperitoneal metastases (pathological stage II disease) or primary adjuvant chemotherapy following inguinal orchiectomy. Each treatment strategy is associated with specific side-effects. In several studies histological characteristics of the primary tumour, particularly the presence of vascular invasion and of embryonal carcinoma cells, have been demonstrated to be significant prognostic factors for the risk of occult retroperitoneal metastases in patients with stage I disease. In addition, new biological prognostic factors determined by flow cytometry, cytogenetic analysis or molecular-biological DNA or RNA analysis have been investigated, among which alterations of the p53 tumour-suppressor gene may represent a promising new prognostic factor. Although alterations of p53 gene expression seem to be associated with advanced tumour stage and may predict retroperitoneal metastatic disease, the independent role of these molecular genetic alterations needs to be prospectively studied. Currently a risk-adapted treatment strategy based on the histological criteria of vascular invasion and the presence of embryonal carcinoma can be used to stratify patients into a "high-" and "low-risk" group with respect to tumour progression. While primary-nerve-sparing retroperitoneal lymphadenectomy or adjuvant chemotherapy with two cycles of platinum, etoposide and bleomycin may be appropriate for patients with a high risk (above 40%) for tumour progression, a "wait-and-see" strategy can be used for "low-risk" (less than 15% risk of progression) patients. Molecular investigations of prognostic factors may be able to improve further the stratification of patients into these different risk categories.

Humans↗
PubMed1996

Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours.

The proto-oncogene c-kit and its ligand stem-cell factor (SCF) may play an important role in the development of normal and malignant testicular tissue. This study investigates the presence of SCF and c-kit protein in 32 orchiectomy specimens of patients with testicular cancer, in 5 specimens of normal testicular tissue and in three established non-seminomatous germ-cell cancer cell lines (H12.1, H32, 577ML) by an immunohistochemical approach. Out of 9 testicular cancer specimens classified as pure seminomas, 7 (78%) showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumour cells. Fourteen non-seminomatous germ-cell tumours composed of embryonal carcinoma were completely negative for both SCF and c-kit proteins and only faint positivity was found in 6 tumours (26%). Differentiated teratomatous structures within the specimens on non-seminomatous tumours showed a strong immunohistochemical reaction for SCF and c-kit protein in 8 of 11 (73%) cases. All three testicular cancer cell lines showed only faint staining reactions for c-kit protein and none for SCF. No secretion of SCF by the three lines in vitro was detected. The addition of high concentrations of SCF (100 ng/ml) to the testicular cancer cell lines in culture conditions without fetal calf serum resulted in a 1.4 to 3-fold growth stimulation compared to cell growth in serum-free medium alone. This effect was not detectable when the cells were cultured in serum-containing media. In the normal testicular tissue the germ-cells displayed a strong immunohistochemical reaction for c-kit protein while SCF positivity was found at the tubular membrane and on the surface of Sertoli cells. The SCF/c-kit system may possess a regulatory function in normal testicular tissue by possibly providing the microenvironment necessary for spermatogenesis. With the development of testicular cancer, this regulatory system seems to be lost, particularly in non-seminomatous germ-cell tumours. A growth-stimulatory effect of high concentrations of SCF on non-seminomatous testicular cancer cell lines can be detected only in culture conditions with serum-free media. The effects achievable by the combination of SCF with other growth factors need to be further studied, as well as the role of the c-kit/SCF regulatory system for normal spermatogenesis and its possible implications for the understanding and treatment of male infertility.

Germinoma↗
PubMed1996

Acquired C 1-inhibitor deficiency with angioedema due to pleomorphic immunocytoma in a patient with three malignant tumors: long-term follow-up data and presentation of an additional case.

Two cases of lymphoma-associated acquired C 1-inhibitor deficiency are described. In both patients, C 1-inhibitor deficiency and related symptoms preceded the diagnosis of the underlying neoplasm by several months. C 1-inhibitor deficiency was most likely due to consumption following immunocomplex formation. In both patients, a close relationship between low levels of C 1-inhibitor and tumor relapse was observed during follow-up. These findings indicate that measurement of C 1-inhibitor and complement factor C4 can be used as markers of disease activity in affected patients.

Angioedema↗
PubMed1996

Endocrinological late effects after chemotherapy for testicular cancer.

Type and extent of endocrinological alterations were studied in long-term disease-free survivors after cisplatin-based chemotherapy for testicular cancer. A total of 63 patients with a median age of 30 (19-53) years, and median follow-up of 42 (16-128) months were included. Elevated serum follicle-stimulating hormone (FSH) levels were found in 63% of patients, 24% showed pathologically elevated luteinising hormone (LH) levels with normal and 10% with subnormal testosterone levels. The degree of gonadotropin elevation was highly significantly correlated with the cumulative platinum (P) dose. Patients treated with platinum-vinblastine-bleomycin regimens showed higher gonadotropin levels than those treated with platinum-etoposide-bleomycin. The adrenal androgen dehydroepiandrosterone (DHEA), pathologically elevated in 68% of patients, was significantly correlated with the cumulative doses of chemotherapy (ctx) used and to the gonadotropin levels. Treatment variables, such as type and dose of cytotoxic agents used, as well as degree of gonadotropin elevation were further correlated with changes in oestron, testosterone and 17 alpha-OH-progesterone levels. Cholesterol levels were elevated in 32% of patients and significant interactions between the steroid hormone levels and cardiovascular risk factors could be shown.

17-alpha-Hydroxyprogesterone↗
PubMed1996

Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity.

Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.

Animals↗
PubMed1996

Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer.

BACKGROUND: Despite generally high cure rates in patients with metastatic testicular cancer, patients with incomplete responses to cisplatin-based first-line therapy or with relapsed disease have an extremely poor prognosis. Paclitaxel represents an antitumor agent with demonstrated activity in cisplatin-sensitive tumors. In addition, responses to paclitaxel have been observed in patients with platin-refractory ovarian cancers. The current phase II trial evaluates the role of paclitaxel in male patients with cisplatin-refractory or relapsed malignant germ cell tumors. PATIENTS AND METHODS: Twenty-four patients with relapsed, mostly cisplatin-refractory metastatic testicular cancer were treated with paclitaxel as three-hour infusions of 225 mg/m2 at 3-weekly intervals. The patients had received a median of 7 platinum-containing treatment cycles (range 3-12) prior to paclitaxel and 12 patients (50%) had previously received high-dose carboplatin/etoposide-based salvage therapy with autologous stem cell support. RESULTS: Six patients (25%) achieved major responses to paclitaxel with 2 CR (8%) and 4 PR with marker normalisation (17%). In addition, 5 patients (21%) showed disease stabilisation. Median duration of responses to paclitaxel was 8 months (3-16+). Toxicity was tolerable, with mainly granulocytopenia occurring in 50% of patients and peripheral neuropathy > or = grade II in 29%. CONCLUSION: Paclitaxel demonstrates significant antitumor activity in 25% of patients with relapsed or cisplatin-refractory testicular cancer. Combination regimens including paclitaxel may be warranted.

Adolescent↗
PubMed1996

A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with 'good-risk' metastatic non-seminomatous germ cell tumors.

BACKGROUND: Cisplatin-based combination chemotherapy will cure 70% to 80% of patients with metastatic non-seminomatous germ cell tumors but is associated with the possibility of severe neuro-, oto- and nephro-toxicities. Carboplatin, a cisplatin analogue, is an active drug in testicular cancer with a more favourable spectrum of side effects. In a randomized trial, the German Testicular Cancer Study Group compared a combination regimen of carboplatin, etoposide and bleomycin (CEB) to standard cisplatin, etoposide and bleomycin (PEB) chemotherapy for patients with 'minimal-' and moderate-disease' non-seminomatous germ cell tumors, according to the Indiana University classification. PATIENTS AND METHODS: PEB was given for three cycles at standard doses (given days 1-5), and the CEB regimen consisted of carboplatin (target AUC of 5 mg/ml x min) on day 1, etoposide 120 mg/m2 on days 1 to 3 and bleomycin 30 mg on days 1, 8 and 15. Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle. Thus, the cumulative doses of etoposide and bleomycin applied in the two treatment arms were comparable. Fifty-four patients were entered on the trial, 29 were treated with PEB and 25 with CEB chemotherapy. Patients were stratified according to disease extent (minimal versus moderate) and the degree of tumor marker elevation. Thirty-two patients (59%) belonged to the group with minimal disease and low markers. RESULTS: No significant difference in response to chemotherapy was seen between the two arms, with CR rates of 81% for the PEB arm and 76% for CEB treatment. However, more patients treated with CEB (32% versus 13%) have relapsed after therapy, and 4 patients (16%) have died of disease progression after CEP in contrast to 1 (3%) after PEB therapy. The first interim analysis of negative events (relapse, vital tumor at secondary resection, death from disease and therapy-associated death) showed a significantly higher rate after CEB than after PEB therapy, and the trial was terminated early. After a median follow-up of 33 months for all patients, the calculation of negative events is still significantly in favour of PEB-treated patient, particularly since three late relapses > 2 years have been observed in the CEB arm (P = 0.03). CONCLUSION: This randomized trial demonstrates that even with the use of adequate doses of etoposide and full-dose bleomycin, carboplatin cannot altogether replace cisplatin in patients with testicular cancer. Treatment with the PEB regimen remains the standard approach in patients with 'good-risk' non-seminomatous germ cell tumors.

Adolescent↗
PubMed1996

Positron emission tomography helps to diagnose tumor emboli and residual disease in choriocarcinoma.

BACKGROUND: Positron emission tomography (PET) has been shown capable of identifying malignant tissues. PATIENTS AND METHODS: WB-PET imaging in two women with metastatic choriocarcinoma is described. RESULTS: In a woman with tumor emboli secondary to a choriocarcinoma, WB-PET was the only noninvasive investigation to differentiate between tumor and blood clots. Moreover, PET helped to localize residual tumor tissue in another woman with persisting high beta-HCG serum levels after chemotherapy. CONCLUSIONS: WB-PET helps to localize tumor tissue in patients suffering from choriocarcinoma.

Adult↗
PubMed1996

Amifostine does not alter the antitumor activity of cisplatin in a pre-clinical model of testicular cancer.

Testicular germ cell tumors are so exquisitely sensitive to cisplatin that the majority of patients with this cancer are now cured with modern platinum-based chemotherapy. In contrast to some other tumor types, testicular germ cell tumors are known to express alkaline phosphatases (ALP). Amifostine is an aminothiol pro-drug which is rapidly dephosphorylated by ALP at the ell surface of healthy tissues and which exerts a clinically proven protective effect against chemotherapy associated toxicity. The aim of this pre-clinical study was to assess the potential of amifostine to protect platinum-sensitive non-seminomatous germ cell tumor (NSGCT) nude mouse xenografts established from an ALP-positive embryonal carcinoma (EC) cell line, from the cytotoxicity of cisplatin when both were administered at their individual maximally tolerated doses (MTD). The %T/C values calculated at day 30 for nude mice carrying H12.1 NSGCT xenografts treated with amifostine alone, amifostine plus cisplatin or cisplatin alone were, respectively, 93, 3 or 3%. Mean tumor volumes were not significantly different between mice treated with the combination versus cisplatin alone at day 14 or 30. The results of this study revealed no evidence of tumor protection by amifostine, confirming previous results in other tumor types.

Adult↗
PubMed1996

High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables.

PURPOSE: To identify prognostic variables for response and survival in male patients with relapsed or refractory germ cell tumors treated with high-dose chemotherapy (HDCT) and hematopoietic progenitor cell support. PATIENTS AND METHODS: Three hundred ten patients treated with HDCT at four centers in the United States and Europe were retrospectively evaluated. Univariate and multivariate analysis of patient, disease, and treatment characteristics were used for comparisons of response rates and failure-free survival (FFS). RESULTS: The actuarial FFS rate was 32% at 1, 30% at 2, and 29% at 3 years. Multivariate analysis identified progressive disease before HDCT, mediastinal nonseminomatous primary tumor, refractory or absolute refractory disease to conventional-dose cisplatin, and human chorionic gonadotropin (HCG) levels greater than 1,000 U/L before HDCT as independent adverse prognostic variables for FFS after HDCT. These variables were used to identify patients with good, intermediate, and poor prognoses. In the good-risk category, the predicted FFS rate at 2 years was 51%, compared with 27% and 5% in the intermediate-risk and poor-risk categories (P < .001). The increased risk for treatment failure was due to both a significantly lower rate of favorable responses and a significantly higher rate of relapses. Within the prognostic categories, the particular HDCT regimen or higher dosages of carboplatin or etoposide did not have a significant influence on treatment outcome. CONCLUSION: Prognostic variables for treatment response after HDCT can be identified. The proposed prognostic model might help to optimize the use of HDCT in germ cell tumors and warrants validation in future trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Evaluation of long-term toxicity after chemotherapy for testicular cancer.

PURPOSE: The current study evaluates the extent and reversibility of late sequelae after chemotherapy in longterm survivors of testicular cancer. The influence of therapy and patient characteristics and the relationship between different toxicities are assessed. PATIENTS AND METHODS: Ninety patients with a median age of 28 years (range, 19 to 53) and a median followup time of 58 months (range, 15 to 159) participated in the clinical examinations, a personal interview, and technical investigations. Overall health and the impact of late toxicity were assessed by the patients. All patients were in complete remission (CR) for at least 1 year. Chemotherapy had consisted of cisplatin (P), bleomycin (B), and vinblastine (V) in 30 patients (33%); P, B, and etoposide (E) in 26 patients (29%); P, B, E, and a vinca alkaloid in 22 patients (24%); and other P-based combination regimens in 12 patients (13%). RESULTS: Alterations of gonadotropin levels (follicle-stimulating hormone [FSH] luteinizing hormone [LH]) in up to 68% of patients and Leydig cell insufficiency in one third of patients were the most frequently detected abnormalities. Approximately 20% of patients had low serum magnesium [Mg] or phosphate levels, or elevated creatinine levels. Cardiovascular risk factors were identified in one third of patients with elevated serum cholesterol levels with or without obesity; 15% had developed arterial hypertension after chemotherapy. The most frequent symptomatic toxicities were Raynaud's phenomenon (RP) in 30% of patients, ototoxicity in 21%, and peripheral neuropathy in 17%. Major risk factors for the development of toxicity were cumulative dose of P (P < .0001 for ototoxicity and neurotoxicity; P < .01 for overall toxicity, gonadal toxicity, and dehydroepiandrosteron elevation; P < .05 for hypertension and Mg depletion) and type of chemotherapy (57% of PVB-treated patients v25% of PEB +/- vincristine-treated patients with RP; P < .01). CONCLUSION: The cumulative dose of P was a major predictor for toxicity. Patients and treatment characteristics such as noise exposure, age, history of smoking, and mode of B application were less important. Further clinical trials should evaluate the sequelae of chemotherapy treatment for testicular cancer prospectively.

Adult↗
PubMed1996

Cisplatin nephrotoxicity and protection by silibinin.

BACKGROUND: The anticancer drug cisplatin is know to have toxic side-effects on different segments of the nephron. The flavonoid silibinin has previously been shown to be protective in models of hepatotoxicity. The aim of the present study was to evaluate, whether silibinin can also ameliorate alterations in renal glomerular and tubular function and tubular morphology induced by cisplatin. METHODS: In a rat model renal damage was induced by a single injection of cisplatin (5 mg/kg body weight). The protective effects of silibinin were studied in rats that received the flavonoid (200 mg/kg body weight, i.v.) 1 h prior to the administration of cisplatin. Kidney function was monitored by analysing urinary markers of glomerular and tubular function over a period of 11 days. Animals of a second group, with identical treatment, were sacrificed 4 days after drug application for an evaluation of tubular morphology at the light-microscopical level. RESULTS: Administration of cisplatin caused a decline in kidney function within a day following treatment. Symptoms observed were for example decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting. The effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Impairment of proximal tubular function was ameliorated, that is enzymuria and magnesium wasting was less pronounced. Silibinin alone had no effect on kidney function. Treatment with silibinin distinctly diminished morphological alterations observed in the S3-segment of the proximal tubule 4 days after cisplatin administration. CONCLUSION: The effects of cisplatin on glomerular and proximal tubular function as well as proximal tubular morphology could totally or partly be ameliorated by silibinin. It is concluded the silibinin can act as a nephroprotectant and it is suggested that it could have beneficial effects on the kidney in clinical settings.

Acetylglucosaminidase↗
PubMed1996

[Effect of biological prognostic factors on therapy of non-seminomatous stage I testicular tumors--an assessment of the current status].

At present patients in whom a testicular germ cell tumour in clinical stage I is diagnosed have a long-term survival rate of 98%. For non-seminomatous germ cell tumours in this stage three different treatment options are available: primary retroperitoneal lymphadenectomy (PRLA), the wait-and-see strategy, and primary adjuvant systemic chemotherapy. These therapeutic approaches do not obviously differ in the long-term survival rate of the patients. Abdominal CT scans yield false-negative results in 20-30% of patients with occult metastases. The identification of certain histological characteristics within the primary tumour (vascular and/or lymphatic invasion, presence of embryonal carcinoma, absence of yolk sac elements) allows stratification of patients into groups at high and low risk for tumour progression and/or the presence of retroperitoneal lymph node metastases. The determination of biological and genetic characteristics of the primary tumour in addition to classic histological parameters, does not actually seem to reveal any further prognostic information relating to the biological behaviour of the individual tumour. Therefore, with regard to the outcome of prospective and retrospective MRC studies, patients should be stratified according to the Freedman score into groups at high and at low risk of tumour progression and consequently undergo an aggressive (retroperitoneal lymphadenectomy/systemic chemotherapy) or less aggressive (wait-and-see) treatment adjusted to the aggressiveness of the individual tumour. Prospective studies should be performed to find whether biological characteristics of the primary tumour might reveal any additional prognostic information superior to that yielded by histological parameters and possibly allow an even more subtle classification of the patients into high- and low-risk groups.

Biomarkers, Tumor↗