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Biomedical subjects

C Bokemeyer

Publications and source records attributed to C Bokemeyer.

At least 181 records · Page 10Linked to original sources
PubMed1995

Detection of p53 gene alteration in renal-cell cancer by micropreparation techniques of tumor specimens.

Alterations in the p53 tumor-suppressor gene have been identified in a variety of human malignancies, including renal-cell cancer. A technique for the isolation of tumor areas from tissue specimens to analyze formalin-fixed and paraffin-embedded tumors and try to avoid a disturbance of the results due to genetic background signal by the presence of tumor-infiltrating lymphocytes, was established. The presence of lymphocytes within the tumor areas investigated was determined by immunohistochemical staining for CD3, a lymphatic surface antigen. Following the isolation of about 100-200 tumor cells, PCR-directed molecular genetic analysis was performed. A highly informative allelotyping approach for the detection of loss of heterozygosity (LOH), determining BstU1- and VNTR-polymorphisms, a 100-bp marker directly localized in intron 1 of the p53 gene, as well as screening for mutations by single-strand conformation polymorphism analysis (SSCP) in exons 5-8, were used. Out of 44 renal-cancer specimens, 33 (75%) were informative for PCR-directed RFLP-analysis. Allelic loss at the p53 gene locus was observed in 10 of 33 cases (33%). No correlation between p53 gene alteration and T-stage, histological grade or histological differentiation could be observed. Alterations in the p53 gene, as detected by a molecular genetic as well as an immunohistochemical approach, were correlated to overall survival. During univariate analysis histological grade, lymphnode status and the presence of distant metastases could be identified as prognostic parameters for overall survival. During multivariate analysis none of the factors investigated remained an independent prognosticator for survival. Summarizing these results, it seems unlikely that p53 gene alterations will serve as an important new factor for the clinical prognosis of patients with renal-cell cancer.

Adult↗
PubMed1995

No synergistic activity of epirubicin and interferon-alpha 2b in the treatment of hepatocellular carcinoma.

Single-agent activity for anthracyclines reflected by response rates of 10%-30% has been reported in patients with advanced hepatocellular carcinoma (HCC). Preclinical data indicate that alpha-interferon could enhance the cytotoxic activity of the anthracycline Adriamycin or its analog epirubicin. In a phase I/II study, 31 patients with biopsy-proven inoperable HCC were treated with interferon-alpha 2b given s.c. at a dose of 3 x 10(6) units/m2 per day for 5 days per week plus weekly epirubicin given at 25 mg/m2 as an i.v. bolus. The protocol called for 4 consecutive weeks of treatment followed by 1 week off treatment. In all, 15 patients had been previously treated; 6 patients had failed hormonal therapy (tamoxifen), 5 patients had failed prior anthracycline treatment, and 4 patients had received chemoembolization of the tumor and had subsequently progressed. A total of 30 patients were evaluable for response. In all, 1 patient (3%) achieved a partial response for 8+ months and 11 patients (35%) achieved stabilization of disease. Six patients had a fall in alphafetoprotein (AFP) values of > 50% during therapy. The median survival for all patients was 9.5 months (range, 3-34+ months). The main side effects were hematological toxicity and fever, both of which were considered tolerable. As an indicator of the immunostimulatory effects of interferon, an elevation in serum markers of inflammation [C-reactive protein (CRP), beta 2-microglobulin] was found in 15%-20% of patients. All patients had measurable Mx protein production during therapy, but these effects were not correlated to the clinical response. The clinical response rate achieved in this trial indicates that the combination of interferon and epirubicin, at least when used on the schedule reported herein, is not superior to treatment with either agent alone for patients with advanced HCC. However, single patients achieved a prolonged progression-free interval (8-10+ months) on this therapy, and it may therefore be an option for patients who have failed prior hormonal or single-agent anthracycline therapy.

Adult↗
PubMed1995

p53 overexpression as a prognostic factor for advanced stage bladder cancer.

Overexpression of the TP53 gene protein detected by immunohistochemistry appears to identify those patients with superficial bladder cancer at risk of the development of muscle invasive or metastatic disease. However, the role of p53 overexpression in patients with advanced or metastatic bladder cancer is not yet well established. In the present study, 44 specimens from 44 patients with advanced stage bladder tumours (T2-T4) undergoing radical cystectomy were investigated for different biological and clinical characteristics as possible prognostic factors: sex, age, depth of tumour infiltration, T-stage, histological grade, lymph node status, application of adjuvant systemic chemotherapy (MVAC), proliferative activity (staining for proliferating cell nuclear antigen (PCNA) by monoclonal antibody (PC10) as well as overexpression of the p53 oncoprotein (monoclonal antibody pAb 1801)). After a median follow-up of 22 months, 16 of the 23 patients (70%) with more than 40% of tumour cells stained positively for p53 (Group B) died from tumour progression compared with 7 of the 21 patients (33%) with less than 40% of tumour cells positive for p53. During univariate analysis, p53 overexpression (P = 0.008), staining for PCNA (> or = 80% of cells positive) (P = 0.01) and tumour stage (P = 0.01) were significant prognostic factors for survival, among which p53 overexpression (P = 0.023) as well as T-stage (P = 0.012) remained independent significant predictors during multivariate analysis. Prospective studies are needed to confirm the independent prognostic potential of p53 overexpression in patients with advanced bladder cancer. The availability of more refined prognostic factors should assist decision making regarding the value of more aggressive treatment options, such as adjuvant or neoadjuvant chemotherapy, for prognostically defined subgroups of patients.

Adult↗
PubMed1995

Secondary Raynaud's phenomenon and other late vascular complications following chemotherapy for testicular cancer.

182 patients treated with cisplatin-based chemotherapy for testicular cancer at Hannover University Medical School who were in complete remission (CR) for more than 1 year after therapy were randomly selected for the evaluation of late vascular toxicity. 90 patients with a mean age of 28 years (19-53) and a median follow-up of 57.9 months (15-159) participated in this examination. Patients were examined clinically and digital photoelectric pulse plethysmography (PP) and Doppler-flow of the digital arteries after cold exposure were performed. Thirty seven per cent of patients developed symptoms of Raynaud's phenomenon (RP) after chemotherapy, which were transient in 7%. PP proved to be highly diagnostic for RP with a sensitivity of 95% and a specificity of 100%. As significant risk factors for the development of RP, the cumulative dose of bleomycin (P < 0.05) and the use of bleomycin in combination with vinblastine (PVB-regimen) instead of etoposide (PEB-regimen) (P < 0.01) were found. A trend for an increased frequency of RP was observed in patients who received bleomycin as a bolus instead of continuous infusion. No significant correlation was seen with the cumulative or single doses of cisplatin, etoposide or vinblastine, serum magnesium levels during or after chemotherapy or a history of smoking. RP was not associated with the occurrence of neuro- or ototoxicity. All 7 patients with hypertensive blood pressure before chemotherapy developed RP. Furthermore, the median postchemotherapy diastolic blood pressure had increased by 8 mmHg compared to prechemotherapy values, leading to significant hypertension in 8 patients (> 20 mmHg increase). 2 patients developed major vascular events with myocardial infarctions at 4 years and 5 years after chemotherapy, respectively. No cerebral infarction was registered. In summary, RP is the main late vascular toxicity affecting one third of patients after curative chemotherapy for testicular cancer. However, the incidence of RP following PEB-therapy in contrast to PVB-therapy appears to be lower. Major vascular events seem to be rare. The prospective evaluation of late toxicity should be part of current chemotherapy treatment for testicular cancer, and long-term follow-up of surviving patients is recommended.

Adult↗
PubMed1995

p53 immunohistochemistry as an independent prognostic factor for superficial transitional cell carcinoma of the bladder.

Although patients with superficial bladder cancer (Ta, T1) have a generally good prognosis, those patients who develop muscle-invasive tumours or metastatic disease at recurrence do poorly clinically. In the current study 69 patients undergoing complete transurethral resection for superficial transitional cell cancer of the bladder were investigated for different clinical and biological characteristics as possible prognostic factors: age, sex, performance of instillation therapy and immunohistochemical determination of mutational inactivation of p53 tumour-suppressor gene (monoclonal antibody PAb 1801) as well as immunohistochemical determination of the proliferation rate by staining for PCNA (proliferating cell nuclear antigen) (monoclonal antibody PC 10). After a median follow-up of 45.8 months, 12 of 14 patients (85.7%) with more than 20% of cells positive for p53 had disease progression with muscle-invasive growth compared with only one of 55 patients (1.8%) negative for p53 (P < 0.01, chi 2 test). During univariate analysis histological grade (G1 vs G2) (P = 0.0373), positivity for PCNA (> 60% of cells) (P = 0.0033) and positivity for p53 (P < 0.001) were significant prognostic factors for disease progression (log-rank test), while during multivariate analysis only positivity for p53 was a significant predictor for relapse of bladder cancer (P = 0.0029) (multivariate Cox regression analysis). The immunohistochemical detection of mutations of the p53 gene has been demonstrated to be a reliable, easily performed and thereby widely available technique for the investigation of fresh-frozen or paraffin-embedded tumour specimens. The results demonstrate the important role of the p53 tumour-suppressor gene protein in the development and for the progression of bladder cancer. If the high prognostic value of p53 mutations in superficial bladder cancer is confirmed in larger prospective trials, more aggressive therapeutic strategies could be discussed for patients with p53 mutations in their tumour specimens.

Aged↗
PubMed1995

Treatment of testicular cancer and the development of secondary malignancies.

PURPOSE: Secondary neoplasia represents one of the worst possible long-term complications of therapy for testicular cancer, frequently leading to death in patients cured of the primary malignancy. The frequency and importance of secondary malignant disease will be reviewed. METHODS: The international literature was screened for reports concerning secondary solid cancers or leukemias in patients treated with chemotherapy or radiotherapy for malignant germ cell tumors. RESULTS: Patients with testicular germ cell tumors appear to have a twofold significantly increased risk (range, 0.7 to 3.4) for the development of secondary neoplasia. Apart from contralateral testicular cancers, which are not treatment-related, a largely elevated inherited risk for secondary cancers in patients with germ cell tumors seems unlikely. Radiotherapy is associated with a two- to threefold increased risk for secondary solid tumors (range, 1.3 to 7.5). A three- to sevenfold increased risk seems to exist for the development of solid tumors arising in the previous irradiation ports, such as stomach, pancreatic, bladder, and renal cell cancer, and sarcomas. To date, no significantly elevated risk for secondary solid tumors was observed after chemotherapy, even including regimens with alkylating agents, eg, cisplatin and ifosfamide. However, the risk associated with chemotherapy needs to be reexamined when the median follow-up of studies will exceed more than 10 years. An increased relative risk for secondary leukemias after chemotherapy (range, 1.3 to 3.4) has been reported in three of eight studies with more than 300 patients. Four large studies indicate a significantly elevated risk (range, 15 to 25) for the use of conventional-dose etoposide (< 2 g/m2 cumulative dose); however, with a 5-year cumulative incidence of less than 0.5% of all patients, this risk seems small. Concerning high-dose etoposide regimens (> 2 g/m2), further studies are necessary. CONCLUSION: Treatment for testicular cancer is associated with a small, but clearly identifiable, risk for secondary solid tumors that can be attributed to radiotherapy, and for secondary leukemia mainly associated with the use of chemotherapy. The frequency of secondary neoplasia observed is rather low, and in the light of the high cure rate, the risk for the individual patient appears negligible and should not alter current treatment strategies for metastatic testicular cancer.

Antineoplastic Agents↗
PubMed1995

Recombinant human granulocyte-macrophage colony-stimulating factor as an adjunct to conventional-dose ifosfamide-based chemotherapy for patients with advanced or relapsed germ cell tumors: a randomized trial.

PURPOSE: Ifosfamide-containing therapy with cisplatin plus either etoposide (VIP) or vinblastine (VeIP) can cure of patients with relapsed germ cell tumors (GCTs), but results in substantial myelotoxicity. This study sought to assess the impact of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on the severity of neutropenia and incidence of infectious complications in patients who receive ifosfamide-based chemotherapy for GCT. PATIENTS AND METHODS: One hundred and four assessable GCT patients from 20 centers were randomized to receive rhGM-CSF with either cycles 1 and 2 or cycles 3 and 4 of chemotherapy. Standard doses of VIP or VeIP were used. Efficacy data were analyzed using a parallel design for cycles 1 and 2 before the crossover. RESULTS: Fewer clinically relevant infections occurred in rhGM-CSF patients (13 of 55, 24%) versus observation patients (22 of 49, 45%) in cycle 1 (P = .01). Decreases were observed in infections during neutropenia (22% v 43%, P = .03), infections requiring intravenous antibiotics (20% v 43%, P = .01), and any infection irrespective of severity (29% v 55%, P = .01) in cycle 1. However, there were no significant differences among the treatment arms in cycle 2 in the proportion of clinically relevant infections (P = .23), infections associated with neutropenia (P = .11), infections requiring antibiotics (P = .22), or any infection (P = .65). rhGM-CSF was discontinued in 14% of cycles because of toxicity related to the growth factor. CONCLUSION: rhGM-CSF reduced the incidence of infections in the first cycle of chemotherapy, but no benefit beyond the initial chemotherapy cycle was evident. Based on the limited clinical impact and the high incidence of rhGM-CSF-related toxicity that required growth factor discontinuation, the routine administration of rhGM-CSF to prevent neutropenia and infection after ifosfamide-based chemotherapy for GCT patients is not recommended.

Adolescent↗
PubMed1995

[Value of the proliferation status (PCNA) and p53 immunohistochemistry as a prognostic factor for the clinical course of superficial cancer of the urinary bladder].

Although patients with superficial bladder cancer (Ta, T1) have a generally good prognosis, those of them who have tumours invading muscle or metastatic disease will have a poor clinical prognosis. In the current study, 41 patients undergoing complete transurethral resection for superficial transitional cell cancer of the bladder were investigated for different clinical and biological characteristics as possible prognostic factors: age, sex, previous instillation therapy, immunohistochemical determination of mutational inactivation of p53 tumour suppressor gene (monoclonal antibody pAb 1801) and proliferation rate determined immunohistochemically by staining for PCNA (proliferating cell nuclear antigen; monoclonal antibody PC 10). After a median follow-up of 54 months 7 of 8 patients (87.5%) with more than 20% of cells positive for p53 had disease recurrence, as against only 1 of 33 patients (3%) negative for p53 detection (P < 0.01; Chi-square test). During univariate analysis histological grade (G1 vs G2; P = 0.007), positivity for PCNA (> 60% of cells; P = 0.003) and positivity for p53 (P = 0.001) were significant prognostic factors for disease progression (log rank test), while during multivariate analysis only positivity for p53 was a significant predictor for relapse of bladder cancer (P = 0.0035; multivariate Cox regression analysis).

Aged↗
PubMed1995

[Differentiated teratoma as late recurrence of metastatic non-seminomatous testicular germ cell tumor. Case report and clinical problems].

This report describes the rare event of late recurring adult teratoma 76 months after the treatment of a metastasized, nonseminomatous germ cell tumor. Following chemotherapy, residual tumor masses localized in the retroperitoneum as well as in the chest were completely resected. At the recurrence serum tumor markers "alpha-fetoprotein" (AFP) and "human chorionic gonadotropin" were not elevated. Abdominal CT scan revealed a cystic tumor without any solid components in the right obturator fossa. This tumor was excised and the histological examination revealed pure adult teratoma. Late recurrence ( > 24 months after initial therapy) following chemotherapy for the treatment of metastasized testicular germ cell tumors is a rare event (2-4%). Whereas overall prognosis of late recurrence is poor, the clinical course of patients with mere teratomatous differentiation within the recurrent tumor is somewhat better if complete surgical resection is performed. Clinical implication of late recurrence following treatment of metastasized nonseminomatous germ cell tumors are discussed.

Adult↗
PubMed1994

Modulation of cytostatic drugs by nifedipine in two heterotransplanted human testicular-cancer cell lines differing in their sensitivity to standard agents.

Drug resistance is an important clinical problem in testicular cancer patients with relapsed or refractory disease after first-line chemotherapy. Here we report that the relative reduction in tumour volume in nude mice heterotransplanted with either H 12.1 or H 23.1 human testicular cancer cell lines was significantly increased by addition of the calcium antagonist nifedipine to the maximum tolerated dose (MTD) of cisplatin (DDP). The mean reduction in relative tumour volume at day 30 (rVR) reached statistical significance for both cell lines following combination therapy of DDP with nifedipine compared to DDP alone (55 +/- 7% versus 12 +/- 4% for H 23.1 and 60 +/- 9% vs. DDP with nifedipine has also been confirmed in H 12.1 cells in vitro. However, in vivo, this combination was associated with a concordant increase in therapeutic toxicity. In contrast, no improvement in in vivo anti-tumour activity was obtained by combining similar dose-schedules of nifedipine with the MTD of epirubicin, or with MTDs of vinblastine or etoposide. These results are in agreement with our immunohistochemical finding that H 12.1 and H 23.1 do not over-express the Pgp 170 glycoprotein which mediates the multiple drug resistance (MDR) phenotype and involves both anthracyclines and vinblastine, but not DDP. We conclude that another Pgp-MDR modulator, nifedipine, is able to increase the anti-tumour activity of DDP in vivo and in vitro via a specific but as yet unknown mechanism, which is most likely not MDR-related. However, the increased anti-tumour activity is, in vivo, associated with a considerable increase in overall toxicity. Further studies are necessary to decrease therapeutic toxicity, before clinically relevant models for modifiers of DDP-resistance could possibly be applied to patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Treatment intensification in disseminated germ-cell tumors.

Despite major improvements in the treatment of germ cell tumors the results remain unsatisfactory in patients with "poor risk" initial presentation, with inadequately responding or relapsed disease. The alternating use of noncrossresistant drugs or dose-intensified treatment regimens have not proved to be superior to conventional regimens, although the role of early treatment intensification with the use of hematopoetic growth factors or hematopoetic stem cell reinfusion warrants further investigation. In phase I/II trials patients considered incurable with conventional treatment regimens have been successfully salvaged by high-dose chemotherapy and autologous stem cell reinfusion. Several phase III trials to define the role of this novel approach are planned or ongoing in the USA and Europe.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Preliminary results of a phase I/II trial of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer.

Paclitaxel represents a novel antitumour agent with demonstrated activity in cisplatin-sensitive tumours, particularly ovarian cancer. In addition, responses to paclitaxel have been observed in patients with cisplatin-refractory ovarian cancer. The role of paclitaxel in the treatment of testicular cancer has not been explored so far. Despite the generally high cure rates in patients with metastatic testicular cancer, patients with relapsed disease not responding to platin-based salvage chemotherapy have an extremely poor prognosis. In a phase I/II trial 10 patients with relapsed, cisplatin-refractory malignant germ-cell tumours were treated with paclitaxel as 6-h infusions (8 patients) or 3-h infusions (2 patients) at doses from 135 mg/m2 to 310 mg/m2 at 3-week intervals. Three patients achieved a response to paclitaxel, but disease recurred shortly in two patients after two and four cycles of therapy, respectively. One patient has remained in marker-negative partial response for more than 5 months. The toxicity of paclitaxel was tolerable for a dose range from 135 mg/m2 to 225 mg/m2. Granulocytopenia, WHO grades 3 and 4, occurred in all patients but was of short duration (median 3 days; range: 2-7 days). Other toxicities such as mucositis (5 patients grade 1), neurotoxicity (1 patient grade 1, 2 patients grade 2), infection (1 patient grade 3) and diarrhoea (1 patient grade 2) were not dose-limiting. There were no hypersensitivity reactions, but 1 patient developed severe myalgias during therapy with paclitaxel. Six patients with documented cisplatin-refractory disease were retreated with cisplatin-based chemotherapy after paclitaxel treatment and, in 4 of these, tumour responses of 3, 4, 5 and more than 5 months duration were achieved. In order to explore the role of paclitaxel in relapsed and/or cisplatin-refractory testicular cancer a phase II study using a 3-h infusion of 225 mg/m2 paclitaxel every 3 weeks, conducted by the German Testicular Cancer Study Group, is ongoing.

Adult↗
PubMed1994

Long-term gonadal toxicity after therapy for Hodgkin's and non-Hodgkin's lymphoma.

With the increasing cure rate of patients treated for Hodgkin's and non-Hodgkin's lymphoma, the evaluation of late effects on gonadal function remains an important issue. The gonadal function of relapse-free long-term survivors with high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) were studied; 24 of 119 patients with NHL treated between 1980 and 1990 and 66 of 364 patients with HD treated between 1975 and 1990 at Hannover University Medical School, who were younger than 45 years of age and in complete remission at the time of evaluation for at least 24 months after completion of therapy, were included into the analysis. Of 24 patients with NHL, 1/10 women (10%) and only 3/14 men (21%) showed signs of gonadal dysfunction. Three of these four patients had been treated with combined modality therapy followed by maintenance COP chemotherapy, resulting in high cumulative doses of cyclophosphamide (range: 12-43 g). In comparison, 13/26 (50%) women with HD suffered from premature ovarian failure, and 26/40 (65%) men showed signs of gonadal dysfunction with significant FSH elevations. No significant difference in the incidence of gonadal toxicity existed in patients treated with combined modality who received irradiation to either supra- or infradiaphragmatic radiation fields in combination with chemotherapy (70% versus 62%). A comparison of the chemotherapy regimens used in patients with NHL or HD shows that patients from both groups had received comparable median cumulative doses of cyclophosphamide, vincristine, and adriamycin, but only patients with HD had additionally received a median cumulative dose of 13.3 g of procarbazine per patient. A tendency towards a higher incidence of gonadal toxicity with higher cumulative doses of procarbazine received was found in patients with HD. The frequency of gonadal dysfunctions is markedly lower in patients treated for non-Hodgkin's lymphoma than in patients treated for Hodgkin's disease, approximately half of whom will be affected by long-term gonadal toxicity. Although the use of more intensive radiotherapy in patients with HD compared with NHL patients makes the evaluation of the influence of radiotherapy on gonadal toxicity more difficult, the current retrospective analysis raises the concern that, in addition to infradiaphragmatic radiotherapy, the use of procarbazine in regimens for the treatment of HD, like COPP or MOPP, may be a possible explanation for the differences in gonadal toxicity observed between patients with HD and those with NHL. Regimens including procarbazine should be avoided in patients wanting to preserve fertility since alternative chemotherapies with at least equal efficacy are available.

Adolescent↗