Biomedical subjects

W Budach

Publications and source records attributed to W Budach.

At least 19 recordsLinked to original sources

PubMed2006

Multifocal epithelioid hemangioendothelioma: case report of a clinical chamaeleon.

Epithelioid hemangioendothelioma is an extremely rare vascular bone tumor with a slow growth and poor prognosis. The term was designed to describe neoplasms that had an appearance in between hemangiomas and sarcomas. Various synonyms for epithelioid hemangioendothelioma are used clinically: low grade anaplastic angiosarcoma, cellular hemangioma, histiocytoid hemangioma and angioendothelioma. However, it represents 1% of all vascular neoplasms and is locally aggressive. We report the course of disease of a 47-year-old man who presented to our clinic with unspecific abdominal and back pain. Radiological findings revealed multiple lesions in the spine as well as liver and spleen involvement. Tumor histology of the bone and liver biopsies confirmed the diagnosis of epithelioid hemangioendothelioma. Although treatment was initiated with thalidomide, the patient developed multiple organ dysfunction syndrome (MODS) and succumbed to his disease. This case report may contribute to the data on clinical findings and natural history of this rare tumor.

Angiogenesis Inhibitors↗

PubMed2006

Repeat 18F-FDG PET for monitoring neoadjuvant chemotherapy in patients with stage III non-small cell lung cancer.

PURPOSE: The relevance of (18)F-FDG PET for staging non-small cell lung cancer (NSCLC), in particular for the detection of lymph node or distant metastases, has been shown in several studies. The value of FDG-PET for therapy monitoring in NSCLC, in contrast, has not yet been sufficiently analysed. Aim of this study was to evaluate FDG-PET for monitoring treatment response during and after neoadjuvant radiochemotherapy (NARCT) in advanced NSCLC. METHODS: Sixty-five patients with histologically proven NSCLC stage III initially underwent three FDG-PET investigations, during NARCT prior to initiating radiation, and post-NARCT. Changes of FDG-uptake in the primary tumour at two time-points during NARCT were analysed concerning their impact on long-term survival. RESULTS: The mean maximum FDG uptake (standardized uptake value, SUVmax) of the whole group decreased significantly during NARCT (SUVmax PET 1: 14.9+/-4.0, SUVmax PET 3: 5.5+/-2.4, p=0.004). The difference between initial FDG uptake (PET 1) and uptake after induction chemotherapy (PET 2) was found to be highly predictive for long-term survival patients which had a greater than 60% decreases in their SUV change had a significantly longer survival than those below this threshold (5-year-survival 60% versus 15%, p=0.0007). Patients who had a lower than 25% decrease in their SUV change had a 5-years-survival lower than 5%. Furthermore, the difference between initial FDG uptake (PET 1) and uptake after completion of the whole NARCT (PET 3) was predictive for survival when 75% was applied as cut-off (p=0.02). However, the level of significance was considerably lower. CONCLUSION: FDG-PET is suitable for therapy monitoring in patients with stage III NSCLC. The decrease of FDG uptake during induction chemotherapy is highly predictive for patient outcome.

Adult↗

PubMed2006

Impact of staging with 18F-FDG-PET on outcome of patients with stage III non-small cell lung cancer: PET identifies potential survivors.

PURPOSE: The aim of this study was to analyse the impact of FDG-PET staging on treatment results of neo-adjuvant radiochemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We compared prospectively the outcome of two patient groups with stage III NSCLC undergoing the same neo-adjuvant radio-chemotherapy (NARCT). In one group, FDG-PET was part of the pretherapeutic staging, whereas in the other group, no PET scans were performed. METHODS: One hundred and eighty-eight patients with advanced stage III NSCLC were selected for a phase II trial of NARCT. The first 115 patients underwent conventional workup (CWU) and FDG-PET before inclusion (group I); the remaining 73 patients underwent CWU only (group II). All patients were followed up according to a standardised protocol for at least 11 months (up to 64 months). Overall survival and disease-free survival were used as parameters of therapeutic success and analysed statistically. RESULTS: After staging, 157/188 patients were included in the clinical trial. Thirty-one were excluded owing to the results of FDG-PET, in most cases because of the detection of previously unknown distant metastases. Overall survival and metastasis-free survival were significantly longer in patients of group I stratified by FDG-PET than in group II (p=0.006 and 0.02 respectively). Another significant factor for survival was complete tumour resection (p=0.02). Gender, histological tumour type, tumour grade and UICC stage had no significant influence. CONCLUSION: Pretherapeutic staging by FDG-PET significantly influences the results of NARCT and subsequent surgery by identifying patients not eligible for curative treatment.

Adult↗

PubMed2006

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo.

We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1-5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

Antibodies, Monoclonal↗

PubMed2006

Combination of celecoxib with percutaneous radiotherapy in patients with localised prostate cancer - a phase I study.

BACKGROUND: Current approaches for the improvement of bNED for prostate cancer patients treated with radiotherapy mainly focus on dose escalation. However molecularly targeted approaches may also turn out to be of value. In this regard cyclooxygenase (COX)-2 inhibitors have been shown to exert some anti-tumour activities in human prostate cancer in vivo and in vitro. Although in vitro data indicated that the combination of COX-2 inhibition and radiation was not associated with an increased toxicity, we performed a phase I trial using high dose celecoxib together with percutaneous radiation therapy. METHODS: In order to rule out any increases of more than 20% incidence for a given side effect level 22 patients were included in the trial. Celecoxib was given 400 mg twice daily with onset of the radiation treatment. Risk adapted radiation doses were between 70 and 74 Gy standard fractionation. RTOG based gastrointestinal (GI) and genitourinary (GU) acute toxicity scoring was performed weekly during radiation therapy, at six weeks after therapy and three month after completing radiation treatment. RESULTS: Generally no major increase in the level and incidence of side effects potentially caused by the combined treatment was observed. In two cases a generalised skin rash occurred which immediately resolved upon discontinuation of the drug. No grade 3 and 4 toxicity was seen. Maximal GI toxicity grade 1 and 2 was observed in 85% and 10%, respectively. In terms of GU toxicity 80% of the patients experienced a grade 1 toxicity and 10 % had grade 2 symptoms. CONCLUSION: The combination of irradiation to the prostate with concurrent high dose celecoxib was not associated with an increased level of side effects.

Aged↗

PubMed2006

A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Former meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria. METHODS: Randomised trials testing curatively intended RT (> or =60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival. RESULTS: Thirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX). CONCLUSION: RT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Is standardised (18)F-FDG uptake value an outcome predictor in patients with stage III non-small cell lung cancer?

PURPOSE: Recent studies have demonstrated the relevance of (18)F-FDG uptake as an independent prognostic factor for recurrence of operable non-small cell lung cancer (NSCLC). This corresponds with the experimental finding that FDG uptake correlates with the proliferative activity of tumour cells (Higashi et al., J Nucl Med 2000;41:85-92). On the basis of these observations, we studied the influence of FDG uptake on prognosis and occurrence of distant metastases in patients with advanced NSCLC. METHODS: One hundred and fifty-nine patients with NSCLC of UICC stage IIIA or IIIB were included in the study. In all patients, neoadjuvant treatment was planned to achieve operability. FDG PET was performed as an additional staging procedure prior to the initiation of therapy. Clinical outcome data in terms of overall survival, disease-free survival and incidence of distant metastases could be obtained for 137 patients and were correlated with the average standardised uptake value of the tumour (SUV(avg)). Furthermore, other factors influencing SUV(avg) and patient outcome (histological tumour type, grading, UICC stage, tumour size) were analysed. RESULTS: SUV(avg) was significantly influenced by tumour histology, UICC stage and tumour size. No significant difference could be shown for grading. In 38 out of the 159 patients (24%), FDG PET revealed previously unsuspected distant metastases. The incidence of distant metastases significantly correlated with SUV(avg). Overall survival tended to decrease with increasing SUV(avg); however, significance was only reached when a cut-off of 12.0 was applied (p=0.05). CONCLUSION: FDG uptake is an independent prognostic factor in patients with UICC stage III NSCLC, although less distinctively so than has been reported for stage I/II tumours.

Adult↗

PubMed2005

Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO.

BACKGROUND: The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy. PATIENTS AND METHODS: Between December 2000 and October 2003, a total of 86 patients were included in both studies. Patients with completely resected gastric adenocarcinoma including a D1 or D2 lymph node dissection (LND) were eligible. Treatment consisted of two cycles of folinic acid 500 mg/m2, 5-FU 2000 mg/m2 continuous infusion over 24 h once weekly for 6 consecutive weeks, paclitaxel 175 mg/m2 in weeks 1 and 4 and cisplatin 50 mg/m2 in weeks 2 and 5 (FLPP; n=41) or two cycles of the same 5-FU/folinic acid schedule but with cisplatin 50 mg/m2 only in weeks 1, 3 and 5 (FLP; n=45). Radiation with 45 Gy plus concomitantly applied 5-FU 225 mg/m2/24 h was scheduled in between the two cycles. RESULTS: Patients characteristics were: D1/D2 LND FLP group 53%/42%; FLPP group 27%/68%; stage distribution: UICC stages III/IV(M0) FLP group 63% and FLPP group 66%. Median follow-up was 10 months (3-25) for FLP and 18 months (2-51) for FLPP patients. CTC grade 3/4 toxicities during the first cycle/chemoradiation/second cycle of FLP: granulocytopenia 3%/0/27%, anorexia 6%/10%/8%; diarrhea 8%/0/4%, nausea 3%/0/4%; FLPP: granulocytopenia 0/0/37%, anorexia 5%/11%/6%; diarrhea 5%/0/3, nausea 3%/8%/0%; early death in one patient due to Pneumocystis carinii pneumonia. Projected 2-year progression-free survival was 64% (95% CI 56% to 68%) for the FLP and 61% (95% CI 42% to 78%) for the FLPP group. CONCLUSIONS: Both chemoradiation regimens appear feasible with an acceptable toxicity profile indicating that cisplatin can be added to 5-FU/FA and that even a four-drug regimen can be investigated further in prospective clinical trials in completely resected gastric cancer patients. Treatment should be given in experienced centres in order to avoid unnecessary toxicity.

Adenocarcinoma↗

PubMed2005

Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection.

BACKGROUND AND PURPOSE: Evaluation of the efficacy of combined hyperthermia and radiotherapy (TRT) in high-risk breast cancer patients with microscopic involved margins (R1) after mastectomy or with resected locoregional, early recurrence with close margins or R1-resection. Main endpoint was local tumour control (LC); secondary endpoints were overall survival (OS), disease free survival (DFS) and acute toxicity. MATERIAL AND METHODS: Between 1997-2001, 50 patients were treated with TRT. Thirteen patients (group 1) received a post-operative TRT in a high-risk situation (free margin <1 cm or R1, N+), 37 patients (group 2) received TRT after close/R1 resection of a locoregional recurrence. Thirteen out of 37 patients in group 2 already had had two-to-seven recurrences prior to TRT. Median radiation dose was 60 Gy (range: 44-66.4 Gy), the additional local hyperthermia (>41 degrees C, 60 min) was given twice a week. Median follow-up for patients at risk was 28 months. All statistical tests were done using Statistica software. RESULTS: Actuarial OS for all patients at 3 years accounted for 89%, DFS for 68% and LC for 80%. Actuarial OS was 90% for group 1 and 89% for group 2, with four patients having died so far. DFS at 3 years was 64% in group 1 and 69% in group 2, actuarial 3 year LC was 75% and 81%, respectively. For patients with recurrent chest wall disease, there was no difference concerning local control between patients who underwent TRT with or without prior radiation. No prognostic factors could be detected due to the small number of patients investigated. The combined modality treatment was well tolerated. Grade IV toxicity, according to the Common Toxicity Criteria, did not occur. CONCLUSION: The results concerning local tumour control and overall survival in these high-risk patients are promising, especially for TRT for the treatment of local recurrences. A longer follow-up is needed to estimate late toxicity.

Breast Neoplasms↗

PubMed2003

A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma.

The overall survival of patients with advanced multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (SCT) depends mainly on the quality of response. Thus, to improve the response rate, a new intensified high-dose chemoradiotherapy was evaluated in a phase I/II study. After induction chemotherapy, 89 patients (median age 51 years, range 32-60 years) with MM stage II/III received a conditioning regimen with total marrow irradiation (9 Gy), busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) followed by SCT. Regimen-related toxicity according to WHO criteria and response rates defined by EBMT/IBMTR were analyzed. The main toxicity was mucositis grade III/IV in 76%, and fever grade >I in 75% of patients. Three patients developed reversible veno-occlusive disease. Transplant-related mortality was 2%. Among patients with de novo and pretreated MM, a CR rate of 48 and 41%, respectively, was documented. With a median follow-up of 45 months, the actuarial median durations of event-free survival (EFS) and overall survival (OS) after transplant were 29 and 61 months for the whole group, 36 and 85 months for patients with de novo MM, respectively. Thus, administration of this intensified conditioning regimen was associated with tolerable toxicity, a high response rate and long EFS and OS.

Adult↗

PubMed2003

Current and potential role of thermoradiotherapy for solid tumours.

The disappointing results for inoperable, locally advanced or recurrent solid tumours of the uterine cervix, rectum, chest wall, liver and deep seated, high-risk sarcomas after conventional radiotherapy alone necessitate the search for improved treatments. A benefit from simultaneous radiochemotherapy with regard to local tumour control and survival has been shown for a rising number of tumour entities. Radiofrequency hyperthermia is established in only a few centres, and represents another option to intensify the effect of radio- and chemotherapy. Altogether 11 randomised phase III trials with more than 1,000 patients proved the combination of hyperthermia (40-42 degrees C for at least 1 h) and radiation therapy in reference to local tumour control. Two of these trials could demonstrate a survival benefit; e.g. in locally advanced cervical cancer, stage FIGO IIB-IVa, the 3-year survival was improved from 27 to 51% with the addition of hyperthermia. Frequently trial design (main endpoint local tumour control), a low number of patients or a short follow- up period are the reasons why most trials of thermoradiotherapy failed to demonstrate a survival benefit. Disadvantageous effects of hyperthermia like an increased rate of distant metastases as a result of hyperthermia-induced elevated perfusion can be largely ruled out. While at the moment the equivalence of thermoradiotherapy and radiochemotherapy is still under evaluation, future studies have to investigate the question whether hyperthermia can add benefits when used in combination with simultaneous radiochemotherapy. An ongoing investigation of hyperthermia in multimodal treatment strategies for locally advanced solid tumours is warranted. These trials will help to improve temperature monitoring and temperature distribution and define particular groups of patients who will profit from the addition of hyperthermia. The 'Interdisziplinäre Arbeitsgruppe Hyperthermie', a working group of the German Cancer Society, introduces clinical protocols, treatment devices, and provides information for patients at www.hyperthermie.org.

Combined Modality Therapy↗

PubMed2002

FDG PET for staging of advanced non-small cell lung cancer prior to neoadjuvant radio-chemotherapy.

The aim of this study was to evaluate positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) for the staging of non-small cell lung cancer (NSCLC) before combined neoadjuvant, i.e. preoperative, radio-chemotherapy (RCT). From November 1998 until September 2001, 101 patients with NSCLC were investigated prospectively. The inclusion criterion was a histologically proven NSCLC of stage IIIA or B according to conventional staging including biopsy. The results of PET were compared with those obtained by mediastinoscopy, computed tomography (CT), bone scan and abdominal ultrasonography. Validation of discrepant findings was achieved by biopsy or repeated CT. PET proved to be highly accurate for the detection of lymph node metastases (sensitivity 96%, specificity 73%, positive predictive value 88%, negative predictive value 89%, accuracy 88%) as well as distant metastases (in 25/101 patients, all previously unknown). PET findings changed further treatment in 29/101 patients (29%). Twenty-five were excluded from RCT due to the presence of previously unknown distant metastases. One patient was free of metastases and therefore was operated on without pre-treatment. Two patients did not receive any further treatment because a malignant tumour could be excluded after PET. In the final patient PET demonstrated a tumour pattern not typical for NSCLC which could be attributed to a seminoma after repeated biopsy. FDG PET is the most accurate non-invasive diagnostic procedure for the staging of advanced NSCLC. Therefore use of FDG PET is highly recommended in order to select patients for neoadjuvant or other stage-dependent treatment modalities.

Adult↗

PubMed2002

Anti-apoptotic Bcl-2 proteins: structure, function and relevance for radiation biology.

PURPOSE: Bcl-2 family members mediate anti-apoptotic signals in a wide variety of human cell systems. Despite its proven antiapoptotic function, several results indicate that overexpression of Bcl-2 is not clearly associated with increased radiation resistance in vitro or in vivo. The reasons for this obvious contradiction are not understood. MATERIALS AND METHODS: Current data on the function of Bcl-2 as an anti-apoptotic protein, its role for the modulation of radiation sensitivity in vitro and its value as prognostic marker in vivo are reviewed. RESULTS: Bcl-2 and related proteins are currently perceived to be the most important anti-apoptotic proteins. Their function is related to their ability to interfere with mitochondrial apoptosis pathways. Contradictory data have been published on the relevance of Bcl-2 and related family members for in vitro and in vivo tumour response. The value of Bcl-2 as a prognostic marker thus remains unclear. CONCLUSIONS: Although Bcl-2-related proteins are currently the most relevant anti-apoptotic modulators, their relevance for radiation responses in vivo or in vitro remain undefined. Furthermore, their determination in a routine clinical setting does not appear to be justified.

Apoptosis↗

PubMed2002

New aspects of adjuvant radiotherapy in primarily resectable rectal cancer.

Local recurrence rates of approximately 30% have been consistently reported after 'conventional surgery' in stage II + III rectal cancer patients. Postoperative radiotherapy decreases the local recurrence rate only moderately and is not associated with a gain in survival. Preoperative radiotherapy with biologically effective doses > 30 Gy dramatically reduces the relative risk of local recurrences by 57% that translates into significant overall survival benefit. Postoperative 5-fluorouracil-based chemotherapy in combination with radiotherapy has also been shown to increase local tumor control and to result in a significantly better survival. However, an improved surgical technique, the total mesorectal excision (TME), has evolved and is considered standard treatment by many surgeons. With this technique, reduced local recurrence rates of below 10% and improved survival rates have been reported from different institutions. Therefore, a discussion has started, whether or not pre- or postoperative radiotherapy and chemotherapy is beneficial, when TME is used. The preliminary results of a recently published trial on radiotherapy before TME partly resolve the current controversy. An expected local failure rate of approximately 15% and an overall survival rate below 60%, 5 years after TME alone in stage II + III rectal cancer patients suggest the need for additional therapy. Preoperative radiotherapy reduced the risk of local recurrence more than 3 times, indicating that the use of radiotherapy is justified at least in patients with stage II + III disease, even if optimal surgery was used. The unsatisfactory overall survival gives indirect evidence that these patients will also benefit from chemotherapy. However, many questions remain open and an optimal therapeutic schedule has not been established.

Chemotherapy, Adjuvant↗

PubMed2001

Radiation induced CNS toxicity--molecular and cellular mechanisms.

Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects.

Central Nervous System↗

PubMed2001

Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL.

A combination of antitumor approaches acting on different death pathways seems ideal for increasing therapeutic responses, especially when defined resistance mechanisms interfere with individual cellular processes. Apoptosis pathways triggered by ionizing radiation (XRT) and the death ligand TRAIL were analysed in Jurkat lymphoma cells. Both induced the activation of caspase-8, caspase-3, BID and mitochondrial potential loss. TRAIL induced apoptosis required caspase-8, whereas it was not essential for radiation induced apoptosis. The inhibition of mitochondrial damage by Bcl-2 abrogated XRT induced apoptosis and caspase activation, but only marginally attenuated TRAIL induced cell death. The combined treatment with TRAIL and XRT exerted additive apoptotic effects in control cells, whereas highly synergistic effects occurred in cells overexpressing Bcl-2. In addition, a strong effect of TRAIL on radiation induced clonogenic cell death was found. In conclusion, TRAIL seems to be of high potential value for a combination with ionizing radiation in tumor therapy.

Apoptosis↗

PubMed2001

Association of tumor growth on nude mice and poor clinical outcome in soft tissue sarcoma patients.

PURPOSE: Permanent growth in nude mice (PGNM) may be associated with poor clinical outcome. We tested this hypothesis in a group of soft tissue sarcoma (STS) patients. METHODS: Small chunks from fresh tumor biopsies of 81 patients with STS were transplanted subcutaneously into NMRI-nu/nu nude mice. Tumor cell lines exhibiting growth in nude mice for more than three tumor passages were considered as permanently established. Clinical outcome of all patients was monitored with a median follow-up of 38 months. RESULTS: 39/81 (48%) STSs exhibited PGNM. High grade, high S-phase proportion, and aneuploidy were significant predictors of PGNM. Overall survival (OS) at 3 years was 21% (+7% standard error of median) for STS patients with PGNM and 53% (+/-8%) for patients without PGNM (P<0.01). Considering only patients without distant metastasis at the time of biopsy (n = 49), 3-year-OS was 25% (+/-10%) and 71% (+/-9%) for STS with PGNM and without PGNM, respectively (P<0.01). In the univariate analysis, PGNM, aneuploidy high S-phase proportion, tumor location at the trunk, high tumor grade, and non-liposarcoma histology were associated with reduced survival time. In the multivariate analysis, aneuploidy and tumor location at the trunk were the only independent predictors of overall survival. CONCLUSION: Permanent growth of STS on nude mice is associated with poor clinical outcome in the univariate analysis, but is not an independent predictor of survival in the multivariate analysis due to a strong co-correlation to other known adverse prognostic factors.

Adolescent↗

PubMed2001

Radiation sensitivity and apoptosis in human lymphoma cells.

PURPOSE: The impact ofapoptosis on radiation-induced eradication of clonogenic tumour cells is uncertain. The aim was to analyse the relationship of different functional stages during the apoptotic process to cell death and clonogenic cell eradication. MATERIALS AND METHODS: Apoptosis in Jurkat T-cells was studied by morphology, light scatter and caspase activation. Mitochondrial integrity was determined by the mitochondrial membrane potential (delta(phi)m). Cell death was quantified using propidium iodide exclusion. Clonogenic cell death was determined using a dilution survival assay. The influence of Bcl-2 was tested using a Bcl-2 transfected Jurkat clone. RESULTS: Irradiation induced profound apoptosis within 48 h associated with caspase activation and breakdown of delta(phi)m. Inhibition of caspases abrogated the apoptotic morphology with no influence on breakdown of delta(phi)m and survival. Over-expression of Bcl-2 abrogated all hallmarks of apoptosis; delayed cell death, however, had no influence on clonogenic survival after irradiation. CONCLUSION: Based on Bcl-2 as a positional marker, radiation-induced apoptosis can be divided into two stages: the initiation/decision phase, characterized by a breakdown of the mitochondrial membrane potential, and the execution phase, characterized by caspase activation. The execution phase had no influence on survival, whereas the initiation/decision phase controls immediate survival. However, abrogation of both phases did not influence radiation sensitivity.

Amino Acid Chloromethyl Ketones↗