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M Bamberg

Publications and source records attributed to M Bamberg.

At least 55 records · Page 3Linked to original sources
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↗
PubMed2000

Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U.S. and German Thyroid Cancer Group.

BACKGROUND: To determine current patterns of care and disease characteristics for patients with thyroid carcinoma, a Patient Care Evaluation Study was initiated in 1996 in the U.S. and Germany. This project addresses ongoing concerns with respect to the diagnostic evaluation and treatment of patients diagnosed with thyroid carcinoma and raises questions concerning how physicians are interpreting current standards and acting on the basis of these recommendations. METHODS: Patients with primary thyroid carcinoma were entered into a prospective multicenter observational study with free choice of treatment (no control group) between January 1, 1996 and December 31, 1996 in Germany. This resulted in a total of 2537 cases under observation and analysis; 1685 patients had papillary carcinoma (66.4%), 691 had follicular carcinoma (27.2%), 70 had medullary carcinoma (2.8%), and 91 had anaplastic carcinoma (3.6%). The 2376 patients with carcinoma of either papillary or follicular histology were included in the current analysis. RESULTS: The major symptoms reported for patients with papillary and follicular thyroid carcinoma was neck mass (reported in 76% and 79%, respectively) followed by dysphagia (reported in 25% and 27%, respectively), stridor (reported in 9% and 14%, respectively), and neck pain (reported in 7% and 8%, respectively). Greater than 50% of the patients with papillary thyroid carcinoma were reported to have American Joint Committee on Cancer/International Union Against Cancer Stage I disease. Between 37-39% of the follicular carcinoma patients had Stage I and Stage II disease. Only slight differences in the diagnostic approach to patients with papillary or follicular carcinoma were noted. The majority of patients underwent an ultrasound of the thyroid region (78.1%), which was suggestive of carcinoma in only 39% of the cases. A thyroid scan was performed on 76.6% of patients, and the results were suggestive of carcinoma in 44.8% of the individuals. In contrast, fine-needle aspiration biopsy of the thyroid is highly recommended in the current Clinical Practice Guidelines (CPG) but results were obtained in only 27.4% of the patients. Total thyroidectomy without lymph node dissection was the most commonly used surgical procedure in the treatment of patients with papillary and follicular thyroid carcinoma. Only approximately 2% of patients at low risk in the group with Stage I disease were treated with a lobectomy. In 80% of the patients with Stage I papillary thyroid carcinoma and approximately 90% of those patients diagnosed with Stage II, III, and IV disease treating physicians chose to utilize radioiodine as adjuvant treatment after disease-directed surgery. External beam radiation was added to the treatment regimen for many patients diagnosed with Stage III and IV disease (30% in patients with papillary thyroid carcinoma and 33% in patients with follicular thyroid carcinoma). CONCLUSIONS: To the authors' knowledge no single effective diagnostic test for thyroid carcinoma currently is available and in the majority of cases a combination of ultrasound, thyroid scan, or fine-needle aspiration biopsy together with the clinical findings (e.g., thyroid mass) led to a diagnosis of carcinoma. The authors suspect that the high prevalence of concomitant pathologic findings such as goiter, even in the healthy population in Germany, reduces the accuracy of all diagnostic test methods and may account for the frequent use of imaging techniques. The majority of patients underwent a total or near-total thyroidectomy. Total thyroidectomy with radical lymph node dissection was used very frequently in those patients with papillary thyroid carcinoma (22%). German physicians tend to surgically treat early stage thyroid carcinoma somewhat more radically than recommended in the CPG. With respect to other treatment options employed as part of the first course of treatment, radioiodine appears to play the most important role. [See commentary o

Adenocarcinoma, Follicular↗
PubMed2000

Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis.

Activation of the CD95 death receptor as well as ionizing radiation induces apoptotic cell death in human lymphoma cells. The activation of caspases is a hallmark of apoptosis induction irrespective of the apoptotic trigger. In contrast to death receptor signaling, the exact mechanisms of radiation-induced caspase activation are not well understood. We provide evidence that both, radiation and CD95 stimulation, induce the rapid activation of caspase-8 and BID followed by apoptosis in Jurkat T-cells. To analyse the relative position of caspase-8 within the apoptotic cascade we studied caspase activation and apoptosis in Jurkat cells overexpressing Bcl-2 or Bcl-xL. Caspase-8 activation, pro-apoptotic BID cleavage and apoptosis in response to radiation were abrogated in these cells, while the responses to CD95 stimulation were only partially attenuated by overexpression of Bcl-2 family members. In parallel, the breakdown of the mitochondrial transmembrane potential (DeltaPsim) in response to radiation was inhibited by overexpression of Bcl-2/Bcl-xL Jurkat cells genetically deficient for caspase-8 were found to be completely resistant towards CD95. However, radiation-induced apoptotic responses in caspase-8-negative cells displayed only a modest reduction. We conclude that ionizing radiation activates caspase-8 and BID downstream of mitochondrial damage suggesting that, in contrast to CD95, both events function as executioners rather than initiators of the apoptotic process.

Apoptosis↗
PubMed2000

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91.

PURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Adolescent↗
PubMed2000

Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91.

PURPOSE: To evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival. METHODS AND MATERIALS: Fifty-five children (n = 27 girls, 28 boys; median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas were treated in the multicenter, prospective trials HIT 88/89 and HIT 91. Macroscopic complete resection was achieved in 28 patients; 27 patients underwent incomplete resection. All patients received chemotherapy before (n = 40) or after irradiation (n = 15). The irradiation volume encompassed either the neuraxis followed by a boost to the primary tumor site (n = 40) or the tumor region only (n = 13). No radiotherapy was administered in two patients. RESULTS: Median follow-up was 38 months. The overall survival rate at 3 years after surgery was 75.6%. Disease progression occurred in 25 children with local progression occurring in 20. The median time to disease progression was 45 months. The only significant prognostic factor was the extent of resection (estimated progression-free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5% after incomplete resection) and the presence of metastases at the time of diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site, mode of chemotherapy, and irradiation volume did not influence survival. CONCLUSIONS: Treatment centers should be meticulous about surgery and diagnostic workup. Because the primary tumor region is the predominant site of failure it is important to intensify local treatment. Dose escalation by hyperfractionation or stereotactic radiotherapy might be a promising approach in macroscopically residual disease. The role of adjuvant chemotherapy requires further study.

Adolescent↗
PubMed2000

[Interdisciplinary consensus on diagnosis and therapy of testicular tumors. Results of an update conference based on evidence-based medicine. German Testicular Cancer study Group (GTCSG)].

BACKGROUND: An "Interdisciplinary Consensus Statement on the Diagnosis and Therapy of Testicular Tumors" was prepared in 1996 by the "Interdisciplinary Testicular Tumor Working Group" (IAH) with input from representatives from diagnostic and therapeutic disciplines of various working groups of the German Cancer Society (Strahlenther Onkol 1997;173:397-406). In 1998 the IAH met again together with the "Testicular Tumor Working Party" of the Urooncology Working Group (AUO) and formed the "German Testicular Cancer Study Group" (GTCSG). Defined and accepted interdisciplinary standards from the initial meeting were revised based on current scientific developments and clinical results. This cooperating effort increased the quality of the initial recommendations and helped to put the recommendations for diagnosing and treating testicular tumor on a broader scientific basis. METHODS: According to the principles of "evidence-based medicine" (EBM), the Consensus from 1996 was modified, based on the current level of evidence from the published literature. The methodological process and evaluation criteria used were that of the "Cochrane Collaboration". RESULTS: An "Interdisciplinary Update Consensus Statement" summarizes and defines the diagnostic and therapeutic standards according to the current scientific practices in testicular cancer. For 21 separate areas scientifically based decision criteria are suggested. For treatment areas where more than one option exist without a consensus being reached for a preferred strategy, such as in seminoma in clinical Stage I or in non-seminoma Stages CS I or CS IIA/B, all acceptable alternative strategies with their respective advantages and disadvantages are presented. This "Interdisciplinary Update Consensus" was presented at the 24th National Congress of the German Cancer Society on March 21st and subsequently evaluated and approved by the various German scientific medical societies.

Evidence-Based Medicine↗
PubMed2000

Biological effects of ionizing radiation on human blood compounds ex vivo.

PURPOSE: Blood compounds are irradiated ex vivo to prevent transfusion-associated graft-versus-host-disease. Recently, ex vivo irradiation of re-transfused wound blood has been proposed to prevent metastatic spread in patients with malignant tumors, an issue requiring different dose concepts. To determine effects on blood cells we examined the impact of various doses of ionizing radiation. METHODS: Full blood was irradiated with doses of 10-150 Gy. Potassium, LDH and hemoglobin levels were determined 2 h-96 h after irradiation. The lymphocyte proliferation after irradiation was measured by means of a lymphocyte-transformation assay. The impact of irradiation on mitogen-induced secretion of cytokines was determined by the ELISA technique, and P-selectin expression as an indicator of platelet activation was analyzed by flow-cytometry. RESULTS: Potassium levels increase with aging and irradiation dose. Mitogenic capacity is reduced by over 90% with moderate doses of 10-20 Gy, but a residual proliferation is still detectable up to 50 Gy. No enhancement of extracellular cytokine levels is detectable, but the cytokine release is reduced by radiation. Neither induction of platelet activation nor abrogation of activation has been detected. CONCLUSIONS: Doses of 30-50 Gy abrogate lymphocyte proliferation almost completely. In this range we did not observe severe adverse effects on blood transfusions. Hemolysis might be enhanced when the samples are stored for a longer period after irradiation.

Blood Platelets↗
PubMed2000

[Value of radiotherapy in interdisciplinary management of testicular germ cell tumors].

Radiotherapy unequivocally has to be regarded as standard therapy in stage I and IIA/B testicular seminoma. Using low dose abdominal irradiation tumour control rates of 95-98% in stage I disease and 80-95% in stage IIA/B can be achieved. Disease specific survival reaches 100%. Likewise, radiotherapy is treatment of first choice in case of testicular intraepithelial neoplasia (TIN) in a solitary testis or in case of a double-sided TIN yielding safe eradication of the in-situ carcinoma of the testis. Objectives of further clinical research in radiotherapy of testicular malignancies aim at reduction of treatment intensity in order to minimize acute and late side effects of irradiation without compromising tumour control rates.

Carcinoma in Situ↗
PubMed2000

Thyroid toxicity of treatment for Hodgkin's disease.

Thyroid disease, especially hypothyroidism, is one of the more frequently encountered late endocrine sequelae of treatment for Hodgkin's disease. We analyzed the thyroid function of 177 patients (92 male and 85 female) who had been treated for Hodgkin's disease between 1970 and 1995; their median age was 38 years (range 18-74) and their median time after therapy was 6 years (range 1-20). Thirty-five (20%) patients were treated with chemotherapy alone (mainly COPP/ABVD), 44 (25%) with radiotherapy (RTX) alone, and 98 (55%) received combined modality treatment according to the protocols of the German Hodgkin's Disease Study Group. All patients had been without evidence of disease for at least 1 year. They were evaluated between 1994 and 1997 for thyroid disease by clinical examination, thyroid function tests, and ultrasound imaging if indicated. Overall, 48 patients (27%) were found to have subclinical (36 patients, 20%) or overt (12 patients, 7%) hypothyroidism. No patient in the group treated with chemotherapy alone developed hypothyroidism, in contrast to 15 of 44 (34%) patients treated with radiotherapy alone and 33 of 98 (34%) patients treated with the combined modality approach who did. All patients with hypothyroidism had received some form of supradiaphragmatic radiation except one patient who underwent infradiaphragmatic RTX but with preceding hemithyroidectomy for staging purposes. After an average follow-up of 6 years, 27% of patients treated for Hodgkin's disease with either radiotherapy alone or a combination of radiotherapy and chemotherapy developed hypothyroidism. Supradiaphragmatic radiation, but not the use of chemotherapy alone, is associated with an increased risk for hypothyroidism. Evaluation of thyroid function after therapy is important, and appropriate substitution medication should be initiated.

Adolescent↗
PubMed2000

Effects of single-dose versus fractionated irradiation on the suppression of heterotopic bone formation--an animal model-based follow-up study in rats.

The histological and enzymatic effects of single-dose irradiation of 7 Gray (Gy) versus fractionated irradiation of 5 x 2 Gy on the suppression of heterotopic ossification were examined over a period of 60 days in adult male Wistar rats (n = 57). The standardized osteogenesis model system in rats 19, 10, 11, 16, 19] was used for this purpose. The course of developing ossifications was documented quantitatively and qualitatively by means of quantitative computed tomography/osteodensitometry and digital luminescence radiography. Assessment of the activities of the enzymes alkaline and acid phosphatase throughout the experiment as well as characterization of the isoenzyme of alkaline phosphatase (AP) in connection with histological observations displayed a metaplasia of the ingrowing connective tissue into bone-typical cells during osteoinduction. Thus, the increase of AP is the first sign of a functional transformation of mesenchymal stem cells into chondroid bone cells. The increase in the acid phosphatase level with a maximum of activity between the 15th and 30th day (according to the respective treatment group) is highly suggestive of a remodeling process paralleling incipient chondroclast and osteoclast activity. In the animal groups undergoing irradiation, the above-mentioned increase of enzymes occurred after a delay. Furthermore, the maximum values observed were lower than those in the group not undergoing irradiation. Both findings were more manifest in the animal group which underwent 5 x 2 Gy of radiation than in the group which underwent single-dose irradiation of 7 Gy. Radiation suppresses matrix-induced osteogenesis. The histological and enzymatic course of this process was unchanged in the animals which did not undergo irradiation. However, it was quantitatively reduced and accompanied by a retardation of osteogenesis. Both effects were again reduced with fractionated irradiation of 5 x 2 Gy, which is theoretically dose-equivalent to a 1 x 7 Gy application. Histological examinations revealed damage to the migratory, proliferating mesenchymal stem cell population by irradiation doses which had relatively small effects on preosteoblasts, osteoblasts, chondroblasts and other specialized cell forms. Therefore, it may be concluded that the smaller degree of heterotopic ossification in the irradiated groups was due to damage of and a decrease in the number of mesenchymal stem cells at the implant site. Our results stress the necessity of instituting postoperative irradiation therapy as early as possible to prevent heterotopic ossification. In view of experimentally proven better effects, fractionated irradiation has to be preferred to a dose-equivalent single-dose radiation, especially considering the fewer side-effects noted with fractionated irradiation.

Acid Phosphatase↗
PubMed2000

A role for preirradiation PCV chemotherapy for oligodendroglial brain tumors.

Oligodendroglial tumors have been identified as a subgroup of glial neoplasms with a distinctly better response to chemotherapy and overall survival than purely astrocytic gliomas. Here we report our experience with adjuvant postirradiation and preirradiation chemotherapy using procarbazine, lomustine, and vincristine (PCV) in 27 patients with WHO grade II or III oligodendroglioma or oligoastrocytoma. The efficacy of chemotherapy was assessed according to the Macdonald response criteria (complete response, CR; partial response, PR; stable disease, SD; progressive disease, PD) and progression-free survival intervals by computed tomography or magnetic resonance imaging. First, we confirm that PCV salvage therapy for patients progressing after radiotherapy is highly effective (n = 11, 1 CR, 5 PR, 5 SD; median progression-free survival has not yet been reached, but is longer than 18 months). Second, 3 patients who received radiotherapy plus PCV as first-line therapy achieved CR and 2 achieved SD, and all 5 are progression-free with a median follow-up of 12 months. Third, given these encouraging results, 11 patients received postoperative preirradiation PCV chemotherapy and were given radiotherapy only upon progression. Preirradiation PCV chemotherapy was also effective (2 CR, 3 PR, 6 SD; median progression-free survival has not been yet reached, but is longer than 14 months). Patients with anaplastic oligoastrocytomas were as likely to respond to PCV chemotherapy, as were patients with anaplastic oligodendroglioma. Three patients who had previously responded to PCV were successfully treated with a second course of PCV upon recurrence. PCV chemotherapy was also effective in patients with leptomeningeal spread of oligodendrogliomas. A randomized prospective trial is required to compare the effectiveness and neurotoxicity of first-line PCV chemotherapy followed by radiotherapy to the traditional reverse sequence.

Adolescent↗
PubMed2000

Activity of extracranial metastases as a prognostic factor influencing survival after radiosurgery of brain metastases.

Information about prognostic factors influencing survival have been only occasionally reported in studies on the use of radiosurgery in the treatment of patients with brain metastasis. To answer the question of whether activity of extracranial metastases is an independent prognostic factor influencing survival in radiosurgery of brain metastases, a review of the literature was performed. Fourteen studies were identified in the English language literature that dealt with this topic. Only three studies showed borderline insignificance of the influence of activity of extracranial metastases when analysed by univariate methods. When multivariate analysis was used to test for the independent influence of this factor on survival, of nine studies that used that statistical approach eight showed that it is an independent prognosticator influencing survival, most often being the strongest one. This review of literature supports the view that the "activity of extracranial metastases" is an independent prognostic factor influencing survival of these patients as documented in published reports. However, prospective randomised trials are necessary to definitely establish the independent influence of this prognostic factor.

Analysis of Variance↗
PubMed2000

Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors.

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.

Adult↗
PubMed2000

First-line high-dose chemotherapy +/- radiation therapy in patients with metastatic germ-cell cancer and brain metastases.

PURPOSE: To examine the feasibility and efficacy of first-line high-dose chemotherapy (HD-CTX) in patients with advanced metastatic germ-cell tumors (GCT) and brain metastases. PATIENTS AND METHODS: Twenty-two patients with brain metastases at initial diagnosis were identified within a cohort of two hundred thirty-one consecutive patients with advanced metastatic disease, entered on a German multicenter trial between January 1993 and July 1998. All patients received first-line HD-CTX with cisplatin-etoposide-ifosfamide (HD-VIP) followed by autologous stem-cell transplantation. Brain irradiation (BRT) with 30-50 Gy +/- 10 Gy boost was applied in patients with symptomatic CNS disease or as consolidation in case of residual CNS lesions after HD-CTX. RESULTS: A median number of 4 HD-CTX cycles (range 2-5) were applied to the 22 patients. Ten patients received HD-CTX alone and twelve patients were treated with HD-CTX plus BRT. Median duration of WHO grade 4 granulocytopenia and thrombocytopenia was seven and five days after each cycle, respectively. Non-hematologic toxicity consisted mainly of mucositis/enteritis (WHO grade 3-4 32%). Two early deaths occurred in twenty-two patients (one CNS-bleeding/one sepsis). Fourteen of twenty patients achieved a CR/PRm- status. Twenty patients (91%) responded in the brain (55% CR/36% PR). Two-year progression-free and overall survival rates were 72% and 81%, respectively. These survival rates are substantially higher compared to the available data in the literature. CONCLUSIONS: High-dose chemotherapy with autologous stem-cell support +/- BRT appears to be feasible without increased therapy-related mortality in patients with advanced metastatic GCT and brain metastases. The results achieved emphasize the high chemosensitivity of CNS metastases from GCT and suggest a potential role for dose intensification. The dose of BRT in addition to HD-CTX may be tailored to the presence of clinical symptoms and the response of CNS metastases to chemotherapy.

Adult↗
PubMed2000

Fibroblast differentiation in subcutaneous fibrosis after postmastectomy radiotherapy.

In order to acquire a better understanding of the mechanism of radiation-induced fibrosis, we studied the differentiation of normal skin fibroblasts cultured from breast cancer radiotherapy patients with different risk of fibrosis. The differentiation state of fibroblasts was characterized in clonal cultures using established cytomorphological criteria. Collagen synthesis was determined by 3H-proline incorporation into pepsin-resistant protein. Radiation-induced inactivation of fibroblasts was paralleled by an increase in terminally differentiated fibrocytes, demonstrating that premature terminal differentiation is an important response to irradiation of fibroblasts from radiotherapy patients. Surviving colony-forming fibroblasts showed a change in differentiation with an increase in the ratio L:E of progenitor fibroblasts in late (L) compared to early (E) differentiation states. Furthermore, increased collagen production was observed after irradiation. The results provide evidence supporting a role of terminal fibroblast differentiation in radiation-induced fibrosis and imply that the progenitor population surviving radiotherapy might be more prone to terminal differentiation than before radiotherapy.

Breast Neoplasms↗
PubMed2000

TGF-beta1-mediated alterations of rat lung fibroblast differentiation resulting in the radiation-induced fibrotic phenotype.

PURPOSE: To study the influence of TGF-beta1 and TGF-beta-neutralizing antibodies on the clonogenic activity and terminal differentiation of rat lung fibroblasts following radiation exposure. MATERIAL AND METHODS: Early passage rat lung fibroblasts were used in this study. Colony formation assays were applied to determine the radiation sensitivity as well as radiation-induced alterations in differentiation pattern. Based on a TGF-beta1-specific ELISA system, the amount of TGF-beta1 in the culture medium of sham-irradiated and irradiated cultures was determined. RESULTS: Applying immediate (ip) and delayed plating (dp) procedures for cells irradiated in the subconfluent state, distinct differences in the radiation dose-response curves could be observed (SF2ip 0.20+/-0.025 versus SF2dp 0.51+/-0.0077). Upon irradiation with a single dose of 4Gy the level of TGF-beta1 found in the culture medium increased by about 60%. Radiation-induced terminal differentiation of progenitor fibroblasts (MF) to postmitotic fibrocytes (PMF) was expressed by the change of the ratio of PMF:MF (0.8 at 0 Gy versus 3.0 at 4 Gy). Neutralizing antibodies directed against TGF-beta inhibited both the radiation-induced reduction in clonogenic activity of rat lung fibroblasts as well as the radiation-induced terminal differentiation of MF progenitor fibroblasts to PMF postmitotic fibrocytes. CONCLUSION: The results indicate the important role of TGF-beta1 in triggering radiation-induced inhibition of clonogenic activity as well as terminal differentiation of rat lung fibroblasts. The data presented support the hypothesis that terminal differentiation is an essential cellular process in the development of radiation-induced fibrosis in the lung.

Animals↗
PubMed2000

Time- and dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabine--a report of three cases.

Gemcitabine is a deoxycytidine analog with broad antitumor activity. Its main toxicities include myelosuppression, flu-like symptoms, bronchospasms and mild skin rash. We report three cases, in which the patients developed time- and dose-limiting erysipeloid skin reactions confined to areas of impaired lymphatic drainage after application of gemcitabine. Three patients with metastatic tumors (breast cancer, endometrial cancer and non-small cell lung cancer) received weekly infusions of gemcitabine (1000 mg/m2). All patients suffered from lymphedema of different origin and developed an erysipeloid erythema 40-48 h after chemotherapy within their preexisting lymphedema. Genuine erysipela was ruled out by laboratory tests and clinical observation. The skin reaction was repeatedly observed and faded after 14 days without specific treatment. Although the pathogenesis of the observed reaction is unclear, it is suspected that the skin symptoms were caused by gemcitabine or its metabolites. Gemcitabine is usually metabolized fast and excreted renally. In areas with impaired lymphatic drainage pharmakocinetics might be altered: inactivation happens slower and the drug might accumulate in the s.c. and cutaneous tissue, thus increasing local toxicity. Clinical judgement and biochemical parameters can help to tell apart genuine erysipela and the erysipeloid reaction.

Aged↗