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J Kühl

Publications and source records attributed to J Kühl.

70 records · Page 4Linked to original sources
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[A study group on brain tumors in childhood. Introduction, establishment and aims].

Tumors of the central nervous system account for 15.7% of all malignancies registered at the documentation center for childhood malignancies in Western Germany. This group constitutes the largest entity of solid tumors. With the exception of medulloblastoma the five-year survival probability of children with cns tumors in only 54%. Prognosis can only be improved by a interdisziplinary and multicentric approach. Recently, the "Gesellschaft für Pädiatrische Onkologie (GPO)" has set up a special Brain Tumor Study Group. Members of this group will come from several fields such as neuropediatrics, neurosurgery, radiotherapy, pediatric endocrinology, neuroradiology, neuro-/paidopathology, experimental neurooncology, medical statistics, and pediatric oncology. The major aims are standardization of current strategies for diagnosis and therapy including concepts for early diagnosis, aftercare, and rehabilitation. Moreover, it is planned to develop clinical and experimental research facilities and to establish a brain tumor research data bank.

Brain Neoplasms↗
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[Local radiotherapy combined with systemic chemotherapy in 3 children with osteosarcoma of an extremity].

Three boys with osteosarcoma of tibia or femur were locally irradiated with 97.5-100 Gy. Additionally they got chemotherapy according to T4-protocol. After 14-26 month two of them relapsed within, the third below the radiation field. There were no serious side effects of radiotherapy. In spite of amputation and chemotherapy they all developed metastases of lung within 18, 19 or 81 months. Two of them died and one is living with disease. We were not able to cure our three patients by combination of radiotherapy and chemotherapy. Radiotherapy is to date no adequate alternative to radically surgery. Only extraordinary cases should be treated by irradiation.

Adolescent↗
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[Chemotherapy of brain tumors in childhood. Review of the literature and pilot protocol].

The evaluation of 29 phase II studies demonstrate a complete, partial, and unequivocal response (CR + PR/UR) in 36% of 739 reported patients. A response rate of 55% has been reached in studies with initial neoadjuvant chemotherapy. Regarding different histologic types chemotherapy produced response rates of 56% in PNETs (primitive neuroectodermale tumors), 49% in medulloblastomas, 32% in ependymomas, 31% in brain stem gliomas, and 30% in astrocytomas/glioblastomas. Concerning a variety of cytotoxic drugs the following response rates have been observed: 59% with cyclophosphamide (monotherapy + combinations), 52% with MOPP/COPP, 48% with "8 in 1", 46% with BCNU/CCNU combinations, 42% with procarbazine combinations, 32% with cisplatin (22% with monotherapy; 64% with combinations), and 24% with AZQ (monotherapy + combinations). Because of the poor outcome of children with malignant brain tumors, and concerning the present evaluation as well as few phase III studies the brain tumor study group of the german society of pediatric oncology (GPO) created a pilot multidrug regimen including procarbazine (or 5-fluorouracil), ifosfamide + VP 16, hd methotrexate, and cisplatin + cytosinarabinoside. We observed one unequivocal response and one stable disease in two children after one course of this regimen without complications.

Antineoplastic Combined Chemotherapy Protocols↗
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[The German Society of Pediatric Oncology Cooperative Ewing Sarcoma Studies CESS 81/86: report after 6 1/2 years].

The GPO Cooperative Ewing's Sarcoma Study (CESS 81 with 10 months four-drug combination chemotherapy (vincristine, actinomycin D, cyclophosphamide, and adriamycin = VACA) and local control with surgery and/or radiation, following week 18, resulted in a Kaplan-Meier estimated disease-free survival of 51% after 6 1/2 years (51/93 patients disease-free). Tumor volume and histological response to primary chemotherapy were identified as most significant prognostic factors. As a consequence, the CESS 86 regimen was stratified according to risk of relapse. Standard risk patients (extremity tumors less than 100 ml tumor volume) were continued on VACA chemotherapy. In high risk patients (extremity tumors greater than 100 ml tumor volume, central tumors), cyclophosphamide in conventional dose (1200 mg/m2/course) was replaced by high doses of ifosfamide (6 g/m2/course) with mesna uroprotection (VAIA). Local control was obtained following week 9. Patients with radiation were randomised for conventional fractionation or accelerated split-course hyperfractionation. The study was piloted from February to December 1985: 27/37 patients were disease-free on October 1, 1987. The ongoing trial was started on January 1, 1986. On October 1, 1987. 63/66 patients were disease-free. In patients with large primaries, according to Kaplan-Meier life-table analysis, the disease-free survival was significantly better in patients receiving VAIA chemotherapy, compared to the previous VACA regimen. The toxicity of both combination chemotherapy regimens was comparable.

Antineoplastic Combined Chemotherapy Protocols↗
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[Results of treatment of primary metastatic Ewing sarcoma. A retrospective analysis of 48 patients].

The clinical presentation of the disease and the results of treatment in 48 patients with metastases at diagnosis of Ewing's sarcoma, entered into the Cooperative Ewing's Sarcoma Studies (CESS) 1981 and 1986 of the German Society of Pediatric Oncology (GPO), were analysed. The period of observation ranged from 1 to 82 months, the median relapse-free time was 26 months. There was a male predominance of 35 to 13, which was even more pronounced in patients older than 15 years. The predominant localization of the primary tumor was the pelvic region, followed by the extremities, the chest wall, and the spine. The most common site of primary metastases were the lungs, followed by bone and bone marrow. Nine patients presented with combined metastases. The disease-free survival according to Kaplan-Meier life-table analysis was 18% after 7 years. Best results were obtained in patients with pulmonary metastases only, who underwent surgical resection of the primary tumor and received radiation to the lungs. Without bone marrow transplantation the prognosis of patients with bone metastases was extremely poor.

Adolescent↗
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[Multifocal osteonecrosis in children and adolescents after polychemotherapy].

Adequate treatment protocols provide excellent results in management of lymphoma, leukemia and other malignancies in children. With improved survival rates, therapy related sequaela like osteonecrosis (avascular necrosis of bone, AVN) have become a matter of increasing concern. From 1982 to 1992 121 patients were treated for acute lymphocytic leukemia, acute myelocytic leukemia, Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma and Langerhanscell-histiocytosis. All patients were treated with multiagent regimes that included low-dose steroid therapy. 23 patients died, but 64 patients could be evaluated 4 to 14 years after chemotherapy. If the patient complained of bone or joint pain or other clinical findings were suspicious for bony lesions, radiological evaluation was made to get prove of AVN. Six out of 64 patients developed AVN at 17 different sites. Four patients had multifocal AVN. The interval between induction chemotherapy and onset of symptoms was at average 12 months. The average cumulative steroid dosage was 4.25 g. AVN did not relate to sex, diagnosis or a single agent, but did relate to age. There were no cases of AVN in patients younger than 10 years of age. Four patients required surgical intervention. AVN after polychemotherapy was only seen in patients over the age of 10 years. AVN developed at an average of 12 months after induction chemotherapy during the maintenance dose phase. Therefore careful clinical monitoring of patients receiving polychemotherapy is indicated and if indicated radiological evaluation for early detection of AVN to prevent further morbidity is necessary.

Adolescent↗
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Prevention of CNS recurrence in childhood ALL: results with reduced radiotherapy combined with CNS-directed chemotherapy in four consecutive ALL-BFM trials.

BACKGROUND: The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute lymphoblastic leukemia (ALL). Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in ALL. The Berlin-Frankfurt-Münster (BFM) Study Group initiated several attempts in certain ALL subgroups to omit or reduce CRT while using more CNS-directed chemotherapy but without extended intrathecal treatment during maintenance therapy. This analysis summarizes the essential results that are in particular relevant because irradiation of the central nervous system (CNS) has been further reduced in the most recent trial ALL-BFM 95. PATIENTS AND METHODS: More than 4000 patients enrolled between 1981 and 1995 in one of the last four ALL-BFM trials have been analyzed to demonstrate the efficiency of intensive systemic and intrathecal chemotherapy with or without reduced CRT in the prevention of CNS relapses. RESULTS: In trial ALL-BFM81, it was shown that only in low-risk (LR) patients preventive radiotherapy can be replaced safely by intermediate dose (0.5 g/m2) methotrexate (MHD-MTX). In intermediate risk (IR) patients this attempt failed: IR pts had 8 times more CNS relapses if treated by MHD-MTX without CRT. In the subsequent trial ALL-BFM 83, all pts received MHD-MTX. IR pts were randomly treated with 12 or 18 Gy of preventive CRT which did not result in a significantly different outcome. The results from the subsequent trial ALL-BFM 86, using a more intensive consolidation with high-dose methotrexate (HD-MTX), demonstrated that the elimination of CRT in low-risk ALL, the reduced CRT of 12 Gy for IR, 18 Gy for medium (MR), and the reduced CRT with 18 Gy for high risk (HR) ALL, respectively, was justified: the incidence of relapses with CNS involvement was reduced to less than 5% (Reiter et al. 1994, Blood 84: 3122). When even less intensive preventive CRT (12 Gy for all medium and high risk patients) was used in trial ALL-BFM 90, the rate of CNS-related relapses was again below 5%. HR patients now treated with more CNS-directed chemotherapy had the lowest rate of CNS-related relapses observed so far in the BFM trials, even though CRT was also reduced to 12 Gy. Patients with T-cell ALL were shown to be protected from CNS recurrence by the combination of CRT (12 Gy) and HD-MTX more effectively than by HD-MTX in consolidation and TIT therapy during maintenance, especially if they presented with high WBC as shown in a joint AIEOP/BFM analysis (Conter et al. 1997, JCO 15: 2786). Patients with overt meningeosis which are characterized by a high leukemic cell load at diagnosis had a rate of recurrences that was comparable to that of patients with high WBC but no CNS disease. CONCLUSION: Low-risk ALL patients can be efficiently prevented from CNS relapse by intensive systemic and intrathecal chemotherapy without CRT. Patients with intermediate or medium risk ALL, including T-cell ALL, did not suffer from more CNS or systemic relapses when CRT was reduced to only 12 Gy. Patients with inadequate response to therapy are at particularly high risk for relapse with CNS involvement. Therefore, more CNS-directed systemic and intrathecal chemotherapy was applied in trial ALL-BFM 90, combined with only 12 Gy cranial irradiation, and improved the control of CNS recurrence. It seems likely that larger subsets of B-precursor ALL can be protected from CNS-related relapse by intensive chemotherapy without extended IT treatment and without CRT. This is being investigated in the ongoing trial ALL-BFM 95.

Adolescent↗
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Advances in treatment techniques and time/dose schedules in external radiation therapy of brain tumours in childhood.

Recent advances in radiotherapy techniques seek to improve the therapeutic ratio in childhood brain tumours by adding potentially more effective treatment in ways that will increase tumour control and limit radiation toxicity. Stereotactic irradiation techniques in conjunction with rigid head fixation systems comprising single high-dose delivery ("radiosurgery"), fractionated convergence therapy and three dimensional conformal therapy focus the dose to tumour while sparing surrounding normal tissue. Although these techniques are well established in adults data for childhood central nervous system malignancies are scarce. Preliminary data reveal low acute toxicity and promising results in recurrent tumours as well as in primary treatment. Whether stereotactic radiation therapy with either of the latter techniques will add substantially to disease control and preserve neurologic function remains to be established and should be part of future investigations. The introduction of quality control procedures assures precise radiotherapy of the tumour site, whole brain and craniospinal axis and is a prerequisite to improve survival and to reduce potential adverse effects. Hyperfractionated radiotherapy has the potential of increasing dose to tumour more safely theoretically sparing children some of the late effects while in particular in craniospinal irradiation. Pilot studies revealed excellent tumour control in medulloblastoma with acceptable acute toxicity. The strategy is part of the subsequent HIT '98 trial both for low and high risk patients. In conclusion, there is considerable enthusiasm among all those caring for children with brain tumours to study modifications of radiation delivery that may result in improved treatment. Rapid accrual to an increasing number of cooperative prospective trials is expected to provide the body of data supporting the selection of novel radiation therapy modalities in the future.

Adult↗
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Preradiation chemotherapy of children and young adults with malignant brain tumors: results of the German pilot trial HIT'88/'89.

BACKGROUND: Preradiation chemotherapy could be beneficial in malignant brain tumors, because the blood-brain tumor-barrier is disrupted after surgery, bone marrow recovery--essential for intense chemotherapy--is still intact, and CNS toxicity and ototoxicity of active drugs are lower before irradiation of a child's brain. PATIENTS AND METHODS: A neoadjuvant phase 2 and a single arm pilot trial were initiated to investigate the efficacy and toxicity of an intense multidrug regimen before radiotherapy in 147 patients aged between 3 and 29; 9 years with medulloblastoma (94), malignant glioma (22), ependymoma (21), and stPNET (10). They were treated with one or two cycles consisting of procarbazine, ifosfamide/mesna with etoposide, high dose methotrexate/CF, and cisplatin with cytarabine. RESULTS: Radiation therapy was delayed for 17-30 weeks (median 23 weeks) in 112 patients who received two cycles. Chemotherapy was well tolerated. Serious infections were observed in 20 patients, with one fatal fungal septicemia. In 69 high risk patients with a residual tumor and/or solid CNS metastases an objective response (CR plus PR) was achieved in 67% medulloblastoma, 57% stPNET, 55% anaplastic ependymoma and 25% malignant glioma. Progression-free survival (PFS) at 5 years was 57% in 14 high risk patients with medulloblastoma, who achieved a complete response (CR). After a less than CR the PFS was 20% (p = 0.01). Overall survival at 5 years was 57% in medulloblastoma, 62% in ependymoma, 36% in malignant glioma and 30% in stPNET. CONCLUSION: The HIT'88/'89 regimen was well tolerated and efficacious in regard to response rates and early PSF particularly in medulloblastoma and anaplastic ependymoma. Based on these results the prospectively randomized trial HIT'91 was designed to investigate the optimal timing of chemotherapy. Preradiation chemotherapy according to the HIT'88/'89 regimen was compared with the standard regimen using CCNU, cisplatin, and vincristine after radiation therapy. Additionally, strict quality control of the three treatment modalities was instituted to help improve the survival rates in both trial arms.

Adolescent↗
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[HIT-GBM: multicenter study of treatment of children with malignant glioma].

The German society for paediatric oncology and hematology starts a clinical study for the treatment of children with glioblastoma, multifocal astrocytoma grade 3, brain stem grade 3 astrocytoma and typical diffuse ponsglioma. Conventional fractionated radiotherapy (54 Gy) will follow surgery. Simultaneously an additional experimental treatment will be given. The experimental treatment study will change every second year and starts with oral trofosfamide 100 mg/m2/d and VP16 25 mg/m2/d.

Antineoplastic Agents, Alkylating↗
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[Endocrinologic after-care of brain tumor patients: initial retrospective analysis of HIT-study documented auxologic and endocrine parameters].

BACKGROUND: In 1987, a pilot trial (HIT 88/89) was initiated by GPOH to investigate the effectivity and toxicity of intense preradiation chemotherapy. The aim of this study was to improve the treatment of children with malignant brain tumors, but provided no standardized recording of auxological and/or endocrinological parameters. In 1993 a sub-project, "Endocrinological late effects", was started during the ongoing study to examine the late effects of treatment, and a retrospective evaluation was performed in order to standardize parameters. PATIENTS: We considered auxological and hormonal data from those patients (n = 133; 78 m, 55 f) who were alive at the time of the survey, and had completed tumor therapy. RESULTS: Analysis of the growth pattern of the children after the end of therapy indicate impaired growth. Group 1 (n = 77, CA < 10 yrs): Mean height SDS at tumor diagnosis was +0.32 (n = 77), and fell constantly after completion of therapy to -0.75 (n = 16) after 3-4.5 yrs. Group 2 (n = 56, CA > 10 yr): Height SDS-CA fell from +0.24 (n = 45) at the time of diagnosis to -0.62 (n = 14) after 3-4.5 yrs. Unfortunately, only body height and weight were recorded regularly, data on sitting height, pubertal stage and bone age were incomplete. Endocrine evaluation after end of therapy was insufficient. CONCLUSIONS: A standardization of endocrinological follow up is necessary as soon as possible, for an adequate description of the endocrinological late effects.

Adolescent↗
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[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphomas in children and adolescents. Part 2: An intermediate term analysis of the non-B-NHL therapy group. BFM Study group].

The goals of study NHL-BFM 90 for the therapy group Non-B NHL are to prospectively evaluate the dynamic of tumor regression and the persistence of a residual mass after induction therapy for its prognostic impact. Patients (pts) of stages I and II receive induction composed of prednisone, vincristine (VCR), daunorubicin, L-asparaginase (L-ASP), cyclophosphamide (CP), cytarabine (ARA-C), 6-mercaptopurine (6-MP) and intrathecally (i.th.) methotrexate (MTX), followed by consolidation (6-MP,MTX 5 g/m2 x 4, MTX i.th.), and maintenance up to 24 months. Pts of stages III and IV receive additionally reinduction (Dexamethasone, VCR, doxorubicin, L-ASP, CP, ARA-C, 6-thioguanine, MTX i.th.) and cranial irradiation. Pts with < 70% tumor regression at day 33 of induction receive an intensified chemotherapy. Pts with > 70% tumor regression at day 33 but a persistent mass at the end of induction have a surgical resection. Pts with a completely necrotic residual mass continue with consolidation therapy. Pts with active residual lymphoma receive an intensified chemotherapy. No local radiotherapy is given. From 4/1990 to 12/1992, 80 pts were registered; 71 pts are evaluable for response. The distribution of stages is as follows: 6, 1, 47, 17 pts of stage I, II, III, IV, respectively. The probability of event free survival at 3 years is 87 +/- 4% for the whole group (median observation time 21 months). 66 pts are evaluable for the dynamic of response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
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Disseminated malignant ectomesenchymoma (MEM): case report and review of the literature.

Malignant ectomesenchymoma (MEM) is a rare soft tissue tumor believed to arise from a pluripotent migratory neural crest cell and composed fo both a mesenchymal element and a neuroectodermal element. The authors report the case of an 11-month-old male who presented with a local abdominal MEM and systemic metastases into lungs, liver, bones, and bone marrow. This is the first reported case of an MEM with initial bone marrow dissemination. The tumor consisted of a neuroblastoma component and a mesenchymal component with sarcomatous features. Diagnosis and therapy were complicated by the histological heterogeneity of the tumor, which also influenced the clinical appearance and course in this case. A literature search revealed 15 other evaluated cases that arose in soft tissue and had adequate clinicopathologic data. Complete surgical resection was the mainstay of treatment, and chemotherapy also appeared to be important. In all reported patients (n = 3) with initial metastases or bone marrow dissemination, as in this case, no cure could be achieved. In patients with disseminated MEM, new therapeutic approaches such as high-dose chemotherapy followed by stem cell rescue should be considered, similar to the current strategy in patients with stage VI neuroblastoma or soft tissue sarcoma.

3-Iodobenzylguanidine↗
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Acute lymphoblastic leukemia with severe skeletal involvement: a subset of childhood leukemia with a good prognosis.

Skeletal radiographic abnormalities are common in children with acute lymphoblastic leukemia (ALL). The impact of severe skeletal involvement (SI) on survival and the correlation between SI and biological markers were analyzed. Therefore, radiographs and medical charts of 106 ALL patients who received a skeletal survey at the time of diagnosis and were treated at the University Children's Hospital Würzburg between 1974 and 1995 were reviewed. On the basis of the skeletal survey, SI was quantified using a score. Fifty-nine patients (55%) showed radiographic abnormalities defined as metaphyseal banding (48%), periosteal reactions (11%), osteolysis (33%), osteosclerosis (31%), or osteopenia (22%). Children with severe SI (n = 32) presented with a higher rate of severe radiographic abnormalities such as geographic destructive osteolysis (37%; P < .001) and periosteal reactions (28%; P < .05) compared with children with moderate SI (0% and 4%, respectively). Patients with severe SI showed a lower peripheral blast count (P < .05) at diagnosis, a more frequent "prednisone good response" (P < .05), and a higher survival rate (83 +/- 7%; P < .05) than patients without SI (54 +/- 9%). Patients with moderate SI (n = 27) showed a higher hemoglobin concentration (P < .05), an enlargement of liver (P < .05) and spleen (P < .01), a higher BFM risk factor (P < .01), but still a higher survival rate (73 +/- 11%) than patients without SI (NS). Patients with severe SI had a higher (P < .001) DNA content of leukemic cells as measured by DNA index (DI) than patients without SI. Thirty-one percent of patients with severe SI, 22% of patients with moderate SI, and no patient without SI had a DI > 1.16. No patient with a DI < 1.0 presented with severe SI. The number of radiographic abnormalities in patients with SI correlated with the DI (rho: 0.46; P < .001). However, patients with euploidy (DI = I) and severe SI also had a higher (P = .05) survival rate (70 +/- 18%; n = 15) than euploid patients without SI (49 +/- 11%; n = 24). Of the patients with severe SI, 78% had common ALL and 22% had an ALL type other than common ALL (P < .05). In patients with ALL types different from common ALL, severe SI was also associated with higher survival rates. We conclude that on the basis of clinical features, two distinct subgroups could be identified in terms of SI. Patients with clinically relevant severe SI had a better prognosis, a higher DI, and more frequently a common ALL than patients without SI. However, the impact of severe SI on prognosis was independent of DI and type of leukemia.

Adolescent↗
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Dexamethasone increases hepatotoxicity of MTX in children with brain tumors.

BACKGROUND: In the treatment of children with brain tumors, dexamethasone and methotrexate are often utilized simultaneously. As previously shown, dexamethasone can reduce the efficacy of methotrexate in vitro (Anticancer Res. 14: 1585-8). Consequently, DEX has been avoided during high dose methotrexate infusions in a pilot study. METHODS: Side effects of methotrexate with dexamethasone (N = 33) were retrospectively compared with the side effects of methotrexate without dexamethasone (N = 24). RESULTS: No serious brain edema in any of the groups was observed; there was no difference in bone marrow toxicity, or mucositis. Liver enzymes, however, were significantly higher when methotrexate was given with dexamethasone: GOT [glutamate oxalacetate transaminase] 76 +/- 73 versus 19 +/- 12, GPT (glutamate pyrovate transaminase) 140 +/- 199 versus 39 +/- 31 IU/I (P < 0.01). This higher hepatotoxicity was not related to differences in methotrexate serum-levels. CONCLUSIONS: Dexamethasone can be eliminated from high dose methotrexate protocols for children.

Adolescent↗