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Das papillare Nierenzellkarzinom beim Kind ist eine seltene Erkrankung und sollte als eigenstandige Entitat betrachtet werden, da sie sich hinsichtlich Symptomatik, Verlauf und Prognose vom Erwachsenentyp unterscheidet. Es wird die klinische und diagnostische Problematik bei Diagnosestellung, Prognose und Therapie dieser im jugendlichen Alter sehr seltenen Erkrankung anhand der Literatur diskutiert.

In hospitals, nursing homes and home-care facilities the emergence and dissemination of antibiotic-resistant bacteria is causing increasing problems in wound care. Methicillinresistant Staphylococcus aureus (MRSA) is one of the most prevalent and recalcitrant pathogens compromising wound healing. Aside from the microenvironmental problem, it is having a big impact on health-care costs.

The purpose of this study was to examine the outcome of attempted radical surgical resection in patients with stage IV neuroblastoma. Between 1989 and 2003, 20 (median age 2.4 years, range 0.5-8.7 years) children with stage IV neuroblastoma were treated at the Department of Pediatrics. Surgery was performed in 7 consecutive children (6 male and 1 female) between July 1997 and February 2002 at the Department of Urology in Bonn. Mean age at diagnosis was 57 months (21-104 months). Mean age at the time of surgery was 54 months (8-390 months). Follow-up was available for all patients (100%) and mean follow-up after the operation was 32.5 months (4-56 months). Primary localization of the tumor was retroperitoneal in all cases; 4 out of 7 patients (57%) also had additional adrenal, 3 out of 7 (42%) paraganglion and 1 out of 7 (14%) thoracic primaries. Bone marrow and lymph node metastases were found in all patients (100%). Surgery led to complete tumor resection in 6 out of 7 patients (85%). Surgical approach was abdominal (chevron incision) in 6 out of 7 (85%) of the patients, in one patient the approach was thoraco-abdominal. After induction chemotherapy and delayed surgery, 6 out of 7 (86%) patients showed a complete remission (CR) and the mean CR lasted for about 27.7 months (range 3.1-55.4 months). At the last time of follow-up 5 out of 7 (71%) patients were alive, 2 had died due to recurrent disease. Mean time to recurrent disease was 24 and 51 months, respectively. Mean overall survival time since diagnosis was 38.3 months (11-64 months) and mean event-free survival was 34.5 months (11-60.3 months). The final outcome, overall survival and event-free survival time was influenced by metastatic or local relapse. Tumor resection is beneficial but the value of surgery can only be judged when we are able to control metastatic disease in stage IV neuroblastoma. The final outcome may rely on the extent of complete surgical resection, but is also related to treatment of metastases. A longer follow-up period is indicated to detect long term outcome.

Background Tumor-free survival from hepatoblastoma could be improved to 75 % of all patients by combining surgery with chemotherapy. This figure reaches 90 % for potentially resectable (SR, standard risk) tumors. The outcome of high risk (HR) hepatoblastomas with multifocally disseminating growth in the liver, invasion of large vessels, extrahepatic extension and metastases is still poor, especially since these tumors often rapidly develop resistance against cytotoxic drugs. In the Study HB 99 of the German Society for Pediatric Oncology and Hematology, it is attempted to reach an improved regression and thereby a better prognosis with inauguration of high dose (HD) chemotherapy. This first interim analysis shall evaluate the preliminary results of this strategy. Patients and methods 53 children with a hepatoblastoma have entered the study. 8 patients were excluded from this analysis because of different or not completed therapy. 10 SR-patients with a small tumor underwent a primary complete (stage I, n = 8) or microscopically incomplete (stage II, n = 2) resection. These received two courses of ifosfamide (3 g/m2), cisplatin (100 mg/m2), and doxorubicin (adriamycin, 60 mg/m2) (IPA). 26 patients with an extended, but potentially resectable tumor (stage III SR) were preoperatively treated with three courses of IPA, followed by a tumor resection and a 4th course of IPA. 9 patients with a HR-hepatoblastoma (3 x stage III HR, 6 x stage IV) were treated with two courses of carboplatin (800 mg/m2) and etoposide (400 mg/m2) (CARBO/VP16). In case of tumor response, they received one or two courses of HD-chemotherapy with carboplatin (2000 mg/m2) and etoposide (2000 mg/m2) after sampling of peripheral stem cells, followed by resection of the primary tumor and metastases, whenever possible. IPA therapy was administered in case of inadequate response to these drugs. The preliminary therapy results were analyzed in relation to the post-surgical stages (I-IV) and to the SIOPEL-PRETEXT (Pretreatment extend of disease) -grouping system (groups I-IV, V, P, E, M). Furthermore, the response of HR-hepatoblastoma to CARBO/VP16, the achieved resectability, and the acute toxicity were evaluated. Results 40 of 45 (89%) of all hepatoblastoma patients are in remission. 34/36 (94%) SR-patients (stage I - III-SR) are tumor-free, two died of therapy complications. 6 HR-patients are tumor-free, one alive with tumor and two died. In relation to the PRETEXT-grouping, a remission was achieved in 4/4 group I, 14/16 group II, 16/16 group III, 5/6 groups I-III, V, P, E, M, and 1/3 group IV tumors. 6/9 HR-hepatoblastomas were good responders to CARBO/VP16, 5 of these are in remission. 3/9 tumors did not respond, only one could be eradicated by a liver transplantation. In 5/9 HR-patients a R0-resection was possible after chemotherapy, in one a R1-resection, one received a liver transplant, and two tumors remained inoperable. In 4/6 cases lung metastases could be completely removed or, in one case, they had vanished in the CT-scan under chemotherapy. These 4 patients remained in remission. The most frequent severe toxicity of CARBO/VP16 concerned leucopenia (23% of courses) and thrombocytopenia (85% of courses). Under HD therapy severe infections (2/7, 28%) and elevation of transaminases occurred. There was no toxic death. Conclusions A cure rate of over 90% can be reached by conventional cisplatin and doxorubicin containing chemotherapy and radical surgery in SR-hepatoblastoma. 50-60% of all hepatoblastomas respond to CARBO/VP16. In these cases HD-therapy with these drugs is highly efficient and enables a remission in the majority of advanced and metastasised HR-hepatoblastoma. A larger number of patients and longer follow-up have to confirm these results. Therefore, the study will be continued.

T-cell progenitors migrate from bone marrow (BM) into the thymus. After maturation they are released as recent thymic emigrants (RTE) into the periphery ensuring the diversification of the T-cell repertoire. Both the kinetics with which RTE migrate through the periphery and the surface molecules they express are still unclear. In 1- and 18-month-old Lewis rats CD4+ RTE were identified in blood, spleen, lymph node, and thoracic duct lymph by flow cytometry (CD45RC− and CD90+), were differentiated from CD4+ naive (CD45RC+) and memory T cells (CD45RC−CD90−), and were characterized regarding the expression of surface molecules. Both in 1- and 18-month-old animals the percentage of RTE among the CD4+ population in blood was comparable to that in all other compartments. Surprisingly, RTE expressed α4-integrin, LFA-1, and interleukin (IL)-2 receptor at a significantly higher level than naive T cells and more comparable to memory T cells. Within lymphoid tissues RTE, naive, and memory T cells significantly upregulated the expression of CD44 and ICAM-1, and downregulated the expression of l-selectin. These changes were reversed before the cells re-entered the blood. Thus, our data indicate that CD4+ RTE travel through the periphery of young and old rats like mature T cells, continuously modulating their surface molecule expression.

Although the liver is known to contain a significant number of lymphocytes, migration of these through the compartments of the liver, parenchyma and periportal field, has not been studied. The periportal field, in particular, is affected in several immunological disorders of the liver. Populations of labeled naive, activated, and memory T cells were injected into congenic rats. The recipient livers and draining lymph nodes were removed at various time points, and cryostat sections were analyzed for the presence of donor cells using quantitative immunohistology. Donor cell proliferation and apoptosis were examined in vivo by BrdU (5 μM 5-bromo-2-deoxyuridine) incorporation and the TUNEL technique, respectively. Early after injection (0.5–1 h), naive, activated, and memory T cells were localized to the parenchyma and periportal field in comparable numbers. With time, all T cell subsets left the parenchyma but remained or, in the case of activated T cells, significantly accumulated in the periportal field. Furthermore, 12% of activated donor T cells proliferated in vivo within the periportal field, and 0.5% showed evidence of apoptosis. Taken together, not only activated and memory, but also naive T cells continuously migrate through the liver, showing a preference for the periportal field, and activated T cells mainly proliferate there. This may explain why many immunological liver diseases predominantly affect the periportal field.

PURPOSE Prenatal plasma concentrations of erythropoietin in fetuses with Rh disease should contribute information to the clinical course and therapeutic control of this disease. METHOD Fetal plasma erythropoietin (Epo) and haemoglobin (Hb) concentrations were measured in 145 umbilical venous blood samples of 30 fetuses with Rh disease at 20 to 38 weeks' gestation. RESULTS Both Epo and Hb concentrations were independent of the gestational age in red blood cell-isoimmunised pregnancies. The Hb concentration correlated significantly with Epo concentration without intrauterine transfusion (IUT) (r = -0.519, p = 0.005) and after IUT (i = -0.212, p = 0.01). A haemoglobin deficit of 3 g/dl at 20 weeks' gestation increased to 6 g/dl at 38 weeks' gestation in spite of IUT (p = -0.354, p < 0.001). CONCLUSION Even with IUT, Epo concentrations increase with gestational age during these pregnancies. This is due to increasing Hb deficits indicating fetal hypoxia which might be prevented by increasing volumes of transfusion.

More than half of the children and adolescents with malignant brain tumors will relapse following initial therapy. Irrespective of the therapeutic modalities the prognosis of patients with recurrent or metastatic brain tumors is still poor. New strategies such as high dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ABSCT) offer the possibility to improve the longterm prognosis of these patients. Following conventional chemotherapy with carboplatin/etoposide and after achieving complete or partial remission (CR or PR) 10 patients aged from 3.2 to 25.5 years (median, 10.3 years) with refractory or recurrent malignant brain tumors (anaplastic astrocytoma/glioblastoma, n = 2; medulloblastoma/PNET, n = 6; ependymoma, n = 1; plexus carcinoma, n = 1) received in a pilot study one course of HDCT with ABSCT. The consolidation regimen consisted of thiotepa (400-600mg/m2/d, i.v. 6 h, d-9), carboplatin and etoposide (500mg/m2/d, CVI 24h, d-8 to d-5, respectively) and was followed by the retransfusion of autologous blood stem cells on day 0. Before starting HDCT 6 patients showed CR and 4 patients had PR or stable disease (SD). Following the HDCT 3 of the 4 patients with residual tumor had CR or PR. 6 patients have remained in continuous CR or SD 8 to 41 months (median 17.2 months) after the HDCT. 2 patients relapsed 8.5 and 9.5 months after HDCT and died from progressive disease. Two patients died therapy-related from systemic aspergillosis and were not evaluable for response. Hematological recovery with an absolute neutrophile count of > 0.5 x 10(9)/l and a platelet count of > 30 x 10(9)/l was reached on days +11 (median; range, +9 to +14) and +16 (median; range, +6 to +47), respectively. The main nonhematological toxic effects were infections, severe mucositis, and hyperbilirubinemia. Although the long-term efficacy of HDCT with ABSCT is still not evaluable and the toxicity of this regimen is high, a multicenter phase II trial seems to be justified in view of the poor prognosis of recurrent or refractory brain tumors in children and adolescents.

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-Munster (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.

β-Laktam-Antibiotikum allein oder in Kombination mit einem Glykopeptidantibiotikum oder einem Aminoglycosidantibiotikum konnte bei erwachsenen Patienten eine hohe Wirksamkeit in der Behandlung der febrilen Neutropenie belegt werden [8, 10, 18]. Umfangreiche klinische Studien zur Wirksamkeit gleichartiger Therapieschemata in der padiatrischen Onkologie sind selten. In einer Multizenterstudie wurde gepruft, ob eine Kombinationstherapie mit Ceftazidim und Teicoplanin als Initialtherapie einer antibiotischen Sequentialtherapie bei Kindern und Jugendlichen mit febriler Neutropenie effektiv ist.

The Cooperative German Paediatric Liver Tumour Study HB89 was conceived to evaluate the efficiency and toxicity of ifosfamide, cisplatin and doxorubicin (IPA) in children with resectable and non-resectable hepatoblastoma (HB) and to determine late sequelae including tubular nephropathy of tumour treatment. The study also assessed the results of a surgical strategy, which adapts the procedure at the initial operation to the tumour's extension in the liver. The relationship of the tumours' histological differentiation to response to chemotherapy was also examined. Patients with a HB restricted to one liver lobe underwent primary resection. Larger tumours were initially treated with IPA chemotherapy and resected at second-look surgery. All patients received IPA adjuvantly after tumour resection. The IPA regimen consisted of ifosfamide 3.5 g/m2 (over 72 h days 1-3), cisplatin 100 mg/m2 (over 5 days 4-8) and doxorubicin 60 mg/m2 (over 48 h, days 9-10). Median follow-up of survivors was 64 months (range 28-82). Long-term disease-free survival (DFS) was for stage I: 21/21; stage II: 3/6; stage III: 28/38; and stage IV: 2/7 (overall 75%). Severe surgical complications occurred in 15% (4/27) of primary and 21% (8/38) of secondary resections with no lethality. 44/45 stage III/IV HB displayed PR after two IPA courses. Drug resistance developed in 8/12 tumours after four or five chemotherapy courses. Acute toxicity was observed in 34/242 (14%) IPA courses. Late sequelae were found in 7/54 (13%) of survivors, and subclinical renal tubulopathy occurred in 7/41 investigated patients (17%). Despite a more favourable prognosis in pure fetal and predominantly fetal histology, statistical analysis revealed no relationship between tumour differentiation and response to chemotherapy. In conclusion, IPA chemotherapy in combination with delayed surgery was highly effective in the treatment of HB.

94 children with a primary liver neoplasm were registered in the Cooperative Pediatric Liver Tumor Study HB-89 of the GPOH from 1988 to 1992. 64 of these had a hepatoblastoma (HB), 12 a hepatocellular carcinoma (HCC), 2 a sarcoma and 16 a benign tumor. 51 (80%) patients with an HB were 6 to 36 months of age, 9 with an HCC above 10 years. Initial serum-alpha-fetoprotein (AFP) was elevated in 51 HB patients and exceeded the 3-fold of normal range in 45. Children with low ( 1,000,000 ng/ml) levels had a significantly worse prognosis than those with intermediate values (p = 0.0014). AFP was moderately elevated in 9 HCC patients. All other tumor markers were only irregularly above normal range. 48 (77%) of HB patients survived, 45 (73%) are tumor free. All of 18 stage I and 4/5 stage II patients are in remission. After chemotherapy 30/36 stage III HBs and 2/5 stage IV HBs could be resected, 9 of these patients suffered from tumor relapse. Disease-free survival was 100% for stage I, 80% for stage II, 68% for stage III and zero for stage IV HB (p = 0.0005). Surgical complications occurred after 8% of biopsies, 13% of limited primary resections and 25% of extended secondary resections. There was no perioperative death. The completeness of tumor resection at primary or delayed surgery correlated significantly with patients disease-free survival (p < 0.0001). Chemotherapy with ifosfamide, cisplatin and adriamycin was effective in HB. 203 courses were given in 61 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

During or immediately following L-asparaginase (L-asp) therapy especially intracranial thromboembolic or hemorrhagic complications due to hemostatic imbalance have been observed. We report about 6 children who had intracranial thrombosis or hemorrhage after 3 to 8 doses of L-asp. Initial symptoms of the cerebral events were similar--seizure, coma, hemiparesis and disorientation. All patients were examined by cerebral computerized tomography (CT) or/and magnetic resonance imaging (MRI). Three patients had a dural sinus thrombosis, one had an intracranial hemorrhage and two a hemorrhagic infarction with typical findings in the cerebral CT or MRI. Two other patients were interpreted as having peripheral thrombosis. They showed nontypical hypodense cortical and subcortical areas without any contrast medium enhancement in CT and hyperintense areas in T2-weighted MRI scan. All patients recovered from neurological symptoms, and showed obvious regression of CT and MRI findings which correlate with the good prognosis of these complications. Both CT and MRI are useful in diagnosis and follow-up of cerebrovascular complications of L-asp therapy. The CT and MRI findings of the reported cases seem to reflect different appearances of the same entity, i.e. thrombosis of venous vessels of different size with or without congestive edema and hemorrhagic complication.

Sensitive parameters of inflammations, are rare or of limited validity in neutropenic patients. Procalcitonin (PCT) proven to be a sensitive inflammatory marker in nonneutropenic patients was evaluated for its diagnostic relevance in febrile episodes of neutropenic patients with cancerPlasma levels of PCT were determined by an immunoluminometric assay in children with febrile neutropenic episodes (n=376) starting at the date of admission until the resolution of fever and were correlated with serum levels of the C-reactive protein (CrP). Febrile episodes were classified as fever of unknown origin (FUO), microbiologically or clinically documented infections and were also differentiated according to the site of the infection (unknown, bacteremia, respiratory, soft tissue, gastrointestinal and urinary tract infection).Independently from the aetiology and the site of infection the PCT peak value occurred mostly on the second hospital day and decreased rapidly in cases of successful antibiotic therapy and with the resolution of fever to the normal range (0.1+/-0.5 microg/l). The highest PCT peak levels at the onset of fever and during the febrile course were observed in patients with gramnegative bacteremia (n = 22, median 12.1 microg/l, range 0.4+/-568.2 microg/l). There was a positive correlation between PCT peak levels and CrP peak levels (r = 0.48, p = 0.001) which mostly were observed 24 h later than for PCT.PCT is a sensitive and specific parameter in the diagnostic and in the sequential assessment of febrile neutropenic episodes, especially in gramnegative infections. Its diagnostic accuracy in neutropenic patients is clearly higher than that of CrP.

We report a 3 year-old boy in Tanzania with an abdominal mass and isosexual precocity due to an hCG-secreting hepatoblastoma. Due to the limited availability of local diagnostic testing, surgery and chemotherapy were completed before immunohistochemical and endocrine results were available.

Though liposomal amphotericin B has been available in Germany since 1992, efficacy and safety of this formulation of amphotericin B are still not well-documented in children. As far as gastrointestinal side-effects are concerned, an elevated alkaline phosphatase and elevated transaminases have been reported. In our department, liposomal amphotericin B had been used since 1994 to treat patients with proven or suspected fungal infections in a daily dose of 1-3 mg kg-1. Additionally, patients with high-dose chemotherapy and autologous stem cell support received liposomal amphotericin B prophylactically in a dose of 1 mg kg(-1) three times per week. We performed a retrospective analysis of all 31 patients who had received liposomal amphotericin B by 1999. In five patients, an isolated transient elevation of the serum lipase level during, or shortly after, the therapy with liposomal amphotericin B was detected. Three of these patients showed clinical signs of pancreatitis, with one patient displaying slightly elevated transaminases. So far, elevated levels of serum lipase have not been described as a possible side-effect of a liposomal amphotericin B therapy. The pathogenesis of this elevation is unclear. As possible reasons, an enzyme induction due to fat overload or a toxic damage of the pancreatic tissue by the liposomes or amphotericin B itself are discussed.

T cells play an important role in protective immune responses and in the pathogenesis of many diseases. Understanding the mechanisms regulating their distribution in vivo may therefore be of therapeutic value. Reviewing studies that have followed the migration of labelled naive, effector and memory T cells in healthy animals reveals that all T-cell subsets enter all organs investigated. Within the tissue, two principally different migration patterns can be identified. First, naive and memory T cells accumulate in lymphoid organs for about 48 h after injection, as the time needed for migration through lymphoid organs is longer than through non-lymphoid organs. During this time, surface molecule expression is temporarily modified. These changes are reversed before leaving the lymphoid organs and entering the blood to start a new cycle of migration. Second, effector T cells are evenly distributed throughout the body, and most die in the tissues within 24 h. However, depending on the presence of cytokines, some are able to survive and to proliferate, and thereby accumulate in defined microenvironments of the body. Analysing the principles regulating T-cell migration and survival within the tissue may lead to the development of new options for the treatment of disease.

Effector T cells generated in mesenteric lymph nodes (mLN) preferentially accumulate in mLN and sites drained by them, such as Peyer's patches and the lamina propria of the gut, after circulation in the blood. The molecular mechanisms mediating this re-distribution are poorly understood. To study this, rat T cells from mLN were activated via the T cell receptor and CD28, and injected either intravenously into congenic recipients, or maintained in culture in the presence of various cytokines. Three days later effector T cells were identified in vivo and in vitro, and surface molecule expression and proliferation rate was determined. The data show that in vivo effector mLN T cells express significantly higher levels of activation markers and maintain a higher proliferation rate after entering the mLN environment (tissue of origin) than after entering the peripheral LN environment (unrelated site). The proliferation is mediated by TGFbeta-1 and IL-4 present in mLN. The requirement for these cytokines is imprinted on effector mLN T cells during the initial activation. Thus, the preferential proliferation of effector mLN T cells in milieus providing the cytokine mixture experienced during activation ensures a privileged accumulation at sites where they are most needed. This can be used to manipulate the effector phase of an immune response.

T-cell progenitors migrate from bone marrow (BM) into the thymus. After maturation they are released as recent thymic emigrants (RTE) into the periphery ensuring the diversification of the T-cell repertoire. Both the kinetics with which RTE migrate through the periphery and the surface molecules they express are still unclear. In 1- and 18-month-old Lewis rats CD4+ RTE were identified in blood, spleen, lymph node, and thoracic duct lymph by flow cytometry (CD45RC- and CD90+), were differentiated from CD4+ naive (CD45RC+) and memory T cells (CD45RC-CD90-), and were characterized regarding the expression of surface molecules. Both in 1- and 18-month-old animals the percentage of RTE among the CD4+ population in blood was comparable to that in all other compartments. Surprisingly, RTE expressed alpha4-integrin, LFA-1, and interleukin (IL)-2 receptor at a significantly higher level than naive T cells and more comparable to memory T cells. Within lymphoid tissues RTE, naive, and memory T cells significantly upregulated the expression of CD44 and ICAM-1, and downregulated the expression of L-selectin. These changes were reversed before the cells re-entered the blood. Thus, our data indicate that CD4+ RTE travel through the periphery of young and old rats like mature T cells, continuously modulating their surface molecule expression.

A group of 28 consecutive patients (mean age 59 years) with primary central nervous system lymphoma (PCNSL) was treated with different regimens, including steroids only, radiotherapy (RT), chemotherapy or combinations of all. Lymphoma was classified as high grade malignant B-cell non-Hodgkin's lymphoma of the diffuse large cell type in each of these cases. RT alone led to tumour remission in more than 70 per cent, survival could be prolonged with additional chemotherapy. Thirteen patients were treated with chemotherapy alone; nine of them received a novel combined intraventricular and systemic polychemotherapy protocol based on high dose methotrexate (MTX) and high dose cytarabine (ara-C). The response rate was 90 per cent with 80 per cent complete responses. Neurotoxicity, i.e. white matter lesions associated with severe cognitive dysfunction affected both patients surviving RT more than a year and patients treated with combination RT/chemotherapy. Confluent white matter hyperintense lesions were detectable on MRI in three out of 13 patients treated with chemotherapy alone, however, cognitive dysfunction has not been detected in these patients.

Background Hepatoblastoma (HB) is the most common liver tumor of childhood, and comprises approximately 1% of all pediatric malignancies. Although recent data from multicenter trials of GPOH, SIOP, CCG and POG indicate a remarkable improvement of therapy results, the prognosis of advanced or recurrent HB is still not satisfying. Patients and methods During 1989 and 1997, the German Cooperative Pediatric Liver Tumor Studies HB 89 and HB 94 registered 141 patients with HB, who were treated according to the study protocols. These patients received standard chemotherapy with ifosfamide, cisplatin and doxorubicin (IPA) pre-operatively and/or post-operatively. Fourteen children with recurrent or advanced HB were additionally treated with carboplatin and etoposide (CARBO/VP 16), the reason being observations of drug resistance in children with HB after four or more courses of IPA-therapy in the HB 89 study. The clinical data and course of these patients were evaluated to investigate the efficiency of CARBO/VP 16 chemotherapy and for analyzing the role of surgery. Results Mean follow-up for survivors was 4.3 years (range 13 months-8 years). Tumor resection was attempted in 13 children but, in only 3 cases, was a complete tumor resection achieved in one operation. There was no perioperative death, and 7 of the patients (50%) are in remission. Two patients underwent adjuvant chemotherapy with CARBO/VP 16 for advanced HB at first operation: all are alive and well. Five patients with local relapse and/or distant metastases responded partially to CARBO/VP 16 therapy, and a complete remission was achieved in one patient. In five patients, progressive disease was observed during therapy with CARBO/VP 16. One patient, stable while on chemotherapy, had a successful resection. Acute toxicity of chemotherapy was observed in 7 patients (50%). Conclusion An aggressive approach using IPA and CARBO/VP 16 chemotherapy and highly developed surgical techniques may improve the prognosis of advanced or recurrent HBs.

Fetuses with homozygous alpha-thalassaemia develop Hb Bart's hydrops fetalis syndrome, which usually leads either to abortion or fetal/neonatal death. We report diagnosis, intrauterine transfusion therapy, neonatal intensive care management and long-term follow-up of a Vietnamese infant who survived Hb Bart's hydrops fetalis syndrome. During the first 2 years the child had normal development. In addition, the patient exhibited penoscrotal hypospadias. Despite a thorough endocrinological work-up the aetiology of genital ambiguity could not be elucidated. A review of the literature showed an association of homozygous alpha-thalassaemia and hypospadias in all surviving male children, suggesting a common aetiology for both entities.On the basis of our findings, we speculate that an unknown gene on chromosome 16 responsible for genital formation is altered in homozygous alpha-thalassaemia.

The Cooperative German Paediatric Liver Tumour Study HB89 was conceived to evaluate the efficiency and toxicity of ifosfamide, cisplatin and doxorubicin (IPA) in children with resectable and non-resectable hepatoblastoma (HB) and to determine late sequelae including tubular nephropathy of tumour treatment. The study also assessed the results of a surgical strategy, which adapts the procedure at the initial operation to the tumour's extension in the liver. The relationship of the tumours' histological differentiation to response to chemotherapy was also examined. Patients with a HB restricted to one liver lobe underwent primary resection. Larger tumours were initially treated with IPA chemotherapy and resected at second-look surgery. All patients received IPA adjuvantly after tumour resection. The IPA regimen consisted of ifosfamide 3.5 g/m2 (over 72 h days 1-3), cisplatin 100 mg/m2 (over 5 days 4-8) and doxorubicin 60 mg/m2 (over 48 h, days 9-10). Median follow-up of survivors was 64 months (range 28-82). Long-term disease-free survival (DFS) was for stage I: 21/21; stage II: 3/6; stage III: 28/38; and stage IV: 2/7 (overall 75%). Severe surgical complications occurred in 15% (4/27) of primary and 21% (8/38) of secondary resections with no lethality. 44/45 stage III/IV HB displayed PR after two IPA courses. Drug resistance developed in 8/12 tumours after four or five chemotherapy courses. Acute toxicity was observed in 34/242 (14%) IPA courses. Late sequelae were found in 7/54 (13%) of survivors, and subclinical renal tubulopathy occurred in 7/41 investigated patients (17%). Despite a more favourable prognosis in pure fetal and predominantly fetal histology, statistical analysis revealed no relationship between tumour differentiation and response to chemotherapy. In conclusion, IPA chemotherapy in combination with delayed surgery was highly effective in the treatment of HB.

The effect of cranial irradiation on possible therapy-induced morphological central nervous system (CNS) side effects of children cured from acute lymphoblastic leukemia (ALL) is controversially discussed. In a retrospective multicenter study, 118 former ALL patients in first continuous remission were investigated using cranial computerised tomography (CCT) or magnetic resonance imaging (MRI) scans to evaluate CNS related impairments. Corresponding to the different kinds of CNS prophylaxis, the patient sample was divided: group A (n = 39) receiving intrathecal methotrexate (ITMTX) and systemical medium-high-dose methotrexate (SMHDMTX), group B (n = 41) cranial irradiated (in mean 16.8 Gy) and administering ITMTX and SMHDMTX, group C (n = 38) irradiated (in mean 17.1 Gy) and getting ITMTX. Pathologic scans showed atrophy, leukoencephalopathy, calcifications or grey matter changes. These findings were compared with the neuropsychological test results. Abnormal MRI or CCI scans were found in 61/118 patients (51.7%). Fifteen belonged to group A (38.5%), 23 to B (56.1%) and 23 to C (60.5%). Patients with definite CNS changes show reduced neuropsychological test results. The prevalence of brain alterations seems to appear twice increased after lengthening the posttherapeutic interval in irradiated patients as in nonirradiated patients. Irradiated patients as an age younger than 2 years at diagnosis may show a lower prevalence for developing CNS alterations. CNS alterations are not sex-related. Children treated with cranial irradiation in combination with SMHDMTX and/or ITMTX were at greater risk of developing morphological brain alterations than patients with chemotherapy alone. These alterations are partly correlated with reduced neuropsychological performances and seem to stay with a longer posttherapeutic interval.

We analyzed the long-term clinical course of 71 patients with RNA-positive hepatitis C virus (HCV) infection after liver transplantation. Patients with reinfection after transplantation for HCV-related liver disease, or de novo infection at transplantation were followed for up to 12 years. Cumulative survival for patients with HCV infection at 2, 5, and 10 years after transplantation was 67%, 62%, and 62%, respectively. It was not significantly different from that in patients transplanted for other nonmalignant diseases without HCV infection. The main factor determining long-term survival was the presence or absence of hepatocellular carcinoma (HCC) at transplantation. The 5-year survival rate for HCV patients with or without HCC was 35% versus 73%, respectively (P.05). No deaths because of viral hepatitis of the graft were observed. Deaths in the first year after transplantation were caused by infectious complications, cardiovascular problems, or rejection; deaths after more than 12 months were exclusively because of recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients, only 16% had normal alanine aminotransferase (ALT) values throughout. Twenty-two percent of patients complained of symptoms, with hepatitis C being the cause in 82% of these. Two patients lost their HCV-RNA for prolonged, ongoing periods of time. The severity of the posttransplantation hepatitis was unrelated to age, sex, severity of liver disease before transplantation, cold ischemic time of the graft, duration of the operation, transfusions, the number of rejection episodes, or the long-term immunosuppressive regime. Only initial short-term therapy with interleukin 2 (IL2) receptor antibodies adversely influenced inflammatory activity. Viral genotype did not influence the course of the graft hepatitis in our series. Histology showed inflammation in 88% of the biopsies and signs of fibrosis in 24%. Mean ALT values correlated with inflammation but not with fibrosis in the biopsies. Porto-portal bridging was observed in six patients, one patient developed cirrhosis within 2 years after orthotopic liver transplantation (OLT). We conclude that chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. Carrier states without significant laboratory abnormalities are observed in approximately 16%, biochemical abnormalities without symptoms are seen in 60%, and symptomatic disease develops in a quarter of the patients. The disease course closely resembles that seen in nontransplanted hepatitis C patients. It is generally mild but little over 10% of patients develop signs of fibrosis of the graft during the first decade.

Clinical data and tumor histology of 37 patients with advanced and/or metastatic hepatoblastoma (32 stage III and 5 stage IV) treated according to the protocol of the German Cooperative Pediatric Liver Tumor Study HB-89 from 1988 to 1992 were studied for prognostic factors. Twenty-three patients (73%) were free of tumor 9 months to 5 years (median, 36 months) after treatment, whereas 4 experienced progressive disease, 7 had local relapse, and 3 had recurrent metastases. None of 2 patients with primary lymph node involvement or 5 with primary metastases remained disease-free. Chemotherapy with ifosfamide, cisplatin, and adriamycin was effective in reduction of tumor to resectability in 33 (89%) patients. Drug resistance developed in 6 of 11 patients treated with four or more courses of chemotherapy as could be shown by monitoring of serum-alpha-fetoprotein (AFP) and serial investigations of tumor expansion with sonography and computed tomographic (CT) scan. Only 1 of these patients survived after a liver transplantation. Completeness of tumor resection at second- or third-look laparotomy was significantly related to disease-free survival (P.0001). Patients with initial serum-AFP values100 ng/mL or1,000,000 ng/mL had a worse outcome than those with immediate levels (P = .044). The rate of decrease of serum-AFP during chemotherapy was significantly related to prognosis (P = .003). Growth pattern of tumor within the liver (ie, defined nodes versus diffusely disseminated) (P = .011) and vascular tumor invasion (P = .026) were valuable prognostic factors, whereas tumor volume, local infiltration of surrounding tissue, histological subtypes, and epithelial differentiation were not significantly related to the outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunsupprimierte Patientinnen nach Nierentransplantationen erkranken 10–20 x haufiger an Ca. colli und seinen Vorstufen als die Normalbevolkerung (Halpert 1986). Die Grunde hierfur sind unbekannt.

Hirntumoren sind im Kindesalter die groste Diagnosegruppe unter den soliden Tumoren (Haaf et al. 1991). Mit Operation und Bestrahlung konnen nicht viel mehr als 50% der Kinder mit einem Medulloblastom oder Ependymom geheilt werden (Berry et al. 1981; Bloom et al. 1990; Kun et al. 1988; Schulte 1984). Fur Kinder mit einem Astrozytom von hohem Malignitatsgrad, mit einem Glioblastom oder einem Hirnstammtumor liegt nach alleiniger Operation und/oder Strahlentherapie die Langzeituberlebensrate unter 30% (Bloom et al. 1990; Finlay et al. 1987; Jenkin et al. 1987). Die hinsichtlich Uberlebensraten und Uberlebensqualitat (Glauser et al. 1991) noch unbefriedigenden Langzeitergebnisse zwingen uns, neue Therapiemodalitaten einzusetzen. In erster Linie bietet sich in Analogie zur Therapie maligner extrakranieller Tumoren die bei kindlichen Krebserkrankungen erfolgreiche zytostatische Chemotherapie an. Die Chemotherapie wurde zunachst als adjuvante Erhaltungstherapie nach Operation und Bestrahlung eingesetzt (Allen et al. 1986; Kuhl 1990 a). Mit CCNU und Vincristin als Erhaltungstherapie konnte die Prognose von Kindern mit fortgeschrittenem Medulloblastom und malignem Astrozytom deutlich verbessert werden (Evans et al. 1990; Tait et al. 1990; Sposto et al. 1989). Bei Kindern mit Ependymom zeichnet sich eine Tendenz zur Verbesserung ab (Bloom et al. 1990; Kun et al. 1988).

Anthracyclines are among the most useful drugs in the treatment of both lymphoblastic (ALL) and nonlymphoblastic (ANLL) acute leukemias of childhood. However, the benefit of the most commonly used anthracyclines daunorubicin and doxorubicin is limited by their cardiotoxicity [1] and by resistance against these compounds. The daunorubicin analog idarubicin (4-demethoxydaunorubicin) might be less cardiotoxic and has shown greater antileukemic efficacy in some preclinical and clinical trials [2]. In addition, the chemical structure of idarubicin leads to appreciable resorption of active drug after oral application [3, 4], allowing therapy in an outpatient setting. We therefore conducted an open, multicenter trial assessing the toxicity and efficacy of oral idarubicin in refractory acute leukemia in children.

Kidney transplantation today is the method of choice to treat end-stage renal disease (ESRD) in more than 50% of the ESRD-population. Due to major improvements in surgical handling, immunosuppressive therapy, and infection control, the one-year survival for patients and first grafts has reached nearly 90% in the recent years. In contrast no comparable achievements have been made in long-term graft survival. A constant number of grafts is lost yearly after the first postoperative year. In addition an increasing number of well functioning grafts is lost due to the death of the recipients caused mainly by cardiovascular and malignant disorders. The extension of kidney transplantation to all suitable recipients is nearly exclusively hampered by the organ shortage, which is further enhanced by failing grafts. This urges us to further improve the prognosis for patient and graft. This must include organ sharing on the basis of improved HLA-typing to achieve highly compatible grafts. The tools for differential diagnosis of acute and chronic graft dysfunction have to be improved. New immunosuppressive agents with higher immunosuppressive power and specificity but fewer nephrotoxic, metabolic and hemodynamic side effects are required at least for chronic rejection. The risk of infectious and malignant complications must be limited.

Es sind 3 Phasen in der Entwicklung erkennbar: In der Anfangsphase der Transplantationsaera wurden prophylaktische Operationen bei Transplantationskandidaten besonders zur Vermeidung von infektiosen Komplikationen und Stresulzera haufig vorgenommen. Bei zunehmender Erfahrung und insbesondere einer generellen Reduktion der Immunsuppression nahm die Notwendigkeit fur solche Masnahmen ab. Heute, bei Einbeziehung von alteren Patienten und solchen mit vielerlei Vorschaden, steigt die Bedeutung einer prophylaktischen Chirurgie gerade zur Behandlung kardiovaskularer Vorerkrankungen. Auserdem konnen Indikationen zur prophylaktischen Chirurgie aus endokriner, onkologischer oder immunologischer Sicht gegeben sein.

The clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg were studied in five patients exhibiting solitary, localized malignant melanoma. Mitoxantrone was given as four 1-min infusions at 15-min intervals into the arterial line of the perfusion system at a total dose of up to 14 mg/m2. The mean half-lives for mitoxantrone in the blood circulation of the leg were: t1/2 alpha (distribution phase), 25.5 s, and t1/2 beta (elimination phase), 14.9 min. The mean volume of distribution at steady state in the leg was 25.6 1. In the arterial part of the perfusion, the mean AUC was 155.9 mg min l-1, and that in the corresponding venous part was 91.6 mg min l-1. Leakage of the drug from the leg into the systemic circulation amounted to 1.2% of the total delivered dose; 91% of the delivered dose remained in the leg after the perfusion had been completed. The mean elimination half-life of mitoxantrone in the systemic circulation was 123 min and the corresponding AUC for systemic concentrations was 8.59 mg min l-1. The present data revealed a high uptake of mitoxantrone into the leg and low systemic drug concentrations due to minor leakage, suggesting that mitoxantrone might be a good candidate for use in isolated, hyperthermic limb perfusion.

Von 1/75 bis 2/91 wurden 1952 Nierentransplantationen (Tx) bei 1639 Pat. durchgefuhrt. Vor Tx wurden 18 Pat. wegen bekannter Divertikuhtis prophylaktisch operiert, ohne Letalitat oder schwere Komphkationen. Nach Tx erlitten 11 Pat. (0,7%) eine Divertikelperforation. Die Haufigkeit war mit dem Alter ansteigend (> 55 J: 2%). Unter reduzierter Immunsuppression (seit 1987) war das Risiko etwas geringer. 5 Perforationen ereigneten sich in den ersten 2 Wochen, weitere 3 bis zum 3. Monat nach Tx. Trotz schwerer Peritonitis bestand meist nur eine geringe Symptomatik, im Mittel war die Diagnose deshalb um 2 Tage verzogert. 4 Pat. verstarben (36%). Fur Pat. mit Divertikulitisanamnese wird eine prophylakt. Op empfohlen.

During the past 5 years, in the German Berlin-Frankfurt-Mimster (BFM) study group a standard treatment has been established for relapse of childhood acute lymphoblastic leukemia (ALL) [1]. In study ALL-REZ BFM 85 remission rates were improved compared with the preceding study ALL-REZ BFM 83. Furthermore, by use of methotrexate (MTX) given at a dose of 1 g/m2 for 36 h there is good evidence for more effective control of bone marrow leukemia (G. Henze et al., this volume). No clear improvement was found, however, in terms of long-term event-free survival of these children, so far, because of an inappropriate high incidence of second extracompartmental relapses, especially in the CNS. The purpose of this report is to evaluate the impact of secondary CNS relapses on the prognosis of children with first isolated marrow relapse and the interrelationship between the duration of systemic disease control and the risk of subsequent extracompartmental leukemia.