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Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. Therefore the German Group of Pediatric Radiation Oncology (APRO) established the "RegIster for the evaluation of late Side effects after radiation in childhood and adolescence" (RiSK). After a pilot phase starting in 2001 documentation has been performed all over Germany since 2004. This analysis shows the first results of "RiSK".Radiation parameters including detailed organ doses as well as toxicity evaluations were collected prospectively from centers all over Germany in the study center. Standardized documentation forms were used. Documentation is planned for all children who receive radiotherapy in one of the German pediatric therapy trials.Until December 31st 2006, 696 documentations of radiotherapy and 526 acute as well as 836 late follow-up documentation forms have been collected. Altogether, 41 patients with late grade 3 and 16 patients with late grade 4-side effects were identified. Side effects mainly concerned joints with functional impairment (after combined radiotherapy and surgery), the bowel, skin and subcutis as well as blood parameters under continued chemotherapy. Patients with late side effects of a higher grade were mainly treated for Ewing's or soft tissue sarcomas (n=235 patients), representing 33.8% of all patients in this study.Fortunately, up to now only a few late grade 3 or 4 side effects of radiotherapy are shown for almost 700 documented patients. For further results, especially for the characterization of dose-effect-relationships, this study has to be continued with a higher patient number and a longer follow-up.

The variety of endocrine late-effects after brain tumour therapy in childhood is well known. Growth is usually impaired first due to a hypothalamo-pituitary growth hormone (GH) deficiency or a radiation-induced neurosecretory dysfunction of GH secretion. Generally, all hypothalamo-pituitary axes can be affected. Disturbances of puberty, gonadal function, thyroid function and adrenal function can manifest after a long posttherapeutic interval. A retrospective analysis of the auxological and endocrinological data assessed within the German brain tumour study HIT 91 showed that endocrinological follow-up of these patients was not satisfactory. Therefore we have developed a concept for the new brain tumour study: auxological and laboratory parameters will be assessed before oncological therapy and in regular intervals (4, 12, 18, 24 months after the end of tumour therapy). 24 months after the end of tumour therapy all hypothalamo-pituitary axes are to be evaluated with pharmacological stimulation tests.

Bislang ist die Diagnostik von Knochentumoren eine Domäne der Radiologie. In der vorliegenden Arbeit werden sonographische und farbdopplersonographische Befunde bei 5 Patienten mit bioptisch gesichertem Osteosarkom beschrieben. Bei allen Patienten fand sich ein ausgedehnter Weichteiltumor mit echogenen osteosklerotischen Bezirken und echoarmen Kavernen. Charakteristisch waren außerdem deutliche Kortikalisdefekte im Bereich des Tumors. Beim Übergang von gesundem zu befallenem Knochen fanden sich typische Periostabhebungen. Farbdopplersonographisch gelang der Nachweis einer deutlich vermehrten Durchblutung des Tumors im Vergleich zu gesundem Gewebe. Sonographie und Farbdopplersonographie stellen eine wichtige Ergänzung zur konventionellen Radiologie dar. Mit der Sonographie können Struktur, Ausdehnung und Durchblutung von Osteosarkomen dargestellt werden.

Nonresponders (NR) are patients (pts.) with no or insufficient response to initial treatment, which may be caused by either initial risk factors or poor therapy realization. In study AML-BFM 87, 49 NR of 307 patients (16%) did not achieve remission until the end of intensive chemotherapy and were analysed to assess the specific contribution of prognostic factors, therapy realization and complications of therapy. THERAPY AND METHODS: Therapy started with an 8-day induction therapy followed by a 6-week consolidation and two 5-day intensification blocks with high-dose cytosine-arabinoside and VP-16. Maintenance therapy was given for a total duration of 1.5 years. To evaluate the impact of treatment intensity in NR, we compared the dose compliance (DC = dose given/intended dose), the dose intensity (DI = dose per time given), the treatment results, and toxicity of the individual therapy phases in responders (CR) and NR.In 19 of 49 NR therapy was stopped before starting intensification blocks. Twenty-six NR received at least one block of intensification, and seven patients between three and six intensification blocks. Six children entered maintenance therapy. Twelve patients received a bone marrow transplant (9 allogeneic, 3 autologous). Six (5 after bone marrow transplantation) of 49 NR are still alive for 64 to 108 months. In nearly all patients induction therapy could be applied according to protocol (mean DC: 98%, range 85%-100%), whereas therapy realization was more difficult in the 2nd phase of therapy (mean DC: 92%, range 12%-113%). Deviations from the protocol in the treatment blocks (changes of dose and/or schedule) were mainly attributable to persistence of blasts (n = 33) and septic complications (n = 24). The mean relative DI of 1.01 was according to protocol. Bleeding and infectious complications in the individual therapy phases varied from 7% to 61%. NR compared to CR patients suffered significantly more often from bleeding during the first and second part of consolidation and from infections during the second part of consolidation. Withdrawal from protocol in NR was mainly due to persistence of blasts (n = 16), followed by bone marrow transplantation or other therapies (n = 13), and sepsis (n = 11).It is difficult to discriminate between nonresponse associated with blast persistence followed by complications and subsequent discontinuation of therapy and nonresponse due to insufficient therapy in patients with complications. Our analyses revealed that therapy with 2 intensifications according to protocol was feasible in 13 NR. Patients' condition permitting, therapy should not be stopped prematurely, in order to sustain the option of BMT after blast cell reduction.

Study objective was to evaluate retrospectively central nervous system (CNS) morbidity of children with acute lymphoblastic leukemia treated with intensive chemotherapy and cranial radiotherapy for a first isolated or combined CNS relapse. Neurological (Touwen), neuropsychological (CFT 20, Wechsler scales, d2 attention test) and neuromorphological (CT, MRI) assessments were performed in 17 children (9 girls, 8 boys) aged between 7 and 14 years. Patients were off therapy for median 4 years; cranial radiotherapy for CNS relapse (12-24 Gy) was given to all patients 2 to 9 years ago (median 5.5 years). Ten patients had received preventive cranial radiotherapy during front-line treatment, previously. In this group, the cumulative radiation dose ranged between 30 and 39 Gy. Patients received 12 to 30 intrathecal methotrexate doses (median 22). Compared with normative levels for age (100 points) performance IQ (89.9) and full scale IQ (92.0), Culture Fair IQ (88.3) and attention and concentration (90.9) were significantly impaired. Verbal IQ (95.5) was not significantly different from normal expectations. Neurological investigations of 16 patients showed mild signs in 7 (44%) of them, mostly of fine-motor skills and coordination, but no major motor disability. In MRI and CT, white matter changes or ventricular enlargement were noted in 10 of 16 patients (63%). Parent-completed questionnaires indicated problem behaviors in 5 children. Cumulative doses of methotrexate correlated significantly with neuropsychological test results. Children irradiated twice as well as girls had poorer cognitive functions, not being statistically significant. Despite pathological test results, all children attended a normal school and did not exhibit obvious impairment in daily life. In conclusion, CNS relapse and attendant therapy, mostly consisting of a second course of cranial radiotherapy, caused measurable intellectual deficits and CNS morbidity, which did not result in severely impaired performance. Periodic psychological und clinical examinations are recommended for recognition of delayed morbiditiy and early intervention.

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.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.Analysis of the growth pattern of the children after the end of therapy indicate impaired growth. Group 1 (n = 77, CA10 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, CA10 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.A standardization of endocrinological follow up is necessary as soon as possible, for an adequate description of the endocrinological late effects.

An increasing number of children suffering from cancer has been treated successfully during the last 25 years using therapy protocols of the Gesellschaft für Pädiatrische Onkologie und Hämatologie. The patients had to undergo an interdisciplinary treatment modality and a mostly intensive chemotherapy. Late effects could result from this approach for the now 20,000 survivors in the Federal Republik of Germany. The executive committee of the GPOH founded a working group for the detection of late effects stretching over all therapy studies. The first report of this group describes a spectrum of relevant late effects and proposes investigations for their detection.

We report the case of a premature female newborn of the 35th gestational week with a congenital mesoblastic nephroma. The tumor was prenatally diagnosed in the 32nd week of gestation. By close sonographic controls, rapid enlargement was verified towards the end of the 35th week of gestation. This was probably caused by hemorrhage into the tumor. Anemia and postnatal disseminated intravascular coagulation followed. Cesarean section was done, because the anemia was suspected by Doppler sonographic evaluation. Disseminated intravascular coagulation could not be sufficiently controlled by conservative means but only by surgical removal of the tumor. The tumor turned out to be a congenital mesoblastic nephroma by histologic evaluation. Despite postoperative anuria and catecholamine dependency, our patient eventually showed a very favourable outcome. Diagnosis, clinical behavior and therapy of this tumor with a generally good prognosis are described and discussed.

Complete remission (CR) rates of 80% are achieved with the AML-BFM protocols but one third of patients relapse within the first three years. There are few reports of treatment of relapsed childhood AML, and these deal with the evaluation of new drugs for frontline therapy. We performed a retrospective analysis to investigate how patients previously treated with the AML-BFM-83 protocol were treated after relapse and how many long term remissions were achieved. 48 of 139 patients relapsed after having achieved complete remission with the AML-BFM-83 protocol which consists of continous infusion of ARA-C 100 mg/m2 day 1-2, ARA-C 200 mg/m2 day 3-8, Daunorubicin 60 mg/m2 day 3, 4, and 5, and VP-16 150 mg/m2 day 6, 7, and 8, and an 8 week consolidation therapy consisting of Prednisolone, Thioguanine, Vincristine, ADR, ARA-C, Cyclophosphamide, intrathecal ARA-C and cranial irradiation followed by maintenance therapy. Duration of first remission ranged from 1.5 months to 66.3 months. Excluding 5 children with either isolated or combined extramedullary relapses and another 4 patients for missing data, 39 children were evaluable. 20 children received no therapy or palliative therapy while 16 patients received chemotherapy and another 3 children were transplanted in relapse. Although 9 different intensive chemotherapy regimens were used for reinduction, a high number (12 of 16 = 75%) of second complete remissions was achieved. Several therapeutic options were used to maintain a second remission: regular maintenance therapy (7 patients), allogeneous bone marrow transplantation (BMT) (2 patients), autologous BMT (3 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Till now bone tumors are diagnosed radiologically. In this paper we describe the characteristic sonographic and colour Doppler sonographic features in 5 patients with histologically confirmed osteosarcoma. A large soft tissue tumor with echogenic osteosclerotic areas and echo-free caverns could be shown in all patients. Characteristic signs were destructions of the cortical layer and reactions of the periosteum. Compared to normal tissue an increased number of blood vessels with increased blood flow were visible by colour coded Doppler sonography in the region of the tumor. Sonography and colour coded Doppler sonography are important additions of conventional radiology to describe the structure, extension and blood supply of an osteosarcoma.

Pain-management in pediatric-oncological patients is an interdisciplinary task. The working group pain--therapy of GPO tries to work up an analgesic concept for this group of patients. Pre-existing experience in the therapy with sustained release Morphine and Metamizol should be considered. The documentation-system is just worked up, we ask all pediatric oncological groups to cooperate.

Cells belonging to the mononuclear phagocytic system may give rise to a wide variety of proliferative disorders. These neoplastic or reactive diseases of monocytes, histiocytes and macrophages are still poorly understood, both from a biological, clinical and pathological point of view. In 1984 a new type of non-Hodgkin's lymphomas has been described, which recently was termed large cell anaplastic lymphoma (LCAL). Since both "true" malignant histiocytosis (MH) and LCAL display some clinico-pathological similarities, we reevaluated eleven children with the primary diagnosis of MH, who entered the multicentric therapy study DAL-HX 83. On the basis of the typical morphology LCAL and not MH has been diagnosed in all cases. The Ki-1 (CD 30) positive tumor cells of LCAL can display different phenotypes, either T-lymphoid, B-lymphoid, histiocytic or neither of them (O-phenotype). Therefore we investigated the lineage specificity of tumor cells in 15 paediatric patients with LCAL. Tumor cells of histiocytic origin could be demonstrated in only one of them. In 7 patients the neoplastic cells were of T cell and in the remaining 7 cases of non T/non B cell (O) phenotypes, confirming the extreme rarity of MH in children. It is our opinion that MH and LCAL seem to be different diseases not only nosologically but also clinico-pathologically. In the multicentric therapy studies NHL-BFM 81 and NHL-BFM 83 the frequency of LCAL in childhood is compared to all other subentities at 3%.

The mesoblastic nephroma is the most common renal tumor among newborn and young infants. The tumor is benign, and metastatic growth has only been described in individual cases. Three patients suffering from histologically proven mesoblastic nephroma were examined with an ultrasonic device. Sonographically, the mesoblastic nephroma is manifest as solid and homogeneous tumor of a fine to medium coarse basic texture and of a medium echogenity which may show individual small cystic areas. The tumor cannot be delimited sharply from the healthy renal tissue although uneventful tissue which often caps the kidney is proved. A secure differential diagnosis against a Wilms' tumor is not possible if metastases cannot be detected sonographically or by means of an excretory urogram. The echopattern and the relation of the mesoblastic nephroma to the kidney in combination with an excretory urogram should, however, make the delimitation of a neuroblastoma possible.

Pain-management in pediatric-oncological patients is an interdisciplinary task. The working group pain--therapy of GPO tries to work up an analgesic concept for this group of patients. Pre-existing experience in the therapy with sustained release Morphine and Metamizol should be considered. The documentation-system is just worked up, we ask all pediatric oncological groups to cooperate.

A 6 1/2 years old boy got completely blind within 3 days. Ophthalmoscopically regular findings suggested a retrobulbar opticus infiltration in a pediatric-diagnosed acute myeloic leukemia FAB-M2. A quick diagnosis and prompt cytostatic therapy combined with irradiation of the retrobulbar space opened the way for complete remission with bilateral optic atrophy. The ophthalmoscopic examination of 12 other leukemic children showed once more the involvement of the central nervous system with bilateral papilloedema, 2 times retinal hemorrhages and one vitreous bleeding; 8 children had no ocular symptoms. Comparing these findings to those described in literature, the authors point out the value of ophthalmoscopy to exclude ophthalmologic damages and to avoid side-effects of cytostatic therapy, fortunately not observed till now.

In rare cases, leukoses can produce tumors before general symptoms and changes in the blood picture appear. Two boys were reported in whom tumors of the eye socket were removed, the tumors were histologically classified as myelosarcoma. During the course of several months, the clinical picture of an acute leukemia developed. The difficulties involved in the exact histologic recognition of myelosarcoma, its localization, the differential diagnosis of tumors of the eye socket in children as well as the therapy and prognosis for children with myelosarcoma were discussed.