Targeted therapeutics in treatment of children and young adults with solid tumors: an expert survey and review of the literature.

Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical experience concerning the efficacy and safety of these drugs is limited. This may possibly discourage oncologists from administering TT to children.We performed a comprehensive review of the literature to identify TT that may be considered for treatment of children and young adults with solid tumors. Moreover, we interviewed an expert panel of the Society for Pediatric Oncology and Hematology (GPOH) using questionnaires in a modified Delphi process in order to describe the experts' experiences in the use of these TT.Among 30 TT identified to be possibly useful in children and young adults, imatinib, bevacizumab and rapamycin were most widely used. These drugs were reported as having mostly little to no severe adverse events and seem to induce at least partial responses in a subset of patients. In addition, our study confirms and expands the present knowledge about adverse events and the potential efficacy of 5 other commonly used TT in this population.This information may be useful for oncologists when administering these TT to children and young adults with solid tumors. Controlled clinical trials are urgently needed to test their safety and efficacy.

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

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

Expression of MDR1/p-glycoprotein and multidrug resistance-associated protein in childhood solid tumours.

We evaluated the expression of MDR1/p-glycoprotein in paediatric tumours using reverse transcriptase polymerase chain reaction (RT-PCR), RNA dot blot analysis, and immunohistochemistry on formalin fixed paraffin-embedded material with JSB-1 and C-219 monoclonal antibodies, and compared these three techniques. The expression of multidrug resistance-associated protein (MRP) gene was examined by RT-PCR assay. We studied MDR1/p-glycoprotein and MRP expression in 13 samples from 10 neuroblastoma patients, 11 samples from 10 nephroblastoma patients, 2 rhabdomyosarcomas, 1 adrenocortical carcinoma and 10 benign tumours or tumour-like lesions. Eleven of 13 neuroblastomas, 7 of 11 nephroblastomas, 2 rhabdomyosarcomas, 1 adrenocortical carcinoma, and 7 of 10 benign tumours or tumour-like lesions showed MDR1 PCR products. By RNA dot blot analysis, MDR1 transcripts were detectable in 11 of 34 specimens. Immunohistochemically, we detected positive reaction products for JSB-1 in 26 of 36 samples. There was a significant correlation between the immunoreactivity for JSB-1 and the expression of MDR1 mRNA expression by RT-PCR (P = 0.0001). However, the presence of p-glycoprotein immunostaining does not correlate with the MDR1 expression shown by RT-PCR in every case. As for MRP mRNA expression, 9 of 13 neuroblastomas and 10 of 11 nephroblastomas revealed PCR products.

Genetic instability in osteoblastic tumors of the skeletal system.

At the histological level, the differential diagnosis of osteoblastic bone tumors is characterized by several problems that cannot be solved by conventional histological methods including immunohistology. Differentiating aneurysmal bone cyst from telangiectatic osteosarcoma or giant cell tumor from giant cell-containing highly malignant osteosarcoma are only two examples reflecting the complexity of this field. To develop a new approach to these diagnostic problems, we analyzed the genetic instability in a large number of bone-forming tumor-like lesions as well as in benign and malignant osteoblastic tumors. Our research concentrated on genetic alterations in cell cycle regulator genes: mutations in the p53 gene and ras gene, loss of heterozygosity at the p53, p16 and Rb-locus, and amplification of the mdm2-gene and the c-myc-gene. In addition to cell cycle regulators, the telomerase activity has also been analyzed. The results show that the number of genetic alterations increases with the malignancy of the tumors. The highest number of genetic alterations could thus be found in conventional intraosseous osteosarcoma. In tumor-like lesions, genetic alterations have rarely been observed. The results of this study show that analyzing the genetic instability probably contributes to an improvement in the differential diagnosis of osteoblastic tumors.

p53 and ras mutations in Ewing's sarcoma.

The role of tumor suppressor genes and oncogenes in the development of Ewing's sarcoma has not yet been fully clarified. In this study, we analyzed the frequency of p53 tumor suppressor gene mutation in exons 4-8 by PCR-SSCP and direct sequencing, and the expression of p53-protein in Ewing's sarcoma (ES) by using immunohistochemistry. The overexpression of MDM2, which acts as a functional inactivator of p53, was studied by immunohistochemistry. In addition, a screening for point mutations in the hot spot regions codon 12 and 13 of exon 1 and codon 61 of exon 2 of ras-genes (H-ras, N-ras, K-ras) was performed. In one case, a p53 gene mutation could be confirmed in codon 238 of exon 7 (1/24). Overexpression of MDM2 was found in five cases; in ras-genes, no mutations were detected. Compared with other highly malignant mesenchymal pediatric tumors such as osteosarcomas, mutations of p53 and ras in Ewing's sarcomas are an extraordinarily rare event. However, their frequency is comparable to that of PNET, suggesting that the low incidence of these mutations in ES and PNET could be group-specific for tumors of neuroectodermal genesis.

[Desmoid tumors of the head and neck]. / Desmoidtumoren im Kopf-Hals-Bereich.

Desmoid tumors of the head and neck, also known as aggressive fibromatoses, are rare. They are soft tissue neoplasms arising from musculoaponeurotic structures and characterized of locally aggressive infiltration and recurrences. Complete surgical excision of desmoid tumors is considered to be the only effective method of cure. It is likewise important to make a function-preserving surgery. In addition to the radicality this aspect should be a primary goal to minimize morbidity. MRI is the first choice in the preoperative evaluation of neck desmoids. We describe the successful treatment of desmoid tumors in two cases (M. sternocleidomastoideus, M. levator scapulae). Intraoperative neuromonitoring was very helpful for identification and protection of the motor nerves.

[Determination of coagulation factor VIII inhibitors]. / Untersuchungen zur Bestimmung des Gerinnungsfaktor VIII-Inhibitors.

Factor VIII inhibitors represent a severe complication of the haemophilia A. Different methodical approach in the diagnostics of the laboratory and various definitions of the inhibitor unit render difficult the comparability of the results of examination. Methods for the unitary performance of the qualitative proof of inhibitors and the quantitative estimation of inhibitors are described and their application in the examination of two patients with factor VIII inhibitors are shown.

[Arthrosonography--a modern method for morphologic and functional joint evaluation in hemophilia]. / Die Arthrosonografie--eine moderne Methode zur morphologischen und funktionellen Gelenkbeurteilung bei der Hämophilie.

The arthrosonography is a new depicting procedure for detection of destructing joint processes in haemophilia. A direct evaluation of the cartilage, of the border between cartilage and bone, of the synovial membrane with proliferative processes as well as the differentiation between soft-tissue bleeding and haemarthros are possible. An essential advantage is given by a combined morphological and functional joint evaluation. The diagnosis of joint instabilities can be recognized easier by sonography than by X-ray. Clinical findings are completed in an excellent manner and lesions of bone and cartilage are detected earlier by arthrosonography.

[Therapy of idiopathic thrombocytopenic purpura in childhood]. / Zur Therapie der idiopathischen thrombozytopenischen Purpura (ITP) im Kindesalter.

Idiopathic thrombocytopenic purpura characterised by an increased bleeding tendency is a well-known clinical entity in childhood. From 1983 to 1992 68 patients suffering from ITP were treated at the Children's Hospital of the Medical Academy of Magdeburg. 11 patients with mild or without clinical symptoms and platelet counts of more than 20 Gpt/l did not receive any treatment; all children recovered spontaneously. 38 patients with severe haemorrhagic manifestations and thrombocytes less than 20 Gpt/l were treated with corticosteroids and had a sustained remission. 10 patients who had responded to corticosteroids initially and subsequently relapsed were given other treatments (Anti-Rhesus-antibodies, HDIVG). All patients achieved a continuous remission. A chronic disease was observed in 8 patients; 3 of them were splenectomised. One child died due to massive gastrointestinal bleeding.

[Antithrombin V--a rare concomitant symptom in plasmacytoma and autoimmune diseases]. / Antithrombin V--ein seltenes Begleitsymptom bei Plasmozytom und Autoimmunerkrankungen.

Antithrombin V as a pathological inhibitor of coagulation may occur in some rare cases as an accompanying symptom of various basic diseases. In the course of two years, antithrombin V could be identified in 8 patients, with plasmocytoma, lupus erythematodes visceralis, glomerulonephritis or colitis ulcerosa existing as basic diseases. Clinical findings in patients and those gained in analyzing coagulation, procedures of laboratory diagnostics for determining characteristic properties of antithrombin V as well as the therapeutic way of influencing the activity of antithrombin V are represented.

Familial urticaria pigmentosa associated with thrombocytosis as the initial symptom of systemic mastocytosis and Down's syndrome.

Most cases of urticaria pigmentosa are confined to the skin, but visceral involvement and/or haematological abnormalities have been observed. It is still a matter of debate whether all forms of mastocytosis are true neoplasias or reactive hyperplasias. Familial inheritance of urticaria pigmentosa is rare. We report on a fraternal set with urticaria pigmentosa as part of a systemic mastocytosis. The first patient additionally revealed persistent thrombocytosis and splenomegaly. His brother developed urticaria pigmentosa, intermittent diarrhoea, hepatomegaly and asthma bronchiale associated with trisomy 21 (Down's syndrome). The association of mastocytosis with thrombocytosis has seldom been described. In our patient it preceded the development of systemic mastocytosis. The association with Down's syndrome has not been reported until now.

[Effect of various therapeutic protocols on growth and final height of children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma]. / Einfluss verschiedener Therapieprotokolle auf das Wachstum und die Endgrösse von Kindern mit akuter lymphoblastischer Leukämie oder Non-Hodgkin-Lymphom.

A total of 74 children suffering from acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL) were involved in a retrospective analysis of their physical growth during and after the therapy. Out of this total number, 54 children were subjected to radiochemotherapy in compliance with the VII/(81) scheme, and another 20 children in compliance with the LSA2L2 scheme. At the beginning of the therapy the average height-standard deviation score (H-SDS) for both groups of patients corresponded with the population average. The patients subjected to the VII/(81) scheme showed, throughout the observation period of five years from the beginning of the therapy, a height normal for their age group. Contrary to this observation, the patients subjected to the LSA2L2 scheme experienced a significantly different growth in the period under observation and continually lost height in comparison to the normal population. The same results were experienced with a smaller group of patients whose growth was followed up for eight years from the beginning of therapy. 16 patients (VII/81 n = 4/LSA2L2 n = 12) reached their final height. For the patients of the VII/(81) scheme the final height showed an average H-SDS of 0.27 and for the patients of the LSA2L2 scheme of -1.22 (p = 0.068). Considering that the same cranial radiotherapy (max. 18 Gy for both schemes) and a comparable intensive induction therapy were applied, it must be concluded that the intensity and duration of the maintenance treatment are the critical factors initiating a different growth behaviour of the two groups subjected to radiochemotherapeutical schemes.

[Factor VIII inhibitors in patients suffering from severe haemophilia A: problems of "very low" responders]. / Faktor VIII-Inhibitoren bei Patienten mit schwerer Hämophilie A: Problematik der "very low" Responder.

Without recognition of any inhibitor until now, low concentrations of factor VIII inhibitors (< 1 Bethesda unit (BU)/mL plasma) can be occasionally measured in patients with severe haemophilia A. The existence of so-called "very low" responders is assessed contradictorily due to a methodically caused inhibitor increase. Plasma from 10 patients with severe haemophilia A was incubated with human plasma or animal plasma from pig, cattle, or cat and assayed for factor VIII inhibitors. No signs of inactivation could be detected in five specimen (0 BU/mL plasma). However, measurable signs of factor VIII inactivation (< 1 BU/mL plasma) did occur in the other five. Therefore, the existence of yet not defined unknown inhibitory substances in certain haemophilic plasmas must be assumed. They are directed against human factor VIII as well as partly against animal factor VIII. These "very low" inhibitors are not identical with factor VIII antibodies of "low" and "high" responding haemophiliacs. The clinical importance of "very low" inhibitors is insignificant because they do not tend to increase after exposure to factor VIII. In fact, a effect of factor VIII therapy is the neutralization of this kind of inhibitors.

[False diagnosis of acute appendicitis: visceral larva migrans syndrome]. / Fehldiagnose Appendicitis acuta: Larva-migrans-visceralis-Syndrom.

A 8 years old girl suffering from the Larva-migrans-Syndrome (Ascariasis) was operated on the false diagnosis of acute appendicitis. The cardinal symptoms of this disease are chronic eosinophilia, hepatomegaly, affection of the lungs, vague abdominal symptoms, in this case simulating acute appendicitis. Diagnostics, therapy, prognosis and prophylaxis are dealt with in detail.

[Echocardiography studies for detection of cardiotoxic side effects of anthracycline therapy in childhood]. / Echokardiographische Untersuchungen zur Erkennung kardiotoxischer Nebenwirkungen der Anthrazyklintherapie im Kindesalter.

An anthracycline-induced cardiomyopathy can already appear at a total cumulative dose of less then 550 mg/m2. Noninvasive cardiological methods have been used in order to detect these fatal side effects early. For cardiological control we applied echo-cardiography with measurements of ventricular size and left ventricular function. 5 out of 39 children who were off anthracycline therapy for 3 months to 8 years showed a decline in left ventricular function, but no clinical symptoms. At present 16 children with anthracycline therapy are controlled by echocardiography. In 2 patients a transient myocardial dysfunction was diagnosed. After stopping anthracycline therapy the left ventricular function improved within 2 to 3 months without specific cardiac treatment.

[Monitoring hearing during ototoxic cisplatin therapy]. / Zur Uberwachung des Gehörs während der ototoxischen Cisplatin-Therapie.

In the 1983-1988 period, the audition of 17 children was studied prior to and during antineoplastic chemotherapy with cumulative total cisplatin doses from 270 to 1530 mg/m2. The hearing tests were conducted by means of an objective method which doses not depend on patients' cooperation: the recording of fast auditory evoked potentials. Tone threshold audiograms were additionally obtained from cooperative children. Of the 17 patients, 14 showed a dose-dependent symmetric hearing loss which in part was severe and related in particular to the high-frequency domain. Three patients exhibited no hearing impairment even though the total cisplatin dose applied ranged from 630 to 810 mg/m2. To conclude, while allowing for reports in the literature, recommendations are given on how hearing impairment can be minimised in view of the priority of the antineoplastic action of cisplatin.

[Coagulation factor IX inhibitor in hemophilia B]. / Gerinnungsfaktor-IX-Inhibitor bei Hämophilie B.

An inhibitor against blood clotting factor IX was observed as a very rare finding in case of an eight year old boy suffering from haemophilia B. By reason of a haemarthros a replacement therapy was successful done using FEIBA (Factor Eight Inhibitor Bypassing Activity). The haemostatic characterization of the inhibitor and its influence by therapy will be presented.

[Detection of soluble fibrin monomer complexes by the netropsin precipitation test in childhood meningitis]. / Nachweis löslicher Fibrinmonomerkomplexe mit dem Netropsinpräzipitationstest bei der Meningitis im Kindesalter.

During a period of two years children with abacterial meningitis as well as bacterial meningitis were examined before treatment and later during disease. The new Netropsin praecipitation test according to Funke and coworkers was used to detect soluble fibrin monomer complexes. Only in a few cases of abacterial meningitis, but in the majority of cases with bacterial meningitis, a positive result had been shown. Excessive increase had been found in Waterhouse-Friderichsen syndrome. According to our results of coagulation tests we conclude 1. the ethanol gelation test is out-of-date, 2. the heparin treatment in bacterial meningitis is further indicated.