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.

Reduced intensity conditioning in unrelated donor transplantation for refractory cytopenia in childhood.

Myelodysplastic syndromes (MDS) are a heterogenous group of acquired hematopoietic stem cell disorders. Refractory cytopenia (RC) is the most common subtype of childhood MDS and hematopoietic stem cell transplantation (HSCT) is the only curative treatment. HSCT following a myeloablative preparative regimen is associated with a low probability of relapse and considerable transplant-related mortality. In the present European Working Groups of MDS pilot study, we investigated whether a reduced intensity conditioning regimen (RIC) is able to offer reduced toxicity without increased rates of graft failure or relapse. Nineteen children with RC were transplanted from an unrelated donor following RIC consisting of fludarabine, thiotepa and anti-thymocyte globulin. Three patients experienced graft failure. Neutrophil and platelet engraftment occurred at a median time of 23 and 30 days, respectively. Cumulative incidence of grade II-IV and grade III and IV acute graft-versus-host disease (GVHD) was 0.48 and 0.13, respectively; three patients developed extensive chronic GVHD. Although infections were the predominant complications, only one patient with extensive chronic GVHD died from infectious complications. Overall and event-free survival at 3 years were 0.84 and 0.74, respectively. In conclusion, our results were comparable to those of patients treated with myeloablative HSCT. Long-term follow-up is needed to demonstrate the expected reduction in long-term sequelae.

Bone marrow Th2 cytokine expression as predictor for relapse in childhood acute lymphoblastic leukemia (ALL).

The immunological environment of leukemic blasts in the bone marrow might play a decisive role in determining an individual's risk for relapse. In order to identify potential predictors of relapse and to elucidate the mechanisms of immune control of leukemic blasts we examined the expression of cytokines, costimulatory molecules and members of the TNF family in leukemic marrow samples in a prospective study. Samples from 49 consecutive pediatric patients with B cell precursor acute lymphocytic leukemia (BCP ALL) were analyzed by semiquantitative RT-PCR. We identified interleukin (IL)-10 expression as a significant adverse prognostic indicator in childhood BCP-ALL. The event free survival (EFS) of patients expressing IL-10 mRNA in high quantity was significantly lower compared with patients expressing low IL-10 mRNA. Taqman RT-PCR of sorted cell populations showed that IL-10 mRNA was synthetized almost exclusively by NK or T cells. In addition, we found an increased expression of IL-1, IL-4, CD86 and VEGF mRNA in patients with late relapses. Possibly, ALL cells mediate a Th2 shift through increased expression of CD86 and thereby influence the individual relapse risk. These findings emphasize the role of the immune system for the outcome of childhood ALL.

Effects of soluble TNF receptor II (sTNF-RII), IL-1 receptor antagonist (IL-1ra), tumor load and hypermetabolism on malnutrition in children with acute leukemia.

OBJECTIVE: Soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin-1 receptor antagonist (IL-1ra) might modulate nutritional status in acute leukemia since they are inhibitors of tumor necrosis factor-alpha and interleukin-1 that can induce tissue wasting. On the other hand, tumor load and hypermetabolism may induce malnutrition. We determined whether serum levels of sTNF-RII and IL-1ra are upregulated to prevent overt malnutrition and whether tumor load and hypermetabolism induce overt malnutrition. METHODS: We examined 31 children with newly diagnosed acute leukemia and correlated sTNF-RII, IL-1ra, tumor load and energy expenditure to anthropometric characteristics (weight, weight for height, height, body mass index, fat free mass) and serum protein concentrations (albumin, transferrin, prealbumin). As controls, 68 healthy children were examined for anthropometric characteristics; 33 healthy controls were included for cytokine analysis and biochemical indices. RESULTS: We found no correlations between sTNF-RII, IL-1ra, tumor load and energy expenditure and anthropometric characteristics or protein concentrations. Mean sTNF-RII level was significantly, mean IL-1ra level slightly increased (223% and 113% of the controls). 29% of the children had a high tumor load (> 100.000/microl white blood cells) and 53% had hypermetabolism (resting energy expenditure > 110% of predicted). Anthropometric characteristics were similar to those in controls, however, serum protein concentrations were decreased. CONCLUSION: sTNF-RII and IL-1ra are upregulated in children with leukemia and may therefore prevent overt malnutrition. Tumor load and hypermetabolism do not induce overt malnutrition. The children presented with an early stage of malnutrition as evidenced by low serum protein concentrations but normal anthropometric characteristics.

[Supratentorial primitive neuroectodermal tumor: a single center experience and comparison with the literature]. / Supratentorieller primitiver neuroektodermaler Tumor: Erfahrungen in einem Zentrum im Vergleich zur Literatur.

Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical resection could be achieved. All had craniospinal irradiation and chemotherapy according to the HIT-91 protocol. The two children with incomplete resection died due to tumor progression after 7 and 10 months. Two of the 4 children with complete tumor resection had local relapses 8 months after diagnosis and died after 14 and 18 months. One child had a diffuse meningeal relapse 12 months after diagnosis. Despite (high-dose) systemic chemotherapy and intraventricular mafosfamide, he died 21 months after diagnosis due to tumor although remission could be achieved. Only one child is still in remission 86 months after diagnosis.

Local environment and dynamics of PO4 tetrahedra in Na-Al-PO3 glasses and melts.

Glasses and melts in the system (NaPO3)(1-x)(Al(PO3)3)x were studied with the aim of obtaining information about the structure on the next larger scale beyond the PO4 group. Magic angle spinning NMR was applied to the pure NaPO3 glass and Raman scattering to systems with x = 0.00, 0.03, 0.06, 0.15, and 0.60 in the temperature range T = 300-1100 K. Comparison of the 31P chemical shift between glass and crystalline forms revealed that polymerization of the metaphosphate into tricyclophosphatelike (PO3)3(3-) rings is the dominant structure, ca. 80%, formed by the twofold vertex-joined PO4 groups in the glass. In the Raman study we focused on the prominent polarized band at ca. 1170 cm(-1) which is due to the symmetric breathing mode of the tetrahedral PO4 group. This band was decomposed into a few Gaussian lines. These component lines could be identified using the NMR results: two narrow components are due to PO4 groups in the tricyclophosphatelike rings, which have either a Na or an Al counterion and a third broad component is due to chain-polymerized (PO3(-))n. The variations of the component lines (peak positions, widths, and intensities) with respect to x and T are presented. We derive the shifts of the symmetric breathing mode frequency which are caused by Na or Al counterions, by ring closure, by x > 0, etc. The relative intensities of the narrow and broad components in the 1170-cm(-1) band of the Raman spectra are discussed. The amount of ring-to-chain transformation on addition of Al3+, and as functions of T and x, is derived. Indications for ordering on a next larger scale, derivable from Raman, NMR, and thermodynamics, are compared.

T-cell-depleted peripheral blood stem cell transplantation for alpha-mannosidosis.

Alpha-mannosidosis (alpha-mannosidosis) is a lysosomal storage disease characterized by accumulation of oligosaccharides in various tissues leading to symptoms such as coarse facial features, dysostosis multiplex, hearing disabilities, mental developmental delay and skeletal involvement (dysostosis multiplex). Without treatment, the severe infantile onset form of this autosomal recessive disease leads to progressive neurodegeneration and sometimes to early death. Stem cell transplantation has been shown to be an effective treatment. In the five patients published so far, correction of skeletal abnormalities and improvement of neuropsychological capabilities have been observed. We report the first patient who received a T-cell-depleted peripheral blood stem cell transplantation (PBSCT) for alpha-mannosidosis. The diagnosis of alpha-mannosidosis was made at the age of 14 months. At the age of 24 months, he underwent PBSCT with T-cell depletion by CD34-positive selection from his HLA phenotypically identical mother. Conditioning was carried out with busulfan (20 mg/kg), cyclophosphamide (200 mg/kg), OKT3 and methylprednisolone. The patient is alive and well 27 months after PBSCT and has made significant developmental progress. The pattern of urinary oligosaccharides has returned to almost normal. CD34-positive-selected PBSCT is a feasible option to reduce risk for GVHD for these patients.

Allogeneic bone marrow transplantation for active Epstein-Barr virus-related lymphoproliferative disease and hemophagocytic lymphohistiocytosis in an infant with severe combined immunodeficiency syndrome.

A 5-month-old male presented with fever, hepatosplenomegaly, leukocytosis with atypical lymphoblasts, anemia and thrombocytopenia. Severe combined imunodeficiency syndrome (T-, B+, NK+), B lymphoproliferative disease and hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus (EBV) were diagnosed. As his clinical situation deteriorated rapidly, BMT was performed with unmanipulated marrow stem cells from his EBV-positive HLA-identical sister after conditioning with dexamethasone (1.75 mg/kg/day), cyclophosphamide (114 mg/kg) and etoposide (10 mg/kg), with no immunosuppression given post transplant. Engraftment occurred on day 6 with explosive proliferation of donor CD8(+) T cells. The patient died 3 days later from acute respiratory distress syndrome. Autopsy revealed full donor engraftment and no signs of hemophagocytic lymphohistiocytosis or B lymphoproliferative disease. Thus, transplanted T cells can expand very rapidly within days after BMT and clear EBV lymphoproliferative disease and hemophagocytic lymphohistiocytosis.

Megestrol acetate to correct the nutritional status in an adolescent with growth hormone deficiency: Increase of appetite and body weight but only by increase of body water and fat mass followed by profound cortisol and testosterone depletion.

Megestrol acetate (MA) is a synthetic, orally active derivative of the naturally occurring hormone progesterone. MA is increasingly used to correct loss of appetite and improve the nutritional status. We used MA in an adolescent with growth hormone (GH) deficiency due to former irradiation therapy in order to evaluate if MA can improve the nutritional status. In fact, MA increased appetite and weight dose-dependent. The energy expenditure measured by indirect calorimetry changed from hypo- to normometabolism. However, weight gain was first primarily due to an increase in body water and then in fat mass. The gain of fat mass was much more prominent than the gain of fat free mass. As important side-effect, MA lead to rapid and profound cortisol and testosterone depletion after only 10 days with a long-lasting effect on testosterone depletion. Therefore, MA as a single therapy cannot be recommended to improve the nutritional status. If MA is given, cortisol and testosterone levels have to be monitored and supplemented as needed.

Griscelli syndrome: report of the first peripheral blood stem cell transplant and the role of mutations in the RAB27A gene as an indication for BMT.

Griscelli syndrome is characterized by partial albinism with variable immunodeficiency. Two different gene loci are responsible for this rare, autosomal recessive disease: the myosin Va gene and the RAB27A gene. As recently reported, only patients with mutations of the RAB27A gene suffer from immunodeficiency and hemophagocytic lymphohistiocytosis. Thus, only patients who suffer from the Griscelli syndrome with mutations of the RAB27A gene should receive BMT/PBSCT, which is the only curative therapy. Due to the risk of early relapse or severe infections, BMT/PBSCT should be carried out as soon as possible; if patients do not have HLA-identical family members, valuable time may be lost by searching for an HLA-identical unrelated donor. We report the first peripheral blood stem cell transplant (PBSCT) with T cell depletion in a 6-month-old girl with Griscelli syndrome, and a deletion of the RAB27A gene. The donor was her phenotypically HLA-identical mother. Conditioning included busulfan, VP16 and cyclophosphamide. The patient was transfused with 15.4 x 10(6)CD34-positive cells/kg and 17.6 x 10(3) CD3-positive cells/kg recipient weight. Three months after the transplant, a curable lymphoproliferative syndrome occurred. 26 months after the transplant, the patient is doing well with stable mixed chimerism (52% donor cells).

Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children.

We performed HLA-mismatched stem cell transplantation with megadoses of purified positively selected mobilized peripheral blood CD34(+) progenitor cells (PBPC) from related adult donors in 39 children lacking an otherwise suitable donor. The patients received a mean number of 20.7 +/- 9.8 x 10(6)/kg purified CD34(+) and a mean number of 15.5 +/- 20.4 x 10(3)/kg CD3(+) T lymphocytes. The first seven patients received short term (<4 weeks) GVHD prophylaxis with cyclosporin A, whereas in all the following 32 patients no GVHD prophylaxis was used. In 38 evaluable patients, five patients experienced primary acute GVHD grade I and one patient grade II. In 32 patients, no signs of primary GVHD were seen and GVHD only occurred after T cell add backs. T cell reconstitution was more rapid if the number of transplanted CD34(+) cells exceeded 20 x 10(6)/kg. Of the 39 patients, 15 are alive and well, 13 died due to relapse and 10 transplant-related deaths occurred. We conclude that the HLA barrier can be overcome by transplantation of megadoses of highly purified mismatched CD34(+) stem cells. GVHD can be prevented without pharmacological immunosuppression by the efficient T cell depletion associated with the CD34(+) positive selection procedure. This approach offers a promising therapeutic option for every child without an otherwise suitable donor.

Pamidronate and calcitonin as therapy of acute cancer-related hypercalcemia in children.

Severe symptomatic hypercalcemia is a rare event in children with malignancies. Up to now there is limited experience treating childhood hypercalcemia with bisphosphonates in addition to calcitonin. We report a 5-year-old boy with acute lymphoblastic lymphoma who presented with malignant hypercalcemia at diagnosis. The maximal serum calcium concentration was 15.2 mg/dl (3.81 mmol/l). Conventional therapy with forced diuresis and furosemide failed. Calcitonin (10 IU/kg/24 h i.v. for 2 days) and pamidronate (1 mg/kg over 2 hours i.v.) were used successfully without adverse effect lowering the serum calcium level within 24 hours to normal values. We recommend the use of calcitonin and pamidronate as first-line therapy together with forced diuresis and furosemide in childhood hypercalcemia secondary to malignancies as it is rapidly effective and has no significant side effects.

Accelerated phase in partial albinism with immunodeficiency (Griscelli syndrome): genetics and stem cell transplantation in a 2-month-old girl.

UNLABELLED: A 2-month-old girl presented with fever, hepatosplenomegaly, pancytopenia, hypertriglyceridaemia and silvery-greyish hair, suggesting the diagnosis of Griscelli syndrome (partial albinism with immunodeficiency). This diagnosis was confirmed by the characteristic agglomeration of melanin in the hair shaft and accumulation of melanosomes in melanocytes of the skin. The patient was homozygous for polymorphic markers around the myosin-Va gene on chromosome 15q21, which co-localize to the Griscelli disease locus. Natural-killer cells were in the lower range. The stimulation of lymphocytes with antigen and mitogen was normal. The patient's accelerated phase, characterized by haemophagocytosis was treated with prednisolone, rabbit anti-thymocyte globulins, and intrathecal methotrexate. Remission was maintained with cyclosporin A until HLA-compatible peripheral blood stem cell transplantation from her mother. CONCLUSION: The silvery-greyish hair associated with fever, pancytopenia and hypertriglyceridaemia is the clue to early diagnosis of Griscelli syndrome and important to prevent death before stem cell transplantation.

Cryopreservation and transplantation of fetal adrenal glands in adrenalectomized rats.

In a syngeneic rat model, the present study investigated the cryobiology of fetal adrenal glands and compared the endocrinological function of cryopreserved versus fresh fetal adrenal transplants in the adrenalectomized hosts. Ultrastructural studies showed no significant tissue damage by the cryopreserving technique: cellular membranes were intact, the mitochondria showed discrete swelling and vacuoles were found in the endoplasmatic reticulum. Following transplantation, maturation and bilateral adrenalectomy in the host, assessment of endocrinological parameters demonstrated that survival was prolonged and Addison crisis could be prevented in both transplant groups with no significant difference between fresh versus cryopreserved grafts. To our knowledge this study presents the first morphological and endocrinological data about the successful transplantation of cryopreserved fetal adrenal glands in rats. In conclusion, cryopreservation is tolerated well by the tissue and long-term banking may therefore contribute to the feasibility and benefit of fetal adrenal transplantation. However, further investigations will be necessary to evaluate fetal adrenal transplantation in an allogeneic and xenogeneic setting.

[Case example: malignant infantile osteopetrosis--pathogenesis and therapeutic options]. / Fallbeispiel: Maligne infantile Osteopetrose--Pathogenese und therapeutische Optionen.

Malignant infantile osteopetrosis is a rare disease but can be clinically unequivocally diagnosed. Normal bone formation in the presence of decreased bone breakdown leads to the typical symptoms. The only proven curative approach, bone marrow transplantation, can reverse most of the symptoms and prevent progression to irreversible nerve damage when done early in infancy. Therefore, early diagnosis is decisive. We present a case report of an infant with osteopetrosis and discuss pathogenesis and therapeutical options.