Malignant Solid Tumors In Children Research Articles

Physical and psychological outcome in long-term survivors of childhood malignant solid tumor in Japan

Few studies have assessed physical and psychological status in long-term survivors of childhood solid tumors in Japan. For children with such diseases diagnosed and treated in our hospital, our purpose was to clarify the physical and psychological status of long-term survivors and their parents. Subjects were 56 patients who were diagnosed at our institution as having a childhood malignant solid tumor between 1982 and 2005 and had been alive for at least 5 years after treatment. Surveys were sent and returned by mail. Of the 56 patients surveyed, 32 responded. The current health condition and psychosocial status of survivors were evaluated as good by their parents. However, psychological tests revealed psychosocial problems in 28.1% of the children. Severe posttraumatic stress associated with the child's disease and its treatment was present in 15.6% of the parents. Physical status of long-term survivors of childhood malignant solid tumors was good in general. However, psychological tests revealed psychosocial problems in some of the children and posttraumatic stress in the parents. Considering the diversity of both the diseases and their clinical course, a qualitative study is warranted for further analysis.

Abstract LB-385: The Hippo pathway component YAP1 promotes cerebellar precursor survival after irradiation and can accelerate medulloblastoma onset

Abstract Medulloblastoma is the most common malignant solid tumor in children. These tumors arise in the developing cerebellum, a region of the brain that undergoes rapid expansion after birth. Current treatments for medulloblastoma include radiation, surgery and chemotherapy, all of which are associated with devastating physical and mental side effects in long-term survivors. Recently, cells within medulloblastomas that survive radiation treatment and can repopulate the tumors post-radiation have been identified. These cells reside in regions adjacent to blood vessels, and their post-radiation survival is promoted by PI3 kinase pathway activity. Ideal medulloblastoma therapies will attack the tumors and eliminate the tumor re-initiating cells but spare the rest of the brain. We have recently published that the oncogenic transcriptional co-activator YAP1, which is negatively regulated by the Hippo pathway, is up regulated and amplified in a subset of human medulloblastomas with aberrant Sonic hedgehog (Shh) signaling. YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly-growing tumor cells. We report here that YAP1 is actively involved in survival post-irradiation. CGNPs that over-express YAP1 in vitro proliferate more and present less apoptosis after irradiation than those over-expressing GFP. Among YAP1 target genes in CGNPs we found Securin, which, apart from its known role in mitosis, it has been shown to have roles in survival after DNA damage. We also found Securin highly expressed in human and mouse medulloblastomas. Moreover, injection of YAP 1 over-expressing medulloblastoma cells in postnatal day 4 wild type mice accelerate medulloblastoma onset compared to GFP over-expressing cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-385.

R-021 The role of the pediatric surgeon for the therapy of the malignant solid tumor in children at our hospital(Requested Theme Session 4 The role of pediatric surgeons in treating pediatric solid tumors,Better Life for Sick Children, Better Future for Pediatric Surgery,the 45th Annual Meeting of Japanese Society of Pediatric Surgeons)

R-021 The role of the pediatric surgeon for the therapy of the malignant solid tumor in children at our hospital(Requested Theme Session 4 The role of pediatric surgeons in treating pediatric solid tumors,Better Life for Sick Children, Better Future for Pediatric Surgery,the 45th Annual Meeting of Japanese Society of Pediatric Surgeons)

P-252A Enhansed color doppler imaging of malignant solid tumors in children(Diagnostic radiology 2, the 44th Annual Meeting of Japanese Society of Pediatric Surgeons)

P-252A Enhansed color doppler imaging of malignant solid tumors in children(Diagnostic radiology 2, the 44th Annual Meeting of Japanese Society of Pediatric Surgeons)

Differential expression of delta-like gene and protein in neuroblastoma, ganglioneuroblastoma and ganglioneuroma

Neuroblastoma is an extremely malignant solid tumor in children, characterized by spontaneous differentiation and regression. An epidermal growth factor-like homeotic protein, delta-like (dlk), has been involved in differentiation of neuroblastoma cell lines, but is unknown in in vivo expression of neuroblastoma. By using in situ hybridization and immunohistochemistry, dlk mRNA and protein expression were studied in formalin-fixed archival tissues from 10 patients with neuroblastoma, five with ganglioneuroblastoma, and five with ganglioneuroma. Three adrenal tissues from children died of diseases other than adrenal tumors and one from an adult with pheochromocytoma were severed as normal and disease controls. The results showed strong immunoreactive dlk staining in endothelial cells in neuroblastoma, ganglioneuroblastoma and ganglioneuroma. Dlk was detectable in mature neuromatous stroma and gangliocytes of ganglioneuroma, but not in neuroblasts of neuroblastoma and ganglioneuroblastoma, neither in gangliocytes of ganglioneuroblastoma. In contrast, dlk mRNA expression was mainly observed in the gangliocytes, but was less intense in the neuroblasts and neuromatous stroma cells. Endothelial cells were essentially devoid of dlk mRNA expression. The findings indicated that there is differential expression of dlk gene and protein among neuroblastoma, ganglioneuroblastoma and ganglioneuroma. The stronger expression of dlk in gangliocytes in ganglioneuroma, in contrast to weaker or no expression in gangliocytes in ganglioneuroblastoma and neuroblasts in neuroblastoma, suggests upregulation of dlk during differentiation of neuroblastoma into more benign form. Furthermore, higher dlk protein expression in the tumor endothelium than in the endothelium of normal adrenal gland implies that dlk may regulate the endothelial function in neuroblastic tumors.

Treatment of advanced malignant solid tumors in children with autologous hematopoietic stem cell transplantation

To investigate the efficacy of autologous hematopoietic stem cell transplantatation in children with advanced solid tumors. Bone marrow was collected from the anterior crista of iliac in both sides in 13 cases while peripheral mononuclear cell was harvested with CS-3000 cell separator in other 15 patients after G-CSF mobilization. Since one of them was suspected to have bone marrow involvement of the neuroblastoma cells, the autograft was purged with CliniMACS based on the CD34 positive selection. Conditioning regimen was CBV protocol (cyclophosphamide + bischloro-nitrosourea, i.e., BCNU + etopside) in two children with Hodgkin's disease and etopside plus carboplatin plus melphalan in others. The number of mononuclear cells collected from bone marrow or peripheral blood was equal to (5.4 +/- 2.1) x 10(8)/kg and (4.1 +/- 1.9) x 10(8)/kg, respectively. Hematopoietic reconstitution was achieved in all patients. Mean time of the neutrophil count recovery to 0.5 x 10(9)/L and mean time of platelet recovery over 2.0 x 10(9)/L were 11.8 +/- 5.7 and 21.0 +/- 9.3 days, respectively. Three units of packed red blood cells and three units of platelet products were transfused in the course of transplantation on average. A total of 12 children developed neutropenic fever and 3 of them had positive blood culture, including staphylococcus epidermal, staphylococcus saprophyte and bacillus subtilis. None of the children died of transplantation-associated complication. One child developed acute renal failure, pulmonary edema and pericardial effusion followed by respiratory distress syndrome. Mechanical ventilation and pulmonary surfactant were used and the patient recovered at last. Another patient developed BCNU associated pulmonary injury, severe pulmonary hypertension and eosinophilosis and recovered after treatment. The mean follow up time was 13 months. Among the 27 children, five died of relapse 5 months after transplantation, and one case of NHL had CNS involvement 3 months after transplantation but has got 17 months of survival till now. The remaining twenty one children were in status of disease-free survival. Autologous stem cell transplantation might be effective in the treatment advanced solid tumors in children.

RECONSTRUCTIVE SURGERY FOR CHILDREN WITH PELVIC RHABDOMYOSARCOMA

Rhabdomyosarcoma is the most common soft-tissue sarcoma found in children and can arise almost anywhere skeletal muscle is found. It represents 4% to 8% of malignant solid tumors in children, ranking behind central nervous system tumors, lymphoma, neuroblastoma, and Wilms' tumor. Reconstructive surgery has become an integral part of the total plan in patients undergoing radical surgery for rhabdomyosarcoma. Advances in surgical techniques can often provide a reasonable lifestyle for patients.

Real-Time Quantitative PCR for the Measurement of MYCN Amplification in Human Neuroblastoma with the TaqMan Detection System

Neuroblastoma is the most common extracranial malignant solid tumor in children under 5 years and is characterized by a wide clinical and biological heterogeneity, from spontaneously regressive forms to cancers with a rapid and fatal progression. MYCN oncogene amplification is considered the most important prognostic factor to evaluate survival and therapeutic choices in these patients. Here we present a new assay for rapid and accurate measurement of MYCN amplification, based on real-time quantitative PCR with the TaqMan(TM) reaction. The degree of MYCN amplification was derived from the ratio of the MYCN oncogene and the single-copy reference gene, beta-actin. The absolute abundance of these two genes in tumor sample DNA was obtained by extrapolation on external calibration curves generated with reference DNA. We found a variable degree of MYCN amplification, from 2 to 29, in 26 of 49 (53%) neuroblastomas. These results were well correlated to those obtained with a competitive PCR assay in the same samples (r = 0. 987). MYCN amplification was associated mainly with advanced cancer stages, and the analysis of overall survival confirmed that the measurement of MYCN amplification is a predictor of patient outcome in neuroblastoma. Patients without MYCN amplification had a cumulative survival significantly higher than patients with low (<9; P = 0.02) and high (>/=9; P = 0.03) oncogene amplification. The assay is rapid and reproducible and does not require any post-PCR analytical procedure.

Late effects of radiotherapy on the neuroendocrine system

When the hypothalamic-pituitary axis (HPA) is included in the treatment field in children and adults, a variety of neuroendocrine disturbances are more common than has been appreciated in the past. Clinical damage to the pituitary and thyroid glands usually occurs months to years after treatment, and is preceded by a long subclinical phase. Primary brain tumors represent the largest group of malignant solid tumors in children. The survival rates of 50% reported in the literature are achieved at the expense of late occurring effects. Radiation-induced abnormalities are generally dose-dependent. Growth hormone deficiency and premature sexual development can occur at doses as low as 18 Gy in conventional fractionation, and is the most common neuroendocrine problem in children. In patients treated with > 40 Gy on the HPA, deficiency of gonadotropins, thyroid stimulating hormone, and adrenocorticotropin can be found. Following high-dose radiotherapy (> 50 Gy), hyperprolactinemia can be seen, especially among young women. Most neuroendocrine disturbances that develop as a result of HPA can be treated efficiently, provided that an early detection of these endocrine dysfunctions abnormalities is done.

Mutation analysis of p53 gene in childhood malignant solid tumors

Alterations of the p53 gene have been extensively investigated in a wide variety of human malignancies. However, data on childhood malignant solid tumors are still limited. Mutations of the p53 gene on exons 5 through 8 were examined in 82 childhood malignant solid tumors by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of these mutations was confirmed by direct sequencing. The 82 tumors examined included neuroblastomas (n = 44), Wilms' tumors (n = 13), hepatoblastomas (n = 11), rhabdomyosarcomas (n = 10), extraosseus Ewing sarcomas (n = 2), undiferentiated sarcoma of the liver (n = 1), and fibrosarcoma (n = 1). Two sarcoma samples were identified as having point mutations. One was a rhabdomyosarcoma with a missense mutation at codon 273, substituting histidine (His) for arginine (Arg). Another was an undifferentiated sarcoma of the liver with a missense mutation at codon 245, substituting serine (Ser) for glycine (Gly). No mutations were detected among neuroblastoma, Wilms' tumors, or hepatoblastomas. The two sarcomas with mutations were localized tumors. Both patients who had these tumors are disease free for 8 and 5 years after treatment, respectively. The overall incidence of p53 mutations was low (2.4%, 2 of 82). However, the incidence, when calculated for sarcomas, was higher at 14.3% (2 of 14). These data indicate that p53 mutations are generally uncommon in childhood malignant solid tumors examined. However, in some childhood sarcomas, p53 mutations appear to have a causative role in the development of these tumors.

Doxorubicin in treatment of malignant solid tumors in children.

Doxorubicin (adriamycin) was administered to 35 children with malignant solid tumors to further evaluate its usefulness and toxicity. Two dosage schedules were used: 25 mg/sq m of body surface area weekly, and 25 mg/sq m on two consecutive days and then every two weeks. The agent produced tumor regression in 17 children; the tumors included osteosarcoma, neuroblastoma, Wilms tumor, reticulum cell (histiocytic) lymphoma, and hepatoblastoma. Toxic reactions including alopecia, hematopoietic depression, vomiting, mucosal ulcerations, and weight loss were similar with each schedule. Administration of doxorubicin in a dosage of 50 mg/sq m at two-week intervals allows time for detection of toxic reactions and evaluation of tumor response before administration of subsequent doses.

Management of malignant solid tumors in children : Charles B. Pratt. Ped. Clin. N. Am 19:1141–1155 (November), 1972

Management of malignant solid tumors in children : Charles B. Pratt. Ped. Clin. N. Am 19:1141–1155 (November), 1972

Management of Malignant Solid Tumors in Children

Multidisciplinary approaches are vital in the treatment of these malignant tumors. Accurate diagnosis and staging must precede any attempt at therapy. Improved pediatric surgical techniques, supervoltage radiotherapy, and the availability of effective chemotherapeutic agents have all contributed to better results.