Congenital intestinal lymphatic hypoplasia presenting as non-immune hydrops in utero, and subsequent neonatal protein-losing enteropathy.
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Adult↗
Biomedical subjects
V Tobias
Publications and source records attributed to V Tobias.
Medulloblastoma/primitive neuroectodermal tumour studied as a Matrigel enhanced subcutaneous xenograft model.
An important role for pre-clinical models of medulloblastoma/primitive neuroectodermal tumour (MB/PNET) is inhibited by the limitations of conventional heterotransplantation. Nine cohorts of MB/PNET were studied for subcutaneous engraftment in nude mice by both conventional and Matrigel supplemented methods. While no subcutaneous tumours resulted from 63 conventional attempts, an aggregate 41 xenografts from 72 injections (57%) were produced when Matrigel was added to the cell suspension. In subsequent passage, engraftment rate approached 100%. To study the response to chemotherapeutic agents in the model, a total of 221 tumours in 3 cohorts were treated using one of the following: cisplatin, carboplatin, vincristine, cyclophosphamide, diaziquone, or saline control. While all agents demonstrated statistically significant activity, cyclophosphamide proved to be particularly effective. The potential applications of this xenograft model in the biologic as well as therapeutic study of MB/PNET deserve continuing investigation.
Animals↗
The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review.
Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.
Age of Onset↗
Brain-invasive meningioma in a 16-month-old boy.
A previously well 16-month-old boy presented to Sydney Children's Hospital with generalised seizures. There was no history of neurofibromatosis and no family history. Imaging revealed a well-demarcated, frontal intracranial mass at the grey-white matter junction with surrounding oedema. At operation, the tumour was adherent to the underlying brain on its deep aspect but superficially connected to the dura. There was an associated peritumoural cyst. The tumour was biopsied for intra-operative frozen section opinion and excised in its entirety. The specimen consisted of a 25 x 25 x 17 mm nodule of firm cream tissue and separate fragments. Histologically, the tumour was a meningioma with frequent mitoses, necrosis and brain invasion. Optimal treatment, in view of the recurrence risk, includes complete excision and postoperative irradiation. The latter was deferred because of the young age. At follow-up at 26 months, the child was well and free of disease on MRI scan. Paediatric meningiomas are rare, with very few brain-invasive examples in reported series. In infants and young children, few meningiomas have been reported. There are several notable differences between meningiomas in children and adults. This report illustrates these differences.
Brain Neoplasms↗
The Sydney Children's Hospital experience with the oral iron chelator deferiprone (L1).
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Australia↗
Nuchal fibroma should be recognized as a new extracolonic manifestation of Gardner-variant familial adenomatous polyposis.
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Adenomatous Polyposis Coli↗
ECLS in pertussis: does it have a role?
OBJECTIVES: To investigate the value of extracorporeal circulatory life support (ECLS) in paediatric patients with severe Bordetella pertussis infection. DESIGN: Single case report and a review of the ECLS database. SETTING: Tertiary referral hospital paediatric intensive care unit. PATIENTS AND PARTICIPANTS: A single case report of an infant with B. pertussis infection is described. Despite receiving ECLS, this infant died from overwhelming cardiac and cerebral insults. Outcome for children receiving ECLS registered on the Extracorporeal Life Support Organization database is reviewed. MEASUREMENTS AND RESULTS: The mortality of infants receiving ECLS for B. pertussis infection is high, with only 5 survivors reported among 22 registered cases. The majority of nonsurvivors had evidence of circulatory collapse in addition to severe respiratory failure, and these patients commonly died of hypoxic-ischaemic cerebral insult. These data suggest the existence of a subgroup of patients with respiratory failure only, who may benefit from ECLS, and a larger subgroup who suffer ischaemic cardiac and cerebral insults which are unlikely to be improved by ECLS. CONCLUSIONS: The value of ECLS in patients with B. pertussis infection who present with major cardiac dysfunction is questionable. Such patients almost invariably have a poor outcome despite maximal therapy.
Diseases in Twins↗
Molecular detection of acute lymphoblastic leukaemia in boys with testicular relapse.
AIMS: To determine the role of polymerase chain reaction (PCR) based minimal residual disease (MRD) detection of leukaemia specific DNA in testicular relapse in childhood acute lymphoblastic leukaemia. METHODS: DNA was obtained from archival testicular and bone marrow samples from boys with acute lymphoblastic leukaemia who relapsed in the testes. Overlapping DJH clone specific primers derived from clonal immunoglobulin heavy chain (IgH) gene rearrangement in each case were used to analyse testicular or bone marrow DNA. RESULTS: Histologically normal end of treatment testicular biopsies in the five patients in longterm remission were all MRD negative, but MRD positive in three of six boys with subsequent testicular relapse. Histologically normal bone marrow samples taken at the end of treatment were MRD negative in five of seven cases, but MRD positive in all cases at the time of isolated testicular relapse. Three boys with unilateral testicular relapse underwent unilateral orchidectomy, rather than bilateral testicular irradiation, as part of their treatment. Two of these boys were MRD positive in the histologically uninvolved testes, and both had subsequent relapses either in the testes or the bone marrow, while the MRD negative patient has not had a testicular relapse. CONCLUSIONS: The presence of MRD in testicular tissue can be assayed with a PCR based method to detect clone specific antigen receptor gene rearrangements. In this setting, PCR is more sensitive than conventional testicular histology for predicting clinical outcomes. MRD assays might be useful in the management of boys at the time of isolated testicular relapse, to confirm the presence of unilateral testicular disease.
Bone Marrow↗
Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase.
Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.
Amino Acid Substitution↗
Prognostic significance of chemotherapy dosage characteristics in children with osteogenic sarcoma.
High-dose methotrexate (HDMTX), adriamycin (ADR), and cisplatinum (CDDP) are effective agents in the treatment of osteogenic sarcoma (OS). Individual patient doses are determined by prior successful clinical trials but may be reduced due to ongoing toxicities. It is unknown whether individualized dose reductions of these drugs influence disease outcome. We retrospectively studied 27 consecutively enrolled children treated with HDMTX, ADR, and CDDP as adjuvant chemotherapy for OS, for correlations between disease outcome and several characteristics of drug dosings the cumulative MTX, CDDP, and ADR doses administered and the mean MTX blood levels for each patient. With a median follow-up of 59 months, the actuarial overall and disease-free survival rates were 70% and 59%, respectively. Factors which favorably influenced prognosis on univariate analysis were a cumulative ADR dose of > 300 mg/m2 (P = 0.0002) and a cumulative MTX dose > 114 gm/m2 (P = 0.0048). By multivariate analysis only the cumulative ADR dose > 300 mg/m2 retained prognostic value. We conclude that adjuvant chemotherapy dosages may need to be adjusted for therapeutic efficacy in addition to adjustments made for toxicity. The effect of different cumulative HDMTX and ADR dosages on prognosis in osteosarcoma patients needs to be evaluated in a prospective trial.
Adolescent↗
Response of brain tumors to chemotherapy, evaluated in a clinically relevant xenograft model.
Chemotherapy for brain tumors remains unsatisfactory. Despite increasing participation in clinical trials, there is a clear need for pre-clinical models. Heterotransplantation of surgical specimens directly into the anterior chamber of the nude mouse eye has been demonstrated to produce evaluable xenografts. Drug access in this model is considered to mimic the blood-brain barrier. Five clinical specimens in 3 children with primitive neuroectodermal tumor/medulloblastoma were the sources of 293 intraocular xenografts (5 cohorts by source). Each tumor-bearing mouse received 1 of 5 drugs or normal saline, by intraperitoneal injection, weekly for 5 weeks. Response was monitored for up to 22 weeks, using a staging system which estimates the proportion of the anterior chamber filled by tumor. Results were analysed both as response rates (shrinkage in excess of 50%) at the conclusion of the treatment course and as time to tumor progression by the life table method. Comparison of response rates within cohorts by source of xenografts (exact chi-square test for overall and 2-sided Fisher's exact test for paired comparisons) indicated cyclophosphamide to be the most effective single agent. In logrank analyses cyclophosphamide achieved significantly longer delays to progression than all other drugs in one cohort and longer delays than all but diaziquone in 2 other cohorts. The intraocular xenograft model is a clinically relevant system for the study of therapeutic agents in brain tumors. The effectiveness of intensive dosage cyclophosphamide in a model dependent on access across the blood-aqueous barrier is important and consistent with recent clinical data.
Animals↗
Heterotransplantation of early B-lineage acute lymphoblastic leukemia using a solubilized attachment matrix (Matrigel).
Maintenance of long term culture and conventional xenografting of early B-lineage acute lymphoblastic leukemia cells is most difficult. Matrigel, a solubilized attachment matrix shown to aid growth of anchorage dependent solid tumors, was studied in heterotransplantation. Material for xenografting was derived from 5 patient bone marrow aspirates and 5 cell lines previously established and maintained by intraocular inoculation in nude mice. Specimens were injected by 3 methods: intraocular (n = 397); s.c. in medium (n = 78); and s.c. in medium supplemented by Matrigel (n = 69). With intraocular injection, 6 of 10 cell sources grew with respective ingraftment rates of 29-76%. Using the conventional s.c. method, no tumors resulted. The addition of Matrigel produced s.c. ingraftment from 8 of 10 cell sources (ingraftment rate, 50-100%). Immunophenotype, histopathology, and karyotype of the cells derived after Matrigel dependent ingraftment correlated with the cells of origin. It is concluded that Matrigel enables establishment and maintenance of early B-lineage acute lymphoblastic leukemia cell growth in a s.c. xenograft model.
Animals↗
Local failure in childhood rhabdomyosarcoma and undifferentiated sarcoma: prognostic factors and implications for curative therapy.
In this retrospective review, the risk factors for local failure in childhood rhabdomyosarcoma and undifferentiated sarcoma were assessed in 49 patients managed by a multi-disciplinary team at the Prince of Wales Children's Hospital, Sydney, between 1970 and 1988. Average follow-up time was 6.1 years. Sixteen of 49 patients experienced local failure defined as local recurrence after complete excision (5/20) or progressive local disease following incomplete resection (11/29). Fourteen of 16 patients who experienced local failure have died. Using logrank analysis of time to local failure, we found significantly increased risk with "non-embryonal" histology (P = 0.032), residual tumour (P = 0.052, higher IRS group (P = 0.088), "inadequate radiotherapy" for residual tumour (P = 0.001), delay in definitive local treatment (P = 0.038) and Adriamycin-containing chemotherapy (P = 0.017). When these factors were examined by multivariate analysis (Cox regression), only the presence of residual tumour after resection, "inadequate radiotherapy" for residual tumour (P < 0.001), and delay in definitive local therapy (P < 0.037) were shown to have independent significant association with local failure. We conclude that local failure may be avoided by prompt local treatment by either complete surgical resection or adequate radiotherapy.
Adolescent↗
Helicobacter pylori infection in children: potential clues to pathogenesis.
Children (227) undergoing endoscopy for upper gastrointestinal symptoms were investigated for the presence of Helicobacter pylori infection. The histological response to H. pylori infection and the presence of antral nodularity and peptic ulceration were noted. Symptomatic adults (258) undergoing endoscopy were also investigated for the presence of nodularity. H. pylori infection was detected histologically in 32 of 227 (14.1%) children. Of those children infected with H. pylori, half (50%) had antral nodular gastritis. Of 139 H. pylori-positive adults 22 (15.8%) showed nodularity. The active component of the histological response was found to be minimal or lacking in the majority of children infected with H. pylori. Twelve of the 227 children (5.3%) had peptic ulcer disease. Of these, nine were duodenal and three gastric ulcers. Of the nine children with duodenal ulceration three (33%) were infected with H. pylori. As a result of this study we conclude that (a) although antral nodularity occurs more frequently in children it is not exclusive to childhood, (b) the polymorphonuclear response in children is less than that reported in adults, and (c) peptic ulcer disease is rare in children and the present study would suggest that in children it is less frequently associated with H. pylori infection than in adults.
Acute Disease↗
Acute Helicobacter pylori infection in an infant, associated with gastric ulceration and serological evidence of intra-familial transmission.
Reports of the clinical picture and laboratory findings associated with naturally acquired acute H. pylori infection are rare and, although family studies have suggested person-to-person transmission, there have been no accounts of serologically proven intra-familial spread. This report describes the clinical and histological features associated with acute H. pylori infection in an infant and includes serological evidence for the possible transmission of this organism within his direct family. The infant, who presented with acute vomiting and severe haemetemesis, was found on endoscopy to have two shallow ulcers in the gastric antrum. Evidence of H. pylori infection was provided by the urease test, histology, and serology, the latter two tests showing the infection to be acute. Serologically, the patient's mother was shown to have an established H. pylori infection prior to her son, his twin brother to have acquired the infection shortly before the patient, and his father to have become infected some 63 days after the patient. Information on the acute presentation of H. pylori in children and evidence of the spread of H. pylori within family members is presented.
Acute Disease↗
Second intracranial neoplasms following treatment of childhood acute lymphoblastic leukaemia.
We report a boy with acute lymphoblastic leukaemia (ALL) treated with chemotherapy and prophylactic cranial irradiation to a dose of 24 Gy. Six years after diagnosis he developed a glioma and died. Prior to 1979, four cases of second malignant neoplasm (SMN) of the brain had been reported in children treated for ALL. These SMNs occurred within 2 years of the original diagnosis (median 1.3 years) and at least two of four patients had not received prior radiotherapy. Since 1979, 28 cases of SMN of the brain have been reported including nine of 468 (1.9%) long-term survivors in one study. All occurred more than 3.7 years from diagnosis (median 6.5 years; range 4-13 years) and all received cranial irradiation (median 24 Gy; range 20-48 Gy). These data indicate a change in the pattern of SMNs which is most likely due to the introduction of cranial irradiation. As well, the frequency of SMNs in children treated for ALL appears to have increased, although it is still no greater than the risk of SMNs developing following the treatment of any other primary childhood neoplasm.
Antineoplastic Combined Chemotherapy Protocols↗
Heterotransplantation of human lymphoid neoplasms using a nude mouse intraocular xenograft model.
There are few effective models for the study of human lymphoid neoplasms, including in vivo xenografts in immunocompromised animals. Exploiting the additional immune privilege of the anterior chamber of the nude mouse eye, a novel method of direct heterotransplantation of cells from childhood leukemias and lymphomas has been developed. The establishment and characterization of 18 lymphoid xenograft cell lines maintained in the nude mouse intraocular model are reported. Cell sources for heterotransplantation were specimens of bone marrow, peripheral blood, or lymphomatous masses obtained at either diagnosis or recurrence of disease in the patients. The 18 patients and resultant cell lines were grouped into four immunophenotypic categories: Category 1, B-lineage (pre-B and early pre-B), "common" acute lymphatic leukemias; Category 2, cell lines of similar immunophenotype derived from patients with unusual features; Category 3, B-cell neoplasms and cell lines; and Category 4, neoplasms and cell lines in part or totally of T-cell origin. With reference to these groupings, rates of ingraftment from clinical specimens varied according to immunophenotype and disease status: Category 1, 1 of 15 at diagnosis, 5 of 7 at relapse; Category 2, 1 of 1 at diagnosis, 2 of 2 at relapse; Category 3, 6 of 6 at diagnosis; and Category 4, 2 of 9 at diagnosis, 1 of 1 with persistent disease. Rearrangements of the genes for immunoglobulin heavy chain or kappa light chain and for beta subunit of the T-cell receptor gene were demonstrated according to immunophenotype, with the exception of one cell line which showed no rearrangements. Evidence of Epstein-Barr virus DNA was shown in only one cell line, of B-cell immunophenotype. Cytology, histopathology, and electron microscopy in representative patient and xenograft samples demonstrated correlations between the specimens of origin and cells or sections from ingrafted tumors in mice. It is concluded that the direct heterotransplantation of cells from childhood leukemias and lymphomas to the anterior chamber of the nude mouse eye provides a relevant and reproducible model for the maintenance and study of human lymphoid neoplasms.
Animals↗
Arrhythmogenic right ventricular dysplasia in a child with congenital enteropeptidase deficiency and hypogammaglobulinaemia.
A case of arrhythmogenic right ventricular dysplasia in a 10 year old girl is described which provides some evidence for an inherited aetiology of this unusual form of heart disease. The parents of this child were first cousins, thus increasing the possibility of inherited disorders in their offspring. She had been known from infancy to have the rare disorder of congenital deficiency of intestinal enteropeptidase, and low serum immunoglobulins G and A. An untyped adenovirus was grown from a myocardial biopsy taken early in the course of her cardiac disease. However, it is unlikely that this virus was a major factor in the aetiology of her cardiac disease. Both the cardiac and intestinal diseases are now commonly believed to result from hereditary factors, and this report provides further support for this view.
Agammaglobulinemia↗