Fifty years of paediatric malignant bone tumours in the West Midlands, UK, 1957-2006: incidence, treatment and outcome.

Malignant bone tumours in the paediatric age group (0-14 years) are uncommon; various aetiological theories exist and few reports of incidence, age and sex distributions have been published. We examined the incidence of childhood malignant bone tumours in one large single region of the UK over an extended period of 50 years. The West Midlands specialist regional children's tumour registry holds data on all malignancies and benign brain tumours in children under 15 years in the West Midlands region, which has a population of around 1 million children. Demographic and clinical data have been abstracted and diagnoses reviewed by a panel of expert pathologists. During the period 1957-2006, 259 cases of malignant paediatric bone tumours were diagnosed. There were 153 osteosarcomas, 78 Ewing sarcomas and 28 other primary bone tumours. The overall age standardised rate was 4.66, with no increase over time, although there was a significant increase in the incidence of Ewing sarcomas in the period 1965-92. Sixty-eight per cent of tumours were in patients over 10 years, whereas the incidence in patients under 10 years showed a non-significant increase. Survival rates increased dramatically post-chemotherapy introduction, with Ewing sarcoma demonstrating better survival overall. This is a large study giving an overview of malignant bone tumours in the childhood population of a single region over an extended period, showing results consistent with national reports. It also examines late effects, which were mostly mobility/orthopaedic, although almost one-fifth of patients had cardiac problems and five went on to develop second malignancies.

Paediatric malignant tumours of the gastrointestinal tract in the West Midlands, UK, 1957-2000: a large population based survey.

BACKGROUND: To investigate the incidence, clinical characteristics and survival of malignant tumours of the gastrointestinal tract in children in the West Midlands in Britain over a 44-year span time, to identify any change over this period and to compare the data with the world literature. PROCEDURE: Retrospective population based study. Fifty-seven patients were identified from the records of the West Midlands Regional Children's Tumour Registry. Age-standardised incidence rates were calculated using the world standardised population method. Statistical tests used were the Log rank test and survival curves were produced using the Kaplan-Meier method. RESULTS: The age-standardised incidence of overall gut tumours during the period 1957-2000 was 1.10/million/year. The age standardised incidence of non-Hodgkin lymphoma (NHL) was calculated as 0.9/million/year and for adenocarcinoma 0.14/million/year. CONCLUSION: Malignant tumours of the gastrointestinal tract remain rare in children. No changing trends in incidence were observed over the 44-year period. NHL was the commonest malignancy overall and of the small bowel while equal number of adenocarcinoma and NHL were identified in the large bowel. There was no significant difference in survival between sexes, site and age groups in both NHL and adenocarcinoma. Survival has improved over the last four decades for NHL patients but remains poor for the adenocarcinoma patients.

Molecular cytogenetic characterization of two non-MYCN amplified neuroblastoma cell lines with complex t(11;17).

The pediatric tumor neuroblastoma is characterized by a very variable, and at times unpredictable, pattern of clinical behavior, ranging from a benign localized tumor to an aggressive malignancy with poor prognosis. Standard clinical and pathological assessments do not always differentiate reliably between tumor subtypes and, therefore, genetic markers are now playing an increasingly important role in treatment decisions. MYCN oncogene amplification, for example, provides a useful marker of poor prognosis. However, less than one-half of all patients who present with, or who later develop, metastatic disease show MYCN amplification. Consequently, the identification of characteristic patterns of genetic alteration in the remaining tumors is of importance. In this report, we describe two new cell lines that we have established from metastatic, non-MYCN amplified, advanced stage neuroblastomas. These cell lines show a number of features in common, including unbalanced translocation between 11q and 17q, loss of 3p, 4p and 11q and gain of 17q. Therefore, they provide a valuable resource for the characterization of genetic pathways leading to aggressive tumor growth in non-MYCN amplified neuroblastomas.

Migration of CD18-deficient neutrophils in vitro: evidence for a CD18-independent pathway induced by IL-8.

Neutrophils isolated from a child with severe leukocyte adhesion deficiency 1 (LAD1) had a complete absence of expression of the CD11/CD18 beta2 integrin family of adhesion molecules, and were shown to be deficient in the in vitro adhesion and migration properties. However, we found that interleukin-8 (IL8), a potent chemoattractant for neutrophils, and sputum sol phase induced these LAD1 neutrophils to migrate through an endothelial cell layer in vitro, and confirmed that this migration was CD18-independent. These findings add to evidence of CD18-independent mechanisms of neutrophil recruitment, in particular neutrophil infiltration into the lungs, where IL8 may be an important recruitment factor.

Pediatric oncology and hematology in Birmingham, England.

The hematology and oncology service at Birmingham Children's Hospital was established in the late 1960s and now is one of the largest in the United Kingdom. It provides comprehensive care for the entire range of childhood malignancies, coagulation disorders, and hemoglobinopathies and other hematological disorders, and undertakes bone marrow transplant and megatherapy/peripheral blood stem cell procedures. Research includes clinical trials of treatments of childhood cancers; molecular biology studies on leukemia, Hodgkin's disease, neuroblastoma, and sarconas; childhood cancer epidemiology, and geographical and racial incidence; and treatment of hemophilia and molecular investigation of coagulation disorders. These activities involve collaboration with local, national, and international research groups.

Paraganglioma of the vagina: the first report of a rare tumor in a child.

Paraganglioma (extra-adrenal pheochromocytoma) is a rare tumor, particularly in childhood. Those in the female genital tract are exceptionally rare, with only 9 cases reported in detail since 1926. All were seen in adults and only two arose in the vagina. This study examined the incidence of this tumor in the childhood population of the West Midlands region of the United Kingdom since 1957 and found 4 cases: 2 abdominal, 1 para-aortic, and 1 carotid body. A recent additional case is reported in the vagina of a child aged 11 years, who presented with heavy vaginal bleeding in the absence of hypertension. Initial diagnosis suggested rhabdomyosarcoma and near complete excision was carried out. Since this is the first such case to be described in a child, the outcome can only be assumed. Although histopathological examination suggested the benign nature of the tumor, implying that surgical excision was sufficient treatment, close follow-up is recommended.

The need for specialist review of pathology in paediatric cancer.

A retrospective histopathological review of 2104 cases of solid tumour was carried out to assess the variability in diagnosis of childhood cancer. Cases were subject to three independent, concurrent opinions from a national panel of specialist pathologists. The conformity between them was analysed using the percentage of agreement and the kappa statistic (kappa), a measure of the level of agreement beyond that which could occur by chance alone, and weighted kappa (w kappa), which demonstrates the degree of variation between opinions. The major groupings of the Birch-Marsden classification were used within which tumours were assigned for kappa analysis according to the clinical significance of the differential diagnoses. The mean agreement for all tumours together was 90%; kappa = 0.82, w kappa = 0.82. Retinoblastoma achieved the highest kappa value (1.0) and lymphoma the lowest (0.66). Of the cases, 16.5% had their original diagnoses amended and the panel confirmed the original diagnosis of paediatric pathologists in 89% of cases compared with 78% for general pathologists. The varying levels of agreement between experts confirm the difficulty of diagnosis in some tumour types, suggesting justification for specialist review in most diagnoses. Specialist training in paediatric pathology is also recommended.

Induction toxicity of a modified Memorial Sloan-Kettering-New York II Protocol in children with relapsed acute lymphoblastic leukemia: a single institution study.

Although the chance of cure for children with acute lymphoblastic leukaemia (ALL) is high, their outlook with subsequent relapse is poor. Bone marrow transplantation may be an option for some, but the need for intensive reinduction chemotherapy regimens remains the best hope for effecting cure in the majority of relapsed children. The authors report the experience of using an intensive chemotherapy protocol (Memorial Sloan-Kettering-New York II Protocol, MSK-NY-II) in a series of relapsed children with ALL. Thirty children presenting to the Royal Alexandra Hospital for Children, Sydney, in their first relapse of ALL were treated according to a modification of the original MSK-NY-II protocol. Three children (10%) died during induction therapy, two from overwhelming Gram-negative sepsis, and one from intracerebral haemorrhage. Of 27 children completing induction, two children failed to enter remission; however, both had planned deviations from the protocol. Infectious complications were prominent with a total of 55 admissions for febrile neutropenic episodes. Eight children required the support of the intensive care unit for infectious complications. A total of 36 microbiological isolates were obtained from the patients during induction therapy. Ten bone marrow transplant procedures have been subsequently performed in these children, of whom five are alive and disease free at the time of writing. The MSK-NY-II protocol is an intensive regimen but with encouraging early remission rates in relapsed childhood ALL. Early sepsis in previously immunosuppressed children is an important cause of induction death.

Ifosfamide nephrotoxicity in children: histopathological features in two cases.

We report on two children with rhabdomyosarcoma who received ifosfamide as part of their chemotherapy schedule. Both children subsequently developed severe ifosfamide-induced nephrotoxicity, necessitating electrolyte supplementation. We describe the histopathological findings of renal biopsies performed in these children after the onset of renal dysfunction and comment on the possible mechanisms involved in ifosfamide nephrotoxicity.

Effectiveness of HB2 (anti-CD7)--saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice.

The transplantation of the human T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2 into severe combined immunodeficient (SCID) mice was found to produce a disseminated pattern of leukaemia similar to that seen in man. The intravenous injection of 10(7) HSB-2 cells was associated with a universally fatal leukaemia. Histopathological examination of animals revealed the spread of leukaemia initially from bone marrow to involve all major organs including the meninges. An immunotoxin (HB2-Sap) was constructed by conjugating the anti-CD7 MAb HB2 to the ribosome-inactivating protein saporin. An in vitro protein synthesis inhibition assay revealed specific delivery of HB2-Sap immunotoxin (IT) to CD7+ HSB-2 target cells with an IC50 of 4.5 pM. When SCID mice were injected with 10(6) HSB-2 cells and then treated 8 days later with a single intravenous dose of 10 micrograms of immunotoxin there was a significant therapeutic effect evidenced by the numbers of animals surviving in the therapy group compared with untreated controls (chi 2 = 5.348, P = 0.021). These results demonstrate the useful application of human leukaemia xenografts in SCID mice and the potential therapeutic effect of an anti-CD7 immunotoxin in human T-ALL.

Immunotoxin studies in a model of human T-cell acute lymphoblastic leukemia developed in severe combined immune-deficient mice.

The transplantation of the human T-cell acute lymphoblastic leukemia (T-ALL) cell line HSB-2 into severe combined immune-deficient (SCID) mice was found to produce a disseminated pattern of leukemia similar to that seen in humans. The iv injection of 10(7) HSB-2 cells was associated with a universally fatal leukemia. Histopathological examination of animals revealed the spread of leukemia initially from bone marrow to involve all major organs including the meninges. An immunotoxin (HB2-Sap) was constructed by conjugating the anti-CD7 monoclonal antibody (MAb) HB2 to the ribosome inactivating protein (RIP) saporin. An in vitro protein synthesis inhibition assay revealed specific delivery of HB2-Sap immunotoxin (IT) to CD7+ HSB-2 target cells with an IC50 of 4.5 pM. In an in vivo study, the IT was shown to significantly prolong the survival of SCID mice injected with HSB-2 cells compared to untreated control animals. This therapeutic effect was seen both with a single injection of 10 micrograms of IT given 7 d after the injection of HSB-2 cells, and was even more effective when IT was administered as three daily injections of 10 micrograms on d 7, 8, and 9. These results demonstrate the useful application of human leukemia xenografts in SCID mice and the potential therapeutic effect of an anti-CD7 IT in human T-ALL.

Cutaneous squamous cell carcinoma following treatment for acute lymphoblastic leukaemia.

The importance of second malignant neoplasms following successful treatment of childhood malignancy is of concern to all professionals involved with the care of these patients. We present an 18 year old patient with a squamous cell carcinoma of his lower lip following prolonged treatment for acute lymphoblastic leukaemia in childhood. The rarity of this tumor in this age group and the aetiological factors involved in developing the second malignancy are discussed.