Carboplatin and neuroblastoma.
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Biomedical subjects
Publications and source records attributed to J Pritchard.
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Retinoblastoma and Wilms' tumor in children are sometimes associated with small constitutional chromosome deletions on chromosomes 13 and 11, respectively. This finding has highlighted regions of the human genome which are potentially important in the predisposition to the development of cancer. By using techniques in molecular biology, it is possible to isolate DNA sequences from specific chromosomes. Then, by using either a panel of somatic cell hybrids containing different overlapping deletions or in situ hybridization, it is possible to assign these DNA sequences to regions of particular chromosomes. DNA sequences isolated from within the frequently deleted regions will prove useful not only to improve understanding of the basic mechanism underlying cancer predisposition, but also to possibly allow prenatal diagnosis for those at risk.
To test its diagnostic potential and sensitivity in paediatric malignancy, serum NSE was measured at diagnosis in 191 children with solid tumours and 25 with acute leukaemia. In stages I + II, III + IV and IVs neuroblastoma median levels were 18.0, 91.0 and 24.0 ng ml-1 respectively. For Wilms' patients, median values for stages I, II, III and IV disease were 16.6, 18.0, 29.0 and 47.0 ng ml-1 respectively. High levels of NSE were also found in patients with other types of tumour. Children in clinical remission after treatment for neuroblastoma invariably had normal NSE levels (mean +/- s.d. = 9.2 +/- 3.0 ng ml-1) even though the majority had radiologically identifiable residual disease. The values rose when relapse was radiologically or clinically obvious. We conclude (a) that, though levels of greater than 100 ng ml-1 are highly suggestive of advanced neuroblastoma, caution should be exercised in using serum NSE as a diagnostic test in children with cancer and (b) that serum NSE levels are not a sensitive index of residual neuroblastoma in patients, with initially elevated levels, that are receiving treatment.
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Twenty-five patients with progressive or recurrent neuroblastoma were treated with single-agent ifosfamide. In 2 of 10 relapsing patients, an objective response was observed. If ifosfamide is administered in a dose of 3000 mg/m2 for 2 days every 3 weeks, a response can be expected in 8% of the cases.
There are still many areas of controversy concerning Langerhans cell histiocytosis. This article addresses the main controversies and highlights the central factors of this disease, which further investigation should elucidate.
Dosimetric data from UJ13A scanning studies using 131I are presented for children with stage IV neuroblastoma and primary brain tumor. The data demonstrate a large variation among patients in dose delivery to vulnerable organs and tumors. Against this background, a phase I toxicity study is under way with escalating amounts of conjugate administered to patients who have stage IV neuroblastoma. Major toxicity has been confined to bone marrow aplasia and necessitates bone marrow harvest prior to therapy. Specific problems encountered include altered kinetics during therapy following tracer studies and adequate dose delivery in large tumor masses.
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We conducted a randomized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves the chances of relapse-free survival in patients with nonmetastatic high-grade osteosarcoma of the extremity, as compared with concurrent controls. After undergoing definitive surgery, 36 patients were randomly assigned to adjuvant chemotherapy or to observation without adjuvant treatment. At two years the actuarial relapse-free survival was 17 percent in the control group, similar to that found in studies before 1970, and 66 percent in the adjuvant-chemotherapy group (P less than 0.001). Similar results were observed among 77 additional patients who declined to undergo randomization but who elected observation or chemotherapy. We conclude that the natural history of osteosarcoma of the extremity has remained stable over the past two decades, that adjuvant chemotherapy increases the chances of relapse-free survival of patients with high-grade osteosarcoma, and that it should be given to all such patients.
Two young patients presented with generalised lymphadenopathy, otorrhoea, otitis, and rash. Over the next few years chronically discharging sinuses began to form over enlarged nodes and histological appearances were typical of histiocytosis X. In neither case were micro-organisms isolated from the lesions, and in both patients healing occurred with immunosuppressive agents. Chronic dermal sinus formation secondary to lymph node disease has never before been recorded as a manifestation of histiocytosis X. Histiocytosis X should therefore be considered in the differential diagnosis of "suppurative" lymphadenopathy so that appropriate treatment may be given without delay.
A 12 year old girl with a localised fibrolamellar hepatoma had a raised serum unsaturated vitamin B12 binding capacity (UBBC) and transcobalamin I (TCI) prior to complete resection and chemotherapy. Regular clinical and radiological follow-up detected no recurrence of her disease, but the UBBC and TCI slowly rose. Local recurrence and pulmonary metastases became detectable 2 1/2 years after diagnosis, 18 months after the UBBC and TCI level became elevated. Measurement of UBBC and TCI can help in the early detection of recurrence long before there is clinical or radiological evidence of recurrent fibrolamellar hepatoma.
Between 1982 and 1984, 24 consecutively diagnosed children from Iraq with non-localised Burkitt lymphoma (Murphy stages II, III, and IV) were eligible for treatment with a multi-drug rotating chemotherapy schedule. This schedule was intensive and included early treatment directed at the central nervous system but was of only six months' duration and fairly inexpensive compared with schedules recently advocated for use in the developed world. Some patients had 'debulking' abdominal surgery, but no radiation treatment was used. There were a number of complications related to early treatment, some of them fatal, but of 13 patients entering complete remission 12 are long term survivors who are free of disease and, hopefully, cured. These results represent a substantial improvement over our experience before 1982 (6.9% survival). A similar treatment approach might be adopted by other centres, especially those in developing countries where cancer accounts for a rising proportion of childhood death but whose resources are limited.
During 1984, 46 women attended the sexually transmitted disease (STD) clinic at St Mary's Hospital alleging that they had been raped. At presentation, 31 (67%) were asymptomatic. Evidence of STD was found in 14 (30%) women, mixed infections occurring in four. Chlamydia trachomatis and Trichomonas vaginalis were each detected in six (13%) patients and Neisseria gonorrhoeae in three (6%). The source of the infection could not confidently be traced to the alleged rapist. Two patients were found to have cervical cytological abnormalities suggestive of cervical intraepithelial neoplasia of grades II or III. One woman became pregnant as a consequence of the sexual assault. Investigations may unveil infection or other abnormalities, which are incidental to the rape but nevertheless require further investigation and treatment.
The experience of 12 children with atypical psychosomatic illness who presented considerable diagnostic difficulties is described. All patients were admitted to the hospital, and using a team approach, it was possible to make a confident diagnosis. No organic disease was identified, and a psychosomatic diagnosis was made. In general, atypical symptoms and signs, false-positive investigations, and differing medical opinion had compounded the diagnostic difficulties. The value of the observations made by ward staff of the childrens' symptoms and behavior is stressed.
A consecutive series of 13 children (five girls) with advanced malignant germ cell tumors (MGCTs) were treated with between four and seven (median, six) courses of cisplatin, bleomycin, and either vinblastine (BVP) or VP-16 (BEP). There were seven gonadal primaries (four testis, three ovary) and six at extragonadal sites (three sacrococcyx, two thoracic, one extradural). Total or subtotal removal of primary tumor was carried out in nine patients at diagnosis and two others after some chemotherapy. Clinical complete remission (CR) was achieved in nine of ten patients with measurable disease and serum markers returned to normal in all 13 patients. Eleven remain disease-free 17 to 48 months (median, 28 months) after diagnosis. One patient (stage IV sacrococcygeal tumor) relapsed at the primary site 3 months after completing treatment, but is disease-free after further surgery, radiotherapy, and chemotherapy. Serial glomerular filtration rates were performed during treatment. Audiometry and pulmonary function tests were carried out where possible. Toxicity led to alteration of drug scheduling in two cases, but there were no permanent clinical renal, auditory, or pulmonary sequelae. These encouraging results confirm that MGCTs in children are as responsive as those in adults to cisplatin-containing chemotherapy and indicate that they may be as curable. The regimens are relatively well-tolerated and, with close monitoring, clinically significant toxicity should be avoidable.
Monoclonal antibody UJ13A radiolabelled with isotopes of iodine has been shown to selectively localize to human neuroblastoma xenografts. When 131I-UJ13A conjugates were given to nude mice at high doses (100-150 microCi), tumours temporarily disappeared, only to regrow. No selection for neuroblastoma cells that were UJ13A - negative was observed. Distribution studies on mice receiving radiolabelled UJ13A demonstrated the antibody is rapidly lost from the blood of animals. This cannot be accounted for by selective uptake into xenografts or any other mouse organ examined. We concluded there is a rapid equilibration of isotope between intra- and extravascular spaces in the animal. The rapid, biphasic loss of UJ13A from the blood of mice may explain why so little injected antibody can target to the human tumour xenografts.