Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92.

Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the most commonly deleted coding sequence. Bi-allelic deletion was associated with high white blood cell count (WBC) (P < 0.001), T cell phenotype (P < 0.001) and mediastinal mass (P < 0.001). Patients with Ink4 locus bi-allelic deletions had an inferior pEFS (P < 0.01) and multivariate analysis indicated that bi-allelic deletion of the p16ink4a and the p14ARF genes was an independent prognostic risk factor (P < 0.05). Sub-group analysis revealed a pronounced impact of deletion status for high-risk patients, ie with high WBC. Deletion-status and clinical risk criteria (WBC) could thus be combined to further differentiate risk within the high-risk group. The analysis of the Ink4 locus adds independent prognostic information in childhood ALL treated by Nordic protocols and may help in selection of patients for alternative treatment.

Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation.

UNLABELLED: Familial haemophagocytic lymphohistiocytosis (FHL) is a rare, autosomal recessive disease of infancy and early childhood clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, rash, neurological symptoms and icterus. Common laboratory findings include cytopenia, elevated liver enzymes, hyperbiliriubinaemia, hypofibrinogenaemia and hypertriglyceridaemia. The natural killer cell function is frequently decreased or absent. A diffuse lymphohistiocytic infiltration is seen in the reticuloendothelial system, often with haemophagocytosis. Molecular diagnosis is available in a minority of FHL families. Without adequate treatment and bone-marrow transplantation, the disease is fatal. A 6-wk-old child with FHL is presented. Shortly before the clinical onset of the disease, blood testing and bone-marrow examination had been carried out. All results were considered normal at that time. CONCLUSION: Blood tests and bone-marrow examination may be normal shortly before the clinical presentation and therefore do not exclude the diagnosis of FHL. There is a need for extended molecular diagnostic possibilities.

Immunoglobulin class and subclass concentrations after treatment of childhood leukemia.

With greatly increased survival rates after childhood leukemia during the last 3 decades, the long-term effects of the treatment have become more evident. The disease and its treatment impair the immune system, but the duration of this impairment is unknown. The authors studied the serum concentrations of immunoglobulins and IgG subclasses in 20 Icelandic children cured of leukemia on average 8 years and 3 months after their treatment ended. Although no marked deviations were found in the concentrations of the main immunoglobulin classes IgA, IgM, IgG, and IgE, the IgG subclass levels were below reference values. The patients had on average 0.9 of age standardized reference values of IgG1, 0.5 of IgG2, 0.8 of IgG3, and 0.7 of IgG4. However, none had any autoimmune diseases or a markedly increased tendency for infections. The results indicate that although the immunoglobulin classes regain their normal values within a few years after cessation of treatment, recovery of the IgG subclasses, especially IgG2, is impaired.

[Wilms' tumor in Iceland 1961-1995. A retrospective study.].

OBJECTIVE: Wilms' tumor is a malignant disease in the kidneys that usually affects young children. Information about the clinical behaviour of this tumor in Iceland has been scarce. The aim of this study was to find the incidence, clinical presentation, treatment and survival of patients with Wilms' tumor. MATERIAL AND METHODS: Included in the study were all patients diagnosed with Wilms' tumor in Iceland from 1st of January 1961 to 31st of December 1995. Altogether, there were 17 patients, 15 children, mean age 33 months (standard deviation 19, range 5-77 months) and two adults (age 25 and 29), with M/F ratio 0.7. Information was gained from each patient's record and the cancer registry of the Icelandic Cancer Society. All the tumors were re-evaluated by a pathologist and staged according to the NWTS staging system. RESULTS: Age adjusted incidence during the study period was 0.2/100,000 per year (1.0 for children under 15 years). Abdominal mass (65%) and abdominal pain (53%) were the most common symptoms. Histology was typical in all cases except one with anaplasia and another with sarcomatous growth. One patient was diagnosed in stage I (6%), six in stage II (35%) and seven in stage III (41 %). Two patients had pulmonary metastases (stage IV) and one had bilateral tumor (stage V). Nephrectomy was performed in all cases. The operative mortality was 12%. Of the 15 patients surviving surgery, 12 received radiotherapy, 12 chemotherapy and nine both treatments. Crude five-year-survival for the whole group was 42%, 25% for the patients diagnosed 1961-1976 and 61% for those diagnosed 1977-1995 (p=0.13). The patient with bilateral tumor was still alive 13 years after diagnosis. CONCLUSION: As in other Western countries, Wilms' tumor is rare in Iceland and has similar incidence and clinical presentation. Two thirds of the patients were diagnosed in stage II or III. Even patients with distant metastases can be cured with multimodal treatment: surgery, chemotherapy and radiotherapy. There was a trend toward better survival during the study period.

Second malignant neoplasms in patients treated for childhood leukemia. A population-based cohort study from the Nordic countries. The Nordic Society of Pediatric Oncology and Hematology (NOPHO).

Among a cohort of 981 children who were followed up 4.3-26.5 years after cessation of antileukemic therapy, eight patients in remission of acute lymphoblastic leukemia (ALL) developed a distinctively new malignant disease. The second malignant neoplasms (SMN) included brain tumors, basal cell carcinomas, thyroid cancer, leiomyosarcoma and finally rhabdomyosarcoma in a patient who also had suffered from Hodgkin's disease while still on antileukemic treatment. Cranial radiation had been given to 58.4% of the patients in the study group, which consisted of 895 ALL patients who had completed various chemotherapy protocols. With one exception, the SMN appeared after 7.5-16.5 years at a location previously exposed to radiotherapy (RT). The estimated cumulative risk of SMN appearing within 20 years after diagnosis was 2.9%, and the corresponding risk for cases with RT was 8.1% compared to 0.3% for those without (p = 0.05). In a Cox regression analysis, the incidence rate ratio of SMN between patients with and without RT was 6.7 (95% CI = 0.8, 57.7). Based on age-, year- and sex-specific cancer incidence figures for Norway, the overall standardized incidence rate ratio (SIR) of SMN after treatment for ALL was 5.9 (95% CI = 2.2, 12.9). The number of brain tumors among patients who had received cranial radiation was nearly 27 times greater than expected, whereas no such tumors were seen after chemotherapy. Individuals treated for childhood ALL are at increased risk of a new malignancy, and this seems mainly to be associated with previous irradiation.