Biomedical subjects
Publications and source records attributed to H Hasle.
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UNLABELLED: Cranial irradiation in children with acute lymphatic leukaemia (ALL) decreases the risk of CNS relapse but is associated with serious long-term side-effects. We present the long-term outcome of 21 children with high-risk ALL who received prolonged intrathecal chemotherapy instead of the recommended cranial irradiation. Intrathecal triple therapy (methotrexate, hydrocortisone, and cytarabine) was administered every 2nd month throughout the maintenance phase. The average number of courses of intrathecal methotrexate was 8.7 and of triple 9.0. The 5-year event-free survival was 79%. No CNS relapses occurred. CT scan was performed at diagnosis, at cessation of therapy, and 3 years thereafter. No density abnormalities, pathological contrast enhancement, ventricular dilatation, or calcifications were found. One child showed cortical atrophy both at diagnosis and at cessation of therapy. There was a slight decrease in height SDS with time but no change in weight SDS. Delayed bone age was found in 5 children. No abnormalities of growth hormone, thyroid, adrenal, or gonadal function were observed. CONCLUSION: The study indicates that extended intrathecal chemotherapy in children with high-risk ALL may provide an effective protection from CNS relapses and is associated with a low risk of long-term side-effects.
Trisomy 8 is a frequently acquired cytogenetic abnormality in myeloid malignancies, but may also represent a constitutional chromosome abnormality with a wide phenotypic variation. We report a case of myelodysplastic syndrome (MDS) that developed in a child with trisomy 8 mosaicism and normal phenotype. Bone marrow (BM) cells all showed trisomy 8 with additional clonal abnormalities in most cells. Based on the present case and a review of previously published cases of myeloid malignancies in patients with trisomy 8 mosaicism, it appears likely that the malignant cells developed from the trisomic cell population, suggesting that constitutional trisomy 8 may be a predisposing condition to myeloid malignancies. Trisomy 8 in malignant cells is usually considered an acquired abnormality, but this implies a risk of ignoring a constitutional trisomy 8 mosaicism. Examination for constitutional trisomy 8, despite a normal phenotype, may therefore be warranted in hematologic malignancies with trisomy 8 of BM cells to evaluate further the possible association and to preclude erroneous use of trisomy 8 as a tumor marker.
Many case reports have suggested an association between Klinefelter syndrome (KS) and cancer, but studies of the cancer incidence in larger groups of men with KS are lacking. A cohort of 696 men with KS was established from the Danish Cytogenetic Register. Information on the cancer incidence in the cohort was obtained from the Danish Cancer Registry and compared with the expected number calculated from the age, period and site specific cancer rates for Danish men. A total of 39 neoplasms were diagnosed (relative risk = 1.1). Four mediastinal tumours were observed (relative risk = 67); all four were malignant germ cell tumours. No cases of breast cancer or testis cancer were observed. One case of prostate cancer occurred within a previously irradiated field. No excess of leukaemia or lymphoma was found. An increased risk of cancer occurred in the age group 15-30 years (relative risk = 2.7). All six tumours in this group were germ cell tumours or sarcomas. The overall cancer incidence is not increased and no routine cancer screening seems to be justified. A considerably elevated risk of mediastinal germ cell tumours occurs in the period from early adolescence until the age of 30.
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Myelodysplastic syndrome (MDS) in childhood is considered to be very rare, but sound epidemiologic data are lacking. We report a population-based study of MDS in Denmark from 1980 to 1991. The medical charts were reviewed of 988 children identified from the Danish National Hospital Discharge Registry with a diagnosis of myeloid leukemia or blood cytopenia. Blood and bone marrow smears from all cases of possible MDS were re-evaluated. The cases were categorized according to the FAB classification, with the exception of chronic myelomonocytic leukemia (CMML) in which more than 5% myeloblasts in the blood was accepted. Juvenile chronic myeloid leukemia (JCML) was included as CMML. MDS was diagnosed in 46 children representing 9% of all hematologic malignancies in children less than 15 years of age. The annual incidence was 4.0/million and did not increase with time. Refractory anemia with excess of blasts and CMML each accounted for one third of the cases. Down syndrome was present in seven children. Other predisposing conditions included Fanconi anemia, neurofibromatosis, constitutional trisomy 8 mosaicism, and familial leukemia. Only one child had therapy-related MDS. The study indicates that the incidence of childhood MDS is higher than generally assumed and approximate to the incidence of acute myeloid leukemia.
Pancytopenia followed by a period of spontaneous recovery may precede the diagnosis of acute lymphoblastic leukemia (pre-ALL). Although both pre-ALL and myelodysplastic syndromes are preleukemic in a strictly temporal sense, there are several marked differences between the two conditions. We present eight children with pre-ALL who represented 2% of all cases of childhood ALL. The bone marrow was normo- or hypocellular with increased reticulin fibrosis during the pre-ALL phase. No cytogenetic abnormalities were found at the pre-ALL phase, but had developed at the time of overt leukemia in four of the six children examined. Based on the findings in our patients and on cases reported in the literature, we argue that pre-ALL is likely to represent a paraneoplastic syndrome early in the leukemic development that might be mediated via inhibitory properties related to clonally expanding but still cytogenetically normal cells. The findings may indicate a multistep pathogenesis of ALL.
Much of the applied terminology of myelodysplastic syndromes (MDS) in childhood is confusing and not mutually exclusive. It is therefore proposed that the FAB classification of MDS is used in children in order to improve diagnostic precision and to facilitate epidemiologic, clinical, and therapeutic comparisons. The true incidence of childhood MDS is unknown but the rate may approximate the incidence of acute myelogenous leukemia. A pooled analysis of eight larger series representing 110 children less than 15 years old at diagnosis with de novo MDS classified according to the FAB recommendations showed that the more aggressive subtypes dominated, which partly may reflect that the less advanced cases are underdiagnosed. The median age at presentation was 6.0 years. The male/female ratio was 1.6. Monosomy 7 was the most frequent cytogenetic abnormality. The median survival was 13 months and the probability of survival three years from diagnosis was 16%. Spontaneous remission may be observed very infrequently. Allogeneic bone marrow transplantation (BMT) represents the only potentially curative treatment. The survival rate three years after BMT is about 50%. Major differences between childhood and adult MDS exist with respect to the distribution of FAB subgroups, the rate of progression, and the cytogenetic findings. The literature on MDS in children is still sparse and there is an obvious need for more studies designed to determine the incidence, clinical and laboratory characteristics, the natural course, and the efficacy of contemporary treatment options.
PURPOSE: We present a report of a child with subclinical immunodeficiency who became chronically infected with parvovirus resulting in pancytopenia and morphologic abnormalities in the bone marrow mimicking myelodysplastic syndrome (MDS). PATIENTS: An 8-year-old boy presented with severe anemia, moderate thrombocytopenia and granulocytopenia. The patient showed hyper-immunoglobulin M (IgM) immunodeficiency but no increased susceptibility to infections. The bone marrow was hypercellular with dysplastic granulocytopoiesis and erythroblastopenia. RESULTS: Treatment with cyclosporine and i.v. Ig resulted in temporary normalization of the hemoglobin level. For several years it was assumed that the patient had MDS. A diagnosis of parvovirus infection was initially rejected due to the lack of specific antibodies and the absence of giant pronormoblasts in the bone marrow. When the polymerase chain reaction technique became available, parvovirus DNA was detected from the entire disease course. CONCLUSIONS: This case report expands our conception of the clinical spectrum of parvovirus infection and emphasizes that parvovirus must be considered as a differential diagnosis in MDS. We recommend performing a parvovirus DNA test despite negative serologic findings in patients with MDS, especially when associated with immunologic abnormalities.
The purpose of the study was to examine the incidence of unrecognised Hodgkin's disease (HD) as cause of death and to search for clinical features that could have ensured a correct pre-mortem diagnosis. A review of cases of HD reported to the Danish Cancer Registry from 1976 through 1987 in patients younger than 70 years old disclosed 27 where HD was the primary cause of death and the diagnosis was unrecognised at the time of death. The majority of the patients had no concurrent diseases and may have benefitted from a correct diagnosis and a potentially curative treatment. Most of the patients had persistent unexplained fever and weight loss. Pancytopenia, hepatic involvement, bone marrow involvement, advanced stage disease, and lymphocytic depletion histology were also frequent findings. Peripheral or retroperitoneal lymphadenopathy was noted in nine patients without biopsy. The many uncommon features of HD together with the frequent findings of falsely negative chest X-ray, bone marrow examination, liver biopsy, and abdominal ultrasound contributed to the difficulty in diagnosis. However, in about 1/3 of the patients clinical findings suggestive of lymphoma did not result in relevant diagnostic procedures.
Human Herpesvirus 6 (HHV-6) is the sixth human pathogenic Herpesvirus. It was isolated for the first time in 1986. The virus is isolated from blood and saliva and it is probable that it is latent in salivary glands and possibly also in blood. The most probable route of infection is droplet infection via saliva and thereafter possibly by blood. Sero-epidemiological investigations demonstrate that newly born infants are practically all passively immunised via maternal antibodies. At about the age of six months, HHV-6 antibody can be demonstrated in a minority of children. From the age of two years and until 50 years, HHV-6 antibody is present in 90-100% of the population. This is in agreement with the extensive HHV-6 infection in the age group from six months to two years. It is demonstrated that HHV-6 is the cause of exanthema subitum. It is uncertain whether HHV-6 is of pathogenetic significance for other diseases.
All cases of Hodgkin's disease (HD) notified to the Danish Cancer Registry from 1976 through 1987 in patients less than 70 years old were reviewed in order to identify patients in whom a correct diagnosis was established only post mortem. The case records of such patients were reviewed in a search for clinical features that could have ensured a correct pre mortem diagnosis. HD was diagnosed after death in 31 patients in this unselected population based study and thus constituting only 2.4% of all patients less than 70 years with HD, but 14.1% of the group aged 65-69 years. Most patients were identified during the first part of the study period, which may reflect a decreasing autopsy rate. HD was considered to be a coincidental finding in four patients and the primary cause of death in 27 patients. Among the later 27 patients a number of unfavourable prognostic factors were a common finding: persistent unexplained fever and weight loss, pancytopenia, hepatic involvement, bone marrow involvement, advanced stage disease, and lymphocytic depletion histology. However, most of the patients had no concurrent diseases and may have benefitted from a correct diagnosis and a potentially curative treatment. The many uncommon features of HD together with the frequent findings of falsely negative chest X-ray, bone marrow examination, liver biopsy, and ultrasound contributed to the difficulty in diagnosis. In about 1/3 of the patients clinical findings suggestive of lymphoma did not result in relevant diagnostic procedures.
This study was performed to examine the cancer risk of Danish gardeners having been highly exposed to pesticides. We have followed a cohort of 4,015 employed gardeners (859 females and 3,156 males) from May 1975 until the end of 1984 with regard to cancer incidence. The observed incidence was compared with expected numbers calculated from national incidence rates. For all cancer sites combined, the standardized morbidity ratio (SMbR) was 104. Among male gardeners a significantly increased incidence was seen for soft tissue sarcoma (SMbR = 526, 95% confidence interval (CI): 109-1,538), an chronic lymphatic leukemia (SMbR = 275, 95% CI: 101-599). The incidence of non-Hodgkin's lymphoma was twice that which was expected (SMbR = 200, 95% CI: 86-393). We suggest that some of the pesticides to which the gardeners have been exposed are capable of initiating or promoting the development of malignant neoplasms in tissues of mesenchymal origin.
A 14-year-old boy with Klinefelter syndrome (KS) and a large mediastinal tumour is presented. Human chorionic gonadotropin and oestradiol were markedly increased. An attempt at radical resection was performed. Histological examination revealed a malignant germ cell tumour of mixed histologic pattern composed of choriocarcinoma and components of mature teratoma. Four courses of cisplatin, bleomycin, and etoposide were given. The patient is without any evidence of tumour recurrence 20 months after diagnosis. A review of the literature revealed another 40 cases of primary mediastinal germ cell tumour (PMGCT) associated with KS. Compiled data from larger series demonstrate that at least 8% of male patients with PMGCT have KS, 50 times the expected frequency. In contrast to PMGCT in patients without KS, all tumours were of nonseminomatous histology, and the average age was considerably lower, Tumours in prepubertal boys were associated with precocious puberty.
Nine cases of de novo myelodysplastic syndromes (MDS) in childhood from a population based study are presented. The annual incidence of MDS was 3.4/1,000,000 in children less than 15 years old, corresponding to 8.7% of all haematological malignancies in childhood. Two patients had Down's syndrome. None of the remaining patients had constitutional anomalies. All patients were classified according to the FAB classification. Five patients presented with refractory anaemia (RA), only one of these did not progress, one showed clonal evolution, and the remaining three patients all progressed to refractory anaemia with excess of blasts (RAEB). Three patients presented with RAEB. Two progressed to overt leukaemia. The last patient was classified as chronic myelomonocytic leukaemia (CMML). Clonal cytogenetic abnormalities were detected in five patients, in three of them as monosomy 7. Five patients have died; two of progressive disease, two of infections, and one of haemorrhage, two of the latter three patients died during therapy induced cytopenia. Of the four patients still alive, one patient showed a complete remission after cyclosporine and later immunoglobulin therapy, one patient is a long-term survivor after allogeneic bone marrow transplantation, and one patient apparently obtained a spontaneous remission several months after chemotherapy.
Alkoxyglycerol derived from shark liver oil is marketed in Denmark and mentioned in popular articles as a supplementary agent in the treatment of cancer. A questionnaire investigation carried out in the Department of Oncology and Haematology in Odense Hospital revealed that approximately 1/3 of the patients in active neoplastic therapy employed shark liver oil preparations. The clinical investigations of alkoxyglycerol were all carried out on patients with cancer of the uterine cervix. All of the investigations were carried out by the same Swedish research group. Only a minority of the experimental material was blinded. No documentation was found for inhibited tumour growth or reduced mortality resulting from treatment with alkoxyglycerol. The number of cases of irradiation damage were found to be fewer in the groups treated with alkoxyglycerol, but the difference may be partially explained by different subdivision into stages. Alkoxyglycerol results in increase in the leukocyte and thrombocyte counts while higher or lower doses have, apparently, the opposite effect. The available literature concerning the clinical effect of alkoxyglycerol is limited and unsystematic and does not support the employment of alkocyglycerol in the treatment of cancer.
The recommended management of localised Merkel cell carcinoma has been wide surgical excision, combined with adjuvant radiotherapy in selected cases. The risk of recurrent regional disease is reported to be between 30% and 45%. A patient with a Merkel cell tumour on the cheek is presented in this paper. The patient was treated exclusively with radiotherapy to a total dose of 40 Gy. The tumour regressed rapidly during the treatment and there were no signs of local recurrence. However, the patient died of metastatic disease 31 months after initial diagnosis. A review of the literature revealed an additional eight cases of localized disease who did not undergo complete surgical excision but were primarily treated with radiotherapy alone. Regional recurrence was not found in any of the cases. One of the patients died of metastatic disease. Together with the review of the literature the present case provides evidence of the radiosensitivity of the Merkel cell carcinoma of the skin. The available data suggest that radiotherapy may be valuable as the primary treatment of localized biopsy-verified disease.