OCCURRENCE OF ACUTE NONLYMPHOBLASTIC LEUKEMIA IN TWO GIRLS AFTER TREATMENT OF RECURRENT, DISSEMINATED LANGERHANS CELL HISTIOCYTOSIS

The occurrence of Langerhans cell histiocytosis (LCH) and acute leukemia in one individual has rarely been observed. Despite few exceptions, two distinct patterns of association appear evident: acute lymphoblastic leukemia preceding LCH and LCH preceding acute nonlymphoblastic leukemia (ANLL). The latency of ANLL after the diagnosis of LCH is suggestive of a therapy-related process. This report describes two new cases in whom ANLL was diagnosed 7 years 8 months and 5 years 8 months after the start of initial treatment of disseminated recurrent LCH. Morphology showed blasts from FAB-type M4/M5 in the first patient, who died due to progression of leukemia. The second patient showed myelodysplastic syndrome (refractory anemia with excess of blasts in transformation; RAEB-t) and is now in remission from leukemia 3 years 11 months after allogeneic bone marrow transplantation. The review of a total of 26 patients with ANLL after LCH suggests that the disease has a poor prognosis and allogeneic BMT seems to be the treatment of choice.     

PERMANENT DISABILITIES IN CHILDHOOD SURVIVORS OF LANGERHANS CELL HISTIOCYTOSIS

This study evaluates the permanent disabilities in children treated for Langerhans cell histiocytosis (LCH). From January 1983 to December 1993, 50 patients with newly diagnosed biopsy proven LCH were seen at the Regional Cancer Centre, Trivandrum, India. Disease pattern, treatment, survival, and disabilities of the patients were studied. Patients with localized disease had surgery, irradiation, or steroids. Patients with disseminated disease had combination chemotherapy. Follow-up ranged from 36 to 156 months (median follow-up 85 months). Twelve of the 41 surviving patients (29.2%) had one or more disabilities. Growth retardation was seen in 8 patients, diabetes insipidus in 7, loss of teeth in 6, and mandibular defect, chronic aural discharge, partial hearing loss, facial palsy, and proptosis in 2 each. In short, a significant proportion of survivors of LCH had sequelae, which affected their quality of life. More intensive chemotherapy at the beginning might be helpful in reducing the disabilities.     

LANGERHANS CELL HISTIOCYTOSIS: Retrospective Evaluation of 123 Patients at a Single Institution

The aim of this study was to retrospectively evaluate clinical characteristics at diagnosis and outcome of patients with Langerhans cell histiocytosis (LCH). From October 1987 to March 1996, 133 patients with confirmed LCH were admitted to Hospital JP Garrahan in Buenos Aires (123 evaluable). Median age was 5 years (range 15 days to 18 years). Initial organ involvement included bone 114 patients, ear 34, skin 30, liver 18, lung 14, lymph nodes 14, spleen 12, diabetes insipidus 9, and bone marrow 2. Nineteen patients had organ dysfunction, pulmonary 14, hematological 14, and hepatic 12. Two groups were defined: Group A included patients with single system disease (unior multifocal) and group B multisystem (with or without organ dysfunction). In group A (n = 82), 24 patients were treated with chemotherapy (prednisone and vinblastine), 21 with surgery, 15 received radiotherapy, and 22 were only observed. Patients of group B ( n = 41) were treated with chemotherapy consisting of prednisone and vinblastine, DALHX 83, or LCH1-based chemotherapy. At a median follow-up of 3 years (range 1 month-8 5/12 years) 93% of patients of group A and 39% of group B survive free of reactivation. In group B, 22% had a reactivation and 39% died of progressive disease. Sequelae were detected in 35 patients (28%), which included diabetes insipidus in 17, hearing loss in 13, bony sequelae in 11, sclerosing cholangitis in 6, and lung fibrosis with bullae in 6. Two patients had a subsequent malignant disease. A total of 17 (14%) patients died and 16 of them belonged to the group B: 13 died of progressive disease, 2 due to sclerosing cholangitis (with sepsis in one case and encephalitis in the other one), 1 with progressive disease and associated myelofibrosis, and 1 patient of group A with active disease and brain stem tumor. Patients who had organ dysfunction had a reactivation free survival of 32%. All these patients survived with sequelae. Logistic regression analysis showed that organ dysfunction and hematological involvement had significant predictive values in relation to death. Patients of group A had an excellent survival rate, whereas in those of group B a high mortality was found, especially in the subgroup of patients with organ dysfunction. Lahey's criteria should be revised. Sequelae were also more common in this group.     

LANGERHANS CELL HISTIOCYTOSIS: Retrospective Evaluation of 123 Patients at a Single Institution

The aim of this study was to retrospectively evaluate clinical characteristics at diagnosis and outcome of patients with Langerhans cell histiocytosis (LCH). From October 1987 to March 1996, 133 patients with confirmed LCH were admitted to Hospital JP Garrahan in Buenos Aires (123 evaluable). Median age was 5 years (range 15 days to 18 years). Initial organ involvement included bone 114 patients, ear 34, skin 30, liver 18, lung 14, lymph nodes 14, spleen 12, diabetes insipidus 9, and bone marrow 2. Nineteen patients had organ dysfunction, pulmonary 14, hematological 14, and hepatic 12. Two groups were defined: Group A included patients with single system disease (unior multifocal) and group B multisystem (with or without organ dysfunction). In group A (n = 82), 24 patients were treated with chemotherapy (prednisone and vinblastine), 21 with surgery, 15 received radiotherapy, and 22 were only observed. Patients of group B ( n = 41) were treated with chemotherapy consisting of prednisone and vinblastine, DALHX 83, or LCH1-based chemotherapy. At a median follow-up of 3 years (range 1 month-8 5/12 years) 93% of patients of group A and 39% of group B survive free of reactivation. In group B, 22% had a reactivation and 39% died of progressive disease. Sequelae were detected in 35 patients (28%), which included diabetes insipidus in 17, hearing loss in 13, bony sequelae in 11, sclerosing cholangitis in 6, and lung fibrosis with bullae in 6. Two patients had a subsequent malignant disease. A total of 17 (14%) patients died and 16 of them belonged to the group B: 13 died of progressive disease, 2 due to sclerosing cholangitis (with sepsis in one case and encephalitis in the other one), 1 with progressive disease and associated myelofibrosis, and 1 patient of group A with active disease and brain stem tumor. Patients who had organ dysfunction had a reactivation free survival of 32%. All these patients survived with sequelae. Logistic regression analysis showed that organ dysfunction and hematological involvement had significant predictive values in relation to death. Patients of group A had an excellent survival rate, whereas in those of group B a high mortality was found, especially in the subgroup of patients with organ dysfunction. Lahey's criteria should be revised. Sequelae were also more common in this group.     

SIMULTANEOUS OCCURRENCE OF ADVANCED NEUROBLASTOMA AND ACUTE MYELOID LEUKEMIA

The authors report the case of a 4-year-old boy with a diagnosis of stage IV neuroblastoma (NB), who had been treated with 6 cycles of cyclophosphamide, doxorubicin, cisplatin, and etoposide for 12 months. The patient reached partial remission and presented a diagnosis of acute myelomonocytic leukemia (M4 AML), confirmed by immunophenotyping. After 2 months of therapy for leukemia, the child died with both malignancies in activity. A necropsy histologically confirmed the simultaneity of the two diseases. The authors review the possibilities of this association. The review leads to the conclusion that AML can occur as a secondary malignancy after the onset of the neuroblastoma, or be suggested by a misdiagnosis. The simultaneous occurrence of both as described here is not, however, found in the literature, to the best of the authors' knowledge.     

SUCCESSFUL TREATMENT OF ASPERGILLUS BRAIN ABSCESS IN A CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Cerebral aspergillosis carries a high mortality in immunocompromised patients. However, favorable outcome can be achieved by the prolonged use of antifungal agents and the maintenance of adequate drug levels. The authors report a 2-year-old girl who developed an aspergillus brain abscess during treatment for acute lymphoblastic leukemia. Predisposing factors for thefungal infection and details of the antifungal therapy are described. Prolonged treatment with AmBisome and 5-flucytosine successfully eradicated the lesion, but the girl's antileukemic therapy was compromised due to the infection. She developed a central nervous system and bone marrow relapse 9 and 15 months, respectively, after the initial presentation. The report emphasizes the need for further consideration of effective, long-term anti fungal prophylaxis and a careful balance between aggressive treatment for severe infection and antileukemic therapy.     

RADIOLOGICAL EVALUATION OF PATIENTS WITH PITUITARY LANGERHANS CELL HISTIOCYTOSIS AT DIAGNOSIS AND AT FOLLOW-UP

This study evaluated pituitary imaging findings in 13 patients with Langerhans cell histiocytosis (LCH) with diabetes insipidus. Nine patients were evaluated with pituitary magnetic resonance imaging (MRI), 3 with brain computed tomography, and 1 with brain MRI. The infundibulum was thickened in 11 (84.6%) patients, thread-like in 1 (7.7%), and normal in 1 (7.7%). Posterior pituitary intensity was absent in 10 patients (76.9%); in 4 patients, the pituitary gland was small in size, and 2 patients had atrophic pituitary. Three had a small sella. Infundibular thickening and absence of posterior pituitary intensity were the most common radiological findings. MRI imaging should be used to follow up patients with pituitary histiocytosis, and patients with LCH and diabetes insipidus should be followed for pituitary atrophy.     

OVERALL AND EVENT-FREE SURVIVALS FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN AT A SINGLE INSTITUTION IN TAIWAN

The results of treatment for childhood acute lymphoblastic leukemia (ALL) have improved dramatically over the past three decades. The authors present the long-term outcome of patients ( n = 151) with ALL enrolled in 4 consecutive clinical trials conducted from 1982 to 1993 at Mackay Memorial Hospital. During this period, the backbone of the treatment remained relatively unchanged, including a 3- to 4-drug remission induction, central nervous system(CNS)-directed therapy, and cyclic pulses of vincristine and dexamethasone during maintenance therapy. More intensive therapy, consisting of reintensification and addition of more drugs during maintenance, was reserved for high-risk and very-high-risk paitents. The overall survival and event-free survival ( &#45 1 SE) were 70 &#45 4.1% and 64 &#45 4.3%, respectively, with follow-up ranging from 7.6 to 18.7 years (median 12.2 year). The isolated CNS relapse rate was 4.3%. The dropout rate significantaly decreased from 35% in 1982-1984 to 0% in 1991-1993. Although the patient population is small, the overall results for childhood ALL at the authors' hospital are encouraging as compared to earlier reports in Taiwan.     

OVERALL AND EVENT-FREE SURVIVALS FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN AT A SINGLE INSTITUTION IN TAIWAN

The results of treatment for childhood acute lymphoblastic leukemia (ALL) have improved dramatically over the past three decades. The authors present the long-term outcome of patients ( n = 151) with ALL enrolled in 4 consecutive clinical trials conducted from 1982 to 1993 at Mackay Memorial Hospital. During this period, the backbone of the treatment remained relatively unchanged, including a 3- to 4-drug remission induction, central nervous system(CNS)-directed therapy, and cyclic pulses of vincristine and dexamethasone during maintenance therapy. More intensive therapy, consisting of reintensification and addition of more drugs during maintenance, was reserved for high-risk and very-high-risk paitents. The overall survival and event-free survival ( ±1 SE) were 70 ±4.1% and 64 ±4.3%, respectively, with follow-up ranging from 7.6 to 18.7 years (median 12.2 year). The isolated CNS relapse rate was 4.3%. The dropout rate significantaly decreased from 35% in 1982-1984 to 0% in 1991-1993. Although the patient population is small, the overall results for childhood ALL at the authors' hospital are encouraging as compared to earlier reports in Taiwan.     

TREATMENT OF CHILDHOOD ACUTE MYELOGENOUS LEUKEMIA WITH ALLOGENEIC AND AUTOLOGOUS STEM CELL TRANSPLANTATION DURING THE FIRST REMISSION: A Report from the Kyushu-Yamaguchi Children's Cancer Study Group in Japan

Hemophilic pseudotumor is an uncommon complication seen in approximately 1–2% of patients with severe hemophilia. Hemophilic pseudotumors are distinguished into two subdivisions based on location, proximal or distal. Plain x-rays and CT are useful in diagnosis, but MR imaging is the diagnostic test of choice because of its sensitivity to the various blood products. The choice of therapy depends on many parameters, such as the size of the tumor, the age of the patient, and the relation with underlying organs. In most cases of asymptomatic hemophilic pseudotumor, conservative treatment with administration of missing factor as well as immobilization is recommended. The authors describe a 13-year-old boy with severe hemophilia A, who presented with a tibial pseudotumor a few months after an injury. He was conservatively treated for a long period, with daily administration of recombinant factor VIII. His clinical condition improved shortly after therapy induction, but radiological improvement has been moderate. Case history, imaging findings, and therapeutic options are discussed.     

NEUROPSYCHOLOGIC SEQUELAE IN THE LONG-TERM SURVIVORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The neurotoxicity of either systemic chemotherapy or central nervous system prophylaxis was studied in 19 children treated for acute lymphoblastic leukemia (ALL). They had completed ALL therapy at least a year before and survived more than 5 years after diagnosis. The duration between age at diagnosis and age at investigation was 8.6 2.7 years (5-15 years). Neuropsychologic tests, cranial magnetic resonance imaging (MRI), and evoked potentials (EP) were studied. Seventeen healthy siblings were taken as a control group. Emotional evaluation was done using the childhood depression inventory and Beck depression inventory. Cognitive functions were evaluated using Wechsler's Intelligence Scale for Children-Revised (WISC-R) or the Wechsler's Adult Intelligence Scale-Revised (WAIS-R) tests, which were adapted to Turkish children. Performance and total IQ scores (94.0 16.8 and 92.2 16.5) were significantly low as compared to the control group (112.1 18.9 and 105.4 14.2) (p=.007 and p=.02). Abnormal MRI findings were found in 33.3% (6/18). Three out of 18 patients (16.6%) had abnormal auditory while 5 out of 17 patients (29.5%) displayed abnormal visual EPs. Abnormal findings in MRI, cognitive examination, and electrophysiologic testing were not associated with age at diagnosis, radiotherapy doses, intermediate/high-dose systemic methotrexate administration or central nervous system involvement. But more patients must be studied to demonstrate discrete outcomes of neurotoxicity in long-term survivors of childhood leukemia.     

THE ROLE OF PARVOVIRUS B19 INFECTION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The authors hypothesized that parvovirus B19 with its hematotropic effects has the potential to precipitate varying forms of cytopenia in patients prior to or at the diagnosis of acute lymphoblastic leukemia (ALL). Consequently, and in view of the increasing number of cases reported, this retrospective study evaluated, for the first time, the possible role of parvovirus B19 infection in pediatric patients suffering from ALL, by investigating the frequency and clinical relevance of this infection at the time of the malignant diagnosis or, when applicable, during a phase of pre-ALL. Furthermore, a review of reported parvovirus B19 infections in pediatric ALL patients is presented. The serum of 65 consecutive pediatric patients with a diagnosis of ALL was examined for possible parvovirus B19 infection employing the polymerase chain reaction and ELISA techniques. Specific IgG was demonstrated in 30% of the patients. One patient diagnosed with pre-ALL had evidence of parvovirus B19 DNA in the serum during pancytopenia 5 months prior to the onset of ALL. The results suggest that there is an insignificant chance of finding a parvovirus B19 infection in pediatric patients with ALL at the time of diagnosis. However, parvovirus B19 infection may infrequently serve as a prodrome to ALL.     

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.     

ACUTE LEUKEMIAS IN CHILDREN FROM THE CITY OF KIEV AND KIEV REGION AFTER THE CHERNOBYL NPP CATASTROPHE

During 1993-1997, 247 cases of childhood acute leukemia (AL) were analyzed among inhabitants of the city of Kiev and Kiev region, excluding the most contaminated areas belonging to the strict control zone. The criteria of an FAB classification supplemented by immunophenotyping data were applied. The AL pattern was shown to be quite typical except for several peculiar features characteristic of this regional group of patients, especially the absence of age peaks in children with acute myelogenous leukemias (AML), increased frequency of the T1 variant in T-cell acute lymphoblastic leukemia (ALL), and higher levels of M4 and M5 variants in AML. A typical variant of M5a-AML with minimal signs of differentiation was found.     

A NOVEL APPROACH TO TREATMENT WITH HIGH-DOSE STEROID AS A DIFFERENTIATION INDUCER IN CHILDREN WITH ACUTE MYELOBLASTIC LEUKEMIA

Several experimental studies have demonstrated that certain steroid hormones can induce differentiation of mouse myeloid leukemic cells to macrophages and granulocytes. We have shown that high-dose methylprednisolone treatment (HDMP, 20-30 mg/kg/day) can induce differentiation of leukemic cells to mature granulocytes in children with different morphological subtypes of acute myeloblastic leukemia (FAB AML M1, M2, M3, M4). In addition, apoptosis can also be induced in vivo and in vitro in AML blast by HDMP treatment. Short-course (3 to 5 days) HDMP treatment increases the hematopoietic CD34- positive progenitor cells in both bone marrow and peripheral blood in children with AML. Acceleration of leukocyte and neutrophil recovery has been obtained by the administration of short-course HDMP in chemotherapy-induced neutropenic children with AML. The addition of HDMP to anti leukemic chemotherapy increased the complete remission rate and prolonged the duration of remission in children with AML and significantly improved the outcome of AML children who presented with extramedullary infiltration. We suggest that the possibility of HDMP-induced differentiation and apoptosis should be evaluated in patients with other malignant diseases.     

MUTATIONS OF RETINOBLASTOMA GENE (Rb-1) AS A PROGNOSTIC FACTOR IN CHILDREN WITH ACUTE LEUKEMIA AND NEUROBLASTOMA

Rb-1 is a tumor suppressor gene encoding for a nuclear phosphoprotein acting as a cell cycle regulator, normally expressed in hematopoietic cells and more often inactivated by point mutations with predominance for exons 20-24. The aim of this study is to correlate the retinoblastoma-1 (Rb-1) gene mutations with the prognosis and progression of childhood acute leukemia and neuroblastoma. Bone marrow slides from 26 children with leukemia (18 acute lymphoblastic leukemia [ALL] and 8 acute myeloid leukemia [AML]) and 4 children with neuroblastoma were studied. Exons 20, 21, and 22 were amplified using the polymerase chain reaction technique. Single strand conformational polymorphism (SSCP) and heterodoublex analysis were performed to detect mutations. In ALL cases, two samples in exon 20 (11.11%), one in exon 21 (5.56%), and four in exon 22 (22.22%) had altered conformation. All but one of these cases were classified as high-risk leukemia patients who either relapsed or never achieved remission. Two of the AML cases who did not achieve remission and one of the neuroblastoma cases with concomitant bone marrow infiltration had altered conformation as well. The SSCP and heterodoublex analysis showed that all but one who did not belong to the high-risk group had the same altered conformation. These data suggest that Rb-1 gene could possibly be used as an independent prognostic factor for the acute leukemia of childhood and result in the intensification of chemotherapy. In solid tumors with bone marrow involvement it could play a role as a marker of aggressive disease.     

SLEEP-RELATED GONADOTROPIN RHYTHMS IN CHILDREN FOLLOWING TREATMENT OF ACUTE LEUKEMIA: RECOVERY OF THE HYPOTHALAMO-PITUITARY-GONADAL AXIS AFTER CHEMOTHERAPY AND CNS-IRRADIATION

ABSTRACT. Twelve children (5 girls and 7 boys, between the ages of 6 and 20 years) in complete remission from previous ALL who had completed their entire anti-leukemic treatment program and who had been off all chemotherapy for at least one year, were included in a study of sleep-related prolactin and gonadotropin rhythms. All the patients had received prophylactic CNS-irradiation. The patients in early puberty showed a sleep-dependent FSH rhythm. Patients in middle-to-late puberty had sleep-related FSH and LH rhythms, and estradiol and testosterone plasma concentrations were normal for their pubertal stage, suggesting recovery of the hypothalamo-pituitary-gonadal feedback system. We conclude that the neuro-endocrine axis is not permanently injured by CNS-irradiation and anti-leukemic therapy.