Hodgkin's disease as a second malignant neoplasm in childhood: report of a case and review of the literature.

There is a known association between lymphoid malignancy and Hodgkin's disease (HD), but the development of HD in children who have been treated for leukemia or lymphoma is very uncommon. Hodgkin's disease is, after retinoblastoma, the most common primary tumor that is associated with development of second malignant neoplasm. For reasons that remain to be determined, HD is very rare as a second malignancy [1, 2, 3]. We report the case of a eight-year-old girl who developed HD 6 years after treatment for common acute lymphoblastic leukemia (ALL). This case prompted us to review the published literature for cases of secondary HD in childhood. Our experience suggests that we should follow strictly our patients with ALL and be ready to intervene with invasive diagnostic procedures at the least suspicion of a second or recurrent neoplasm. The most frequent causes of second tumors are radiotherapy, genetic susceptibility and prior treatment with certain chemotherapeutic agents, such as nitrogen mustards. It is likely that any type of immunodeficiency, even without symptoms, might play a role in the development of second tumors in childhood.

Art therapy as support for children with leukemia during painful procedures.

BACKGROUND: Children with leukemia undergo painful procedures such as lumbar puncture and bone marrow aspiration. To overcome pain, certain units offer total anesthesia; others offer generic support; others offer no preparation at all. Since September, 1997, we have provided leukemic children with art therapy (AT), a nonverbal and creative modality that develops coping skills. Our goal is to prevent anxiety and fear during painful interventions as well as prolonged emotional distress. PROCEDURE: We treated 32 children aged 2-14 years. The modes of AT before, during, and after the punctures were as follows: clinical dialogue to calm children and help them cope with painful procedures; visual imagination to activate alternative thought processes and decrease the attention towards overwhelming reality and raise the peripheral sensitivity gate; medical play to clarify illness, eliminate doubts, and offer control over threatening reality; structured drawing to contain anxiety by offering a structured, predictable reality (the drawing) that was controllable by children; free drawing to allow children to externalize confusion and fears; and dramatization to help children accept and reconcile themselves to body changes. RESULTS: Children hospitalized before September, 1997, exhibited resistance and anxiety during and after painful procedures. By contrast, children provided with AT from the first hospitalization exhibited collaborative behavior. They or their parents asked for AT when the intervention had to be repeated. Parents declared themselves better able to manage the painful procedures when AT was offered. CONCLUSION: AT was shown to be a useful intervention that can prevent permanent trauma and support children and parents during intrusive interventions.

Acute neurotoxicity in children with B-lineage acute lymphoblastic leukemia (B-ALL) treated with intermediate risk protocols.

BACKGROUND: This study describes the incidence of acute neurotoxicity (NT) in children with B-lineage acute lymphoblastic leukemia (ALL) treated with three intermediate risk protocols that differ in the intensity of central nervous system (CNS) "prophylaxis. " PROCEDURE: A total of 122 patients (64 boys; median age 5.3 years) with B-lineage ALL without CNS leukemia diagnosed between February 1987 and December 1997 were enrolled in the intermediate risk (IR) protocols: Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-ALL 87 (n = 33), 91 (n = 51), and 95 (n = 38). Presymptomatic CNS therapy consisted of intrathecal methotrexate (six doses) and cranial irradiation (18 Gy) in the IR AIEOP 87 study, and extended triple intrathecal therapy with methotrexate, cytarabine, and prednisone depending on age in the IR AIEOP-ALL 91 and 95 protocols (20 and 17 total doses, respectively). World Health Organization (WHO) grade 4 acute neurotoxicity criteria were employed. Patients with neurologic symptoms, in addition to physical examination, underwent EEG, computed tomography (CT) and/or magnetic resonance imaging (MRI), and lumbar puncture to exclude CNS leukemia and infection. RESULTS: Acute NT was not reported in AIEOP-ALL 87 treated patients, but we observed acute NT in 3 out of 51 (5.8%) AIEOP-ALL 91 patients, and in 7 out of 38 (18.4%) AIEOP-ALL 95 patients. CONCLUSIONS: There was an increased incidence of acute NT in our patients with ALL treated with current intermediate risk protocols. The intensification of treatment, however, bettered event free survival (EFS) to 58%, 72% and 85% in IR AIEOP 87, 91 and 95 studies, respectively.

Deletions in the mitochondrial DNA and decrease in the oxidative phosphorylation activity of children with Fanconi syndrome secondary to antiblastic therapy.

The aim of this study is to verify whether there are deletions in mitochondrial DNA (mtDNA) and disorders in oxidative phosphorylation (Ox-phos) complexes in the pathogenesis of secondary Fanconi syndrome (FS). We studied 18 children with tumors who were previously treated with chemotherapy and were off therapy for at least 1 year. All the children had normal renal function at diagnosis. Only 4 children received ifosfamide (IFO) and platinum compounds. We evaluated renal function, Ox-phos activity measured on platelets, and mtDNA extracted from platelets for all patients. Only 2 patients, both treated with IFO and carboplatinum (CARBO) for Wilms' tumor and germ-cell tumor, respectively, developed FS 1 and 3 years after termination of therapy. They had decreased activities of Ox-phos that were statistically significant only for nicotinamide adenine dinucleotide (NAD)-reduced cytochrome-c reductase and cytochrome-c oxidase and specific and unidentified deletions in mtDNA that were not maternally inherited. Our data suggest that treatment with IFO and CARBO might be responsible for deletions in mtDNA, decreased activity of Ox-phos, and impaired rates of transport of D-glucose, phosphate, and amino acids.

Clonal stability in children with acute lymphoblastic leukemia (ALL) who relapsed five or more years after diagnosis.

Although most relapses of childhood acute lymphoblastic leukemia (ALL) occur 24-36 months after first CR has been achieved, few patients relapse 5 or more years after CR achievement. The assessment of clonality has proved to be useful in determining whether even those very late events represent the reoccurrence of the original clone or alternatively a secondary leukemia. To gain further information on clonal stability in such late relapse, we performed detailed comparative Southern blotting and PCR analyses of TcRdelta and TcRgamma gene rearrangements in five ALL at presentation and subsequent relapse which occurred more than 5 years after diagnosis. At least one stable rearranged allele of the TcRdelta and TcRgamma loci was traced in all cases at presentation and clinical relapse despite a wide heterogeneity of the pattern of rearrangements. Our study extends to a larger series of patients previous findings which have sought to analyze the phenomenon of clonal evolution in children relapsed after more than 5 years of CCR. With respect to the potential pitfalls in monitoring minimal residual disease in childhood ALL for the presence of clonal evolution, our results highlight the combination of two target genes (such as TcRgamma and TcRdelta) as a tool to reduce false negative MRD results.

The use of artificial neural networks methodology in the assessment of "vulnerability" to heroin use among army corps soldiers: a preliminary study of 170 cases inside the Military Hospital of Legal Medicine of Verona.

This article describes a preliminary study of screening/diagnostic instruments for prediction for large-scale application in the military field at the Neuropsychiatric Department of the Military Hospital of Legal Medicine of Verona and for the prevention of self-destructive behaviors, particularly through the use of drugs. 170 subjects divided into three subsamples were examined. The first subsample was characterized by a strong tendency towards normalcy, the second by a strong tendency towards pathology, and the third by a great variety of expressions of psychological and social problems, which were not necessarily related to drug use. These subjects were administered a questionnaire designed according to Squashing Theory principles (Buscema, 1994a). Answers were processed by an Artificial Neural Network created by Semeion in Rome (Buscema, 1996) and were compared with a standard clinical psychiatric assessment report and with the results of psychodiagnostic tests. Results document ANNs' remarkable ability to recognize subjects with declared, in exordium and "at risk" pathological behaviors. Blind results on learning and trial samples show a very high predictive capacity (over 90%). A comparison with the examined subjects' clinical report and the results of the first follow-up also document very high agreements. The broad variation of answers obtained in the third subsample allows further methodological reflections on the contribution of Artificial Neural Networks and Squashing Theory to the study of deviance, for both sociologists and clinicians, and not only for those in the field of drug addiction.

Detection of minimal residual disease: methods and relationship to outcome in T-lineage acute lymphoblastic leukemia.

The molecular basis of acute lymphoblastic leukemia (ALL) of both B-cell and T-cell lineages seems better understood using polymerase chain reaction (PCR) methods. The analysis of clone-specific junctional regions of rearranged genes for both Immunoglobulin (Ig H) and T-cell receptor (TcR) is the most sensitive tool for detection of minimal residual disease (MRD) in ALL. Because of the heterogeneity of all ALL patients examined in several studies, the detection of MRD at different times of treatment has not as yet been correlated with disease outcome. In contrast, T-ALL is a homogeneous disease characterized by expansion of a single clone showing a specific Rearranged junctional region of TcR delta and/or gamma genes. The use of a clone-specific probe allows detection of residual leukemia throughout treatment. However, 60 % of patients with T-ALL relapse during treatment or towards the end of therapy, with resurgence of the original leukemic clone. It is possible that the detection of MRD at a specific time-point after diagnosis, as well as at the beginning of maintenance, may help to identify a group of T-ALL patients at high risk of relapse. The correlation between detection of MRD and treatment phase may be used in the future to evaluate whether treatment regimens can be improved allowing for stratification, based on PCR-mediated detection of MRD.

Detectable molecular residual disease at the beginning of maintenance therapy indicates poor outcome in children with T-cell acute lymphoblastic leukemia.

The aims of this study were twofold: (1) to assess the marrow of patients with T-lineage acute lymphoblastic leukemia (T-ALL) for the presence of molecular residual disease (MRD) at different times after diagnosis and determine its value as a prognostic indicator; and (2) to compare the sensitivity, rapidity, and reliability of two methods for routine clinical detection of rearranged T-cell receptor (TCR). Marrow aspirates from 23 patients with T-ALL diagnosed consecutively from 1982 to 1994 at the Division of Pediatric Hematology and Oncology, University of Catania, Italy, were obtained at diagnosis, at the end of induction therapy (6 to 7 weeks after diagnosis), at consolidation and/or reinforced reinduction (12 to 15 weeks after diagnosis), at the beginning of maintenance therapy (34 to 40 weeks after diagnosis), and at the end of therapy (96 to 104 weeks after diagnosis). DNA from the patients' marrow was screened using the polymerase chain reaction (PCR) for the four most common TCR delta rearrangements in T-ALL (Vdelta1 Jdelta1, Vdelta2 Jdelta1, Vdelta3 Jdelta1, and Ddelta2 Jdelta1) and, when negative, further tested for the presence of other possible TCR delta and TCR gamma rearrangements. After identification of junctional rearrangements involving V, D, and J segments by DNA sequencing, clone-specific oligonucleotide probes 5' end-labeled either with fluorescein or with [gamma-32P]ATP were used for heminested PCR or dot hybridization of PCR products of marrows from patients in clinical remission. For 17 patients with samples that were informative at the molecular level, the estimated relapse-free survival (RFS) at 5 years was 48.6% (+/-12%). The sensitivity and specificity for detection of MRD relating to the outcome were 100% and 88.9% for the heminested fluorescence PCR and 71.4% and 88.9% for Southern/dot blot hybridization, respectively. Predictive negative and positive values were 100% and 90.7% for heminested fluorescence PCR, respectively. The probability of RFS based on evidence of MRD as detected by heminested fluorescence PCR at the time of initiation of maintenance therapy was 100% and 0% for MRD-negative and MRD-positive patients, respectively. Thus, the presence of MRD at the beginning of maintenance therapy is a strong predictor of poor outcome, and the molecular detection of MRD at that time might represent the basis for a therapeutic decision about such patients. By contrast, the absence of MRD at any time after initiation of treatment strongly correlates with a favorable outcome. The heminested fluorescence PCR appears to be more accurate and more rapid than other previously used methods for the detection of residual leukemia.

Liver involvement in white patients with sickle-cell disease.

BACKGROUND: Liver involvement and cholelithiasis are common complications of sickle-cell disease. The incidence of clinically evident hepatic damage reported in the literature for black people varies from 15% to 30%, while no data are reported for white people. OBJECTIVE: To evaluate the liver involvement in 40 patients with homozygous sickle cell anemia (the beta 5 beta 5 form of sickle-cell disease) and 102 patients with double-heterozygous hemoglobin S and beta-thalassemia (65 with the beta 5 beta 0th and 37 with the beta 5 beta +th form of sickle-cell disease). SETTING: The Department of Pediatric Hematology and Oncology, University of Catania, Catania, Italy. PATIENTS: Outpatients with sickle-cell disease. RESULTS: We found that, in our patients, liver disease seems to be clinically irrelevant: only 2 of the 142 patients examined had notable alterations in hepatic function. Cholelithiasis was found in 42.1% of the subjects with the beta 5 beta 5 form of sickle-cell disease and in 26.8% of the subjects with the beta 5 beta th form. Age-related analysis revealed a greater incidence of cholelithiasis during the first years of life in the patients with the beta 5 beta 5 form of the disease than in patients with the beta 5 beta th form. CONCLUSION: Our data showed that liver involvement in sickle-cell disease is clinically irrelevant, reflecting the fact that the clinical expression of sickle-cell disease in Sicilian patients is moderate.

Is intensive follow-up for early detection of tumors effective in children with Beckwith-Wiedemann syndrome?

Two cases of Beckwith-Wiedemann syndrome who developed malignant tumor and eventually died are reported. The patients followed two different screening programs for early detection of cancer, and the most appropriate schedule of follow-up in carriers of this syndrome is discussed.

Micromegakaryocytes in a patient with partial deletion of the long arm of chromosome 11 [del(11)(q24.2qter)] and chronic thrombocytopenic purpura.

Thrombocytopenia or pancytopenia is frequently reported in patients with partial 11q deletion but there are no reports on bone marrow morphology of these patients. We report on a patient with partial deletion of the long arm of chromosome 11 [del(11)(q24.2qter)] and its classical clinical manifestations including chronic thrombocytopenic purpura in whom micromegakaryocytes were found in the bone marrow aspirate. This is the first report of the presence of micromegakaryocytes in the bone marrow of a patient with 11q deletion. Accurate examination of the bone marrow of other patients with the 11q deletion may clarify whether the observation of micromegakaryocytes is common in these patients. Micromegakaryocytes may indicate a defect of development. Two genes for two DNA binding proteins that are likely to be involved in hematopoiesis map in the 11q region: Ets-1, that maps to 11q24, close to D11S912, and the nuclear-factor-related-kB gene that maps to 11q24-q25. It is possible that these genes, when present in only one copy, result in thrombocytopenia or pancytopenia as observed in this patient.

Low serum levels of interleukin-6 in children with post-infective acute thrombocytopenic purpura.

Interleukin-6 plays an important role in host defense mechanisms and it appears to be a major mediator of the acute-phase response. IL-6 is also an important thrombocytopoietic factor. High serum levels of IL-6 are present in reactive thrombocytosis. The number and function of circulating platelets are the major factors that affect megakaryocytopoiesis by thrombopoietin. High levels of thrombopoietin have been observed in patients with thrombocytopenic purpura. To evaluate a possible thrombopoietin-like function of IL-6, we measured IL-6 levels in the serum of patients affected by post-infective acute thrombocytopenic purpura using a sensitive ELISSA assay. As controls, we studied normal subjects and patients with reactive thrombocytosis. No significant difference was observed between thrombocytopenic patients and normal controls. High IL-6 levels were present in patients with reactive thrombocytosis. In conclusion, we had not observed high levels of IL-6 in acute thrombocytopenic purpura and, very probably, IL-6 is not involved in the regulation of platelet mass for the hemostatic function. The thrombocytopoietic activity of IL-6 is another acute-phase response and it is consistent with the other functions of this cytokine. This suggests an active participation of platelets in host defense mechanisms.