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Biomedical subjects

M Aricò

Publications and source records attributed to M Aricò.

At least 19 recordsLinked to original sources
PubMed1999

RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML).

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder of early childhood with excessive proliferation of the myeloid and monocytic lineage. Deregulation of the RAS signal transduction pathway is thought to play a key role in its pathogenesis. We examined peripheral blood or bone marrow cells of 36 children with JMML for activating point mutations in codons 12, 13 and 61 of the NRAS and KRAS proto-oncogenes by allele-specific restriction assay, single-strand conformation polymorphism and/or direct sequencing. Codons 12, 13 and 61 of HRAS were examined in 26 of these patients. We detected RAS mutations in six cases (17%) located at N12 (n = 2), N13 (n = 3) and K13 (n = 1). In addition, we performed clonality studies on different cell lineages in four of these patients applying the RAS mutation, the karyotype and X-chromosome inactivation patterns as clonal markers. Erythroid cells carried mutant RAS, indicating clonal origin. In EBV B cell lines, one of three patients studied harbored a RAS mutation, while the other two patients had polyclonal B cells with wild-type RAS. T lymphocytes were examined in one patient; they were polyclonal and had wild-type RAS. It is likely that JMML is a heterogeneous disease with respect to clonal involvement of different lineages.

Amino Acid Substitution↗
PubMed1999

Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS).

We reviewed the clinical features, treatment, and outcome of 100 children with myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (-7) or deletion of the long arm of chromosome 7 (7q-). Patients with therapy-induced disease were excluded. The morphologic diagnoses according to modified FAB criteria were: MDS in 72 (refractory anemia (RA) in 11, RA with excess of blasts (RAEB) in eight, RAEB in transformation (RAEB-T) in 10, JMML in 43), and AML in 28. The median age at presentation was 2.8 years (range 2 months to 15 years), being lowest in JMML (1.1 year). Loss of chromosome 7 as the sole cytogenetic abnormality was observed in 75% of those with MDS compared with 32% of those with AML. Predisposing conditions (including familial MDS/AML) were found in 20%. Three-year survival was 82% in RA, 63% in RAEB, 45% in JMML, 34% in AML, and 8% in RAEB-T. Children with -7 alone had a superior survival than those with other cytogenetic abnormalities: this was solely due to a better survival in MDS (3-year survival 56 vs 24%). The reverse was found in AML (3-year survival 13% in -7 alone vs 44% in other cytogenetic groups). Stable disease for several years was documented in more than half the patients with RA or RAEB. Patients with RA, RAEB or JMML treated with bone marrow transplantation (BMT) without prior chemotherapy had a 3-year survival of 73%. The morphologic diagnosis was the strongest prognostic factor. Only patients with a diagnosis of JMML fitted what has previously been referred to as the monosomy 7 syndrome. Our data give no support to the concept of monosomy 7 as a distinct syndrome.

Acute Disease↗
PubMed1999

The breakpoints of a constitutional inversion of chromosome 9 associated with haemophagocytic lymphohistiocytosis are not linked to the disease gene.

Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder of early infancy consistent with an autosomal recessive inheritance. Neither the genetic locus nor the biochemical defect is known for the disease. A constitutional pericentric inversion of chromosome 9, with breakpoints in bands 9p23 and 9q31, has been reported in a case of HLH, suggesting a possible relationship between this chromosome abnormality and the disease. We investigated such an association, performing a genetic linkage analysis in a set of five consanguineous HLH families. 27 polymorphic markers on chromosome 9 were studied, excluding most of chromosome 9 as a putative site for the HLH gene.

Chromosome Breakage↗
PubMed1999

GB virus type C infection in patients treated for childhood acute lymphoblastic leukemia.

BACKGROUND: The purpose of this study was to determine the prevalence of GB virus type C (GBV-C) infection in subjects treated for childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma. STUDY DESIGN AND METHODS: One hundred forty patients (82 males) aged 4 to 27 years (median, 11) diagnosed with ALL between 1976 and 1993, were prospectively followed for a median of 5 years (range, 0.1-17) after completion of therapy. Stored sera were tested for antibody to hepatitis C virus (HCV), HCV RNA, antibody to GBV-C E2 (anti-E2), and GBV-C RNA. RESULTS: Thirty-eight patients (27%) were exposed to GBV-C: 30 were positive for GBV-C RNA (mostly type 2) and 8 were positive for anti-E2. Anti-E2 and GBV-C RNA were mutually exclusive: 61 patients (43%) were positive for HCV RNA, 16 (11%) were coinfected with GBV-C and HCV. Alanine aminotransferase (ALT) levels were increased (>35 mU/mL) in 32 (23%) of 137: 3 of 20 who were positive for GBV-C and negative for HCV, 7 of 15 who were positive for GBV-C and HCV, 15 of 44 who were negative for GBV-C and positive for HCV, and 7 of 58 who were negative for GBV-C and HCV (p<0.001). Median ALT values were significantly higher in patients positive for GBV-C and HCV than in those who were positive for GBV-C and negative for HCV (35 vs. 13 mU/mL, p = 0.003). Thirty-one of 38 patients with GBV-C markers were retested: GBV-C RNA was lost in 16 of 30 tested, but 7 were still GBV-C RNA positive up to 50 months later, 3 tested positive for anti-E2 up to 27 months later, and 1 was positive for GBV-C RNA and anti-E2 26 months later, while 20 tested negative for both. CONCLUSION: GBV-C did not behave as a liver pathogen, because ALT alterations were unrelated to GBV-C status, but, rather, were related to HCV infection or coinfection. GBV-C RNA was frequently lost over a relatively short period, though in some cases, it was retained for a longer time. Anti-E2 rarely coexisted with GBV-C RNA and might be short-term.

Adolescent↗
PubMed1998

Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome.

Among 4,760 acute lymphoblastic leukemia (ALL) patients enrolled from 1986 to 1995 in two subsequent trials of the BFM and AIEOP study group, 61 patients were found to have Philadelphia chromosome-positive (Ph+) ALL. These patients were analyzed for presenting features and treatment outcome to identify specific prognostic factors. Treatment stratification was based on initial cell mass and early response as determined by blast count in peripheral blood after a 7-day induction prephase with prednisone and one dose of intrathecal methotrexate on day 1. All patients were treated by similar intensive Berlin-Frankfurt-Münster (BFM) protocols. The median age of Ph+ patients was 7.5 years, the median white blood cell count (WBC) was 75 x 10(9)/L, 77% of patients had common ALL, and 29% coexpressed myeloid markers. After a median observation time of 4.2 years, 29 of 61 patients are alive (survival probability [pSUR] at 4 years, 0.49; standard error [SE], 0.06), and 24 of 61 are in first complete remission (CR1; probability of event-free survival [pEFS] at 4 years, 0.38; SE, 0.06). Twenty (35%) of 57 evaluable patients had >/=1,000 leukemic blasts per microliter of blood on day 8 of induction (defined as prednisone-poor-response [PPR]). These patients were older (10.0 v 6.88 years; P = .02) and had a higher WBC (144 v 29 x 10(9)/L; P = .0016) as compared with patients with prednisone good response (PGR; <1,000 blasts/microL at day 8). Only 2 of 20 patients (10%) with PPR remained in CR1 and alive: 6 patients with PPR did not survive after allogeneic bone marrow transplantation (BMT) due to recurring disease (n = 3) and toxicity (n = 3), and 12 nontransplanted patients died due to progression (n = 5) or relapse (n = 7). In contrast, 26 (70%) of the 37 patients with PGR are alive. Of 18 patients transplanted by allo-BMT, 1 relapsed (now in CR2) and 4 died after BMT. Among the 19 patients with PGR treated by chemotherapy alone, 8 remained in CR1 and 11 relapsed, of which 4 are in CR2 or CR3. The prednisone response emerged as the only independent prognostic factor for survival in Cox regression analysis. Thus, two thirds of Ph+ childhood ALL cases can be identified early by PGR, which, when treated with intensive BFM chemotherapy, with or without BMT, have a significantly lower risk of treatment failure. With a median continuous complete remission (CCR) time of 4.1 years, pEFS for PGR is 0.55 (SE, 0.08) compared with 0.10 (SE, 0.07) in patients with PPR (P = .0001). PGR is also an indicator for treatment responsiveness and durable second remission after relapse, which in turn may provide a second chance for BMT.

Adolescent↗
PubMed1998

Clinical aspects of Langerhans cell histiocytosis.

Langerhans cell histiocytosis remains an enigmatic disease with protean manifestations. It may be self-limited in some, whereas in others, even intensive treatment is unsuccessful. The outcome depends on whether vital organ function is compromised at diagnosis or shortly thereafter, in which case the prognosis is grave.

Adult↗
PubMed1998

The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society.

The frequency of Langerhans cell histiocytosis (LCH) and a malignant neoplasm occurring in the same individual appears to be greater than previously recognized. To define the occurrence and the pattern of these events, a Study Group of the Histiocyte Society initiated a registry of patients in whom this association occurred synchronously or asynchronously. Evaluation of 54 patients detected two patterns of associations between LCH and other disorders. First, it is possible that therapy of LCH promotes a secondary malignancy. Second, it is possible that a genetic predisposition, with or without the immunosuppression associated therapy for the malignancy, plays a role in the development and expression of disseminated LCH. Data collected by the LCH-Malignancy Study Group may provide insights into the etiology and pathophysiology of LCH.

Adolescent↗
PubMed1998

Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis represents a spectrum of pathogenetically different diseases including the rapidly fatal autosomal recessive disease of familial hemophagocytic lymphohistiocytosis (FHL). The onset is usually during the first years of life with fever, cytopenia, and hepatosplenomegaly. Neurologic symptoms may supervene. Similar symptoms may occur in the infection-(virus-)associated or malignancy-associated hemophagocytic syndromes (IAHS/MAHS). Triggering infections can be found in all these diseases and do not allow for reliable differentiation. An international treatment protocol (HLH-94) has been developed for FHL, but immunomodulatory treatment may be justified in IAHS and MAHS as well, since they also have a high fatality rate.

Adolescent↗
PubMed1998

Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associzione Italiana Emato-Oncologia Pediatrica.

The purpose of this study was to assess the role of ABMT in children with ALL who are in 2nd CR after an early isolated CNS relapse. All children experiencing an isolated CNS relapse at 10 AIEOP centers (Associazione Italiana Emato-Oncologia Pediatrica) from 1986 to 1992 were eligible for this study. The series included 69 patients who relapsed within 3 years from diagnosis: 19 underwent ABMT, nine patients underwent ALLO-BMT from an HLA-identical sibling, and 41 received conventional chemotherapy (CHEMO). Statistical analysis was performed using a Cox's regression model, adjusting for the waiting time before transplantation and prognostic factors. The 5 years DFS was 56.3% (s.e. 12.3) for patients in the ABMT group. This compared favorably with the poor result (12.6% (s.e. 5.9)) seen in the CHEMO group. The risk of failures was reduced by one-third in the ABMT group as compared to the CHEMO group in the multivariate analysis (P < 0.01). In the ALLO group four out of nine patients were in CCR 4-5 years post-transplant. This study suggests that ABMT may also represent a valuable therapeutic choice for patients lacking a matched familiar donor in 2nd CR after an early isolated CNS relapse.

Adolescent↗
PubMed1998

Reticulate postinflammatory hyperpigmentation with band-like mucin deposition.

BACKGROUND: Mucinoses of the skin are a group of disorders sharing accumulation of mucin in the skin or hair follicles. Postinflammatory hyperpigmentation, with pigmentary incontinence, is due to loss of melanin from epidermal basal cells and its accumulation in dermal macrophages. METHODS: We describe clinicopathologic features of two patients presenting with the association of pigmentary incontinence with an unusual diffuse, band-like dermal deposition of mucin, clinically presenting with reticular pigmented macular lesions. RESULTS: Two patients were observed with asymptomatic, persistent, reticular, pigmented patches located in the flexures, thighs, neck and back. Histology showed melanophages with a diffuse, band-like dermal deposition of mucin, an increased number of fibroblasts, a slight T-cell infiltrate and scattered mast cells. Blood markers of lupus erythematosus were negative. CONCLUSIONS: These findings may draw attention to pigmentary disorders such as lichen planus pigmentosus, erythema dyschromicum perstans, pigmentatio maculos eruptiva idiopathica, dermatopathia pigmentosa reticularis, prurigo pigmentosa and frictional melanosis. None of these entities, however, includes mucin deposition among its microscopic features. Macules were not preceded by erythema or any other lesions. We suggest that our cases could belong to group II of Rongioletti and Rebora's classification, i.e. they could be cases of secondary mucin deposition in postinflammatory hyperpigmentation, possibly in an unusual form of lichen planus pigmentosus or, less likely, frictional melanosis.

Adult↗
PubMed1998

Dynamic endocrine testing and magnetic resonance imaging in the long-term follow-up of childhood langerhans cell histiocytosis.

Children treated for Langerhans cell histiocytosis (LCH) are at risk for short and long term endocrine sequelae, but biological predictors of specific deficits are not well defined. We evaluated the frequency and progression of LCH-related endocrine deficits during long term follow-up and assessed the ability of dynamic endocrine testing to identify patients at risk for late anterior or posterior pituitary hormone dysfunction. The 17 patients (5 males and 12 females) were followed a median of 10 yr after diagnosis of single system (n = 6) or multisystem (n = 11) disease. Study evaluations, performed a median of 4.1 yr after the diagnosis, comprised pituitary hormone responses to the appropriate challenge, 7-h water deprivation test, 3% hypertonic saline infusion, and magnetic resonance imaging (MRI). The six patients with GH deficiency at the time of evaluation had a significantly lower GH response to GHRH than the other patients [median peak, 7.3 vs. 21.5 micrograms/L (P = 0.03); median area under the curve, 4.7 vs. 13.5 micrograms/L (P = 0.03)]; levels in the latter group did not differ significantly from those in 20 age- and sex-matched controls with constitutional or familial short stature. Two patients who had GH responses to GHRH of 20.6 and 23 ng/mL at 2.8 and 9.5 yr of age developed GH deficiency at 6.5 and 11.2 yr of age, respectively. The TSH response to TRH was less than 10 mU/L in three patients, two of whom later developed central hypothyroidism. ACTH and cortisol responses to CRF, and PRL responses to TRH were normal in all cases, and LH and FSH responses to GnRH were compatible with pubertal stage. Abnormalities in arginine vasopressin responses to water deprivation or hypertonic saline infusion were seen only in four patients who had preexisting diabetes insipidus (DI); one patient who later developed DI had normal findings. On standard MRI, posterior pituitary hyperintensity was absent only in the patients with DI. Pituitary stalk thickening was seen in seven patients, including three who did not have DI and had normal arginine vasopressin responses. Delayed posterior and anterior enhancement on dynamic MRI was present in two patients, both of whom later developed central hypothyroidism. Patients with single system disease had a lower 5-yr probability of LCH reactivation (41% vs. 83% for those with multisystem disease; P = 0.21) and a significantly lower risk of endocrine dysfunction (P = 0.007). In this series, dynamic evaluation of pituitary function was not a useful predictor of late endocrine sequelae, with the possible exception of the progressively decreasing TSH response to TRH. Similarly, a standard MRI was not predictive, although dynamic imaging may be informative regarding evolving pituitary hormone deficiency.

Adolescent↗
PubMed1998

Evolution of childhood central diabetes insipidus into panhypopituitarism with a large hypothalamic mass: is 'lymphocytic infundibuloneurohypophysitis' in children a different entity?

We report on a 15-year-old girl who had presented with acute onset central diabetes insipidus at the age of 8 years; this was followed by growth failure due to acquired growth hormone deficiency. Initial magnetic resonance imaging showed a uniformly enlarged pituitary stalk and absence of posterior pituitary hyperintensity. Frequent patient examination and magnetic resonance imaging gave unchanged results until after 5 years a large hypothalamic mass and panhypopituitarism were found. Dynamic magnetic resonance imaging documented hypothalamic-pituitary vasculopathy. Histopathological examination revealed perivascular inflammatory lymphoplasmic infiltrates with no granulomatosis or necrosis and negative staining for S-100 protein, suggesting autoimmune inflammatory disease (lymphocytic infundibuloneurohypophysitis?). The response to glucocorticoid pulses (30 mg/kg per day for 3 days i.v.) was favorable. the hypothalamic mass being halved and partial anterior pituitary function recovery maintained for 2 years after the start of treatment. We suggest that long-term surveillance is needed for isolated and chronic thickening of the pituitary stalk and that dynamic magnetic resonance imaging can contribute to the demonstration of hypothalamic-pituitary vascular impairment associated with local vasculitis.

Age of Onset↗
PubMed1998

Thyroid volume is progressively reduced as a sequela of neck irradiation for childhood Hodgkin's disease.

Thyroid volume reduction was observed, among 25 subjects off-therapy after Hodgkin's disease. The volume reduction was related to dose (p = 0.014) and time from radiotherapy (p = 0.01). The correlation was very specific since all patients with reduced volume had hypothyroidism, but not very sensitive since 25% of subjects with thyroid dysfunction had normal gland volume.

Adolescent↗
PubMed1998

Intensive BFM chemotherapy for childhood ALL: interim analysis of the AIEOP-ALL 91 study. Associazione Italiana Ematologia Oncologia Pediatrica.

BACKGROUND AND OBJECTIVE: Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported. DESIGN AND METHODS: From 1991 to 1995, 1194 children (< 15 years) with non-B ALL, were enrolled and assigned to the standard risk [SR: age > 1 year, non-T-ALL, BFM risk factor (RF) < 0.8], intermediate risk (IR: RF > or = 0.8 but < 1.7, or with RF < 0.8 and age < 1 year, or T-ALL), or high risk [HR: RF > or = 1.7, or t(9;22), or t(4;11) or prednisone poor response or late response or CNS involvement] groups. All patients received initially protocol Ia. Thereafter SR patients received HD-MTX 2 g/m2, a modified protocol II, and continuation therapy with triple intrathecal chemotherapy (TIT); IR patients received protocol Ib, HD-MTX 5 g/m2, protocol II and continuation therapy with TIT; HR patients received 9 polychemotherapy blocks, cranial irradiation and continuation therapy. Duration of treatment was 24 months. A randomized study was conducted to evaluate the impact of high-dose asparaginase in non high risk patients: the results of this study cannot be disclosed yet. RESULTS: One thousand one hundred and fifty-two (96.5%) patients achieved CR. Overall EFS (SE) at 5-years was 71.0% (1.4), with a survival of 80.3% (1.3). Relapse occurred in 262 children (21.9%), either in the marrow (n = 192 isolated and 32 with other sites, 18.7%), in the CNS (n = 18, 1.5%), or elsewhere (n = 20, 1.7%). 5-year EFS (SE) was 83.3% (2.4) in SR, 74.7% (1.8) in IR, and 39.7% (3.5) in HR groups, respectively. INTERPRETATION AND CONCLUSIONS: Overall cure rate was higher than in the previous AIEOP-ALL 88 study. Treatment intensification with polychemotherapy blocks did not improve results in HR. Cranial irradiation can be safely omitted in over 80% of children treated with BFM based chemotherapy.

Adolescent↗
PubMed1998

Clinical relevance of CD10 expression in childhood ALL. The Italian Association for Pediatric Hematology and Oncology (AIEOP).

BACKGROUND AND OBJECTIVE: Previous studies have considered the prognostic significance of CD10 expression in childhood acute lymphoblastic leukemia (ALL) and showed its linkage to a more favorable prognosis. The aim of this study was to assess the independent significance of CD10 expression in a large population of ALL patients. DESIGN AND METHODS: We revised the independent clinical relevance of CD10 expression in 2038 children with acute lymphoblastic leukemia (ALL), who were consecutively entered in 4 sequential trials of the Italian Association for Pediatric Hematology and Oncology (i.e. AIEOP studies 82, 87, 88, 91); 1142 were males and 896 females, age ranged between 1 and 14 years (yrs) at diagnosis. Of the whole group, 1471 children (72.2%) were defined as having standard risk, 567 (27.8%) as having a high risk. RESULTS: CD10 was detected in blast cells from 1706 of 1784 (95.6%) patients with B-lineage ALL and 46 of 254 (18.1%) with T-cell ALL. In the B-lineage subgroup CD10 expression was associated with presenting features such as age < 9 yrs and inclusion in the standard risk category. No significant differences were found between CD10+ and CD10- cases in T-lineage ALL, concerning presenting features, except for FAB L2 in the former group. We compared the event-free survival (EFS) rates for patients with T-ALL or B-lineage ALL, regarding CD10 positivity, overall and by individual study. Patients with T-ALL fared worse than those with B-lineage ALL (5 and 10 yrs EFS: 46.8% vs. 68.5% and 44.5% vs. 63.7% respectively, p = 0.0001). In multivariate analysis of B-lineage subgroup poorer EFS was associated with male sex, higher WBC (> or = 20 x 10(9)/L), age > 9 yrs. Only WBC > or = 20 x 10(9)/L and age > 9 yrs were parameters linked to poorer EFS in the T-lineage subgroup. Finally, we compared EFS rates for four groups of patients categorized as having high or standard risk, and according to CD10+ and CD10- expression. High-risk patients fared statistically worse than standard risk patients both in the CD10- and in the CD10+ groups (42% vs. 50.7% and 63.6% vs. 66.8%, respectively). INTERPRETATION AND CONCLUSIONS: CD10 expression does not have independent prognostic significance in either the larger subgroup of B-ALL patients or in T-cell ALL.

Adolescent↗
PubMed1997

How important is hepatitis C virus (HCV)-infection in persons with acute leukemia?

Hepatitis C virus (HCV)-infection is common in persons with leukemia. Blood transfusions are the typical source and HCV-related chronic hepatitis a common outcome. Development of HCV-infection and -related hepatitis raises important questions about subsequent leukemia treatment including the natural history of the infection and need for treatment modification. Although the natural history of HCV-infection and -related hepatitis in this setting is unknown, data from normal persons with HCV-infection suggest that short-term survival is not likely to be decreased in persons with leukemia and these complications. In contrast, long-term survival may decrease because of a high rate of chronic hepatitis, cirrhosis, and possibly hepatocellular carcinoma. There are no convincing data that HCV-infection or -related hepatitis or alterations in anti-leukemia drug dose or schedule prompted by abnormal liver function tests, alter leukemia outcome. Consequently, it is uncertain whether drug doses and/or schedule should be modified in persons with leukemia and HCV-infection or -related hepatitis. Short-term outcome of blood cell and bone marrow transplants is also unaffected by HCV-infection or -related hepatitis.

Acute Disease↗