Armando Pinto

Genetic and clinical characterization of 45 acute leukemia patients with MLL gene rearrangements from a single institution

Chromosomal rearrangements affecting the MLL gene are associated with high‐risk pediatric, adult and therapy‐associated acute leukemia. In this study, conventional cytogenetic, fluorescence in situ hybridization, and molecular genetic studies were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL‐related leukemia treated in a single institution between 1998 and 2011. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL–AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL–MLLT3 (27%), a MLL–MLLT1 (20%), or MLL–MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloid leukemia was the MLL–MLLT3 fusion (42%), followed by MLL–MLLT10 (23%), MLL–MLLT1 (8%), MLL–ELL (8%), MLL–MLLT4 (4%), and MLL–MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL–MLLT4 fusion variant.

TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset

The Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant disease caused by TP53 germline mutations. This study aimed to characterize the TP53 mutational spectrum in patients suspected to have LFS in Portugal and to evaluate the influence of the MDM2-SNP309 and TP53-72Arg variants and of telomere length on age of tumor onset. Probands were primarily selected using the classical LFS criteria (two cases) or the more sensitive Chompret Li-Fraumeni-like (LFL) criteria (13 cases), but 12 additional patients that did not comply with those LFS or LFL criteria were included in the analysis based on clinical suspicion (LFS suspects). Nine of the 27 probands (33.3%) presented germline TP53 mutations, two of them occurring de novo and two of them being novel. Three of the nine TP53 mutations were found in families that did not comply with any of the commonly used criteria for TP53 testing, leaving room to recommend the use of less stringent criteria. An association was found between the presence of the TP53-72Arg (but not the MDM2-SNP309) variant and earlier age of onset in TP53 carriers. A negative correlation between telomere length and age of cancer onset was found in patients with germline TP53 mutation, whereas no such correlation was found in controls or in patients with wild-type TP53.

Psychometric study of the European Portuguese version of the PedsQL 3.0 Cancer Module

BackgroundHealth-related quality of life (HRQoL) is an important outcome to assess the impact of cancer. This article examines the psychometric properties of the European Portuguese self-report version of the Pediatric Quality of Life Inventory™ Cancer Module (PedsQL™ 3.0 Cancer Module) in children and adolescents with cancer.MethodsThe participants, 332 children/adolescents diagnosed with cancer (8–18 years old), completed measures to assess HRQoL (PedsQL™ 3.0 Cancer Module and DISABKIDS Chronic Generic Measure; DCGM-12) and anxiety (Revised Children’s Manifest Anxiety Scale - second edition; RCMAS-2). A subsample (n = 52) completed the PedsQL™ 3.0 Cancer Module a second time following one-week. The pediatric oncologists completed the Intensity of Treatment Rating Scale 3.0 (ITR 3.0).ResultsFor the whole sample, the PedsQL™ 3.0 Cancer Module demonstrated good item discrimination (rs = .30 to .54). The confirmatory factor analysis testing the presence of eight first-order factors loading significantly in a second-order factor revealed an acceptable fit (CFI = .91; RMSEA = .05). The correlation of PedsQL™ 3.0 Cancer Module with DCGM-12 (rs = .17 to .58), and with RCMAS-2 (rs = −.16 to–.51) attested convergent validity. This inventory demonstrated minimally acceptable to very good internal consistency (αs = .65 to .87) and temporal stability (ICCs = .61 to .81).ConclusionsThese findings demonstrate that the European Portuguese self-report version of the PedsQL™ 3.0 Cancer Module is a valid and reliable instrument for assessing HRQoL in pediatric cancer.

Posterior Reversible Encephalopathy Syndrome in Children With Hematologic Malignancies.

Since its original description 2 decades ago, posterior reversible encephalopathy syndrome has been reported in children with several predisposing conditions. Epidemiologic data of posterior reversible encephalopathy syndrome in children with hematologic malignancies is still scarce. Herein, we describe the clinical and radiologic features along with the outcome and follow-up of posterior reversible encephalopathy syndrome complicating the treatment of children with hematologic malignancies. Ten patients with a median age of 6.3 years were diagnosed with posterior reversible encephalopathy syndrome. Six of them were undergoing chemotherapy and the remaining 4 were at 37, 52, 78, and 857 days after allogenic hematopoietic stem cell transplant. The median follow-up was 27.6 months. Even though follow-up imaging showed complete resolution of abnormalities in those 10 children, 2 developed secondary epilepsy. Despite accurate diagnosis of posterior reversible encephalopathy syndrome and immediate intervention, neurologic sequelae may still develop. Thus, a close follow-up should be considered in all patients.

Childhood Hypopigmented Mycosis Fungoides: A Rare Diagnosis

Primary cutaneous lymphomas (PCL) are rare in pediatrics. Mycosis fungoides (MF) is the most frequent PCL diagnosed in childhood. There are various clinical variants of MF, including the hypopigmented MF (HMF). We present a 5-year-old boy with an 18-month history of progressive, generalized, nonpruritic hypopigmented lesions with central lacy erythema. He had no improvement with emollients. Skin biopsy showed typical features of HMF. He was treated with topical corticosteroids and tacrolimus and narrow-band ultraviolet B (NBUVB) phototherapy, with good response. HMF may mimic multiple skin disorders. Unusual hypopigmented skin lesions should be biopsied. Though phototherapy is effective, recurrence is common.

Autoimmune Hemolytic Anemia and Hodgkin's Disease: An Unusual Pediatric Association.

Autoimmune hemolytic anemia (AIHA) is a recognized complication of lymphoproliferative disorders. AIHA associated with Hodgkins disease (HD) is uncommon especially in the pediatric population. The diagnosis of AIHA is usually associated with HD at the time of initial presentation or during the course of disease, but it could precede it by years to months. In adults the association of AIHA and HD is more frequent in advanced stages and in the nodular sclerosis and mixed cellularity type HD. Warm immune hemolytic anemia is mainly controlled with steroids and chemotherapy. We report a case of a pediatric patient with direct antiglobulin positive test at the diagnosis of a late relapse of stage III B mixed cellularity type HD.

Much more than anxiety

Pheochromocytoma and paraganglioma are rare neuroendocrine tumours in paediatric ages. We report a case of a 14-year-old girl referred to our oncology centre due to an abdominal mass. She had an 11-month history of paroxysmal episodes of headache, nausea, dizziness, palpitations and visual disturbances. Imaging studies showed a left paravertebral mass measuring 5.8×4.6×3.5 cm. Metaiodobenzylguanidine scintigraphy revealed an abnormal hyperfixation on the left upper quadrant. Chromogranin A was elevated, as well as normetanephrine. The patient was submitted to surgery during which a connection between this mass and the adrenal gland was found. A diagnosis of pheochromocytoma was performed.

PO-0164 Paediatric Soft Tissue Sarcoma: A Ten Year Review

Background and aims Paediatric soft tissue sarcomas are rare tumours that account for about 7% of all childhood cancers. 50–60% of these are rhabdomyosarcoma (RMS), while the remainder are non rhabdomyosarcoma soft tissue sarcomas (NRSTS). To evaluate the clinical characteristics, treatment modalities and outcome of paediatric soft tissue sarcomas. Methods A retrospective analysis of data from 51 patients diagnosed and treated from 2003 to 2013. Results 51 patients, 30 male and 21 female, median age of 10 years old at diagnosis. 92% showed a mass at diagnosis. The most common site of disease was the extremities (20 cases). Histology: 51% RMS (embryonal: 12 patients; alveolar: 12 patients; other: 2 patients) and 49% NRSTS (PNET 5 patients; malignant peripheral nerve sheath tumour: 3 patients; other: 17 patients). IRS group: 29% group I, 14% group II, 28% group III and 29% group IV. Most patients received multimodality therapy (radiotherapy, chemotherapy and surgery). 31% (16 patients) died due to disease progression: 7 alveolar RMS, 11 ≥ 10 years old and 13 group III-IV. Time from diagnosis to death was between 7 months and 5 years. Of the 34 living patients, 74% were in first complete remission. The median follow-up time was 38 months. Conclusions Alveolar RMS is more common in the extremities and the embryonal in the genitourinary tract. NRSTS are more common in children ≥10 years. The absence of metastases and the tumour size ≤5 cm were associated with a better prognosis (p < 0.05).

PO-0154 Symptomatic Osteonecrosis Ocurring In Portuguese Children And Adolescents Treated For Hemato-oncologic Diseases – A 15-year Longitudinal Observational Study

Background and aims Along with the improved cure rate in paediatric cancer, awareness of treatment related late effects has become increasingly important. Osteonecrosis is an emerging complication of intensive chemotherapy including high doses of steroids. We aimed to describe clinical and imagiologic characteristics of survivors of paediatric hematologic malignancies who developed osteonecrosis. Material and methods We evaluated 6 patients with osteonecrosis as a complication of leukaemia or lymphoma treatment between September 1998 and September 2013. Osteonecrosis was confirmed by magnetic resonance imaging (MRI) of the symptomatic joints. Results Of 563 patients, 6 (4 girls, 2 boys) (1,1%) developed symptomatic osteonecrosis, in a total of 11 joints. The median age at diagnosis of malignancy was 14 years (range 10–18 years) and the median interval between primary diagnosis and onset of osteonecrosis related symptoms was 33 months (range 11–120 months). Underlying malignancies were acute lymphoblastic leukaemia (n = 3) and Hodgkin Lymphoma (n = 3). Affected joints were hip (n = 7), knee (n = 3) and elbow (n = 1). All patients had received previous corticosteroid therapy at a median dose in prednisone equivalent of 4239 mg/m2 (range 3918–4600 mg/m2). Treatment of osteonecrosis included restriction of weight-bearing, physiotherapy and analgesics. One patient had to undergo arthrotomy. All patients showed improvement in pain and motor function. Conclusions In our cohort, there has been a predominance of female adolescents. Weight-bearing joints were the most commonly affected. Increased awareness for skeletal symptoms during follow-up of patients with hematologic malignancies allows early detection of osteonecrosis, leading to prompt intervention and may prevent more severe morbidity.