Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype.

Lymphotoxin-mediated activation of the lymphotoxin-β receptor (LTβR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-α and LTβ (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTα1 β2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTβR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr(-/-) mice present markedly less leukaemic thymocytes than age-matched TEL-JAK2;Ltbr(+/+) mice and interference with LTβR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTβR signalling in thymic stromal cells, thus promoting leukaemogenesis.Grants from Fundação para a Ciencia e a Tecnologia (PTDC/SAU-OBD/103336/2008 and PEst-OE/EQB/LA0023/2013), Nucleo Regional Sul da Liga Portuguesa Contra o Cancro (NRS/LPCC-Terry Fox) and Fundacao MSD to NRdS; grants from the Sao Paulo Research Foundation (FAPESP 08/10034-1 and 12/12802-1) to JAY; and Plan Cancer Action 29 to ED. MTF (SFRH/BD/75137/2010) MNG (SFRH/BD/80503/2011), and RKK (SFRH/BPD/70718/2010) were recipients of FCT PhD or postdoctoral fellowships. ABS and JAY are supported by PhD and Productivity Fellowships, respectively, from the Brazilian National Council for Scientific and Technological Development (CNPq). NRdS has been supported by FCT Ciencia 2007 and FCT Investigator contracts (IF/00056/2012)

Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia

<p>Abstract</p> <p>Background</p> <p>Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether <it>NOTCH1 </it>mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases.</p> <p>Methods</p> <p>T-ALL subtypes, status of <it>SIL-TAL1 </it>fusion, ectopic expression of <it>TLX3</it>, and mutations in <it>FBXW7</it>, <it>KRAS</it>, <it>PTEN </it>and <it>NOTCH1 </it>were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test.</p> <p>Results</p> <p>The frequencies of mutations were 43.5% for <it>NOTCH1</it>, while <it>FBXW7</it>, <it>KRAS </it>and <it>PTEN </it>exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of <it>NOTCH1 </it>mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between <it>NOTCH1 </it>mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. <it>SIL-TAL1 </it>was identified as an adverse prognostic factor. <it>NOTCH1 </it>mutation status was not associated with outcome, while the presence of <it>NOTCH1 </it>complex mutations (indels) were associated with a longer overall survival (<it>p </it>= 0.031) than point mutations.</p> <p>Conclusion</p> <p><it>NOTCH1 </it>mutations alone or in combination with <it>FBXW7 </it>did not impact T-ALL prognosis. Nevertheless, complex <it>NOTCH1 </it>mutations appear to have a positive impact on OS and the <it>SIL-TAL1 </it>fusion was validated as a negative prognostic marker in our series of T-ALL.</p

Childhood Hodgkin's disease in Campinas, Brazil

Purpose: Little clinical information about Hodgkin's disease in children is available from poor countries. The object of this study is to evaluate our data in Campinas, Brazil and hope ''to make one dot on the geographic map of this disease more clear.'' Patients and Methods: Between 1978 and 1988, 46 patients under the age of 17 years with biopsy-proven Hodgkin's Disease (HD) were referred for evaluation at Centro Boldrini in Campinas, Sad Paulo state, in Brazil. Thirty-seven of them were treated and followed-up only at this Center and are the subjects of this analysis. All the original histological slides were obtained, reviewed, and classified according to the Rye system. Staging procedures included exploratory laparotomy in 33 of 37 children, but none had lymphangiography. Treatment was individualized until January 1986 when the German protocol was adopted. Results: Nineteen cases were classified as nodular sclerosis, 14 as mixed cellularity, and three as lymphocyte depleted. Mean age was 7 years; male/female ratio was 2:1. Fifty percent were advanced stages III and IV and 46% (17/37) had at least one of the systemic B symptoms. Mean follow-up was 81 months (range from 41 to 174 months). Five-year actuarial overall survival was 78%. Two children (5%) had acute myeloid leukemia at 25 and 49 months after diagnosis. Conclusions: Although distribution of histological subtypes of our cases is similar to other reports in developed countries, as well as percentage of advanced stages III/IV, our patients fared worse when compared to those reports. The reason for this continues to remain unclear but it does not seem to be related to histology subtypes. (C) 1996 Wiley-Liss, Inc.262909

Retinoblastoma Diagnosis: A Proposal Based on the Experience of Centro Infantil Boldrini, Brazil

Advanced disease is a risk factor for eye loss in patients with retinoblastoma (RB). We still record critical rates of enucleation, especially for unilateral RB due to advanced stages of disease at diagnosis. This retrospective study of 223 RB patient records referred to treatment at Centro Infantil Boldrini, Brazil, between 1978 and 2008, showed that 176 patients (79%) presented intraocular tumors while 47 (21%) already had extraocular involvement. At the time of diagnosis, the age of patients was 26.2 months in the group that had enucleated eyes and 13.7 months in the group that preserved both eyes. Under a multiple logistic regression model, familial history (OR = 0.195; p = .01) and age at diagnosis in months (OR = 1.047; p = .04) were significantly correlated with enucleation. Strategies to early detect RB must be changed in order to offer better chances of ocular preservation with visual function. Authors propose a systematic referral of all children to the ophthalmologist for an indirect ophthalmoscopy once a year in the first two years of life, as a measure to be adopted by all pediatricians in daily routine to early detect the tumor.30537938

NEUTROPENIC ENTEROCOLITIS IN CHILDREN AND YOUNG ADULTS WITH CANCER: Prognostic Value of Clinical and Image Findings

Intensive chemotherapy regimens can result in severe toxicities, particularly those that involve the digestive systems, leading to morbidity and mortality in this group of patients. Acute enterocolitis can be a frequent complication. The authors performed a retrospective review or patients treated at their institution to ascertain the prognostic value of the clinical symptoms and signs of acute enterocolitis, the corresponding abdominal ultrasonographic findings, and the impact of previous chemotherapy. Amongst 1159 patients with cancer treated at the Centro Infantil Boldrini from 2003 to 2007, 188 (16.2%) patients had 1 or more episode of enterocolitis. An intestinal wall thickness of >= 3 mm on ultrasound was considered diagnostic of enterocolitis. There were 231 episodes of enterocolitis with a death rate of 11.7%. Previous therapy with cytarabine and the presence of abdominal distention affected survival. An intestinal wall thickness of >= 10 mm in the ultrasonographic examination was associated with greater mortality. In multivariate analysis, age, gender, tumor type, degree of neutropenia, intestinal wall thickness, and number of intestinal segments were not statistically significant difference. In children and young adults with cancer and enterocolitis, the clinical findings of 4 or more symptoms and presence of abdominal distention were associated with higher risk of death. Use of cytarabine and an intestinal wall thickness of >= 10 mm were associated with a higher death rate.27646247

Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia

Background. The Wilms Tumor gene (WT1) encodes a transcription factor involved in kidney development and malignancy. WT1 expression in a subpopulation of early CD34+ cells has suggested its involvement in hematopoiesis. WT1 is aberrantly expressed in leukemias. High expression of WT1 at diagnosis has been associated With unfavourable prognosis in adult acute myeloid leukemia (AML). The prognostic relevance of WT1 expression in pediatric AML was evaluated in only one study, including 47 patients, which Showed that very low levels of WT1 at presentation were associated with an excellent outcome. To test the validity of these findings we measured levels of WT1 in 41 newly diagnosed pediatric AML of the non-M3 FAB subtype. Procedure. Patients were treated according to an AML-BFM 83-based protocol in a single institution. Mononucleated cells, obtained from presentation BM aspirates were cryopreserved and later thawed and used for total RNA extraction and cDNA synthesis. The quantitative assessment of WT1 transcripts was made by real-time PCR (RQ-PCR). WT1 transcripts values were normalized with respect to the number of ABL transcripts. Results. WT1 levels were significantly higher in patients bearing favorable chromosome abnormalities, t(8;21) and inv(16) (P = 0.002). Higher levels of WT1 expression were Unexpectedly associated with a higher probability of overall survival by Cox regression analysis (P = 0.002). Multivariate regression analysis could not discriminate between the effects of WT1 and cytogenetics on survival. Conclusions. Higher WT1 expression was associated with favorable cytogenetics subtypes and accordingly with better outcome in children with AML in this study.49213313

Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2-and gamma-secretase inhibitors

T-cell acute lymphoblastic leukemia (T-ALL) patients frequently display NOTCH1 activating mutations and Notch can transcriptionally down-regulate the tumor suppressor PTEN. However, it is not clear whether NOTCH1 mutations associate with decreased PTEN expression in primary T-ALL. Here, we compared patients with or without NOTCH1 mutations and report that the former presented higher MYC transcript levels and decreased PTEN mRNA expression. We recently showed that T-ALL cells frequently display CK2-mediated PTEN phosphorylation, resulting in PTEN protein stabilization and concomitant functional inactivation. Accordingly, the T-ALL samples analyzed, irrespectively of their NOTCH1 mutational status, expressed significantly higher PTEN protein levels than normal controls. To evaluate the integrated functional impact of Notch transcriptional and CK2 post-translational inactivation of PTEN, we treated T-ALL cells with both the gamma-secretase inhibitor DAFT and the CK2 inhibitors DRB/TBB. Our data suggest that combined use of gamma-secretase and CK2 inhibitors may have therapeutic potential in T-ALL.95467467

Selective surgical indication in the management of neutropenic children presenting with acute abdomen

As the treatment of pediatric malignancies improves and survival increases, the diagnosis of acute abdomen in these patients also becomes more common. Nevertheless, the management of this condition is still controversial. The authors report their experience in treating 12 neutropenic children with acute abdomen. The charts of 12 neutropenic patients with a diagnosis of acute abdomen treated at Boldrini Children's Cancer Center in Campinas, Brazil, between 1991 and 1996, were reviewed. Therapeutic strategy included an initial period of bowel rest, general supportive measures, and broad-spectrum antibiotics while waiting for the neutrophil count to rise. Three patients recovered completely without surgery, 8 underwent late surgery without complications, and 1 died due to uncontrolled sepsis before surgery. The treatment of acute abdomen in neutropenic children remains controversial. As shown in the present series, an initial nonoperative approach with selective surgical indication appears to be safe and to yield good results. Supportive treatment, until the neutrophil count rises, followed by surgery, if necessary, appears to be a sound therapeutic approach for neutropenic children with acute abdomen.17648348