Preexisting conditions in pediatric ALL patients: Spectrum, frequency and clinical impact.

INTRODUCTION: The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development. METHODS: Retrospective database and study chart review included all patients from Germany, Austria and Switzerland (n = 4939) enrolled into multicenter clinical trial AIEOP-BFM ALL 2000 between July 1999 and June 2009. Patients enrolled into study AIEOP-BFM ALL 2009 - which was initiated subsequent to AIEP-BFM ALL 2000 - who were reported with a cancer prone syndrome or chromosomal abnormality were additionally included in this study to increase conclusiveness of observations. RESULTS: A total of 233 patients with at least one reported condition could be identified. The following conditions were reported in more than one patient: Gilbert's disease (n = 13), neurofibromatosis type I (n = 8), ataxia telangiectasia (n = 8), thalassemia (n = 7), Nijmegen Breakage syndrome (n = 6), cystic fibrosis (n = 4), glucose-6-phosphate dehydrogenase deficiency (n = 4), Noonan syndrome (n = 2), Klinefelter syndrome (n = 2), alpha-1-antitrypsin deficiency (n = 2), primary ciliary dyskinesia (n = 2). Especially those syndromes with a known cancer predisposition (NF type I, Ataxia telangiectasia, Nijmegen Breakage syndrome etc.) were associated with certain general and ALL-related characteristics, high therapy-related toxicity and reduced survival. CONCLUSION: The spectrum of underlying diseases within ALL patients is dispersed. A small number of ALL patients are reported with cancer predisposition syndromes at initial diagnosis which are associated with high rates of therapy-related toxicity and a markedly reduced chance of survival. The true prevalence of these conditions within the ALL population remains unknown due to inapparent clinical presentation. A targeted clinical and/or genetic examination for certain diagnoses like NF type I, Ataxia telangiectasia or Nijmegen Breakage syndrome could identify patients who benefit from adjustment of antileukemic therapy or intensification of supportive care.

Diagnostic accuracy of the Amsler grid and the preferential hyperacuity perimetry in the screening of patients with age-related macular degeneration: systematic review and meta-analysis.

OBJECTIVE: To clarify the screening potential of the Amsler grid and preferential hyperacuity perimetry (PHP) in detecting or ruling out wet age-related macular degeneration (AMD). EVIDENCE ACQUISITION: Medline, Scopus and Web of Science (by citation of reference) were searched. Checking of reference lists of review articles and of included articles complemented electronic searches. Papers were selected, assessed, and extracted in duplicate. EVIDENCE SYNTHESIS: Systematic review and meta-analysis. Twelve included studies enrolled 903 patients and allowed constructing 27 two-by-two tables. Twelve tables reported on the Amsler grid and its modifications, twelve tables reported on the PHP, one table assessed the MCPT and two tables assessed the M-charts. All but two studies had a case-control design. The pooled sensitivity of studies assessing the Amsler grid was 0.78 (95% confidence intervals; 0.64-0.87), and the pooled specificity was 0.97 (95% confidence intervals; 0.91-0.99). The corresponding positive and negative likelihood ratios were 23.1 (95% confidence intervals; 8.4-64.0) and 0.23 (95% confidence intervals; 0.14-0.39), respectively. The pooled sensitivity of studies assessing the PHP was 0.85 (95% confidence intervals; 0.80-0.89), and specificity was 0.87 (95% confidence intervals; 0.82-0.91). The corresponding positive and negative likelihood ratios were 6.7 (95% confidence intervals; 4.6-9.8) and 0.17 (95% confidence intervals; 0.13-0.23). No pooling was possible for MCPT and M-charts. CONCLUSION: Results from small preliminary studies show promising test performance characteristics both for the Amsler grid and PHP to rule out wet AMD in the screening setting. To what extent these findings can be transferred to a real clinic practice still needs to be established.

RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance.

Chemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLXL. Mechanistically, FGFR2 was shown to activate protein kinase C-δ to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB.

Pemetrexed, a multitargeted antifolate drug, demonstrates lower efficacy in comparison to methotrexate against osteosarcoma cell lines.

The folate inhibitor methotrexate (MTX) is an important component of osteosarcoma (OS) treatment regimens. New generation multitargeted antifolates, such as pemetrexed (PMX), have shown promise in the treatment of various solid tumors. In this study, the in vitro efficacy of MTX and PMX was compared in OS cell lines. MTX demonstrated a superior cytotoxic effect in comparison to PMX in all tested cell lines. Apoptosis assays revealed that both MTX and PMX induce apoptosis but MTX demonstrated superior efficacy. These in vitro results suggest that PMX as a single agent may not demonstrate improved efficacy compared to MTX in OS patients.

Mediastinal widening on chest radiography caused by combined aortic valve disease and primary large B-cell lymphoma.

Poststenotic aortic root dilatation in patients with aortic valvular stenosis may result in mediastinal widening on chest radiograph. Main differential diagnosis of mediastinal widening is a tumour. In fact, besides atypical chest pain or dyspnoea at exertion secondary to compression of intrathoracic structures in the latter, symptoms may be absent. We report a case of combined aortic valve disease and additional primary large B-cell lymphoma.