Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS

Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series

Peer reviewe

Dynamic oscillatory signatures of central neuropathic pain in spinal cord injury

Central Neuropathic Pain (CNP) is believed to be accompanied by increased activation of the sensory and motor cortices. Our knowledge on this interaction is based mainly on fMRI studies, but there is little direct evidence on how these changes manifest in terms of dynamic neuronal activity. This study reports on the presence of transient EEG based measures of brain activity during motor imagery in spinal cord injured patients with CNP. We analyse dynamic EEG responses during imaginary movements of arms and legs in 3 groups of 10 volunteers each, comprising able-bodied people, paraplegic patients with CNP (lower abdomen and legs) and paraplegic patients without CNP. Paraplegic patients with CNP had increased event-related desynchronisation in the theta, alpha and beta bands (16-24 Hz) during imagination of movement of both non-painful (arms) and painful limbs (legs). Compared to patients with CNP, paraplegics with no pain showed a much reduced power in relaxed state and reduced event-related desynchronisation during imagination of movement. Understanding these complex dynamic, frequency-specific activations in CNP in the absence of nociceptive stimuli could inform the design of interventional therapies for patients suffering from CNP and possibly further understanding of the mechanisms involved

Obstructive sleep apnea, verbal memory, and executive function in a community-based high-risk population identified by the Berlin Questionnaire Akershus Sleep Apnea Project

Purpose Cognitive functions in community-dwelling adults at high risk of obstructive sleep apnea have not been described and nor are associations between cognitive functions and obstructive sleep apnea severity fully understood. The study aimed to describe verbal memory and executive function in community-dwelling adults identified by the Berlin Questionnaire and to investigate associations between these cognitive domains and different obstructive sleep apnea severity indicators. Methods Among 29,258 age- and gender-stratified persons 30–65 years who received the Berlin Questionnaire by mail, 16,302 (55.7%) responded. From 654 randomly drawn respondents with BQ high risk who were approached for study participation, 290 participants (55.9% males, mean age 48.2 years) were included. Verbal memory was assessed by Rey Auditory Verbal Learning Test and executive function by Stroop test. Obstructive sleep apnea severity indicators were assessed by polysomnography

Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force

Disseminating disease is a predictive and prognostic indicator of poor outcome in children with neuroblastoma. Its accurate and sensitive assessment can facilitate optimal treatment decisions. The International Neuroblastoma Risk Group (INRG) Task Force has defined standardised methods for the determination of minimal disease (MD) by immunocytology (IC) and quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) using disialoganglioside GD2 and tyrosine hydroxylase mRNA respectively. The INRG standard operating procedures (SOPs) define methods for collecting, processing and evaluating bone marrow (BM), peripheral blood (PB) and peripheral blood stem cell harvest by IC and QRT-PCR. Sampling PB and BM is recommended at diagnosis, before and after myeloablative therapy and at the end of treatment. Peripheral blood stem cell products should be analysed at the time of harvest. Performing MD detection according to INRG SOPs will enable laboratories throughout the world to compare their results and thus facilitate quality-controlled multi-centre prospective trials to assess the clinical significance of MD and minimal residual disease in heterogeneous patient groups

High tumour contamination of leukaphereses in patients with small cell carcinoma of the lung: a comparison of immunocytochemistry and RT-PCR

In small-cell lung carcinoma (SCLC) tumour cell contamination of leukaphereses is unknown. The present study was performed to define appropriate markers for reverse transcriptase polymerase chain reaction (RT-PCR), then to assess the contamination rate of leukaphereses and corresponding bone marrow samples. Immunocytochemistry (ICC) and RT-PCR methods were also compared. Among the 33 patients included, analyses were performed in 16 who had multiple leukaphereses and 17 who had only bone marrow. Leukapheresis products and bone marrow were analysed by ICC using several specific monoclonal antibodies against neural-cell adhesion molecule (N-CAM), epithelial glycoprotein (EGP-40) and cytokeratins (CK). Samples were also analyzed by RT-PCR for expression for N-CAM, synaptophysin, neuron-specific enolase, chromogranin, cytokeratin-18/-19, CEA, EGP-40, apomucin type 1 (MUC-1) and human endothelial cell-specific molecule (ESM-1). Using ICC staining, contaminating tumour cells were detected in 34% of leukaphereses (27% in patients with limited disease and 43% in those with extensive disease). N-CAM was the most reliable marker for detection of contamination. For RT-PCR, CK-19 and CEA were the only appropriate markers. Positive signal rate in leukaphereses increased to 78% (89% for patients with limited disease and 67% for extensive disease). In bone marrow, both techniques were in agreement whereas in leukaphereses, RT-PCR was better than ICC. A high rate of tumour cell contamination was demonstrated not only in bone marrow but also in leukaphereses from SCLC patients. The most appropriate technique was RT-PCR mainly in patients with limited disease. © 2001 Cancer Research Campaign http://www.bjcancer.co

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations

Is the Concept of Quality of Life Relevant for Multiple Sclerosis Patients with Cognitive Impairment? Preliminary Results of a Cross-Sectional Study

Background: Cognitive impairment occurs in about 50 % of multiple sclerosis (MS) patients, and the use of self-reported outcomes for evaluating treatment and managing care among subjects with cognitive dysfunction has been questioned. The aim of this study was to provide new evidence about the suitability of self-reported outcomes for use in this specific population by exploring the internal structure, reliability and external validity of a specific quality of life (QoL) instrument, the Multiple Sclerosis International Quality of Life questionnaire (MusiQoL). Methods: Design: cross-sectional study. Inclusion criteria: MS patients of any disease subtype. Data collection: sociodemographic (age, gender, marital status, education level, and occupational activity) and clinical data (MS subtype, Expanded Disability Status Scale, disease duration); QoL (MusiQoL and SF36); and neuropsychological performance (Stroop color-word test). Statistical analysis: confirmatory factor analysis, item-dimension correlations, Cronbach’s alpha coefficients, Rasch statistics, relationships between MusiQoL dimensions and other parameters. Principal Findings: One hundred and twenty-four consecutive patients were enrolled. QoL scores did not differ between the 69 cognitively non-impaired patients and the 55 cognitively impaired patients, except for the symptoms dimension. The confirmatory factor analysis performed among the impaired subjects showed that the structure of the questionnaire matched with the initial structure of the MusiQoL. The unidimensionality of the MusiQoL dimensions was preserved, and th

Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Metastatic progression due to development or enrichment of therapy-resistant tumor cells is eventually lethal. Molecular characterization of such chemotherapy resistant tumor cell clones may identify markers responsible for malignant progression and potential targets for new treatment. Here, in a case of stage IV adenocarcinoma of the gastroesophageal junction, we report the successful genome wide analysis using array comparative genomic hybridization (CGH) of DNA from only fourteen tumor cells using a bead-based single cell selection method from a bone metastasis progressing during chemotherapy.</p> <p>Case presentation</p> <p>In a case of metastatic adenocarcinoma of the gastroesophageal junction, the progression of bone metastasis was observed during a chemotherapy regimen of epirubicin, oxaliplatin and capecitabine, whereas lung-, liver and lymph node metastases as well as the primary tumor were regressing. A bone marrow aspirate sampled at the site of progressing metastasis in the right iliac bone was performed, and single cell molecular analysis using array-CGH of Epithelial Specific Antigen (ESA)-positive metastatic cells, and revealed two distinct regions of amplification, 12p12.1 and 17q12-q21.2 amplicons, containing the KRAS (12p) and ERBB2 (HER2/NEU) (17q) oncogenes. Further intrapatient tumor heterogeneity of these highlighted gene copy number changes was analyzed by fluorescence in situ hybridization (FISH) in all available primary and metastatic tumor biopsies, and ErbB2 protein expression was investigated by immunohistochemistry.</p> <p>ERBB2 was heterogeneously amplified by FISH analysis in the primary tumor, as well as liver and bone metastasis, but homogenously amplified in biopsy specimens from a progressing bone metastasis after three initial cycles of chemotherapy, indicating a possible enrichment of erbB2 positive tumor cells in the progressing bone marrow metastasis during chemotherapy. A similar amplification profile was detected for wild-type KRAS, although more heterogeneously expressed in the bone metastasis progressing on chemotherapy. Correspondingly, the erbB2 protein was found heterogeneously expressed by immunohistochemical staining of the primary tumor of the gastroesophageal junction, while negative in liver and bone metastases, but after three initial cycles of palliative chemotherapy with epirubicin, oxaliplatin and capecetabine, the representative bone metastasis stained strongly positive for erbB2.</p> <p>Conclusion</p> <p>Global analysis of genetic aberrations, as illustrated by performing array-CGH analysis on genomic DNA from only a few selected tumor cells of interest sampled from a progressing bone metastasis, can identify relevant therapeutic targets and genetic aberrations involved in malignant progression, thus emphasizing the importance and feasibility of this powerful tool on the road to more personalized cancer therapies in the future.</p

Physiotherapeutic interventions in multiple sclerosis across Europe: Regions and other factors that matter.

BACKGROUND: A wide variety of interventions exists in physical therapy (PT), but knowledge about their use across different geographical regions is limited. This study investigated the use of PT interventions in people with multiple sclerosis (MS) across Europe. It aimed to determine whether regions differ in applying interventions, and explore whether factors other than regions play a role in their use. METHODS: In an online cross-sectional survey, 212 respondents from 115 European workplaces providing PT services to people with MS representing 26 countries (four European regions) participated. Cluster analysis, Pearson Chi-squared test and a Poisson regression model were used to analyze the data. RESULTS: Thirteen of 45 listed PT interventions were used by more than 75% of centers, while nine interventions were used by less than 25%. For 12 interventions, regions differed markedly in their use. Cluster analysis of centers identified four clusters similar in their intervention use. Cluster assignment did not fully align with regions. While center region was important, center size, number and gender of physical therapists working in the center, and time since qualification also played a role. Cluster analysis exploring the use of the interventions provided the basis for a categorization of PT interventions in line with their primary focus: 1. Physical activity (fitness/endurance/resistance) training; 2. Neuroproprioceptive "facilitation/inhibition"; 3. Motor/skill acquisition (individualized therapy led); 4. Technology based interventions. CONCLUSIONS: To our knowledge this is the first study that has explored this topic in MS. The results broaden our understanding of the different PT interventions used in MS, as well as the context of their use