No abstract

Amplification of MYCN is the signature genetic aberration of 20–25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN‐FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di‐ or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di‐ or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment.

Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrowderived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224-32.Ó2017 AACR.

Recent studies have shown improvement in both the mortality and the morbidity associated with the neurologic complications of acute and chronic sinusitis. However, there are still a large portion of patients with long-term sequelae, and the literature reports a morbidity rate of approximately 30%. The most common post-treatment morbidities include permanent changes in vision, seizures, and hemiparesis. Although the overall incidence of neurologic complications from a sinogenic source are rare, the potential long-term complications can be devastating making prompt diagnosis and treatment vital to improving outcomes.

Chronic peripheral arterial occlusive disease of the lower limbs may cause tissue damage. Type and extent of peripheral nerve involvement is controversial. We examined 25 patients with peripheral arterial occlusive disease in various grades of severity and 37 age-matched healthy controls using conventional angiography and motor and sensory nerve conduction tests. Subjects with confounding factors for peripheral neuropathies were excluded. We found prolongation of distal motor latencies, decrease of motor and sensory nerve conduction velocities, and reduction in amplitude of the compound muscle action potential. Amplitudes of the compound muscle action potentials were lower in patients with pain at rest than in patients with intermittent claudication and decreased with increasing neurological disability score. Sural nerve conduction velocity, peroneal nerve F-wave chronodispersion, and tibial nerve F-wave persistence were the most frequent abnormal findings. Therefore we concluded that chronic peripheral arterial occlusive disease causes axonal degeneration, resulting in axonal polyneuropathy.