Understanding tumor heterogeneity as functional compartments - superorganisms revisited

Compelling evidence broadens our understanding of tumors as highly heterogeneous populations derived from one common progenitor. In this review we portray various stages of tumorigenesis, tumor progression, self-seeding and metastasis in analogy to the superorganisms of insect societies to exemplify the highly complex architecture of a neoplasm as a system of functional "castes.

How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies?

Introduction and Background: Familial medullary thyroid cancer (FMTC) is caused by gain of function mutations in the proto-oncogene RET (rearranged during transfection). Missense mutations within exon 14 including p. Val804Met are known to cause FMTC and multiple endocrine neoplasia type 2a/b. The clinical significance of other novel missense variants within this hotspot region of exon 14 is not delineated. Case Description: A three-generation pedigree of FMTC is presented with the co-occurrence of two missense variants within exon 14 of the RET gene, the known variant p.Val804Met and the novel variant p.Val826Met. The female index patient developed medullary thyroid cancer at the age of 42 years and was heterozygous for both missense variants. Her younger sister was also tested to be compound heterozygous for both mutations, and five further relatives were heterozygous for only one of both sequence variants. Prophylactic thyroidectomy was recommended for the two carriers of the RET mutation p.Val804Met, revealing a C-cell hyperplasia for one of them at the age of 19 years. Medical surveillance of 6 heterozygous carriers including repeated neck ultrasound examination as well as basal and calcium (pentagastrin)-stimulated calcitonin levels were recommended. Conclusion: Our data emphasize the importance of an interdisciplinary approach to assess the functional and clinical significance of novel RET variants. In the absence of functional studies, the plausibility of the pathologic significance of a detected endocrine genetic variant can be estimated by in silico methods such as computational analysis of protein structure and biophysical differences or comparative database search for evolutionary conservation. (C) 2016 European Thyroid Association Published by S. Karger AG, Base

LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs

Background: Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug resistant epilepsy within the first year. Aim: To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly. Method: Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers. Results: All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic clonic seizures, with generalized tonic clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p < 0.05) and sulthiame (p < 0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p < 0.05) and topiramate (p < 0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients. Conclusion: Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital. (c) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved

Bactericidal Efficacy of Cold Plasma at Different Depths of Infected Root Canals In Vitro

OBJECTIVES: Cold plasma (CP) has been shown to be effective even against multiresistant microorganisms. As previous investigations on the effect of CP in root canals showed promising results, the aim of the present study was to analyze the bactericidal efficacy of CP in different depths of infected dentin. METHODS: 32 standardized root canals of human mandibular premolars were infected with Enterococcus faecalis and incubated for one week. Specimens were randomly selected for one of four disinfection methods: control (5mL NaCl), 5mL chlorhexidine (CHX), CP alone (CP), and a combination of 5mL CHX and cold plasma (CHX+CP). CHX was ultrasonically activated for 30s, while cold plasma was used for 60s in the root canals. Dentin samples at depths of 300, 500 and 800 µm were obtained and diluted serially. Colony forming units (CFUs) were counted on agar plates after 24h of incubation. RESULTS: The highest overall logarithmic reduction factors (RF) were obtained from CHX+CP (log RF 3.56 p<0.01; Mann-Whitney U test), followed by CP (log RF 3.27 p<0.01) and CHX alone (log RF 2.65 p<0.01) related to the control. All disinfection methods showed significantly lower CFU counts compared to the control group in 300 µm and 800 µm (both p<0.01, Kruskal-Wallis test). DISCUSSION: The adjuvant use of CP might be beneficial in highly infected root canals to improved disinfection. However, the disinfection effect against Enterococcus faecalis of CP is comparable to ultrasonically activated CHX