Macrofollicular Variant of Follicular Thyroid Carcinoma (MV-FTC) with a Somatic DICER1 Gene Mutation: Case Report and Review of the Literature

Benign thyroid lesions such as multinodular goiter and adenomatoid nodules are well-circumscribed lesions displaying a macrofollicular growth pattern and lack of nuclear atypia. The highly unusual macrofollicular variant of follicular thyroid carcinoma (MV-FTC) mirrors these attributes and is thereby misclassified by cytological examination of fine-needle aspiration biopsies. The MV-FTC diagnosis is instead suggested following histological investigation, in which malignant attributes, most commonly capsular invasion, are noted. The bulk of MV-FTCs described in the literature arise in younger female patients and carry an excellent prognosis. A recent coupling to mutations in the DICER1 tumor suppressor gene has been proposed, possibly indicating aberrancies in micro-RNA (miRNA) patterns as responsible of the tumorigenic process. We describe the cytological, histological and molecular phenotype of a 35 mm large MV-FTC arising in the right thyroid lobe of a 33-year-old female with a family history of multinodular goiter. The tumor was encapsulated and strikingly inconspicuous in terms of cellularity and atypia, but nevertheless displayed multiple foci with capsular invasion. A next-generation molecular screening of tumor DNA revealed missense variants in DICER1 (p. D1709N) and MET (p. T1010I), but no established fusion gene events. After sequencing of germline DNA, the DICER1 mutation was confirmed as somatic, while the MET variant was constitutional. The patient is alive and well, currently awaiting radioiodine treatment. This MV-FTC mirrors previous publications, suggesting that these tumors carry a favorable prognosis and predominantly arise in younger females. Moreover, DICER1 mutations should be considered a common driver event in the development of MV-FTCs.     

Allelic loss in clinically and screening-detected primary hyperparathyroidism

OBJECTIVE: Parathyroid adenomas frequently harbour deletions of genomic DNA at chromosome regions 1p, 6q and 11q. In this study we related clinical characteristics in 56 patients with primary hyperparathyroidism (pHPT) to loss of heterozygosity (LOH) in these chromosome regions. DESIGN: LOH analysis was performed on 56 sporadic parathyroid tumours using a total of 18 microsatellite markers for chromosome regions 1p, 6q and 11q. LOH was identified, for either radioactive or fluorescent labelled markers, as total absence or reduction of > or = 50% of the signal intensity of an allele in the tumour DNA vs. constitutional DNA. PATIENTS: Twenty-one of the patients were recruited by a population-based screening for pHPT and the remaining pHPT patients were gathered from routine clinical practice. RESULTS: In total, 27%, 23% and 23% of the tumours showed LOH at 1p, 6q and 11q, respectively. LOH at both 1p and 11q was more common in the screening-detected pHPT patients compared to those recruited from clinical practice (38% vs. 20%; P = 0.02 and 43% vs. 11%; P = 0.001, respectively), while allelic loss at 6q was more prevalent in the latter group (11% vs. 31%; P = 0.001). No apparent relationships between LOH at 1p, 6q, and 11q and clinical characteristics, such as glandular weight, serum levels of PTH or calcium, were demonstrated. Moreover, additional LOH analysis of chromosome 1p suggested a putative parathyroid tumour suppressor gene(s) in the region between markers DS214 and D1S503, spanning approximately 6 cM. CONCLUSION: A high frequency of LOH at 1p and 11q in tumours of screening-detected pHPT patients is intriguing, and may suggest that inactivation of known (the MEN1 gene) and putative tumour suppressor genes at these chromosomal regions is associated with a more benign disease.     

Whole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene

As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole‐exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis‐related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well‐established cancer gene lysine (K)‐specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome‐sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D‐mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.     

On the role of peptide hydrolysis for fibrillation kinetics and amyloid fibril morphology

Self-assembly of proteins into amyloid-like nanofibrils is not only a key event in several diseases, but such fibrils are also associated with intriguing biological function and constitute promising components for new biobased materials. The bovine whey protein β-lactoglobulin has emerged as an important model protein for the development of such materials. We here report that peptide hydrolysis is the rate-determining step for fibrillation of β-lactoglobulin in whey protein isolate. We also explore the observation that β-lactoglobulin nanofibrils of distinct morphologies are obtained by simply changing the initial protein concentration. We find that the morphological switch is related to different nucleation mechanisms and that the two classes of nanofibrils are associated with variations of the peptide building blocks. Based on the results, we propose that the balance between protein concentration and the hydrolysis rate determines the structure of the formed nanofibrils.

Peptide hydrolysis determines the fibrillation rate and the morphology of amyloid-like nanofibrils formed by β-lactoglobulin at low pH.     

Fatal Mycoplasma pneumoniae pneumonia in a previously healthy 18-year-old girl

A case of fatal Mycoplasma pneumoniae pneumonia in a previously healthy 18-year-old girl is reported. On hospital day 9, the antibody titer to M. pneumoniae was 1:512 in the complement fixation test and 1:5120 in the microparticle agglutination assay. After five weeks in the intensive care unit, the patient died from necrotizing hemorrhagic pneumonia with multi-organ failure. No significant superinfections occurred during ICU treatment. Corticosteroids (hospital day 8 onward) did not influence the course of the disease. It is noteworthy that, as in some previously reported cases, the clinical state deteriorated during presumably adequate antibiotic treatment (2 days before admission onward), and despite documented eradication of the pathogen from the respiratory tract (PCR from bronchoalveolar fluid on hospital day 22 was negative). However, the illness had lasted for several days before admission to the hospital, therefore the potentially beneficial effect of antibiotic treatment at an early stage of the disease cannot be assessed. Clearly, in default of other treatment options, correct diagnosis and early treatment of mycoplasma community-acquired pneumonia seems mandatory. This is the third case of fatal mycoplasma pneumonia reported from Austria in recent years, making this topic worthy of further scientific attention.     

Cerebrospinal fluid opening pressure in clinical practice – a prospective study

Journal of Neurology - Measurement of CSF opening pressure (CSFOP) is valuable and much used in the investigation of several neurological conditions. However, there are different opinions regarding...     

Oncologic,Functional, and Complications Outcomes of Robot-assisted Radical Cystectomy with Totally Intracorporeal Neobladder Diversion

Background

Robot-assisted radical cystectomy (RARC) with totally intracorporeal neobladder diversion is a complex procedure that has been reported with good outcomes in small series.

Objective

To present complications and oncologic and functional outcomes of this procedure.

Design, setting, and participants

Between 2003 and 2012 in a tertiary referral center, 70 patients were operated on by two experienced robotic surgeons. Data were collected prospectively and reviewed retrospectively.

Intervention

RARC with totally intracorporeal modified Studer ileal neobladder formation.

Outcome measurements and statistical analysis

The overall outcome of RARC with a totally intracorporeal neobladder was presented by assessing (1) surgical margins, (2) recurrence or cancer-specific death at 24 mo, (3) 30-d and 90-d complications graded according to the modified Clavien-Dindo system, (4) daytime and nighttime continence (no or one pad per day) at 6 and 12 mo, and (5) satisfactory sexual activity or potency at 6 mo and 12 mo. Survival rates were estimated by Kaplan-Meier plots.

Results and limitations

Median follow-up of the cohort was 30.3 mo (interquartile range: 12.7–35.6). We recorded negative margins in 69 of 70 patients (98.6%). Clavien 3–5 complications occurred in 22 of 70 patients (31.4%) at 30 d and 13 of 70 (18.6%) at >30 d. At 90 d, the overall complication rate was 58.5%. Clavien <3 and Clavien ≥3 complications were recorded in 15 of 70 patients (21.4%) and 26 of 70 (37.1%), respectively. Kaplan-Meier estimates for recurrence-free, cancer-specific, and overall survival at 24 mo were 80.7%, 88.9%, and 88.9%, respectively. Daytime continence and satisfactory sexual function or potency at 12 mo ranged between 70% and 90% in both men and women. Limitations of this study include its retrospective design, selection bias due to the learning curve phase, and missing data.

Conclusions

In this expert center for RARC, outcomes after RARC with totally intracorporeal neobladder diversion appear satisfactory and in line with contemporary open series.     

A finite element analysis of a T12 vertebra in two consecutive examinations to evaluate the progress of osteoporosis

Osteoporosis is a metabolic disease that causes bones to become fragile and be more likely to break. As basic clinical examinations to detect osteoporosis, dual energy X-ray absorptiometry (DXA) and quantitative computer tomography (QCT) are used. In the framework of a typical clinical examination, QCT scans were obtained from the T12 vertebra of an elderly woman and osteoporosis was diagnosed. One year later, new QCT scans were obtained in order to evaluate her clinical condition. Using both sets as primary information, two patient-specific finite element (FE) models were created and analyzed under compressive load. Vertebral bone was treated as orthotropic material and its elastic modulus was set as an indirect function of Hounsfield Units (HU). Commercial software for medical image processing and FE analysis, along with in house codes, were used for the mechanical analysis of the FE models. Alterations in the geometry/shape of the vertebra as well as in the distributions of several mechanical quantities were detected between the two FE models.As far as the volume of the vertebra is concerned, it augmented by a percentage of 9.7% while the volume of the vertebral body alone increased by 5.6%. In all the maximum values of the mechanical quantities a measurable reduction was observed (axial compressive displacement: 37.9%, von Mises stress: 23.8%, von Mises strains: 15.1%) and all the investigated distributions in the second FE model became smoother. Finally, the percentage of volume with von Mises strains greater than 4500 μstrain dropped from 8.9%, in the first examination, to 4.9% in the second one. Clinically, the prescribed medication seems to have reinforced the structural stability of the vertebra as a whole and through external remodeling the shape of the vertebra changed in a way that the majority of its volume was relieved from stresses and strains of high magnitude.