Diagnosis and workup of 522 consecutive patients with neuroendocrine neoplasms in Switzerland.

BACKGROUND Neuroendocrine neoplasms (NENs) are difficult to diagnose. We used SwissNET data to characterise NEN patients followed in the two academic centres of western Switzerland (WS), and to compare them with patients followed in eastern Switzerland (ES) as well as with international guidelines. METHOD SwissNET is a prospective database covering data from 522 consecutive patients (285 men, 237 women) from WS (n = 99) and ES (n = 423). RESULTS Mean ± SD age at diagnosis was 59.0 ± 15.7 years. Overall, 76/522 experienced a functional syndrome, with a median interval of 1.0 (IQR: 1.0-3.0) year between symptoms onset and diagnosis. A total of 51/522 of these tumours were incidental. The primary tumour site was the small intestine (29%), pancreas (21%), appendix (18%) and lung (11%) in both regions combined. In all, 513 functional imaging studies were obtained (139 in WS, 374 in ES). Of these, 381 were 111In-pentetreotide scintigraphies and 20 were 68Ga-DOTATOC PET. First line therapy was surgery in 87% of patients, medical therapy (biotherapy or chemotherapy) in 9% and irradiation in 3% for both regions together. CONCLUSION Swiss NEN patients appear similar to what has been described in the literature. Imaging by somatostatin receptor scintigraphy (SRS) is widely used in both regions of Switzerland. In good accordance with published guidelines, data on first line therapy demonstrate the crucial role of surgery. The low incidence of biotherapy suggests that long-acting somatostatin analogues are not yet widely used for their anti-proliferative effects. The SwissNET initiative should help improve compliance with ENETS guidelines in the workup and care of NEN patients.

Consistent nuclear expression of thyroid transcription factor 1 in subependymal giant cell astrocytomas suggests lineage-restricted histogenesis.

Thyroid transcription factor 1 (TTF-1) is encoded by the NKX2-1 homeobox gene. Besides specifying thyroid and pulmonary organogenesis, it is also temporarily expressed during embryonic development of the ventral forebrain. We recently observed widespread immunoreactivity for TTF-1 in a case of subependymal giant cell astrocytoma (SEGA, WHO grade I) – a defining lesion of the tuberous sclerosis complex (TSC). This prompted us to investigate additional SEGAs in this regard. We found tumor cells in all 7 specimens analyzed to be TTF-1 positive. In contrast, we did not find TTF-1 immunoreactivity in a cortical tuber or two renal angiomyolipomas resected from TSC patients. We propose our finding of consistent TTF-1 expression in SEGAs to indicate lineage-committed derivation of these tumors from a regionally specified cell of origin. The medial ganglionic eminence, ventral septal region, and preoptic area of the developing brain may represent candidates for the origin of SEGAs. Such lineagerestricted histogenesis may also explain the stereotypic distribution of SEGAs along the caudate nucleus in the lateral ventricles.

Tall cell papillary thyroid carcinoma: new diagnostic criteria and mutations in BRAF and TERT

The tall cell (TC) variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent, and the role of a minor TC component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations. Using a novel approach, we enriched a collective with PTCs that harbored an adverse outcome, which overcame the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of which had an adverse outcome. The proportion of TCs that constituted a poor prognosis was assessed. All of the tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody to detect the BRAF V600E mutation. A 10% cutoff for TCs was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that TCs above 10% were the only significant factor for overall, tumor-specific, and relapse-free survival. Seven percent of the cases had a TERT promoter mutation, whereas 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (P<0.001). PTCs comprised of at least 10% TCs are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for TCs. TERT promoter mutations are a strong predictor of tumor relapse, but their role as a surrogate marker for TCs is limited.

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell-derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33-expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.

Genetics of recurrent airway obstruction (RAO)

Recurrent airway obstruction (RAO) is a multifactorial and polygenic disease. Affected horses are typically 7 years of age or older and show exercise intolerance, increased breathing effort, coughing, airway neutrophilia, mucus accumulation and hyperreactivity as well as cholinergic bronchospasm. The environmental factors responsible are predominantly allergens and irritants in haydust, but the immunological mechanisms underlying RAO are still unclear. Several studies have demonstrated a familiar predisposition for RAO and it is now proven that the disease has a genetic basis. In offspring, the risk of developing RAO is 3-fold increased when one parent is affected and increases to almost 5-fold when both parents have RAO. Segregation analysis in two high-prevalence families demonstrated a high heritability and a complex inheritance with several major genes. A whole genomescan showed chromosome-wide significant linkage of seven chromosomal regions with RAO. Of the microsatellites, which were located near atopy candidate genes, those in a region of chromosome 13 harboring the IL4R gene were strongly associated with the RAO phenotype in the offspring of one RAO-affected stallion. Furthermore, IgE-levels are influenced by hereditary factors in the horse, and we have evidence that RAO-affected offspring of the same stallion have increased levels of specific IgE against moldspore allergens. The identification of genetic markers and ultimately of the responsible genes will not only allow for an improved prophylaxis, i.e. early identification of susceptible individuals and avoidance of high-risk matings, but also improve our ability to find new therapeutic targets and to optimize existing treatments.

The genetics of reproductive organ morphology in two Petunia species with contrasting pollination syndromes

Main conclusion Switches between pollination syndromes have happened frequently during angiosperm evolution. Using QTL mapping and reciprocal introgressions, we show that changes in reproductive organ morphology have a simple genetic basis. In animal-pollinated plants, flowers have evolved to optimize pollination efficiency by different pollinator guilds and hence reproductive success. The two Petunia species, P. axillaris and P. exserta, display pollination syndromes adapted to moth or hummingbird pollination. For the floral traits color and scent, genetic loci of large phenotypic effect have been well documented. However, such large-effect loci may be typical for shifts in simple biochemical traits, whereas the evolution of morphological traits may involve multiple mutations of small phenotypic effect. Here, we performed a quantitative trait locus (QTL) analysis of floral morphology, followed by an in-depth study of pistil and stamen morphology and the introgression of individual QTL into reciprocal parental backgrounds. Two QTLs, on chromosomes II and V, are sufficient to explain the interspecific difference in pistil and stamen length. Since most of the difference in organ length is caused by differences in cell number, genes underlying these QTLs are likely to be involved in cell cycle regulation. Interestingly, conservation of the locus on chromosome II in a different P. axillaris subspecies suggests that the evolution of organ elongation was initiated on chromosome II in adaptation to different pollinators. We recently showed that QTLs for pistil and stamen length on chromosome II are tightly linked to QTLs for petal color and volatile emission. Linkage of multiple traits will enable major phenotypic change within a few generations in hybridizing populations. Thus, the genomic architecture of pollination syndromes in Petunia allows for rapid responses to changing pollinator availability.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Risk factors for development of internal neoplasms in koi carp (Cyprinus carpio koi)

Fish, like mammals, can be affected by neoplastic proliferations. As yet, there are only a very small number of studies reporting on the occurrence of tumours in koi carp Cyprinus carpio koi and only sporadic reports on the nature of the tumours or on risk factors associated with their development. Between 2008 and 2012, koi with abdominal swelling were examined pathologically: neoplastic lesions were diagnosed and classified histologically. We evaluated possible risk factors for the development of these internal neoplasms in koi carp in Switzerland, using an online 2-part questionnaire sent to fish keepers with koi affected by internal tumours and to fish keepers who had not previously reported any affected koi. Part 1 addressed all participants and focused on general information about koi husbandry and pond technical data; Part 2 addressed participants that had one or several case(s) of koi with internal tumour(s) between 2008 and 2012, and consisted of specific questions about affected koi. A total of 112 internal tumours were reported by the 353 koi keepers participating in the survey. Analysis of the obtained data revealed that tumour occurrence was significantly associated with the location (indoors vs. outdoors) and volume of the pond, frequency of water changes, origin of the koi, number of koi kept in a Pond and the use of certain pond disinfectant/medication products. Our results contribute to the identification of possible risk factors, which in turn could help to establish prophylactic measures in order to reduce the occurrence of internal neoplasms in koi.

Overview of Genetically Engineered Mouse Models of Papillary and Anaplastic Thyroid Cancers: Enabling Translational Biology for Patient Care Improvement.

The prognosis from thyroid cancer subtypes in humans covers a spectrum from "cured at almost 90%" to "100% lethal." Invasive and poorly differentiated forms of thyroid cancer are among the most aggressive human cancers, and there are few effective therapeutic options. Genetically engineered mice, based on mutations observed in patients, can accurately recapitulate the human disease and its progression, providing invaluable tools for the preclinical evaluation of novel therapeutic approaches. This overview details models developed to date as well as their uses for identifying novel anticancer agents. © 2015 by John Wiley & Sons, Inc.