Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay, and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2′-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region, and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation, and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.
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Elham Barazeghi, Per Hellman, Gunnar Westin and Peter Stalberg
Manjunath Goroshi, Swati S Jadhav, Vijaya Sarathi, Anurag R Lila, Virendra A Patil, Ravikumar Shah, Priya Hira, Rajaram Sharma, Shettepppa Goroshi, Gwendolyn Fernandes, Amey Rojekar, Abhay Dalvi, Ganesh Bakshi, Gagan Prakash, Nalini S Shah and Tushar R Bandgar
Rationale and introduction
To evaluate the computerised tomography (CT) characteristics of phaeochromocytoma (PCC) that differentiate them from other non-benign adrenal masses such as adrenocortical carcinoma (ACC), primary adrenal lymphoma (PAL) and adrenal metastases (AM).
This retrospective study was conducted at a tertiary health care institute from Western India. Patients presented between January 2013 and August 2016 with histological diagnosis of PCC or other non-benign adrenal mass having adequate reviewable imaging data comprising all four CECT phases were included.
The study cohort consisted of 72 adrenal masses from 66 patients (33 PCC, 22 ACC, 4 PAL, 13 AM). Unlike other masses, majority of PCC (25/33) showed peak enhancement in early arterial phase (EAP). PCC had significantly higher attenuation in EAP and early venous phase (EVP), and higher calculated percentage arterial enhancement (PAE) and percentage venous enhancement (PVE) than other adrenal masses (P < 0.001). For diagnosis of PCC with 100% specificity, PAE value ≥100% and EAP attenuation ≥100 HU had 78.8 and 63.6% sensitivity respectively. ACC were significantly larger in size as compared to PCC and metastasis. The adreniform shape was exclusively found in PAL (two out of four) and AM (4 out of 13). None of the enhancement, wash-in or washout characteristics were discriminatory among ACC, PAL and AM.
Peak enhancement in EAP, PAE value ≥100% and EAP attenuation ≥100 HU differentiate PCC from other malignant adrenal masses with high specificity.
Sylvia Thiele, Anke Hannemann, Maria Winzer, Ulrike Baschant, Heike Weidner, Matthias Nauck, Rajesh V Thakker, Martin Bornhäuser, Lorenz C Hofbauer and Martina Rauner
Glucocorticoids (GC) are used for the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited, amongst others, by adverse effects on bone. The Wnt and bone formation inhibitor sclerostin was recently implicated in the pathogenesis of GC-induced osteoporosis. However, data are ambiguous. The aim of this study was to assess the regulation of sclerostin by GC using several mouse models with high GC levels and two independent cohorts of patients treated with GC. Male 24-week-old C57BL/6 and 18-week-old DBA/1 mice exposed to GC and 12-week-old mice with endogenous hypercortisolism displayed reduced bone formation as indicated by reduced levels of P1NP and increased serum sclerostin levels. The expression of sclerostin in femoral bone tissue and GC-treated bone marrow stromal cells, however, was not consistently altered. In contrast, GC dose- and time-dependently suppressed sclerostin at mRNA and protein levels in human mesenchymal stromal cells, and this effect was GC receptor dependent. In line with the human cell culture data, patients with rheumatoid arthritis (RA, n = 101) and polymyalgia rheumatica (PMR, n = 21) who were exposed to GC had lower serum levels of sclerostin than healthy age- and sex-matched controls (−40%, P < 0.01 and −26.5%, P < 0.001, respectively). In summary, sclerostin appears to be differentially regulated by GC in mice and humans as it is suppressed by GCs in humans but is not consistently altered in mice. Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.
Changjiao Yan, Meiling Huang, Xin Li, Ting Wang and Rui Ling
To investigate the mutant status of BRAF gene and analyze its relationship to epidemiological risk factors and clinical outcomes among patients with papillary thyroid cancer (PTC) in the largest, single-institution Chinese cohort to date.
The medical records of 2048 PTC patients were reviewed in this retrospective study. Single-factor and multiple logistic regression analyses were applied to identify risk factors for BRAF V600E mutation. Survival outcomes including distant metastatic and persistent or recurrent PTC were examined, with a mean follow-up time of 23.4 (5–47) months.
The BRAF V600E mutation was present in 83.7% of patients (1715 of 2048). Correlation was found between BRAF V600E mutation and several epidemiological features, including age, concomitant hypertension and Hashimoto thyroiditis (HT). For the clinicopathological features, BRAF V600E was significantly associated with bilateral multifocality (odds ratio (OR) 1.233, 95% confidence interval (CI) 1.063–1.431, P < 0.01) and less lateral lymph node metastases (OR 0.496, 95% CI 0.357–0.689, P < 0.01). Smaller tumor size and advanced disease stage were significant in single-factor analyses but became insignificant after multivariate adjustment. No association was found between BRAF V600E mutation and extrathyroidal invasion, distant metastatic and disease persistence or recurrence.
Part of epidemiological features are independent risk or protective factors for BRAF V600E mutation. The presence of BRAF V600E mutation is not an aggressive prognosis on poor clinical outcomes in PTC. However, the high prevalence of BRAF V600E may provide guidance for surgery strategy and opportunity for targeted treatment in recurrent and advanced stage disease.
Karim Gariani, Pedro Marques-Vidal, Gérard Waeber, Peter Vollenweider and François R Jornayvaz
Excessive glucocorticoid secretion has been associated with type 2 diabetes mellitus (T2DM) and other features of the metabolic syndrome. We aimed to evaluate whether basal or evening salivary cortisol may predict the occurrence of incident insulin resistance (IR) or T2DM.
This was a prospective, population-based study derived from the CoLaus/PsyCoLaus study including 1525 participants (aged 57.7 ± 10.3 years; 725 women). A total of 1149 individuals were free from T2DM at baseline. Fasting plasma glucose and insulin were measured after a follow-up of 5.3 years. Basal and evening salivary cortisol were measured at baseline. The association between basal or evening salivary cortisol level and incidence of IR or T2DM were analyzed by logistic regression, and the results were expressed for each independent variable as ORs and 95% CI.
After a median follow-up of 5.3 years, a total of 376 subjects (24.7%) developed IR and 32 subjects (2.1%) developed T2DM. Basal and evening salivary cortisol divided in quartiles were not associated with incidence of IR or T2DM. Multivariable analysis for age, gender, body mass index, physical activity and smoking status showed no association between basal or evening salivary cortisol and incidence of IR or T2DM.
In the CoLaus/PsyCoLaus study of healthy adults, neither basal nor evening salivary cortisol was associated with incident IR or T2DM.
Machine learning methods in sellar region diseases present a particular challenge because of the complexity and the necessity for reproducibility. This systematic review aims to compile the current literature on sellar region diseases that utilized machine learning methods and to propose a quality assessment tool and reporting checklist for future studies.
PubMed and Web of Science were searched to identify relevant studies. The quality assessment included five categories: unmet needs, reproducibility, robustness, generalizability and clinical significance.
Seventeen studies were included with the diagnosis of general pituitary neoplasms, acromegaly, Cushing’s disease, craniopharyngioma and growth hormone deficiency. 87.5% of the studies arbitrarily chose one or two machine learning models. One study chose ensemble models, and one study compared several models. 43.8% of studies did not provide the platform for model training, and roughly half did not offer parameters or hyperparameters. 62.5% of the studies provided a valid method to avoid over-fitting, but only five reported variations in the validation statistics. Only one study validated the algorithm in a different external database. Four studies reported how to interpret the predictors, and most studies (68.8%) suggested possible clinical applications of the developed algorithm. The workflow of a machine-learning study and the recommended reporting items were also provided based on the results.
Machine learning methods were used to predict diagnosis and posttreatment outcomes in sellar region diseases. Though most studies had substantial unmet need and proposed possible clinical application, replicability, robustness and generalizability were major limits in current studies.
Hanbaro Kim, Ki Byung Song, Dae Wook Hwang, Jae Hoon Lee, Shadi Alshammary and Song Cheol Kim
This study aimed to evaluate the evolving trends in clinicopathological features of pancreatic neuroendocrine tumors and to analyze the predictors of recurrence after curative resection. Data collected retrospectively from a single center between January 1990 and December 2017 were analyzed. Patients were categorized chronologically into three groups for evolving time-trend analysis. Overall, 542 patients (300 female, 55.4%) underwent surgical resection for pancreatic neuroendocrine tumors, including 435 (80.3%) with non-functional tumors. Time-trend analysis revealed that the surgically resected pancreatic neuroendocrine tumor number increased consistently; however, the incidental non-functional pancreatic neuroendocrine tumor number also increased over time (P < 0.001). The 5- and 10-year disease-free survival rates were 86.4 and 81.3%, respectively. The overall recurrence rate was 13.7%, and the most common site of recurrence was the liver. The median time to recurrence after primary surgery was 19.0 (range 0.8–236.3) months, and the median survival time after recurrence was 22.6 (range 0.4–126.9) months. On multivariate analysis, grade G3 pancreatic neuroendocrine tumors (hazard ratio 4.51; P < 0.001), lymph node metastasis (hazard ratio 2.46; P = 0.009), lymphovascular invasion (hazard ratio 3.62; P = 0.004), perineural invasion (hazard ratio 2.61; P = 0.004) and resection margin (hazard ratio 4.20; P = 0.003) were independent prognostic factors of disease-free survival. The surgically resected pancreatic neuroendocrine tumor number increased over time mainly because of an increase in incidentally discovered non-functional pancreatic neuroendocrine tumors. Grade G3 pancreatic neuroendocrine tumors, lymph node metastasis, lymphovascular invasion, perineural invasion and a positive resection margin were significant predictors of worse disease-free survival in patients with surgically resected pancreatic neuroendocrine tumors.
Masafumi Tetsuka and Misato Tanakadate
The bovine cumulus-oocyte complex (COC) is capable of converting cortisone, an inert glucocorticoid to active cortisol. This mechanism is mediated by 11β-hydroxysteroid oxidoreductase type 1 (HSD11B1), whose expression dramatically increases in the mature COC. In this study, we investigate the time course expression of HSD11B1 and the enzyme activity in the bovine COC undergoing maturation and fertilization in relation to key events taking place in the COC. Bovine COCs were subjected to in vitro maturation (IVM) and fertilization (IVF). The activities of HSD11B1 and HSD11B2, which mediates the opposite reaction, were measured by using a radiometric conversion assay. In parallel studies, cumulus expansion, P4 production, and the expression of genes associated with ovulation were measured. The reductive activity of HSD11B1 increased in the latter half of IVM and remained high during IVF, whereas the oxidative activity of HSD11B2 remained unchanged over both periods. Consequently, the net glucocorticoid metabolism in the bovine COC shifted from inactivation to activation around the time of ovulation and fertilization. The increase in HSD11B1 expression lagged behind that of P4 increase and cumulus expansion but ahead of the expressions of genes responsible for PGE2 synthesis. The reductive activity of HSD11B1 was well correlated with the cumulus expansion rate. This outcome indicates that the ability of the cumulus to activate glucocorticoids is related to its ability to synthesize hyaluronan. These results also indicate that the activation of HSD11B1 is an integral part of the sequential events taking place at the ovulation and fertilization in the bovine COC.
Kosmas Daskalakis, Marina Tsoli, Anna Angelousi, Evanthia Kassi, Krystallenia I Alexandraki, Denise Kolomodi, Gregory Kaltsas and Anna Koumarianou
Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1–38.9) vs 9 months (95% CI: 0–18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1–19.9) vs 13 months with sunitinib (95% CI: 9.3–16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5–8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3–31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.
Vito Francic, Martin Keppel, Verena Schwetz, Christian Trummer, Marlene Pandis, Valentin Borzan, Martin R Grübler, Nicolas D Verheyen, Marcus E Kleber, Graciela Delgado, Angela P Moissl, Benjamin Dieplinger, Winfried März, Andreas Tomaschitz, Stefan Pilz and Barbara Obermayer-Pietsch
Cardiovascular disease manifestation and several associated surrogate markers, such as vitamin D, have shown substantial seasonal variation. A promising cardiovascular biomarker, soluble ST2 (sST2), has not been investigated in this regard – we therefore determined if systemic levels of sST2 are affected by seasonality and/or vitamin D in order to investigate their clinical interrelation and usability.
sST2 levels were measured in two cohorts involving hypertensive patients at cardiovascular risk, the Styrian Vitamin D Hypertension Trial (study A; RCT design, 8 weeks 2800 IU cholecalciferol daily) and the Ludwigshafen Risk and Cardiovascular Health Study (LURIC; study B; cross-sectional design).
The effects of a vitamin D intervention on sST2 levels were determined in study A using ANCOVA, while seasonality of sST2 levels was determined in study B using ANOVA.
The concentrations of sST2 remained unchanged by a vitamin D intervention in study A, with a mean treatment effect (95% confidence interval) of 0.1 (−0.6 to 0.8) ng/mL; P = 0.761), despite a rise in 25(OH)D (11.3 (9.2–13.5) ng/mL; P < 0.001) compared to placebo. In study B, seasonal variations were present in 25(OH)D levels in men and women with or without heart failure (P < 0.001 for all subgroups), while sST2 levels remained unaffected by the seasons in all subgroups.
Our study provides the first evidence that systemic sST2 levels are not interrelated with vitamin D levels or influenced by the seasons in subjects at cardiovascular risk.