Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands.

CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

A Pituitary Society update to acromegaly management guidelines.

Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.

Comparison of predictive value of NT-proBNP, sST2 and MMPs in heart failure patients with different ejection fractions.

BACKGROUND: This study sought to compare the predictive value of NT-proBNP, sST2 and MMPs in HF with different ejection fractions from a population in southern China. METHODS: A cross-sectional study was conducted on 113 HF patients admitted to Fujian Provincial Hospital from December 2016 to March 2018.The patients were divided into three subgroups: 60 cases in HFpEF group (LVEF≥50%), 28 cases in HFmrEF group (41% ≤ LVEF≤49%) and 25 cases in HFrEF group (LVEF≤40%). ELISA method was applied to detect the concentrations of sST2, MMP-2 and MMP-9. Electrochemical luminescence immunoassay was applied to detect the concentration of plasma NT-proBNP. Univariate and multivariate Cox and logistic regression models were used to analyze the diagnostic significance of these plasma biomarkers in HF patients. Kaplan-Meier survival curves were used to assess the prognostic value of sST2 in the incidence of long-term adverse events during study. RESULTS: This study showed that plasma sST2 levels in HFrEF or HFmrEF patients were significantly higher than in HFpEF patients. Plasma levels of MMP-2 and MMP-9 in HFrEF patients were apparently higher than in HFpEF or HFmrEF patients. For the diagnosis of HFpEF, the AUC of NT-proBNP was higher than that of sST2, MMP-2 and MMP-9, which were 0.881, 0.717, 0.705 and 0.597, respectively. For the diagnosis of HFmrEF, the AUC of plasma sST2 was higher than that of MMP-2, MMP-9 and NT-proBNP, which were 0.799, 0.678, 0.676 and 0.793, respectively. For the diagnosis of HFrEF, the AUC of plasma NT-proBNP, sST2, MMP-2, and MMP-9 were 0.945, 0.820, 0.814, and 0.774 respectively. Spearman correlation analysis showed that plasma sST2 levels were significantly correlated with plasma MMP-2, MMP-9 and NT-proBNP levels. Further logistic regression analysis showed that except MMP-9, the biomarkers sST2 (OR = 1.960), MMP-2 (OR = 0.805) and NT-proBNP (OR = 0.002) were all independent risk factors for patients with heart failure. Survival analysis results suggested that for patients with HFmrEF, a higher level of plasma sST2 (≥ 0.332 ng/ml at admission) may predict a higher risk of endpoint events and a lower survival rate (P < 0.025). CONCLUSIONS: The circulating biomarkers sST2, MMP-2 and NT-proBNP were all independent risk factors for patients with heart failure. The sST2 can be a useful biomarker with both diagnostic and prognostic value in patients with HFmrEF. The higher sST2 level in patients with heart failure was related to a higher incidence of combined endpoint outcome.

T2-signal intensity, SSTR expression, and somatostatin analogs efficacy predict response to pasireotide in acromegaly.

OBJECTIVE: T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). DESIGN: The PAPE study is a cohort study. METHODS: We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. RESULTS: Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0-6.0) vs 12.0 (7.5-12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (ß: -0.29, 95% CI: -0.56 to -0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). CONCLUSIONS: Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

Tumor-to-Blood Ratio for Assessment of Somatostatin Receptor Density in Neuroendocrine Tumors Using 68Ga-DOTATOC and 68Ga-DOTATATE.

PET/CT with 68Ga-DOTA-somatostatin analogs has been tested for therapy monitoring in patients with neuroendocrine tumors (NETs). However, SUVs in tumors do not correlate with the net influx rate (Ki), as a representation of the somatostatin receptor expression. In this study, tumor-to-blood ratio (TBR) was evaluated as an alternative tool for semiquantitative assessment of 68Ga-DOTATOC and 68Ga-DOTATATE tumor uptake and as a therapy monitoring tool for patients with NETs. Methods: Twenty-two NET patients underwent a 45-min dynamic PET/CT scan after injection of 68Ga-DOTATOC or 68Ga-DOTATATE. Ki was determined using the Patlak method, and TBR was calculated for the 40- to 45-min interval. Results: A linear relation was found between Ki and TBR, with a square of Pearson correlation of 0.98 and 0.93 for 68Ga-DOTATOC and 68Ga-DOTATATE, respectively. Conclusion: A high correlation was found between Ki and TBR. Hence, TBR reflects somatostatin receptor density more accurately than SUV and is suggested as the preferred metric for semiquantitative assessment of 68Ga-DOTATOC and 68Ga-DOTATATE tumor uptake.

Prognostic value of sST2 and NT-proBNP at admission in heart failure with preserved, mid-ranged and reduced ejection fraction.

OBJECTIVE: The aim of this study was to compare sST2 at admission with N-terminal pro B-type natriuretic peptide (NT-proBNP) in prognostic accuracy among different types of heart failure (HF) and clarifying the enhanced prognostic value in patients with HF by the combination of the two biomarkers. METHODS AND RESULTS: A total of 164 consecutive patients admitted to our institution for HF were divided into three groups of HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF). Circulating sST2 and NT-proBNP were measured using the enzyme-linked immunosorbent assay (ELISA). The sST2 level was only significantly higher in HFrEF when compared with HFpEF. At ROC analysis to one-year adverse events, only sST2 showed predictive value in HFmrEF with an optimal cut-off value of 147.66 ng/ml (AUC 0.697, p = .045, sensitivity 75%, specificity 75.8%), while both NT-proBNP and sST2 showed a significant predictive value in HFpEF (p = .036 vs .042; AUC 0.683, sensitivity 71.4%, specificity 55.6%; AUC 0.677, sensitivity 64.3%, specificity 83.3%) with an optimal cut-off value of 1054.50 pg/ml and 117.80 ng/ml. Multivariate regression analysis suggested that sST2 and NT-proBNP could be biomarkers for predicting 1-year adverse events of HF (OR = 4.384, 95% CI = 1.661-11.570 vs. OR = 3.451, 95% CI = 1.254-9.497). Adverse events occurred frequently within one year both in sST2 and in NT-proBNP above the median. CONCLUSIONS: sST2 can provide different prognostic information in distinct types of HF, and even be superior to NT-proBNP. sST2 combined with NT-proBNP can improve predicting accuracy.

Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure.

Chronic heart failure (CHF) represents a major cause of hospitalization and death. Recent evidence shows that novel biomarkers such as soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) are correlated with inflammatory and ischemic responses in CHF patients. In this study we examined the effects of Ivabradine that inhibited the hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel, also called funny current If), thereby leading to selective heart rate reduction and improved myocardial oxygen supply on the cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in 50 CHF patients at the University Hospital of Jena. Patients were divided into three groups based on the etiology of CHF: dilated cardiomyopathy (DCM, n=20), ischemic cardiomyopathy (ICM, n=20) and hypertensive cardiomyopathy (HCM, n=10). The patients were administered Ivabradine (5 mg, bid for 3 months, and 7.5 mg bid for further 3 months). Analyses of cardiovascular biomarkers were performed at baseline as well as at 3- and 6-month follow-ups. At 6-month follow-up, GDF-15 levels were significantly reduced compared to baseline levels (P=0.0215), indicating a reduction in the progress of cardiac remodeling. H-FABP concentration was significantly lower in DCM patients compared to ICM (1.89 vs 3.24 µg/mL) and HCM patients (1.89 vs 3.80 µg/mL), and decreased over the 6-month follow-up (P=0.0151). suPAR median levels remained elevated, implying major ongoing inflammatory processes. As shown by significant decreases in GDF-15 and H-FABP levels, a reduction in ventricular remodeling and sub-clinical ischemia could be assumed. However, markers of hemodynamic stress (sST2) and inflammation (suPAR) showed no change or progression after 6 months of Ivabradine treatment in CHF patients. Further studies are necessary to validate the clinical applicability of these novel cardiovascular biomarkers.

Somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma.

PURPOSE: Medullary thyroid carcinoma (MTC) is a malignant neoplasm of parafollicular cells. Because it is a neuroendocrine tumor, it has known somatostatin receptors (SSTRs). The actual frequencies of the SSTR subtypes and their potential influences (by binding with endogenous somatostatin) on MTC cell proliferation have not been fully elucidated to date. The present study evaluated the occurrence of SSTR subtypes 1, 2, 3 and 5 as well as the possible role that each subtype plays in the clinical evolution of patients with MTC. METHODS: This retrospective, longitudinal study analyzed thyroid surgical material from 42 patients with MTC. Immunohistochemical staining was performed with monoclonal antibodies against subtypes 1, 2, 3 and 5 of SSTR. The histological material was classified as negative, focal positive or diffuse positive, in relation to each of the SSTR subtypes. The initial response to treatment, clinical course and patient mortality rate were assessed and related to the presence of SSTR subtypes. RESULTS: The most prevalent SSTR subtype was SSTR 3, which was found in 81% of the patients, when considering any pattern of positivity. However, subtype 2 had the lowest number of positive patients, with 28.6% demonstrating any positive pattern. Subtypes 1 and 5 had an intermediate prevalence of positivity, with subtype 1 present in 45.2% of the patients and subtype 5 positive in 54.8% of the patients, when considering any pattern of positivity. The presence of STR 1, in the form of diffuse positivity, independently predicted a better response to the initial therapy, with a hazard ratio (HR) of 4.80 (p = 0.03). CONCLUSION: This is the first study to show the correlation of the presence of SSTR1, detected by monoclonal immunohistochemical techniques, and better response to initial treatment and possibly better long-term clinical response in patients with MTC. In addition, these patients had low positivity rates for SSTR2, which might explain the low sensitivity of diagnostic and limited therapeutic response to octrotide based radioisotopes.

Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NET) overexpress somatostatin receptors (SSTR) that can be targeted for therapy. Somatostatin receptor expression is routinely measured by molecular imaging but the resolution is insufficient to define heterogeneity. We hypothesised that SSTR expression could be measured on circulating tumour cells (CTCs) and used to investigate heterogeneity of expression and track changes during therapy. METHODS: MCF-7 cells were transfected with SSTR2 or 5 and spiked into donor blood for analysis by CellSearch. Optimum anti-SSTR antibody concentration and exposure time were determined, and flow cytometry was used to evaluate assay sensitivity. For clinical evaluation, blood was analysed by CellSearch, and SSTR2/5 immunohistochemistry was performed on matched tissue samples. RESULTS: Flow cytometry confirmed CellSearch was sensitive and that detection of SSTR was unaffected by the presence of somatostatin analogue up to a concentration of 100 ng ml-l. Thirty-one NET patients were recruited: grade; G1 (29%), G2 (45%), G3 (13%), primary site; midgut (58%), pancreatic (39%). Overall, 87% had SSTR-positive tumours according to somatostatin receptor scintigraphy or 68-Ga-DOTATE PET/CT. Circulating tumour cells were detected in 21 out of 31 patients (68%), of which 33% had evidence of heterogeneous expression of either SSTR2 (n=5) or SSTR5 (n=2). CONCLUSIONS: Somatostatin receptors 2 and 5 are detectable on CTCs from NET patients and may be a useful biomarker for evaluating SSTR-targeted therapies and this is being prospectively evaluated in the Phase IV CALMNET trial (NCT02075606).

Prognostic Value of Soluble ST2 During Hospitalization for ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Studying the role of soluble ST2 (sST2) during hospitalization for myocardial infarction (MI) can be helpful for predicting the course of the hospitalization and development of complications. METHODS: We included 88 patients with MI (median age, 58 yr). Depending on the course of the hospitalization, the patients were divided into two groups: the favorable (n=58) and unfavorable (n=30) outcome groups. On days 1 and 12 after MI, serum sST2 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured by ELISA. RESULTS: On day 1, the concentrations of sST2 and NT-proBNP increased 2.4- and 4.5-fold, compared with the controls. Measurements on day 12 showed a significant decrease in the sST2 level (P=0.001), whereas the NT-proBNP level did not change. On day 1, the sST2 level in the unfavorable outcome group was 2-fold higher than that in the favorable outcome group and 3.7-fold higher than in the controls. On day 12, the marker level decreased in both groups. On day 1, the NT-proBNP level in the unfavorable outcome group was 6.8-fold higher than in the controls and 1.8-fold higher than in the favorable outcome group. On day 12, the level of NT-proBNP remained elevated in both groups. Determining the levels of both sST2 and NT-proBNP increases their diagnostic significance (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.7-3.2; areas under curve [AUC] 0.89; P=0.004). CONCLUSIONS: The level of sST2 is a more sensitive indicator during MI hospitalization than NT-proBNP.

Elevated circulating sST2 associated with subclinical atherosclerosis in newly diagnosed primary hypertension.

The aims of this study were to measure the levels of interleukin-33 (IL-33) and soluble Suppression of Tumorigenicity 2 (sST2) in patients with newly diagnosed primary hypertension (HT) and to determine the relationship between carotid intima-media thickness (CIMT) and IL-33/sST2. Eighty-two patients with newly diagnosed primary HT and ninety healthy volunteers were included in the study. CIMT ⩾0.9 mm was considered as significant for subclinical atherosclerosis. The sST2 levels of patients with primary HT were higher than those of the control group, whereas the IL-33 levels of these patients were much lower than those of the control group. The sST2 levels were higher in patients with subclinical atherosclerosis than in control subjects or patients with primary HT but not with subclinical atherosclerosis. In the primary HT group, sST2 had a positive correlation with CIMT, 24-h systolic-diastolic blood pressure, low-density lipoprotein and C-reactive protein, whereas sST2 had a negative correlation with the IL-33 level. A stepwise multivariable logistic regression analysis revealed that sST2 is an independent risk factor for subclinical atherosclerosis. Although the diagnostic predictive value of HT risk was determined as >51.8 pg l(-1) in the receiver operating characteristic curve analysis in respect of the sST2 level, the diagnostic predictive value for subclinical atherosclerosis risk was determined to be >107.2 pg l(-1). The sST2 level displays a positive correlation with atherosclerotic changes, and is an independent risk factor for subclinical atherosclerosis expressed as increased CIMT.

Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation.

Cerebral stroke induces massive Th1-shifted inflammation both in the brain and the periphery, contributing to the outcome of stroke. A Th1-type response is neurotoxic whereas a Th2-type response is accompanied by secretion of anti-inflammatory cytokines, such as interleukin-4 (IL-4). Interleukin-33 (IL-33) is a cytokine known to induce a shift towards the Th2-type immune response, polarize macrophages/microglia towards the M2-type, and induce production of anti-inflammatory cytokines. We found that the plasma levels of the inhibitory IL-33 receptor, sST2, are increased in human stroke and correlate with a worsened stroke outcome, suggesting an insufficient IL-33-driven Th2-type response. In mouse, peripheral administration of IL-33 reduced stroke-induced cell death and improved the sensitivity of the contralateral front paw at 5days post injury. The IL-33-treated mice had increased levels of IL-4 in the spleen and in the peri-ischemic area of the cortex. Neutralization of IL-4 by administration of an IL-4 antibody partially prevented the IL-33-mediated protection. IL-33 treatment also reduced astrocytic activation in the peri-ischemic area and increased the number of Arginase-1 immunopositive microglia/macrophages at the lesion site. In human T-cells, IL-33 treatment induced IL-4 secretion, and the conditioned media from IL-33-exposed T-cells reduced astrocytic activation. This study demonstrates that IL-33 is protective against ischemic insult by induction of IL-4 secretion and may represent a novel therapeutic approach for the treatment of stroke.

Elevations of inflammatory markers PTX3 and sST2 after resuscitation from cardiac arrest are associated with multiple organ dysfunction syndrome and early death.

BACKGROUND: A systemic inflammatory response is observed after cardiopulmonary resuscitation. We investigated two novel inflammatory markers, pentraxin 3 (PTX3) and soluble suppression of tumorigenicity 2 (sST2), in comparison with the classic high-sensitivity C-reactive protein (hsCRP), for prediction of early multiple organ dysfunction syndrome (MODS), early death, and long-term outcome after out-of-hospital cardiac arrest. METHODS: PTX3, sST2, and hsCRP were assayed at ICU admission and 48 h later in 278 patients. MODS was defined as the 24 h non-neurological Sequential Organ Failure Assessment (SOFA) score ≥ 12. Intensive care unit (ICU) death and 12-month Cerebral Performance Category (CPC) were evaluated. RESULTS: In total, 82% of patients survived to ICU discharge and 48% had favorable neurological outcome at 1 year (CPC 1 or 2). At ICU admission, median plasma levels of hsCRP (2.8 mg/L) were normal, while levels of PTX3 (19.1 ng/mL) and sST2 (117 ng/mL) were markedly elevated. PTX3 and sST2 were higher in patients who developed MODS (p<0.0001). Admission levels of PTX3 and sST2 were also higher in patients who died in ICU and in those with an unfavorable 12-month neurological outcome (p<0.01). Admission levels of PTX3 and sST2 were independently associated with subsequent MODS [OR: 1.717 (1.221-2.414) and 1.340, (1.001-1.792), respectively] and with ICU death [OR: 1.536 (1.078-2.187) and 1.452 (1.064-1.981), respectively]. At 48 h, only sST2 and hsCRP were independently associated with ICU death. CONCLUSIONS: Higher plasma levels of PTX3 and sST2, but not of hsCRP, at ICU admission were associated with higher risk of MODS and early death.

Single sST2 protein measurement predicts adverse outcomes at 1-year follow-up in patients with chronic heart failure.

INTRODUCTION: sST2 protein is a new biomarker. Its prognostic value in chronic heart failure (CHF) is still unclear. OBJECTIVES: The aim of the study was to evaluate the value of sST2 protein in patients with CHF during 1-year follow-up after hospitalization for prediction of adverse events: cardiovascular death, rehospitalization, an increase in diuretic doses, and/or worsening of the New York Heart Association functional class, defined as the composite endpoint. PATIENTS AND METHODS: The study involved 145 consecutive patients (mean age, 62.16 ±11.25 y; men, 82.76%) with left ventricular (LV) ejection fraction of 30% or less and symptomatic CHF. We analyzed clinical and biochemical data along with the serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and sST2. The optimal cut-off points for significant predictors of the composite endpoint were determined using receiver operating characteristi c curves. RESULTS: Patients with elevated levels of sST2 and NT-proBNP had more than a 4-fold higher risk of composite endpoint (odds ratio [OR], 4.033; 95%CI, 1.540-10.559) compared with patients in whom both biomarkers were below the cut-off points. The C-statistic for predicting the composite endpoint was improved when both biomarkers were incorporated into the model (C-statistic, 0.692; P = 0.0001) compared with an individual analysis for NT-proBNP (C-statistic, 0.606; P = 0.009) and sST2 (C-statistic, 0.613; P = 0.003). Moreover, after the addition of sST2 to NT-proBNP, the continuous net reclassification improvement index (OR, 0.256; 95% CI, 0.090-0.401; P = 0.007) and the integrated discrimination improvement index (OR, 0.104; 95% CI 0.011-0.221; P = 0.007) significantly improved. CONCLUSIONS: A single measurement of sST2 levels on admission in patients with poor LV systolic function and stable CHF is useful in short-term risk stratification and, in combination with NT-proBNP, it could be more useful in identifying patients with unfavorable c ourse of CHF.

Somatostatin receptor scintigraphy in sarcoidosis: relation to selected clinical and laboratory markers.

INTRODUCTION: Discriminating between active and inactive sarcoidosis may be problematic in everyday clinical practice. There are numerous biochemical markers used in the diagnosis and monitoring of sarcoidosis. Somatostatin receptor (SR) scintigraphy with the use of 99mTc-octreotide may be used to estimate disease activity. OBJECTIVES: The aim of the paper was to assess the value of traditional biomarkers (serum angiotensin-converting enzyme [SACE], C-reactive protein, markers of calcium metabolism, bronchoalveolar lavage fluid [BALF] lymphocytes) and a novel biomarker, 8-isoprostane (8-IP) in exhaled breath condensate (EBC), in the assessment of sarcoidosis activity in relation to somatostatin receptor scintigraphy. PATIENTS AND METHODS: The study included 32 patients with sarcoidosis. Scintigraphy was performed using somatostatin analogue, 99mTc-HYNIC-TOC; planar and SPECT/CT images were recorded. The study group was divided into a subgroup with positive radiotracer uptake (n = 20) and without a visible uptake (n = 12). 8-IP levels were measured in EBC by an immunoenzymatic assay. RESULTS We observed a significantly higher EBC 8-IP levels in the subgroup with positive uptake compared with those with negative uptake (19.1 ± 19.8 vs. 5.4 ± 3.5 pg/ml, P = 0.02). The levels of SACE and the percentage of BALF lymphocytes were also nonsignificantly elevated. In the group of patients with positive scintigraphy results, a positive correlation was observed between the uptake ratio and SACE (r = 0.44, P = 0.041). CONCLUSIONS: The results indicate low value of biochemical markers in the assessment of disease activity. SR scintigraphy may have practical usefulness in the monitoring of sarcoidosis.

Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival.

BACKGROUND: Somatostatin (SST) inhibited cell proliferation and negatively regulated the release of growth hormones by means of specific receptors (SSTR). Genetic variation in SSTR had been associated with risk of human cancers but had never been investigated in pancreatic cancer. METHODS: In this retrospective study the SSTR5 gene in paired tumor and blood samples from 33 pancreatic adenocarcinoma patients using the Sanger method were sequenced. Three single nucleotide polymorphisms (SNPs) in samples from 863 patients with pancreatic ductal adenocarcinoma and 876 healthy controls using the TaqMan method were analyzed. The associations between gene polymorphisms and pancreatic cancer risk and survival were analyzed by multivariate logistic regression and Cox proportional hazard models, respectively. RESULTS: No somatic mutations were identified, but 3 nonsynonymous SSTR5 SNPs (P109S, L48M, and P335L) in pancreatic tumors were identified. The SSTR5 P109S variant allele was associated with a 1.62-fold increased risk of pancreatic cancer (95% confidence interval [CI]: 1.08-2.43, P = 0.019). Furthermore, the SSTR5 L48M AC variant and smoking had a joint effect on pancreatic cancer risk (p(interaction) = 0.035). The odds ratios (95% confidence intervals) were 0.58 (0.34-0.97), 1.49 (1.18-1.89), and 2.27 (1.35-3.83) for the variant genotype alone, smoking alone, and both factors, respectively, compared with no factors. Finally, SSTR5 P335L CC and P109S CC combined were associated with lower overall survival durations in patients with resectable disease. CONCLUSIONS: These data suggest that SSTR5 genetic variants play a role in pancreatic cancer development and progression.

Gene expression of somatostatin receptor subtypes SSTR2a, SSTR3 and SSTR5 in peripheral blood of neuroendocrine lung cancer affected patients.

BACKGROUND: Somatostatin (SS) acts as a universal endocrine off-switch, and also inhibits the growth of neuroendocrine tumours through its specific receptors (SSTRs). Somatostatin receptors are G-protein-coupled receptors, which are encoded by five separate genes (SSTR1-5). Short peptide analogues demonstrate specific binding only for the subgroup consisting of SSTR2a, SSTR3 and SSTR5. Moreover, previous studies reported that expression of mRNA for SSTR2a correlated with therapeutic outcome in patients with carcinoid tumours treated with somatostatin analogs. PURPOSE: To develop and apply a Real Time Quantitative PCR technique (RT-qPCR) to compare and contrast the mRNA levels of SSTR2a, SSTR3 and SSTR5 in Neuroendocrine Lung Cancer affected patients. METHODS: Peripheral blood samples from 21 neuroendocrine lung cancer affected patients (14 SCLC, 6 LC and 1 LCNEC) subjected to scintigraphy with (111)In-DTPA-D-Phe(1)-octreotide (OctreoScan) and 24 healthy blood donors were investigated by RT-qPCR. mRNA levels for SSTR2a, SSTR3 and SSTR5 were measured in peripheral blood samples with a relative quantification method using plasmid dilutions as calibration curves and GAPDH as reference gene. RESULTS: A statistically significant increase in target genes/GAPDH copy number ratio was found for SSTR2a (median 38; IQR 22-141) and SSTR5 (median 51; IQR 19-499) in neuroendocrine lung cancer affected patients as compared with samples from healthy blood donors (P ≤ 0.0003 and P ≤ 0.0005). Since low levels of expression were detected in the control group for all three genes, optimal cut-off values were assessed using ROC curve analyses and were equal to 9.05 for SSTR2a and 16.97 for SSTR5. These cut off values resulted in a sensitivity of 86% (95%IC 65-95) for both markers and a specificity of 83% (95%IC 64-93%) and 79% (95%IC 60-91%) for SSTR2a and SSTR5 respectively. Comparison between OctreoScan results and RT-qPCR analysis demonstrated agreement in 76% of the cases. CONCLUSIONS: Our results suggest that SSTR2a and SSTR5 mRNAs are detectable in peripheral blood of neuroendocrine lung cancer affected patients using real-time quantitative PCR, with a good agreement with OctreoScan. The high sensitivity of this non-invasive molecular technique suggests that this method could represent a useful tool in the clinical management of neuroendocrine lung cancers.