Molecular identification of bronchopulmonary neuroendocrine tumours and neuroendocrine genotype in lung neoplasia using the NETest liquid biopsy.

OBJECTIVES: Diagnosing lung neuroendocrine neoplasia (NEN) requires a biopsy or an operation. We evaluated a 'liquid biopsy' (NETest) as an in vitro diagnostic tool for identifying NEN and compared it to chromogranin A (CgA). METHODS: We identified 4 study cohorts: patients with bronchopulmonary carcinoids (n = 99, including 62 typical and 37 atypical carcinoids), lung cancers [n = 101, including 41 adenocarcinomas, 37 squamous carcinomas (SQC), 16 small-cell lung cancers and 7 large-cell neuroendocrine carcinomas]; benign disease (50 idiopathic pulmonary fibrosis) and healthy controls (n = 102). Transcript levels measured quantitatively (activity scores: 0-100) were compared to CgA (enzyme-linked immunosorbent assay; normal < 109 ng/ml) levels. RESULTS: The results of the NETest were positive (>20) in 94% of patients with bronchopulmonary carcinoid compared to 8% of the controls (Fisher's exact test; P < 0.001) and were significantly more accurate as a diagnostic test (McNemar's test; P < 0.001, χ2 = 72) than was CgA (positive: 19% bronchopulmonary carcinoid, 15% controls). Small-cell lung cancers (87%), large-cell neuroendocrine carcinomas (86%), adenocarcinoma (42%) and SQC (35%) were also NETest-positive. Increasing the NETest cut-off score to >40 was useful for detecting all NENs and differentiating these tumours from either controls/benign lung diseases (specificity 97%) or adenocarcinoma/SQC (specificity 94%). CgA was positive in 15-44% irrespective of pathology and had no diagnostic value. CONCLUSIONS: A gene-based liquid biopsy is an effective and accurate method for diagnosing lung tumours with neuroendocrine gene expression. CgA has no value. An NETest score >40 provides an accurate (94-97%) rule-in for the diagnosis of NEN and a rule-out for benign and other neoplastic diseases. Because neuroendocrine gene expression is associated with a poor prognosis, NETest levels may have utility both in the diagnosis of and the treatment stratification for lung neoplasia.

Plasma concentration and expression of adipokines in epicardial and subcutaneous adipose tissue are associated with impaired left ventricular filling pattern.

BACKGROUND: Adipokines in serum derive mainly from subcutaneous and visceral adipose tissues. Epicardial adipose tissue (EAT), being a relatively small but unique fat depot, probably does not make an important contribution to systemic concentrations of adipokines. However, proximity of EAT to cardiac muscle and coronary arteries allows cells and proteins to penetrate between tissues. It is hypothesized that overexpression of proinflammatory cytokines in EAT plays an important role in pathophysiology of the heart. The aim of the study was to analyze the relationship between echocardiographic heart parameters and adipokines in plasma, epicardial, and subcutaneous fat in patients with obesity and type 2 diabetes mellitus (T2DM). Additionally, we evaluate proinflammatory properties of EAT by comparing that depot with subcutaneous adipose tissue. METHODS: The study included 55 male individuals diagnosed with coronary artery disease (CAD) who underwent planned coronary artery bypass graft. Plasma concentrations of leptin, adiponectin, resistin, visfatin, apelin, IL-6, and TNF-α, as well as their mRNA and protein expressions in EAT and subcutaneous adipose tissue (SAT) were determined. RESULTS: Obesity and diabetes were associated with increased leptin and decreased adiponectin plasma levels, higher protein expression of leptin and IL-6 in SAT, and higher visfatin protein expression in EAT. Impaired left ventricular (LV) diastolic function was associated with increased plasma concentrations of leptin, resistin, IL-6, and adiponectin, as well as with increased expressions of resistin, apelin, and adiponectin in SAT, and leptin in EAT. CONCLUSIONS: Obesity and T2DM in individuals with CAD have a limited effect on adipokines. Expression of adipokines in EAT and SAT is linked to certain heart parameters, however diastolic dysfunction of the LV is strongly associated with circulating adipokines.

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease.

BACKGROUND: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status. AIM: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study. MATERIAL AND METHODS: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means ± SD. RESULTS: NETest levels were significantly increased in BPC (45 ± 25) versus controls (9 ± 8; p < 0.0001). The area under the ROC curve was 0.96 ± 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 ± 32) and LCNEC (28 ± 7). NETest accurately distinguished progressive (61 ± 26) from stable disease (35.5 ± 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 ± 21) and SCC (12 ± 11) and benign disease (IPF) (18 ± 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31). CONCLUSIONS: Elevated -NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.

Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature.

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.

Nontoxic Goiter (NTG) and Radioiodine: What Do Patients Think About It? Quality of Life in Patients with NTG Before and After 131-I Therapy.

OBJECTIVE: Despite numerous publications regarding nontoxic goiter (NTG) treatment and an increasing interest in patients' quality of life, few studies present the outcome of 131-I treatment from the patients' perspective. Our study's main aim was to verify whether there is any improvement in life quality following 131-I treatment. MATERIALS AND METHODS: Thirty-five patients with NTG qualified to participate in the study. All patients completed a Thyroid-Related Health-Related Quality of Life (Thy-R-HRQoL) questionnaire created by us and the Medical Outcomes Study 36-item Short Form (SF-36), right before and 1 year after 131-I. RESULTS: We observed an improvement in six out of eight SF-36 and three out of seven Thy-R-HRQoL domains. In comparison with the control group, we observed worse results in two out of eight, prior to treatment, and one out of eight SF-36 afterward, as well as in all Thy-R-HRQoL domains. We did not find any correlation between improvement of Thy-R-HRQoL and SF-36 and goiter size reduction, except for Bodily Pain. There was also no correlation between improvement of SF-36 and Thy-R-HRQoL domains, and goiter size before treatment. The older the patient, the less noticeable improvement was observed in Physical and Social Functioning, and Vitality in SF-36, but age had no influence on the assessment by Thy-R-HRQoL. CONCLUSION: Radioiodine treatment improves life quality in patients with NTG. Use of the Health-Related Quality of Life questionnaire should be taken into consideration when evaluating life quality of patients with NTG. Relentless pursuit of maximal goiter size reduction in 131-I treatment is worth consideration. In our study, life quality improvement did not depend directly on the goiter size reduction. Life quality improvement after 131-I might not depend on initial goiter size, and for certain domains of SF-36 might be less clearly expressed in older patients.

The utility of blood neuroendocrine gene transcript measurement in the diagnosis of bronchopulmonary neuroendocrine tumours and as a tool to evaluate surgical resection and disease progression.

OBJECTIVES: The management of bronchopulmonary neuroendocrine tumours (BPNETs) is difficult, since imaging, histology and biomarkers have a limited value in diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection. METHODS: (i) Diagnostic cohort: BP carcinoids (n = 118)-typical carcinoid, n = 67 and atypical carcinoid, n = 51; other lung NEN (large-cell neuroendocrine carcinoma and small-cell lung carcinoma, n = 13); adenocarcinoma, (n = 26); squamous cell carcinoma (n = 23); controls (n = 90) and chronic obstructive pulmonary disease (n = 18). (ii) Surgical cohort, n = 28: BP carcinoids (n = 16: typical carcinoid 12; atypical carcinoid 4); large-cell neuroendocrine carcinoma, n = 3; lung adenocarcinoma, n = 8 and squamous cell carcinoma, n = 1. Blood sampling was performed presurgery and 30 days post-surgery. Transcript levels measured by quantitative polymerase chain reaction were calculated as activity scores (0-100% scale: normal < 14%) and compared with chromogranin A (enzyme-linked immunosorbent assay; normal <109 ng/ml). RESULTS: NETest was significantly elevated in carcinoids (48.7 ± 27%) versus controls (6 ± 6%, P < 0.001) with metrics: sensitivity 93%, specificity 89%, positive predictive value 92% and negative predictive value 91%. NETest differentiated progressive disease (73 ± 22%) from stable disease (36 ± 19%, P < 0.001) and R0 resections (10 ± 5%, P < 0.001, area under the curve: 0.98). Levels in chronic obstructive pulmonary disease and lung cancers were 18-24% while elevated in small-cell lung carcinoma/large-cell neuroendocrine carcinoma (59 ± 10%). In BPNETs on postoperative Day 30, NETest decreased by 60% (P < 0.001). Chromogranin A was elevated in only 40% of carcinoids and not altered by surgery. CONCLUSIONS: Blood NET gene levels accurately identified BPNETs (100%) and differentiated these from controls, benign and malignant lung disease. Progressive disease could be identified and surgical resection verified. Chromogranin A had no clinical utility. Monitoring NET transcript levels in blood will facilitate management by detecting residual tumour and identifying progressive disease.

Molecular strategies in the management of bronchopulmonary and thymic neuroendocrine neoplasms.

Thoracic NETs [bronchopulmonary NETs (BPNETs) and thymic NETs (TNET)] share a common anatomic primary location, likely a common cell of origin, the "Kulchitsky cell" and presumably, a common etiopathogenesis. Although they are similarly grouped into well-differentiated [typical carcinoids (TC) and atypical carcinoids (AC)] and poorly differentiated neoplasms and both express somatostatin receptors, they exhibit a wide variation in clinical behavior. TNETs are more aggressive, are frequently metastatic, and have a lower 5-year survival rate (~50% vs. ~80%) than BPNETs. They are typically symptomatic, most often secreting ACTH (40% of tumors) but both tumor groups share secretion of common biomarkers including chromogranin A and 5-HIAA. Consistently effective and accurate circulating biomarkers are, however, currently unavailable. Surgery is the primary therapeutic tool for both BPNET and TNETs but there remains little consensus about later interventions e.g., targeted therapy, or how these can be monitored. Genetic analyses have identified different topographies (e.g., significant alterations in chromatin and epigenetic remodeling in BPNETs versus frequent chromosomal abnormalities in TNETs) but there is an absence of clinically actionable mutations in both tumor groups. Liquid biopsies, tools that can measure neoplastic signatures in peripheral blood, can potentially be leveraged to detect disease early i.e., recurrence, predict tumors that may respond to specific therapies and serve as real-time monitors for treatment responses. Recent studies have identified that mRNA transcript analysis in blood effectively identifies both BPNET and TNETs. The clinical utility of this gene expression assay includes use as a diagnostic, confirmation of completeness of surgical resection and use as a molecular management tool to monitor efficacy of PRRT and other therapeutic strategies.

Epidemiology, risk factors and prognosis of Interferon alpha induced thyroid disorders. A Prospective Clinical Study.

INTRODUCTION: Hepatitis C virus (HCV) infection is a worldwide problem and hepatitis, which is its natural unfavourable course, is still a challenge for hepatologist. At present, standards of treatment are changing from combined therapy with interferon alpha (IFN-α) and ribavirin to new antiviral drugs. The current classification divides interferon induced thyroid diseases (IITD) into two groups: autoimmune (Hashimoto disease, Graves disease, positive antithyroid autoantibodies in euthyroid patients) and non-autoimmune (destructive thyroiditis, non-autoimmune hypothyroidism). A common complication of cytokine therapy is the induction of antithyroid autoantibodies de novo without thyroid dysfunction. During therapeutic regimens combined with ribavirin, destructive thyroiditis with typical biphasic course is more common than in IFN-α monotherapy. Clinically, overt pathologies often have discrete symptoms, which cause diagnostic and therapeutic dilemmas. AIMS: The aim of this study was to estimate IITD occurrence, to find risk factors for IITD development. MATERIAL AND METHODS: The study group consisted of 66 patients treated for HCV infection. Before and during antiviral therapy, hormonal (TSH, fT4, fT3), immunological (thyroid autoantibodies), ultrasonographic and genetic (HLA-A2) parameters were evaluated. RESULTS: Hormonal disturbances were detected in 24.2% of patients; however, 43.9% of patients had positive thyroid autoantibodies (de novo) without hormonal imbalance. Multivariate analysis revealed the following: female sex, elevated TSH level, occurrence of anti-TPO autoantibodies (TPO-Ab), and increased blood velocity in thyroid arteries are risk factors for IITD development. IN CONCLUSION: Thyroid disorders are common during IFN-α therapy. Previous epidemiological data seem to be underestimated. Important risk factors for IITD development are: female sex, elevated serum TSH concentration (≥2.5 µU/mL), positive TPO-Ab and increased blood velocity in thyroid arteries.

Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors.

AIM: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. PATIENTS & METHODS: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. The primary end point was overall survival. RESULTS: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression. CONCLUSION: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold.

Evaluation of Head and Neck Paragangliomas by Computed Tomography in Patients with Pheochromocytoma-Paraganglioma Syndromes.

BACKGROUND: Hereditary head and neck paragangliomas (HNP) are very often associated with pheochromocytoma-paraganglioma syndromes, which are caused by mutations in genes encoding subunits of succinate dehydrogenase (SDHx) complex. The aim of this study was to determine the frequency and location of HNP among SDHx carriers. MATERIAL/METHODS: A total of 72 patients with SDHx mutations underwent computed tomography examinations of the head and neck. HNP were present in 44 (61.1%) out of 72 patients (31 SDHD, 11 SDHB, 2 SDHC); 113 HNP were found; the most common were carotid paragangliomas (59) and vagal paragangliomas (27). RESULTS: The HNP were statistically more frequent in carriers of SDHD mutations compared to carriers of SDHB mutations (72.1% vs. 43.5%, p=0.033). Multiple tumors more often occurred in patients with SDHD mutations 26/31 (83.9%) than in patients with SDHB mutations 6/11 (54.5%) p=0.05. There was a significant difference in the prevalence of carotid paragangliomas between patients with SDHB and SDHD mutations (7/11 [63.6%] vs. 30/31 [96.8%], respectively, p=0.004). Patients with SDHD mutations more often had carotid paragangliomas located on the left side than on the right side, as compared to SDHB mutations 25/31 (80.6%) vs. 4/11 (36.4%), p=0.006. CONCLUSIONS: SDHx mutations predispose to multifocal and bilateral HNP. Carotid and vagal paragangliomas occurred most often. Patients with SDHD mutations are characterized by higher frequency of HNP than patients with SDHB mutations, which is mainly driven by higher frequency of carotid body tumors in patients with SDHD mutations. No difference in the frequency of head and neck paragangliomas in other locations was found.

Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms.

AIM: To determine the efficacy of (90)Y [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) in 67 patients with pancreatic and small bowel neuroendocrine tumors (NETs). PATIENTS & METHODS: The primary efficacy end point was overall survival (OS) and secondary end points were progression-free survival (PFS) and tumor response. RESULTS: Median PFS in pancreatic and small bowel NETs was 25 and 28 months, respectively, and median OS was 42 and 38.5 months, respectively. No intergroup differences in median OS (p = 0.945) or PFS (p = 0.174) were found, also after adjustment for tumor origin, secretory status and grade, and patient's gender. CONCLUSION: (90)Y-DOTATATE may have similar efficacy in pancreatic and small bowel NETs. Better WHO performance status at baseline seems to be associated with more favorable outcomes.

Large multinodular goiter--outpatient radioiodine treatment.

INTRODUCTION: 131-I treatment of nodular, especially nontoxic, goitre is still reserved mainly for elderly patients, whose numerous concomitant diseases disqualify them from surgery. Therapy often involves isolation and is available only in selected centres, which may be located far from some patients' places of residence, which is inconvenient for elderly people. The aim of the study was to assess the effectiveness of outpatient fractionated 131-I treatment of patients with large nodular goitres, as well as to evaluate complications and the factors affecting treatment results. MATERIAL AND METHODS: The study included 35 patients with a large nodular goitre. Thyroid volume and treatment results were evaluated using US and CT neck examination. RESULTS: Mean thyroid volume prior to treatment was 104.36 mL (range 36.23-301.09 mL). An average administered 131-I activity was 1806 MBq (range 800-4000). The average reduction of goitre volume was 43.18% (range -17.23-89.66%). Final treatment results correlated with the thyroid size reduction obtained three months after treatment (r = 0.74; p = 0.001). Symptoms of transient hyperthyroidism were observed in 8.57% of patients, in 5.4% Graves disease was induced (including severe Graves' orbitopathy in 2.7%), and in 2.86% TRAb increase without development of hyperthyroidism was observed. The treatment results were not influenced by initial thyroid volume (r = -0.01; p = 0.95). An increase in thyroid volume during the treatment was reported in 20% of patients, with a mean increase of 22.3% (range 0.63-55.03%). Post-treatment hypothyroidism was diagnosed in 42.9% of patients. One patient was diagnosed with salivary gland damage. CONCLUSIONS: Fractionated 131-I treatment of large nodular goitres is an effective method, the results of which are comparable to those obtained from the administration of one-time high doses of radioiodine.

Usefulness of Somatostatin Receptor Scintigraphy (Tc-[HYNIC, Tyr3]-Octreotide) and 123I-Metaiodobenzylguanidine Scintigraphy in Patients with SDHx Gene-Related Pheochromocytomas and Paragangliomas Detected by Computed Tomography.

AIMS: The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using (99m)Tc-[HYNIC, Tyr3]-octreotide (TOC) and 123I-metaiodobenzylguanidine (mIBG) in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography and to establish an optimal imaging diagnostic algorithm in SDHx mutation carriers. METHODS: All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and 123I-mIBG. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis. RESULTS: We evaluated 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 SDHD, 16 SDHB and 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients, and malignant disease was diagnosed in 7 patients. In benign tumors, the sensitivity of SRS was estimated at 77% and of 123I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region dependent (p < 0.001). The highest SRS sensitivity was found in head and neck paragangliomas (HNP; 91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40 and 42.9%, respectively). The highest 123I-mIBG sensitivity was found in pheochromocytomas (sensitivity of 100%) and the lowest in HNP (sensitivity of 3.7%). In metastatic disease, SRS was superior to mIBG (sensitivity of 95.2 vs. 23.8%, respectively). CONCLUSION: SRS and 123I-mIBG single photon emission computed tomography (SPECT) sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I-mIBG SPECT.

Gel electrophoretic separation of proteins from cultured neuroendocrine tumor cell lines.

Neuroendocrine tumors (NET) often develop asymptomatically and are detected at a late stage. Currently, there exist certain markers of NET that occur only in the advanced stages of the disease. Still, there is need to develop markers specific of the early stage of cancer development. Nevertheless, biomarkers are mostly low­abundant proteins and require separation from complex protein mixtures, which remains a major challenge. The goal of the present study was to optimize one­dimensional­polyacrylamide gel electrophoresis (1D­PAGE) for separation and comparison of protein composition from neuroendocrine tumor samples. 1D­PAGE was optimized by modification of the gel concentration and by comparison of different gel staining protocols. In addition, several steps prior to electrophoresis were carried out to purify and preliminarily reduce the complexity of the sample. The results of these optimization steps indicated that use of an albumin removal kit can considerably decrease the amount of albumin in the samples, thereby allowing to detect proteins of low abundance. Optimal separation of the sample was obtained using a 12% polyacrylamide gel. Furthermore, the use of silver staining allowed detection of proteins at nanogram levels, whereas for Coomassie Brilliant Blue staining, the detection limit was 10 times higher. Optimization of the sample preparation workflow and parameters of the electrophoretic separation allowed to reduce the complexity of the studied material and facilitated further identification of proteins of low abundance in the sample. This study demonstrated that analysis of the secreted proteome of NET cells by 1D­PAGE is a simple and suitable tool for the identification of potential NET protein biomarkers.

US not bright but right method of thyroid volume estimation even in large and substernal extended goitres. Comparison of US and three methods of CT thyroid evaluation ­ prospective study.

BACKGROUND: Ultrasound is nowadays a method of choice for thyroid volume assessment. However, its disadvantage is some inaccuracy, which is said to be higher in huge, especially substernally extended goitres. AIMS: The aim of the study was to compare the US and CT thyroid volumetric measurements: multi-observers (CT MO) and one-observer (CT OO) to CT planimetry results (CT Pl) in patients with large goitres. MATERIALS & METHODS: The study material comprised 70 thyroid imaging examinations obtained from 35 patients with nontoxic goitres, scanned twice before and after radioiodine treatment. Mean thyroid volume was 88·97 ± 60·21 ml. Thirty-three thyroid scans revealed the extension below the jugular notch (mean of 2·46 cm). Thyroid volume in US, CT MO and CT OO was estimated using the ellipsoid formula. CT Pl was established a reference method. RESULTS: The mean thyroid volume in CT Pl was 88·97 ml (median 80·73, range 11·81 to 315·97). US underestimates thyroid volume by 7·55 ml (7·7%) with a sufficient correlation (R(2) = 0·89) and precision (20·37). CT OO is the closest and CT MO the most distant from CT Pl, with US between them in thyroid volume estimation. The percentage US bias is constant through all range of thyroid volume. There is no difference for percentage bias between US and CT Pl for goitres with (8·67%), and without (6·70%) substernal part. CONCLUSION: US examination is sufficient for epidemiological studies, radioiodine activity calculation and goitre size assessment in everyday medical practice. Neither initial size of the goitre nor its substernal extension affects US assessment precision.

Blood flow velocity in the middle cerebral artery during transnasal endoscopic skull base surgery performed in controlled hypotension.

BACKGROUND AND PURPOSE: To assess blood flow velocity in the middle cerebral artery (MCA) during transnasal endoscopic procedures performed with decreased hemodynamic parameters. MATERIALS AND METHODS: In 40 patients who underwent endoscopic skull base surgery in controlled hypotension (studied group) and in 13 patients operated without reduction of hemodynamic parameters (control group), blood flow velocity in MCA was assessed with transcranial color Doppler sonography. RESULTS: Blood flow velocity in MCA remained within the range of age-specific reference values in all patients before operation. It decreased significantly in both groups after induction of anesthesia and then dropped even further in studied group of patients when hemodynamic parameters were reduced; the systolic velocity fell below the normal reference values in 25% of patients, the mean velocity in 50% and the diastolic velocity in 57% of patients. The diastolic velocity was much more heavily influenced by diminished hemodynamic parameters than systolic velocity in the studied group as opposed to the control group where reduction of blood flow velocity pertained equally systolic and diastolic velocity. CONCLUSION: During transnasal endoscopic procedures performed in moderate hypotension, in addition to significant drop of blood flow velocity to values well below the normal reference range, a divergent reduction of systolic and diastolic velocity was detected. Since divergent systolic and diastolic velocity may indicate an early phase of cerebral autoregulation compromise, and the decrease of mean blood flow velocity in MCA corresponds with a decrease of cerebral blood flow, further investigations in this field seem warranted.

Chemometric evaluation of urinary steroid hormone levels as potential biomarkers of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of the NET markers can be used to fulfil the criteria of high specificity and high sensitivity for the screening procedure. However, by combining the measurements of different NET markers, they become highly sensitive and specific diagnostic tests. The aim of the work was to identify whether urinary steroid hormones can be identified as potential new biomarkers of NETs, which could be used as prognostic and clinical course monitoring factors. Thus, a rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection has been developed for the determination of cortisol, cortisone, corticosterone, testosterone, epitestosterone and progesterone in human urine. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification were 0.5 and 1 ng mL-1 for each steroid hormone, respectively. Linearity was confirmed within a range of 1-300 ng mL-1 with a correlation coefficient greater than 0.9995 for all analytes. The described method was successfully applied for the quantification of six endogenous steroid levels in human urine. Studies were performed on 20 healthy volunteers and 19 patients with NETs. Next, for better understanding of tumor biology in NETs and for checking whether steroid hormones can be used as potential biomarkers of NETs, a chemometric analysis of urinary steroid hormone levels in both data sets was performed.

Thrombocytopenia and perioperative complications after stentless Freedom Solo valve implantation.

BACKGROUND: Freedom Solo (FS) stentless bioprostheses have superior haemodynamic performance compared to stented valves; however, the data of thrombocytopenia after FS implantations is disturbing. AIM: To compare platelet count and perioperative complications between stentless and stented biological valves in patients undergoing aortic valve replacement. METHODS: In 29 patients, FS bovine valves (Sorin Group, Saluggia, Italy) were implanted. Platelet counts were analysed before surgery, on the day of operation, on four consecutive postoperative days (POD) as well as at discharge, and compared to 29 control patients with biological stented porcine valves (Labcor Laboratorios TLBP-A Supra). The analysis of the perioperative variables extracorporeal circulation (ECC), aortic cross clamping (XC) and mechanical ventilation times, as well as blood supply, was performed. RESULTS: Initial platelet counts were comparable in both groups. In the FS group, platelet levels on the four consecutive POD were significantly lower. The lowest platelet value (13 × 10³/µL), related to fatal thrombotic thrombocytopenic purpura, was found in one patient from the FS group. ECC as well as XC and mechanical ventilation times, were significantly longer in the FS group, and more blood transfusions in these patients were required. In multiple regression analysis, ECC and XC times did not correlate with platelet count. CONCLUSIONS: Implantations of FS stentless bioprostheses are related to significantly lower platelet counts. Severe perioperative complications and their relation to thrombocytopenia need further evaluation.

Gastroduodenal neuroendocrine neoplasms including gastrinoma - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological and localisation diagnosis. The principles of treatment are discussed, including endoscopic, surgical, pharmacological and radionuclide treatment. Finally, recommendations on patient monitoring are given.

Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.