Maciej Bączyk

Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls

Chromogranin A, despite a number of limitations, is still the most valuable marker of neuroendocrine tumors (NETs). Granins belong to the family of acidic proteins that constitute a major component of secretory granules of various endocrine and neuroendocrine cells, which are components of both the classical endocrine glands and the diffuse neuroendocrine system. These cells are a potential source of transformation into neuroendocrine tumors. The awareness of potential causes influencing the false results of its concentrations simplifies diagnosis and treatment. One of the disadvantages of this marker is its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration, which often results in confusion and diagnostic difficulties. The molecular structure is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides. Presumably they act as precursors of active proteins. Chromogranin expression correlates with the amount of secretory vesicles in neuroendocrine cells. The peptide chain during biochemical changes becomes a precursor of biologically active proteins with a wide range of activities. There are a number of commercially available kits for the determination of chromogranin A, which differ in methodology. We present the evaluation of chromogranin A as a marker of neuroendocrine tumors in clinical practice and the possible factors that may affect the outcome of its concentration.

The Usefulness of Standardized Uptake Value in Differentiation between Benign and Malignant Thyroid Lesions Detected Incidentally in 18F-FDG PET/CT Examination

Introduction In the last decade, (18)F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET and PET/CT) has become one of the major diagnostic tools used in oncology. A significant number of patients who undergo this procedure, due to non-thyroidal reasons, present incidental uptake of (18F-FDG) in the thyroid. The aim of the study was to compare the SUVmax (standardized uptake value) of thyroid focal lesions, which were incidentally found on PET/CT, in relation to the results of thyroid fine-needle aspiration biopsy (FNAB) and/or histopathological evaluation. Materials and Methods Patients referred for PET/CT examination, due to non-thyroidal illness, presented focal 18F-FDG uptake in the thyroid and were advised to undergo ultrasonography (US), hormonal evaluation, FNAB and/or total thyroidectomy at our institution. Results 6614 PET/CT examinations performed in 5520 patients were analyzed. Of the 122 patients with focal thyroid 18F-FDG activity, 82 patients (67.2%) underwent further thyroid evaluation using FNAB. Benign lesions were diagnosed in 46 patients, malignant - in 19 patients (confirmed by post-surgical histopathology), while 17 patients had inconclusive results of cytological assessment. Mean SUVmax of benign lesions was 3.2±2.8 (median = 2.4), while the mean SUVmax value for malignant lesions was 7.1±8.2 (median = 3.5). The risk of malignancy was 16.7% for lesions with a SUVmax under 3, 43.8% for lesions with a SUVmax between 3 and 6, and 54.6% for lesions with a SUVmax over 6. In the group of malignant lesions, a positive correlation between the lesion’s diameter and SUVmax was observed (p = 0.03, r = 0.57). Conclusions Subjects with incidental focal uptake of 18F-FDG in thyroid are at a high risk of thyroid malignancy. A high value of SUVmax further increases the risk of malignancy, indicating the necessity for further cytological or histological evaluation. However, as SUVmax correlated with the diameter of malignant lesions, small lesions with focal uptake of 18F-FDG should be interpreted cautiously.

Therapy of large multinodular goitre using repeated doses of radioiodine.

ObjectiveTo evaluate the efficacy of radioiodine therapy using 131I in a group of patients with large multinodular goitre (LMG). MethodsThe study was carried out in patients with goitre volume greater than 100 cm3 and in patients with LMG who were disqualified from surgery. The study included 34 female participants (age range: 62–84 years) with LMG: 26 patients were hyperthyroid and eight patients had a nontoxic goitre. The patients were treated with 800 MBq of radioiodine administered four times at 3-month intervals (total activity of 3.2 GBq). Before each therapy course, serum thyrotropin, free thyroxin, free triiodothyronine and antithyroid antibodies were measured, ultrasonography and thyroid scan were performed. Patients were followed up for a minimum of 24 months. Fine-needle biopsy was done before qualification to the study. ResultsBefore therapy, median thyroid volume was 145 cm3. It decreased during therapy to 65–76 cm3 after 12 months and to 50–62 cm3 after 24 months. After 24 months, 60% of patients were euthyroid and 40% of patients were hypothyroid. During therapy, significant increases in TSHRAb, TPOAb and TgAb levels were observed. No correlation between the levels of antithyroid antibodies, radioiodine uptake, reduction of goitre volume and hormonal status was found. ConclusionIn most cases of LMG, repeated administration of radioiodine is safe and effective. The highest response of the thyroid volume is observed after the first course of treatment. On account of a high incidence of hypothyroidism, the patients should be monitored during and after therapy.

Familial syndromes associated with neuroendocrine tumours.

Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue.

Management of the hormonal syndrome of neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 – receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea.

Efficacy of samarium 153 and strontium 89 treatment for bone metastases in prostate cancer patients: monotherapy vs. treatment combined with external beam radiotherapy. Preliminary report

Summary Background Approximately 60–80% of metastatic prostate cancer patients suffer from pain caused by bone metastases. Bone metastases have a negative impact on patient performance status. Aim The aim of study was to compare the efficacy of treatment with strontium 89 or samarium 153 in monotherapy vs. radioisotope treatment combined with external beam radiotherapy (EBRT) in prostate cancer patients with bone metastases. Materials/Methods We retrospectively analyzed one hundred (n=100) metastatic prostate cancer patients aged between 53 and 84 years, who we divided into four treatment groups: 30 pts received Sr-89 monotherapy; 30 patients received Sm-153 monotherapy; 20 pts received Sr-89 combined with EBRT; and 20 pts received Sm-153 combined with EBRT. Follow-up was 4 months. All patients prior to therapy had their bone metastases confirmed by bone scan examination. Pathologic fractures were excluded and the nature of metastases (osteoblastic/mixed) was evaluated with X-ray films and/or CT and/or MRI. Sr-89 therapy consisted of a standard dose of 150MBq, while Sm-153 was administered proportionally to body weight (37MBq/kg). In combined treatment groups EBRT was given to the dominant metastatic site with 8Gy in one fraction or 20Gy in five daily fractions. Treatment efficacy was determined by change in pain intensity evaluated according to visual analogue scale (VAS), changes in Karnofsky performance status (KPS) and in the use of analgesics. Results Complete pain relief (VAS 5) was noted in 20% of patients in both monotherapy groups and in 10% and 15% of patients in Sm-153 and Sr-89 combined with EBRT, respectively. Decrease in pain intensity and in the use of analgesics as well as improvement in performance status were statistically significant for combined therapy vs. monotherapy (p Conclusions Radioisotope therapy with Sr-89 or Sm-153 combined with external beam radiotherapy in comparison with radioisotope monotherapy improves efficacy of treatment. Treatment toxicity is low.

Clinical features of gastroenteropancreatic tumours

Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively.

Fractionated dosage of radioiodine for the ablation of low-risk differentiated thyroid cancer has no impact on survival

INTRODUCTION Due to a limited number of hospital beds dedicated to radioiodine therapy (RIT) in some countries, a fractionated dose of radioiodine may be considered as the ablation therapy of differentiated thyroid cancer (DTC). The aim of the study was to compare the late effects of ablation therapy with single and fractionated dose of radioiodine in patients with DTC. PATIENTS AND METHODS Patients with low-risk DTC referred to our institution 5-16 weeks after thyroidectomy, treated with 2.2 GBq of 131I, either in a single dose (2.2 GBq, group 1) or in two fractions (1.1 GBq+1.1 GBq administered with a 24 h interval, group 2) were retrospectively included. Clinical outcome of the treatment and overall survival (OS) was evaluated. RESULTS 83 patients treated with single dose and 186 patients treated with fractionated dose of radioiodine were included. Mean duration of follow-up was 8.0 vs.7.8 years, respectively (p=ns). There were no significant differences between the groups in male to female ratio, age at the time of the first RIT, proportion of papillary thyroid cancers, volume of the thyroid tissue, thyroid-stimulating hormone and thyroglobulin levels before first RIT. RIT was repeated in 55.4% and 54.8% of patients from group 1 and 2 respectively (p=ns). There were no significant differences including the course and outcomes of the treatment between the groups, measured by: cumulative dose of 131I, mean number of 131I administrations and mean thyreoglobulin concentration at the follow-up. Also the overall survival did not differ significantly between the groups. Probability of 5-year OS was 98.6% for patients treated with single and 99.5% with fractionated dose of 131-I, 10 year OS - 98.6 and 97.1% respectively, 15 year OS - 95.5 and 92.9% respectively (p=ns). CONCLUSIONS In the long-term follow-up, radioiodine ablation therapy with fractionated doses in low-risk DTC patients is equally effective as with single dose. < p > < /p >.

Hindgut neuroendocrine neoplasms – characteristics and prognosis

Introduction The aim of the study was to analyze the clinicopathologic characteristics and prognostic factors of hindgut-rectal neuroendocrine neoplasms. Material and methods The study included 38 patients with rectal neuroendocrine tumors who were treated at the Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland from February 2010 to December 2015. The clinicopathological data were retrospectively reviewed, extracted, analyzed, and patients were followed up to determine their survival status. Follow-up data were available for all 38 patients. Uni- and multivariate Cox regression analyses were performed to determine the prognostic factors significantly associated with overall survival. Results The tumors occurred mostly in the middle and lower rectum, and the most typical symptoms experienced by patients were hematochezia and diarrhea. The median distance between the tumors and the anal edges was 4.7 ±1.3 cm, and the median diameter of the tumors was 0.9 ±1.2 cm. The major pathological types were neuroendocrine neoplasm G1 in 31 patients, and neuroendocrine neoplasm G2 in 7 patients. Tumor-node-metastasis (TNM) stages I, II, III and IV tumors accounted for 76.3% (29/38), 5.3% (2/38), 7.9% (3/38) and 10.5% (4/38) of patients, respectively. The main treatment method was transanal extended excision or endoscopic resection. The 1-, 3- and 5-year survival rates of the whole group of patients were 100%, 83.7%, and 75.3%, respectively. Conclusions Univariate analysis showed that age (p = 0.022), tumor diameter (p < 0.001), histological type (p < 0.001), and TNM stage (p < 0.001) were all prognostic factors.

Purification of pituitary autoantigen by column liquid chromatography and chromatofocusing

Introduction Pituitary autoantibodies can be determined both in patients with pituitary disease as well as patients with autoimmune endocrine diseases. The purpose of the study was to isolate and purify pituitary autoantigen using sera of patients and the microsomal fraction of the pituitary. Material and methods To isolate a pituitary autoantigen, patient sera were used, which showed a strong immune response to pituitary antigens. Pituitary microsomal fractions were prepared from pituitary tissue homogenates. In the study, sera of patients with pituitary disease, Addison and Graves’ disease were used. The initial stages were carried out by affinity chromatography on CN -Br sepharose column whereas purification was continued by column liquid chromatography on AcA54 Ultrogel. Chromatofocusing was performed by Polybuffer exchanger PBE 94. Results 125I-labeled pituitary antigens after isolation appeared in column chromatography in three peaks. The first peak contained 50-70 kDa proteins, the second peak – 17 to 22 kDa proteins and the third peak contains 125-iodides. Three fractions obtained from filtration on Ultrogel were separated in a polyacrylamide gel. In the first peak two bands 67 and 55 kDa appeared. The second peak contained low molecular weight substances, and the third peak contained 125I. The first peak from Ultrogel was isolated by chromatofocusing – the first peak with pH 5.9 and the second one with pH 4.9. Conclusions Isolation and purification of pituitary autoantigen with the use of column liquid chromatography and chromatofocusing resulted in obtainment of two antigenic proteins of specific gravity of 67 and 55 kDa.