Combined use of 177 Lu-DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well-differentiated neuroendocrine tumors: A preclinical study.

Peptide receptor radionuclide therapy (177 Lu-DOTATATE) causes DNA strand breaks and has been validated for well-differentiated neuroendocrine tumor treatment. Poly-(ADP-ribose)-polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly-(ADP-ribose)-polymerase inhibitor fluzoparib could enhance the anti-tumor effects of 177 Lu-DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI-H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177 Lu-DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77 Lu-DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI-H727 cells and tumor xenografts. 177 Lu-DOTATATE (22.20 MBq mL-1 ) and fluzoparib (50 µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177 Lu-DOTATATE (22.20 MBq mL-1 , 4.4-fold) and fluzoparib (50 µm, 2.1-fold). 177 Lu-DOTATATE caused cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to 177 Lu-DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with 177 Lu-DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti-tumor effect of 177 Lu-DOTATATE in NCI-H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings.

Improved Personalised Neuroendocrine Tumours' Diagnosis Predictive Power by New Receptor Somatostatin Image Processing Quantification.

Although neuroendocrine tumours (NETs) are intensively studied, their diagnosis and consequently personalised therapy management is still puzzling due to their tumoral heterogeneity. In their theragnosis algorithm, receptor somatostatin scintigraphy takes the central place, the diagnosis receptor somatostatin analogue (RSA) choice depending on laboratory experience and accessibility. However, in all cases, the results depend decisively on correct radiotracer tumoral uptake quantification, where unfortunately there are still unrevealed clues and lack of standardization. We propose an improved method to quantify the biodistribution of gamma-emitting RSA, using tissular corrected uptake indices. We conducted a bi-centric retrospective study on 101 patients with different types of NETs. Three uptake indices obtained after applying new corrections to areas of interest drawn for the tumour and for three reference organs (liver, spleen and lung) were statistically analysed. For the corrected pathological uptake indices, the results showed a significant decrease in the error of estimating the occurrence of errors and an increase in the diagnostic predictive power for NETs, especially in the case of lung-referring corrected index. In conclusion, these results support the importance of corrected uptake indices use in the analysis of 99mTcRSA biodistribution for a better personalised diagnostic accuracy of NETs patients.

Nephrotoxicity/renal failure after therapy with 90Yttrium- and 177Lutetium-radiolabeled somatostatin analogs in different types of neuroendocrine tumors: a systematic review.

BACKGROUND/OBJECTIVE: Data regarding the nephrotoxicity of the peptide receptor radionuclide therapy (PRRT) with Yttrium- and Lutetium-radiolabeled somatostatin analogs (RSA) are inconclusive. We aimed to evaluate the short- and long-term nephrotoxicity following PRRT usage in patients with all types of neuroendocrine tumors (NETs). METHODS: A systematic review of observational studies reporting data about nephrotoxicity after treatment with Yttrium and Lutetium RSA was performed. Data on serum creatinine, creatinine clearance, glomerular filtration rate (GFR) and need for renal replacement therapy were compiled. We included patients with progressive, inoperable symptomatic G1, G2 and G3 different types of NETs. After searching in three electronic databases PubMed, Scopus and the Cochrane Library, from 1 January 1978 to November 2018, data were extracted and summarized using a random-effects model. RESULTS: The final analysis included 34 studies, comprising 5386 participants, enrolling patients with G1, G2, G3 NETs and a follow-up from 12 up to 191 months. Compared with renal function before treatment, measured/estimated glomerular filtration rate (m/eGFR) values changed after PRRT, with a mean annual decrease following PRRT between 2 and 4 mL/min/1.73 m suggesting different grades of nephrotoxicity after PRRT. When compared, Y-RSA and the Y-RSA-Lu-RSA combination are associated with a higher m/eGFR decline compared to Lu-RSA alone. CONCLUSIONS: PRRT can be followed by potentially serious long-term nephrotoxicity, despite kidney protection. The use of the quantified renal function combined with a long follow-up period and personalized dosimetry-based PRRT can reduce nephrotoxicity, in order to use the whole PRRT potential in the management of NETs.

Somatostatin receptor molecular imaging in a misdiagnosed gastrinoma case.

Gastrin-secreting tumors, hypergastrinemia and severe ulcer disease form the trademarks of Zollinger-Ellison syndrome (ZES). We report a case of gastrinoma, in a patient who was misdiagnosed for almost five years. The case emphsizes the the special role of functional imaging in the personalized approach to the patient with suggestive symptomatology for NETs. Taking into account that in 80 to 100% of cases of gastroenteropancreatic (GEP) NETs are expressing somatostatin receptors, the functional imaging with radiolabeled somatostatin analogues can be used in order to improve its diagnosis, respectively the treatment of GEP NETs. In the approach to the patient with tremendous digestive symptomatology, physicians from different specialties should evaluate NETs specific markers and then insist on structural-functional complementarity, avoiding the waste of time and high cost of repeated structural investigations. The conclusion of our study is that functional imaging is mandatory in the diagnostic algorithm of gastrinoma.

99mTc-bisphosphonate-coated magnetic nanoparticles as potential theranostic nanoagent.

Novel theranostic nanoplatform is expected to integrate imaging for guiding and monitoring of the tumor therapy with great therapeutic efficacy and fewer side effects. Here we describe the preparation of a multifunctional 99mTc-bisphosphonate-coated magnetic nanoparticles (MNPs) based on Fe3O4 and coated with two hydrophilic bisphosphonate ligands, i.e., methylene diphosphonate (MDP) and 1-hydroxyethane-1,1- diphosphonate (HEDP). The presence of the bisphosphonates on the MNPs surface, enabled their biocompatibility, colloidal stability and successful binding of the radionuclide. The morphology, size, structure, surface charge and magnetic properties of obtained bisphosphonate-coated Fe3O4 MNPs were characterized by transmission electron microscopy, X-ray powder diffraction, dynamic light scattering, laser Doppler electrophoresis, Fourier transform infrared spectroscopy and vibrating sample magnetometer. The specific power absorption values for Fe3O4-MDP and Fe3O4-HEDP were 113 W/g and 141 W/g, respectively, indicated their heating ability under applied magnetic field. Coated MNPs were radiolabeled with 99mTc using stannous chloride as the reducing agent in a reproducible high yield (95% for Fe3O4-MDP and 97% for Fe3O4-HEDP MNPs) and were remained stable in saline and human serum for 24 h. Ex vivo biodistribution studies presented significant liver and spleen uptake in healthy Wistar rats after intravenous administration at all examined time points due to the colloidal nature of both 99mTc-MNPs. Results of scintigraphy studies are in accordance with ex vivo biodistribution studies, demonstrating high in vivo stability of radiolabeled MNPs and therefore results of both methods were proved as accurate information on the biodistribution profile of investigated MNPs. Overall, in vitro and in vivo stability as well as heating ability, indicate that biocompatible radiolabeled bisphosphonate magnetic nanoparticles exhibit promising potential as a theranostic nanoagent.

Clinical usefulness of 99mTc-HYNIC-TOC, 99mTc(V)-DMSA, and 99mTc-MIBI SPECT in the evaluation of pituitary adenomas.

BACKGROUND: The aim of this study was to evaluate the behavioral uptake and ability to diagnose pituitary adenoma (PA) using tumor-seeking radiopharmaceuticals, and to provide a semiquantitative analysis of tracer uptake in the pituitary region. PATIENTS AND METHODS: The study included 33 (13 hormonally active and 20 nonfunctioning) patients with PA and 45 control participants without pituitary involvement. All patients (n=78) underwent single photon emission computed tomography (SPECT) imaging with technetium-99m-labeled hydrazinonicotinyl-tyr-octreotide (Tc-HYNIC-TOC), dimercaptosuccinic acid (Tc(V)-DMSA) and hexakis-2-methoxyisobutylisonitrile (Tc-MIBI). A semiquantitative analysis of abnormal uptake was carried out by drawing identical regions of interest over the pituitary area and the normal brain on one transverse section that shows the lesion most clearly. The pituitary uptake to normal brain uptake (P/B) ratio was calculated in all cases. RESULTS: The result of this study confirms that the SPECT semiquantitative method, with all three tracers, showed statistically significant differences between the PA group and the controls. However, Tc-HYNIC-TOC scintigraphy could have the highest diagnostic yield because of the smallest overlap between the P/B ratios between adenoma versus nonadenoma participants (the receiver operating characteristic curve P/B ratio cut-off value was 13.08). In addition, only Tc-MIBI SPECT have the diagnostic potential to detect secreting PAs, with statistically significant differences between groups (P<0.001), with an receiver operating characteristic curve P/B ratio cut-off value of 16.72. CONCLUSION: A semiquantitative analysis of increased focal tracer uptake in the sellar area showed that Tc-HYNIC-TOC is a highly sensitive and reliable tumor-seeking agent for detecting PA, whereas Tc-MIBI SPECT is a highly sensitive and specific method in differentiating hormone-secreting pituitary tumor.

A five-compartment biokinetic model for 90 Y-DOTATOC therapy.

PURPOSE: Neuroendocrine tumors (NETs) are now routinely treated by radiopeptide targeted therapy using somatostatin receptor-binding peptides such as 90 Y- and 177 Lu-DOTATOC. The objective of this work was to develop a biokinetics model of 90 Y labelled DOTATOC, which is applied in the therapy of NETs to estimate doses in kidney and tumor. METHODS: A multi-compartment model described by two sets of differential equations, one set for the actual 30-min infusion and the other set for the post-infusion period was developed and activities were measured by liquid scintillation counting in blood (compartment 1) and the urine (compartment 3). The inter-compartment transfer coefficients, λij , were varied to yield the best fit of the calculated to the measured time-activity data and the 90 Y-DOTATOC time-activity data in the five-compartments comprising the human body were thus determined. The resulting time-activity curves were integrated over the interval from 0 to 72 h post administration to obtain the number of radioactive decays in each compartment and, in case of the kidneys and tumor, then multiplied by the self-dose 90 Y beta particle absorbed fraction, determined by Monte Carlo (MC) simulation, the kidney and tumor absorbed doses. RESULTS: Transfer coefficients λij , were determined for five-compartments for all patients. Time- activity curves of 90 Y-DOTATOC in 14 patients were determined, and two typical ones are shown graphically. Absorbed doses in the tumor and kidneys, obtained by the developed method, were determined. The mean absorbed dose in a kidney per unit of administered activity is 1.43 mGy/MBq (range 0.73-2.42 mGy/MBq). The tumor dose was determined as 30.94 mGy/MBq (range 20.05-42.31 mGy/MBq). CONCLUSION: Analytical solution of a biokinetic model for 90 Y-DOTATOC therapy enabled determination of the transfer coefficients and derivation of time-activity curves and kidney and tumor absorbed doses for 14 treated patients. The model can be applied to other radionuclides where elimination is predominantly through urine, which is often the case in radiopharmaceuticals.

Hybrid Vision-Fusion system for whole-body scintigraphy.

Radioiodine therapy in the treatment of differentiated thyroid carcinoma (DTC) is used in clinical practice for the ablation of thyroid residues and/or destruction of tumour tissue. Whole-body scintigraphy for visualization of the spatial 131I distribution performed by a gamma camera (GC) is a standard procedure in DTC patients after application of radioiodine therapy. A common problem is the precise topographic localization of regions where radioiodine is accumulated even in SPECT imaging. SPECT/CT can provide precise topographic localization of regions where radioiodine is accumulated, but it is often unavailable, especially in developing countries because of the high price of the equipment. In this paper, we present a Vision-Fusion system as an affordable solution for 1) acquiring an optical whole-body image during routine whole-body scintigraphy and 2) fusing gamma and optical images (also available for the auto-contour mode of GC). The estimated prediction error for image registration is 1.84 mm. The validity of fusing was tested by performing simultaneous optical and scintigraphy image acquisition of the bar phantom. The fusion result shows that the fusing process has a slight influence and is lower than the spatial resolution of GC (mean value ±â€¯standard deviation: 1.24 ±â€¯0.22 mm). The Vision-Fusion system was used for radioiodine post-therapeutic treatment, and 17 patients were followed (11 women and 6 men, with an average age of 48.18 ±â€¯13.27 years). Visual inspection showed no misregistration. Based on our first clinical experience, we noticed that the Vision-Fusion system could be very useful for improving the diagnostic possibility of whole-body scintigraphy after radioiodine therapy. Additionally, the proposed Vision-Fusion software can be used as an upgrade for any GC to improve localizations of thyroid/tumour tissue.

The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin-positive interneurons.

The aim of this study was to evaluate the behavioral effects of chronic (six weeks) nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose) administration (in order to mimic heavy human abuse), and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break), applied alone and simultaneously with ND, in male rats (n = 40). Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV) content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF) test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone) and in elevated plus maze (EPM) test (decrease in frequency and cumulative duration in open arms, and total exploratory activity), that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region), followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters), and in evoked beam-walking test (increase in time to cross the beam), compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system) may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols.

An innovative method for precise lymph node detection before surgical treatment in breast cancer.

OBJECTIVE: To describe a new method of 3D interactive modeling which integrates images obtained by separate SPET and multi slice computed tomography (MSCT) modalities using an original software in order to better localize SNL in BC patients. SUBJECTS AND METHODS: We used technetium-99m-colloid rhenium sulphate for identifying SNL in seven patients with BC. Markers were made of lead pearls wrapped with cotton wool soaked in 99mTc-pertechnetate and placed on the skin of the patients forming of a triangle. Using an original software, two separate 3D models were made after SPET and MSCT imaging and then merged into a hybrid 3D model which enabled precise visualization and localization of the SNL. RESULTS: In all cases the position of the SNL established by our method was successfully verified using a gamma probe. Duration of SNL identification and extirpation were significantly reduced in less than 10 minutes per patient. The reproducibility of this method was confirmed by precise identification and biopsy of the SNL. CONCLUSION: We found this integrated SPET/MSCT 3D model to be much faster and easier to use as compared with the "classic" method, which was based on a radioactivity detection probe. In addition, our method was reproducible, accurate and of low cost. In other words, the method described in this paper could be very useful for health facilities with modest budget, because it obviates the need for buying expensive integrated SPET/MSCT hybrid imaging systems while detecting SNLs more accurately and in shorter time.

The role of neuropeptide-Y in nandrolone decanoate-induced attenuation of antidepressant effect of exercise.

Since the increased prevalence of anabolic androgenic steroids abuse in last few decades is usually accompanied by various exercise protocols, the scope of our study was to evaluate the effects of chronic nandrolone decanoate administration in supraphysiological dose and a prolonged swimming protocol (alone and simultaneously with nandrolone decanoate) on depressive state in male rats. Simultaneously, we investigated the possible alterations in neuropeptide Y (NPY) content in blood and the hippocampus, in order to determine the role of NPY in the modulation of depressive-like behavior.Exercise induced antidepressant effects in tail suspension test (decrease of the total duration of immobility), as well as significant increase in the number of hippocampal NPY-interneurons in CA1 region. Chronic nandrolone decanoate treatment attenuated the beneficial antidepressant effects of exercise as measured by the tail suspension test parameters. Simultaneously, nandrolone decanoate treatment resulted in diminution of NPY content both in blood (decreased serum levels) and in hippocampus (the significant decrease in NPY expression in all three investigated hippocampal regions-CA1, CA2/3 and DG). Our findings indicate that alterations in serum and hippocampal NPY contents may underlie the changes in depressive state in rats. The exercise was beneficial as it exerted antidepressant effect, while chronic nandrolone decanoate treatment resulted in depressive-like behavior. Furthermore, the behavioral indicators of depression showed strong correlations with the serum levels and the hippocampal content of NPY.

Our solution for fusion of simultaneusly acquired whole body scintigrams and optical images, as usesful tool in clinical practice in patients with differentiated thyroid carcinomas after radioiodine therapy. A useful tool in clinical practice.

OBJECTIVE: After radioiodine therapy of differentiated thyroid cancer (DTC) patients, whole body scintigraphy (WBS) is standard procedure before releasing the patient from the hospital. A common problem is the precise localization of regions where the iod-avide tissue is located. Sometimes is practically impossible to perform precise topographic localization of such regions. METHOD: In order to face this problem, we have developed a low-cost Vision-Fusion system for web-camera image acquisition simultaneously with routine scintigraphic whole body acquisition including the algorithm for fusion of images given from both cameras. For image acquisition in the gamma part of the spectra we used e.cam dual head gamma camera (Siemens, Erlangen, Germany) in WBS modality, with matrix size of 256×1024 pixels and bed speed of 6cm/min, equipped with high energy collimator. For optical image acquisition in visible part of spectra we have used web-camera model C905 (Logitech, USA) with Carl Zeiss® optics, native resolution 1600×1200 pixels, 34o field of view, 30g weight, with autofocus option turned "off" and auto white balance turned "on". Web camera is connected to upper head of gamma camera (GC) by a holder of lightweight aluminum rod and a plexiglas adapter. Our own Vision-Fusion software for image acquisition and coregistration was developed using NI LabVIEW programming environment 2015 (National Instruments, Texas, USA) and two additional LabVIEW modules: NI Vision Acquisition Software (VAS) and NI Vision Development Module (VDM). Vision acquisition software enables communication and control between laptop computer and web-camera. Vision development module is image processing library used for image preprocessing and fusion. Software starts the web-camera image acquisition before starting image acquisition on GC and stops it when GC completes the acquisition. Web-camera is in continuous acquisition mode with frame rate f depending on speed of patient bed movement v (f=v/∆cm, where ∆cm is a displacement step that can be changed in Settings option of Vision-Fusion software; by default, ∆cm is set to 1cm corresponding to ∆p=15 pixels). All images captured while patient's bed is moving are processed. Movement of patient's bed is checked using cross-correlation of two successive images. After each image capturing, algorithm extracts the central region of interest (ROI) of the image, with the same width as captured image (1600 pixels) and the height that is equal to the ∆p displacement in pixels. All extracted central ROI are placed next to each other in the overall whole-body image. Stacking of narrow central ROI introduces negligible distortion in the overall whole-body image. The first step for fusion of the scintigram and the optical image was determination of spatial transformation between them. We have made an experiment with two markers (point radioactivity sources of 99mTc pertechnetate 1MBq) visible in both images (WBS and optical) to find transformation of coordinates between images. The distance between point markers is used for spatial coregistration of the gamma and optical images. At the end of coregistration process, gamma image is rescaled in spatial domain and added to the optical image (green or red channel, amplification changeable from user interface). SUBJECTS: We tested our system for 10 patients with DTC who received radioiodine therapy (8 women and two men, with average age of 50.10±12.26 years). Five patients received 5.55Gbq, three 3.70GBq and two 1.85GBq. Whole-body scintigraphy and optical image acquisition were performed 72 hours after application of radioiodine therapy. CONCLUSION: Based on our first results during clinical testing of our system, we can conclude that our system can improve diagnostic possibility of whole body scintigraphy to detect thyroid remnant tissue in patients with DTC after radioiodine therapy.

Parameters of Calcium Metabolism Fluctuated during Initiation or Changing of Antipsychotic Drugs.

OBJECTIVE: Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. METHODS: Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. RESULTS: Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42±0.12 vs. 2.33±0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6±5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p<0.001; OR=4.75, 95% CI 2.14-10.51), phosphorous (45/33 vs. 9/40, p<0.001; 6.06, 2.59-14.20) and 25(OH)D concentrations (57/21 vs. 13/35, p<0.001; 7.31, 3.25-16.42), respectively. Calcemia positively correlated with magnesemia, phosphatemia and 25(OH)D values. Parathyroid hormone and C-telopeptide showed only subtle oscillations of their absolute concentrations or changes from baseline; calcitonin and osteocalcin did not change. Adjustment of final calcemia trend (depletion/accumulation) for relevant risk factors, generally, did not change the results. CONCLUSION: In patients with psychotic disorders and several risks for bone metabolism disturbances antipsychotic treatment was associated with the decrease of calcemia and changes in levels of the associated ions.

Three reasons for on-line remote telemonitoring of patients treated with high doses of radionuclide therapy. Our experience.

OBJECTIVE: Following radionuclide therapy, patients usually must remain hospitalised in special "restricted access area" 2-5 days, until radiation in their body drops below a certain level. During this period medical personnel can be faced with some challenges. Based on our previous experience, we used telemedicine approach as solution for it. We have developed comprehensive telemedicine system, which consists of three own developed hardware & software modules which are accessible remotely. SUBJECTS AND METHODS: Challenge #1 Some of patients can experiencing serious complications related to radionuclide therapy or related to co-morbidities, if they have any of it. In some of those cases audio-visual contact with patients and follow-up their vital functions can be of high importance in case of patient needs urgent intervention. Solution #1 System for on-line remote monitoring of patients' vital functions registered with bed side monitor and video surveillance of area which use patients during hospitalisation. This system is established by IP cameras and bedside patient monitor, equipped with appropriate network card and software. Using remote connection (LAN or internet), a physician can watch at personal computer or mobile phone the waves and vital signs patterns from the bedside monitor, as well as live video from surveillance cameras. It provides prompt intervention in case of emergency. Challenge #2 Having in mind the overall costs of radionuclide therapy and patients hospital stay on the one hand, and limited capacity of the hospital premises for radionuclide therapy, on the other, it is of high importance to estimate as early as possible the time period after which the radiation in a patient's body will drop below the limit imposed by the law. Solution #2 On-line remote radiation monitoring system, which measures the radiation exposure rate by means of a pancake probe, which is connected to a PTZ (Pan-tilt-zoom) device and DVR (Digital video recorder). Those devices enable precise positioning of the detector on target region of the patient's body. The positioning of the detector can be visually controlled by a micro camera, placed at the center of detector's plane. Furthermore, there are three LASER pointers placed around the detector in order to mark the area where it is directed. In addition, two ultrasound sensors placed on the edge of the detector holder in order to estimate the exact distance between the probe and the patient's body. All those devices are controlled by the DVR. The data collected by the detector are acquired and processed by a PC, using customized hardware/software system developed by Italian ThereminoR group. Using remote connection, a physician can watch on-line radiation exposure rate in any time and can use commands of PTZ and DVR device for proper positioning of probe during measurement and control it by micro camera, LASER pointers and US sensors. Physician demands from the patients to take the same position for 5 minutes on each hour, during first 10 hours. Those data we use as reference points for further processing by our software. Based on two exponential matematical model, our software estimates the whole process of elimination of radioactivity from the patient's body, using reference points collected during the first day after radionuclide therapy. Based on that, physician can predict (on first day after therapy!) when patient will be able to leave the restricted access area". Challenge #3 Despite strict instructions given to them by physician and nurse before administration of radionuclide therapy, some patients sometimes try to leave "restricted access area". Solution #3 We have developed a system which continuously monitors the corridor which a patient must use in case of an attempt to leave the "restricted access area". Our system consists of a survey meter equipped with pancake probe directed towards the corridor. The survey meter is connected to a trigger circuit which gives signal in the case when the measeured count rate exceeds previously adjusted value. Trigger circuit is connected to the programmable siren, blinking light, alarm device unit with SIM card and IP surveillance camera. On the siren we previously recorded the voice alarm. In the case when the system is triggered, the patient will hear warning message and see blinking light. When the alarm device is triggered it will call responsible physician and nurse on mobile phone and IP camera simultaneously records this event. System also sending via email appropriate data about each event, when it happens. CONCLUSION: From our experience gained over the past 4 years, our telemonitoring system dedicated for patients receiving radionuclide therapy ensures a high level of safety for the patient and medical staff.

THYRPAN-TM Prototype: New System for Online Telemonitoring of Patients with Thyroid Carcinoma During the Treatment with a High Dose of Radioiodine.

BACKGROUND: Our team devised a real-time telemonitoring system (THYRPAN-TM) for measurement of the radiation exposure rate during the hospitalization of patients treated with high doses of radioiodine in the special premises with restricted access ("restricted area" [RA]). SUBJECTS AND METHODS: The THYRPAN-TM prototype was tested for stability, efficacy, and linearity in a 32-day measurement of a 110 MBq (131)I source. Furthermore, it was tested on 15 patients with differentiated thyroid carcinoma who stayed in the RA for 3 days, following their radioiodine treatment. RESULTS: Minor deviation from the theoretical values was detected when the (131)I source was measured by the THYRPAN-TM, but only at the beginning of the measurement (7.20%). CONCLUSIONS: THYRPAN-TM is a stable, user-friendly detection system for the measurement of the exposure rate following radioiodine administration. It enables the telemonitoring of patients, as well as real-time and online measurement of the whole-body burden of (131)I.

Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults.

OBJECTIVES: The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. METHODS: Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 ± 1.82 years and 21.31 ± 2.69 kgm-2, respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. RESULTS: In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 x DD + 0.618 x PHO. CONCLUSIONS: The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults.

Surgical management of well-differentiated thyroid carcinoma in children and adolescents: 33 years of experience of a single institution in Serbia.

Well-differentiated thyroid carcinoma in children and adolescents is rare but demonstrates aggressive behavior. Gross lymph node metastases and distant metastases are common upon first clinical presentation. During a 33-year period (1981-2014) at the Institute of Oncology and Radiology of Serbia, 62 children and adolescents underwent surgery due to well-differentiated thyroid carcinoma. Mean age was 16.7 (range 7-21) years. At the time of diagnosis 6% of patients had lung metastases. Total thyroidectomy or completion thyroidectomy was performed for all patients followed by central neck dissection and frozen section examination of jugular-carotid compartments. Median follow-up was 10.9 (range 0.69-33.05) years and median tumor size was 20 (range 2-60) mm. Papillary carcinoma was found in 96%, and follicular and Hürthle cell carcinoma in 2% of patients. Multifocal tumors were found in 50% and capsular invasion in 60% of patients. Lymphonodal metastases in either central or lateral neck compartments were found in 73% of patients. Multifocality and capsular invasion were significantly more frequent in patients less than 16 years of age (both p < 0.01). Median disease-free interval had not been reached and overall survival rate was 100%. Well-differentiated thyroid carcinoma in children and adolescents is characterized by a high rate of loco-regional aggressiveness, multifocality, capsular invasion, lymph node metastases and distant metastases at the time of diagnosis. Adequate surgical approaches should be performed for both primary and recurrent disease in young patients with well-differentiated thyroid carcinoma in order to achieve loco-regional disease control and longer disease-free survival.

Is there a link between Hashimoto's thyroiditis and primary hyperparathyroidism? A study of serum parathormone and anti-TPO antibodies in 2267 patients.

According to various authors, thyroid disorders like Hashimoto's thyroiditis (HT), diffuse goiter or multinodular goiter, Graves' disease, medullary or papillary carcinoma could be found in a number of patients with primary hyperparathyroidism (PHPT). This association is more common in elderly women. Neck irradiation, lithium treatment and elevated TSH levels have been suggested as some of the possible causes of this co-existance. The aim of this study was to investigate and determine the prevalence of patients having both HT and PHPT, and the possible relation between these two diseases. We conducted a prospective study during three and a half years. This study included 45,231 patients, which were referred by their general practitioner or endocrinologist, under suspicion of having thyroid and/or parathyroid disease. In these patients we measured serum levels of the following parameters: anti-thyroid peroxidase antibodies (antiTPO-Ab), anti-thyroglobulin antibodies (Tg-Ab), anti-TSH-receptor antibodies (TSHR-Ab), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium (Ca). In 2,267 of these 45,231 patients (5.01%) we noticed elevated antiTPO-Ab (3542±3407IU/mL), with statistical significant difference from normal values (normal range 0-70IU/mL), P<0.05, and normal levels of other antithyroid antibodies (Tg-Ab, TSHR-Ab). All patients with elevated antiTPO-Ab were assumed to have HT. Within this group, 43 patients (1.89%) also had elevated serum levels of PTH (112.4±33.2pg/mL, normal range 8-76pg/mL) as well as elevated serum levels of calcium (2.92±0.06mmol/L, normal range 2.2-2.65mmol/L). These laboratory findings, accompanied with clinical symptoms, satisfied the criteria for PHPT. The mean age in this subgroup was 60.5±12.2 years. All 2,267 patients had normal or slightly elevated TSH levels. In conclusion, although the reported rate of prevalence of PHPT in the general population is about 0.3%, our results indicated a 1.89% occurrence of PHPT in 2267 patients with HT in central Serbia. This may be due to the autoimmune inflammatory process in HT supporting PHPT to PTH or calcium supporting HT or to common genetical predisposition of both entities.