The use of a new analogue DGlu-Octagastrin in scintigraphy of medullary thyroid carcinoma

Introduction: Medullary thyroid carcinomas (MTC) reveal overexpression of several peptide receptors particularly of gastrin and cholecystokinin 2 (CCK2). Experimental studies of various CCK-2/gastrin analogues found that a C-terminal, 8-aminoacid peptide, DGlu-octagastrin, has optimal properties. Thus, the aim of our studies was to prepare 99mTc-labelled HYNIC-octagastrin, to evaluate its biologic tolerance in animals and introduce for scintigraphy in patients with MTC. Material and methods: HYNIC-DGlu-octagastrin was from piCHEM (Graz, Austria), 99mTc generator from Amersham (Health), other reagents were purchased from Sigma. Labelling of the peptide was performed in phosphate buffer of pH 6.0 for 10 minutes at 100oC using EDDA and tricine as coligands. Results: The labeling yields were high (above 95%); the specific activity amounted to 1200 to 1430 μCi/μg. Radiochemical purity on SepPak cartridge and ITLC ranged from 94 to 98%. No adverse effects were observed in mice after administration of 10 to 50 times greater doses that those used in patients. Clinical studies comprised 20 patients with MTC and high serum calcitonin. 99mTc-EDDA/HYNIC-DGlu-octagastrin, 500 to 700 MBq, was administered iv and whole body scintigraphy was performed using a double head gamma-camera (Varicam, Elscint) 2 and 4 hours later. Increased accumulation of the tracer in foci of MTC and its metastases was found in 8 patients. Conclusions: Scintigraphy with a new gastrin analogue (DGlu-octagastrin) makes it possible to detect MTC with overexpression of CCK-2/gastrin receptors and to select patients for receptor-mediated radiopeptide therapy using DOTA-gastrin analogues labelled with 177Lu and 90Y.Wstęp: Rak rdzeniasty tarczycy (MTC, medullary thyroid cancers) wykazuje nadekspresję receptorów kilku peptydów, zwłaszcza receptorów gastryny i cholecystokininy 2 (CCK2). W badaniach eksperymentalnych różnych analogów CCK2 i gastryny wykazano, że najlepsze właściwości posiada C-końcowy 8-aminokwasowy peptyd DGlu-Oktagastryna. Dotychczas brakuje doniesień na temat klinicznego zastosowania tego analogu. Celem pracy było opracowanie zestawu do uzyskania znakowanej 99mTc-Oktagastryny, sprawdzenie tolerancji biologicznej preparatu i określenie przydatności tego peptydu w scyntygrafii. Materiał i metoda: HYNIC-DGlu-minigastryna (piCHEM, Austria), 99mTc (Amersham), trycyna, EDDA, SnCl2-2H2O (Sigma). Znakowanie wykonano w buforze fosforanowym o pH 6,0 w temp. 100oC przez 10 minut z koligandami EDDA i trycyną. Wyniki: Wydajność znakowania była wysoka; aktywność wynosiła 1200-1430 mCi/mg. Czystość radiochemiczna określana metodą chromatografii odwrotnej fazy na minikolumnach SepPaku i chromatografii cienkowarstwowej wynosiła 94-98%. W badaniu biologicznym u myszek szczepu Balb/c wykazano brak działań niepożądanych po zastosowaniu preparatu w dawkach 10- i 50-krotnie wyższych niż stosowanych u ludzi. Badania kliniczne objęły 20 chorych z MTC z wysokim stężeniem kalcytoniny; rozpoznanie było potwierdzone badaniem histopatologicznym i immunohistochemicznym usuniętego guza. Chorym podano 500-700 MBq 99mTc-EDDA/HYNIC-DGlu-oktagastryny i po 2 oraz 4 godzinach wykonano scyntygrafię całego ciała z użyciem gammakamery dwugłowicowej Varicam (Elscint). U 8 chorych scyntygrafia wykazała gromadzenie znacznika w ognisku raka rdzeniastego i jego przerzutach. Wnioski: Scyntygrafia z użyciem nowego analogu DGlu- -Oktagastryny pozwala na wykrycie guzów z nadekspresją receptorów CCK2/gastrynowych i wskazuje na możliwość zastosowania terapii radioizotopowej z użyciem DOTA-oktagastryny znakowanej 177Lu i 90Y

The role of scintigraphy with the use of 99mTc-HYNIC-TOC in the diagnosis of medullary thyroid carcinoma

Wstęp: W ostatnim czasie próbuje się zastąpić oktreotyd znakowany 111In analogami somatostatyny znakowanymi 99mTc. Celem pracy była ocena znaczenia scyntygrafii z użyciem analogu somatostatyny 99mTc-HYNIC-TOC w diagnostyce raka rdzeniastego tarczycy (MTC, medullary thyroid carcinoma). Materiał i metody: Badaniem objęto 30 chorych z MTC w wieku od 22 do 83 lat w różnych stadiach choroby. U 6 chorych (grupa 1.) scyntygrafię wykonano po ustaleniu rozpoznania MTC bezpośrednio przed tyreoidektomią. Do badań w fazie remisji po leczeniu operacyjnym, potwierdzonej niskimi stężeniami kalcytoniny, zakwalifikowano 4 pacjentów (grupa 2.). U 20 chorych (grupa 3.) diagnostykę przeprowadzono w stadium stagnacji lub wznowy stwierdzanej na podstawie utrzymującej się hiperkalcytoninemii. Scyntygrafię z użyciem 99mTc-HYNIC-TOC (Tektrotyd, POLATOM) wykonywano 2 i 4 godziny po podaniu znacznika o aktywności 740 MBq (20 mCi). Do analizy wykorzystano również inne wykonane badania obrazowe (USG, tomografia komputerowa [CT, computed tomography], scyntygrafię z 99mTc(V)-DMSA, 131I-MIBG, 99mTc-MDP, 111In-oktreotyd i PET z FDG). Wyniki: Obrazy uzyskane po 2 i po 4 godzinach nie różniły się istotnie. W grupie 1. u wszystkich chorych stwierdzano wychwyt znacznika w guzie odpowiadającym MTC. W grupie 2. w 1 na 6 przypadków wynik był fałszywie dodatni, natomiast u pozostałych nie stwierdzono ognisk patologicznych. W grupie 3. wychwyt w loży tarczycy stwierdzono u 3 z 20 chorych, natomiast w węzłach chłonnych - u 14 z 20. U 3 z 20 uwidoczniono gromadzenie znacznika w przerzutach do kości. Czułość scyntygrafii z zastosowaniem 99mTc-HYNIC-TOC oceniono na 86,4%, swoistość na 75,0%, a dokładność na 84,6%. Wniosek: W scyntygrafii przeprowadzonej z użyciem 99mTc-HYNIC-TOC wykazano wysoką przydatność w diagnostyce MTC. Potwierdzenie za pomocą tej metody obecności receptorów dla somatostatyny w komórkach MTC można wykorzystać do planowania terapii: leczenia chirurgicznego lub izotopowego.Introduction: Recently a new somatostatin analogue labelled with 99mTc (99mTc-HYNIC-TOC) has been synthetized. Aim of this study was to evaluate the utility of 99mTc-HYNIC-TOC in the radionuclide imaging in patients with medullary thyroid carcinoma (MTC). Material and methods: 30 patients with MTC aged 22-83 years in different stages of the disease were investigated. In 6 patients (group 1) scintigraphy was performed before surgery directly after diagnosis of MTC. Four patients (group 2) were qualified to the study in the phase of remission after surgical treatment that had been confirmed by low concentrations of calcitonin. Twenty patients (group 3) were investigated due to stagnation or recurrence confirmed by persistent hypercalcitoninemia. The scintigraphy using 99mTc-HYNIC-TOC (Tektrotyd, POLATOM) was performed 2 and 4 hours post injection of 20 mCi (740 MBq) of the tracer. Other imaging techniques were also employed and analysed in individual cases (US, CT, 99mTc(V)-DMSA, 131I-MIBG, 99mTc-MDP, 111In-octreotide and FDG-PET). Results: Images obtained 2 and 4 hours p.i. were similar. In group 1, uptake of the tracer was found in the primary tumour of MTC in all patients. In group 2, a false positive result was found in 1 of 6 patients. In the remaining 5 of 6 cases no pathological foci were visualised. In group 3, uptake in the thyroid bed was found in 3 of 20 cases and in the lymph nodes in 14 of 20 patients. In 3 of 20 cases uptake in the bone metastases was found. Globally, sensitivity of the scintigraphy using 99mTc-HYNIC-TOC was 86.4%, specificity - 75.0%, and accuracy - 84.6%. Conclusion: The scintigraphy using 99mTc-HYNIC-TOC showed high utility in the diagnosis of MTC. Confirmation of the presence of somatostatin receptors with this method may be used for treatment planning: surgery or radionuclide therapy

Recommendations for diagnosis and treatment planning, and treatment during the pregnancy, postpartum and breastfeeding period in patients with antiphospholipid syndrome

The antiphospholipid syndrome (APS) is an interdisciplinary condition with a clinical picture in which thrombotic complications and obstetric failures play the most significant role. It has been demonstrated on the basis of multicentre clinical observations that the most common pregnancy-related complications in the course of APS include: recurrent miscarriage in the first trimester of pregnancy, pregnancy loss in the second and third trimester of pregnancy, early preeclampsia and preterm delivery. Any APS female patient planning a pregnancy should be advised about the risk of complications which may occur in the course of pregnancy. The treatment of pregnant APS patients should be conducted by a multidisciplinary team including specialists in rheumatology, obstetrics, and in justified cases also in haematology. The most important element of the pregnant APS patient management is secondary thromboprophylaxis with low dose aspirin and heparins. The introduction of hydroxychloroquine is recommended in patients with systemic lupus erythematosus. The visits should take place every 4 weeks and starting from week 26–28 of pregnancy every 1–2 weeks. The patients should be strictly monitored for signs of preeclampsia and/or thrombosis

Selected principles of proper education of women with rheumatic diseases in respect of pregnancy planning

One of the more important problems resulting from the specificity of a chronic disease, its treatment and associated adverse effects is a permanent inability or limited ability to initiate and realize the requirements relevant to a given developmental stage of the patient. For women at reproductive age this includes family planning and giving birth to babies. The problem of pregnancy in women with the diagnosis of rheumatic disease is associated not only with physical but also psychological factors. A significant percentage of women with rheumatic diseases make no attempts to conceive. It is caused among other things by lacking knowledge on the possibilities of realization of the motherhood plans and the influence of social stereotypes concerning limitations resulting from disability. Therefore, an important element of influencing the patients’ attitudes is solid education providing information and instrumental support including practical training in precise ways of management of a given situation

Fertility, pregnancy and breastfeeding in systemic lupus erythematosus patients

The majority of patients with systemic lupus erythematosus (SLE) are at reproductive age. The mean age of SLE onset is 29 years. In contrast to rheumatoid arthritis, in pregnant patients with SLE the disease is still active or even may be exacerbated. Pregnancy – preparation for it, its course, and the breastfeeding period – is a major therapeutic and organizational challenge for doctors taking care of patients with SLE. The management of pregnancy and puerperium in a patient with SLE requires close cooperation of doctors of various specialities, including in the first place rheumatologists and obstetricians. In the paper the recommendations are presented concerning preparation for pregnancy, treatment of the underlying disease and complications during pregnancy and the breastfeeding period in SLE patients. Particular attention is paid to the treatment according to the recently published recommendations for patients with lupus nephritis

Recommendations for obstetric management and principles of cooperation between rheumatologists and obstetricians in systemic connective tissue disease patients

Systemic connective tissue diseases, notably rheumatoid arthritis and systemic lupus erythematosus, frequently affect women of reproductive age. The significant impact of the diseases on the course of pregnancy is well established, and vice versa – the course of systemic connective tissue diseases may be affected by pregnancy. The risk of developing serious pregnancy complications and obstetric failures is markedly higher in the mentioned disease group. The foundation of obstetric success, i.e. giving birth to a healthy child and pregnancy having no effect on the course of a given autoimmune disease, is cooperation between rheumatologists and obstetricians so as to plan procreation at an optimal period and provide accurate pregnancy monitoring. The article delineates recommendations relating to contraception management, obstetric supervision and fetus wellbeing monitoring, from the point of view of the obstetrician

HTCC: Broad Range Inhibitor of Coronavirus Entry.

To date, six human coronaviruses have been known, all of which are associated with respiratory infections in humans. With the exception of the highly pathogenic SARS and MERS coronaviruses, human coronaviruses (HCoV-NL63, HCoV-OC43, HCoV-229E, and HCoV-HKU1) circulate worldwide and typically cause the common cold. In most cases, infection with these viruses does not lead to severe disease, although acute infections in infants, the elderly, and immunocompromised patients may progress to severe disease requiring hospitalization. Importantly, no drugs against human coronaviruses exist, and only supportive therapy is available. Previously, we proposed the cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), and its hydrophobically-modified derivative (HM-HTCC) as potent inhibitors of the coronavirus HCoV-NL63. Here, we show that HTCC inhibits interaction of a virus with its receptor and thus blocks the entry. Further, we demonstrate that HTCC polymers with different degrees of substitution act as effective inhibitors of all low-pathogenic human coronaviruses

HTCC: Broad Range Inhibitor of Coronavirus Entry

<div><p>To date, six human coronaviruses have been known, all of which are associated with respiratory infections in humans. With the exception of the highly pathogenic SARS and MERS coronaviruses, human coronaviruses (HCoV-NL63, HCoV-OC43, HCoV-229E, and HCoV-HKU1) circulate worldwide and typically cause the common cold. In most cases, infection with these viruses does not lead to severe disease, although acute infections in infants, the elderly, and immunocompromised patients may progress to severe disease requiring hospitalization. Importantly, no drugs against human coronaviruses exist, and only supportive therapy is available. Previously, we proposed the cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), and its hydrophobically-modified derivative (HM-HTCC) as potent inhibitors of the coronavirus HCoV-NL63. Here, we show that HTCC inhibits interaction of a virus with its receptor and thus blocks the entry. Further, we demonstrate that HTCC polymers with different degrees of substitution act as effective inhibitors of all low-pathogenic human coronaviruses.</p></div

HCoV-NL63 internalization into susceptible cells is hampered by HTCC.

<p>Pre-cooled LLC-Mk2 cells were incubated with cold HCoV-NL63 at 4°C, followed by incubation with HTCC (50–200 μg/ml) or control PBS for 2 h at 32°C. Next, unbound virus was removed by washing with acidic buffer and cells were further incubated at 32°C for 5 days. Virus yield was determined with quantitative RT-PCR and is presented as Log Reduction Value (LRV). The data shown are representative of at least three independent experiments, each performed in triplicate. * <i>P</i> < 0.05.</p