Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with 111In-CP04 in medullary thyroid carcinoma patients

Introduction: From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methods: Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing do

Efficacy and complications of neurosurgical treatment of acromegaly

The aim of the study was to evaluate the frequency of occurrence of pituitary failure following neurosurgery and the efficacy of transsphenoidal tumour resection in acromegalic patients. We retrospectively evaluated 85 patients (60 female and 25 male), of mean age 43.9 ± 13.2 years, treated by transsphenoidal neurosurgery. Macroadenoma and microadenoma of pituitary were found in 66 (77.6%) and 19 (22.4%) of these patients, respectively. Criteria of cure following neurosurgery were: basal GH < 2.5 μg/l, GH at 120 min in OGTT < 1.0 μg/l and serum concentration of IGF-1 within normal ranges for age and sex. After surgery 32 patients (37.6%) were cured and 53 patients (62.4%) required somatostatin analogue treatment. In patients cured by surgery, lower levels of basal GH (P < 0.05), IGF-1 (P < 0.001), GH at 120 min in OGTT and smaller size of pituitary tumour (P < 0.05) were found at diagnosis, as compared to patients in whom surgery was unsuccessful. Significant correlation between basal serum level of GH at diagnosis and size of pituitary tumour was found (P < 0.001). Invasive tumours were found in 45 of 53 (84.9%) patients not cured and in only 8 of 32 (25.0%) patients cured (P < 0.001). Impaired function of pituitary anterior lobe after surgery was observed in 30% and 4% of patients with macro- and microadenoma, respectively (P < 0.05). The efficacy of neurosurgery is affected by concentration of basal serum GH and IGF-1, GH at 120 min in OGTT, tumour size and invasiveness. Hypopituitarism after surgery is more frequent in patients with macroadenoma. Pituitary insufficiency, as a consequence of surgery, was found in 21% of patients with normal pituitary function prior to operation

Postępowanie w chorobach tarczycy u kobiet w ciąży

The management of thyroid disorders during pregnancy is one of the most frequently disputed problems in modern endocrinology. It is widely known that thyroid dysfunction may result in subfertility, and, if inadequately treated during pregnancy, may cause obstetrical complications and influence fetal development. The 2007 Endocrine Society Practice Guideline endorsed with the participation of the Latino America Thyroid Association, the American Thyroid Association, the Asia and Oceania Thyroid Association and the European Thyroid Association, greatly contributed towards uniformity of the management of thyroid disorders during pregnancy and postpartum. Despite the tremendous progress in knowledge on the mutual influence of pregnancy and thyroid in health and disease, there are still important areas of uncertainty. There have been at least a few important studies published in the last 3 years, which influenced the thyroidal care of the expecting mother. It should also be remembered that guidelines may not always be universally applied in all populations with different ethnical, socio-economical, nutritional (including iodine intake) background or exposed to different iodine prophylaxis models. The Task Force for development of guidelines for thyroid dysfunction management in pregnant women was established in 2008. The expert group has recognized the following tasks: development of the coherent model of the management of thyroid dysfunction in pregnant women, identification of the group of women at risk of thyroid dysfunction, who may require endocrine care in the preconception period, during pregnancy and postpartum &#8211; that is in other words, the development of Polish recommendations for targeted thyroid disorder case finding during pregnancy, and the development of Polish trimester-specific reference values of thyroid hormones. Comprehensive Polish guidelines developed by the Task Force are to systematize the management of the thyroid disorders in pregnant women in Poland. (Pol J Endocrinol 2011; 62 (4): 362&#8211;381)Jednym z aktualnie szeroko dyskutowanych problemów współczesnej endokrynologii jest opieka tyreologiczna nad kobietą ciężarną. Powszechnie wiadomo, że dysfunkcja tarczycy może być przyczyną zaburzeń płodności, a nieleczona prawidłowo w czasie ciąży zwiększa ryzyko powikłań położniczych oraz ma wpływ na rozwój płodu. Opublikowane w 2007 roku wytyczne Towarzystwa Endokrynologicznego (Endocrine Society), opracowane przy współudziale Towarzystwa Tyreologicznego Ameryki Łacińskiej (LATS), Towarzystwa Tyreologicznego Azji i Oceanii (AOTA), Amerykańskiego Towarzystwa Tyreologicznego (ATA) oraz Europejskiego Towarzystwa Tyreologicznego (ETA), w dużym stopniu usystematyzowały zasady postępowania w chorobach tarczycy w czasie ciąży i w okresie poporodowym. Pomimo ogromnego postępu wiedzy na temat wzajemnego wpływu ciąży i funkcji gruczołu tarczowego w zdrowiu i chorobie, jaki osiągnięto w ciągu ostatnich kilkunastu lat, nadal pewne obszary wymagają dalszych badań. W ciągu 3 lat, które minęły od publikacji wytycznych, przybyło danych, które wpłynęły na niektóre zasady prowadzenia ciężarnej z chorobą tarczycy. Wytyczne nie zawsze mają charakter uniwersalny i nie mogą być w prosty sposób transponowane na społeczeństwa zróżnicowane etnicznie i ekonomicznie, o odmiennych zwyczajach dietetycznych, w tym w spożyciu nośników jodu, oraz stosujące odmienne modele profilaktyki jodowej. W 2008 roku powołano Zespół Ekspertów do spraw Opieki Tyreologicznej w Ciąży. Za cele prac Zespołu przyjęto: opracowanie modelu opieki nad ciężarną z zaburzeniami funkcji tarczycy, określenie grupy kobiet z ryzykiem zaburzeń funkcji tarczycy wymagających oceny tyreologicznej podczas planowania ciąży, w trakcie jej trwania oraz w okresie poporodowym &#8212; czyli przygotowanie polskich wskazań do badań przesiewowych oraz ustalenie wartości referencyjnych stężeń hormonów tarczycy w poszczególnych trymestrach ciąży. Opracowane przez Zespół wytyczne systematyzują zasady opieki tyreologicznej nad kobietą ciężarną w Polsce. (Endokrynol Pol 2011; 62 (4): 362&#8211;381

Neuroendocrine neoplasms of the small intestine and the appendix - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered