Agata Bałdys-Waligórska

Increased prevalence of hyperthyroidism as an early and transient side-effect of implementing iodine prophylaxis

OBJECTIVE To assess the prevalence of hyperthyroidism just after implementation of iodine prophylaxis among adults from an area with iodine deficiency. STUDY DESIGN AND SUBJECTS A total of 1648 adults (age 16 years and older) were sampled from an area of southern Poland during two nationwide epidemiological surveys. Of these, 1424 adults with negative medical history for thyroid disorders qualified for final analysis. The authors compared thyroid dysfunction in participants prior to (1989-1990) and after implementation of iodine prophylaxis (1997-1999). SETTING The southern part of Poland. RESULTS We found an increase in the serum concentration of anti-thyroid microsomal antibodies from 4.9% in the years 1989-1990 to 12.1% after introduction of iodised household salt (P < 0.0001). The prevalence of hyperthyroidism (defined as thyroid-stimulating hormone < 0.4 microU ml- 1) significantly increased in the equivalent period from 4.8 to 6.5% (P = 0.009). CONCLUSIONS We concluded that a sudden rise in iodine intake after implementation of iodine prophylaxis among adults from the area with iodine deficiency may lead to an increase in thyroid autoimmunity and prevalence of hyperthyroidism. Those possible early side-effects appear to be only temporary and are acceptable when compared with the evident benefits of adequate iodine intake.

Acromegaly--a novel view of the patient. Polish proposals for diagnostic and therapeutic procedures in the light of recent reports.

is usually delayed and is often associated with the development of various complications causing premature mortality. In patients with hypertension, heart failure, diabetes, and arthropathy that is non-specific for age, attention should be paid to the occurrence of somatic signs of acromegaly. As a screening test, insulin-like growth factor-1 (IGF-1) concentration should be assessed. Further diagnostic and treatment procedures are possible in specialised centres. The first-line therapy is selective transsphenoidal adenomectomy. Patients with a good prognosis related to a surgical removal of the pituitary tumour should be referred only to centres experienced in performing this type of procedure, after pharmacological preparation. Other patients, and those who have not recovered after surgical treatment, should be subjected to long-term pharmacotherapy with long-acting somatostatin analogues. In each case, the complications of acromegaly should be followed-up long-term and actively treated. This proposed new recommendation should be helpful for the management of patients with acromegaly.

Zalecenia ogólne dotyczące postępowania diagnostyczno-terapeutycznego w nowotworach neuroendokrynnych układu pokarmowego (rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)

Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Żelechów near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs.

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.

Comment on long-term risk in radioiodine treatment of hyperthyroidism

Dear Sir, A recently published article “Long-term risk in hyperthyroid patients treated with radioiodine: is there anything new?” by Giovanni Lucignani [1] stimulated us to express our views on the controversy concerning therapeutic and ethical aspects of I radioiodine treatment of Graves’ disease, solitary toxic thyroid nodules and toxic multinodular goitre, as discussed by Lucignani. Our experience as an endocrinologist and a specialist in nuclear medicine is based on a large body of clinical evidence gathered in our university centre where I radioiodine has been applied to treat hyperthyroid and differentiated thyroid cancer patients since 1998. Over this period, we have treated over 4,000 hyperthyroid patients in our out-patient division. First, we would like to address the benefits of I treatment of patients with severe cardiovascular diseases, such as circulatory insufficiency, cardiomyopathy, cardiac defects or arrhythmias—most frequently atrial fibrillation, but also severe heart rhythm disturbances requiring cardioverter-pacemakers, and co-existing hyperthyroidism. Such patients are being referred to our Department by the University Departments of Cardiology and Cardiosurgery with which we closely collaborate. These patients should receive thyrostatics to be rendered almost euthyroid before I application and also require special cardiological care after I treatment, often in the hospital environment. In some cases, to decrease the risk of cardiological and neurological complications, thyrostatic treatment is required after I administration in which case it is commenced 4 days after radioiodine treatment. In severe cardiological patients, radical treatment is intended; therefore, appropriate I activity is individually applied. In some cases, thyroid ablation (30 mCi) is planned, the patient remaining in hospital, in accordance with radiation protection practices. Frequent screening for hypothyroidism and introduction of L-thyroxine at suitable periods does not affect the cardiological condition of these patients negatively. After euthyroidism in the group of patients with cardiac disorders, we usually observe significant improvement in their circulatory status and arrhythmias, in their quality of life and, most importantly, less frequent hospitalisations. In our clinical judgement, mortality in these patients is due to their primary cardiological condition and hyperthyroidism and not to radioiodine treatment per se. We are not able to support this statement by comparative analysis as, for ethical reasons, we never deprive our patients with cardiological problems and hyperthyroidism of the benefit of I. We further believe that such patients benefit most from this non-invasive treatment of hyperthyroidism. Patients with hyperthyroidism and life-threatening arrhythmias treated with amiodarone deserve special comment. In this group of patients, thyroid I ablation may be considered before commencement of treatment with amiodarone. Yearly, we admit 10–15 patients with amiodaroneinduced severe hyperthyroidism and, among them, five to six require radioiodine treatment to enable them to continue their indispensable treatment with amiodarone, as recommended by the consulting cardiologist. I administration is commenced after recovery of thyroid radioiodine uptake which usually takes 3–6 months. We appreciate the thoughtful comments of Flux [2] concerning the dosimetry of I-treated patients and related ethical considerations, quoted in Lucignani’s review. We agree that recommendations, such as those issued by Eur J Nucl Med Mol Imaging (2008) 35:1738–1739 DOI 10.1007/s00259-008-0852-8

Prothymosin-alpha and Ki-67 expression in pituitary adenomas.

INTRODUCTION Prothymosin alpha (PTMA), a nuclear oncoprotein involved in cell cycle regulation, is used as a prognostic marker in many cancers. The histopathology of pituitary carcinomas and locally invasive adenomas is indistinguishable from that of benign tumors. A new marker is needed to differentiate these lesions. We evaluated PTMA in pituitary adenomas to determine its usefulness as a prognostic factor of tumor proliferation. MATERIAL/METHODS We conducted a retrospective analysis of a group of 27 patients, including 15 females (56%) and 12 males (44%) with a mean age of 58.6±12 years, who underwent pituitary tumor surgery between 2003 and 2012. The Ki-67 and PTMA-nuclear (PTMA-n) and PTMA-cytoplasmic (PTMA-c) indices were determined by immunohistochemical staining. We studied histopathological features, clinical symptoms, and magnetic resonance imaging or computed tomography performed before surgery and one year following surgery to evaluate tumor size and progression. RESULTS The expression of Ki-67 was revealed in 77.8% of adenomas, PTMA-n in 81.5% and PTMA-c in 92.6%. The mean value of the Ki-67 index was 1.8%, PTMA-n was 1.84%, and PTMA-c was 35.6%. There was a significant positive correlation between Ki-67 and PTMA-n (p=0.009). We did not find any correlation between Ki-67, PTMA-c, and tumor progression. PTMA-n was found to be correlated with tumor size (p=0.045) and was higher in the case of gonadotropinomas (p=0.026). CONCLUSIONS The positive nuclear expression of Ki-67 and PTMA was observed in the majority of pituitary adenomas. Neither the expression of Ki-67 nor that of PTMA-c was related to tumor recurrence or local invasion.

Factors affecting the efficacy of radioiodine therapy in patients with Graves' disease

Agata Baldys-Waligorska DOI: 10.3252/pso.eu.17ece.2015 Thyroid non-cancer Conclusions: The efficacy of 131-I treatment in GD patients with or without focal lesions evaluated after 6 months was negatively affected by larger thyroid volumes. The efficacy of 131-I treatment in GD patients with focal lesions evaluated after 6 months was negatively affected by anti-thyroid medication. Factors affecting the efficacy of radioiodine therapy in patients with Grave’s disease

Topoisomerase 2 alpha as a prognostic factor in pituitary tumors

Introduction: In pituitary tumors markers of proliferation and progression essential for treatment and follow-up are searched Objectives: We studied topoisomerase 2 alpha (Topo2A) expression in different types of pituitary adenomas in order to evaluate its prognostic potential in patients with hypophyseal tumors. Patients and methods: In a retrospective study of 60 patients of mean age 46.7±17.6 years who underwent pituitary tumor surgery, expression of Topo2A, by immunohistochemistry, was analysed quantitatively with respect to histopathology, tumor features, clinical symptoms, MR imaging and post-operative recurrence/progression of disease. Results: Topo2A was expressed in 73% of (44/60) pituitary adenoma. The highest Topo2A indices were observed in ACTH-secreting pituitary tumors (median:1.13% [0.37-1.21]), followed by silent-ACTH tumors (0.94%[0.89-1.0]), and hormone immunonegative adenomas (0.8%[0.65-1.55]). No differences in expression with respect to patient age or gender were observed. Statistically significant relations were found between Topo2A index and tumor size, its invasiveness, pathological ocular tests and recurrence of tumor growth in postoperative observation. In patients with Topo2A index >1% the relative risk of tumor recurrence is higher by a factor of 3.5 (95%CI:1.8-6.9), P<0.001. After pre-treatment acromegaly patients with somatostatin analogues decrease in median Topo2A expression was observed, compared with untreated patients (0.0% [0.0-0.22] vs 0.71%[0.17-1.0], P<0.05). Conclusions: In our study group, Topo2A index exceeding 1% was found to be a prognostic factor for recurrence/progression of tumors, especially in patients with hormonally inactive adenomas, to be selected for intensive postoperative treatment. In acromegaly, application of somatostatin analogues inhibits Topo2A expression, providing molecular evidence of the effectiveness of these analogues.

Combined glucocorticoid and orbital radiation therapy – literature review and clinical experience

The aim of immunosuppressive treatment of Grave’s orbitopathy (GO) is to limit acute inflammation and congestion of orbital tissues. Application of intra-venous glucocorticoid (GCS) pulses is presently the treatment of choice in active (CAS≥3/7), moderate-to-severe, and severe GO. Randomised trials (RTC) have proved this treatment to be more efficient than oral glucocorticoid therapy. The response rate of this regimen is about 80%. However, exact schedules of GCS treatment have not yet been uniquely established and depend on the experience acquired in different centres. According to the EUGOGO (2008) Consensus, to avoid acute liver damage, the total GCS dose should not exceed 8.0g in a single therapy cycle. Typically, in current schedules, the applied CGS dose per pulse per week is limited and the duration of therapy extended to 12 weeks to deliver a total methylprednisolone dose of 4.5g. While this may not always be the optimum dose, according to the EUGUGU (2012) randomised trial of the efficacy and safety of three different cumulative doses of intravenous methylprednisolone (2.5; 5.0 or 7.5 g) for moderate to severe and active GO, the dose of 7.5g was found to be most effective. It appears therefore that intravenous methylprednisolone treatment should be individualised depending on the severity of GO (NOSPECS criteria) and inflammation activity (CAS). Orbital radiotherapy (RT) is less efficient in GO than in GCS but, as based on rather scarce RCT reports, oral glucocorticoid therapy combined with orbital radiotherapy (20 Gy) appears to give better results than GCS alone (efficacy of about 70-80%). Again, no single schedule of combined GCS and RT has been established since no randomised trials with intravenous glucocorticoid have been conducted. According to our experience of over a decade, GCS pulse treatment followed by orbital irradiation improves the treatment outcome, especially in patients with eye muscle involvement, and reduces the frequency of recurrence. Restoring permanent euthyroidism is very important in GO therapy. Radioiodine therapy should be considered in patients with poorly controlled hyperthyroidism. Oral GCS should be given to patients with risk factors or active GO for radioiodine use, however no randomised clinical trials have been performed to ascertain the optimum GCS dose. According to our experience, ablative 131-I doses should be applied to efficiently control thyroid function. Radioiodine therapy can also take place while GCS pulses are delivered, with RT supplied after completion of methylprednisolone treatment. Randomised prospective trials are also necessary to assess the efficacy of these treatment schedules. In our investigations, we have found that the group of patients who, following 131-I therapy, have reported to our Department with severe GO, demonstrated significantly higher levels of TSH and TRAb, than patients treated with anti-thyroid drugs. It is for this reason that to avoid hypothyroidism, early control of Grave’s disease patients treated with 131-I is essential. According to the Amsterdam Declaration, detailed knowledge of the course of disease, avoiding recurrence of hyperthyroidism, and prompt qualification for well-selected treatment by an experienced endocrinologist- ophthalmologist team will improve the efficacy of GO treatment and protect the patient against severe orbitopathy.

PTTG and Ki-67 expression in pituitary adenomas

INTRODUCTION The unpredictable biology of pituitary adenomas makes it a therapeutic challenge. Moreover ,histopathology of pituitary carcinomas and locally invasive adenomas are indistinguishable from benign tumors and a new marker which would enable to differentiate those lesions is vital. The aim of the study was to evaluate Ki-67 and PTTG (pituitary tumour--transforming gene) expression in pituitary adenomas and their applicationas markers of tumour aggressiveness. MATERIAL AND METHODS A retrospective analysis of 55 patients: 32 females(58%) and 23 males (42%), mean age 50 ± 16 years who underwent pituitary tumor surgery between 2003-2012. Ki-67 and PTTG indices were determined by immunohistochemical staining. Magnetic resonance imaging or computed tomography was performed beforehand and one year after surgery to figure a potential tumour progression, tumour size and correlation to adjacent tissues. RESULTS The expression of Ki-67and PTTG was revealed in cell nucleiin 88% and 85% of adenomas, respectively. The median Ki-67 and PTTG indices were 1.4 and 1.0, respectively(p = 0.006). In the group with macroadenoma as compared with the group with microadenoma, median Ki-67 index was higher (1.4% vs. 1.03%; p = 0.02). We did not find correlation between both Ki-67 and PTTG indices and tumour progression. Tumours with positive immunostaining towards FSH revealed lower Ki-67 and PTTG indices than the rest with a negative one (0.6% vs.1.84%, p = 0.0004 and 0.67% vs 1.23%,p = 0.047; respectively). However, PTTG index was higher in the group with acromegaly as compared to the group with clinically non-functioning pituitary adenoma (NFPA) (1.28% vs.0.35%; p = 0.02). CONCLUSIONS Positive nuclear expression of Ki-67 and PTTG was observed in the majority of pituitary adenomas. Only higher Ki-67 expression was related to the tumour invasiveness found on MRI/CT. Tumour progressionwas not related to both Ki-67 and PTTG expression.