Jan Cap

Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone

OBJECTIVE To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120  mg/month) and pegvisomant (40-120  mg/week) in acromegaly. DESIGN This is a 28-week, multicenter, open-label, single-arm sequential study. METHODS Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120  mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120  mg/month plus pegvisomant (60  mg once weekly, adapted every 8 weeks based on IGF1 levels to 40-80  mg once weekly or 40 or 60  mg twice weekly). RESULTS In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60  mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60  mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (-0.6 ± 1.6) and soft tissue swelling (-0.6 ± 1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related - thrombocytopenia, urticaria; not treatment related - abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5 × upper limit of normal with normalization after withdrawal). CONCLUSIONS In patients partially controlled by SSAs, LA (120  mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60  mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

Benign fine-needle aspiration cytology of thyroid nodule: to repeat or not to repeat?

CONTEXT Fine-needle aspiration cytology (FNAC) is the gold standard for evaluating thyroid nodules. It has a sensitivity rate of about 95%, i.e. false negative results represent up to 5% of cases. The value of repeated FNAC during follow-up is still controversial. OBJECTIVE To evaluate the usefulness of repeating the FNAC for initially benign nodules. DESIGN AND METHODS All 5017 patients who underwent FNAC of the thyroid nodule in years 1991-2008 were retrospectively evaluated. RESULTS Repeated FNAC was performed in 574 nodules with initially benign results. The number of repetitions varied from one to six. Repeatedly benign results were found in 498 cases, and malignant/suspicious results with initially benign cytology were found in 76 nodules (13.2%). Carcinoma was present in 13 out of the 58 surgically treated malignant/suspicious results of initially benign cytology. CONCLUSIONS A change from a benign FNAC result to a malignant/suspicious one was present in more than 13% of the patients with initially benign cytology; malignancy has been recognised on the basis of repeated FNAC in 2.3% patients. In the majority of cases, the repetition corrected wrong cytological interpretation of results other than colloidal goitre, especially Hashimotos thyroiditis and regressive changes. We believe that repeating FNAC in patients with benign cytology in about a 1-year horizon can reduce the rate of undiagnosed tumours.

Dopamine 2 receptor expression in various pathological types of clinically non-functioning pituitary adenomas

Clinically non-functioning pituitary adenomas account for about one-third of pituitary tumors. The majority of them are pathologically classified as gonadotropinomas or null-cell adenomas without hormonal expression. The rest represent silent corticotroph adenomas and plurihormonal tumors. Conservative therapy with dopamine agonists is effective in some cases only depending on the expression of dopamine 2 receptors (D2R). The aim of this study was to quantitatively estimate D2R expression in clinically non-functioning pituitary adenomas and correlate the results with adenoma type according to pathological classification. Out of the 87 adenomas investigated, 63 expressed gonadotropins, 7 were silent corticotroph adenomas, 7 were plurihormonal tumors, and only 6 did not express any pituitary hormone on immunohistochemical investigation. With the use of the reverse transcriptase PCR technique, D2R mRNA was expressed in all adenomas with very heterogeneous quantity. The expression was very low in corticotroph adenomas (relative median quantity after normalization to housekeeping gene 0.01) and lower in plurihormonal tumors (median 0.4) than in gonadotroph (median 1.3) and null-cell adenomas (median 1.9). The difference between corticotroph adenomas and plurihormonal tumors in comparison with other pathological types was statistically significant. The expression of D2R did not depend on the presence or absence of gonadotropins. We conclude that D2R expression is very low in corticotroph adenomas and significantly lower in plurihormonal tumors. The positivity of gonadotropins does not predict the D2R quantity.

Paraganglioma-like medullary thyroid carcinoma: fine needle aspiration cytology features with histological correlation

Objectives:  Two cases of an extremely rare paraganglioma‐like variant of medullary thyroid carcinoma (MTC) are reported.

The role of apoptosis in pituitary adenomas in the field of conventionally used therapeutic approaches.

Abstract: The aim of the study was to investigate the mechanism of action of somatostatin analogues (SSA), ionizing radiation, and their combination on pituitary adenoma cells with special emphasis on proliferative and apoptotic activity. In the 14 GH‐secreting adenomas pretreated with SSA before surgery, more prominent regressive changes were found accompanied by compensatory increase in perivascular fibrosis than in the reference group of 17 unpretreated adenomas. The proliferative Ki‐67 labeling index was significantly lower in the treated group (median 1.6 per 1000) than in the untreated patients (median 5.0 per 1000). Apoptosis was detected in only 2 of the 14 pretreated adenomas, and it was more frequent (9/17) and more prominent in the untreated group. In cell lines, the SSA had minimal antiproliferative effect, and they were unable to induce apoptosis. Ionizing radiation at doses of 5–20 Gy induced apoptosis in the corticotroph cell line AtT20 with no cell‐cycle block. In the somatotroph GH3 cell line, the early (premitotic) apoptosis was detectable using only a high dose of 200 Gy; after irradiation with doses of 20–50 Gy, apoptosis appeared with the latency of 48–72 hours, and was preceded by cell‐cycle arrest in the G2/M phase. The treatment with somatostatin‐14 during irradiation increased the percentage of apoptotic cells in culture 10 days after irradiation (11% versus 3% using 20 Gy).

Pneumocystis pneumonia during medicamentous treatment of Cushing's syndrome--a description of two cases.

Only a few cases of pneumocystis pneumonia (PCP) in Cushings syndrome have been published in the literature so far. In the majority of these patients, the pneumonia occurred after reduction of the hypercortisolism with medicamentous treatment. We report two cases of PCP during conservative treatment of hypercortisolism. We describe clinical, imaging and laboratory findings in two patients and review published cases of pneumocystits pneumonia in Cushings syndrome. A 60-year-old woman and 20-year-old man with Cushings syndrome due to ectopic ACTH syndrome were treated at our department. Both developed pneumocystis pneumonia early after treatment with ketoconazole and ethomidate bromide had been introduced and the levels of cortisol rapidly decreased. PCP prophylaxis in patients with high cortisolemia should be started before treatment of hypercortisolism in current practice. Gradual lowering of plasma cortisol should also reduce the risk of infection by Pneumocystis jiroveci.

Impact of Hashimoto's thyroiditis, TSH levels, and anti-thyroid antibody positivity on differentiated thyroid carcinoma incidence.

INTRODUCTION The relationship between Hashimotos thyroiditis (HT) and thyroid cancer (TC) is controversial. While most surgical studies report a high incidence of malignancy among patients with HT, cytological studies do not. The role of autoantibodies in the incidence of malignancy is unclear. MATERIAL AND METHODS A single-centre retrospective observational study was conducted in patients evaluated for thyroid nodules by US-guided fine-needle aspiration cytology (FNAC) and, if indicated, by surgery. The levels of thyroid-stimulating hormone (TSH) and anti-thyroid antibodies were measured at the time of FNAC. RESULTS Of 4947 patients, 599 (12.1%) were diagnosed with HT. A malignant/suspicious cytological result was found in 14.2% of the patients with HT and in 15.2% of the others. The odds ratio (OR) for malignancy in HT was 0.921 (0.716-1.183, p = 0.51). Of 1603 patients who underwent surgery, differentiated thyroid carcinoma was found in 29.5% of the HT patients and in 15.2% of the others (OR 2.33, 95% confidence interval CI, 1.403-3.854, p < 0,001). Low TSH (< 0.4 mIU/L) decreased the malignancy rate in the entire patient population, both when considering the cytological results and the surgical results. This was not confirmed in the subgroup diagnosed with HT. No relationship was observed between autoantibodies against thyroid peroxidase (ATP) or thyroglobulin (ATG) and malignancy rate. CONCLUSIONS No association between HT and thyroid cancer was observed cytologically; a positive relationship in histological series was caused by selection bias. Low TSH levels decreased the risk of TC in patients with nodular goitre, but this has not been proven in patients with HT.

Expression profiles of somatostatin, dopamine, and estrogen receptors in pituitary adenomas determined by means of synthetic multilocus calibrators

AIMS Pituitary adenomas (PA) are non-invasive benign tumors with a high autopsy prevalence. They are classified according to the type of hormone secreted (prolactin, growth hormone, adrenocorticotropin, thyrotropin, folitropin, or luteinizing hormone). Clinically non-functioning adenomas (CNFA) lacking the typical hypersecretion of hormones make up a significant portion of PA. The aim of the study was to determine the complete expression profiles of somatostatin receptors (SSTR1-SSTR5), dopamine receptors type 2 (D2R), and estrogen receptors (ER1) in various types of PA. METHODS Adenoma specimens were obtained from 206 patients during transsphenoidal resection. For quantitative analysis, reverse transcription and consequent real-time PCR with synthetic multilocus calibrators (SMC) were used. The obtained data were normalized to the number of transcripts of the beta-glucuronidase gene. RESULTS The use of SMC enabled the alignment of individual calibration functions for all the receptors. No relationships between the expression of the receptors and the tumor size, site of extension, gender or age at diagnosis were significant. In growth hormone-secreting adenomas, D2R and SSTR2 transcripts were extensively expressed, followed by ER1, SSTR5, SSTR3, and SSTR1. In patients with macroprolactinomas, transsphenoidal resection was indicated because dopamine agonists did not normalize prolactin levels. D2R, ER1 and SSTR1 transcripts were significantly transcribed. Corticotroph adenomas showed high levels of D2R and ER1 transcripts and lower amounts of SSTR2 and SSTR1 transcripts. SSTR5 transcripts were very low. Subjects with CNFA dominantly expressed D2R and ER1, followed by SSTR2 and SSTR3 mRNA. CONCLUSION We evaluated SSTR1-SSTR5, D2R, and ER1 expressions in a large group of pituitary adenomas and we found that determining their individual expression profiles could help when choosing the optimal postoperative treatment.

Cellular cohesiveness in benign and malignant thyroid follicular tumours varies significantly, but the difference is not useful in diagnosis of individual cases.

T. Rozkos, A. Ryska, J. Cap, F. Sobande and J. Laco 
Cellular cohesiveness in benign and malignant thyroid follicular tumours varies significantly, but the difference is not useful in diagnosis of individual cases

Treatment of Multifocal Multisystem BRAF Positive Langerhans Cell Histiocytosis with Cladribine, Surgery and Allogenic Stem Cell Transplantation

Langerhans cell histiocytosis (LCH) is a very rare disease in adults and as well a very rare cause of sellar expansion. The clinical presentation can be heterogeneous, from a single bone lesion to potentially fatal, widespread disease. We describe the difficulties with the diagnosis and treatment of LCH as well as successful treatment with cladribine chemotherapy and allogeneic stem cell transplantation.