In patients with well-differentiated neuroendocrine tumours, there is no apparent benefit of somatostatin analogues after disease control by peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) and somatostatin analogues (SSAs) are commonly combined as primary treatment for neuroendocrine neoplasms (NEN), and SSAs given as maintenance. We sought to evaluate whether sequential therapy with PRRT followed by SSAs has progression or survival benefits in patients with NEN after disease control by PRRT. METHODS: This prospective, randomised, single-centre study had as principal eligibility criteria: unresectable, locally advanced, or metastatic, histologically confirmed well-differentiated NEN; no symptoms/biochemical diagnosis of carcinoid syndrome; no SSAs or ≤ 3 months of SSAs before PRRT; and stable disease or partial or complete response after PRRT. Altogether, 115 patients were randomised 2:1 to an SSA group (n = 74) given octreotide acetate LAR every 4 weeks, or a control group (n = 41) receiving only best supportive care. Octreotide treatment was to stop upon intolerable toxicity or patient refusal, or, at physician/patient discretion, upon NEN progression. The primary endpoint was progression-free survival (PFS), the secondary endpoint, and overall survival (OS). RESULTS: Median (25th-75th percentile) follow-up from the first PRRT activity to death or latest observation was 6.6 (3.18-10.22) years. During that time, 71/115 patients (62%) progressed, 52/74 (70%) in the SSA group, and 19/41 (46%) in the control group (p = 0.01). Eighty-eight/115 patients (76%) died, 58/74 (78%) in the SSA group, and 30/41 (73%) in the control group (p = 0.52). Median (95% CI) PFS was 4.7 (2.8-7.7) years in the SSA group, and 6.4 (4.1-not reached) years in controls. Overall, median OS was 6.6 years. Neither PFS nor OS differed between groups (p = 0.129, p = 0.985, respectively). CONCLUSIONS: In patients with disease control after PRRT, subsequent SSA treatment appeared not to be associated with better PFS or OS. Whether to continue SSA administration upon progression after PRRT requires evaluation in a prospective, randomised, controlled multicentre study with a relatively homogeneous sample.

Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study.

BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.

Heterogeneity of the Clinical Presentation of the MEN1 LRG_509 c.781C>T (p.Leu261Phe) Variant Within a Three-Generation Family.

Multiple neuroendocrine neoplasia type 1 (MEN1) is a rare genetic disorder with an autosomal dominant inheritance, predisposing carriers to benign and malignant tumors. The phenotype of MEN1 syndrome varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. We describe a heterogenic phenotype of the MEN1 variant c.781C>T (LRG_509t1), which was previously reported only once in a family with isolated hyperparathyroidism. A heterozygous missense variant in exon 4 of the gene was identified in the sequence of the MEN1 gene, i.e., c.781C>T, leading to the amino acid change p.Leu261Phe in a three-generation family. In the screened family, 5/6 affected members had already developed hyperparathyroidism. In the index patient and two other family members, an aggressive course of pancreatic neuroendocrine tumor (insulinoma and non-functioning neuroendocrine tumors) with dissemination was diagnosed. In the index patient, late diagnosis and slow progression of the disseminated neuroendocrine tumor have been observed (24 years of follow-up). The very rare variant of MEN1, LRG_509t1 c.781C>T /p.Leu261Phe (LRG_509p1), diagnosed within a three-generation family has a heterogenic clinical presentation. Further follow-up of the family members should be carried out to confirm the spectrum and exact time of clinical presentation.

Only peak thyroglobulin concentration on day 1 and 3 of rhTSH-aided RAI adjuvant treatment has prognostic implications in differentiated thyroid cancer.

OBJECTIVE: In patients with differentiated thyroid carcinoma (DTC), serum thyroglobulin levels measured at the time of remnant ablation after thyroid hormone withdrawal were shown to have prognostic value for disease-free status. We sought to evaluate serial thyroglobulin measurements at the time of recombinant human thyroid-stimulating hormone (rhTSH)-aided iodine 131 (131I) adjuvant treatment as prognostic markers of DTC. METHODS: Six hundred-fifty patients with DTC given total/near-total thyroidectomy and adjuvant radioiodine post-rhTSH stimulation were evaluated. Thyroglobulin was measured on day 1 (Tg1; at the time of the first rhTSH injection), day 3 (Tg3; 1 day after the second, final rhTSH injection), and day 6 (Tg6; 3 days post-radioiodine administration). Treatment failure was defined as histopathologically confirmed locoregional recurrence, or radiologically-evident distant metastases (signs of disease on computer tomography (CT) or magnetic resonance imaging (MRI), or abnormal foci of radioiodine or [18F] fluorodeoxyglucose ([18F]FDG) uptake. RESULTS: In univariate analysis, Tg1 (p < 0.001) and Tg3 (p < 0.001), but not Tg6, were significantly associated with structural recurrence. In multivariate analysis of the overall cohort, only Tg3 was independently associated with structural recurrence. In multivariate analysis of the subgroup (n = 561) with anti-Tg antibodies titers below the institutional cut-off, 115 IU/mL, Tg1 was an independent prognostic marker. Tg1 and Tg3 cutoffs to best predict structural recurrence were established at 0.7 ng/mL and 1.4 ng/mL, respectively. CONCLUSIONS: Tg1 and Tg3, measurements made after rhTSH stimulation but before radioiodine treatment, independently predict a low risk of treatment failure in patients with DTC. Levels measured post-radioiodine application (e.g., Tg6) are highly variable, lack prognostic value, and hence can be omitted.

Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas.

INTRODUCTION: Pheochromocytomas and paragangliomas are derived from neural crest cells and are localized mainly in adrenal medulla and sympathetic or parasympathetic ganglia. They can be inherited (25%) and be part of multi-endocrine syndromes such as MEN2 syndrome, von Hippel-Lindau syndrome, pheochromocytoma/paraganglioma syndrome, neurofibromatosis type 1, and Sturge-Weber syndrome. Clinical presentation can sometimes be atypical and does not always allow proper diagnosis. In such situations, DNA analysis can be helpful, especially when the pheochromocytoma is the first and only symptom. MATERIAL AND METHODS: We analyzed DNA from 60 patients diagnosed and treated in the Centre of Oncology with a diagnosis of pheochromocytoma or paraganglioma. DNA analysis was carried out for RET (exons 10, 11, 13, and 16), SDHB, SDHD, and VHL genes. Techniques used for the analysis were direct sequence analysis, MSSCP, and RFLP. RESULTS: Germinal mutations were found in 16 patients (26,7%). Most frequent were mutations in RET proto-oncogene, followed by VHL gene, one mutation in SDHB, and one in SDHD genes. A comparison of some of the clinical features of both groups (with and without mutation) showed statistically significant differences. CONCLUSIONS: The results of our study show that genetic predisposition is frequent in chromaffin tissue tumours, which indicates that DNA analysis is necessary in every case, also because of possible atypical clinical presentation. (Pol J Endocrinol 2010; 61 (1): 43-48).

Laparoscopic cortical-sparing adrenal surgery in pheochromocytomas associated with hereditary neoplasia syndromes.

INTRODUCTION: Pheochromocytomas in hereditary syndromes tend to grow multifocal with adrenal involvement on both sides. Surgical treatment with bilateral adrenalectomy inevitably leads to life-long hormonal dependence, which significantly affects quality of life. The development of minimally invasive adrenal surgery has created a chance to preserve adrenal cortex function in these patients. The aim of the present study was to evaluate the safety of laparoscopic cortical-sparing adrenal surgeries and their efficacy in the prevention of postoperative adrenal insufficiency in patients with hereditary pheochromocytomas. MATERIAL AND METHODS: We retrospectively analysed the medical histories of 10 patients, who underwent 10 laparoscopic cortical sparing adrenal surgeries from January 2015 to January 2019 in our centre. The decision to perform sparing surgery was based on preoperative diagnosis of hereditary syndrome in line with the result of DNA analysis or its diagnosis based on the clinical appearance. All surgeries were performed laparoscopically from transperitoneal access in the lateral decubitus position, with preserving 1/3-1/4 adrenal tissue. The sufficiency of remnant adrenal tissue was assessed in all patients. The median time of follow-up was three years (ranged 0.5-4 years). RESULTS: No intraoperative complications were observed. One case of acute heart failure was the only early postoperative adverse event. There were no late postoperative complications and no local recurrences observed. In one out of three patients undergoing sparing surgery as a second procedure after former total adrenalectomy, adrenal cortex failure occurred. In all patients after unilateral surgery or after bilateral surgery performed simultaneously (total adrenalectomy at one side and sparing surgery contralaterally), function of remnant adrenal tissue was preserved. CONCLUSIONS: In hereditary pheochromocytomas, with minimal risk of malignant process, laparoscopic cortical sparing adrenal surgeries are the safe approach and provide the chance to preserve adrenal cortex function.

Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study.

OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. DESIGN AND METHODS: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. RESULTS: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. CONCLUSIONS: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.

Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures: Total or cortical-sparing adrenalectomy. Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study.

BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

[131I-MIBG therapy in the treatment of pheochromocytoma in children--own experiences]. / Terapia 131I-MIBG w leczeniu guzów chromochlonnych u dzieci--doswiadczenia wlasne.

Three cases of pheochromocytoma in children/adolescents or young adults treated by 131I-MIBG are presented in this study. In one patient 131I-MIBG was administrated after ineffective surgical treatment and chemotherapy of a benign retroperitoneal tumor, whereas in two other patients 131I-MIBG therapy was carried out because of malignant pheochromocytoma dissemination. In a child with retroperitoneal paraganglioma decrease of tumor size and its fibrosis after 131I-MIBG therapy allowed radical surgery and complete recovery. In two other cases partial remission was achieved. All patients showed a good subjective response with improvement of the general condition and better blood pressure control. In two children adverse reactions such as leucopenia, hypothyroidism or hypogonadism were observed. The presented data confirm effectiveness and acceptable tolerance of 131I-MIBG treatment in pheochromocytoma, what is very important in pediatric patients.

131-I MIBG therapy of malignant pheochromocytoma and paraganglioma tumours - a single-centre study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare tumors deriving from chromaffin cells of adrenal medulla or paraganglia. They are usually benign but 10-35% of them present malignant behavior. The aim of the study was to evaluate the efficacy and safety of 131-I MIBG therapy in malignant pheochromocytoma /paraganglioma patients (MPPGL). MATERIAL AND METHODS: 18 patients (7 women and 11 men) were included in this study. Between 2002 and 2016 they underwent 131-I MIBG therapy because of MPPGL and their medical data were analyzed retrospectively. Clinical indications for the treatment included progressive disease or massive tissue involvement independently from disease progression. Tumor response for the first time was assessed 3 months after the last treatment according to Response Evaluation Criteria in Solid Tumors criteria and by 131-I MIBG scans. RESULTS: The mean single dose used was 7.25 GBq (196 mCi) and mean cumulative dose 33.08 GBq ( 894 mCi). In 2 (11%) patients complete tumor response was achieved. In 1 (6%) patient partial response was obtained. In 13 (72%) patients stable disease was observed. In 2 (11%) patients progression was diagnosed three months after treatment discontinuation. In the whole studied group the progression free survival time was 85 months and overall 5-year survival was 87%. CONCLUSIONS: Radionuclide treatment with use of 131-I MIBG may be effective form of palliative treatment for patients with inoperative neoplasm spread, progressive disease or patients requiring alleviation of symptoms. < p > < /p >.

Guidelines of Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma. 2018 Update.

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1].

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves' disease: the impact of DRB1*07.

OBJECTIVE: To study interactions between the two most widely confirmed Graves' disease (GD) loci: HLA-DRB1 and CTLA-4. HLA-DRB1*03 (risk allele) and DRB1*07 (protective allele) were analyzed in this aspect, the linked TNF G(-308)A polymorphism was also considered. DESIGN: A case-control study of 429 patients with GD compared to 308 healthy subjects. The impact of genes and their interactions were analyzed by stepwise logistic regression. RESULTS: The independent effects of DRB1*03 and DRB1*07 were confirmed in our study both by stratification studies and logistic regression. CTLA-4 did not appear to be associated with GD when the interactions with other genes were considered. By logistic regression we observed a significant interaction between DRB1*07 and CTLA-4 and revealed that CTLA-4 49G attenuated the DRB1*07-related protection, the effect noticed also in three-way stratification studies. We confirmed that the TNF G(-308)A polymorphism is only a marker of the DRB1 status. CONCLUSION: Our results stress the importance of complex gene interactions in the multigene predisposition to GD. The interactions between two predisposing loci, DRB1 and CTLA-4, are exerted rather by DRB1*07 than DRB1*03 allele: CTLA-4 acts via switching off the protective DRB1*07 influence, whereas the effect of DRB1*03 is independent.

[Hypoparathyroidism after surgery on thyroid cancer: is there a delayed chance for recovery after a prolonged period of substitutive therapy?]. / Niedoczynnosc przytarczyc po operacji raka tarczycy: czy istnieje szansa na opóznione samoistne wyrównanie funkcji gruczolów?

INTRODUCTION: Transient and persistent hypoparathyroidism (HPT) belong to the well known complications of total thyroidectomy performed because of thyroid carcinoma. The true frequency of persistent hypoparathyroidism is often higher than estimated in the reports published by the specialized centers with low rate of complications. THE AIM OF THE STUDY: Investigation whether the repeated check-up, performed over 2 years post thyroidectomy, reveals some cases of recovery in patients diagnosed with persistent HPT post thyroid cancer surgery. MATERIAL AND METHODS: In total, 115 patients were included into the study, all of them treated with vitamin D derivatives and calcium supplementation. In 17 of them a diagnosis of transient hypoparathyroidism was made on the basis of evaluation performed 6 months after surgery, the remaining 98 were diagnosed with persistent HPT. Parathyroid (PTH) function was reevaluated after withdrawal of active vitamin D derivatives for 10 days and of calcium carbonate for two days during the hospital stay in patients admitted for radioiodine scan, thus after thyroxine withdrawal. The control group consisted of 123 DTC (differentiated thyroid carcinoma) patients without parathyroid dysfunction. On the basis of intact PTH serum level and calcium and phosphorus estimations HPT was unequivocally confirmed in 49 patients (50%). The remaining 49 patients exhibited normal PTH level and in 43 (86%) of them Ca(2+) level was also within normal range, thus delayed, recovery from HPT was stated. RESULTS: Our results indicate that reevaluation of hypoparathyroidism post total thyreoidectomy is necessary, as delayed recover of parathyroid dysfunction is a frequent phenomenon. We also propose criteria of reevaluation of HTP in patients on chronic substitutive therapy.

[Relapse of differentiated thyroid carcinoma in low-risk patients]. / Nawrót zróznicowanego raka tarczycy u chorych z grupy niskiego ryzyka.

INTRODUCTION: The low incidence of relapse in differentiated thyroid carcinoma (DTC), primarily treated by total thyroidectomy and (131)I ablation, stimulates the search for optimal follow-up algorithms which do not include too many tests but are not connected with a risk of missing early recurrence. The aim of the study was to analyze the impact of the routine follow up examinations for early detection of DTC recurrence in low risk DTC patients. MATERIAL AND METHODS: The group consisted of 617 DTC patients diagnosed in 1995-1996. In 513 (83%) total thyroidectomy was performed. 449 (73%) received ablative (131)I therapy. After primary approach complete remission (CR) was stated in 453 (73%), persistent disease in 116 (19%), asymptomatic hyperthyroglobulinaemia in 14 (2%). Patients with CR constituted the low risk group analyzed in this study. The median follow up was 4.16 yrs. RESULTS: Recurrent disease appeared in 28 (6%) patients (23 locoregional, 9 distant metastases, both in 4). Serum Tg (thyroglobulin) level at the moment of relapse diagnosis was detectable in 44% while neck sonography was the first examination to detect recurrence in 56% of cases. CONCLUSION: In the selected group of DTC patients treated by radical primary approach and showing a low risk of recurrence only half of all relapse cases are diagnosed by the rise of serum Tg level. Regular sonography contributes to the second half of diagnoses. Thus, a special weight should be put on neck sonography as the important element of regular follow up in low risk DTC patients.

[Recombinant human TSH stimulation in radioiodine treatment of disseminated differentiated thyroid cancer--update of current and our own experiences]. / Stymulacja rhTSH w leczeniu jodem promieniotwórczym funkcjonalnych przerzutów zaawansowanego zrósnicowanego raka tarczycy--omowienie aktualnego stanu wiedy i przeglad doswiadczen wlasbych.

Traditionally, for diagnostic and therapeutic application of radioiodine in patients with differentiated thyroid cancer (DTC), a 4 to 6 week withdrawal of thyroid hormone was applied. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and associated morbidity. The results of rhTSH administration and endogenous TSH stimulation are equivalent in detecting recurrent DTC. At the present time rhTSH is approved as an adjunct for diagnostic procedures and thyroid ablation in patients with DTC. In addition, rhTSH has potential for use in facilitating the treatment of metastases in patients with DTC. In this review we have summarized our own experiences with rhTSH aided radioiodine therapy in patients with disseminated thyroid cancer. Generally, rhTSH was very well tolerated and treatment results were comparable to those achieved with thyroid hormone withdrawal.

Occurrence of phaeochromocytoma tumours in RET mutation carriers - a single-centre study.

INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant genetic syndrome caused by germline mutation in RET proto-oncogene. The most common mutations are in a cysteine rich domain. Phaeochromocytoma will develop in approximately 50% of RET proto-oncogene carriers. MATERIAL AND METHODS: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy). RESULTS: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma. CONCLUSIONS: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma.

Molecular classification of pituitary adenomas: in search for criteria useful for high-throughput studies.

INTRODUCTION: The mechanism of pathogenesis of pituitary adenomas is still unknown, and it shows differences in pituitary cells of different origin. The aim of our study was to analyse the gene expression profile of pituitary hormones and their precursor genes: PRL, GH, POMC, TSHb, LHb, FSHb, and CGA by QPCR in particular types of pituitary adenomas, and to evaluate the results in the context of sample selection for microarray studies. MATERIAL AND METHODS: Analysis of the gene expression profile was performed in 84 samples of pituitary adenomas, by real-time quantitative PCR (QPCR). RESULTS: As expected, expression of GH gene was significantly higher in somatotropinomas than in prolactinomas (p < 0.05). For POMC gene we noticed lower expression in all pituitary adenomas, except adrenocorticotropinomas (p < 0.05). In the case of PRL gene, the highest expression was observed; PRL+ adenomas were in third place. LHb and FSHb genes showed the highest expression, respectively, in LH-producing and FSH-producing pituitary adenomas; however, our analysis did not show statistically significant differences between LH-producing and FSH-producing adenomas. CONCLUSIONS: Our study showed that GH is a characteristic gene for somatotropinomas. We drew a similar conclusion for POMC gene and adrenocorticotropinomas. However, the results that we obtained for PRL, TSHb, LHb, FSHb, and CGA genes indicate that evaluation of gene expression is not sufficient for classification of particular subtypes of pituitary adenomas.