[Neuroendocrine tumors : Classification, clinical presentation and imaging]. / Neuroendokrine Tumoren : Klassifikation, Klinik und Bildgebung.

CONTEXT: Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms found in all organs. They often present with characteristic clinical syndromes due to hormone hypersecretion. DIAGNOSTICS: In addition to hormone diagnostics molecular-genetic work-up can play an important role. IMAGING: Morphological imaging comprises ultrasound, endoscopy, computed tomography (CT) and magnetic resonance imaging (MRI) scans. Functional imaging of NET relies on radioligands that bind to specific receptors or transporters (Ga-68-DOTATATE-PET-CT, Tc-99-tektrotyd-SPECT/CT, F­18-DOPA-PET/CT). THERAPY: Somatostatin analogs either native or coupled to radionuclides are potent drugs for treating various neuroendocrine tumors. CONCLUSION: The requirements of imaging are determined by clinical presentation, laboratory findings, tumor stage, the presence of a tumor syndrome and the need of a personalized systemic treatment modality.

Phaeochromocytoma in multiple endocrine neoplasia type 2: RET codon-specific penetrance and changes in management during the last four decades.

OBJECTIVES: We describe phaeochromocytoma (phaeo) penetrance in multiple endocrine neoplasia type 2 (MEN2) according to RET protooncogene-specific mutations and report changes in phaeo diagnosis and management from 1968 to 2015. DESIGN: This retrospective chart review included 309 MEN2 patients from one specialized ambulatory care centre. Phaeo patients were categorized by diagnosis date: early, 1968-1996, n=40, and recent, 1997-2015, n=45. RESULTS: Phaeochromocytoma was diagnosed in 85/309 patients with RET mutations in the following exons (phaeos/all carriers, %): exon 11 (56/120, 46.6%); exon 16 (7/17, 41.2%), exon 10 (14/47, 29.8%), and exon 13-15 (2/116, 1.7%). Age at phaeo diagnosis differed according to affected exon: 21.9±1.5 years, exon 16; 34.1±11.6 years, exon 11; and 41.8±8.8 years, exon 10. Age-related phaeo penetrance differed among five amino acid substitutions at codon 634 and was highest for Cys634Arg and Cys634Tyr. Age at diagnosis was 34.4±11.6 years in the early and recent groups. Phaeochromocytoma and medullary thyroid carcinoma (MTC) were diagnosed synchronously in 21/40 (early) vs 8/45 (recent) and metachronously in 19/40 vs 37/45 cases. Diagnostic methods significantly changed from clinical (22/40 vs 4/45) to biochemical and/or imaging based (14/40 vs 35/45). Phaeochromocytoma diameter at diagnosis was 4.6 vs 2.6 cm. CONCLUSION: Phaeochromocytoma penetrance and age of diagnosis are highly correlated with MTC aggressiveness based on RET mutation status, with higher penetrance and younger age of diagnosis associated with more aggressive MTC. Penetrance steadily increases with age. At-risk patients require lifelong follow-up.

Long-Term Follow-Up and Treatment of Postoperative Permanent Hypoparathyroidism in Patients with Medullary Thyroid Carcinoma: Differences in Complete and Partial Disease.

This study aimed to identify factors influencing long-term outcome in complete or partial postoperative hypoparathyroidism (parathyroid hormone ≤10 or >10 ng/l, respectively) in medullary thyroid carcinoma (MTC). It was designed as retrospective, long-term follow-up with single-center outpatient visits. Quality of treatment, renal calcification, and function were evaluated. In 33 patients with MTC and postoperative hypoparathyroidism, current medication includes: calcium (73%), calcitriol (73%), alfacalcidol (6%), dihydrotachysterol (3%), and cholecalciferol supplements (21%). Mean hypoparathyroidism duration was 15.9±9.4 years. Initially, 15% of patients received high cholecalciferol dosages. Initial calcium dosages were higher (1 542±1 179 mg/day) than final dosages (1 188 ± 595 mg/day) (p<0.05); calcitriol dosages remained constant. Over the median observation period of about 12 years it was found that serum calcium was within the target range (2.0-2.3 mmol/l) in 63% of visits, decreased (<2.0 mmol/l) in 20.4%, high-normal (2.4-2.6 mmol/l) in 15.8%, and increased (>2.65 mmol/l) in 0.9% of visits. Calcitriol dosages were 0.73±0.22 µg/day and 0.47±0.20 µg/day in patients with complete (n=13) and partial (n=20) hypoparathyroidism, respectively (p=0.008). Renal function decreased slightly during follow-up (eGFR: 102±22 vs. 90±27 ml/min). eGFR was negatively correlated with hypoparathyroidism duration (r=-0.35, p=0.05). Of 9 patients with renal calcification, 5 had received high initial cholecalciferol doses. eGFR was lower in patients with than in those without calcification (77±17 vs. 95±29 ml/min) (p=0.07). At least one tetanic episode occurred in 60.6% of patients, and 9% had repeated tetanic complaints. In conclusion, severity of hypoparathyroidism affects treatment: Partial hypoparathyroidism required lower calcitriol dosages than complete hypoparathyroidism. Renal calcifications occurred more frequently in patients treated initially with high cholecalciferol dosages. Impaired renal function was related to hypoparathyroidism duration and renal calcification.

2012 European thyroid association guidelines for genetic testing and its clinical consequences in medullary thyroid cancer.

Twenty-five percent of medullary thyroid cancers (MTC) are familial and inherited as an autosomal dominant trait. Three different phenotypes can be distinguished: multiple endocrine neoplasia (MEN) types 2A and 2B, in which the MTC is associated with other endocrine neoplasias, and familial MTC (FMTC), which occurs in isolation. The discovery that germline RET oncogene activating mutations are associated with 95-98% of MEN 2/FMTC syndromes and the availability of genotyping to identify mutations in affected patients and their relatives has revolutionized the diagnostic and therapeutic strategies available for the management of these patients. All patients with MTC, both those with a positive familial history and those apparently sporadic, should be submitted to RET genetic screening. Once an RET mutation has been confirmed in an index patient, first-degree relatives should be screened rapidly to identify the 50% who inherited the mutation and are therefore at risk for development of MTC. Relatives in whom no RET mutation is identified can be reassured and discharged from further follow-up, whereas RET-positive subjects (i.e. gene carriers) must be investigated and a therapeutic strategy initiated. These guideline recommendations are derived from the most recent studies identifying phenotype-genotype correlations following the discovery of causative RET gene mutations in MEN 2 eighteen years ago. Three major points will be discussed: (a) identification of patients and relatives who should have genetic screening for RET mutations, (b) management of asymptomatic gene carriers, and (c) ethics.

[Secondary osteoporosis - relevant clinical characteristics in diagnosis and therapy]. / Sekundäre Osteoporose - praxisrelevante Besonderheiten bei der Diagnostik und Therapie.

Osteoporosis is a systemic skeletal disease causing increased fracture risk. According to pathogenesis, primary (70 - 80 %) and secondary osteoporosis (20 - 30 %) are distinguished. Secondary osteoporosis comprises all entities in which osteoporosis is predominantly and causally associated with certain diseases or conditions. The aim of this review article is to put attention to special features in diagnosis, prophylaxis and treatment of secondary osteoporosis in general and to demonstrate some forms of secondary osteoporosis which seem particularly important during clinical practice. The manuscript refers to the guidelines of the DVO 2009 for prevention, diagnosis and therapy of osteoporosis and selective original papers considering the special types of secondary osteoporosis. History, clinical examination and basic laboratory tests are indicative for the diagnosis of secondary osteoporosis. Its clinical presentation is frequently characterized by rapid development and multiple fractures. Therefore, early diagnosis, prophylaxis and causal treatment is decisive. If causal treatment is impossible, risk adaption of bone mineral density (BMD) for osteoporosis specific treatment is essential. Common causes are medications, endocrine, gastrointestinal and hematologic diseases. Glucocorticoid induced osteoporosis, antihormonal therapy (aromatase inhibitor in women with breast cancer, androgen deprivation therapy in men with prostate cancer) and vitamin D deficiency causing secondary hyperparathyroidism are presented in detail. History and basic laboratory testing are decisive to identify possible causes for secondary osteoporosis and to initiate early diagnostic procedures. The risk of severe osteoporosis can be reduced by early and causal treatment or by risk stratified early bone specific medication if causal therapy is impossible.

[Hereditary variants of primary hyperparathyroidism--MEN1, MEN2, HPT-JT, FHH, FIHPT]. / Hereditäre Formen des primären Hyperparathyreoidismus. MEN1, MEN2, HPT-JT, FHH, FIHPT.

OBJECTIVE: The challenge in diagnosing primary hyperparathyroidism (HPT) is to detect hereditary cases before first surgery. About 5% of cases are hereditary and integral component of multiple endocrine neoplasia type 1 and 2 (MEN1/MEN2), hyperparathyroidism-jaw tumor syndrome (HPT-JT), familial hypocalciuric hypercalcemia (FHH), and familial isolated hyperparathyroidism (FIHPT). Aim of this study was to evaluate similarities and differences in hereditary varieties of HPT. PATIENTS: 80 patients with hereditary HPT were evaluated in a retrospective analysis between 1980 and 2010 concerning clinical findings, family history, therapy, biochemical and molecular-genetic findings and follow-up. RESULTS: 80 patients with hereditary HPT are described, 52 belonged to MEN1, 15 to MEN2, 7 to HPT-JT, 4 to FHH and 2 to FIHPT kindreds. Penetrance of HPT was highest in MEN1 (85%), followed by HPT-JT (64%), FHH (28.5%), and MEN2 (8%). Youngest age at diagnosis of HPT was 7 and 16 years in the MEN2/HPT-JT group. Serum Calcium was highest in the HPT-JT group (3.6 mM), recurrencies of HPT were highest in the MEN1 group (40.5%). Parathyroid cancer solely occurred in the HPT-JT group. In single cases HPT occurs in FHH. CONCLUSION: Among the different varieties of hereditary HPT MEN1-HPT is most frequent and carries the utmost recurrence rate. Early diagnosis of HPT-JT syndrome is important because of the occurrence of parathyroid cancer. Single cases of HPT in FHH are described. Preoperative diagnosis of hereditary HPT has therapeutic consequences concerning extent of surgery and implications concerning patient and family care.

Rapid response to sorafenib in metastatic medullary thyroid carcinoma.

OBJECTIVE: To investigate the efficacy of sorafenib in progressive metastatic Medullary Thyroid Carcinoma (MTC), for which there is currently no effective treatment. DESIGN: Off-label observational study. METHODS: Sorafenib 400 mg twice daily was evaluated. The primary endpoint was the objective Response Evaluation Criteria in Solid Tumours (RECIST) score assessed on day 28 and every 12 weeks thereafter. Additional endpoints were time to response, duration of tumour response, tumour-related symptoms, and changes in tumour markers, calcitonin, and CEA measured initially, at 2 weeks, and then every 4 weeks. Therapy duration was 2 weeks, and 3-12 months. RESULTS: The 5 patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. 2 patients showed a partial response with tumour regression of -46% and -36% after 6 and 9 months, respectively, and 2 patients exhibited tumour regression of -14% and -29%, respectively (stable disease). Ultrasound-documented regression of -37% within 2 weeks occurred in 1 patient. Calcitonin decreased within 2 weeks in all patients by -69, -90, -75, -96, and -39%, respectively. 1 patient died because of progressive ascites from acute renal and hepatocellular failure. 2 patients developed grade 3 hand-foot syndrome within the first month, so that sorafenib was interrupted or reduced; other side effects were rash, fatigue, and hair loss. 3 patients remain on sorafenib, 2 at a reduced dosage (600 mg/d). CONCLUSION: These data suggest a possible role for sorafenib in the treatment of progressive metastatic MTC.

Are commonly recommended dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D levels--an observational study during clinical practice conditions.

UNLABELLED: Vitamin D deficiency is associated with increased fracture risk. The observational study aimed to investigate vitamin D status and supplementation in ambulatory patients. Only 20% of patients had optimal serum 25-hydroxyvitamin D [25(OH)D] levels. Commonly recommended dosages were insufficient to achieve clinically relevant increase of 25(OH)D levels. Higher dosages were safe and effective under clinical practice conditions. INTRODUCTION: Vitamin D deficiency is associated with adverse health outcome. The study aimed to investigate vitamin D status and supplementation in ambulatory patients. METHODS: Nine hundred seventy-five women and 188 men were evaluated for bone status from January 2008 to August 2008 within an observational study; 104 patients (n = 70 osteoporosis) received follow-up after 3 months. Dosage of vitamin D supplementation was documented and serum 25(OH)D and parathyroid hormone (PTH) determined. RESULTS: In all patients (age, 60.4 ± 14.1 years), distribution of 25(OH)D was 56.3 ± 22.3 nmol/L (normal range, 52-182 nmol/L) and PTH 53.8 ± 67.5 ng/L (normal range, 11-43 ng/L). The proportion of patients with 25(OH)D < 25, 25 to <50, 50 to <75, ≥75 nmol/L was 7.5%, 33.3%, 38.9% and 20.2% in the total group and 20.1%, 38.5%, 30.8%, 10.6% at baseline in the follow-up group, respectively. After 3 months, 3.9% had still 25(OH)D < 25 nmol/L; only 12.5% achieved 25(OH)D ≥ 75 nmol/L. In osteoporosis patients, 25(OH)D increased more in those taking ≥1,500 (median, 3,000) IU vitamin D per day (33.1 ± 14.7 nmol/L) compared with ≤1,000 (median, 800) IU/day (10.6 ± 20.0 nmol/L) (p < 0.0008). PTH decreased more in patients taking ≥1,500 IU/day (-13.2 ± 15.2 ng/L) compared with ≤1,000 IU/day (-7.6 ± 19.2 ng/L; p = 0.29). 25(OH)D was negatively correlated to PTH (r = -0.49, p < 0.0001). An increase of 25(OH)D ≥ 75 nmol/L resulted in normalised PTH. CONCLUSION: Supplementation with higher vitamin D dosages (2,000-3,000 IU/day) is required to achieve a relevant increase of 25(OH)D and normalisation of PTH.

New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour.

UNLABELLED: Clinical studies are needed to classify rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC) into one of the clinical risk groups. Here we describe two new RET mutations/variants, R770Q and L881V, in patients with MTC and analyzed genotype-phenotype correlations associated with these RET mutations in the gene carriers. FAMILY 1: Calcitonin screening in a 42-year-old female patient with multinodular goiter showed elevated levels. RET mutation analysis revealed a new variant in exon 13 R770Q (CGA>CAA) in the patient. A thyroidectomy with central and lateral node dissection was done. Histology showed MTC in a mixed variance with follicular cancer of 2 cm diameter (T2N0M0). Postoperatively there was no increase of calcitonin after pentagastrin stimulation. The patient is biochemically cured concerning MTC and FTC after radioiodine therapy. In the sister of the index patient surprisingly another, previously not described amino-acid substitution Y791N (TAT><) in the RET protooncogene was found. In the parents the R770Q variant was detected in the mother, the Y791N mutation in the father. Another sister carries the R770Q variant. In all other gene carriers (aged 44-70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed. FAMILY 2: In a 46-year-old female patient with nodular goiter thyroidectomy, central and left lateral lymph node dissection was done because of elevated calcitonin levels. Histology revealed a microcarcinoma with one lymph node metastasis (T1N1(1/8)Mx). RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). The L881V mutation was detected in five other family members. In the first generation stimulated calcitonin levels were in the normal range, therefore thyroidectomy had not yet been performed. In the sons of the index case thyroidectomy revealed CCH in the older one, no MTC in both. In a cousin thyroidectomy is intended because of elevated basal and stimulated calcitonin. CONCLUSION: Our clinical findings indicate that the L881V mutation may be associated with late-onset nonaggressive disease. If the germline RET R770Q variant has a causative role in the pathogenesis of the mixed medullar/follicular derived histology of the thyroid tumour in the index patient of family 1 has to be proven. The recommendations for prophylactic thyroidectomy in these mutations should be individualized depending on basal and stimulated calcitonin levels until more data are available.

[Hyperparathyroidism-jaw tumor syndrome. A hereditary form of primary hyperparathyroidism with parathyroid carcinoma]. / Hyperparathyreoidismus-Kiefertumor-Syndrom. Eine hereditäre Form des primären Hyperparathyreoidismus mit Nebenschilddrüsenkarzinom.

HISTORY: A 29-year-old man presented with a giant cell granuloma of the maxilla that had initially been diagnosed as a "brown tumor" (a bone replacing mass of fibrous tissue containing hemosiderin-pigmented macrophages and multinucleated giant cells). Because serum calcium and PTH were elevated, primary hyperparathyroidism was diagnosed. Three months later a parathyroid carcinoma and a brown tumour in the left femur were identified and removed surgically. Hyperparathyroidism-jaw tumor syndrome was suspected. INVESTIGATIONS AND DIAGNOSIS: Mutation analysis of the DNA revealed heterozygous nonsense mutation R234X in exon 7 of the HRPT2 gene, a tumor suppressor gene responsible for the HPT-JT syndrome. Subsequent studies indicated that the patient had inherited the HRPT2 mutation from his father who was now 68 years old. He showed no symptoms of the hyperparathyroidism-jaw tumor syndrome; serum calcium and PTH were normal. The R234X mutation was also found in the patient}s sister. She had been diagnosed for primary hyperparathyroidism at the age of 32 years. Serum calcium and PTH levels were within the normal range after subtotal parathyroidectomy. FURTHER COURSE: Follow up over 3 years showed no clinical, morphological or biochemical relapse of primary hyperparathyroidism. CONCLUSION: The identification of the R234X mutation is not only important for the patient himself, but also for other family members who could benefit from being identified as mutation carriers. This information can be used for the early detection and removal of malignant parathyroid tumours.

The role of the extracellular calcium-sensing receptor in health and disease.

The calcium-sensing receptor has a key role in calcium homeostasis, it is involved in the regulation of the serum calcium level within minutes via the secretion and action of parathyroid and the excretion of calcium in the kidney in a negative feedback manner. Mutations of the calcium sensing receptor gene leads to inactivating and activating mutations resulting in diseases with hypercalcaemia and hypocalcaemia. The loss of function mutations are associated with familial benign hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease characterised by lifelong mild hypercalcaemia, low urinary calcium excretion, and inappropriate high parathyroid hormone levels, sometimes difficult to distinguish from mild asymptomatic primary hyperparathyroidism. Patients with FHH did not profit from parathyroidectomy, a calcium lowering therapy is not necessary. The gain of function mutations of the calcium-sensing receptor are associated with autosomal dominant hypocalcaemia (ADH), a disease characterised by a generally asymptomatic hypocalcaemia, inappropriately high urinary calcium excretion and normal PTH levels. A therapy to raise the serum calcium concentration has to be done carefully and is only indicated in symptomatic patients, because of enhancement of hypercalciuria with the risk of nephrocalcinosis and nephrolithiasis. Molecular genetic analysis of the calcium sensing receptor gene facilitates the sometimes difficult diagnosis. The development of compounds modulating the calcium sensing receptor function and thereby the section of PTH may become an important role in treatment of diseases of calcium metabolism.

Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype.

OBJECTIVE: In children with RET proto-oncogene mutation, curative treatment of medullary thyroid carcinoma (MTC) is possible by prophylactic thyroidectomy. Recommendations on the timing and extent of thyroidectomy are based upon a model that utilises genotype-phenotype correlations to stratify mutations into three risk groups. DESIGN: We evaluated the long-term outcome (mean follow-up 6.4 years, 15 patients more than 10 years, 26 patients more than 5 years) of operated gene carriers stratified into two risk groups (levels 1 and 2) based on the biological aggressiveness of MTC. RESULTS: In 46 RET gene carriers, prophylactic thyroidectomy was carried out between the ages of 4 and 21 years. Level 1 mutations were harboured by 11 patients (codons 790, 791, 804 and 891). Histology was completely normal in two patients; in seven patients C-cell hyperplasia (CCH) and in two patients T1 tumours were diagnosed. All patients with level 1 mutations were cured. Level 2 mutations were harboured by 35 patients (codons 618, 620, 630 and 634). Histology of these patients showed CCH in 11 patients, T1 tumours in 21, T2 tumour in 1, T3 tumour in 1 and Tx in 1 patient. Histology showed no lymph node involvement. Five patients with level 2 mutations failed to be cured; in two patients, persistence of MTC was diagnosed directly after thyroidectomy and in three during follow-up. In two patients carrying a 634 mutation, other endocrinopathies (hyperparathyroidism and bilateral pheochromocytoma) manifested during follow-up. CONCLUSIONS: If prophylactic thyroidectomy is done at early ages, cure rate is high. Timing and extent of prophylactic thyroidectomy can be modified by individual RET mutation.

[Hereditary medullary thyroid carcinoma--genotype-phenotype characterization]. / Hereditäres medulläres Schilddrüsenkarzinom--Genotyp-Phänotyp Charakterisierung.

BACKGROUND AND OBJECTIVE: Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations of the RET proto-oncogene. A genotype - phenotype correlation has been established, showing clustering of mutations in exons 10 and 11 in classical MEN 2 A syndrome, in exon 16 codon 918 in MEN 2 B syndrome and in exons 13-15 in familial MTC. A line of evidence suggested that the development and the aggressiveness of MTC in the different cancer syndromes is variable. Aim of this study was to compare the phenotype of exon 13-15 mutations with that of exon 11 mutation and possibly draw therapeutical consequences. PATIENTS AND METHODS: We compared the phenotype of 47 patients with mutations in exon 13-15 with 66 patients with exon 11, codon 634 mutation, the classical MEN2A. Patients were further subdivided as index and screening patients. RESULTS: Mean age of 19 index patients with codon 790, 791, 804 or 891 mutation was significant higher compared with 18 index patients with codon 634 mutation (mean age at diagnosis 50+/-12 years; range 30-69 y vs mean age 31+/-9 years; range 17-49 y), tumor stage at operation was favourable (C-cell hyperplasia n = 1; stage I n = 8; II n = 3; III n = 2; IV n = 2; no operation n = 1; no information n = 2 vs stage I n = 3; stage II n = 6; stage III n = 4, no information n =5), cure rate was better (56 % vs 38 %) and the death rate was lower (n = 2 vs n = 4). In screening patients no differences concerning the age, tumor stage, cure and death rate between patients with exons 13-15 and codon 634 mutations were seen. CONCLUSIONS: MTC in patients with exon 790, 791, 804, 891 mutations displayed a late onset and an indolent course compared to codon 634 mutation, this has to be taken into account when recommending timing and extent of prophylactic surgery.

Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas.

BACKGROUND: This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). METHODS: Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. RESULTS: Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P = .011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P = .005). CONCLUSIONS: Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC.

Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential.

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in >90% of MTCs but in a high percentage of small cell lung cancers and potentially a variety of gastrointestinal adenocarcinomas. In a pilot study, we have demonstrated the feasibility of radiolabeled gastrin-I to target CCK-B receptor-expressing tissues in vivo in animals and patients (T. M. Behr et al., Eur. J. Nucl. Med., 25: 424-430, 1998). The aim of the present study was to systematically optimize, in a preclinical model, suitable radioligands for targeting CCK-B receptors in vivo. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK-receptor binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the Iodogen or Bolton-Hunter procedures. The peptides tested were members of the gastrin- or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety (occurring in native or sulfated form). Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing s.c. human MTC xenografts. Diethylene-triamine-pentaacetate derivatives of suitable peptides were synthesized, evaluated, and labeled with (111)In. All members of the CCK or gastrin family were stable in serum (with t(1/2)s of several hours at 37 degrees C); nevertheless, the stability of those peptides was highest that bore the NH2-terminal pGlu residues (e.g., big gastrin, gastrin-I, caerulein, and others) or D-amino acids. In accordance to their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues (e.g., the stomach). Sulfated CCK derivatives performed significantly better but additionally displayed a high uptake in normal, CCK-A receptor-expressing tissues (such as the liver/gallbladder, pancreas, and bowel). Best tumor uptake and tumor:nontumor ratios were obtained with members of the gastrin family, probably because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC bearing animals showed significant antitumor efficacy as compared with untreated controls. (111)In-Labeled diethylene-triamine-pentaacetate derivatives of minigastrin showed excellent targeting of CCK-B receptor-expressing tissues in animals and a normal human volunteer. These data suggest that CCK/gastrin analogues may be a useful new class of receptor binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, and hence, lower accretion in normal CCK-A receptor-expressing organs. Further preclinical as well as clinical studies are ongoing.

Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience.

When mutations of the RETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i. e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age

Prophylactic thyroidectomy in MEN IIA: does the calcitonin level correlate with tumor spread?

BACKGROUND: The fate of patients with multiple endocrine neoplasia of type II A (MEN II A) is determined by medullary thyroid carcinoma, which occurs in all cases. This has led to the therapeutic concept of prophylactic thyroidectomy in affected family members with the goal of removing the thyroid before the manifestation of carcinoma. We investigated a prophylactically thyroidectomized MEN II A population to determine whether the highly specific and sensitive tumor marker calcitonin correlates with tumor spread. PATIENTS AND METHODS: Fifteen patients with MEN II A (aged 4-24 years) who had undergone prophylactic thyroidectomy since 1990 were included in the study. Baseline and pentagastrin-stimulated calcitonin levels were preoperatively determined in all cases. The indication for surgery was established on the basis of pathologic calcitonin levels in the first seven patients and on the basis of detected RET proto-oncogene mutation in the other eight patients. Bilateral central lymphadenectomy was performed in all patients in addition to thyroidectomy. RESULTS: Histology demonstrated C-cell hyperplasia in five patients (aged 4-13 years), unilateral medullary microcarcinoma in six (aged 9-17 years) and a bilateral medullary microcarcinoma in three cases (aged 17-24 years). One 9-year-old boy with bilateral microcarcinoma already had a lymph node metastasis. The mean baseline calcitonin level correlated with the histologic findings (r=0.71, P=0.003) but there was no correlation between pentagastrin-stimulated calcitonin levels and histology (r=0.21, P=0.47). CONCLUSION: In MEN II A patients undergoing prophylactic thyroidectomy, baseline but not stimulated calcitonin levels already correlate with the histologic tumor stage at the stage of clinically occult C-cell hyperplasia or medullary microcarcinoma. However, biochemical screening cannot reliably discriminate the transition from C-cell hyperplasia to invasive microcarcinoma. Individuals with MEN IIA should therefore undergo early prophylactic thyroidectomy once the diagnosis is confirmed by molecular genetic testing.

A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.

One hundred and eighty-one families with multiple endocrine neoplasia type 2A (MEN-2A) or familial medullary thyroid carcinoma (FMTC) have been investigated for mutations in the ret protooncogene in Germany. In 8 families with FMTC or MEN-2A, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11 of the ret protooncogene. DNA sequencing of additional exons (no. 13-15) revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors. Two different mutations in codon 790 (TTG-->TTT, TTG-->TTC; Leu790Phe) and one mutation in codon 791 (TAT-->TTT; Tyr791Phe) created a phenylalanine residue. We conclude that codons 790 and 791 of the ret protooncogene represent a new hot spot for FMTC/MEN-2A causing mutations. With the discovery of these considerably common mutations in codons 790 and 791 and the identification of some rare mutations, 100% of the German FMTC/MEN-2A families could be characterized by a mutation in the ret protooncogene.

[Mutations of ret-proto-oncogene in thyroid medullary carcinoma]. / Mutationen des ret-Protoonkogens bei medullärem Schilddrüsenkarzinom.

OBJECTIVE: To determine the importance of the molecular-genetic demonstration of germ-line mutation in the ret protooncogene for therapeutic measures in sporadic and hereditary medullary thyroid carcinoma (MTC). PATIENTS AND METHODS: Several molecular-genetic tests were performed on DNA of 35 families with hereditary and 81 patients with the sporadic form of MTC (isolation of genomic DNA; PCR amplification; DNA sequencing: demonstration of mutation in codon 918 with restriction enzyme FOK 1). RESULTS: A disease risk was demonstrated in 178 individuals among the 35 families, 159 of whom were investigated by molecular-genetic tests: 84 family members were found to be gene carriers. Germ-line mutation had already been suspected on clinical grounds in 76% of the carriers, 24% being discovered in a presymptomatic stage. Six children among the latter were treated prophylactically by thyroidectomy, histological evidence of C-cell hyperplasia being found in all of them, microcarcinomas in three of the older children. There were four patients among the non-carriers on whom thyroidectomy had been performed previously because of a false-positive pentagastrin-test; but germ-line mutation was now excluded. In one family, with familial MTC in two brothers, no mutation in ret-proto-oncogene has been demonstrated. The members of this family must now, as used to be routine, undergo a pentagastrin-test. Three of the 81 patients with "sporadic" MTC had a germ-line mutation, presumably a new one. CONCLUSION: Molecular-genetic tests have further improved the management of families with hereditary MTC and they thus take first place among essential diagnostic procedures. The diagnosis of sporadic MTC can be confirmed by excluding germ-line mutation in the ret-proto-oncogene.