Cardiac Magnetic Resonance Reveals Incipient Cardiomyopathy Traits in Adult Patients With Phenylketonuria.

Background Phenylketonuria is the most common inborn error of amino acid metabolism, where oxidative stress and collateral metabolic abnormalities are likely to cause cardiac structural and functional modifications. We aim herein to characterize the cardiac phenotype of adult subjects with phenylketonuria using advanced cardiac imaging. Methods and Results Thirty-nine adult patients with phenylketonuria (age, 30.5±8.7 years; 10-year mean phenylalanine concentration, 924±330 µmol/L) and 39 age- and sex-matched healthy controls were investigated. Participants underwent a comprehensive cardiac magnetic resonance and echocardiography examination. Ten-year mean plasma levels of phenylalanine and tyrosine were used to quantify disease activity and adherence to treatment. Patients with phenylketonuria had thinner left ventricular walls (septal end-diastolic thickness, 7.0±17 versus 8.8±1.7 mm [P<0.001]; lateral thickness, 6.1±1.4 versus 6.8±1.2 mm [P=0.004]), more dilated left ventricular cavity (end-diastolic volume, 87±14 versus 80±14 mL/m2 [P=0.0178]; end-systolic volume, 36±9 versus 29±8 mL/m2 [P<0.001]), lower ejection fraction (59±6% versus 64±6% [P<0.001]), reduced systolic deformation (global circumferential strain, -29.9±4.2 % versus -32.2±5.0 % [P=0.027]), and lower left ventricular mass (38.2±7.9 versus 47.8±11.0 g/m2 [P<0.001]). T1 native values were decreased (936±53 versus 996±26 ms [P<0.001]), with particular low values in patients with phenylalanine >1200 µmol/L (909±48 ms). Both mean phenylalanine (P=0.013) and tyrosine (P=0.035) levels were independently correlated with T1; and in a multiple regression model, higher phenylalanine levels and higher left ventricular mass associate with lower T1. Conclusions Cardiac phenotype of adult patients with phenylketonuria reveals some traits of an early-stage cardiomyopathy. Regular cardiology follow-up, tighter therapeutic control, and prophylaxis of cardiovascular risk factors, in particular dyslipidemia, are recommended.

Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). RESULTS: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. CONCLUSION: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

GnRH antagonist treatment of malignant adrenocortical tumors.

Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse Cα1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin α promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

Personality Traits and Physical Complaints in Patients With Acromegaly: A Cross Sectional Multi-Center Study With Analysis of Influencing Factors.

Objective: Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities. Design: Cross sectional, multicentric. Methods: 129 patients (M/W 65/64, 58.3 ± 12.7 years, 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented. Results: Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable. Conclusions: We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity.

Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome.

CONTEXT: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). OBJECTIVE: To determine the role of LHCGR in transient, pregnancy-induced CS. DESIGN SETTING PATIENT AND INTERVENTION: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. MAIN OUTCOME MEASURES AND RESULTS: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient's adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. CONCLUSION: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus.

Pregnancy in patients with mucopolysaccharidosis: a case series.

The mucopolysaccharidoses (MPS disorders) are rare inherited diseases associated with multi-organ accumulation of glycosaminoglycans, leading to musculoskeletal, respiratory, cardiac, neurological, ophthalmological, otolaryngological, and gastrointestinal abnormalities. As a result of improvements in diagnosis, multi-disciplinary care, and therapies such as enzyme replacement therapy and hematopoietic stem cell transplantation, an increasing number of patients with MPS are reaching adulthood and are involved in family planning. Data on fertility and pregnancy outcome in MPS is sparse and comprises primarily isolated case reports. To address this evidence gap, we present a case series on fertility and pregnancy in eight mothers and five fathers with MPS. This case series demonstrates that women with MPS have high-risk pregnancies and deliveries secondary to their underlying disease. However, with appropriate pre-conceptual multi-disciplinary evaluation, optimization and discussion regarding potential risks, combined with regular multi-disciplinary maternal and fetal surveillance in a tertiary center, the outcome of most pregnancies in this case series seems to be favorable with all babies developing normally. Partners of fathers with MPS had uncomplicated pregnancies and deliveries. All children were healthy, with normal growth and development.

Potential role of (68)Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease.

PURPOSE: Neuroendocrine tumours of the pancreas (pNET) are observed in 8 - 17 % of patients with von Hippel-Lindau disease (vHLD), and 11 - 20 % of these patients develop metastatic disease. MRI and CT have a very high resolution; however, their sensitivity and specificity for the detection of pNET amongst cystic lesions in the pancreas of vHLD patients are generally considered insufficient. In contrast, (68)Ga-DOTATOC PET/CT demonstrates a high sensitivity for the diagnosis and staging of neuroendocrine tumours. In this study we investigated the potential role of (68)Ga-DOTATOC PET/CT in screening of patients with vHLD. METHOD: (68)Ga-DOTATOC PET/three-phase contrast-enhanced CT was performed according to guidelines in all consecutive vHLD patients between January 2012 and November 2015. All patients underwent additional MRI imaging of the abdomen, spine, and head. Chromogranin A (CgA) was determined at the time of the PET/CT examination. A lesion seen on (68)Ga-DOTATOC PET in the pancreas was defined as positive if the uptake was visually higher than in the surrounding tissues. Lesions were quantified using maximum SUV. RESULTS: Overall, 20 patients (8 men, 12 women; mean age 44.7 ± 11.1 years) were prospectively examined. Genetically, 12 patients had type 1 vHLD and 8 had type 2 vHLD. (68)Ga-DOTATOC PET/CT detected more pNET than morphological imaging (CT or MRI): 11 patients (55 %; 8 type 1, 3 type 2) vs. 9 patients (45 %; 6 type 1, 3 type 2). The concentration of CgA was mildly elevated in 2 of 11 patients with pNET. The mean SUVmax of the pancreatic lesions was 18.9 ± 21.9 (range 5.0 - 65.6). Four patients (36.4 %) had multiple pNETs. The mean size of the lesions on CT and/or MRI was 10.4 ± 8.3 mm (range 4 - 38 mm), and 41.1 % were larger than 10 mm. In addition, somatostatin receptor-positive cerebellar and spinal haemangioblastomas were detected in three patients (SUVmax 2.1 - 10.1). One patient presented with a solitary somatostatin receptor-positive lymph node metastasis. pNETs were observed more frequently in vHLD type 1 than type 2 (66.7 % vs. 37.5 %, p = 0.089). None of the patients showed progressive disease during follow-up. CONCLUSION: In this study, (68)Ga-DOTATOC PET detected pNETs in a higher proportion of patients with vHLD than found in previous studies with (111)In-octreoscan, the imaging method recommended by the NCCN. We therefore suggest (68)Ga-DOTATOC PET/CT as the more sensible screening tool.

Role of (68)Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study.

PURPOSE: To explore the role of (68)Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia. METHODS: We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases. RESULTS: Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up. CONCLUSION: This explorative study suggests that SR PET in combination with CT may play a significant role in the detection and management of patients with pancreatogenic hyperinsulinaemic hypoglycaemia. A large proportion of insulinomas express SSR2a, and a larger study is needed to fully assess the diagnostic accuracy of SR PET in patients with insulinoma and nesidioblastosis compared with current localizing studies used in clinical practice.

Expert Opinions on Managing Fertility and Pregnancy in Patients With Mucopolysaccharidosis

Abstract The mucopolysaccharidosis (MPS) disorders are rare genetic diseases caused by deficiencies in lysosomal enzymes involved in the degradation of glycosaminoglycans, leading to pulmonary, cardiac and neurological dysfunctions, skeletal anomalies, impaired vision, and/or hearing and shortened life spans. Whereas in the past, few individuals with MPS reached adulthood, better diagnosis, multidisciplinary care, and new therapies have led to an increasing number of adult patients with MPS. Therefore, fertility and pregnancy questions in this patient population are becoming more important. Management of fertility issues and pregnancy in patients with MPS is challenging due to the lack of documented cases and a dearth in the literature on this topic. This review presents multidisciplinary expert opinions on managing fertility and pregnancy based on case studies and clinical experience presented at a meeting of MPS specialists held in Berlin, Germany, in April 2015. An overview of the existing literature on this subject is also included.

Inflammatory bowel disease (IBD)-like disease in a case of a 33-year old man with glycogenosis 1b.

BACKGROUND: Inflammatory bowel disease (IBD)-like conditions in glycogen storage disease (GSD) type Ib have been predominantly described in children. Signs and symptoms of GSD type Ib are hypoglycemia, pancytopenia and hepatosplenomegaly. Based on few published cases, there is evidence that granulocyte-colony stimulating factor (G-CSF) in patients with glycogenosis-related pancytopenia might ameliorate the IBD-like disease through leukocyte increase. CASE PRESENTATION: Here we firstly describe a case of an adult 33-year-old Caucasian male patient with GSD type Ib accompanied with IBD-like disease with persistent pancytopenia despite moderate-dose G-CSF treatment. Recent vomiting and abdominal discomfort were due to a high-grade stenosis in the transverse colon. A dose increase of the G-CSF successfully normalized his leukocyte count. However, the stenosis worsened and surgical therapy was needed. CONCLUSION: We suggest that symptomatic patients with GSD type Ib should undergo endoscopic examination in order to detect IBD-like disease and to initiate early treatment.

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study.

CONTEXT: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. OBJECTIVE: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. DESIGN: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. INTERVENTION: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. RESULTS: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. CONCLUSIONS: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry.

Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors.

Chronic kidney disease in adolescent and adult patients with phenylketonuria.

OBJECTIVES: A lifelong phenylalanine-restricted diet with supplementation of a phenylalanine-free amino acid formula is recommended in patients with phenylketonuria (PKU). The effect of a long-term PKU diet on renal function and blood pressure has not been investigated yet. DESIGN: We analyzed renal function in 67 patients with PKU, aged 15-43 years, by measuring glomerular filtration rate (GFR) and effective renal plasma flow by isotope clearance ((51)Cr-EDTA, (123)J-Hippuran), estimated GFR, blood retention parameters, urinary protein and electrolyte excretion. Renal ultrasound and 24 h ambulatory blood pressure monitoring were performed additionally. Patients were divided into three groups according to their: 1) current diet (CD), i.e., daily protein intake: ICD <0.8 g/kg, IICD 0.8-1.04 g/kg, IIICD >1.04 g/kg; 2) life-long diet time (LDT), i.e., cumulative years of life in which daily protein intake exceeded dietary recommendations: ILDT <15 years, IILDT 15-19 years, IIILDT >19 years. RESULTS: GFR was decreased in 19 % of the patients. With increasing protein intake, GFR decreased significantly (ICD 111 ml/min; IICD 105 ml/min; IIICD 99 ml/min. ILDT 112 ml/min; IILDT 103 ml/min; IIILDT 99 ml/min). Proteinuria was detected in 31 %, microalbuminuria in 7 %, and hypercalciuria in 23 % of the patients. 23 % of the patients had arterial hypertension, and 41 % revealed a nocturnal non-dipping status. CONCLUSIONS: In patients with PKU on a lifelong diet we could detect impaired renal function in 19 %, proteinuria in 31 %, and arterial hypertension in 23 %. Thus, chronic kidney disease may develop in PKU patients, and routine renal function tests should be performed during long-term follow-up.

Diagnosis and Treatment of Gastrinomas in Multiple Endocrine Neoplasia Type 1 (MEN-1).

Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease. It is associated with a broad range of endocrine tumours, most frequently arising in the parathyroid glands, the pituitary and the pancreas. Most neuroendocrine tumours will be diagnosed in the pancreas as non-functioning neuroendocrine tumours or insulinomas. Forty-two percent of the patients will develop a gastrin-secreting neuroendocrine tumour, a gastrinoma. Gastrinomas in MEN-1 tend to be small, multiple and preferentially located in the duodenum. This paper will focus on the specific characteristics of gastrinomas in the setting of MEN-1 compared to sporadic gastrinomas. The developments in understanding the tumorigenesis of these tumours and the consequences for diagnosis and therapy will be discussed.

Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia.

BACKGROUND: Thyroid dysfunction is a well-known adverse effect of first-generation tyrosine kinase inhibitors (TKIs), like sunitinib. The aim of this study was to investigate the effect of second-generation TKIs on thyroid function. METHODS: We retrospectively assessed the effect of the first-generation TKI imatinib and the second-generation TKI nilotinib and dasatinib on thyroid function tests in 73 Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia patients. RESULTS: Overall, 33 of 73 (45%) had one or more thyroid function test abnormalities during follow-up. Hypothyroidism or hyperthyroidism were found in 18 of 73 (25%) and 21 of 73 (29%) cases after a median of 6 and 22 weeks, respectively. In most patients (29 of 39, 74%) thyroid dysfunction was transient without clinical symptoms. Therapy of hypo-/hyperthyroidism was required in three patients. Thyroid dysfunction never resulted in the discontinuation of TKI therapy. Under treatment with imatinib, nilotinib, and dasatinib, thyroid abnormalities were detected in 25%, 55%, and 70%, respectively. Four of 55 patients (7%) treated with nilotinib had evidence for an autoimmune thyroiditis (antibody positive in 3 of 4 patients) with an episode of hyperthyroidism preceding hypothyroidism. CONCLUSIONS: Thyroid dysfunction is a common adverse event with second-generation TKI therapy in patients with Ph-positive chronic myeloid leukemia. Although the mechanism is still unclear, the high frequency of thyroid abnormalities, including autoimmune thyroiditis, warrants regular and long-term monitoring of thyroid function in these patients.

Multimodal management of neuroendocrine liver metastases.

BACKGROUND: The incidence of neuroendocrine tumours (NET) has increased over the past three decades. Hepatic metastases which occur in up to 75% of NET patients significantly worsen their prognosis. New imaging techniques with increasing sensitivity enabling tumour detection at an early stage have been developed. The treatment encompasses a panel of surgical and non-surgical modalities. METHODS: This article reviews the published literature related to management of hepatic neuroendocrine metastases. RESULTS: Abdominal computer tomography, magnetic resonance tomography and somatostatin receptor scintigraphy are widely accepted imaging modalities. Hepatic resection is the only potentially curative treatment. Liver transplantation is justified in highly selected patients. Liver-directed interventional techniques and locally ablative measures offer effective palliation. Promising novel therapeutic options offering targeted approaches are under evaluation. CONCLUSIONS: The treatment of neuroendocrine liver metastases still needs to be standardized. Management in centres of expertise should be strongly encouraged in order to enable a multidisciplinary approach and personalized treatment. Development of molecular prognostic factors to select treatment according to patient risk should be attempted.