Defining disease status in gastroenteropancreatic neuroendocrine tumors: Choi-criteria or RECIST?

PURPOSE: Adequate monitoring of changes in tumor load is fundamental for the assessment of the course of disease and response to treatment. There is an ongoing debate on the utility of RECIST v1.1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: In this retrospective real-life cohort study, Choi-criteria were compared with RECIST v1.1. The agreement between both criteria and the association with survival endpoints were evaluated. RESULTS: Seventy-five patients were included with a median follow-up of 35 months (range 8-53). Median progression-free survival (mPFS) according to RECIST v1.1 was 15 months (range 2-50) compared to 14 months (range 2-50) in Choi. According to RECIST, 33 (44%) patients were classified as having stable disease (SD), 40 (53%) as progressive disease (PD) and two (3%) patients as partial response (PR), compared to 9 (12%) patients classified as SD, 50 (67%) as PD and 16 (21%) as PR according to Choi-criteria. Overall concordance between the criteria was moderate (Cohen's Kappa = 0.408, p < 0.001) and agreement varied between 57 and 69% at each consecutive scan (p < 0.001). Survival analysis showed significant differences in overall survival (OS) for RECIST v1.1 categories PD and non-PD (log-rank p = 0.02), however, in Choi no significant differences in OS were found (p = 0.27). CONCLUSION: RECIST v1.1 had a better clinical utility and prognostic value compared to Choi-criteria. Still, RECIST were also not sufficient to adequately predict OS. This outlines the need for new tools that provides accurate information on the disease course and treatment response to support precise prognostication in patients with GEP-NETs.

A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility.

BACKGROUND: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS: Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification (chi-square = 180, OR = 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%. CONCLUSION: NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.

Reducing failures in daily medical practice: Healthcare failure mode and effect analysis combined with computer simulation.

This study proposes a risk analysis approach for complex healthcare processes that combines qualitative and quantitative methods to improve patient safety. We combine Healthcare Failure Mode and Effect Analysis with Computer Simulation (HFMEA-CS), to overcome widely recognised HFMEA drawbacks regarding the reproducibility and validity of the outcomes due to human interpretation, and show the application of this methodology in a complex healthcare setting. HFMEA-CS is applied to analyse drug adherence performance in the surgical admission to discharge process of pheochromocytoma patients. The multidisciplinary team identified and scored the failure modes, and the simulation model supported in prioritisation of failure modes, uncovered dependencies between failure modes, and predicted the impact of measures on system behaviour. The results show that drug adherence, defined as the percentage of required drugs received at the right time, can be significantly improved with 12%, to reach a drug adherence of 99%. We conclude that HFMEA-CS is both a viable and effective risk analysis approach, combining strengths of expert opinion and quantitative analysis, for analysing human-system interactions in socio-technical systems. Practitioner summary: We propose combining Healthcare Failure Mode and Effects Analysis with Computer Simulation (HFMEA-CS) for prospective risk analysis of complex and potentially harmful processes, to prevent critical incidents from occurring. HFMEA-CS combines expert opinions with quantitative analyses, such that the results are more reliable, reproducible, and fitting for complex healthcare settings.

Surgery for multiple endocrine neoplasia type 1-related insulinoma: long-term outcomes in a large international cohort.

BACKGROUND: Insulinomas are found in 10-15 per cent of patients with multiple endocrine neoplasia type 1 (MEN1) and lead to life-threatening hypoglycaemia. Surgical outcome and the optimal surgical strategy for MEN1-related insulinoma are unknown. METHODS: Patients with MEN1-related insulinomas were identified in 46 centres in Europe and North America between 1990 and 2016. Insulinomas were considered localized if the lesion was in the pancreatic head or body/tail. Patients with pancreatic neuroendocrine tumours throughout the pancreas were suspected of having multifocal insulinoma. The primary outcome was postoperative hypoglycaemia, defined as persistent hypoglycaemia, or recurrent hypoglycaemia caused by a new insulinoma or insulin-producing liver metastases. Hypoglycaemia-free survival was estimated by the Kaplan-Meier method. RESULTS: Ninety-six patients underwent resection for MEN1-related insulinoma. Sixty-three and 33 patients had localized and multifocal insulinomas respectively. After a median follow-up of 8 (range 1-22) years, one patient (1 per cent) had persistent disease and six (6 per cent) had developed recurrent disease, of whom four had a new insulinoma. The 10-year hypoglycaemia-free survival rate was 91 (95 per cent c.i. 80 to 96) per cent. Of those with localized disease, 46 patients underwent pancreatic resection and 17 enucleation. One of these patients had persistent disease and one developed recurrent insulinoma. Among patients with multifocal disease, three developed new insulinomas and two developed insulin-producing liver metastases. CONCLUSION: Surgery for MEN1-related insulinoma is more successful than previously thought.

ANTECEDENTES: Del 10% al 15% de los pacientes con MEN1 presentan insulinomas que pueden desencadenar una hipoglucemia potencialmente mortal. Se desconoce el resultado de la cirugía y la estrategia quirúrgica óptima para el tratamiento del insulinoma relacionado con el MEN1. MÉTODOS: Se identificaron los pacientes con insulinomas relacionados con el MEN1 en 46 centros de Europa y América del Norte entre 1990 y 2016. Los insulinomas se consideraron localizados si el tumor se localizaba en la cabeza o en el cuerpo/cola del páncreas. Se sospechó la existencia de un insulinoma multifocal en los pacientes con tumores neuroendocrinos pancreáticos (pNETs). El objetivo primario de este estudio fue evaluar la hipoglucemia postoperatoria, definida como hipoglucemia persistente, hipoglucemia recidivante causada por un nuevo insulinoma o debida a metástasis hepáticas productoras de insulina. La supervivencia libre de hipoglucemia se estimó mediante el método de Kaplan-Meier. RESULTADOS: A 96 se les realizó una resección por insulinoma en el contexto del MEN1. Un total de 63 y 33 pacientes presentaron insulinomas localizados y multifocales, respectivamente. Después de una mediana de seguimiento de 7,8 años (rango 1-22), un paciente (1%) tenía enfermedad persistente y seis pacientes (6%) presentaron enfermedad recidivante, de los cuales cuatro desarrollaron un nuevo insulinoma. La supervivencia libre de hipoglucemia fue del 91% a los 10 años (i.c. del 95%, 80%-96%). De los pacientes con enfermedad localizada, 46 fueron sometidos a resección pancreática y 17 pacientes a enucleación. Entre éstos, un paciente tenía enfermedad persistente y uno desarrolló insulinoma recidivante, respectivamente. De los pacientes con enfermedad multifocal, tres desarrollaron nuevos insulinomas y dos desarrollaron metástasis hepáticas productoras de insulina. CONCLUSIÓN: La cirugía para el insulinoma en el contexto del MEN1 es más exitosa de lo que parecía en principio.

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature.

Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

[Regional healthcare labels: differences in care needs and psychosocial functioning]. / Regionale zorgvignetten: verschillen in zorgbehoeften en psychosociaal functioneren.

BACKGROUND: Severe mental illnesses (SMI) are associated with high mental healthcare and other healthcare costs. In 2012, mental healthcare labels were developed to create more transparency between insurance companies, municipalities, and mental healthcare. The labels are based on care intensity, and should provide a regional overview of the present groups of patients with SMI.
AIM: Explore the functionality and validity of the used labels in relation to needs for care and psychosocial functioning.
METHOD: The ROM data (needs for care, functioning) from 706 patients were tested per label by Chi-square tests and ANOVAs. For two high complex labels (alarming care avoiders and persons with safety risks), repeated measures ANOVAs and McNemar tests were used to analyse changes in functioning and needs over time.
RESULTS: To a limited extent, the labels were distinctive in care needs and functioning. The most restrictions in functioning and (unfulfilled) needs were present in the labels 'alarming care avoiders' and 'avoiding danger'. These findings were stable over time.
CONCLUSION: The labels are not sufficiently distinctive. To enhance regional care planning, it is desirable to combine existing information on healthcare labels with information on care needs and functioning. KEY WORDS functioning, mental healthcare labels, needs for care, routine outcome monitoring, severe mental illness.

Molecular prognostic factors in small-intestinal neuroendocrine tumours.

BACKGROUND: Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis. AIM: We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs. METHOD: A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019. RESULTS: The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44-100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs. CONCLUSION: SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.

Influence of lanreotide on uptake of 68Ga-DOTATATE in patients with neuroendocrine tumours: a prospective intra-patient evaluation.

INTRODUCTION: Somatostatin receptor imaging with PET is the standard of care for patients with a neuroendocrine tumour (NET). Since therapy and imaging with somatostatin analogues utilize the same receptor, current guidelines recommend withdrawing long-acting somatostatin analogues for 3-4 weeks prior to somatostatin receptor PET imaging. The aim of this study is to prospectively assess the effect of lanreotide use on the uptake of 68Ga-DOTATATE intra-individually 1 day prior to and 1 day post injection of lanreotide. METHODS: Thirty-four patients with metastatic and/or unresectable NET and currently on lanreotide therapy for at least 4 months were included in the study. A 68Ga-DOTATATE PET/CT scan was performed on the day before and the day after lanreotide injection. In each patient 68Ga-DOTATATE uptake (SUVmax, mean, peak) was assessed in both tumour lesions and normal tissue. All scans were assessed by two blinded nuclear medicine physicians for visual analysis. Paired T-tests were performed to determine the differences between the scans. RESULTS: Of the 34 patients included, 31 were available for analyses in which 190 tumour lesions were measured. Uptake of 68Ga-DOTATATE in tumour lesions was increased significantly after lanreotide, but decreased significantly in the liver, spleen, and thyroid gland resulting in a higher tumour-to-liver ratio. CONCLUSION: Lanreotide injection prior to 68Ga-DOTATATE PET/CT does not result in decreased tumour uptake. In contrast, tumour uptake was increased, whereas the uptake in normal organs is decreased, leading to an increased tumour-to-liver ratio. However, these differences were small and not deemed clinically relevant. These results strongly suggest that discontinuation of lanreotide injections in the weeks prior to 68Ga-DOTATATE PET examinations is unnecessary and does not compromise nuclear medicine imaging results.

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.

OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors.

PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Carcinoid heart disease: a guide for screening and timing of surgical intervention.

The cardiac manifestations of a neuroendocrine tumour are referred to as carcinoid heart disease (CaHD) and are associated with a poor prognosis. Surgical intervention is the only proven therapeutic option and may prolong survival and quality of life. No consensus has been reached internationally with regard to screening for CaHD and the optimal timing for surgery. Although limited evidence is available on this matter, a trend towards early surgery and subsequent reduced mortality has been observed. In this review we provide an overview of the current understanding and propose a protocol to guide cardiologists in the screening for CaHD and the timing of referral to a specialised surgical centre.

[Cushing's syndrome in a manic patient with a long-standing bipolar disorder: cause or coincidence?]. / Het syndroom van Cushing bij een manische patiënte met een lang bestaande bipolaire stoornis: oorzaak of bijvangst?

Hypercortisolism is associated with mood disorders such as depression and bipolar disorder. A 75-year-old female patient who had been diagnosed with bipolar disorder forty years ago was admitted to our hospital with a severe, therapy-resistant mania. Careful diagnostic considerations, resulted in the patient being diagnosed with Cushing's syndrome. Treatment with metyrapone led to a swift improvement of the patient's symptoms. Could Cushing's syndrome underlie this patient's psychiatric history? Or are two co-existing, intertwining causes responsible for the psychiatric symptoms? The case illustrates that even if a patient has a long history of psychiatric problems that have been plausibly diagnosed over time, clinicians and psychiatrists should always consider the possibility that there may be an underlying somatic cause for the patient's psychiatric symptoms.

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis.

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature.

Based on the current medical literature, the worldwide incidence of neuroendocrine tumours (NETs) seems to have increased; however, a systematic literature overview is lacking. This study aimed to collect all available data on the incidence of gastroenteropancreatic (GEP)-NETs and characteristics of population to establish their epidemiology. A sensitive MEDLINE search was carried out. The papers were selected via a cascade process that restricted the initial pool of 7991 articles to 33, using predefined inclusion and exclusion criteria. Original articles evaluating the incidence of sporadic GEP-NETs in regional, institutional and national registries were considered. The majority of data originated from the US National Cancer Institute Surveillance, Epidemiology and End Results database and from national cancer registries in Western Europe. Generally, because of the retrospective nature of existing databases the outcomes of studies might be biased, which hinders the drawing of firm conclusions. The age-adjusted incidence of GEP-NETs has increased steadily over the past four decades (1973-2007), increasing 3.65-fold in the USA and 3.8- to 4.8-fold in the UK. Incidence has changed variably from one anatomical site to another. The greatest increase in incidence occurred for gastric and rectal NETs, while the smallest increase occurred for small intestine NETs. There were gender and racial differences, which differed site by site and, in some cases, changed over time. The incidence rates (IRs) of GEP-NETs have increased significantly in the last 40 years. Data are only available from North America, Western Europe and Japan. A site-by-site analysis revealed that the IRs of some NETs increased more than those of others.

Radioactive iodine in the treatment of medullary thyroid carcinoma: a controlled multicenter study.

OBJECTIVE: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients. DESIGN: Retrospective multicenter study in eight University Medical Centers in The Netherlands. METHODS: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease. RESULTS: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification. CONCLUSIONS: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

The value of miRNA in diagnosing thyroid cancer: a systematic review.

Thyroid cancer is the most common endocrine neoplasm accounting for approximately 1,7% of total cancer diagnoses. The gold standard for evaluation of thyroid nodules is cytology from fine needle aspiration. In 30% of biopsies there is no conclusive diagnosis and patients undergo a diagnostic hemithyroidectomy. Somatic mutations occur frequently in thyroid cancer, the value of testing FNA biopsies on different mutation is analyzed, it improves accuracy, but their sensitivity is low. Another class of molecules with potential diagnostic value are miRNAs (miRNA, miR). MiRNAs function as gene regulators thereby controlling many cellular processes including cell growth, differentiation, proliferation, and apoptosis. Several studies have analyzed the expression of miRNAs in thyroid cancer, either by performing microarray analyses or validating a set of miRNAs. Recent reports focused on the diagnostic value of miRNAs in indeterminate FNA biopsies. In this systematic review we will provide an overview of all miRNAs found to be up- or downregulated in the different types of thyroid carcinomas, give an overview of the value of validated sets of microRNAs or single microRNAs in distinguishing malignant from benign lesions and conclude with a clinical view on future study strategies.

Life-threatening complications of ibogaine: three case reports.

Ibogaine is a naturally occurring psychoactive alkaloid extracted from the roots of the Tabernanthe iboga plant, which in alternative medicine is used to treat drug dependency. However, this upcoming, online advocated therapy can be dangerous due to its potentially lethal adverse effects. We present three cases in which toxic side effects were noted. We used the Naranjo scale to estimate the probability of a causal relationship between these effects and ibogaine. Findings in these three cases are suggestive of a causal relationship between the use of ibogaine and serious respiratory and cardiac problems (including lengthening of the QT interval). In our opinion it is of great importance that clinicians are aware of these potentially serious side effects and realise that widespread online marketing practices will give many more people access to ibogaine.

Reduced growth hormone secretion after cranial irradiation contributes to neurocognitive dysfunction.

The objective of this study was to investigate the relation between growth hormone (GH) and attentional electro-cortical responses to task-relevant stimuli (N2b), target detections, speed of responding, P300 latencies, and performance on neuropsychological tests in 19 patients who received external beam radiation therapy for brain tumors in adulthood. In addition, we studied the association between IGF-I and activation of the motor cortex responses (lateralized readiness potential, LRP). Brain function was assessed using event-related potentials (ERPs) during a go/no go selective-attention task, including N2b, P300 and selective motor preparation as reflected in the LRP. Correlations were calculated between peak GH levels after a standardized growth hormone-releasing hormone (GHRH)-arginine test, plasma IGF-I, and cognitive functions. We separately studied four patients who were diagnosed with GHD according to the GHRH-arginine test. Performance on WAIS digit span backward and the Rey-Osterrieth complex figure test correlated positively with GH peak. GHD patients performed worse than non-GHD patients on Stroop interference, trail making B/A attentional shifting and Rey-Osterrieth complex figure test. At trend-level significance, trails A performance was better in patients with lower GH levels and higher radiation doses, and GHD participants detected fewer targets in the go/no go selective attention task. N2b was not significantly altered by GH status. Furthermore, plasma IGF-I was positively correlated with the sum of digit span forward and backward. No relations with P300 were observed. In this study only 21% (4/19) of the patients who received fractionated radiotherapy for a non-endocrine brain tumor were diagnosed with GHD. GHD in these patients was associated with impaired interference control, attentional shifting, and visual long-term memory. The results for interference control and attentional shifting suggest an additional effect of the radiation history.