The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now ...routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors.
Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (
= 198 cases).
NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community.
This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.
Carcinoid heart disease (CHD) is a serious cardiac condition which is caused by elevated serotonin in the systemic circulation, secreted by neuroendocrine tumours (NET). It mostly affects the ...right‐sided heart valves, where it causes fibrotic disturbances and is associated with worse survival. In this study, we describe a large cohort of patients with CHD and provide an insight into their survival over the past decades. All consecutive patients with a serotonin producing NET and CHD referred to the Netherlands Cancer Institute that presented with CHD or developed CHD during their follow up time were included from 1984 until 2021. Patients were divided into three time periods: 1984–2000, 2000–2010 and 2010–2018. Median N‐terminal pro B‐type natriuretic protein (NT‐proBNP) and serum serotonin levels were stratified according to tricuspid regurgitation severity. Kaplan–Meier curves and log rank test were used for visualisation of survival. Cox regression was used for identification of the characteristics associated with disease specific mortality (DSM). A total of 84 patients with CHD were included of whom 49 (58.3%) were male. Median age at NET diagnosis was 62.3 (range 23.9–81.7) years, and median time to development of CHD was 1.1 (range 0–24.2) years. NT‐proBNP was significantly higher when more severe tricuspid regurgitation (TR) was present (p = .027). Median survival from CHD diagnosis for 1984–2000, 2000–2010 and 2010–2018 were 1.3 (confidence interval CI: 0.9–1.6), 1.9 (CI: 1.2–2.6) and 3.9 (CI: 1.7–6.2) years (p = .025). Valve replacement surgery (VSR) occurred more frequent in later time periods. VSR (hazard ratio HR 0.33, p = .005) and NT‐proBNP (HR 1.003, 1.00–1.005, p = .036) were significantly associated with DSM. The prognosis of patients with CHD has improved over the past decades, possibly caused by more VSR. NT‐proBNP is a valuable biomarker in patients with CHD. Clinical practice should be aimed at timely diagnosis and intervention of CHD.
Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. ...There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor-promoting roles in several cancer types.
We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines.
Through an international collaboration between The University of Texas MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht, plasma polyamine levels were assessed using mass spectrometry in 84 patients with MEN1 (20 with distant metastatic dpNETs patients and 64 with either indolent dpNETs or no dpNETs controls). A mouse model of MEN1-pNET, Men1fl/flPdx1-CreTg, was used to test time-dependent changes in plasma polyamines associated with disease progression.
A 3-marker plasma polyamine signature (3MP: N-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the 3 participating centers. The fixed 3MP yielded an area under the curve of 0.84 (95% CI, 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing patients from controls in an independent test set from MDACC. In Men1fl/flPdx1-CreTg mice, the 3MP was elevated early and remained high during disease progression.
Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.
Abstract
Purpose
Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of ...disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression.
Experimental Design
Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls). Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl).
Results
A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice.
Conclusions
Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.
Assessment of the diagnostic value of ultrasound (US), single photon-emission computed tomography-computed tomography (SPECT-CT) and (18)F-fluorocholine (FCH) PET-CT for preoperative localization of ...hyper-functioning parathyroid(s) in order to create a more efficient diagnostic pathway and enable minimal invasive parathyroidectomy (MIP) in patients with biochemical proven non-familial primary hyperparathyroidism (pHPT).
A single-institution retrospective study of 63 consecutive patients with a biochemical diagnosis of non-familial pHPT who received a Tc-99m-sestamibi SPECT-CT and neck ultrasound. Surgical findings were used in calculating the sensitivity and the positive predictive value (PPV) of both imaging modalities. Furthermore we present 5 cases who received additional FCH PET-CT.
A total of 42 (66.7%) patients underwent MIP. The PPV and sensitivity of SPECT-CT, 93.0% and 80.3%, were significantly higher than those of US with 78.3% and 63.2%, respectively. Adding US to SPECT-CT for initial pre-operative localization did not significantly increase sensitivity but did significantly decrease PPV. Performance of US was significantly better when performed after SPECT-CT. (18)F-fluorocholine PET-CT localized the hyper-functioning parathyroid gland in 4/5 cases with discordant conventional imaging, enabling MIP.
SPECT-CT is the imaging modality of choice for initial pre-operative localization of hyper-functioning parathyroid gland(s) in patients with biochemical pHPT. Ultrasound should be performed after SPECT-CT for confirmation of positive SPECT-CT findings and for pre-operative marking allowing MIP. In cases with negative or discordant imaging additional FCH PET-CT should be considered since this might enable the surgeon to perform MIP.
OBJECTIVE:The aldosterone-to-renin ratio is widely used and is the recommended screening modality for primary aldosteronism by the Endocrine Society Guideline. However, studies on its diagnostic ...accuracy have been inconsistent, which is mainly because of methodological limitations. We set out to evaluate this diagnostic value by using a highly standardized study protocol, which is in line with the Endocrine Society Guideline recommendations regarding indications for screening, testing conditions and reference standards in daily clinical practice.
METHODS:In this prospective study, 233 consecutive patients referred to the University Medical Center Utrecht with difficult-to-control hypertension were enrolled. In addition to aldosterone-to-renin ratio measurements, all patients underwent a saline infusion test as a reference standard. A plasma aldosterone concentration greater than 280 pmol/l after saline infusion was considered diagnostic for aldosteronism and the plasma renin activity was assessed to exclude patients with secondary aldosteronism from the final primary aldosteronism diagnosis.
RESULTS:Correlation of the aldosterone-to-renin ratio (cut-off >5) with primary aldosteronism diagnosis showed 16 true positive, 29 false positive, 188 true negative and 0 false negative aldosterone-to-renin ratios, resulting in a sensitivity of 100% (CI 75.9–100), specificity of 86.7% (CI 81.2–90.7), positive-predictive value of 35.6% (CI 22.3–51.3) and negative-predictive value of 100% (CI 97.5–100.0). The corresponding area under the curve was 0.933 (CI 0.900–0.966).
CONCLUSION:These findings show that the aldosterone-to-renin ratio is a good screening modality for primary aldosteronism and is without a high risk of missing a primary aldosteronism diagnosis whenever performed under well standardized conditions.
Decrease in blood pressure (BP) is the major goal of adrenalectomy for primary aldosteronism. Nevertheless, the optimal timing to assess these outcomes and the needed duration of follow-up are ...uncertain. We systematically reviewed the literature regarding trends in BP-related outcomes during follow-up after adrenalectomy.
A systematic literature search of medical literature from PubMed, Embase and the Cochrane Library regarding BP-related outcomes (i.e. cure of hypertension rates, BP and antihypertensives) was performed. The Quality In Prognosis Studies risk of bias tool was used.
Of the 2057 identified records, 13 articles met the inclusion criteria. Overall study quality was low. In multiple studies, the biggest decrease in BP was shown within the first month(s) after adrenalectomy and afterwards BP often remained stable during long-term follow-up.
Based on the available studies one might suggest that long follow-up is unnecessary, since outcomes seem to stabilize within the first months.
•The needed follow-up duration after surgery for primary aldosteronism is not clear.•This systematic review clarifies the course of blood pressure decrease post surgery.•Studies show that blood pressure seems to decrease the most within the first months.•Long follow-up after surgery might be unnecessary.
Abstract
Introduction
Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung ...NET do occur, and therefore the management of individual patients is challenging.
Aim
To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up.
Methods
The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior.
Results
In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6–94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course.
Conclusion
MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging.
Objective
Multiple endocrine neoplasia 2B (MEN2B) is characterised by early‐onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is ...often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood.
Design
It is a retrospective case series.
Methods
Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height.
Results
Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI.
Conclusions
This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a ‘marfanoid’ body habitus.
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