In multiple endocrine neoplasia type 1 (MEN1), endoscopic ultrasound (EUS) is used for identification and follow-up of pancreatic neuroendocrine tumors (PNETs). The role of EUS in surveillance of ...small ( < 20 mm) PNETs is unclear, mostly because the natural course of these lesions is largely unknown. We aimed to determine annual growth and incidence rate of small PNETs in patients with MEN1 using EUS-based surveillance.
Linear array EUS procedures in patients with MEN1 between 2002 and 2015 were identified. Number, size, and location of PNETs were recorded. Annual growth of PNETs < 20 mm identified at the initial EUS ("prevalent" PNETs) and during follow-up ("incident" PNETs) was calculated using mixed model linear regression analysis.
A total of 54 patients were identified and 38 patients were included. In all, 226 PNETs were identified (median size 5.0 mm, interquartile range 3.7 - 7.5) of which 124 (55 %) were prevalent and 102 (45 %) were incident PNETs. Annual incidence rate was 0.79 PNETs/year (95 % confidence interval CI 0.73 to 0.87). Overall growth rate was 0.10 mm/year (95 %CI 0.02 to 0.19;
= 0.01); PNETs < 10 mm (n = 198) did not grow (
= 0.23), whereas PNETs ≥ 10 mm (n = 28) grew 0.44 mm/year (95 %CI 0.10 to 0.78;
= 0.01). Prevalent PNETs grew 0.21 mm/year (95 %CI 0.10 - 0.32;
< 0.001), whereas incident PNETs did not grow (
= 0.26).
The annual growth rate of small, solid PNETs in patients with MEN1 is lower than previously thought. Surveillance intervals could probably be prolonged without compromising safety.
Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas ...have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and
CDKN2A
status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (
p
value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of
CDKN2A
as opposed to absence of ARX expression, ALT, or
CDKN2A
deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.
Carcinoid heart disease (CHD) is a rare fibrotic cardiac complication of neuroendocrine tumors. Besides known biomarkers N-Terminal pro-B-type natriuretic peptide (NT-proBNP) and serotonin, activin ...A, connective tissue growth factor (CTGF), and soluble suppression of tumorigenicity 2 (sST2) have been suggested as potential biomarkers for CHD. Here, we validated the predictive/diagnostic value of these biomarkers in a case-control study of 114 patients between 1990 and 2021. Two time-points were analyzed: T0: liver metastasis without CHD for all patients. T1: confirmed CHD in cases (CHD+, n = 57); confirmed absence of CHD five or more years after liver metastasis in controls (CHD−, n = 57). Thirty-one (54%) and 25 (44%) females were included in CHD+ and CHD− patients, respectively. Median age was 57.9 years for CHD+ and 59.7 for CHD- patients (p = 0.290). At T0: activin A was similar across both groups (p = 0.724); NT-proBNP was higher in CHD+ patients (17 vs. 6 pmol/L, p = 0.016), area under the curve (AUC) 0.84, and the most optimal cut-off at 6.5 pmol/L. At T1: activin A was higher in CHD+ patients (0.65 vs. 0.38 ng/mL, p = 0.045), AUC 0.62, without an optimal cut-off value. NT-pro-BNP was higher in CHD+ patients (63 vs. 11 pmol/L, p < 0.001), AUC 0.89, with an optimal cut-off of 27 pmol/L. Serotonin (p = 0.345), sST2 (p = 0.867) and CTGF (p = 0.232) levels were similar across groups. This large validation study identified NT-proBNP as the superior biomarker for CHD. Patients with elevated serotonin levels and NT-proBNP levels between 6.5 and 27 pmol/L, and specifically >27 pmol/L, should be monitored closely for the development of CHD.
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.
Ulceration of the feet, which can result in loss of limbs and even death, is one of the major health problems for people with diabetes mellitus.
To assess the effects of patient education on the ...prevention of foot ulcers in patients with diabetes mellitus.
Eligible studies were identified by searching The Cochrane Wounds Group Specialised Register (searched 1 August 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7); Ovid MEDLINE (2009 to July Week 3 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, July 31, 2012); Ovid EMBASE (2009 to 2012 Week 30); and EBSCO CINAHL (2009 to 26 July 2012).
Prospective randomised controlled trials (RCTs) that evaluated educational programmes for preventing foot ulcers in people with diabetes mellitus.
Two review authors independently undertook data extraction and assessment of risk of bias. Primary end points were foot ulceration or ulcer recurrence and amputation.
Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias.
In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.
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.
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