Advances in Radionuclide Therapies for Patients with Neuro-endocrine Tumors.

PURPOSE OF REVIEW: To provide insights into the role of peptide receptor radionuclide therapy (PRRT) in patients with advanced neuroendocrine tumors (NET) and an overview of possible strategies to combine PRRT with locoregional and systemic anticancer treatments. RECENT FINDINGS: Research on combining PRRT with other treatments encompasses a wide variety or treatments, both local (transarterial radioembolization) and systemic therapies, chemotherapy (i.e., capecitabine and temozolomide), targeted therapies (i.e., olaparib, everolimus, and sunitinib), and immunotherapies (e.g., nivolumab and pembrolizumab). Furthermore, PRRT shows promising first results as a treatment prior to surgery. There is great demand to enhance the efficacy of PRRT through combination with other anticancer treatments. While research in this area is currently limited, the field is rapidly evolving with numerous ongoing clinical trials aiming to address this need and explore novel therapeutic combinations.

Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites.

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.

Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression.

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.

Prognostic Value of Microscopic Tumor Necrosis in Adrenal Cortical Carcinoma.

Adrenal cortical carcinoma (ACC) is an uncommon neoplasm with variable prognosis. Several histologic criteria have been identified as predictors of malignancy in adrenal cortical tumors. The Weiss score is the system most widely employed for diagnostic purposes, but also possesses prognostic value. We aim to determine the relative impact of each Weiss parameter on ACC patient survival. A multicenter retrospective analysis was conducted on a series of 79 conventional ACCs surgically treated at the Florence and Utrecht centers of the European Network for the Study of Adrenal Tumors (ENSAT). Weiss classification was recapitulated using principal component analysis (PCA). The Kaplan-Meier and Cox multivariate regression analyses were applied in order to estimate the prognostic power of Weiss versus other clinical parameters. PCA reduced the nine Weiss parameters to the best fitting 4-component model, each parameter clustering with a single component. Necrosis and venous invasion clustered together with the highest scores, thus establishing the most relevant component (Component 1) to explain Weiss distribution variability. Only Component 1 significantly predicted overall survival (OS, log-rank = 0.008) and disease-free survival (DFS, log-rank < 0.001). When considering the prognostic power of Weiss parameters, necrosis alone could independently assess OS (log-rank = 0.004) and DFS (log-rank < 0.001) at both the Kaplan-Meier and multivariate Cox regression analyses [hazard ratio (HR) = 7.8, 95% confidence interval [CI] = 1.0-63.5, p = 0.05, and HR = 12.2, 95% CI = 1.6-95.0, p = 0.017, respectively]. The presence of necrosis significantly shortened time to survival (TtS) and time to recurrence (TtR), 57.5 [31.5-103.5] vs 34 [12-78] months (p = 0.05) and 57.5 [31.5-103.5] vs 7 [1.0-31.5] months (p < 0.001), respectively. Our study suggests that, of the Weiss parameters, necrosis is the most powerful adverse factor and the best predictor of OS and DFS in ACC patients.

Lifestyle Factors and Development and Natural Course of Gastroenteropancreatic Neuroendocrine Tumors: A Review of the Literature.

INTRODUCTION: The rarity of neuroendocrine tumors (NETs) and their heterogeneous presentation complicate the identification of risk factors for their development and natural course. Several tumor-specific prognostic factors have been identified, but less attention has been given to lifestyle factors as risk and prognostic factors. This review aimed to identify studies on smoking, alcohol use, physical activity, diet, body mass index (BMI), and diabetes and their association with the development and course of gastroenteropancreatic (GEP-) NETs. METHODS: The literature was systematically searched for articles on lifestyle factors and NETs available via PubMed and Embase. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: A total of 25 eligible studies out of 3,021 screened articles were included. Most studies reported on smoking and alcohol, reporting conflicting results. Diet seems to have an influence on NET development, but few studies were published. Articles reporting on BMI were not unanimous on the effect on GEP-NETs. Diabetes was reported as a risk factor for NETs, while a protective effect was observed with metformin use. CONCLUSION: Different tissues, i.e., the pancreas and small intestine, may respond differently to exposure to alcohol and smoking. Evidence for diet so far is too limited to draw conclusions. Diabetes seems to be an important risk factor for the development of pancreatic NETs with a protective role in disease progression, while BMI is not unequivocally associated with the development and prognosis of NETs. Hence, our findings suggest that lifestyle factors play an important role in NET development as a disease course. Future research should consider lifestyle as an influence on disease progression and treatment response.

The co-occurrence of both breast- and differentiated thyroid cancer: incidence, association and clinical implications for daily practice.

BACKGROUND: Breast cancer (BC) and differentiated thyroid cancer (TC) are two common cancer types with the highest incidence in women. BC and TC can develop synchronous or metachronous and the occurrence of both is higher than expected by chance. This study aimed to examine the association between BC and TC in the Netherlands. METHODS: This is a retrospective cohort study during the period of 1989-2020 retrieved from the Netherlands Cancer Registry (NCR). Patients diagnosed with BC-TC and BC alone as control group and TC-BC and TC alone as control group were included. The primary outcome was the standardized incidence ratio (SIR) of BC-TC and TC-BC. Secondary outcomes included data on the demographics, type of malignancy, treatment and overall survival (OS). RESULTS: The incidence of TC among 318.002 women with BC (BC-TC) was 0.1% (423 patients) (SIR = 1.86 (95% CI: 1.40-2.32)) and the incidence of BC among 12,370 patients with TC (TC-BC) was 2.9% (355 patients) (SIR = 1.46 (95% CI: 1.09-1.83)). BC-TC patients were younger compared to the BC alone group at BC diagnosis (55 vs 60 years, p < 0.001). The age-adjusted odds ratio to develop TC was not significantly increased for patients who received chemotherapy and radiotherapy. Most TC cases were synchronous tumors after BC diagnosis (19%) with a TNM stage 1. Only 6% of the BC tumors after TC occurred synchronous with a TNM stage 1 in most cases. The OS of all groups was the most favorable in patients with both BC and TC compared to BC- and TC alone. CONCLUSION AND RELEVANCE: The SIR of TC after BC diagnosis and BC after TC diagnosis was higher than predicted based on the rates of the general population. TC and BC as second primary tumors were diagnosed in an early stage and did not affect overall survival. Therefore, Dutch women who have been treated for BC or TC require no special surveillance for their thyroid- and breast gland.

FDG PET/CT in differentiated thyroid cancer patients with low thyroglobulin levels.

Objective: To evaluate the usefulness of [18F]fluorodeoxyglucose (FDG) positron emissive tomography (PET)/CT in patients with low detectable thyroglobulin levels suspicious for persistent or recurrent differentiated thyroid cancer (DTC). Methods: A retrospective case series study evaluating FDG PET/CT in patients with detectable thyroglobulin (Tg) levels (≥0.20 and <10.00 ng/mL) after initial treatment with total thyroidectomy and I-131 thyroid remnant ablation for pT1-3aN0-1bM0 DTC. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of FDG PET/CT were calculated. Results: Twenty-seven patients underwent FDG PET/CT. Median Tg level at FDG PET/CT was 2.00 ng/mL (range 0.30-9.00). FDG PET/CT was positive in 14 patients (51.9%): lesions suspicious for lymph node metastases were depicted in 12 patients, and lung metastases in 2. DTC was confirmed in 13/14 FDG PET/CT-positive patients. In 9/13 patients with a negative FDG PET/CT, DTC was confirmed ≤3 months after FDG PET/CT. The sensitivity, PPV, specificity and NPV were 59.1, 92.9, 80.0 and 30.8%, respectively. Conclusions: This case series shows that FDG PET/CT might be useful to detect persistent or recurrent DTC in patients with low detectable Tg. However, when FDG PET/CT is negative, this does not rule out DTC and further investigations are necessary.

Multidisciplinary integrated care pathway for von Hippel-Lindau disease.

BACKGROUND: Clinical pathways are care plans established to describe essential steps in the care of patients with a specific clinical problem. They translate (inter)national guidelines into local applicable protocols and clinical practice. The purpose of this article is to establish a multidisciplinary integrated care pathway for specialists and allied health care professionals in caring for individuals with von Hippel-Lindau (VHL) disease. METHODS: Using a modified Delphi consensus-making process, a multidisciplinary panel from 5 Dutch University Medical Centers produced an integrated care pathway relating to the provision of care for patients with VHL by medical specialists, specialized nurses, and associated health care professionals. Patient representatives cocreated the pathway and contributed quality criteria from the patients' perspective. RESULTS: The panel agreed on recommendations for the optimal quality of care for individuals with a VHL gene mutation. These items were the starting point for the development of a patient care pathway. With international medical guidelines addressing the different VHL-related disorders, this article presents a patient care pathway as a flowchart that can be incorporated into VHL expertise clinics or nonacademic treatment clinics. CONCLUSIONS: Medical specialists (internists, urologists, neurosurgeons, ophthalmologists, geneticists, medical oncologists, neurologists, gastroenterologists, pediatricians, and ear-nose-throat specialists) together with specialized nurses play a vital role alongside health care professionals in providing care to people affected by VHL and their families. This article presents a set of consensus recommendations, supported by organ-specific guidelines, for the roles of these practitioners in order to provide optimal VHL care. This care pathway can form the basis for the development of comprehensive, integrated pathways for multiple neoplasia syndromes.

Health-Related Quality of Life in Adrenocortical Carcinoma: Development of the Disease-Specific Questionnaire ACC-QOL and Results from the PROFILES Registry.

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties.

A Multinational Pilot Study on Patients' Perceptions of Advanced Neuroendocrine Neoplasms on the EORTC QLQ-C30 and EORTC QLQ-GINET21 Questionnaires.

Among the available neuroendocrine neoplasm (NEN)-specific HR-QoL scales, only the EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires have been validated in several languages. We aim to assess patients' perceptions of these questionnaires. A cross-sectional qualitative pilot study was conducted among 65 adults from four countries with well-differentiated advanced gastro-entero-pancreatic (GEP) or unknown primary NENs. Patients completed the EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires and then a survey containing statements concerning the questionnaires. The majority of patients had a small intestine NET (52%). Most tumors were functioning (55%) and grade 2 NET (52%). Almost half of the patients identified limitations in the questionnaires, with nine (14%) patients scoring the questionnaires as poor and 16 (25%) patients as moderate. Overall, 37 (57%) patients were positive towards the questionnaires. Approximately a quarter of patients considered the questionnaires not suitable for all ages, missing some of their complaints, not representative of their overall HR-QoL regarding the treatment of their NET and too superficial. The current validated EORTC QLQ-C30 and EORTC QLQ-G.I.NET21 questionnaires may show some limitations in the design of questions and the patients' final satisfaction reporting of the questionnaire. Large-scale, high-quality prospective studies are required in HR-QoL assessment regarding NETs.

Is There a Role for Biomarkers in Surveillance of Pancreatic Neuroendocrine Neoplasms in Von Hippel-Lindau Disease?

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess their clinical relevance in diagnosing panNENs in VHL patients. We searched the databases of PubMed/Medline, Embase, and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.

Retrospective analysis of PSMA PET/CT thyroid incidental uptake in adults: incidence, diagnosis, and treatment/outcome in a tertiary cancer referral center and University Medical Center.

PURPOSE: A prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) is an unexpected, PSMA-avid thyroid lesion, newly detected during the investigation of an unrelated condition using PSMA PET/CT. The aim of this study is to examine the incidence and clinical significance of PTI and the associated management strategies since the implementation of the PSMA PET/CT scan. METHODS: This study involves a retrospective cohort study of 61 PTI cases depicted on PSMA PET/CT scans performed between January 2016 and July 2021, almost exclusively for (re)staging prostate cancer. The medical records of the included cases were retrospectively reviewed and data of the PSMA PET/CT scans, primary malignancy, thyroid diagnostics, treatment, and follow-up were collected. RESULTS: PTI was reported in 1.1% of the patients who underwent oncologic PSMA PET/CT scans included in this study. Two PTI cases had a histologically proven thyroid cancer: one a benign thyroid lesion and one a metastasis of a renal cell carcinoma. In none of the cases in whom any form of further thyroid workup was withheld, the PTI became clinically relevant during follow-up (median 1.8 years (1.1-3.3)). Six patients (10%) died due to their primary cancer. CONCLUSION: The incidence of thyroid incidentalomas on PSMA PET/CT was low (1.1%) in this large, two-center experience. Less than half of the PTI cases were analyzed and the risk of malignancy, despite being low, was not negligible. The clinical outcome was good using a standard diagnostic workup for PTI, while the prognosis of the patient was determined by the primary malignancy. The consideration to analyze and treat PTI cases should be part of the shared decision-making in cancer patients.

Gallium-68-somatostatin receptor PET/CT parameters as potential prognosticators for clinical time to progression after peptide receptor radionuclide therapy: a cohort study.

BACKGROUND: Early [68Ga]Ga-DOTA-TOC PET/CT imaging after peptide receptor radionuclide therapy (PRRT) in neuroendocrine neoplasm patients is often used as a prognosticator for survival, but lacks validity. This study investigates the prognostic value of changes in PET parameters after PRRT. METHODS: Baseline and follow-up [68Ga]Ga-DOTA-TOC PET/CT scans of all patients treated with PRRT were delineated automatically. Total lesion somatostatin receptor expression (TL-SSTR) and somatostatin receptor expressing tumor volume (SSTR-TV) were used as covariates in Cox proportional hazard models to predict time-to-new treatment. RESULTS: In twenty patients, median time-to-new treatment was 19.3 months (range [3.8; 36.2]). Absolute and percentual changes in both PET parameters were not associated with time-to-new treatment. A significant relation between independent baseline and follow-up SSTR-TV and follow-up TL-SSTR, and time-to-new treatment was identified. CONCLUSIONS: Automatically derived [68Ga]Ga-DOTA-TOC PET/CT parameters are easy to acquire and may be of prognostic value after completing PRRT. Acquiring SSTR-TV or TL-SSTR parameters at baseline and during follow-up can be of value in identifying a patient's prognosis.

Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity.

INTRODUCTION: Until now, well-differentiated bronchopulmonary neuroendocrine tumors (bpNET) occurring either sporadically (sp-bpNET) or in the context of multiple endocrine neoplasia type 1 (MEN1) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are regarded as similar entities. However, in contrast to sp-bpNET: MEN1-related and DIPNECH-related bpNET rarely metastasize or lead to bpNET-related death. We aimed to describe and compare the course of the disease of sp-bpNET, DIPNECH- and MEN1-related bpNET. METHODS: All patients with histologically confirmed MEN1-related bpNET from the DutchMEN Study Group database (1990-2017), patients with resected sp-bpNET and DIPNECH patients referred to a Dutch European Neuroendocrine Tumor Society center between 2000 and 2018 were included. Fisher's exact test was used for comparison between groups. The primary end point was disease-specific mortality (DSM). Kaplan-Meier and logrank test were used to compare survival. Cox regression was used to identify risk factors for DSM in the sp-bpNET subgroup. RESULTS: We included 112 sp-bpNET, 29 MEN1, and 27 DIPNECH patients. Tumor classification was similar across subgroups. A total of 20 patients (18%) with sp-bpNET died because of bpNET, compared with none in the MEN1 group and DIPNECH group. Median disease-specific survival was 12.3 (confidence interval: 6.3-18.3) years for patients with sp-bpNET, and not estimable for the other subgroups (p < 0.001). Differences in baseline characteristics did not explain worse survival in sp-bpNET. Tumor classification and age at diagnosis were independent risk factors for DSM in sp-bpNET. CONCLUSIONS: Patients with sp-bpNET have a significantly higher DSM compared with MEN1 or DIPNECH-related bpNET, unexplained by differences in baseline characteristics. This implies that not all bpNET are similar entities.

Retrospective Analyses of 18FDG-PET/CT Thyroid Incidentaloma in Adults: Incidence, Treatment, and Outcome in a Tertiary Cancer Referral Center.

Background: A thyroid incidentaloma (TI) is an unexpected, asymptomatic thyroid lesion discovered during the investigation of an unrelated condition. The aim of the present study is to examine the incidence of 18Fluorodeoxyglucose (FDG)-positron emission tomography (PET) TI, the associated management strategies and the outcomes in a tertiary cancer referral center. Methods: This study involves a retrospective cohort study of 1003 patients with TI found on 18FDG-PET/CT scans performed between January 2010 and January 2020 for a nonthyroidal malignancy. The Kaplan-Meier method was used for survival analyses in patients concerning an underlying malignancy, with a prevalence of 5% or higher in this cohort. Logistic- and cox regression analyses were performed to analyze predictors of thyroid malignancy and mortality. A propensity score weighted method was used to control for baseline differences between the intervention (additional TI diagnostics) and control (no TI diagnostics) group. Results: FDG-positive TI occurred in 1.9% (1003/52,693) of the oncologic 18FDG-PET/CT scans performed in our center. Thyroid surgery was performed in 47 patients (6%) and a thyroid malignancy was detected in 31 of them, which is 66% of those who had an operation and 4% of all patients. During the follow-up (median 6 years), 334 deaths (42%) related to different types of cancer (38%) or other causes (4%) were observed. One patient died from medullary thyroid cancer. In multivariate analysis adjusted for age, gender and the type- and stage of nonthyroidal malignancy, were independent predictors of survival (P < .05). Conclusions: The incidence of TI in this tertiary cancer referral center was comparable to current literature. Further thyroid workup was performed in less than half of the patients, and only a minority of patients underwent thyroid surgery. Since only one patient died from thyroid cancer, the strategy to withhold from thyroid diagnostics and treatment seems valid for most TI. Active thyroid treatment might benefit a subgroup of patients in whom the primary nonthyroidal malignancy is successfully treated or presumably stable. A wait-and-see policy with ultrasound follow-up could be an alternative strategy. These considerations should be part of the shared decision making in cancer patients with a TI.

Initiating Pancreatic Neuroendocrine Tumor (pNET) Screening in Young MEN1 Patients: Results From the DutchMEN Study Group.

CONTEXT: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the optimal age to initiate screening for pNETs is under debate. OBJECTIVE: The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients. METHODS: Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size ≥ 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease. RESULTS: Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively. CONCLUSION: Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified. The psychological and medical burden of screening at a young age should be considered.

A Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression.

CONTEXT: 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. OBJECTIVE: We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Diagnostic and management strategies for pNETs in Von Hippel-Lindau: a systematic review.

Pancreatic neuroendocrine tumors (pNETs) in Von Hippel-Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly contribute to VHL-related mortality. Evidence-based guidelines are needed for timely detection, management and intervention of these tumors. However, the value of several diagnostic tools is controversial, and evidence-based management strategies are lacking. This systematic review aims to update current literature on diagnostic and management strategies of pNETs in VHL and proposes evidence-based recommendations. The databases of PubMed/Medline, Embase and Web of Science were systematically searched to identify relevant studies. Studies were screened independently and cross-checked by two authors to assess eligibility for inclusion. Eighty-four articles were eligible for full text reading, and thirteen were critically appraised using the modified Quality Assessment of Diagnostic Accuracy Studies or modified Quality in Prognostic Studies tool. Six studies assessed the diagnostic value of imaging modalities, five focused on the optimal timing for surgical intervention, and one article studied the growth rate of pNETs. Quality of the available evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluations tool. Studies recommended CT or MRI as the primary screening modalities for pNETs. For detection of metastases, 68Gallium-DOTATATE/TOC PET/CT is advised. For pNETs <2 cm a watch-and-wait approach is recommended, while for pNETs ≥2.5 cm surgical resection is advised. Due to limited data, no strong recommendations on surveillance could be proposed.