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BackgroundSurgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date.ObjectiveThe aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence.Patients and MethodsThis was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000–2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan–Meier method and risk factor analysis was performed using the Cox regression model.ResultsOverall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01).ConclusionsApproximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

BackgroundIdentifying the correct location of a parathyroid adenoma in patients with primary hyperparathyroidism (pHPT) is crucial as it can guide surgical treatment. This study aimed to determine the diagnostic performance of 11C-choline PET/CT in patients with pHPT as a next in-line scan after primary negative or discordant first-line imaging.MethodsThis was a retrospective single-center cohort study. All patients with pHPT that were scanned utilizing 11C-choline PET/CT, after prior negative or discordant imaging, between 2015 and 2019 and who subsequently underwent parathyroid surgery were included. The results of the 11C-choline PET/CT were evaluated lesion-based, with surgical exploration and histopathological examination as the gold standard.ResultsIn total, 36 patients were included of which three patients were known to have Multiple Endocrine Neoplasia (MEN) syndrome. In these 36 patients, 40 lesions were identified on 11C-choline PET/CT and 37 parathyroid lesions were surgically removed. In 34/36 (94%) patients a focused parathyroidectomy was performed, in one patient a cervical exploration due to an ectopically identified adenoma, and in one patient a bilateral exploration was performed because of a double adenoma. Overall, per-lesion sensitivity of 11C-choline PET/CT was 97%, the positive predictive value was 95% and the accuracy was 94% for all parathyroid lesions.ConclusionsIn patients with pHPT and prior negative or discordant first-line imaging results, pathological parathyroid glands can be localized by 11C-choline PET/CT with high sensitivity and accuracy.

Purpose Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [ 11 C]methionine PET/CT, [ 11 C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. Methods We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99m Tc-sestamibi. All patients underwent [ 11 C]methionine PET/CT, [ 11 C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. Results A total of 32 patients were included in the study. With blinded evaluation, [ 11 C]choline PET/CT was positive in 28 patients (88%), [ 11 C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [ 11 C]choline PET/CT, [ 11 C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [ 11 C]choline PET/CT differed significantly from that of [ 11 C]methionine PET/CT and 4D-CT ( p  = 0.031 and p  < 0.0005, respectively). Conclusion In the setting of pHPT with negative first-line imaging, [ 11 C]choline PET/CT is superior to [ 11 C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost–benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

Background: Medullary thyroid cancer (MTC) is a heterogeneous disease. While the International MTC Grading System (IMTCGS) provides baseline risk stratification, it lacks therapeutic relevance. In several cancers, EZH2 overexpression harbors an adverse prognosis, with several EZH2 inhibitors undergoing investigation. This study validated the IMTCGS and examined the prognostic value of EZH2 and other biomarkers. Methods: Clinical data were collected and MTC specimens were retrospectively reviewed and morphologically assessed. Immunohistochemistry (IHC) of Ki-67 allowed IMTCGS validation. IHC of EZH2, PD-L1 and PSMA was evaluated on a tissue microarray (TMA). Results: Of 64 MTCs, the median tumor size was 28 mm (IQR 15–40). Coagulative necrosis, ≥5 mitoses, and Ki-67 ≥ 5% was seen in nineteen (30%), three (5%) and seven (11%) cases. Median Ki-67 was 0.9% (IQR 0.4–2.1). Forty-three (67%) and twenty-one (33%) were classified as IMTCGS low- and high-risk, respectively. High-risk tumors were associated with lower distant metastasis-free survival (DMFS) (HR 5.651, p = 0.017), locoregional recurrence-free survival (LRFS) (HR 18.323, p < 0.001) and disease-specific survival (DSS) (HR 10.001, p = 0.002), but not with overall survival (OS) (HR 2.109, p = 0.146). EZH2 expression was identified in 39/46 (85%) cases on the TMA. An expression of ≥10% (9/46, 20%) was predictive for DMFS (HR 4.747, p = 0.030), LRFS (HR 4.242, 0.039), DSS (HR 19.736, p < 0.001) and OS (HR 8.386, p = 0.004). PD-L1 and PSMA had no prognostic value. Conclusions: This study validates the prognostic value of the IMTCGS and identifies EZH2 as a novel prognostic biomarker in MTC patients. The therapeutic potential of EZH2 warrants further investigation in larger cohorts.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from the parafollicular C-cells of the thyroid gland. PET imaging, with various PET tracers, is performed when distant metastatic disease is suspected. After the recognition of progressive disease on imaging, targeted therapy may be initiated to prolong survival. Mutations in the gene encoding the REarranged during Transfection (RET) tyrosine kinase play a key role in the development of MTC. It seems that tyrosine kinase inhibitors (TKIs) inhibit tumor proliferation, but it remains challenging to determine the best patient specific treatment option. Here, we aim to set up an in vitro MTC organoid model to study its potential for patient-tailored drug-screening and uptake of PET tracers. Dispersed cells obtained from surgical MTC biopsies were suspended in Matrigel with defined medium allowing MTC organoid formation. To study putative MTC stem cells, the self-renewal potential of organoids was tested by dissociation to single cells and re-plating. To check MTC origin, MTC-specific gene expression and proteins were characterized by qPCR and immunofluorescent (IF) staining. To investigate cytotoxicity, MTC-organoids (MTOs) were exposed to various TKIs after which hormone (calcitonin and CEA) excretion levels were determined. Lastly, we evaluated cell-specific uptake of clinically used Positron Emission Tomography (PET) tracers. Nine MTC biopsies were processed and cultured as MTOs. Eight MTO lines were used to determine organoid formation efficiency (OFE), which yielded a maximum OFE of 6.3% in passage 1 (p1), 5.9% in p2, and 9.4% in p3, indicating the presence of putative stem cells. IF staining showed expression of MTC-specific markers in both tissue and MTOs showing tissue resemblance. Tumor marker measurements in MTO medium showed MTC-specific production of calcitonin and CEA with changed concentrations after exposure to TKIs. Exposure to PET tracers showed significant uptake in the MTOs. MTC organoids can be successfully cultured and resemble the tissue of origin in gene expression, protein expression and functionality. In addition, MTOs can take up PET tracers, and have the potential to be used as a prediction model for TKI treatment in the future.

Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions. Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions.

Background Problems in social functioning (e.g., unemployment, social isolation), are common in people with a psychotic disorder. Social cognition is a treatment target to improve social functioning, as it is a proximal predictor of social functioning. Social Cognition Training (SCT) improves social cognition, but may not generalize (enduringly) to social functioning, perhaps due to insufficient opportunity to practice in daily-life social situations. Using virtual reality (VR) for SCT could address this problem, as VR is customizable, accessible, and interactive. We will test the effect of a VR SCT, ‘DiSCoVR’, on social cognition and social functioning in a randomized controlled trial (RCT). Methods In total 100 people with a psychotic disorder and deficits in social cognition will be recruited for this multicenter randomized controlled trial (RCT). Participants will be randomized to VR SCT (DiSCoVR) or VR relaxation training (VRelax; active control). DiSCoVR is a 16-session individual SCT, consisting of three modules: 1) emotion perception (recognizing facial emotions in a virtual shopping street); 2) social perception and theory of mind (observing social interactions between virtual characters and assessing their behavior, emotions and thoughts); and 3) application of higher-order social cognition in social interaction (role-playing personalized situations in VR). People receiving VRelax complete sixteen individual sessions, in which they receive psycho-education about stress, identify personal stressors, learn relaxation techniques, and explore relaxing immersive virtual environments. Assessments will be performed at baseline, post-treatment, and 3-month follow-up. Primary outcomes are emotion perception (Ekman 60 Faces), social perception and theory of mind (The Awareness of Social Inference Test). Secondary outcomes include social functioning (Personal and Social Performance Scale), experiences and social interactions in daily life (experience sampling of emotions, social participation and subjective experience of social situations), psychiatric symptoms (e.g., depression, perceived stress, anxiety, positive and negative symptoms) and self-esteem. Discussion To our knowledge, this will be the first RCT testing the efficacy of VR SCT. It will also investigate generalization to daily life social situations, the durability of treatment effects, and moderators and mediators of treatment success. Trial registration On December 5, 2017, this trial was registered prospectively in the Dutch Trial Register as NTR6863 .

Virtual reality (VR) may improve psychological treatments for psychotic disorders. We investigated the effects of VR-based cognitive behavior therapy for paranoid ideation (VR-CBTp) compared to standard CBTp. We conducted a pragmatic, single-blind, randomized clinical trial in seven mental health centers across the Netherlands and Belgium. A total of 98 participants with a psychotic spectrum disorder and paranoid ideation were randomized to a maximum of 16 sessions of VR-CBTp (  = 48) or CBTp (  = 50). The primary outcome was momentary paranoia, measured with the experience sampling method (ESM) at posttreatment. Secondary measures, assessed at baseline, posttreatment, and 3-month follow-up, included symptoms (paranoia, hallucination, depression, cognition, and anxiety related), social functioning, self-esteem, and schemes. Both groups showed reductions in momentary paranoia between baseline and posttreatment (  = 56,  = -15.0, effect size [ES] = 0.65), but those were greater for VR-CBT (interaction  = 8.3, ES = 0.62). Reductions remained at follow-up (  = 50,  = -10.7, ES = 0.57) but not the interaction. Limited ESM compliance resulted in data loss; however, secondary paranoia measures did confirm improvements (ES range = 0.66-1.15,  = 78-81), but not the interaction. Both groups improved in symptoms, self-esteem, and social functioning. Interaction effects in favor of VR-CBTp were found for safety behavior, depression, and self-esteem at posttreatment, and self-esteem and anxiety at follow-up. For VR-CBTp, 37.5% did not complete treatment; for CBTp, this was 24.0%. Completers, on average, received 12.7 (VR-CBTp: standard deviation [SD] = 3.9) and 15.1 (CBTp: SD = 2.5) sessions. Both CBTp and VR-CBTp are efficacious treatments for paranoid ideation, but VR-CBTp may be somewhat more effective. Limitations concern missing primary outcome data and a lower sample size than anticipated.

Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.