Objectives The aetiology of primary chronic pain syndromes (CPS) is highly disputed. We performed a systematic review and meta-analysis aiming to assess differences in circulating cytokines levels in patients with diffuse CPS (fibromyalgia) versus healthy controls (HC). Methods Human studies published in English from the PubMed and MEDLINE/Scopus and Cochrane databases were systematically searched from inception up to January 2020. We included full text cross-sectional or longitudinal studies with baseline cytokine measurements, reporting differences in circulating cytokine levels between fibromyalgia patients and HC. Random-effects meta-analysis models were used to report pooled effects and 95% CIs. This study is registered with PROSPERO(CRD42020193774). Results Our initial search yielded 324 papers and identified 29 studies (2458 participants) eligible for systematic review and 22 studies (1772 participants) suitable for meta-analysis. The systematic analysis revealed reproducible findings supporting different trends of cytokine levels when fibromyalgia patients were compared to HC, while the chemokine eotaxin, was consistently raised in fibromyalgia . Meta-analysis showed significantly increased tumour necrosis factor alpha (TNF-α) (SMD=0.36, p = 0.0034, 95%CI=0.12-0.60; I2=71%, Q2 p = 0.0002), interleukin (IL)-6 (SMD=0.15, p = 0.045, %95CI=0.003-0.29; I2=39%, Q2 p = 0.059), IL- 8 (SMD=0.26, p = 0.01, 95%CI =0.05-0.47; I2=61%, Q2 p = 0.005) and IL-10 (SMD=0.61; %95 = 0.34-0.89, p < 0.001; I2 = 10%, Q2 p = 0.34) in fibromyalgia patients compared to HC. Conclusion We found evidence of significant differences in the peripheral blood cytokine profiles of fibromyalgia patients compared to HC. However, the distinctive profile associated with fibromyalgia includes both pro-inflammatory (TNF-α, IL-6, IL-8), and anti-inflammatory cytokines (IL-10) in pooled analysis, as well as chemokine (eotaxin) signatures. Further research is required to elucidate the role of cytokines in fibromyalgia.

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Purpose: Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) are widely heterogeneous in their biological behavior, and predicting prognosis and optimal treatment strategies can be challenging. 68 Ga-DOTATATE PET/CT is a sensitive imaging modality for well-differentiated NEN and indicates a favorable prognosis, whereas 18 F-FDG PET/CT avidity indicates disease that is potentially more aggressive. There has been emerging interest in the combined interpretation of 68 Ga-DOTATATE and 18 F-FDG PET and its prognostic significance. We aimed to assess the prognostic utility of a classification system that incorporates the complex findings of 68 Ga-DOTATATE and 18 F-FDG PET interpreted side-by-side in patients with metastatic GEP NEN. Methods: We defined 3 68 Ga-DOTATATE/ 18 F-FDG "dual-tracer PET" groups: D1 ( 68 Ga-DOTATATE positive/ 18 F-FDG negative), D2 ( 68 Ga-DOTATATE positive/ 18 F-FDG positive), and D3 ( 68 Ga-DOTATATE negative/ 18 F-FDG positive). We retrospectively assessed the association between the dualtracer PET classification and progression-free and overall survival (OS) using Kaplan-Meier analysis. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Results: Eighty-seven patients with metastatic GEP NEN and contemporaneous 68 Ga-DOTATATE and 18 F-FDG PETwere included. The dual-tracer PET classification was an independent predictor of OS (multivariate P = 0.016) and also predicted progression-free survival (univariate P = 0.030). Other independent predictors of OS included chromogranin A and World Health Organization (WHO) grade. WHO grade was not associated with OS from the time of dual-tracer PET but was an independent predictor of OS from the date of histological diagnosis (multivariate P = 0.003). Conclusion:Our study demonstrates that a classification system combining the complex findings of 68 Ga-DOTATATE and 18 F-FDG PET is correlated with prognosis. Further research is needed to prospectively validate these findings and to explore whether dual-tracer PET scores may also be able to predict response to treatment.

Background Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are heterogeneous in clinical course, biology, and outcomes. The NETPET score predicts survival by scoring uptake on dual [68Ga]DOTATATE and [18F]FDG PET/CT scans. We aimed to validate previous single-centre findings in a multicentre, international study. Methods Dual scans were assigned a NETPET score of P1 (DOTATATE positive/FDG negative), P2–4 (DOTATATE positive/FDG positive), or P5 (DOTATATE negative/FDG positive). NETPET score, histological grade, age at diagnosis, and presence/absence of extrahepatic disease were compared to overall survival/time to progression on univariate and multivariate analysis. Results 319 metastatic/unresectable GEPNEN patients were included. The NETPET score was significantly associated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01). Median overall survival/time to progression was 101.8/25.5 months for P1, 46.5/16.7 months for P2–4, and 11.5/6.6 months for P5. Histological grade correlated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01), while presence/absence of extrahepatic disease did not. Age at diagnosis correlated with overall survival on univariate and multivariate analysis (p < 0.01). The NETPET score also correlated with histological grade (p < 0.001). Conclusion This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging.

<b><i>Background:</i></b> Cardiac metastases (CM) from neuroendocrine tumours (NET) are rare; however, with the introduction of new molecular imaging modalities, such as ⁶⁸Ga-DOTATATE PET-CT for NET diagnosis and re-staging, they are now identified more frequently. This study presents a single-institution experience on the NET CM characteristics, management, and prognostic implications. <b><i>Methods:</i></b> Between January 1998 and January 2020, 25 NET patients with CM were treated in our unit. A retrospective review of electronic records was performed. Overall survival (OS) was assessed by the Kaplan-Meier method. Cox regression models were used to evaluate the association of various clinical variables with OS. <b><i>Results:</i></b> The median age in the NET CM cohort was 64 years, with small intestine being the most common primary (84%). Nearly half of the patients suffered either from shortness of breath (48%) or had palpitations (12%). Peptide receptor radionuclide therapy (PRRT) was applied in more than half of the patients (64%), who had an improved trend for a longer median OS compared to those patients who did not receive PRRT (76.0 vs. 14.0 months, <i>p</i> = 0.196). The multivariate analysis demonstrated that concomitant skeletal or pancreatic metastases, as well as N-terminal pro-B-type natriuretic peptide (NT pro-BNP) &#x3e;2 × upper limit of normal (ULN), were independent poor prognosticators. <b><i>Conclusions:</i></b> Clinical features of NET CM ranged from asymptomatic patients to heart failure. Concomitant bone or pancreatic metastases and NT pro-BNP levels &#x3e;2 ULN predicted shorter survival time. PRRT serves as a feasible therapy with promising survival benefits; however, more data are needed.