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Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be add

Purpose: Peptide receptor radionuclide therapy (PRRT) using [177Lu]Lu-DOTATATE has been shown to effectively prolong progression free survival in grade 1–2 gastroenteropancreatic neuroendocrine tumours (GEP-NET), but is less efficacious in patients with extensive liver metastases. The aim was to investigate whether tumour uptake in liver metastases can be enhanced by intra-arterial administration of [177Lu]Lu-DOTATATE into the hepatic artery, in order to improve tumour response without increasing toxicity. Methods: Twenty-seven patients with grade 1–2 GEP-NET, and bi-lobar liver metastases were randomized to receive intra-arterial PRRT in the left or right liver lobe for four consecutive cycles. The contralateral liver lobe and extrahepatic disease were treated via a “second-pass” effect and the contralateral lobe was used as the control lobe. Up to three metastases (> 3 cm) per liver lobe were identified as target lesions at baseline on contrast-enhanced CT. The primary endpoint was the tumour-to-non-tumour (T/N) uptake ratio on the 24 h post-treatment [177Lu]Lu-SPECT/CT after the first cycle. This was calculated for each target lesion in both lobes using the mean uptake. T/N ratios in both lobes were compared using paired-samples t-test. Findings: After the first cycle, a non-significant difference in T/N uptake ratio was observed: T/NIA = 17·4 vs. T/Ncontrol = 16·2 (p = 0·299). The mean increase in T/N was 17% (1·17; 95% CI [1·00; 1·37]). Of all patients, 67% (18/27) showed any increase in T/N ratio after the first cycle. Conclusion: Intra-arterial [177Lu]Lu-DOTATATE is safe, but does not lead to a clinically significant increase in tumour uptake.

Rationale: When compared to other types of cancer, the prevalence of midgut neuroendocrine tumors (NET) has disproportionally increased over the past decades. To date, there has been very little progress in discovering (epi)genetic drivers and treatment options for these tumors. Recent microbiome research has revealed that enteroendocrine cells communicate with the intestinal microbiome and has provided novel treatment targets for various other cancer types. Hence, our aim was to analyze the role of the gut microbiome in midgut NET patients. Methods: Fecal samples, prospectively collected from patients and control subjects, were analyzed with next generation 16S sequencing. Patients with neuroendocrine carcinomas and recent antibiotics use were excluded. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between groups within the patient cohort. Results: 87 midgut NET patients and 95 controls were included. Midgut NET patients had a less rich and diverse gut microbiome than controls (p < 0.001). Moreover, we identified 31 differentially abundant species and a gut microbial signature consisting of 17 species that was predictive of midgut NET presence with an area under the receiver operating characteristic curve of 0.863. Gut microbial composition was not directly associated with the presence of the carcinoid syndrome, tumor grade or multifocality. Nonetheless, we did observe a potential link between microbial diversity and the presence of carcinoid syndrome symptoms within the subset of patients with elevated 5-hydroxyindolacetic acid levels. Conclusion: Midgut NET patients have an altered gut microbiome which suggests a role in NET development and could provide novel targets for microbiome-based diagnostics and therapeutics.

Item does not contain fulltext, BACKGROUND: Non-AT-III mediated heparin-resistance during CPB occurs by complex-forming with heparin-binding proteins. Currently, there are no specific recommendations for non-AT-III mediated heparin-resistance. CASE PRESENTATION: We present a fatal case of a 70-yr-old male-patient undergoing cardiac-surgery in which refractory heparin-resistance was observed. The massive AL amyloidosis found at autopsy is thought to be responsible and illustrates that awareness and knowledge of the etiology and perioperative strategies of non-AT-III mediated heparin-resistance is important. CONCLUSION: For anticoagulation during cardiopulmonary bypass surgery in case of a non-AT-III medicated heparin resistance, we refer to the decision tree added to this manuscript and if necessary to consider direct thrombin inhibitors, such as bivalirudin or argatroban, as it bypasses the complexing pathway.

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis. Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Neuroendocrine ovarian metastases (NOM) predominantly derive from midgut neuroendocrine tumors (NETs) and develop in about 25% of women with advanced stage of this malignancy. Little is known of the growth rate and treatment response of NOM. We therefore evaluated the efficacy of different management options for patients with NOM, including peptide receptor radionuclide therapy (PRRT), somatostatin analogues (SSAs) and oophorectomy. Records were screened for patients with well-differentiated NOM of midgut origin that presented in our NET referral center between 1991 and 2022. Progression-free survival (PFS) and tumor growth rate (TGR) of ovarian and extra-ovarian metastases were determined using RECIST (response evaluation criteria in solid tumors) 1.1. In 12 available patients undergoing PRRT, NOM were associated with a shorter PFS than extra-ovarian metastases (P = 0.003). While PRRT induced a similar decrease in TGR for ovarian and extra-ovarian lesions in nine patients with available data (-2.3 vs -1.4, P > 0.05), only the TGR of NOM remained positive after PRRT. In 16 patients treated with SSAs, the TGR of NOM was almost three times that of extra-ovarian lesions during treatment (2.2 vs 0.8, P = 0.011). Oophorectomy was performed in 46 of the 61 included patients and was significantly associated with a prolonged OS (115 vs 38 months, P < 0.001). This association persisted after propensity score matching and correction for tumor grade and simultaneous tumor debulking. In conclusion, NOM have a higher TGR compared to extra-ovarian metastases, resulting in a shorter PFS after PRRT. Bilateral salpingo-oophorectomy should be considered for postmenopausal women with NOM undergoing surgery for metastatic midgut NETs.

Background: Specific data regarding coronavirus disease 2019 (COVID-19) in patients with neuroendocrine neoplasms (NENs) are lacking. The aim of this study is to describe the characteristics of patients with NENs who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive. Material and methods: This is a worldwide study collecting cases of patients with NENs along with a positive nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between June 1, 2020, and March 31, 2021. Centres treating patients with NENs were directly contacted by the principal investigator. Patients with NENs of any primary site, grade and stage were included, excluding small-cell lung carcinoma and mixed adenoneuroendocrine carcinoma. Results: Among 81 centres directly contacted, 88.8% responded and 48.6% of them declined due to lack of cases or interest. On March 31st, 2021, eight recruiting centres enrolled 89 patients. The median age was 64 years at the time of COVID-19 diagnosis. Most patients had metastatic, non-functioning, low-/intermediate-grade gastroenteropancreatic NENs on treatment with somatostatin analogues and radioligand therapy. Most of them had comorbidities. Only 8% of patients had high-grade NENs and 12% were receiving chemotherapy. Most patients had symptoms or signs of COVID-19, mainly fever and cough. Only 3 patients underwent sub-intensive treatment, whereas most of them received medical therapies, mostly antibiotics. In two third of cases, no changes occurred for the anti-NEN therapy. More than 80% of patients completely recovered without sequelae, whereas 7.8% patients died due to COVID-19. Conclusions: Patients included in this study reflect the typical NEN population regardless of SARS-CoV-2. In most cases, they overcome COVID-19 without need of intensive care, short-term sequelae and discontinuation of systemic oncological therapy.

Item does not contain fulltext, BACKGROUND: Previous studies have shown that preoperative anaemia in patients undergoing cardiac surgery is associated with adverse outcomes. However, most of these studies were retrospective, had a relatively small sample size, and were from a single centre. The aim of this study was to analyse the relationship between the severity of preoperative anaemia and short- and long-term mortality and morbidity in a large multicentre national cohort of patients undergoing cardiac surgery. METHODS: A nationwide, prospective, multicentre registry (Netherlands Heart Registration) of patients undergoing elective cardiac surgery between January 2013 and January 2019 was used for this observational study. Anaemia was defined according to the WHO criteria, and the main study endpoint was 120-day mortality. The association was investigated using multivariable logistic regression analysis. RESULTS: In total, 35 484 patients were studied, of whom 6802 (19.2%) were anaemic. Preoperative anaemia was associated with an increased risk of 120-day mortality (adjusted odds ratio [aOR] 1.7; 95% confidence interval [CI]: 1.4-1.9; P<0.001). The risk of 120-day mortality increased with anaemia severity (mild anaemia aOR 1.6; 95% CI: 1.3-1.9; P<0.001; and moderate-to-severe anaemia aOR 1.8; 95% CI: 1.4-2.4; P<0.001). Preoperative anaemia was associated with red blood cell transfusion and postoperative morbidity, the causes of which included renal failure, pneumonia, and myocardial infarction. CONCLUSIONS: Preoperative anaemia was associated with mortality and morbidity after cardiac surgery. The risk of adverse outcomes increased with anaemia severity. Preoperative anaemia is a potential target for treatment to improve postoperative outcomes.

Contains fulltext : 232791.pdf (Publisher’s version ) (Open Access), OBJECTIVES: To determine the safety and efficacy of human chorionic gonadotropin hormone-derivative EA-230 in cardiac surgery patients. Cardiac surgery induces systemic inflammation and may impair renal function, affecting patient outcome. EA-230 exerted immunomodulatory and renoprotective effects in preclinical models and was safe and showed efficacy in phase I and II human studies. DESIGN: Double-blinded, placebo-controlled, randomized study. SETTING: Collaboration of the Cardiothoracic Surgery, Anesthesiology, and the Intensive Care departments of a tertiary hospital in the Netherlands. PATIENTS: One hundred eighty patients undergoing an on-pump coronary artery bypass procedure with or without concomitant valve surgery. INTERVENTIONS: Ninety mg/kg/hr EA-230 or placebo administered during surgery. MEASUREMENTS AND MAIN RESULTS: During the study, no safety concerns emerged. EA-230 did not modulate interleukin-6 plasma concentrations (area under the curve 2,730 pg/mL x hr [1,968-3,760] vs 2,680 pg/mL x hr [2,090-3,570] for EA-230 and placebo group, respectively; p = 0.80). Glomerular filtration rate increased following surgery (mean +/- SEM increase in the EA-230 vs placebo groups: glomerular filtration rateiohexol measured using iohexol plasma clearance: 19 +/- 2 vs 16 +/- 2 mL/min/1.73 m2; p = 0.13 and estimated glomerular filtration rate with the Modification of Diet in Renal Disease equation using creatinine: 6 +/- 1 vs 2 +/- 1 mL/min/1.73 m2; p = 0.01). The "injury" stage of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria for acute kidney injury was 7% in the EA-230 group versus 18% in the placebo group (p = 0.07). In addition, EA-230-treated patients had a less positive fluid balance compared with placebo-treated patients (217 +/- 108 vs 605 +/- 103 mL; p = 0.01), while the use of vasoactive agents was similar in both groups (p = 0.39). Finally, hospital length of stay was shorter in EA-230 treated patients (8 d [7-11]

Background: Steroid hormones are essential signalling molecules in prostate cancer (PC). However, many studies focusing on liquid biomarkers fail to take the hormonal status of these patients into account. Steroid measurements are sensitive to bias c

Around two-thirds of patients with small intestinal neuroendocrine tumours are present with a metastatic mesenteric mass. This mass is known to cause intestinal complications, however, little is known on its development over time in the era of targeted therapy. Therefore, we conducted a retrospective study to assess the growth and response to therapy. We found that the growth of the mesenteric mass was detectable in 13.5% over a median time of 3.4 years and peptide receptor radionuclide therapy resulted in size reduction in only 3.8%. This site-specific static growth behavior is important to note when assessing disease progression and therapeutic options. Background: A metastatic mesenteric mass is a hallmark of small intestinal neuroendocrine tumours (SI-NETs). However, little is known on its development over time. Therefore, we conducted a study to assess the evolution of a SI-NET-associated mesenteric mass over time. Methods: Retrospectively, 530 patients with proven SI-NET were included. The presence and growth of a mesenteric mass was assessed using RECIST 1.1 criteria on every consecutive CT-scan until the end of follow-up or resection. Results: At baseline, a mesenteric mass was present in 64% of the patients, of whom 13.5% showed growth of the mesenteric mass with a median time to growth of 40 months. Male gender was the only independent predictor of growth (OR 2.67). Of the patients without a mesenteric mass at the first evaluation, 2.6% developed a pathological mesenteric mass. Treatment with peptide receptor radionuclide therapy (PRRT; N = 132) resulted in an objective size reduction of the mesenteric mass in 3.8%. Conclusion: The metastatic mesenteric mass in SI-NETs has a static behavior over time. Therefore, site-specific growth behavior should be taken into account when selecting target lesions and assessing disease progression and therapeutic response. PRRT appears not to be effective for size reduction of the mesenteric mass.

Purpose of Review: Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3] octreotate is an effective and safe second- or third-line treatment option for patients with low-grade advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). In this review, we will focus on possible extensions of the current use of PRRT and on new approaches which could further improve its treatment efficacy and safety. Recent Findings: Promising results were published regarding PRRT in other NENs, including lung NENs or high-grade NENs, and applying PRRT as neoadjuvant or salvage therapy. Furthermore, a diversity of strategic approaches, including dosimetry, somatostatin receptor antagonists, somatostatin receptor upregulation, radiosensitization, different radionuclides, albumin binding, alternative renal protection, and liver-directed therapy in combination with PRRT, have the potential to improve the outcome of PRRT. Also, novel biomarkers are presented that could predict response to PRRT. Summary: Multiple preclinical and early clinical studies have shown encouraging potential to advance the clinical outcome of PRRT in NEN patients. However, at this moment, most of these strategies have not yet reached the clinical setting of randomized phase III trials.

Radboud University, 21 februari 2020, Promotores : Meijerink, W.J.H.J., Wolff, A.P. Co-promotores : Calsbeek, H., Hofland, J., Contains fulltext : 216171.pdf (publisher's version ) (Open Access)

Contains fulltext : 218905.pdf (publisher's version ) (Open Access), BACKGROUND: Serious preventable surgical events still occur despite considerable efforts to improve patient safety. In addition to learning from retrospective analyses, prospective risk-assessment methods may help to decrease preventable events further by targeting perioperative hazards. The aim of this systematic review was to assess the methods used to identify perioperative patient safety risks prospectively, and to describe the risk areas targeted, the quality characteristics and feasibility of methods. METHODS: MEDLINE, Embase, CINAHL and Cochrane databases were searched, adhering to PRISMA guidelines. All studies describing the development and results of prospective methods to identify perioperative patient safety risks were included and assessed on methodological quality. Exclusion criteria were interventional studies, studies targeting one specific issue, studies reporting on structural factors relating to fundamental hospital items, and non-original or case studies. RESULTS: The electronic search resulted in 16 708 publications, but only 20 were included for final analysis, describing five prospective risk-assessment methods. Direct observation was used in most studies, often in combination. Direct (16 studies) and indirect (4 studies) observations identified (potential) adverse events (P)AEs, process flow disruptions, poor protocol compliance and poor practice performance. (Modified) Healthcare Failure Mode and Effect Analysis (HFMEA) (5 studies) targeted potential process flow disruption failures, and direct (P)AE surveillance (3 studies) identified (P)AEs prospectively. Questionnaires (3 studies) identified poor protocol compliance, surgical flow disturbances and patients' willingness to ask questions about their care. Overall, quality characteristics and feasibility of the methods were poorly reported. CONCLUSION: The direct (in-person) observation appears to be the primary prospective risk-assessment method that currently may best help to target periop

Thrombocytopenia is a risk factor for increased morbidity and mortality in patients with the new severe acute respiratory syndrome corona virus, SARS-CoV-2 infection (COVID-19 infection).1 Thrombocytopenia in COVID-19 patients may be caused by disseminated intravascular coagulation (DIC), sepsis or drug-induced. Recently a single case report suggested immune thrombocytopenia (ITP) may be associated with COVID-19 infection.2 ITP is a rare autoimmune disease characterized by a platelet count < 100x109/L, leading to an increased bleeding risk.3 Several risk factors have been described for ITP including environmental (e.g. infection, malignancy and drugs) and genetic predisposition.4 We report here the first case series of three patients with ITP associated with COVID-19 infection.

Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis. Over the past 15 years, critical developments in tumor grading, diagnostic biomarkers, radionuclide imaging, randomized controlled drug trials, evidence-based guidelines, and superior prognostic outcomes have substantially altered the field of NET care. Here, we review the relevant advances to clinical practice that have significantly upgraded our approach to NET patients, both in diagnostic and in therapeutic options.

Contains fulltext : 202155.pdf (publisher's version ) (Open Access)