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Tessa Brabander ENETS Center of Excellence, Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Julie Nonnekens ENETS Center of Excellence, Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

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Johannes Hofland ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands

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Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-[Tyr3]octreotate has been successfully developed in the last decades for the treatment of neuroendocrine neoplasms. However, different methods to improve the objective response rate and survival are under investigation. This includes changes of the radioligand, dosimetry and combination therapy with different agents, such as radiosensitisers. Hofving et al. recently reported, in the April 2019 issue of Endocrine-Related Cancer, the use of heat-shock protein 90 (Hsp90) modulation to augment radiation effects as a new promising target for radiosensitisation. In this commentary, new developments in the field of PRRT are discussed, placing these new findings about Hsp90 inhibitors into context.

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Julie Refardt ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands
ENETS Center of Excellence, Department of Endocrinology, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Wouter T Zandee ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

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Tessa Brabander ENETS Center of Excellence, Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Richard A Feelders ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

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Gaston J H Franssen Department of Surgery, Section of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands

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Leo J Hofland ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

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Emanuel Christ ENETS Center of Excellence, Department of Endocrinology, University Hospital Basel, Basel, Switzerland
Department of Clinical Research, University of Basel, Basel, Switzerland

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Wouter W de Herder ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

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Johannes Hofland ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

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Sufficient expression of somatostatin receptor (SSTR) in well-differentiated neuroendocrine tumors (NETs) is crucial for treatment with somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) using radiolabeled SSAs. Impaired prognosis has been described for SSTR-negative NET patients; however, studies comparing matched SSTR-positive and -negative subjects who have not received PRRT are missing. This retrospective analysis of two prospectively maintained NET databases aimed to compare matched metastatic grade 1 or 2 SSTR-positive and –negative NET patients. SSTR-negativity was defined as having insufficient tumor uptake on diagnostic SSTR imaging. Patients that underwent PRRT were excluded. Seventy-seven SSTR-negative and 248 SSTR-positive grade 1–2 NET patients were included. Median overall survival rates were significantly lower for SSTR-negative compared to SSTR-positive NET patients (53 months vs 131 months; P < 0.001). To adjust for possible confounding by age, gender, grade and site of origin, 69 SSTR-negative NET patients were propensity score matched to 69 SSTR-positive NET patients. Group characteristics were similar, with the exception of SSTR-negative patients receiving more often chemotherapy and targeted treatment. The inferior survival outcome of SSTR-negative compared to SSTR-positive NET patients persisted with a median overall survival of 38 months vs 131 months (P = 0.012). This relationship upheld when correcting for the main influencing factors of having a higher grade tumor or receiving surgery in a multivariate Cox regression analysis. In conclusion, we showed that propensity score-matched SSTR-negative NET patients continue to have a worse prognosis compared to SSTR-positive NET patients despite receiving more aggressive treatment. Differences in tumor biology likely underlie this survival deficit.

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Julie Refardt ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center and Erasmus Cancer Institute, Rotterdam, The Netherlands
ENETS Center of Excellence, Department of Endocrinology, University Hospital Basel, Basel, Switzerland

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Caroline M den Hoed Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands

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Janneke Langendonk Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands

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Wouter T Zandee Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Ayoub Charehbili ENETS Center of Excellence, Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Richard A Feelders ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center and Erasmus Cancer Institute, Rotterdam, The Netherlands

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Wouter W de Herder ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center and Erasmus Cancer Institute, Rotterdam, The Netherlands

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Tessa Brabander ENETS Center of Excellence, Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Johannes Hofland ENETS Center of Excellence, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center and Erasmus Cancer Institute, Rotterdam, The Netherlands

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Neuroendocrine neoplasms (NENs) are rare, usually slow-growing tumors, often presenting with extensive liver metastases. Hyperammonemia due to insufficient hepatic clearance has been described in NEN cases; however, no systematic evaluation of risk factors and outcomes of NEN-associated hyperammonemia exists so far. This case report and retrospective review of NEN patients developing hyperammonemia from the years 2000 to 2020 at the Erasmus Medical Center in Rotterdam, the Netherlands, aimed to describe these patients and determine prognostic factors to improve evaluation and treatment. Forty-four NEN patients with documented hyperammonemia were identified. All patients had liver metastases with 30% (n = 13) showing signs of portal hypertension. Patients who developed encephalopathy had higher median ammonia levels, but there was no association between the severity of hyperammonemia and liver tumor burden or presence of liver insufficiency. Eighty-four percent (n = 37) of patients died during follow-up. The median (IQR) time from diagnosis of hyperammonemia to death was 1.7 months (0.1–22.7). Hyperbilirubinemia, hypoalbuminemia, elevated international normalized ratio, presence of liver insufficiency, encephalopathy and ascites were associated with worse outcomes. Their role as independent risk factors for mortality was confirmed using the Child–Pugh score as a summary factor (P  < 0.001). No difference was seen concerning overall survival between our hyperammonemia patients and a propensity score-matched control stage IV NEN cohort. In conclusion, hyperammonemia comprises a relevant and potentially underdiagnosed complication of NEN liver metastases and is associated with worse outcomes. Assessment of signs of encephalopathy, risk factors and the Child–Pugh score could be helpful in selecting patients in whom ammonia levels should be measured.

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Tessa Brabander Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Wouter A van der Zwan Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Jaap J M Teunissen Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Boen L R Kam Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Wouter W de Herder Department of Internal Medicine, ENETS Center of Excellence, Erasmus Medical Center, Rotterdam, The Netherlands

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Richard A Feelders Department of Internal Medicine, ENETS Center of Excellence, Erasmus Medical Center, Rotterdam, The Netherlands

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Eric P Krenning Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Dik J Kwekkeboom Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) is a treatment with good results in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEPNETs). However, there are some pitfalls that should be taken into consideration when evaluating the treatment response after PRRT. 354 Dutch patients with GEPNETs who were treated with 177Lu-DOTATATE between March 2000 and December 2011 were retrospectively selected. Liver function parameters and chromogranin A were measured before each therapy and in follow-up. Anatomical imaging was performed before therapy and in follow-up. An increase in aminotransferases by ≥20% compared to baseline was observed in 83 of 351 patients (24%). In patients with an objective response (OR) and stable disease (SD) this increase was observed in 71/297 (24%) and in patients with progressive disease (PD) it was observed in 12/54 patients (22%). An increase in chromogranin A by ≥20% compared to baseline was observed in 76 patients (29%). This was present in 34% of patients who eventually had PD and 27% of patients who had OR/SD. In 70% of patients this tumour marker returned to baseline levels after therapy. An increase in liver enzymes and chromogranin A is not uncommon after PRRT. In the vast majority of patients this will resolve in follow-up. Clinicians should be aware that these changes may occur due to radiation-induced inflammation or disease progression and that repeated measurements over time are necessary to differentiate between the two.

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Anela Blazevic Department of Internal Medicine, section Endocrinology, Erasmus MC, Rotterdam,

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Martijn P A Starmans Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands

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Tessa Brabander Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands

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Roy S Dwarkasing Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands

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Renza A H van Gils Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands

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Johannes Hofland Department of Internal Medicine, section Endocrinology, Erasmus MC, Rotterdam,

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Gaston J H Franssen Department of Surgery, Erasmus MC, Rotterdam, the Netherlands

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Richard A Feelders Department of Internal Medicine, section Endocrinology, Erasmus MC, Rotterdam,

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Wiro J Niessen Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
Faculty of Applied Sciences, Department of Radiology and Nuclear Medicine, Delft University of Technology, Delft, the Netherlands

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Stefan Klein Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands

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Wouter W de Herder Department of Internal Medicine, section Endocrinology, Erasmus MC, Rotterdam,

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Metastatic mesenteric masses of small intestinal neuroendocrine tumors (SI-NETs) are known to often cause intestinal complications. The aim of this study was to identify patients at risk to develop these complications based on routinely acquired CT scans using a standardized set of clinical criteria and radiomics. Retrospectively, CT scans of SI-NET patients with a mesenteric mass were included and systematically evaluated by five clinicians. For the radiomics approach, 1128 features were extracted from segmentations of the mesenteric mass and mesentery, after which radiomics models were created using a combination of machine learning approaches. The performances were compared to a multidisciplinary tumor board (MTB). The dataset included 68 patients (32 asymptomatic, 36 symptomatic). The clinicians had AUCs between 0.62 and 0.85 and showed poor agreement. The best radiomics model had a mean AUC of 0.77. The MTB had a sensitivity of 0.64 and specificity of 0.68. We conclude that systematic clinical evaluation of SI-NETs to predict intestinal complications had a similar performance than an expert MTB, but poor inter-observer agreement. Radiomics showed a similar performance and is objective, and thus is a promising tool to correctly identify these patients. However, further validation is needed before the transition to clinical practice.

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Louis de Mestier Université de Paris, Department of Gastroenterology-Pancreatology, Beaujon University Hospital (APHP), Clichy, France

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Angela Lamarca Division of Cancer Sciences, Department of Medical Oncology, The Christie NHS Foundation, University of Manchester, Manchester, United Kingdom

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Jorge Hernando Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Wouter Zandee Department of Internal Medicine, Sector Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands
Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Teresa Alonso-Gordoa Department of Medical Oncology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain

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Marine Perrier Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France

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Annemiek ME Walenkamp Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

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Bipasha Chakrabarty Department of Pathology, The Christie, Manchester, United Kingdom

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Stefania Landolfi Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain

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Marie-Louise F Van Velthuysen Department of Pathology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Gursah Kats-Ugurlu Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Alejandra Caminoa Department of Pathology, University Hospital Ramon y Cajal, Madrid, Spain

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Maxime Ronot Université de Paris, Department of Radiology, Beaujon University Hospital (APHP), Clichy, France

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Prakash Manoharan Department of Radiology and Nuclear Medicine, The Christie, Manchester, United Kingdom

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Alejandro Garcia-Alvarez Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Tessa Brabander Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

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María Isabel García Gómez-Muriel Department of Radiology, University Hospital Ramon y Cajal, Madrid, Spain

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Guillaume Cadiot Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France

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Anne Couvelard Université de Paris, Department of Pathology, Beaujon/Bichat University Hospital (APHP), Clichy/Paris, France

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Jaume Capdevila Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Marianne E Pavel Department of Endocrinology, Erlangen University Hospital, Erlangen, Germany

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Jérôme Cros Université de Paris, Department of Pathology, Beaujon/Bichat University Hospital (APHP), Clichy/Paris, France

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There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5–12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0–24.0)) and targeted therapies (12.0 months (8.2–15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8–8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2–9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61–8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01–3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

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