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.

The global leadership into malnutrition criteria reveals a high percentage of malnutrition which influences overall survival in patients with gastroenteropancreatic neuroendocrine tumours.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.

Sarcopenia and Neuroendocrine Neoplasms.

PURPOSE OF THE REVIEW: To summarise the current literature regarding the presence of sarcopenia in patients with neuroendocrine neoplasms (NENs). These are uncommon cancers separated into well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinoma (NECs). For the diagnosis of sarcopenia, there needs to be low muscle strength and low muscle quantity/quality. RECENT FINDINGS: Five studies exist describing either low muscle strength or low muscle quantity in patients with NETs. The studies used different techniques to analyse muscle strength and muscle quantity, included heterogeneous populations, and performed the analysis at different time points following the diagnosis of the NET. Only 2 studies regarding patients with NECs could be found, both included mainly patients with a mixed adenoneuroendocrine carcinoma (MiNEN) and are, therefore, difficult to interpret for patients with a NEC. The main findings of this review are to describe the presence of sarcopenia in patients with NENs. However, results should be interpreted with caution, and future research should focus on the correct technique, homogenous population and same time point.

Avelumab treatment for patients with metastatic Merkel cell carcinoma can be safely stopped after 1 year and a PET/CT-confirmed complete response.

BACKGROUND: Immune checkpoint inhibitor treatment of patients with metastatic Merkel cell carcinoma (mMCC) has shown high response rates, ranging from 33% to 73%. The ideal duration of treatment, however, is currently unknown. The aim of this study was to evaluate if avelumab treatment for mMCC can be safely stopped after 1 year of treatment and a complete response (CR) confirmed by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging. METHODS: Patients who received more than one dose of avelumab treatment for mMCC between November 2017 and February 2022 were included in this study. Treatment was discontinued in case of a FDG-PET/CT confirmed CR after 1 year (26 cycles) of avelumab or a CR and unacceptable toxicity earlier. The primary end point was recurrence-free survival (RFS). RESULTS: Sixty-five patients were included: 25 (38%) had a FDG-PET/CT-confirmed CR at discontinuation of avelumab. In those 25 patients, reasons for discontinuation of treatment were completion of 1 year of treatment in 13 (52%), toxicity in five (20%), and patient preference in seven (28%). Median duration of treatment in this group was 11 months (interquartile range, 6.1-11.7). Median follow-up was 27 months (interquartile range, 15.8-33.8). The 12-month RFS was 88% (95% CI, 0.74-1) and median RFS was not reached. Two patients (8%) had a recurrence at 4 and 7 months after discontinuation of treatment. CONCLUSIONS: Patients with mMCC who acquire a CR on PET/CT imaging appear to have durable responses after discontinuation of treatment after 1 year.

Relation between WHO Classification and Location- and Functionality-Based Classifications of Neuroendocrine Neoplasms of the Digestive Tract.

Practice of neuroendocrine neoplasms (NENs) of the digestive tract, which comprise of a highly diverse group of tumors with a rising incidence, faces multiple biological, diagnostic, and therapeutic issues. Part of these issues is due to misuse and misinterpretation of the classification and terminology of NENs of the digestive tract, which make it increasingly challenging to evaluate and compare the literature. For instance, grade 3 neuroendocrine tumors (NETs) are frequently referred to as neuroendocrine carcinomas (NECs) and vice versa, while NECs are, by definition, high grade and therefore constitute a separate entity from NETs. Moreover, the term NET is regularly misused to describe NENs in general, and NETs are frequently referred to as benign, while they should always be considered malignancies as they do have metastatic potential. To prevent misconceptions in future NEN-related research, we reviewed the most recent terminology used to classify NENs of the digestive tract and created an overview that combines the classification of these NENs according to the World Health Organization (WHO) with location- and functionality-based classifications. This overview may help clinicians and researchers in understanding the current literature and could serve as a guide in the clinic as well as for writing future studies on NENs of the digestive tract. In this way, we aim for the universal use of terminology, thereby providing an efficient foundation for future NEN-related research.

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.

Feasibility of Home Parenteral Nutrition in Patients with Intestinal Failure Due to Neuroendocrine Tumours: A Systematic Review.

INTRODUCTION: Maintaining adequate nutritional status can be a challenge for patients with small bowel neuroendocrine tumours (NETs). Surgical resection could result in short bowel syndrome (SBS), whilst without surgical resection there is a considerable risk of ischemia or developing an inoperable malignant bowel obstruction (IMBO). SBS or IMBO are forms of intestinal failure (IF) which might require treatment with home parenteral nutrition (HPN). Limited data exist regarding the use of HPN in patients with small bowel neuroendocrine tumours, and it is not frequently considered as a possible treatment. METHODS: A systematic review was performed regarding patients with small bowel NETs and IF to report on overall survival and HPN-related complications and create awareness for this treatment. RESULTS: Five articles regarding patients with small bowel NETs or a subgroup of patients with NETs could be identified, mainly case series with major concerns regarding bias. The studies included 60 patients (range 1-41). The overall survival time varied between 0.5 and 154 months on HPN. However, 58% of patients were alive 1 year after commencing HPN. The reported catheter-related bloodstream infection rate was 0.64-2 per 1000 catheter days. CONCLUSION: This systematic review demonstrates the feasibility of the use of HPN in patients with NETs and IF in expert centres with a reasonable 1-year survival rate and low complication rate. Further research is necessary to compare patients with NETs and IF with and without HPN and the effect of HPN on their quality of life.

Surgical Management of the Primary Tumor in Stage IV Small Intestinal Neuroendocrine Tumors: To Operate or Not to Operate, That Is the Question.

PURPOSE OF REVIEW: Small intestinal neuroendocrine tumors (SI-NET) are rare tumors, often with distant metastases at diagnosis. The objective of this review is to provide an overview of the latest literature regarding surgical management of the primary tumor in stage IV SI-NET. RECENT FINDINGS: Primary tumor resection (PTR) seems to be associated with improved survival in patients with stage IV SI-NET, independent of treatment of distant metastases. A watch and wait approach of the primary tumor increases the risk of needing an emergency resection. PTR improves survival in patients with stage IV SI-NET, decreases the risk of emergency surgery, and should be considered in all patients with stage IV disease and unresectable liver metastasis.

Outcomes and survival in patients with advanced intestinal neuroendocrine tumours on home parenteral nutrition, an international multicentre retrospective cohort study.

BACKGROUND AND AIMS: Only limited information is available on the use of home parenteral nutrition (HPN) in patients with advanced neuroendocrine tumours (NETs) causing intestinal failure (IF). This study aims to report the outcomes of the explore the use of HPN in this patient cohort, in the largest case series to date. METHODS: A retrospective study in the United Kingdom and the Netherlands was performed, using the UK National British Artificial Nutrition Survey (BANS) and local databases in the Netherlands. Data regarding age, sex, NET grading, staging, treatment, HPN characteristics and survival outcomes were collected. RESULTS: Data were collected on 41 patients (n = 18 males, 44%) with a median age of 65. Most primary tumours were in the small bowel (n = 35, 85%). The NETs were Grade 1 (n = 16, 39%), Grade 2 (n = 7, 17%), Grade 3 (n = 1, 2%). In 28 patients (n = 68%) there was stage IV disease with metastases located in the peritoneum, mesentery and or liver. There were two indications for HPN; short bowel syndrome (n = 27, 66%) and inoperable malignant bowel obstruction (n = 14, 34%). The median period on HPN was 11 months (interquartile range 4-25 months). 11 patients were still alive and receiving HPN treatment after 2 years, and 6 patients after 3 years. Six patients (22%) with short bowel syndrome (SBS) could be weaned from HPN. There was a statistically significant improved survival for patients with short bowel syndrome (median 24 months) compared to inoperable malignant bowel obstruction (median 7 months). The catheter-related bloodstream infection rate was comparable to other HPN patient cohorts at 1.0 per 1000 catheter days. CONCLUSION: This study shows that HPN can be used safely in patients with NET and IF to increase survival beyond that reasonably expected in the context of either short bowel syndrome or inoperable malignant bowel obstruction. Patients with short bowel syndrome are most likely to benefit. Further prospective studies are necessary to validate survival benefits and to demonstrate the effect of HPN on quality of life.

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma.

This ENETS guidance paper, developed by a multidisciplinary working group, provides up-to-date and practical advice on the diagnosis and management of digestive neuroendocrine carcinoma, based on recent developments and study results. These recommendations aim to pave the road for more standardized care for our patients resulting in improved outcomes. Prognosis is generally poor for digestive NEC, most are advanced at diagnosis and median survival in metastatic disease is 11-12 months. Surgery can be of benefit for localized disease after extensive preoperative imaging. Carboplatin in combination with etoposide is recommended as first-line treatment for metastatic disease. Irinotecan with fluoropyrimidines has the best evidence as second-line treatment. Immunotherapy plays a minor role in biomarker-unselected patients. Molecular profiling if available is encouraged to identify new targets. More prospective clinical trials are highly needed to fulfil the unmet needs in this field, especially on new predictive and prognostic biomarkers and to improve survival of patients with advanced disease.

Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours.

Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52-68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1-13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life.

The effect of long-acting somatostatin analogues on the uptake of [177Lu]Lu-HA-DOTATATE.

PURPOSE: According to IAEA/EANM/SNMMI guidelines, long-acting somatostatin analogues (LA-SSAs) should be discontinued 4-6 weeks prior to peptide receptor radionuclide therapy (PRRT) to prevent somatostatin receptor saturation. The aim of this study was to determine the effect of continued use of long-acting SSAs during PRRT on the uptake of [177Lu]Lu-HA-DOTATATE on SPECT/CT. METHODS: Consecutive patients with neuroendocrine tumours who were treated with PRRT receiving 7.4 GBq of [177Lu]Lu-HA-DOTATATE were included. Patients were divided into 3 groups: (1) control (LA-SSA stopped > 6 weeks prior to PRRT), or continued treatment with (2) long-acting octreotide < 6 weeks prior to PRRT, or (3) long-acting lanreotide < 6 weeks prior to PRRT. The uptake of [177Lu]Lu-HA-DOTATATE was quantified in healthy tissues (spleen, liver, kidneys, bone marrow) and tumour lesions on SPECT/CT performed 24 h after PRRT. A Mann-Whitney U test was used to determine differences in uptake between the long-acting octreotide and long-acting lanreotide groups compared to the control group. RESULTS: Forty-two patients with 135 cycles of PRRT were included: 28 with lanreotide, 50 with octreotide, and 57 cycles without LA-SSAs. Uptake of [177Lu]Lu-HA-DOTATATE was significantly decreased in liver parenchyma in patients with lanreotide (p < 0.001) and in the spleen in patients with either octreotide or lanreotide (both p < 0.001). No differences were observed for uptake in kidneys, bone marrow, and blood pool. Uptake of [177Lu]Lu-HA-DOTATATE in tumours was the same in patients with lanreotide compared to the control (p = 0.862) and in patients with octreotide compared to the control (p = 0.201), independent of tumour location. CONCLUSION: Long-acting octreotide and lanreotide do not interfere with the uptake of [177Lu]Lu-HA-DOTATATE in tumour lesions 24 h post-injection. Uptake in healthy liver parenchyma significantly decreases after lanreotide administration prior to PRRT, while uptake in healthy spleen tissue significantly decreases with both octreotide and lanreotide administration.

CT-based radiomics to distinguish progressive from stable neuroendocrine liver metastases treated with somatostatin analogues: an explorative study.

BACKGROUND: Accurate response evaluation in patients with neuroendocrine liver metastases (NELM) remains a challenge. Radiomics has shown promising results regarding response assessment. PURPOSE: To differentiate progressive (PD) from stable disease (SD) with radiomics in patients with NELM undergoing somatostatin analogue (SSA) treatment. MATERIAL AND METHODS: A total of 46 patients with histologically confirmed gastroenteropancreatic neuroendocrine tumors (GEP-NET) with ≥1 NELM and ≥2 computed tomography (CT) scans were included. Response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST1.1). Hepatic target lesions were manually delineated and analyzed with radiomics. Radiomics features were extracted from each NELM on both arterial-phase (AP) and portal-venous-phase (PVP) CT. Multiple instance learning with regularized logistic regression via LASSO penalization (with threefold cross-validation) was used to classify response. Three models were computed: (i) AP model; (ii) PVP model; and (iii) AP + PVP model for a lesion-based and patient-based outcome. Next, clinical features were added to each model. RESULTS: In total, 19 (40%) patients had PD. Median follow-up was 13 months (range 1-50 months). Radiomics models could not accurately classify response (area under the curve 0.44-0.60). Adding clinical variables to the radiomics models did not significantly improve the performance of any model. CONCLUSION: Radiomics features were not able to accurately classify response of NELM on surveillance CT scans during SSA treatment.

Four decades of experience with carcinoid heart disease: An analysis of 84 patients.

Carcinoid heart disease (CHD) is a serious cardiac condition which is caused by elevated serotonin in the systemic circulation, secreted by neuroendocrine tumours (NET). It mostly affects the right-sided heart valves, where it causes fibrotic disturbances and is associated with worse survival. In this study, we describe a large cohort of patients with CHD and provide an insight into their survival over the past decades. All consecutive patients with a serotonin producing NET and CHD referred to the Netherlands Cancer Institute that presented with CHD or developed CHD during their follow up time were included from 1984 until 2021. Patients were divided into three time periods: 1984-2000, 2000-2010 and 2010-2018. Median N-terminal pro B-type natriuretic protein (NT-proBNP) and serum serotonin levels were stratified according to tricuspid regurgitation severity. Kaplan-Meier curves and log rank test were used for visualisation of survival. Cox regression was used for identification of the characteristics associated with disease specific mortality (DSM). A total of 84 patients with CHD were included of whom 49 (58.3%) were male. Median age at NET diagnosis was 62.3 (range 23.9-81.7) years, and median time to development of CHD was 1.1 (range 0-24.2) years. NT-proBNP was significantly higher when more severe tricuspid regurgitation (TR) was present (p = .027). Median survival from CHD diagnosis for 1984-2000, 2000-2010 and 2010-2018 were 1.3 (confidence interval [CI]: 0.9-1.6), 1.9 (CI: 1.2-2.6) and 3.9 (CI: 1.7-6.2) years (p = .025). Valve replacement surgery (VSR) occurred more frequent in later time periods. VSR (hazard ratio [HR] 0.33, p = .005) and NT-proBNP (HR 1.003, 1.00-1.005, p = .036) were significantly associated with DSM. The prognosis of patients with CHD has improved over the past decades, possibly caused by more VSR. NT-proBNP is a valuable biomarker in patients with CHD. Clinical practice should be aimed at timely diagnosis and intervention of CHD.

NETest: serial liquid biopsies in gastroenteropancreatic NET surveillance.

Objective: Up to now, serial NETest measurements in individuals assessing the disease course of gastroenteropancreatic neuroendocrine tumors (GEPNETs) at long-term follow-up and treatment response were not studied. Design: The study was a longitudinal validation study of serial NETest measurements - a blood-based gene expression signature - in 132 patients with GEPNETs on therapy or watch-and-wait strategy. Methods: Serial samples were collected during 46 (range: 6-71) months of follow-up. NETest scores were compared with Response Evaluation Criteria in Solid Tumors version 1.1-defined treatment response (e.g. no evidence of disease (NED), stable disease (SD) or progressive disease (PD)). Results: Consecutive NETest scores fluctuated substantially (range: 0-100) over time in individuals with SD (n = 28) and NED (n = 30). Follow-up samples were significantly higher in SD (samples 3-5) and NED subgroups (samples 2-5) compared with baseline results, without changes in imaging. In 82% of untreated patients with PD, consecutive NETest scores consistently remained high. In patients undergoing systemic treatment, the median pre-treatment NETest score in treatment-responders was 76.5 (n = 22) vs 33 (n = 12) in non-responders (P = 0.001). Patients with low pre-treatment scores had 21 months reduced progression-free survival (10 vs 31 months; P = 0.01). The accuracy of the NETest for treatment response prediction was 0.73 (P = 0.009). Conclusion: In patients not undergoing treatment, consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch and wait requires further study.

GEP-NET radiomics: a systematic review and radiomics quality score assessment.

OBJECTIVE: The number of radiomics studies in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is rapidly increasing. This systematic review aims to provide an overview of the available evidence of radiomics for clinical outcome measures in GEP-NETs, to understand which applications hold the most promise and which areas lack evidence. METHODS: PubMed, Embase, and Wiley/Cochrane Library databases were searched and a forward and backward reference check of the identified studies was executed. Inclusion criteria were (1) patients with GEP-NETs and (2) radiomics analysis on CT, MRI or PET. Two reviewers independently agreed on eligibility and assessed methodological quality with the radiomics quality score (RQS) and extracted outcome data. RESULTS: In total, 1364 unique studies were identified and 45 were included for analysis. Most studies focused on GEP-NET grade and differential diagnosis of GEP-NETs from other neoplasms, while only a minority analysed treatment response or long-term outcomes. Several studies were able to predict tumour grade or to differentiate GEP-NETs from other lesions with a good performance (AUCs 0.74-0.96 and AUCs 0.80-0.99, respectively). Only one study developed a model to predict recurrence in pancreas NETs (AUC 0.77). The included studies reached a mean RQS of 18%. CONCLUSION: Although radiomics for GEP-NETs is still a relatively new area, some promising models have been developed. Future research should focus on developing robust models for clinically relevant aims such as prediction of response or long-term outcome in GEP-NET, since evidence for these aims is still scarce. KEY POINTS: • The majority of radiomics studies in gastroenteropancreatic neuroendocrine tumours is of low quality. • Most evidence for radiomics is available for the identification of tumour grade or differentiation of gastroenteropancreatic neuroendocrine tumours from other neoplasms. • Radiomics for the prediction of response or long-term outcome in gastroenteropancreatic neuroendocrine tumours warrants further research.

Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers.

INTRODUCTION: Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease. OBJECTIVE: The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait. METHODS: This was a retrospective cohort study of patients with stage IV SI-NETs at diagnosis, between 2000 and 2018, from two tertiary referral centers (Netherlands Cancer Institute [NKI] and Aintree University Hospital [AUH]) who had adopted contrasting treatment approaches: upfront surgical resection and watch and wait, respectively. Patients without symptoms related to the primary tumor were included. Multivariable intention-to-treat (ITT), per-protocol (PP), and instrumental variable (IV) analyses using 'institute' as an IV were performed to assess the influence of PTR on disease-specific mortality (DSM). RESULTS: A total of 557 patients were identified, with 145 patients remaining after exclusion of stage I-III disease or symptoms of the primary tumor (93 from the NKI and 52 from AUH). The cohorts differed in performance status (PS; p = 0.006) and tumor grade (p < 0.001). PTR was independently associated with reduced DSM irrespective of statistical methods employed: ITT hazard ratio [HR] 0.60, p = 0.005; PP HR 0.58, p < 0.001; and IV HR 0.07, p = 0.019. Other factors associated with DSM were age, PS, high chromogranin A, and somatostatin analog treatment. CONCLUSION: Taking advantage of contrasting institutional treatment strategies, this study identified PTR as an independent predictor of DSM. Future prospective studies should aim to validate these results.

Post-PRRT scans: which scans to make and what to look for.

AIM: The aim of this study was to evaluate the clinical utility of SPECT/CT (imaging of uptake in tumor lesions and additional findings) and the additional value of planar imaging in order to simplify clinical imaging protocols and decrease patients burden. MATERIALS AND METHODS: One hundred consecutive patients with metastatic neuroendocrine tumor (NET) treated with PRRT were included. Post-therapy imaging was performed 24 h after each PRRT cycle by both whole-body planar imaging and abdominal- and thoracic SPECT/CT. All images were evaluated for (1) the presence of new lesions, (2) discordant lesions between the two acquisitions (planar or SPECT), (3) location of lesions on SPECT (abdominal, thoracic, or both), and (4) additional findings on non-contrast enhanced CT imaging. RESULTS: In total 368 PRRT cycles including post-therapy imaging were performed in 100 patients. 45 patients had abdominal disease only, whilst in 55 patients the disease was observed on both abdominal and thoracic SPECT. 16 patients had known bone lesions that were visible only on planar imaging as these were out of range of the SPECT/CT. During PRRT, one patient developed multiple new bone metastases after the second cycle of PRRT, which were visible on both planar and SPECT/CT images. In 11 patients additional findings were found on CT images, the most common and relevant being bowel obstruction, pleural effusion, and ascites. Patients who developed ascites during PRRT appeared to do extremely poor; a post-hoc analysis showed that overall survival was 13.2 months in patients that showed ascites during PRRT at any moment and 37.9 months in patients without ascites (p < 0.001). CONCLUSION: From a clinical point of view, thoracoabdominal SPECT/CT imaging is the preferred method for post-PRRT imaging; planar imaging had no added value over SPECT/CT in this cohort. In patients with abdominal disease only on baseline imaging, SPECT/CT of the abdomen only might be sufficient for imaging during the PRRT course. All accompanying CT images should be reviewed for additional findings, especially ascites, which is suggested to be a poor prognostic factor in patients receiving PRRT.

Elevated Serotonin and NT-proBNP Levels Predict and Detect Carcinoid Heart Disease in a Large Validation Study.

Carcinoid heart disease (CHD) is a rare fibrotic cardiac complication of neuroendocrine tumors. Besides known biomarkers N-Terminal pro-B-type natriuretic peptide (NT-proBNP) and serotonin, activin A, connective tissue growth factor (CTGF), and soluble suppression of tumorigenicity 2 (sST2) have been suggested as potential biomarkers for CHD. Here, we validated the predictive/diagnostic value of these biomarkers in a case-control study of 114 patients between 1990 and 2021. Two time-points were analyzed: T0: liver metastasis without CHD for all patients. T1: confirmed CHD in cases (CHD+, n = 57); confirmed absence of CHD five or more years after liver metastasis in controls (CHD−, n = 57). Thirty-one (54%) and 25 (44%) females were included in CHD+ and CHD− patients, respectively. Median age was 57.9 years for CHD+ and 59.7 for CHD- patients (p = 0.290). At T0: activin A was similar across both groups (p = 0.724); NT-proBNP was higher in CHD+ patients (17 vs. 6 pmol/L, p = 0.016), area under the curve (AUC) 0.84, and the most optimal cut-off at 6.5 pmol/L. At T1: activin A was higher in CHD+ patients (0.65 vs. 0.38 ng/mL, p = 0.045), AUC 0.62, without an optimal cut-off value. NT-pro-BNP was higher in CHD+ patients (63 vs. 11 pmol/L, p < 0.001), AUC 0.89, with an optimal cut-off of 27 pmol/L. Serotonin (p = 0.345), sST2 (p = 0.867) and CTGF (p = 0.232) levels were similar across groups. This large validation study identified NT-proBNP as the superior biomarker for CHD. Patients with elevated serotonin levels and NT-proBNP levels between 6.5 and 27 pmol/L, and specifically >27 pmol/L, should be monitored closely for the development of CHD.