Endoscopic submucosal dissection for rectal neuroendocrine tumours: A multicentric retrospective study.

INTRODUCTION: Endoscopic Submucosal Dissection (ESD) has been reported as a feasible and effective treatment for Rectal Neuroendocrine Tumours (R-NETs). However, most of the experience on the topic comes from retrospective tertiary centre from Eastern Asia. Data on ESD for R-NETs in Western centres are lacking. MATERIALS AND METHODS: This is a retrospective study, including patients who underwent endoscopic resection of R-NETS by ESD between 2015 and 2020 in Western Centres. Important clinical variables such as demographic, size of R-NETs, histological type, presence of lymphovascular invasion or distant metastasis, completeness of the endoscopic resection, recurrence, and procedure related complications were recorded. RESULTS: 40 ESD procedure on R-NETs from 39 patients from 8 centres were included. Mean R-NETs size was 10.3 mm (SD 4.01). Endoscopic en-bloc resection was achieved in 39/40 ESD (97.5 %), R0 margin resection was obtained in 87.5 % (35/40) of the procedures, one patient was referred to surgery for lymphovascular invasion, two procedures (5 %) reported significant episodes of bleeding, whereas a perforation occurred in one case (1/40, 2.5 %) managed endoscopically. Recurrence occurred in 1 patient (2.5 %). CONCLUSION: ESD is an effective and safe treatment for R-NETs in western centres.

Endoscopic Management of Gastro-Entero-Pancreatic Neuroendocrine Tumours: An Overview of Proposed Resection and Ablation Techniques.

A literature search of MEDLINE/PUBMED was conducted with the aim to highlight current endoscopic management of localised gastro-entero-pancreatic NETs. Relevant articles were identified through a manual search, and reference lists were reviewed for additional articles. The results of the research have been displayed in a narrative fashion to illustrate the actual state-of-the-art of endoscopic techniques in the treatment of NETs. Localised NETs of the stomach, duodenum and rectum can benefit from advanced endoscopic resection techniques (e.g., modified endoscopic mucosal resection, endoscopic full thickness resection, endoscopic submucosal dissection) according to centre expertise. Radiofrequency thermal ablation can be proposed as an alternative to surgery in selected patients with localised pancreatic NETs.

Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

Management Strategies and Outcomes for Small Intestinal Neuroendocrine Tumours with Involvement of the Superior Mesenteric Vessels: A Systematic Review.

Small intestinal neuroendocrine tumours (SI-NETs) are the most common small intestinal tumours. A particularly challenging subset of these tumours is those that involve the superior mesenteric artery or vein for which the role and feasibility of surgery are often questioned. This systematic review aimed to identify and evaluate the management strategies used for these complex SI-NETs. The identified studies showed positive outcomes with surgery and multimodality therapy.

Response heterogeneity as a new biomarker of treatment response in patients with neuroendocrine tumors.

Aim: The RAISE project aimed to find a surrogate end point to predict treatment response early in patients with enteropancreatic neuroendocrine tumors (NET). Response heterogeneity, defined as the coexistence of responding and non-responding lesions, has been proposed as a predictive marker for progression-free survival (PFS) in patients with NETs. Patients & methods: Computerized tomography scans were analyzed from patients with multiple lesions in CLARINET (NCT00353496; n = 148/204). Cox regression analyses evaluated association between response heterogeneity, estimated using the standard deviation of the longest diameter ratio of target lesions, and NET progression. Results: Greater response heterogeneity at a given visit was associated with earlier progression thereafter: week 12 hazard ratio (HR; 95% confidence interval): 1.48 (1.20-1.82); p < 0.001; n = 148; week 36: 1.72 (1.32-2.24); p < 0.001; n = 108. HRs controlled for sum of longest diameter ratio: week 12: 1.28 (1.04-1.59); p = 0.020 and week 36: 1.81 (1.20-2.72); p = 0.005. Conclusion: Response heterogeneity independently predicts PFS in patients with enteropancreatic NETs. Further validation is required.

Neuroendocrine tumors (NET) are rare, slow-growing cancers that can grow in various parts of the body. By understanding how NETs are responding to treatment, doctors can choose the best treatment for a patient and monitor whether the treatment needs to be changed. Treatment response is determined using 'Response Evaluation Criteria in Solid Tumors (RECIST)': a technique which measures the size of tumors to assess whether they are shrinking. However, RECIST is not always useful in NETs, which grow slowly and rarely shrink. 'Response heterogeneity' describes the situation in which some tumors respond well to treatment, while other tumors in the same patient do not. Response heterogeneity may be important in understanding how tumors are responding to treatment and predicting outcomes for patients. Until now, the link between response heterogeneity and treatment response has not been studied in patients with NETs. The RAISE project examined data from a clinical trial of patients with NETs treated with lanreotide. In RAISE, response heterogeneity was estimated using imaging scans of NETs. Response heterogeneity was compared with factors such as tumor size and amounts of certain molecules found in the blood, to see how well response heterogeneity could predict outcomes for patients with NETs. In this study, response heterogeneity was linked with worse outcomes for patients. Therefore, it may be useful in understanding how NETs respond to treatment. Further research is needed in a different group of patients with NETs, and in patients receiving other treatments, to better understand response heterogeneity.

The use of deep learning models to predict progression-free survival in patients with neuroendocrine tumors.

Aim: The RAISE project assessed whether deep learning could improve early progression-free survival (PFS) prediction in patients with neuroendocrine tumors. Patients & methods: Deep learning models extracted features from CT scans from patients in CLARINET (NCT00353496) (n = 138/204). A Cox model assessed PFS prediction when combining deep learning with the sum of longest diameter ratio (SLDr) and logarithmically transformed CgA concentration (logCgA), versus SLDr and logCgA alone. Results: Deep learning models extracted features other than lesion shape to predict PFS at week 72. No increase in performance was achieved with deep learning versus SLDr and logCgA models alone. Conclusion: Deep learning models extracted relevant features to predict PFS, but did not improve early prediction based on SLDr and logCgA.

Safety and Efficacy of 177 Lu-DOTATATE in Neuroendocrine Tumor Patients With Extensive Bone Disease.

AIM: The aim of this study was to assess the efficacy and safety of 177 Lu-DOTATATE in patients with neuroendocrine tumors (NETs) and extensive bone metastases, that is, more than 50% of the skeleton involved. METHOD: A single-center retrospective analysis was performed in 30 patients (13 women and 17 men, mean age, 60 years; range, 35-77 years) undergoing 177 Lu-DOTATATE therapy. Patients had progressive metastatic NETs with extensive skeletal metastases (>50% skeletal involvement seen on baseline 68 Ga-DOTATATE PET/CT). The average administered activity was 7.308 (SD, 0.02) GBq per cycle with average treatment interval of 15 weeks. Survival analyses (progression-free survival [PFS], overall survival), radiological response assessment, toxicity assessment, and health-related quality of life (QoL) was performed. RESULTS: Overall, 26 patients completed 4 cycles, and 4 patients had less than 4 cycles of 177 Lu-DOTATATE. One patient (3%) did not complete treatment because of hematological toxicity. The estimated median PFS and median overall survival were calculated at 27 and 35 months, respectively. End-of-treatment radiological assessment showed partial response in 5 patients (17%), stable disease in 20 patients (66%), and radiological progressive disease in 3 patients (10%). Clinical progression was seen in a further 2 patients (7%).The incidence of grade 3/4 bone marrow toxicity was 10%. No patient had grade 3/4 peptide receptor radionuclide therapy-related nephrotoxicity. There was overall improvement in global QoL score (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Gastrointestinal NET-21) ( P = 0.019). CONCLUSION: 177 Lu-DOTATATE seems to have satisfactory therapeutic outcome in patients with advanced metastatic NET with extensive bone disease, with reasonable PFS and significant improvement in the global health-related QoL. The bone marrow toxicity was within the accepted range. Increasing the interval between cycles does not seem to reduce efficacy and may reduce toxicity, ensuring the bone marrow has sufficient time to recover between cycles.

Single centre retrospective review of outcome of 177 Lu-DOTATATE peptide receptor radionuclide therapy in the treatment of progressive metastatic neuroendocrine tumours: Survival, toxicity, and prognostic factors.

The aim of this study was to evaluate the efficacy and safety of 177 Lu-DOTATATE therapy in advanced metastatic disease. A retrospective analysis of 395 patients (180 female, 215 males, mean age 62) with progressive metastatic neuroendocrine tumours (NETs) who were treated with 177 Lu-DOTATATE was performed. Overall, 115 patients had less than four cycles and 280 completed four cycles of treatment. Progression-free survival (PFS) and overall survival (OS) was performed using Kaplan-Meier analysis. Analysis of survival predictors was performed using Cox regression model. Toxicity was defined using the Common Terminology Criteria for Adverse Events version 5 (CTCAE 5.0). The percentage of patients with liver and skeletal metastases were 91 and 57%, respectively. Median PFS and OS were calculated at 33 months (95% CI: 29-37 months) and 46 months (95% CI: 48-56 months), respectively. End of treatment response assessment was performed using cross sectional imaging demonstrated partial response in 22%, stable disease in 64% and progressive disease in 14% of patients. Overall, grade 3 and 4 bone marrow toxicity was seen in 8%. One patient (0.3%) developed irreversible grade 4 nephrotoxicity. Myelodysplastic disease was recorded in one patient (0.3%). Univariate analysis of PFS predictors showed that body mass index (BMI), baseline chromogranin A (CgA) >400 ng/l, baseline alkaline phosphatase (ALP) >130 mg/dl, liver tumour volume and overall tumour burden were significant. On multivariate analysis only Ki67, high CgA and low BMI retained significance. 177 Lu-DOTATATE is an effective treatment in advanced NETs with generally high-volume metastases. It is well-tolerated. Ki-67, CgA and BMI appear to be predictors for PFS.

Diagnostic features and management options for duodenal neuroendocrine neoplasms: a retrospective, multi-centre study.

Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32-87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9-130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54-13) (p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56-29.5) (p < 0.05) in the multivariate analysis. Lesions 11-20 mm in size had OR 11.1 (1.16-106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (p < 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81-0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed.

What Causes Desmoplastic Reaction in Small Intestinal Neuroendocrine Neoplasms?

PURPOSE OF REVIEW: Mesenteric desmoplasia in small intestinal neuroendocrine neoplasms (SINENs) is associated with increased morbidity and mortality. In this paper, we discuss the development of desmoplasia in SINENs. RECENT FINDINGS: The fibrotic reactions associated with these tumours could be limited to the loco-regional environment of the tumour and/or at distant sites. Mesenteric fibrotic mass forms around a local lymph node. Formation of desmoplasia is mediated by interactions between the neoplastic cells and its microenvironment via number of profibrotic mediators and signalling pathways. Profibrotic molecules that are mainly involved in the desmoplastic reaction include serotonin, TGFß (transforming growth factor ß) and CTGF (connective tissue growth factor), although there is some evidence to suggest that there are a number of other molecules involved in this process. Desmoplasia is a result of autocrine and paracrine effects of multiple molecules and signalling pathways. However, more research is needed to understand these mechanisms and to develop targeted therapy to minimise desmoplasia.

Safety of Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients with Chronic Kidney Disease.

Our purpose was to assess the efficacy and safety of 177Lu-DOTATATE in neuroendocrine tumor patients with reduced renal function. Methods: A single-center retrospective analysis was performed on 33 patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 Of these, 26 had chronic kidney disease (CKD) stage 3a (eGFR, 45-60 mL/min/1.73 m2) and 7 had CKD 3b (eGFR, 30-45 mL/min/1.73 m2). Renal toxicity and temporal changes in eGFR were recorded. The association between potential risk factors and any kidney function deterioration (>10% reduction in eGFR) was evaluated. Data on survival, the radiologic response assessment, and quality of life were collected. Results: The incidence of permanent grade 3 or 4 nephrotoxicity was 3% (a single patient with grade 4 nephrotoxicity). The mean annual reduction in eGFR was estimated at 2.5%. A permanent decline of less than 10% in eGFR of any grade was recorded in 45% of patients (n = 15). Nine patients moved into higher CKD categories (8 patients who moved from CKD 3a to CKD 3b and 1 patient who moved from CKD 3b to CKD 5). No significant relationship was found between renal risk factors and a permanent reduction in renal function. Grade 3 or 4 bone marrow toxicity was observed in 9% of patients. The estimated median progression-free survival was 42 mo, and the median overall survival was 47 mo. At the end of treatment, the radiologic assessment showed a partial response in 33%, stable disease in 55%, and progressive disease in 12%. There was an improvement in global quality of life and endocrine score (European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Gastrointestinal NET-21) (P = 0.046 and 0.041, respectively). Conclusion: 177Lu-DOTATATE appears to be generally well tolerated in patients with preexisting CKD 3, with a low incidence of permanent major nephrotoxicity. 177Lu-DOTATATE appears to have a good therapeutic effect, with most patients reporting improvement in quality of life.

Development of a quality of life questionnaire for patients with pancreatic neuroendocrine tumours (the PANNET module).

Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1-3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire.

Prognostic stratification for patients with neuroendocrine tumours receiving 177Lu-Dotatate.

177Lu-Dotatate is increasingly used in patients with advanced neuroendocrine tumour (NET). However, few prognostic markers are available to stratify progression-free survival (PFS) of patients who received 177Lu-Dotatate. Clinicopathological data including baseline circulating biomarkers of patients with advanced NET who received 177Lu-Dotatate were routinely collected and were retrospectively analysed. Continuous variables were normalized by dividing them by their upper normal limits. The whole data set was randomly divided into a training set and a validation set. Univariate and multivariate logistic regression analyses were used to identify independent markers and to develop a scoring model to predict treatment failure at 1 year. In total, 195 patients were included. Elevated baseline chromogranin A (CgA), normal creatinine and previous chemotherapy were three risk factors independently associated with 1-year treatment failure. By combining these risk factors, a scoring model was developed which could accurately predict 1-year treatment failure both in the training set (area under curve, AUC, 0.813; 95% CI, 0.731-0.895; P< 0.001) and in the validation set (AUC, 0.816; 95% CI, 0.644-0.968; P< 0.001). After selecting a score of 29.7 as the cut-off value of the scoring model, patients could be stratified into two groups namely low-risk and high-risk with significantly different 1-year treatment failure rate, PFS and overall survival (OS; P< 0.001) both in the training set and validation set. In conclusion, baseline CgA, creatinine level and previous chemotherapy were independently associated with 1-year treatment failure of patients with advanced NET who received 177Lu-Dotatate and the scoring model and prognostic stratification based on these markers could accurately predict 1-year treatment failure, PFS and OS.

Is local excision sufficient in selected grade 1 or 2 type III gastric neuroendocrine neoplasms?

PURPOSE: Type III gastric neuroendocrine neoplasms (g-NENs) have historically been regarded as aggressive tumours, hence current guidelines advocate radical surgery with lymph node dissection. Data on the roles of endoscopic or less extensive surgical resections are more limited. The aim of our study is to evaluate the clinicopathological features and long-term outcomes of patients undergoing endoscopic or limited surgical resection for localised grade 1 or 2 type III g-NENs when compared to radical surgery. METHODS: Retrospective analysis of all patients diagnosed with a localised grade 1 or 2 type III g-NENs across six tertiary NEN centers between 2006 and 2019. RESULTS: Forty-five patients were diagnosed with a potentially resectable grade 1 or 2 type III g-NEN of whom 36 underwent either endoscopic or surgical resection. No statistically significant differences were found between the three resection groups in terms of patient age, tumour location, grade or size. Only tumour size was found to be significantly associated with poor clinical outcome (p = 0.012) and ROC curve analysis identified tumour size >10 mm as a negative predictor (AUC:0.8030, p = 0.0021). Tumours >10 mm were also more likely to be associated with lymph node metastases on imaging and histology (p = 0.039 and p = 0.026 respectively). CONCLUSIONS: Localised grade 1 or 2 type III g-NENs had a good prognosis in this series. Tumour size >10 mm was the most significant prognostic factor affecting patient outcome. Endoscopic resection or limited surgical resection is feasible and safe in small type III g-NENs which demonstrate favourable grade 1/2, well differentiated histology.

High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Improved Prognostic Stratification With the New World Health Organization 2019 Classification: A Validation Study From a Single-Institution Retrospective Analysis.

OBJECTIVES: There is a pressing need to develop clinical management pathways for grade 3 (G3) gastroenteropancreatic neuroendocrine neoplasms (GEP NEN). METHODS: We performed a retrospective study on patients with metastatic G3 GEP NEN. The relationship between baseline characteristics and progression-free survival and overall survival was analyzed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS: We included 142 patients (74 well-differentiated neuroendocrine tumors [WDNETs], 68 poorly differentiated neuroendocrine carcinomas [PDNECs]). Patients with WDNET had prolonged survival compared with PDNEC (median, 24 vs 15 months, P = 0.0001), which persisted in both pancreatic and nonpancreatic cohorts. Well-differentiated morphology, Ki-67 <50% and positive somatostatin receptor imaging were independently associated with prolonged survival. Of the subgroup treated with first-line platinum-based chemotherapy, response rates were favorable (partial response, 47%; stable disease, 30%); there was no significant difference in response rates nor progression-free survival between WDNET and PDNEC despite significantly prolonged overall survival in the WDNET cohort. CONCLUSIONS: Our study corroborates the knowledge of 2 prognostically distinct subgroups within the World Health Organization 2019 G3 GEP NEN population, observed in both pancreatic and nonpancreatic gastrointestinal cohorts. Definitive management pathways are needed to reflect the differences between G3 WDNET and PDNEC.

177Lu-DOTATATE in older patients with metastatic neuroendocrine tumours: safety, efficacy and health-related quality of life.

PURPOSE: The safety and efficacy of 177Lu-DOTATATE in older patients with advanced neuroendocrine tumours (NET) are not well understood. METHODS: Patients ≥70 years of age and treated with 177Lu-DOTATATE were included. Toxicity, health-related quality of life (HRQoL), objective response, progression-free survival (PFS) and overall survival (OS) were assessed. The relationship between baseline characteristics and PFS and OS was analysed using the Kaplan-Meier method. Univariate analyses were performed using the Cox proportional hazards model. RESULTS: In total, 71 patients were included (76.1% midgut primary). The median age at diagnosis and age at 177Lu-DOTATATE treatment were 70 and 74 years, respectively. The majority (78.9%) of patients completed 4 cycles of 177Lu-DOTATATE. Clinically significant myelosuppression was rare (2.8%). There was no deterioration in HRQoL and 'disease-specific worries' significantly improved (P = 0.029). Radiological response assessment was available in 66 patients. Partial response, stable disease and progression of disease were found in 10 (15.2%), 52 (78.8%) and 4 patients (6.1%), respectively. Median PFS and OS were 36.0 and 47.0 months, respectively. Increased baseline alkaline phosphatase was associated with poorer PFS (P = 0.002) and OS (P = 0.006). CONCLUSION: Patients ≥70 years of age with advanced NET treated with 177Lu-DOTATATE have efficacy and toxicity profiles similar to the wider NET population, without deterioration of HRQoL.

Transcriptomic Profiling of In Vitro Tumor-Stromal Cell Paracrine Crosstalk Identifies Involvement of the Integrin Signaling Pathway in the Pathogenesis of Mesenteric Fibrosis in Human Small Intestinal Neuroendocrine Neoplasms.

AIM: Analysis of the pathophysiology of mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs) in an in vitro paracrine model and in human SI-NET tissue samples. METHODS: An indirect co-culture model of SI-NET cells KRJ-I and P-STS with stromal cells HEK293 was designed to evaluate the paracrine effects on cell metabolic activity, gene expression by RT2 PCR Profilers to analyse cancer and fibrosis related genes, and RNA sequencing. The integrin signaling pathway, a specific Ingenuity enriched pathway, was further explored in a cohort of human SI-NET tissues by performing protein analysis and immunohistochemistry. RESULTS: RT Profiler array analysis demonstrated several genes to be significantly up- or down-regulated in a cell specific manner as a result of the paracrine effect. This was further confirmed by employing RNA sequencing revealing multiple signaling pathways involved in carcinogenesis and fibrogenesis that were significantly affected in these cell lines. A significant upregulation in the expression of various integrin pathway - related genes was identified in the mesenteric mass of fibrotic SI-NET as confirmed by RT-qPCR and immunohistochemistry. Protein analysis demonstrated downstream activation of the MAPK and mTOR pathways in some patients with fibrotic SI-NETs. CONCLUSION: This study has provided the first comprehensive analysis of the crosstalk of SI-NET cells with stromal cells. A novel pathway - the integrin pathway - was identified and further validated and confirmed in a cohort of human SI-NET tissue featured by a dual role in fibrogenesis/carcinogenesis within the neoplastic fibrotic microenvironment.

Understanding the Treatment Algorithm of Patients with Metastatic Pancreatic Neuroendocrine Neoplasms: A Single-Institution Retrospective Analysis Comparing Outcomes of Chemotherapy, Molecular Targeted Therapy, and Peptide Receptor Radionuclide Therapy in 255 Patients.

BACKGROUND: The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities. METHODS: We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type, and time to treatment failure (TTF), time to progression (TTP), and overall survival (OS) was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS: Two hundred and fifty-five patients with metastatic PNEN had 491 evaluable lines of therapy. Independent predictors of TTF included treatment type, Ki-67, tumour grade, and chromogranin A. To reduce selection bias, a subgroup of 114 patients with grade 2 (G2) metastatic pancreatic neuroendocrine tumours (PNET) was analysed separately. These patients had received 234 lines of treatment (105 chemotherapy, 82 molecular targeted therapy, and 47 peptide receptor radionuclide therapy [PRRT]). In the G2 cohort, TTF and TTP were superior for PRRT compared with both chemotherapy and molecular targeted therapy. OS in the G2 cohort was also superior for those that had received PRRT compared with those that had not (median 84 vs. 56 months; HR 0.55, 95% CI: 0.31-0.98, p = 0.04). CONCLUSIONS: This study suggests that PRRT is associated with superior clinical outcomes relative to other systemic therapies for G2 metastatic PNET. Prospective studies are required to confirm these observations.

Cardiac Metastases in Patients with Neuroendocrine Tumours: Clinical Features, Therapy Outcomes, and Prognostic Implications.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, p = 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) >2 × upper limit of normal (ULN), were independent poor prognosticators. CONCLUSIONS: Clinical features of NET CM ranged from asymptomatic patients to heart failure. Concomitant bone or pancreatic metastases and NT pro-BNP levels >2 ULN predicted shorter survival time. PRRT serves as a feasible therapy with promising survival benefits; however, more data are needed.

Home Total Parenteral Nutrition for Intestinal Failure in Patients with Advanced Small Intestinal Neuroendocrine Neoplasms.

The role of total parenteral nutrition (TPN) in cancer patients is controversial, but it may be a treatment option for some patients with indolent but advanced small intestinal neuroendocrine neoplasms (SI-NENs). The aim of this study is to investigate whether home TPN was associated with long-term survival and to assess the indications, duration and complications of TPN in patients with advanced SI-NENs. Patients with advanced SI-NENs who received home TPN were retrospectively included. Electronic records were reviewed for clinical information. Five patients receiving home TPN were identified out of 1011 patients with SI-NENs in our center. The median duration of TPN administration was 12 mo. Small bowel obstruction was the most common reason for TPN initiation. TPN-related complications included two catheter infections, one thrombosis and one episode of TPN-related transaminitis. At the last follow-up, three patients had died and two were alive. The median survival was 12 mo. Overall estimated 1-yr probability of survival on home TPN by Kaplan-Meier analysis was 40%. In conclusion, home TPN may be a treatment option in highly selected advanced SI-NEN patients with severe gastrointestinal tract dysfunction. The initiation of home TPN is associated with long-term survival (≥1 yr), and complication rates appear acceptable.