Histopathological Features Predicting Neuroendocrine Morphology in Primary Breast Tumors: A Retrospective Analysis.

Objective: Neuroendocrine neoplasms of primary breast tumors are rare compared to locations, such as the respiratory system and gastrointestinal system, where they are frequently observed. The diagnostic criteria for primary neuroendocrine tumors of the breast have been changed since first description. Morphological and immunohistochemical features helpful in their diagnosis, which vary due to the heterogeneous nature of these tumors, are highlighted in this retrospective study. The purpose was to determine specific histopathological features that can identify neuroendocrine morphology in primary breast tumors. Materials and Methods: Cases diagnosed with invasive breast carcinoma from resection materials in a single center between 2011 and 2022 and in which neuroendocrine markers were investigated were included. Demographic information, initial histopathological diagnosis, presence of tumor in another organ, tumor location, size and surgical details of the cases were obtained from the hospital database and pathology reports. The slides were re-evaluated in terms of tumor growth pattern, cribriformity, tubule formation, nuclear features, prominence of nucleoli, palisading and basal location of nuclei, presence of grooves, cytoplasmic features and evidence of cytoplasmic border. Results: The presence of basally located nuclei, absence of tubule formation, inconspicuous nucleoli, fine nuclear chromatin, granular cytoplasm and inconspicuous cytoplasmic borders were frequent findings in tumors with neuroendocrine features (p<0.05). These features may help differentiate primary breast tumors with neuroendocrine features from other breast carcinomas. Conclusion: The histopathological features that are different from the specific features seen in classical neuroendocrine tumors, the absence of specific clinical and radiological findings, the inability to study neuroendocrine markers in every laboratory and the need to prove that the breast tumor is not a metastasis all create diagnostic difficulties for primary breast neuroendocrine neoplasms. We believe that the results of this study may help diagnose and identify more specific histomorphological features that help determine neuroendocrine morphology in primary breast tumors.

Novel ensemble feature selection techniques applied to high-grade gastroenteropancreatic neuroendocrine neoplasms for the prediction of survival.

BACKGROUND AND OBJECTIVE: Determining the most informative features for predicting the overall survival of patients diagnosed with high-grade gastroenteropancreatic neuroendocrine neoplasms is crucial to improve individual treatment plans for patients, as well as the biological understanding of the disease. The main objective of this study is to evaluate the use of modern ensemble feature selection techniques for this purpose with respect to (a) quantitative performance measures such as predictive performance, (b) clinical interpretability, and (c) the effect of integrating prior expert knowledge. METHODS: The Repeated Elastic Net Technique for Feature Selection (RENT) and the User-Guided Bayesian Framework for Feature Selection (UBayFS) are recently developed ensemble feature selectors investigated in this work. Both allow the user to identify informative features in datasets with low sample sizes and focus on model interpretability. While RENT is purely data-driven, UBayFS can integrate expert knowledge a priori in the feature selection process. In this work, we compare both feature selectors on a dataset comprising 63 patients and 110 features from multiple sources, including baseline patient characteristics, baseline blood values, tumor histology, imaging, and treatment information. RESULTS: Our experiments involve data-driven and expert-driven setups, as well as combinations of both. In a five-fold cross-validated experiment without expert knowledge, our results demonstrate that both feature selectors allow accurate predictions: A reduction from 110 to approximately 20 features (around 82%) delivers near-optimal predictive performances with minor variations according to the choice of the feature selector, the predictive model, and the fold. Thereafter, we use findings from clinical literature as a source of expert knowledge. In addition, expert knowledge has a stabilizing effect on the feature set (an increase in stability of approximately 40%), while the impact on predictive performance is limited. CONCLUSIONS: The features WHO Performance Status, Albumin, Platelets, Ki-67, Tumor Morphology, Total MTV, Total TLG, and SUVmax are the most stable and predictive features in our study. Overall, this study demonstrated the practical value of feature selection in medical applications not only to improve quantitative performance but also to deliver potentially new insights to experts.

Metronomic Temozolomide (mTMZ) and Bevacizumab-The Safe and Effective Frontier for Treating Metastatic Neuroendocrine Tumors (NETs): A Single-Center Experience.

Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment's efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide-capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials.

Myasthenia gravis as initial presentation of a pancreatic neuroendocrine tumor: A case report.

Myasthenia gravis (MG) is a heterogeneous autoimmune disease, which is characterized by a postsynaptic neuromuscular transmission defect, with antibodies directly targeting the acetylcholine receptor (AChR) or other structural proteins of the neuromuscular junction. The majority of MG cases are associated with thymic pathologies, including thymoma, thyroiditis, autoimmune diseases or malignant hematologic neoplasia. The present study reported a rare case of AChR-positive and late-onset ocular MG, which rapidly progressed to a generalized myasthenic syndrome as an initial presentation of a pancreatic neuroendocrine neoplasia (pNEN). Following complete surgical resection of the pNEN, the myasthenic syndrome was improved and the anti-AChR antibody titers were reduced. It has been reported that MG is a paraneoplastic syndrome in thymic neoplasms and less common in hematologic malignancies. However, currently, only few cases of MG as initial presentation of a solid tumor, and more particular of a neuroendocrine neoplasm, have been reported in the literature. In conclusion, surveillance for extrathymic solid malignancies in newly diagnosed patients with MG could promote the early diagnosis of associated tumor diseases.

Gastroenteropancreatic Neuroendocrine Tumors-Current Status and Advances in Diagnostic Imaging.

Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) is a heterogeneous and complex group of tumors that are often difficult to classify due to their heterogeneity and varying locations. As standard radiological methods, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT) are available for both localization and staging of NEN. Nuclear medical imaging methods with somatostatin analogs are of great importance since radioactively labeled receptor ligands make tumors visible with high sensitivity. CT and MRI have high detection rates for GEP-NEN and have been further improved by developments such as diffusion-weighted imaging. However, nuclear medical imaging methods are superior in detection, especially in gastrointestinal NEN. It is important for radiologists to be familiar with NEN, as it can occur ubiquitously in the abdomen and should be identified as such. Since GEP-NEN is predominantly hypervascularized, a biphasic examination technique is mandatory for contrast-enhanced cross-sectional imaging. PET/CT with somatostatin analogs should be used as the subsequent method.

Three Dimensional Models of Endocrine Organs and Target Tissues Regulated by the Endocrine System.

Immortalized cell lines originating from tumors and cultured in monolayers in vitro display consistent behavior and response, and generate reproducible results across laboratories. However, for certain endpoints, these cell lines behave quite differently from the original solid tumors. Thereby, the homogeneity of immortalized cell lines and two-dimensionality of monolayer cultures deters from the development of new therapies and translatability of results to the more complex situation in vivo. Organoids originating from tissue biopsies and spheroids from cell lines mimic the heterogeneous and multidimensional characteristics of tumor cells in 3D structures in vitro. Thus, they have the advantage of recapitulating the more complex tissue architecture of solid tumors. In this review, we discuss recent efforts in basic and preclinical cancer research to establish methods to generate organoids/spheroids and living biobanks from endocrine tissues and target organs under endocrine control while striving to achieve solutions in personalized medicine.

Efficacy of Capecitabine and Temozolomide Regimen in Neuroendocrine Tumors: Data From the Turkish Oncology Group.

INTRODUCTION: This study aims to report the efficacy and safety of capecitabine plus temozolomide (CAPTEM) across different lines of treatment in patients with metastatic neuroendocrine tumors (NETs). METHODS: We conducted a multicenter retrospective study analyzing the data of 308 patients with metastatic NETs treated with CAPTEM between 2010 and 2022 in 34 different hospitals across various regions of Turkey. RESULTS: The median follow-up time was 41.0 months (range: 1.7-212.1), and the median age was 53 years (range: 22-79). Our results across the entire patient cohort showed a median progression-free survival (PFS) of 10.6 months and a median overall survival (OS) of 60.4 months. First-line CAPTEM treatment appeared more effective, with a median PFS of 16.1 months and a median OS of 105.8 months (median PFS 16.1, 7.9, and 9.6 months in first-, second- and ≥third-line respectively, P = .01; with median OS values of 105.8, 47.2, and 24.1 months, respectively, P = .003) In terms of ORR, the first-line treatment again performed better, resulting in an ORR of 54.7% compared to 33.3% and 30.0% in the second and third or higher lines, respectively (P < .001). Grade 3-4 side effects occurred only in 22.5% of the patients, leading to a discontinuation rate of 9.5%. Despite the differences in outcomes based on treatment line, we did not observe a significant difference in terms of side effects between the first and subsequent lines of treatment. CONCLUSIONS AND RELEVANCE: The substantial superior outcomes in patients receiving first-line CAPTEM treatment highlight its potential as an effective treatment strategy for patients with metastatic NET.

Endoscopic and Surgical Management of Non-Metastatic Ampullary Neuroendocrine Neoplasia: A Multi-Institutional Pancreas2000/EPC Study.

INTRODUCTION: Ampullary neuroendocrine neoplasia (NEN) is rare and evidence regarding their management is scarce. This study aimed to describe clinicopathological features, management, and prognosis of ampullary NEN according to their endoscopic or surgical management. METHODS: From a multi-institutional international database, patients treated with either endoscopic papillectomy (EP), transduodenal surgical ampullectomy (TSA), or pancreaticoduodenectomy (PD) for ampullary NEN were included. Clinical features, post-procedure complications, and recurrences were assessed. RESULTS: 65 patients were included, 20 (30.8%) treated with EP, 19 (29.2%) with TSA, and 26 (40%) with PD. Patients were mostly asymptomatic (n = 46; 70.8%). Median tumor size was 17 mm (12-22), tumors were mostly grade 1 (70.8%) and pT2 (55.4%). Two (10%) EP resulted in severe American Society for Gastrointestinal Enterology (ASGE) adverse post-procedure complications and 10 (50%) were R0. Clavien 3-5 complications did not occur after TSA and in 4, including 1 postoperative death (15.4%) of patients after PD, with 17 (89.5%) and 26 R0 resection (100%), respectively. The pN1/2 rate was 51.9% (n = 14) after PD. Tumor size larger than 1 cm (i.e., pT stage >1) was a predictor for R1 resection (p < 0.001). Three-year overall survival and disease-free survival after EP, TSA, and PD were 92%, 68%, 92% and 92%, 85%, 73%, respectively. CONCLUSION: Management of ampullary NEN is challenging. EP should not be performed in lesions larger than 1 cm or with a endoscopic ultrasonography T stage beyond T1. Local resection by TSA seems safe and feasible for lesions without nodal involvement. PD should be preferred for larger ampullary NEN at risk of nodal metastasis.

Neuroendocrine carcinoma of cervix and review literature.

INTRODUCTION: Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer with poor prognosis and high mortality. Recurrence is seen with multi-organ metastasis including liver. CASE PRESENTATION: A 65 year old female presented with vaginal bleeding for the past one year. Cervical cancer screening and biopsy demonstrated poorly differentiated squamous carcinoma. Immunohistochemistry showed positive expression of chromogranin, synaptophysin, pancytokeratin, TTP1, and CEA and negative expression of p40 and estrogen receptors. An adenocarcinoma with neuroendocrine tumor was suggested. Hysterectomy with bilateral salpingo-oophrectomy was performed. This was followed by carboplatin and etoposide therapy to have clinical remission for a year. Then recurrence was observed to start same drugs again resulting in to partial improvement. It was followed by radiotherapy. The patient succumbed to death approximately after three months. CONCLUSION: A metastatic lesion in liver may be a case of Neuroendocrine tumor of cervix, a rare condition that can be easily missed on histopathological examination. More studies are required to establish a standard therapeutic protocol.

Sex Differences in Survival from Neuroendocrine Neoplasia in England 2012-2018: A Retrospective, Population-Based Study.

Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England's National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73-5.90) to 10.26 (6.6-14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor.

Analyses of sex-based clinicopathological differences among patients with gastrointestinal neuroendocrine neoplasms in Europe.

BACKGROUND: Previous studies have found variations in cancer types, tumor progression, and disease outcomes between men and women. However, there is limited knowledge of the effect of sex on gastrointestinal neuroendocrine neoplasms (GI-NENs). METHODS: We identified 1354 patients with GI-NEN from the IQVIA's Oncology Dynamics database. Patients were derived from four European countries (Germany, France, the United Kingdom (UK), Spain). Clinical and tumor related characteristics including patients' age, tumor stage, tumor grading and differentiation, frequency and sites of metastases, as well as co-morbidities were analyzed as a function of patients´ sex. RESULTS: Among the 1354 included patients, 626 were female and 728 were male. The median age was similar between both groups (w: 65.6 years, SD: 12.1 vs. m: 64.7 years; SD: 11.9; p = 0.452). UK was the country with the most patients, however, there was no differences in the sex ratio between the different countries. Among documented co-morbidities, asthma was more often diagnosed in women (7.7% vs. 3.7%), while COPD was more prevalent in men (12.1% vs. 5.8%). The ECOG performance states was comparable between females and males. Of note, the patients´ sex was not associated with tumor origin (e.g., pNET or siNET). Females were overrepresented among G1 tumors (22.4% vs. 16.8%), however, median proliferation rates according to Ki-67 were similar between both groups. In line, no differences in tumor stages was found and rates of metastases as well as the specific sites of metastases were similar between males and females. Finally, no differences in the applied tumor specific treatments between the both sexes became apparent. CONCLUSION: Females were overrepresented among G1 tumors. No further sex-specific differences became apparent, highlighting that sex-related factors might play a rather subordinate role in the pathophysiology of GI-NENs. Such data may help to better understand the specific epidemiology of GI-NEN.

On the Chopping Block: Overview of DICER1 Mutations in Endocrine and Neuroendocrine Neoplasms.

Mutational inactivation of the DICER1 gene causes aberrant micro-RNA maturation, which in turn may have consequences for the posttranscriptional regulation of gene expression, thereby contributing to tumor formation in various organs. Germline DICER1 mutations cause DICER1 syndrome, a pleiotropic condition with an increased risk of various neoplastic conditions in the pleura, ovaries, thyroid, pituitary, pineal gland, and mesenchymal tissues. Somatic DICER1 mutations are also frequently observed in a wide variety of solid tumors, thereby highlighting the importance of this gene in tumor development. In this review, the importance of DICER1 inactivation in endocrine tumors is discussed.

Immuno-histochemical correlation of fibrosis-related markers with the desmoplastic reaction of the mesentery in small intestine neuroendocrine neoplasms.

INTRODUCTION: Small intestine neuroendocrine neoplasms (siNENs) will attain more importance due to their increasing incidence. Moreover, siNENs might lead to a desmoplastic reaction (DR) of the mesentery causing severe complications and deteriorating prognosis. The expression of fibrosis-related proteins appears to be the key mechanisms for the development of this desmoplastic reaction. Therefore, this study aimed to investigate the association of the desmoplastic mesentery with specific fibrosis-related protein expression levels. MATERIALS AND METHODS: By immunohistochemistry, the protein expression levels of four fibrosis-related markers (APLP2, BNIP3L, CD59, DKK3) were investigated in primary tumors of 128 siNENs. The expression levels were correlated with the presence of a desmoplastic reaction and clinico-pathological parameters. RESULTS: In the primary tumor, APLP2, BNIP3L, CD59 and DKK3 were highly expressed in 29.7% (n = 38), 64.9% (n = 83), 92.2% (n = 118) and 80.5% (n = 103), respectively. There was no significant correlation of a single marker or the complete marker panel to the manifestation of a desmoplastic mesentery. The desmoplastic mesentery was significantly associated with clinical symptoms, such as flushing and diarrhea. However, neither the fibrosis-related marker panel nor single marker expressions were associated with clinical symptoms. DISCUSSION: The expression rates of four fibrosis-related markers in the primary tumor display a distinct pattern. However, the expression patterns are not associated with desmoplastic altered mesenteric lymph node metastases and the expression patterns did not correlate with prognosis. These findings suggest alternative mechanisms being responsible for the desmoplastic reaction.

Appendiceal neuroendocrine neoplasia: analysis of 50 patients.

OBJECTIVE: The objective of this study was to investigate the clinical, surgical, and pathological findings of appendiceal neuroendocrine neoplasms (ANNs). MATERIALS AND METHODS: The demographic, clinical, surgical, and pathological characteristics of 50 patients with ANN were analyzed. The patients were also classified as Group 1 (< 40 years, n = 37) and Group 2 (≥ 40 years, n = 13), and compared each other in terms of all parameters. RESULTS: Acute appendicitis was the pre-operative clinical presentation in 48 (96%) patients. Appendectomy (94%) was the most common surgical procedure. Mean tumor size was 8.6 mm (1-70 mm). Approximately half of the tumors (46%) were T1. There was no lymphatic and distant metastasis. The patients in Group 2 (15.4 mm) had a higher mean tumor size than patients in Group 1 (6.3 mm) (p < 0.001). The two groups were similar in other characteristics (p > 0.05). CONCLUSIONS: ANNs are usually diagnosed after histopathological evaluation due to the lack of specific clinicoradiological signs. Therefore, carefull intraoperative examination of appendectomy specimens may increase the possibility of suspecting these tumors. The results also showed that ANNs were bigger in patients above 40-years-old. Although not statistically significant, ANNs tended to have higher grade and to be more located at the base of the appendix in this group of patients.

OBJETIVO: Investigar los hallazgos clínicos, quirúrgicos y patológicos de las neoplasias neuroendocrinas (RNA) apendiculares. MÉTODO: Se analizaron las características demográficas, clínicas, quirúrgicas y patológicas de 50 pacientes con RNA. Los pacientes también fueron clasificados como Grupo 1 (< 40 años, n = 37) y Grupo 2 (≥ 40 años, n = 13), y se compararon entre sí en términos de todos los parámetros. RESULTADOS: La apendicitis aguda fue la presentación clínica preoperatoria en 48 (96%) pacientes. La apendicectomía (94%) fue el procedimiento quirúrgico más común. El tamaño medio del tumor fue de 8,6 mm (1-70 mm). Aproximadamente la mitad de los tumores (46%) eran T1. No hubo metástasis linfáticas ya distancia. Los pacientes del Grupo 2 (15.4 mm) tenían un tamaño tumoral medio mayor que los pacientes del Grupo 1 (6.3 mm) (p < 0.001). Los dos grupos fueron similares en otras características (p > 0.05). CONCLUSIONES: Las RNA suelen diagnosticarse tras evaluación histopatológica debido a la falta de signos clínico-radiológicos específicos. Por lo tanto, el examen intraoperatorio cuidadoso de las muestras de apendicectomía puede aumentar la posibilidad de sospechar estos tumores. Los resultados también mostraron que las ANN eran más grandes en pacientes mayores de 40 años. Aunque no estadísticamente significativas, las ANN tendieron a tener mayor grado y estar más ubicadas en la base del apéndice en este grupo de pacientes.

Visceral Obesity Is Associated with Shorter Progression-Free Survival in Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine Neoplasia.

The association of well-differentiated gastro-entero-pancreatic neuroendocrine neoplasia (WD GEP-NEN) with metabolic syndrome (MetS), abdominal obesity, and fasting glucose abnormalities was recently described. However, whether obesity and metabolic syndrome risk factors are associated with GEP-NEN adverse outcomes and the poorer prognosis was unknown. The present study aimed to evaluate whether the presence of MetS or any of its individual components at WD GEP-NEN diagnosis influenced disease outcomes. A cohort of patients with non-localized WD GEP-NETs (n = 81), was classified according to the primary tumor site (gastrointestinal or pancreatic), pathological grading (G1 (Ki67 ≤ 2%) and G2 (3% ≤ Ki67 ≤ 20%) (WHO 2010)), disease extension (loco-regional or metastatic disease), presence of hormonal secretion syndrome (functioning or non-functioning), and evaluated for the presence of MetS criteria at diagnosis. MetS was present in 48 (59.3%) patients. During a median follow-up of 95.0 months (16.8-262.5), 18 patients died of the disease (10 with MetS vs. 8 without MetS). Overall survival (OS) at 5 years was 87.1% (95% CI: 73.6-94.0) for MetS and 90.9% (95% CI: 74.4-97.0) for non-Mets group, while OS at 10 years was 72.5% (95% CI: 55.3-84.0) for MetS, and 76.4% (95% CI: 53.6-89.0) for non-MetS group. Progression-Free Survival (PFS) at 5 years was 45.9% (95% CI: 30.8-59.8) for MetS and 40.0% (95% CI: 21.3-58.1) for non-MetS group, and PFS at 10 years was 18.1% (95% CI: 7.0-33.5) for MetS and 24.4% (95% CI: 9.0-43.7) for non-MetS group. Waist circumference (WC), a surrogate measure for visceral obesity, was associated with significantly shorter PFS (HR = 1.03; 95% CI: 1.01-1.06), although did not influence OS (HR = 1.01; 95% CI: 0.97-1.06). The findings of this study reinforce a potential link between visceral obesity and GEP-NEN and further suggest that obesity could influence disease prognosis.

Incidence and survival of neuroendocrine neoplasia in England 1995-2018: A retrospective, population-based study.

Background: Neuroendocrine neoplasia (NEN) incidence is rising internationally. We aimed to evaluate the epidemiology of NEN in England and examine changes in survival over time. Methods: A retrospective, population-based study using nationally representative data between 1995 and 2018 from the National Cancer Registry and Analysis Service (NCRAS) in England was conducted on 63,949 tumours. Age-standardized incidence was calculated using Office for National Statistics (ONS) data. Overall survival (OS) was calculated using the Kaplan-Meier estimator. Multivariable analysis was performed using an accelerated failure time model. Findings: Of 63,949 cases, 50.5% (32,309) were female. Age-adjusted incidence increased 3.7-fold between 1995 and 2018 from 2.35 to 8.61 per 100,000. In 2018, highest incidence occurred in lung (1.47 per 100,000), small intestine (1.46 per 100,000), pancreas (1.00 per 100,000) and appendix (0.95 per 100,000). In multivariable analysis, age, sex, morphology, stage, site and deprivation were independent predictors of survival (p < 0.001). Survival of the entire cohort, and by primary site, is improving over time. Interpretation: NEN incidence continues to rise in England with survival improving over time. Relatively high survival compared to other cancers is an issue for long-term outcomes and funding of care. Funding: Data were extracted and transferred using a grant from Neuroendocrine cancer UK.

ArTisaN trial protocol: a single Centre, open-label, phase II trial of the safety and efficacy of TheraSphere selective internal radiation therapy (SIRT) in the treatment of inoperable metastatic (liver) neuroendocrine neoplasia (NENs).

BACKGROUND: Neuroendocrine neoplasias (NENs) are a rare type of malignancy that arise from the cells of the neuroendocrine system. Most patients present with advanced, unresectable disease, typically with metastases to the liver. The presence of liver metastases dictates prognosis and there has been a number of studies investigating therapies that reduce the burden of liver disease. Selective Internal Radiation Therapy (SIRT) allows the delivery of targeted high dose radiation directly to tumours, with relative sparing of the surrounding liver tissue. Here, we describe the design and rationale of ArtTisaN, a phase II study to assess efficacy and tolerability of SIRT using TheraSpheres for the management of liver metastases secondary to NENs. METHODS: Twenty-four eligible participants will be recruited to receive SIRT with TheraSpheres. The primary objective is to determine the objective response rate to treatment, defined as the rate of best overall response in the treated liver volume. In addition, total hepatic response and overall response will be assessed according to RECIST 1.1. The second co-primary objective is to determine the incidence of adverse and serious adverse device events. The secondary objectives are progression free survival, overall survival and quality of life. Additional exploratory objectives include investigation of circulating biomarkers of response and identification of a radiomic signature of response. DISCUSSION: This trial will provide prospective evidence on the efficacy of SIRT using TheraSpheres for the management of liver metastases. TRIAL REGISTRATION: NCT04362436 .