Search

Introduction: The available data for the safety and efficacy of repeat peptide receptor radionuclide therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence. Methods: We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177Lu DOTATATE or 90Y DOTATOC) and following radiographic disease progression were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates, and toxicities after PRRT 1 and PRRT 2. Results: A total of 11 patients were included in the analysis. 45.5% (5/11) of patients received 177Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) of patients received 90Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3–6 months), 18.2% (2/11), 36.4% (4/11), and 27.3% (3/11) of patients had PR, SD, and PD, respectively; 2/11 patients (18.2%) died before the first restaging scan. Therefore, 5/11 (45.5%) patients were noted to have disease progression. Median PFS for PRRT1 was 25.4 months and median PFS for PRRT2 was 13.1 months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2. Conclusion: We show that repeat PRRT may benefit select patients and have an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs. [ABSTRACT FROM AUTHOR]

Inositols have demonstrated a role in cancer prevention and treatment in many kinds of neoplasms. Their molecular mechanisms vary from the regulation of survival and proliferative pathways to the modulation of immunity and oxidative stress. The dysregulation of many pathways and mechanisms regulated by inositols has been demonstrated in endocrine and neuroendocrine tumors but the role of inositol supplementation in this context has not been clarified. The aim of this review is to summarize the molecular basis of the possible role of inositols in endocrine and neuroendocrine tumors, proposing it as an adjuvant therapy. [ABSTRACT FROM AUTHOR]

Introduction Neuroendocrine neoplasms (NENs) are heterogeneous group of neoplasms with relatively low incidence. Diagnosis of NENs requires an integrated approach of histology, immunohistochemistry, and molecular study. In the present study, we evaluated insulinoma-associated protein 1 (INSM1) expression in NENs and correlated it with other established neuroendocrine markers. Materials and Method Retrospective cross-sectional study was conducted in a tertiary care center. Consecutively, 100 cases from year November 2019 to January 2021 were enrolled in the study and all relevant data were noted. Results The mean (±standard deviation) age of the patients was 55.5 (±10.6) years with a male preponderance. Total 59% of the tumors were located in the lung of which 67% were poorly differentiated neuroendocrine carcinoma. INSM1 were positive in 97% cases, while synaptophysin (SYN) in 96% and chromogranin A (CgA) in 86%. Correlation of INSM1 expression with SYN and CgA was statistically significant (p -value < 0.05). Mean H-score of INSM1 was significantly higher than SYN and CgA and it was statistically significant (p -value < 0.001). Conclusion In the present study, the expression of INSM1 was seen in 97% cases of NENs. A statistically significant association was found between INSM1 and traditional NE markers. As a nuclear marker it is easy to interpret and it showed higher H-score. We conclude that INSM1 is a highly sensitive marker and recommend to incorporate it in the routine practice to aid in the diagnostic workup. However, a larger cohort is required to establish the organ-specific sensitivity and specificity of INSM1. [ABSTRACT FROM AUTHOR]

The 5th edition of the World Health Organization (WHO) classification of neuroendocrine neoplasms (NENs) is built to achieve a uniform terminology and to define a similar diagnostic scheme across different anatomic locations. Since the 4th edition, a chapter discussing NENs in nonneuroendocrine organs has been introduced, which proposes a binary system for classification segregating well-differentiated neoplasms, termed neuroendocrine tumors (NETs), and poorly differentiated neoplasms, termed neuroendocrine carcinomas (NECs). A grading system for NETs is based on mitotic index and/or Ki-67 index and/or necrosis, depending on the different locations. Although this approach has been already well established in the digestive system, it modifies and homogenizes the classification of NENs in the urinary tract, in female genital organs, and in the male genital system. In the lung and thymus, the double terminology of carcinoid/NET, already introduced in the 5th edition of the WHO classification of thoracic tumors, is endorsed. This approach undoubtedly helps the multidisciplinary approach for the diagnosis and clinical management of patients affected by these neoplasms, without losing site-specific characteristics that influence the clinical and biological behavior of tumors in different anatomical sites. Other major advances of the new WHO scheme are the homogenization of epidemiological data and the correct integration of data from prospective future studies aimed at the definition of molecular profiles and at the identification of tumor type-specific and patient-specific therapeutic approaches. [ABSTRACT FROM AUTHOR]

Primary neuroendocrine neoplasms (NENs) of the breast are characterized by neuroendocrine architectural and cytological features, which must be supported by immunohistochemical positivity for neuroendocrine markers (such as Chromogranin and Synaptophysin). According to the literature, making a diagnosis of primary neuroendocrine breast cancer always needs to rule out a possible primary neuroendocrine neoplasm from another site. Currently, the latest 2022 version of the WHO of endocrine and neuroendocrine neoplasms has classified breast NENs as well-differentiated neuroendocrine tumours (NETs) and aggressive neuroendocrine carcinomas (NECs), differentiating them from invasive breast cancers of no special type (IBCs-NST). with neuroendocrine features. The current review article describes six cases from our series and a comprehensive review of the literature in the field of NENs of the breast. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of new treatments for patients with neuroendocrine neoplasms (NENs) is imperative. Immunotherapy has shown efficacy in various neoplasms, such as small cell lung cancer and Merkel cell carcinoma. Although immunotherapy's effectiveness is more limited in NENs, combining immune checkpoint inhibitors with other therapeutic strategies like chemotherapy or targeted therapies could improve outcomes. Additionally, identifying predictive immune biomarkers could enhance patient selection. Our objective was to review the current evidence of immunotherapy in NENs, covering efficacy results and potential predictive biomarkers. A raise in the incidence of NENs is expected. Therefore, the identification of new therapeutic strategies, such as immunotherapy, remains crucial. To date, immune checkpoint inhibitors as monotherapy have shown modest activity in unselected NENs. Although immunotherapy combos (plus another immune agents or chemotherapy, among others) are potentially more active than single agents, this has not been uniformly confirmed, even in high-grade NENs. Other immunotherapeutic strategies under development include bispecific antibodies, targeting specific tumor antigens like DLL3, and cell therapy. Currently, no predictive immune biomarkers are available to guide clinical decisions. A comprehensive tumor molecular profiling approach needs to be developed for the selection of patients with NEN who could potentially benefit from immunotherapy. Ideally, clinical trials should incorporate this tumor molecular profiling to identify predictive biomarkers and improve efficacy. Achieving this goal requires an international collaborative effort. [ABSTRACT FROM AUTHOR]

Copyright of Die Radiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Neuroendocrine neoplasms (NENs) represent a complex group of tumors arising from neuroendocrine cells, characterized by heterogeneous behavior and challenging diagnostics. Despite advancements in medical technology, NENs present a major challenge in early detection, often leading to delayed diagnosis and variable outcomes. This review aims to provide an in-depth analysis of current diagnostic methods as well as the evolving and future directions of diagnostic strategies for NENs. The review extensively covers the evolution of diagnostic tools for NENs, from traditional imaging and biochemical tests to advanced genomic profiling and next-generation sequencing. The emerging role of technologies such as artificial intelligence, machine learning, and liquid biopsies could improve diagnostic precision, as could the integration of imaging modalities such as positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrids and innovative radiotracers. Despite progress, there is still a significant gap in the early diagnosis of NENs. Bridging this diagnostic gap and integrating advanced technologies and precision medicine are crucial to improving patient outcomes. However, challenges such as low clinical awareness, limited possibility of noninvasive diagnostic tools and funding limitations for rare diseases like NENs are acknowledged. [ABSTRACT FROM AUTHOR]

This case report describes a 62-year-old male with a notable medical history, including surgically treated bladder cancer and the suspicion of metastatic disease. He underwent 18F-FDG PET/CT imaging as part of the initial diagnostic workup, which identified several marginally hypodense hepatic lesions. These lesions exhibited metabolic activity that was slightly lower than the surrounding hepatic parenchyma, raising concerns for metastatic involvement. Subsequent 18F-DOTATATE PET/CT imaging significantly expanded the diagnostic perspective by identifying multiple somatostatin receptor (SSTR)-positive lesions, not only in the liver but also in lymph nodes and bones. This marked an important diagnostic advancement over the initial FDG PET/CT findings, showcasing the superior sensitivity of 18F-DOTATATE PET/CT in detecting SSTR-expressing tumors. Pathological evaluation after these imaging studies confirmed the diagnosis of a rectal neuroendocrine tumor (NET) with extensive hepatic metastasis, altering the clinical management and therapeutic approach for the patient. This case underscores the pivotal role of integrating 18F-DOTATATE and FDG PET/CT in the diagnostic and therapeutic management of neuroendocrine tumors, highlighting the complementary nature of these imaging modalities. The findings advocate for the use of 18F-DOTATATE PET/CT in cases where NETs are suspected, particularly for its enhanced sensitivity in detecting SSTR-positive lesions across various sites, thereby facilitating a more comprehensive disease assessment and informed therapeutic planning.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a diverse group of tumors with varying clinical behaviors. Their incidence has risen due to increased awareness, improved diagnostics, and aging populations. The 2019 World Health Organization classification emphasizes integrating radiology and histopathology to characterize NENs and create personalized treatment plans. Imaging methods like CT, MRI, and PET/CT are crucial for detection, staging, treatment planning, and monitoring, but each of them poses different interpretative challenges and none are immune to pitfalls. Treatment options include surgery, targeted therapies, and chemotherapy, based on the tumor type, stage, and patient-specific factors. This review aims to provide insights into the latest developments and challenges in NEN imaging, diagnosis, and management. [ABSTRACT FROM AUTHOR]

Purpose: Somatostatin receptor antagonists have shown promising performance for imaging neuroendocrine neoplasms. However, there is a lack of studies exploring the diagnostic performance of SSTR antagonists or comparing them with agonists in a large cohort of patients with NENs. This study aimed to retrospectively review all SSTR antagonist PET/CT scans conducted at Peking Union Medical College Hospital since November 2018 in patients with confirmed or suspected NENs. Methods: Four types of SSTR antagonists were utilized, including [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11, and [68Ga]Ga-DOTA-JR11. The reference standard was based on a combination of histopathology, clinical evaluation, imaging results, and follow-up. Patient-based sensitivity, specificity, and accuracy were evaluated. The SUVmax and tumor-to-liver ratio (TLR) of the hottest lesions was recorded and compared between antagonists and [68Ga]Ga-DOTATATE. Results: A total of 622 antagonist scans from 549 patients were included in the analysis. The patient-level sensitivity, specificity, and accuracy of antagonist imaging (all tracers combined) were 91.0% (443/487), 91.9% (57/62), and 91.1% (500/549), respectively. In 181 patients with a comparative [68Ga]Ga-DOTATATE PET/CT scan, the patient-level sensitivity, specificity, and accuracy were 87.5% (147/168), 76.9% (10/13), and 86.7% (157/181), respectively. For the hottest lesions, SSTR antagonists all tracers combined demonstrated an overall comparable SUVmax to [68Ga]Ga-DOTATATE (40.1 ± 32.5 vs. 39.4 ± 23.8, p = 0.772). While [68Ga]Ga-NODAGA-LM3 showed significantly higher uptake than [68Ga]Ga-DOTATATE (57.4 ± 38.5 vs. 40.0 ± 22.8, p<0.001), [68Ga]Ga-NODAGA-JR11 (39.7 ± 26.5 vs. 34.3 ± 23.9, p = 0.108) and [68Ga]Ga-DOTA-LM3 (38.9 ± 32.1 vs. 37.2 ± 22.1, p = 0.858) showed comparable uptake to [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-JR11 showed lower uptake (28.9 ± 26.1 vs. 44.0 ± 25.7, p = 0.001). All antagonists exhibited significantly higher TLR than [68Ga]Ga-DOTATATE (12.1 ± 10.8 vs. 5.2 ± 4.5, p<0.001). Conclusion: Gallium-68 labeled SSTR antagonists could serve as alternatives to SSTR agonists for imaging of NENs. Among various antagonists, [68Ga]Ga-NODAGA-LM3 seems to have the best imaging profile. [ABSTRACT FROM AUTHOR]

Simple Summary: Sufferers of neuroendocrine neoplasms (NENs) of unknown primary origin are a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, treatment should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. The aim of this review is to explore the evidence relating to available treatment options for NENs of unknown primary and to offer insights into future perspectives. Particular attention is given to molecular characterization and genomic profiling of NENs with potential therapeutic implications, mainly through the identification of druggable targets for agnostic treatments. Moreover, a treatment algorithm for both well-differentiated and poorly differentiated NENs of unknown primary is proposed. Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting. [ABSTRACT FROM AUTHOR]

Peptide receptor radionuclide therapy (PRRT) can be a very useful treatment for patients with neuroendocrine neoplasms and metastatic castration‐resistant prostate cancer but it is routinely avoided in those with advanced kidney disease because it can adversely affect the renal function. Accordingly, no clear guidelines exist on the use of PRRT for patients on hemodialysis (HD). We performed a literature review to identify publications on HD patients who received PRRT with Lutetium‐177 (Lu177) Dotatate and Y‐90 and obtained information on Lu177 pharmacokinetics and early testing data from the manufacturer. We also perused the most recent North American Neuroendocrine Tumor Society (NANETS)/European Neuroendocrine Tumor Society (ENETS) recommendations. Seven relevant publications with a total of 15 patients were included. Patients received dose‐adjusted fractions of PRRT with HD occurring usually within 24 h. There were no immediate or long‐term serious adverse events attributed to the radioligand, although data was limited. Using available evidence and input from a multidisciplinary group, we have created an institutional workflow. Dose‐adjusted PRRT can be offered to patients undergoing HD under careful, multidisciplinary supervision. [ABSTRACT FROM AUTHOR]

Midgut neuroendocrine neoplasms (NENs) are one of the most common subtypes of NEN, and their incidence is rising globally. Despite being the most frequently diagnosed malignancy of the small intestine, little is known about their underlying molecular biology. Their unusually low mutational burden compared to other solid tumors and the unexplained occurrence of multifocal tumors makes the molecular biology of midgut NENs a particularly fascinating field of research. This review provides an overview of recent advances in the understanding of the interplay of the genetic, epigenetic, and transcriptomic landscape in the development of midgut NENs, a topic that is critical to understanding their biology and improving treatment options and outcomes for patients. [ABSTRACT FROM AUTHOR]

Objective To investigate the typical CT imaging features of small cell lung cancer (SCLC) and the corresponding pathophysiological basis, in order to improve the understanding and diagnosis of SCLC. Methods The imaging data of 36 patients with SCLC confirmed by pathological examination admitted to the hospital from June 2016 to September 2023 were collected, and the CT plain scan, CT enhanced image signs and pathological basis were compared and analyzed. Results There were 28 males and eight females in the 36 patients. The median age was 62. 05 years old. CT examination showed 31 cases of central SCLC (seven cases of left upper lobe, five cases of left lower lobe, five cases of left hilum, three cases of right upper lobe, four cases of right lower lobe and seven cases of right hilum),including 20 cases of frozen mediastinum, 12 cases of frozen hilum, nine cases of needle-like trachea, 16 cases of vascular embedding sign, 10 cases of clear pleural effusion sign, 22 cases of swamp-like enhancement, six cases of duck web sign, six cases of round and blunt edge of mass, and five cases of tiny sand-like calcification sign. There were five cases of peripheral SCLC (one case of right lower lung, one case of right upper lobe, one case of left lower lung and two cases of left upper lobe),including two cases of female pup large sign, three cases of worm sign, one case of subpleural hill sign and one case of peach tip sign at the edge of the mass. Secondary changes were pleural effusion in 15 cases, obstructive pneumonia in five cases, and obstructive atelectasis in two cases. Conclusion However, its pathological basis is related to the characteristics of SCLC cancer cells, such as large and deep staining of nucleus, less cytoplasm, dense cells, loose/chaotic tumor nests, less fiber components, short value-added time, rapid growth, weak contractility, strong invasiveness, soft lesions, and easy to be pushed and deformed. Although SCLC has various manifestations, there are some typical imaging signs, which have characteristic, but the diagnosis still needs to be combined with pathological examination. [ABSTRACT FROM AUTHOR]

Objective: To analyze the CT and MR features of Primary hepatic neuroendocrine neoplasms (PHNENs) in order to enhance the diagnostic accuracy of this disease. Methods: A retrospective analysis was conducted on patients diagnosed with hepatic neuroendocrine neoplasms, excluding other sites of origin through general examination and postoperative follow-up. The CT and MR signs were analyzed according to the 2018 version of Liver Imaging Reporting and Data System (LI-RADS), along with causes of misdiagnosis. Results: Twelve patients, including 6 males and 6 females, were enrolled in this study. There was no significant increase in liver tumor markers among all cases. Most masses were multiple (9/12), exhibiting low attenuation on pre-contrast CT scans, T1-hypointense signal, T2-hyperintense signal, and restricted diffusion. The majority of these masses (7/10) demonstrated similar rim arterial phase hyper-enhancement as well as peripheral “washout” during venous portal phase and delayed phase imaging. Three cases had incomplete capsules while one case had a complete capsule. Cyst/necrosis was observed in 7 out of all cases following administration of contrast agent, with 5 mainly distributed in the periphery. All masses lacked fat, calcification, vascular or bile duct tumor thrombus formation. Conclusion: The imaging findings associated with PHNENs possess certain specificity, often presenting as multiple masses within the liver accompanied by peripheral cyst/necrosis, similar rim arterial phase hyper-enhancement during venous portal phase and delayed phase imaging. [ABSTRACT FROM AUTHOR]

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium‐68‐DOTA‐somatostatin analogues (68Ga‐SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra‐abdominal metastases on 68Ga‐DOTATOC‐PET/CT in a cohort of patients with small intestinal (Si‐NET) and pancreatic NET (Pan‐NET), as well as that of pancreatic metastasis in patients with Si‐NET. Among 2090 patients examined by 68Ga‐DOTATOC‐PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si‐ or Pan‐NET, were identified. The most recent 68Ga‐DOTATOC‐PET/CT report for each patient was reviewed, and the location and number of metastases of interest were recorded. Lesions outside the liver and abdominal nodes were found in 26% of patients (n = 310/1177), of whom 21.5% (255/1177) were diagnosed with Si‐NET and 4.5% (55/1177) Pan‐NET. Bone metastases were found in 18.4% (215/1177), metastases to Virchow's lymph node in 7.1% (83/1177), and lung/pleura in 4.8% (56/1177). In the subset of 255 Si‐NET patients, 5.4% (41/255) manifested lesions in the pancreas, 1.5% in the breast (18/255), 1.3% in the heart (15/255) and 1% in the orbita (12/255). In Si‐NET patients, the Ki‐67 proliferation index was higher in those with ≥2 metastatic sites of interest, than with 1 metastatic site, (p <0.001). Overall, extra‐abdominal or pancreatic metastases were more often found in patients with Si‐NET (34%) than in those with Pan‐NET (13%) (p <0.001). Bone metastases were 2.6 times more frequent in patients with Si‐NET compared to Pan‐NET patients (p <0.001). Lesions to the breast and orbita were encountered in almost only Si‐NET patients. In conclusion, lesions outside the liver and abdominal nodes were detected in as many as 26% of the patients, with different prevalence and metastatic patterns in patients with Si‐NET compared to Pan‐NET. The impact of such metastases on overall survival and clinical decision‐making needs further evaluation. [ABSTRACT FROM AUTHOR]

Objective To investigate the endoscopic combined serological diagnosis strategy for G1 and G2 gastric neuroendocrine neoplasms (G-NENs), and to evaluate the safety, short-term, and long-term efficacy of two endoscopic treatment procedures: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Methods This study retrospectively analyzed the clinical data of 100 consecutive patients with G-NENs who were hospitalized at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2011 to October 2023. These patients underwent endoscopic treatment, and propensity score matching (PSM) was used to compare clinicopathological characteristics, as well as short-term and long-term efficacy of lesions in the EMR group and ESD group before and after treatment. Results Among the 100 patients with G-NENs, the median age was 54 years old. Before surgery, 29 cases underwent endoscopic combined serological examination, and 24 of them (82.2%) had abnormally elevated plasma chromogranin A. The combined diagnostic strategy for autoimmune atrophic gastritis (AIG) achieved a diagnostic accuracy of 100%(22/22). A total of 235 G-NEN lesions were included, with 84 in the ESD group and 151 in the EMR group. The median size of the lesions in the ESD group (5.0 mm) was significantly larger than that in the EMR group (2.0 mm, P＜0.001). Additionally, the ESD group had significantly more lesions with pathological grade G2[23.8%(20/84) vs. 1.3%(2/151), P＜0.001], infiltration depth reaching the submucosal layer [78.6%(66/84) vs. 51.0%(77/151), P＜0.001], and more T2 stage compared to the EMR group[15.5%(13/84) vs. 0.7%(1/151), P＜0.001]. After PSM, 49 pairs of lesions were successfully matched between the two groups. Following PSM, there were no significant differences in the en bloc resection rate [100.0%(49/49) vs. 100.0%(49/49)], complete resection rate [93.9%(46/49) vs. 100.0%(49/49)], and complication rate [0(0/49) vs. 4.1%(2/49)] between the two groups. During the follow-up period, no recurrence or distant metastasis was observed in any of the lesions in both groups. Conclusions The combination of endoscopy and serology diagnostic strategy has the potential to enhance the accuracy of diagnosing G1 and G2 stage G-NENs and their background mucosa. Endoscopic resection surgery (EMR, ESD) is a proven and safe treatment approach for G1 and G2 stage G-NENs. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs. [ABSTRACT FROM AUTHOR]

As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life. [ABSTRACT FROM AUTHOR]

Gallbladder cancers are the most common biliary tract malignancies in the world. Adenocarcinoma constitutes the most common histology in gallbladder cancer. Neuroendocrine neoplasms of the gallbladder account for about 0.5% of all neuroendocrine neoplasms and 2.1% of all gallbladder tumors. They are rare tumors and present with non-specific symptoms such as abdominal pain, weight loss, anorexia, and obstructive jaundice, and, therefore, are often challenging to diagnose and treat. Mixed neuroendocrine-non-neuroendocrine neoplasm is a subtype of neuroendocrine neoplasm. To add to the literature, we report a rare case of a patient who presented with pain in the abdomen and non-bilious vomiting and was diagnosed with mixed neuroendocrine-non-neuroendocrine gallbladder cancer, identified by immunohistochemistry, and treated with palliative chemotherapy. Due to non-specific symptoms, patients may present at an advanced stage. Further, immunohistochemistry may assist in clinching the diagnosis.

Somatostatin analogs (SSA), specifically octreotide and lanreotide, have demonstrated antiproliferative effects in patients with neuroendocrine tumors (NET), a group of rare malignancies of diverse origin and presentation. A prominent feature of NET cells is the expression of G protein-coupled receptors called somatostatin receptors (SSTR). Although these SSTR are not uniformly present in NET, they can be instrumental in the diagnosis and treatment of NET. Apart from their application in nuclear imaging and radionuclide therapy, SSA have proven invaluable in the treatment of hormonal syndromes associated with certain NET (antisecretory effects of SSA), but it took more than two decades to convincingly demonstrate the antiproliferative effects of SSA in metastatic NET with the two pivotal studies PROMID and CLARINET. The current review summarizes three decades of SSA treatment and provides an overview of the clinical trial landscape for SSA monotherapy and combination therapy, including clinical implications and quality of life aspects, as well as ongoing fields of research. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine neoplasms (NENs) are rare tumours that develop from neuroendocrine cells in various parts of the body. The management of this disease poses a significant challenge because of the heterogeneous clinical presentation and varying degrees of aggressiveness. A multidisciplinary approach is often required in complex clinical situations. Radiotherapy (RT) plays a key role in managing NETs in both curative and palliative settings. Summary: In this review, we summarize and discuss recent developments in the field of advanced RT in early-stage, locally advanced, and metastatic NENs. We highlight limitations in current approaches and discuss future potential treatment strategies for patients with NENs. [ABSTRACT FROM AUTHOR]

Background. The optimal management of duodenal neuroendocrine neoplasms (dNENs) sized 10–20 mm remains controversial and although endoscopic resection is increasingly performed instead of surgery, the therapeutic approach in this setting is not fully standardized. We performed a systematic review of the literature and a meta-analysis to clarify the outcomes of endoscopic resection for 10–20 mm dNENs in terms of efficacy (i.e., recurrence rate) and safety. Methods. A computerized literature search was performed using relevant keywords to identify pertinent articles published until January 2023. Results. Seven retrospective studies were included in this systematic review. The overall recurrence rate was 14.6% (95%CI 5.4–27.4) in 65 patients analyzed, without significant heterogeneity. When considering studies specifically focused on endoscopic mucosal resection, the recurrence rate was 20.5% (95%CI 10.7–32.4), without significant heterogeneity. The ability to obtain the free margin after endoscopic resection ranged between 36% and 100%. No complications were observed in the four studies reporting this information. Conclusions. Endoscopic resection could be the first treatment option in patients with dNENs sized 10–20 mm and without evidence of metastatic disease. Further studies are needed to draw more solid conclusions, particularly in terms of superiority among the available endoscopic techniques. [ABSTRACT FROM AUTHOR]

Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the thorax (lungs and thymus), thus representing a well-established target for medical treatment with SST ligands (SRLs). However, the response to SRLs is highly heterogeneous between tumors. Two main factors can contribute to this variability: (i) the differential SST expression among tumor types and (ii) the differential expression/modulation of the SST-related intracellular machinery. In this literature review, we provide an overview of available data on the variable expression of SSTs in pituitary tumors and NENs, together with the resulting clinical implications. Moreover, we aim to describe the complex intracellular machinery involved in SST signaling and trafficking. Particularly, we will focus on ß-arrestins and describe their role in receptor internalization and recycling, as well as the various functions of these scaffold molecules in tumor pathogenesis and progression. This review highlights the interplay between membrane receptors and intracellular machinery, together with its role in determining the clinical behavior of the tumor and the response to treatment in patients with pituitary tumors or NENs. [ABSTRACT FROM AUTHOR]

Purpose: Neuroendocrine neoplasms (NENs) are tumors that arise from cells of the endocrine system and are most common in the gastrointestinal tract, the pancreas, and the lungs. Their incidence is rapidly increasing and the therapeutic options available are limited. Methods: Since the immune system can interfere with tumor growth and response to therapy, using flow cytometry we investigated the immunophenotype in samples of peripheral blood leukocytes from patients with pancreatic (Pan-NENs) and pulmonary NENs (Lung-NENs). Moreover, we performed a multiplex analysis of 13 key cytokines and growth factors essential for the immune response in the plasma of NEN patients and controls. Results: Patients presented with a higher percentage of granulocytes, a lower percentage of lymphocytes, and an increase in the granulocytes to lymphocytes ratio compared to healthy donors. These alterations were more marked in patients with metastasis. Somatostatin analogs (SSAs) restored the immunophenotype of patients to that seen in healthy donors. Finally, Pan-NEN patients showed a higher plasma concentration of IP-10, MCP-1, and IL-8 compared to healthy donors, suggesting a potential role for these cytokines as diagnostic biomarkers. Conclusion: This study highlighted differences in the immunophenotype of patients with Pan- and Lung-NENs compared to healthy individuals; these alterations were partially restored by therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine neoplasms' (NENs) rarity and heterogeneity represent a clinical challenge. Somatostatin receptor (SST) positron emission tomography/computed tomography (PET/CT) availability and different reimbursement policies across countries account for its heterogenous employment on a single-case basis. The aim of this study was to prospectively collect data of the real-life use of and indications for [68Ga-DOTA0-1NaI3]octreotide ([68Ga]Ga-DOTANOC) PET/CT in a prospective 5-year electronic archive at a single center. Overall, more than 2000 scans were included. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the trends of [68Ga]Ga-DOTANOC PET/CT use across different clinical indications and primary tumor sites. The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting. [ABSTRACT FROM AUTHOR]

Objective：To describe the preparation process of domestic carrier ⁃free lutetium［177Lu］and the method for labeling of 177Lu with 1, 4, 7, 10⁃tetraazacyclododecane⁃1u⁃, 4, 7, 10⁃tetraacetic acid conjugated Tyr3⁃octreotide（DOTA⁃TOC), and to explore the safety and efficacy of the preliminary clinical application of domestically produced 177Lu⁃DOTA⁃TOC. Methods：Domestic carrier⁃free lutetium［177Lu］was prepared by multistage sequential isolation and purification, and fully automated modular labeling was used to synthesize 177Lu ⁃DOTA ⁃TOC. The data of 4 patients with neuroendocrine neoplasms（NEN) in Naning Hospital Affiliated to Nanjing Medical University who only received domestic carrier⁃free lutetium［177Lu］labeled DOTA⁃TOC peptide receptor radionuclide therapy (PRRT) were retrospectively analyzed. Results：The domestic carrier⁃free lutetium［177Lu］had good quality control, with copper（Cu) <0.01, zinc（Zn) <0.01, iron（Fe) <0.01, lead（Pb) <0.15, and thulium（Yb) undetectable, radiochemical purity >99%, and bacterial endotoxin <2 EU/mL. The yield of domestic automated labeling of 177Lu⁃DOTA⁃TOC was（98.85±0.97) %, and the specific activity of the product was（80.96 ± 7.47) GBq/μmol. Sterility and endotoxin tests of the labeled product met the specified standards, and the ethanol content in the labeled product was 0, with a radiochemical purity greater than 99%. Among the 4 patients who received only domestic 177Lu⁃DOTA⁃TOC only, 1 patient showed almost complete disappearance of the primary and metastatic lesions after only one treatment, while another patient experienced grade 3 bone marrow toxicity one month after treatment, which recovered to normal after three months. None of the patients showed renal toxicity. Conclusion; Domestic carrier⁃free lutetium［177Lu］labeled DOTA⁃TOC meets quality control standards, has a high yield, good safety, and tolerability, and has good therapeutic efficacy for patients with inoperable NEN. The domestication and large⁃scale production of carrier⁃free lutetium［177Lu］will promote the integrated development of nuclear medicine diagnosis and treatment in China. [ABSTRACT FROM AUTHOR]

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. Summary: 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. [ABSTRACT FROM AUTHOR]

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

Purpose: Cabozantinib is an oral multi-tyrosine kinase inhibitor (TKI) that has been approved in Europe for advanced renal cell carcinoma, hepatocellular carcinoma, locally advanced and metastatic medullary thyroid carcinoma (MTC) and radioiodine-refractory differentiated thyroid cancer. Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous malignant neuroendocrine tumour that usually presents in sun-exposed skin areas of immunosuppressed patients. Conflicting data exist about cabozantinib for MCC and this TKI is currently under investigation in several onco-endocrine frameworks. Methods: We herein report a case of an 83-year-old man who was diagnosed with MCC during the treatment of an advanced metastatic MTC. The diagnosis of MCC was established based on clinical, histopathologic evaluation and immunohistochemistry. A systematic review of the literature on cabozantinib use for advanced endocrine and neuroendocrine tumours has been performed. Results: The patient was initially treated with surgery and adjuvant radiotherapy. Cabozantinib was therefore started to control both MTC and MCC. After 24 months, no sign of local or metastatic MCC relapse was evidenced. Conclusion: Promising data on cabozantinib treatment for endocrine and neuroendocrine neoplasms is recently emerging in the literature. In our clinical case, we reported that, besides the good response for the MTC, cabozantinib also seems to effectively control metastatic MCC, along with efficient surgery and adjuvant radiotherapy. Further investigations are needed to determine the efficacy and safety of cabozantinib in MCC patients and in off-label endocrine tumours. [ABSTRACT FROM AUTHOR]

Abstract Background Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. Methods We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. Results The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. Conclusions These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

Inositols have demonstrated a role in cancer prevention and treatment in many kinds of neoplasms. Their molecular mechanisms vary from the regulation of survival and proliferative pathways to the modulation of immunity and oxidative stress. The dysregulation of many pathways and mechanisms regulated by inositols has been demonstrated in endocrine and neuroendocrine tumors but the role of inositol supplementation in this context has not been clarified. The aim of this review is to summarize the molecular basis of the possible role of inositols in endocrine and neuroendocrine tumors, proposing it as an adjuvant therapy.

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.

A raise in the incidence of NENs is expected. Therefore, the identification of new therapeutic strategies, such as immunotherapy, remains crucial. To date, immune checkpoint inhibitors as monotherapy have shown modest activity in unselected NENs. Although immunotherapy combos (plus another immune agents or chemotherapy, among others) are potentially more active than single agents, this has not been uniformly confirmed, even in high-grade NENs. Other immunotherapeutic strategies under development include bispecific antibodies, targeting specific tumor antigens like DLL3, and cell therapy. Currently, no predictive immune biomarkers are available to guide clinical decisions. A comprehensive tumor molecular profiling approach needs to be developed for the selection of patients with NEN who could potentially benefit from immunotherapy. Ideally, clinical trials should incorporate this tumor molecular profiling to identify predictive biomarkers and improve efficacy. Achieving this goal requires an international collaborative effort.

Background: Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. Methods: We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. Results: The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. Conclusions: These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10. [ABSTRACT FROM AUTHOR]

Objective: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma. Design and Methods: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least 1 major criterion (necrolytic migratory erythema [NME] and/or recent-onset diabetes, and/or weight loss ≥ 5 kg) associated with either glucagonemia > 2 x upper limit of normal or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT). Results: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonoma symptoms at diagnosis were NME (86.8%), weight loss (68.4%), and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75%, and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8), and somatostatin analogs (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival (OS) was 17.3 years. The Ki-67 index > 3% was associated with shorter OS (hazard ratio 5.27, 95% CI [1.11-24.96], P = .036). Conclusion: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, peptide receptor radionuclide therapy, or liver-directed therapy seems to provide both substantial antitumor and antisecretory efficacies. [ABSTRACT FROM AUTHOR]