Spatial profiling reveals tissue-specific neuro-immune interactions in gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor-derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone-secreting and non-functional GEP-NETs. By combining this approach with in vitro studies of human-derived organoids, we demonstrated the convergence of cell autonomous immune and pro-inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural- and immune-related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal-appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro-inflammatory signaling was confirmed using patient-derived duodenal organoids. Gastrin-secreting and non-functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non-MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro-inflammatory and pro-neural factor IL-17B. Treatment of human duodenal organoids with IL-17B activated NF-κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue-specific neuro-immune signatures in GEP-NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro-inflammatory factors, including tumor-derived IL-17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.

Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

PURPOSE: The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. METHODS: Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. RESULTS: Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. CONCLUSION: Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide.

MENIN-mediated regulation of gastrin gene expression and its role in gastrinoma development.

The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

Epidemiological characteristics of neuroendocrine neoplasms in Beijing: a population-based retrospective study.

BACKGROUND: The incidence of neuroendocrine neoplasms (NENs) is rising rapidly worldwide. However, there are few reports on these heterogeneous diseases in China. Our study aimed to explore the epidemiological characteristics of NENs in Beijing. METHODS: We conducted a retrospective cohort study using population-based cancer surveillance data in Beijing, China. All data were extracted from the Beijing Cancer Registry with incidence dates from 1 January 1998 to 31 December 2018; the follow-up period was through 31 December 2021. Segi's world standard population was used to estimate the age-standardized rate. Survival was estimated using the Kaplan-Meier method. RESULTS: From 1998 to 2018, the incidence of NENs in Beijing initially showed a significant increasing trend, from 1.07/100,000 to 3.53/100,000; this began to plateau after 2013. The age-specific incidence rate increased with age and peaked in the age group 70-74 years. The incidence in men was significantly higher than that in women (4.41/100,000 vs. 1.69/100,000). The most common sites of NENs were the lung (2.38/100,000) and rectum (0.14/100,000). Most NENs were diagnosed at a late stage. We found that NENs originating from the lung had worse overall survival than extrapulmonary NENs, and male patients had worse survival than female patients. CONCLUSIONS: This study retrospectively analyzed the epidemiological characteristics of NENs in Beijing from 1998 to 2018. Our findings provide a reference regarding the epidemiological statistics of NENs in Beijing to contribute to the prevention, diagnosis, and treatment of these specific tumors.

Patterns of emergency department visits before diagnosis with digestive neuroendocrine neoplasms.

OBJECTIVE: To evaluate the patterns of emergency department visits before diagnosis with digestive neuroendocrine neoplasms (NENs). METHODS: Linked administrative databases from the province of Alberta, Canada, were examined, and patients diagnosed with digestive NENs from 2004 to 2019 were reviewed. Incidents of emergency department visits in the 3 months before histological diagnosis were reviewed. Multivariable logistic regression analyses were used to examine factors associated with at least one emergency department (ED) visit as well as factors associated with more than one ED visit. The impact of pre-diagnosis ED visits on overall survival was further assessed in a multivariable Cox regression model, which included (in addition to ED visits), age at diagnosis, sex, histology, Charlson comorbidity index, and stage. RESULTS: A total of 2120 patients were considered eligible for the study, and they were included in the analysis (including 1041 patients (49.1%) with at least one ED visit in the 3 months before diagnosis). The following factors were associated with a higher likelihood of an ED visit prior to diagnosis: younger age (OR with increasing age: 0.983; 95% CI: 0.977-0.989), higher comorbidity index (OR: 1.332; 95% CI: 1.215-1.460), female sex (OR: 1.292; 95% CI: 1.084-1.540), and stage IV (OR: 1.515; 95% CI: 1.106-2.075). Likewise, the following factors were associated with more than one ED visit within 3 months before diagnosis: younger age (OR with increasing age: 0.985; 95% CI: 0.979-0.992), higher comorbidity index (OR: 1.280; 95% CI: 1.167-1.405), and female sex (OR: 1.516; 95% CI: 1.230-1.868). Using multivariable Cox regression modeling, the following factors were associated with worse overall survival (higher risk of death): older age (HR: 1.050; 95% CI: 1.043-1.056), higher comorbidity index (HR: 1.280; 95% CI: 1.209-1.356), stage IV (HR: 3.163; 95% CI: 2.562-3.905), neuroendocrine carcinoma histology (HR: 1.645; 95% CI: 1.350-2.003), pre-diagnosis ED visit (HR: 1.784; 95% CI: 1.529-2.083). CONCLUSION: Almost one-half of patients with NENs visit the ED within 3 months before diagnosis. ED visits were associated with younger age, female sex, advanced disease, and higher comorbidity. Moreover, pre-diagnosis ED visit(s) were associated with worse overall survival in the current cohort.

Immunotherapy for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a 2021 update.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous malignancies, arising from the neuroendocrine system. These neoplasms are divided into two distinct groups, the low-proliferating, well-differentiated neuroendocrine tumors (NETs), and the highly-proliferating, poorly-differentiated neuroendocrine carcinomas (NECs). Recent data demonstrate that the incidence of gastroenteropancreatic (GEP) neuroendocrine neoplasms, GEP-NETs and GEP-NECs, has increased exponentially over the last three decades. Although surgical resection is considered the best treatment modality, patients with GEP-NETs often present with advanced disease at diagnosis associated with a 5-year survival rate of 57% for well-differentiated tumors, and only 5.2% for small-cell tumors. Immunotherapy is a novel treatment approach, which has demonstrated effective and promising therapeutic results against several types of cancers. In the present study, we review the current ongoing clinical trials and to evaluate the efficacy of immunotherapy in GEP-NENs. Furthermore, we analyze the importance of tumor genetic profiling and its clinical implications in immunotherapy response.

How to Select Patients Affected by Neuroendocrine Neoplasms for Surgery.

PURPOSE OF REVIEW: The aim of this review was to discuss how to select patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) for surgery. RECENT FINDINGS: Surgical resection represents the mainstay for the curative treatment of GEP-NENs. Conservative strategies, such as endoscopic resection and active surveillance, have been recently advocated for the management of patients with small and asymptomatic GEP-NENs. On the other hand, patients with GEP-NENs showing features of aggressiveness should be managed by surgical resection with lymphadenectomy, when the surgical risk is considered acceptable. An accurate selection is important also in the setting of advanced disease, where surgery can provide a survival benefit in the context of a multimodal treatment strategy. Surgical and oncological risk should be always assessed in order to define indications for surgery in patients with GEP-NENs. Given the variety of available treatment options, surgical indication should be always shared with a dedicated multidisciplinary team.

Impact of baseline body mass index on the outcomes of patients with neuroendocrine neoplasms.

OBJECTIVE: To assess the impact of baseline body mass index (BMI) on the outcomes of patients with neuroendocrine neoplasms (NENs) in a population-based setting. METHODS: Linked provincial administrative databases (within the province of Alberta, Canada), 2004-2019, were accessed, and patients with NENs and complete information about BMI near the time of diagnosis were reviewed. The impact of BMI on overall survival was evaluated through the use of Kaplan-Meier survival estimates and multivariable Cox regression modeling. RESULTS: A total of 1010 patients with NENs and BMI information were included. Using Kaplan-Meier survival estimates, survival outcomes were best with individuals with obesity and were worst with underweight individuals (P < 0.0001). The following factors were associated with worse overall survival, older age (HR: 1.02; 95% CI: 1.01-1.03), male sex (HR: 1.60; 95% CI: 1.32-1.93), higher Charlson comorbidity index (HR: 1.22; 95% CI: 1.13-1.31), non-small intestinal primary (HR for gastric primary versus small intestinal primary: 2.36; 95% CI: 1.44-3.85), stage 4 disease (HR: 2.67; 95% CI: 2.16-3.31), neuroendocrine carcinoma histology (HR: 1.76; 95% CI: 1.43-2.17), and underweight BMI (HR versus normal BMI: 1.74; 95% CI: 1.11-2.73). When the model was repeated using BMI as a continuous variable (rather than as a categorical variable), increasing BMI was associated with better overall survival (HR with increasing BMI: 0.97; 95% CI: 0.95-0.98). CONCLUSIONS: Lower BMI is associated with worse overall survival among patients with NENs. This finding was demonstrable regardless of the tumor's stage or histology.

Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis.

PURPOSE: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. PATIENTS AND METHODS: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. RESULTS: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). CONCLUSION: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a radiomic model to predict tumor grade.

PURPOSE: The aim of this single-center retrospective study is to assess whether contrast-enhanced computed tomography (CECT) radiomics analysis is predictive of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) grade based on the 2019 World Health Organization (WHO) classification and to establish a tumor grade (G) prediction model. MATERIAL AND METHODS: Preoperative CECT images of 78 patients with GEP-NENs were retrospectively reviewed and divided in two groups (G1-G2 in class 0, G3-NEC in class 1). A total of 107 radiomics features were extracted from each neoplasm ROI in CT arterial and venous phases acquisitions with 3DSlicer. Mann-Whitney test and LASSO regression method were performed in R for feature selection and feature reduction, in order to build the radiomic-based predictive model. The model was developed for a training cohort (75% of the total) and validated on the independent validation cohort (25%). ROC curves and AUC values were generated on training and validation cohorts. RESULTS: 40 and 24 features, for arterial phase and venous phase, respectively, were found to be significant in class distinction. From the LASSO regression 3 and 2 features, for arterial phase and venous phase, respectively, were identified as suitable for groups classification and used to build the tumor grade radiomic-based prediction model. The prediction of the arterial model resulted in AUC values of 0.84 (95% CI 0.72-0.97) and 0.82 (95% CI 0.62-1) for the training cohort and validation cohort, respectively, while the prediction of the venous model yielded AUC values of 0.7877 (95% CI 0.6416-0.9338) and 0.6813 (95% CI 0.3933-0.9693) for the training cohort and validation cohort, respectively. CONCLUSIONS: CT-radiomics analysis may aid in differentiating the histological grade for GEP-NENs.

A Case of Pancreatic Neuroendocrine Tumor G3 Which Responded Remarkably to Chemotherapy.

Pancreatic neuroendocrine carcinoma (NEC) as classified in the World Health Organization (WHO) 2010 was reclassified in the WHO 2017 as either neuroendocrine tumor (NET) G3 or NEC. An accurate diagnosis based on the WHO 2017 classification is important in order treating this disease appropriately. We report a case diagnosed as NET G3 that responded remarkably well to treatment with streptozocin. The patient would likely not have received the streptozocin treatment if she had been diagnosed with NEC. The WHO 2017 classification is reasonable for the treatment of advanced pancreatic neuroendocrine neoplasms.

Outcomes of non-metastatic poorly differentiated gastroenteropancreatic neuroendocrine neoplasms treated with surgery: a real-world population-based study.

OBJECTIVE: To assess the outcomes of non-metastatic poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with radical surgery. METHODS: Surveillance, Epidemiology, and End Results (SEER) database (1998-2015) was accessed, and patients with non-metastatic poorly differentiated/undifferentiated GEP-NENs were reviewed. Multivariable Cox regression analysis was used to evaluate factors affecting overall survival (OS) and cancer-specific survival (CSS). Patients treated with radical surgery were matched to those who did not undergo surgery through propensity score matching and Kaplan-Meier survival estimates were used to evaluate the impact of surgery in the post-propensity cohort. RESULTS: A total of 1517 patients were included. Within multivariable Cox regression models and compared to no surgery, radical surgery was associated with improved OS (HR: 0.41; 95% CI: 0.34-0.50) and CSS (HR: 0.37; 95% CI: 0.29-0.47). A total of 233 patients who underwent no surgery were then matched to 233 patients who underwent radical surgery. Within the post-propensity cohort, radical surgery was associated with improved OS (P < 0.001). CONCLUSIONS: Radical surgery is associated with improved survival outcomes in patients with non-metastatic poorly differentiated GEP-NENs. Further studies are required to better identify the best timing of radical surgery within the context of multimodal management.

Immunotherapy in Neuroendocrine Neoplasms: Where Are We Now?

OPINION STATEMENT: Immune checkpoint inhibitors (ICIs) represent a breakthrough in the management of many hard-to-treat cancers over the past decade with demonstrable improvement in survival outcomes. We reviewed the state of the art of ICIs in neuroendocrine neoplasms (NENs). While ICIs have become part of the standard of care for the management of small cell lung cancer (SCLC), their role is still unclear in the management of extra-pulmonary (EP) poorly differentiated neuroendocrine carcinomas (NECs) as well as in the management of well-differentiated neuroendocrine tumors (NETs). Conflicting results derived from the various studies in NETs and EP NECs therefore for specific settings, such as the lung NETs, or therapeutic regimen, e.g., combo vs single agent, for ICIs benefit. Therefore, at the moment, no ICIs approach is justified for NETs and EP NECs in clinical practice. Future investigations should be designed with the aim to overcome the several limitations of the current trials, e.g., lacking of a central pathology review or heterogeneity of the cohorts, in order to reduce the risk of biases. Future trials combining ICIs with other biological agents are welcome. This review aims to provide a comprehensive overview of the biological rationale and evolving clinical applications of the use of ICIs in the management of NENs (both well-differentiated and poorly differentiated groups).

Treatment personalization in gastrointestinal neuroendocrine tumors.

OPINION STATEMENT: The clinical scenario of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is continuously changing due to significant improvements in the definition of their molecular landscapes and the introduction of innovative therapeutic approaches. Many efforts are currently employed in the integration of the genetics/epigenetics and clinical information. This is leading to an improvement of tumor classification, prognostic stratification and ameliorating the management of patients based on a personalized approach.

Aberrant Expression of Long Non Coding RNA HOTAIR and De-Regulation of the Paralogous 13 HOX Genes Are Strongly Associated with Aggressive Behavior of Gastro-Entero-Pancreatic Neuroendocrine Tumors.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

Management of neuroendocrine tumors of unknown primary.

Neuroendocrine neoplams (NENs) are mostly relatively indolent malignancies but a significant number have metastatic disease at diagnosis mainly to the liver. Although in the majority of such cases the primary origin of the tumor can be identified, in approximately 11-22% no primary tumor is found and such cases are designated as NENs of unknown primary origin (UPO). This has significant therapeutic implications with respect to potentially resectable hepatic disease and/or application of appropriate medical therapy, either chemotherapeutic agents or targeted treatment, as the response to various treatments varies according to the origin of the primary tumor. This lack of tumor specific orientated treatment may also account for the relatively poorer prognosis of NENs of UPO compared to metastatic NENs with a known primary site. In the majority of cases the primary tumors are located in the small bowel and the lung, but a number may still elude detection. Occasionally the presence of a functional syndrome may direct to the specific tissue of origin but in the majority of cases a number of biochemical, imaging, histopathological and molecular modalities are utilized to help identify the primary origin of the tumor and direct treatment accordingly. Several diagnostic algorithms have recently been developed to help localize an occult primary tumor; however, in a number of cases no lesion is identified even after prolonged follow-up. It is expected that the delineation of the molecular signature of the different NENs may help identify such cases and provide appropriate treatment.

Feasibility and utility of re-treatment with (177)Lu-DOTATATE in GEP-NENs relapsed after treatment with (90)Y-DOTATOC.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 - 3 years. In the present study, we investigated the use of low dosage re-treatment with (177)Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with (90)Y-DOTATOC (Y-PRRT). METHODS: Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 - 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. RESULTS: Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6%, median PFS was 22 months (95% CI 16 months - not reached) compared to 28 months (95% CI 20 - 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. CONCLUSION: Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment.

Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives.

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.

The crucial role of age and site in incidence and prognosis of female neuroendocrine neoplasms in the United States: a population-based study from 2000 to 2018.

BACKGROUND: As the incidence continues to rise, global concern about neuroendocrine neoplasms (NENs) is mounting. However, little is known about how NENs affect women patients. METHODS: The annual percentage change (APC) was calculated to describe the incidence. Cox proportional hazards multivariable regression was used to identify risk factors. The nomograms were employed to estimate prognosis. RESULTS: A total of 39,237 female NENs (fNENs) cases were identified. The incidence of fNENs increased annually (APC = 4.5, 95% CI 4.1-4.8, P < 0.05), and the incidence pattern and survival outcomes showed age and site-specificity. Appendiceal, rectal, and pulmonary fNENs were major contributors to the incidence of patients younger than 40, between 40-59, and over 60 years old, respectively. The Cox proportional hazards regression model revealed that age, tumor size, grade, stage, and primary sites were closely related to survival. The worst survival outcomes appeared in breast, reproductive system, and liver fNENs for patients under 40, between 40-49, and over 50 years old, respectively. A nomogram based on these developed with higher predictive accuracy of prognosis, with a C index of 0.906 in the training cohort and 0.901 in the validation cohort. CONCLUSIONS: Our findings revealed distinct site-specific tendencies in the incidence and survival patterns among fNEN patients across various age groups. Thus, reasonable patient screening and stratification strategies should be implemented, especially for young patients.