Clinicopathological features and prognosis of primary small bowel adenocarcinoma: a large multicenter analysis of the JSCCR database in Japan.

BACKGROUND: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan. METHODS: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum. RESULTS: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA. CONCLUSIONS: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis.

Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database.

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083).

Gastroenteropancreatic neuroendocrine carcinoma in children and adolescents: a population-based study.

PURPOSE: Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC) in children is an exceptionally rare and aggressive form of cancer. We aimed to conduct a population-based cohort study to predict overall survival (OS) in pediatric patients with GEP-NEC. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was employed to identify all pediatric patients with GEP-NEC diagnosed between 2000 and 2019. To create survival curves based on various criteria, Kaplane-Meier estimations were utilized. The log-rank test was used to compare survival curves. The variables associated with OS were determined using Cox proportional-hazards regression. Furthermore, we developed a nomogram to predict overall survival in pediatric GEP-NEC patients. RESULTS: A total of 103 pediatric GEP-NEC patients were identified. The tumors primarily affected females (62.2%). The majority of GEP-NEC was found in the appendix (63.1%), followed by the pancreas (23.3%) and the intestinal tract (13.6%). The highest rates of localized stage (76.9%) and surgery (98.5%) were found in the NEC of appendix origin. However, pancreatic origins had the largest proportion of distant disease (66.7%) but the lowest percentage of surgery (37.5%). Overall 1-year, 3-year, and 5-year survival rates for all patients were 94.4%, 85.4%, and 85.4%, respectively. Tumors of pancreatic origin had the worst survival compared with those of the appendix and intestinal tract. The Cox proportional hazard regression revealed that only site was an important independent predictor of survival. CONCLUSIONS: Our study revealed that only the primary site was found to be the most important predictor of the OS in pediatric GEP-NEC. It's important to work closely with a multidisciplinary team, including oncologists, surgeons, and other specialists, to determine the most appropriate treatment plan for pediatric GEP-NEC.

SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022)

'Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided (AU)

Updates in the diagnosis and management of small-bowel tumors.

Small-bowel tumors represent a rare entity comprising 0.6% of all new cancer cases in the US, and only 3% of all gastrointestinal neoplasms. They are a heterogenous group of neoplasms comprising of about forty different histological subtypes with the most common being adenocarcinoma, neuroendocrine tumors, stromal tumors and lymphomas. Their incidence has been reportedly increasing over recent years, partly owing to the advances and developments in the diagnostic modalities. Small-bowel capsule endoscopy, device assisted enteroscopy and dedicated small-bowel cross-sectional imaging are complimentary tools, supplementing each other in the diagnostic process. Therapeutic management of small-bowel tumors largely depends on the histological type and staging at diagnosis. The aim of the present review article is to discuss relevant advances in the diagnosis and management of small-bowel tumors.

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma.

Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.

Precision medicine in gastroenteropancreatic neuroendocrine neoplasms: Where are we in 2023?

Precision medicine describes a target-related approach to tailoring diagnosis and treatment of the individual patient. While this personalized approach is revoluzionizing many areas of oncology, it is quite late in the field of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), in which there are few molecular alterations to be therapeutically targeted. We critically reviewed the current evidence about precision medicine in GEP NENs, focusing on potential clinically relevant actionable targets for GEP NENs, such as the mTOR pathway, MGMT, hypoxia markers, RET, DLL-3, and some general agnostic targets. We analysed the main investigational approaches with solid and liquid biopsies. Furthermore, we reviewed a model of precision medicine more specific for NENs that is the theragnostic use of radionuclides. Overall, currently no true predictive factors for therapy have been validated so far in GEP NENs, and the personalized approach is based more on clinical thinking within a NEN-dedicated multidisciplinary team. However, there is a robust background to suppose that precision medicine, with the theragnostic model will yield new insights in this context soon.

Small bowel neuroendocrine tumours - casting the net wide.

PURPOSE OF REVIEW: Our aim is to provide an overview of small bowel neuroendocrine tumours (NETs), clinical presentation, diagnosis algorithm and management options. We also highlight the latest evidence on management and suggest areas for future research. RECENT FINDINGS: Dodecanetetraacetic acid (DOTATATE) scan can detect NETs with an improved sensitivity than when compared with an Octreotide scan. It is complimentary to small bowel endoscopy that provides mucosal views and allows the delineation of small lesions undetectable on imaging. Surgical resection is the best management modality even in metastatic disease. Prognosis can be improved with the administration of somatostatin analogues and Evarolimus as second-line therapies. SUMMARY: NETs are heterogenous tumours affecting most commonly the distal small bowel as single or multiple lesions. Their secretary behaviour can lead to symptoms, most commonly diarrhoea and weight loss. Metastases to the liver are associated with carcinoid syndrome.

Consideration of quality of life in the treatment decision-making for patients with advanced gastroenteropancreatic neuroendocrine tumors.

INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a complex and heterogenous family of solid malignancies that originate from neuroendocrine tissue in the gastrointestinal tract or pancreas. Most patients diagnosed with GEP-NETs present with advanced or metastatic disease, and quality of life (QoL) is often an important priority when selecting treatments for these patients. Patients with advanced GEP-NETs often experience a substantial and persistent symptom burden that undermines their QoL. Addressing a patient's individual symptoms through judicious selection of treatment may improve QoL. AREAS COVERED: The objectives of this narrative review are to summarize the impact of advanced GEP-NETs on patient QoL, assess the potential value of current treatments for maintaining or improving patient QoL, and offer a clinical framework for how these QoL data can be translated to inform clinical decision-making for patients with advanced GEP-NETs. EXPERT OPINION: Patients with advanced GEP-NETs experience a significant and persistent symptom burden that impacts their daily lifestyle, activities, work life, and financial health, leading to erosion of their QoL. Ongoing and future studies incorporating longitudinal QoL assessments and head-to-head treatment evaluations will further inform the incorporation of QoL into clinical decision-making.

Carcinoid heart disease in patients with midgut neuroendocrine tumours.

Carcinoid heart disease (CHD) is the main complication of carcinoid syndrome (CS) associated with metastatic small intestine neuroendocrine tumours (NETs). The pathophysiology of CHD is partly understood but vasoactive hormones secreted by NETs, especially serotonin, play a major role, leading to the formation of fibrous plaques. These plaque-like deposits involve the right side of the heart in >90% of cases, particularly the tricuspid and pulmonary valves, which become thickened, retracted and immobile, resulting in regurgitation or stenosis. CHD represents a major diagnostic and therapeutic challenge for patients with NET and CS and is associated with increased risk of morbidity and mortality. CHD often occurs 2-5 years after the diagnosis of metastatic NET, but diagnosis of CHD can be delayed as patients are often asymptomatic for a long time despite severe heart valve involvement. Circulating biomarkers (5HIAA, NT-proBNP) are relevant tools but transthoracic echocardiography is the key examination for diagnosis and follow-up of CHD. However, there is no consensus on the optimal indications and frequency of TTE and biomarker dosing regarding screening and diagnosis. Treatment of CHD is complex and requires a multidisciplinary approach. It relies on antitumour treatment, control of CS and surgical valve replacement in cases of severe CHD. However, cardiac surgery is associated with a high risk of mortality, notably due to perioperative carcinoid crisis and right ventricular dysfunction. Timing of surgery is the most crucial point of CHD management and relies on the case-by-case determination of the optimal compromise between tumour progression, cardiac symptoms and CS control.

Progress in the Treatment of Small Intestine Cancer.

OPINION STATEMENT: Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.

Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN).

PURPOSE OF REVIEW: Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS: In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.

Characteristics and outcome of patients with small bowel adenocarcinoma (SBA).

BACKGROUND: Small bowel adenocarcinoma (SBA) remains a rare malignancy accounting for less than 5% of all the gastrointestinal tract cancers. However, only limited data and expert guidelines are available for this entity. As a result, treatment concepts are predominantly derived from colorectal cancer. METHODS: To substantiate data on the course of disease, diagnosis and treatment of SBA, we performed a population-based analysis from a Bavarian population of 2.2 million people. RESULTS: We identified 223 patients with SBA. Mean age at diagnosis was 67.8 years and patients were diagnosed rather late (34.5% UICC stage IV). Largest proportion of these patients were diagnosed with adenocarcinoma of the duodenum (132 patients, 59.2%) and most patients were diagnosed with late stage cancer, stage IV (70 patients, 31.4%). With respect to treatment, most patients underwent primary surgery (187 patients, 84.6%). Systemic therapy seemed to have an impact in UICC stage IV patients but not in UICC stage IIB or III. The 5-year survival rate was 29.0%. This was significantly less compared to colon cancer in the same cohort, which was 50.0%. Furthermore, median survival of patients with small bowel cancer was only 2.0 years (95% CI 1.4-2.5) compared to 4.9 years (95% CI 4.8-5.1) of patients with colon cancer. CONCLUSION: SBA showed a distinct epidemiology compared to colon cancer. Thus, data acquisition particularly on systemic treatment are paramount, with the objective to complement the available guidelines.

[Gastroenteropancreatic neuroendocrine tumors : (GEP-NENs)]. / Neuroendokrine Neoplasien des Gastrointestinaltrakts : (GEP-NENs).

The entity of NENs represent a highly heterogenous group of malignancies that require a multidisciplinary approach during the treatment of patients. The following article aims to provide a concise overview of the current state of the art in diagnostics and therapy. One specific feature of G1/G2 NENs is that the indication for surgery is given even in metastatic settings. Specific details regarding the treatment of its various different subgroups need to be gathered from available guidelines or current clinical studies. The field of nuclear medicine offers promising options for diagnostics and therapy which needs further investigation.

[Chinese expert consensus on gastroenteropancreatic neuroendocrine neoplasms (2022 edition)].

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are highly heterogeneous tumors. According to the 2019 World Health Organization classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract and hepatopancreatobiliary organs, GEP-NENs include well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). GEP-NETs may present as hormonally functioning or nonfunctioning tumors and may have distinct clinical features based on their sites of origin. The Expert Committee of Neuroendocrine Tumors, Chinese Society of Clinical Oncology revised and updated the 2016 version of Chinese expert consensus on GEP-NENs. The update the consensus includes the epidemiology, clinical manifestations, biochemical and imaging examinations, pathological features, and treatment and follow-up of GEP-NENs.

A Real-World, Population-Based Study for the Incidence and Outcomes of Neuroendocrine Neoplasms of Nondigestive, Nonpulmonary Primary.

OBJECTIVES: The aim of this study was to assess incidence and outcomes of neuroendocrine neoplasms (NENs) arising from primary sites other than digestive organs, lung, or thymic gland. METHODS: Surveillance, Epidemiology, and End Results database (1975-2016) was accessed, and cases of NENs arising from primary sites other than digestive organs, lung, or thymic gland were reviewed. Overall and cancer-specific survival outcomes for NENs arising from different organs compared with small intestinal NENs were evaluated. RESULTS: A total of 4405 patients were included in the study. Compared with small intestinal NENs, some NENs arising from uncommon sites in the current study have worse cancer-specific survival (hazard ratio [HR] for genitourinary vs small intestinal NENs, 1.80; 95% confidence interval [CI], 1.44-2.25; HR for gynecological vs small intestinal NENs, 1.88; 95% CI, 1.52-2.33). When the analysis was limited for patients with distant stage only, small intestinal NENs have better outcomes compared with genitourinary and gynecological NENs (HR for genitourinary NENs with distant stage vs small intestinal NENs with distant stage, 1.38; 95% CI, 1.01-1.88; HR for gynecological NENs with distant stage vs small intestinal NENs with distant stage, 2.02; 95% CI, 1.54-2.66). CONCLUSIONS: Compared with small intestinal NENs, NENs arising from uncommon sites (such as genitourinary, gynecological) have worse survival outcomes.

Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common type of neuroendocrine tumors and are being increasingly identified in clinical practice. The diagnosis, staging, management, and surveillance of GEP-NETs rely heavily on endoscopy, and consequently, it is important for gastroenterologists to have a solid understanding of these tumors. This article reviews the presentation, diagnosis, and management of both localized and advanced GEP-NETs, with increased emphasis on the role of endoscopy, to enable gastroenterologists and other practitioners to have the necessary tools for the care of patients with these tumors.

Evaluation of multidisciplinary team decisions in neuroendocrine neoplasms: Impact of expert centres.

OBJECTIVE: To evaluate the impact of multidisciplinary team (MDT) meetings on the management of patients with neuroendocrine neoplasms (NENs). METHODS: All newly referred gastro-entero-pancreatic (GEP)-NEN patients discussed from 1 April to 1 October 2017 in the MDT of seven European expert centres were prospectively included. The impact on patients' management was defined as a change in diagnosis, grade, stage or treatment. RESULTS: A total of 292 patients were included, mainly small intestinal (siNENs) (32%) and pancreatic NENs (28%), with distant metastases in 51%. Patients had received prior surgery in 43% of cases and prior medical treatment in 32%. A significant change occurred in 61% of NENs: 7% changes in diagnosis, 8% in grade and 16% in stage. The MDT recommended a new treatment for 51% of patients, mainly surgery (9%) or somatostatin analogues (20%). A significant change was most frequently observed in patients with Stage IV disease (hazard ratio [HR] 3.6, 95% confidence interval [CI]: 1.9-6.9 vs. Stage I) and G2 NENs (vs. G1, HR 2.1 95% CI: 1.2-3.8). CONCLUSION: NEN-dedicated MDT discussion in expert centres yields significant management changes in over 60% of patients and thus represents the gold standard for the management of these patients.

[The diagnosis and treatment of G3 neuroendocrine tumors according to the new NCCN guideline].

Gastrointestinal pancreas (GEP) is the most common site of neuroendocrine neoplasms (NENs). In 2019, the World Health Organization (WHO) classification for GEP NET was updated to include a new category of well-differentiated high-grade (Ki 67>20%) GEP-NET G3, distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). As a new category, NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The management of NET G3 remains a challenge awaiting future trials taking into consideration the unique characteristics of this new category. The latest NCCN clinical guidelines of neuroendocrine and adrenal tumors firstly gave the recommendation of diagnosis and treatment of G3 NET separately from NEC and G1/G2 NET. Hereon,we aim to summarize the management of G3 NET in combination with the new NCCN guidelines and the current evidences.