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Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

Simple Summary: Cancers of the gallbladder arise in dogs and humans. Neuroendocrine neoplasms are the rarest type of gallbladder cancer in both species. This review summarizes the characteristics of canine and human gallbladder neuroendocrine neoplasms with the objective of comparatively modeling clinical and diagnostic features of these spontaneously occurring neoplasms. Gallbladder neuroendocrine neoplasms (GB NENs) are among the rarest cancers reported in humans and dogs. This review provides a detailed review of the canine GB NEN literature and an interspecies comparison of demographics, clinical pathophysiology, pathobiology, and therapeutic response of GB NENs. The aim of this work is to explore the relevance of dogs as a spontaneous model for human GB NENs. [ABSTRACT FROM AUTHOR]

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Copyright of Die Gastroenterologie 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.)

The chemotherapy regimen capecitabine/temozolomide (CAPTEM) is routinely used in neuroendocrine tumors (NET), with antitumor activity particularly demonstrated in pancreatic or high-grade neuroendocrine neoplasms (NEN). However, different dosing regimens are used, and the optimal schedule remains to be defined. This single-center retrospective analysis assessed the efficacy and safety of CAPTEM in patients with NEN using a schedule starting both compounds simultaneously (temozolomide on days 1-5 and capecitabine on days 1-14 of a 28-day cycle) rather than sequentially. The primary parameters of interest were response rates, progression-free survival (PFS), and toxicities following this treatment regimen, hereinafter referred to as TEMCAP. The study population comprised 40 patients, half of whom (n = 20) had pancreatic NEN, and 9 patients (22.5%) had pulmonary or thymic NETs. The most common histology was NET G3 (n = 15, 37.5%), and 8 patients (20.0%) had a neuroendocrine carcinoma (NEC). Most patients (77.5%) had at least one prior systemic therapy, and 16 patients (40.0%) prior chemotherapy. The median number of TEMCAP cycles was 6 (range 1-16). Median PFS for the highly heterogeneous population was 13.3 months, while the median overall survival was 31.9 months. In total, 14/36 patients (38.9%) exhibited a partial response, and the disease control rate was 75.0%. The safety profile of TEMCAP (at a below-target mean temozolomide dose of 118.85 mg/m2) in our cohort was remarkably good with no toxicities of grade 3 or 4. Taken together, the results of this analysis further support the use of temozolomide/capecitabine in NEN and prompt further assessment of our modified TEMCAP schedule. [ABSTRACT FROM AUTHOR]

Purpose: Poorly differentiated neuroendocrine carcinoma (PDNEC) of the rectum and anus is a rare disease exhibiting aggressive biological behaviour, even if diagnosed early. Currently, there are no agreed standard treatment approaches and management of locally advanced (LA) and metastatic PDNEC usually follows treatments used in pulmonary neuroendocrine carcinomas because of the similarities with small cell lung cancer. The role of surgery in PDNEC is still debated and the benefit of chemoradiotherapy (CRT) is unknown. This report summarises the experiences of CRT application in anorectal PDNEC in a single Danish institution. Methods: All patients with PDNEC treated with concomitant CRT between May 2019 and January 2021 at a University hospital in Denmark were evaluated. Demographics, treatment and survival outcomes were collected and analysed. Results: Six patients were identified. Five patients received radiotherapy with 50.4 Gy/28 fractions, and four were eligible for curative resection after the CRT. Distant metastasis was observed in four patients at diagnosis. Two patients with synchronous liver metastases were treated with RFA, and one received a liver resection. The treatment was well tolerated with limited side effects. The median follow-up time was 17 months (range 10–36 months), and the median duration of response was 11.2 months (range 8.1 to 24.2 months). One patient achieved a complete response. Conclusion: A multimodal treatment approach with CRT in advanced stages of PDNEC in a highly selected patient group is well tolerated and with a high chance of achieving local control and, combined with surgery, even complete response in a single case. [ABSTRACT FROM AUTHOR]

Neuroendocrine Neoplasms (NENs) account for 0.5% of all malignancies. Skeletal colonisation is often regarded as a rare event, and metastasis to the bone marrow occurs in the advanced stage of the disease, carrying a poor prognosis. In this report, the authors present three rare cases of Neuroendocrine Carcinomas (NEC) of the lung, diagnosed among 6766 bone marrow aspirations and biopsies performed at our institution between January 2019 and December 2022, highlighting the rarity of these cases. All three cases (63 years, 56 years and 73 years old male patients) presented to our institute at an advanced stage of the disease, with bone marrow involvement at the time of presentation. They exhibited nonspecific symptoms and had normal haematological parameters. Bone marrow aspiration and biopsy confirmed metastatic NEC. The aim of this case series was to investigate bone marrow involvement in NECs, along with their clinical and radiographic features, treatment, and follow-up. Bone marrow biopsy plays a crucial role not only in diagnosing haematological diseases but also in diagnosing and staging solid tumours. Future prospectives include adopting a multimodal approach for early diagnosis and treatment of NECs.

Gallbladder neuroendocrine neoplasms (GB NENs) are among the rarest cancers reported in humans and dogs. This review provides a detailed review of the canine GB NEN literature and an interspecies comparison of demographics, clinical pathophysiology, pathobiology, and therapeutic response of GB NENs. The aim of this work is to explore the relevance of dogs as a spontaneous model for human GB NENs.

Neuroendocrine Neoplasms (NENs) account for 0.5% of all malignancies. Skeletal colonisation is often regarded as a rare event, and metastasis to the bone marrow occurs in the advanced stage of the disease, carrying a poor prognosis. In this report, the authors present three rare cases of Neuroendocrine Carcinomas (NEC) of the lung, diagnosed among 6766 bone marrow aspirations and biopsies performed at our institution between January 2019 and December 2022, highlighting the rarity of these cases. All three cases (63 years, 56 years and 73 years old male patients) presented to our institute at an advanced stage of the disease, with bone marrow involvement at the time of presentation. They exhibited nonspecific symptoms and had normal haematological parameters. Bone marrow aspiration and biopsy confirmed metastatic NEC. The aim of this case series was to investigate bone marrow involvement in NECs, along with their clinical and radiographic features, treatment, and follow-up. Bone marrow biopsy plays a crucial role not only in diagnosing haematological diseases but also in diagnosing and staging solid tumours. Future prospectives include adopting a multimodal approach for early diagnosis and treatment of NECs. [ABSTRACT FROM AUTHOR]

Primary hepatic neuroendocrine carcinomas (PHNECs) are extremely rare, with only about 90 cases having been reported in the English-language literature. Among all neuroendocrine neoplasms, primary hepatic neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are extremely rare, accounting for 0.3% of NETs and 0.28–0.46% of malignant liver tumors. Additionally, primary hepatic NECs occur infrequently. The clinical diagnosis of primary hepatic NEC remains challenging because of its rarity and the lack of information about its characteristic appearance on images. Consequently, pathological examination through the performance of a preoperative liver tumor biopsy is essential for diagnosis. Due to the lack of availability of substantial high-quality data, there is no standard therapy for primary hepatic NEC. We present the first case of PHNEC metastasized to the mesentery reported in the English-language literature.

Objective: We examined the clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas (NECs) to offer additional guidance for the clinical treatment of small-cell lung cancer (SCLC), which is a type of advanced intrapulmonary NEC (IPNECs). Materials and Methods: The clinical data and survival of 123 patients with advanced IPNECs and extrapulmonary NECs (EPNECs) were obtained. We retrospectively examined the corresponding clinical diagnosis and treatment and investigated the significant factors influencing the survival prognosis of patients with NECs. Results: There were 90 cases of IPNECs (including 81 cases of SCLC), and 33 cases of EPNECs. The median overall survival (OS) of IPNECs was significantly longer than that of the EPNECs in the gastrointestinal tract and in the other regions ( P < 0.05). The median OS of patients with other IPNECs was longer than that of patients with SCLC ( P > 0.05). Multivariate analysis demonstrated that age, liver metastasis, number of cycles of first-line chemotherapy, and chest radiotherapy were risk factors influencing OS in patients with NECs ( P < 0.05). Conclusions: The survival of IPNECs was significantly longer than that of EPNECs in the gastrointestinal tract and other regions. Nevertheless, patients with advanced NECs who were older and had liver metastases had a poorer prognosis. Multidisciplinary treatments including multicycle chemotherapy and a combination of chemotherapy and radiotherapy should function significantly in extending the survival of NECs. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs—both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs)—have appreciably evolved. Diagnosis of NEN mostly follows a suspicion from clinical features or incidental imaging findings. Hormonal or non-hormonal biomarkers (like serum serotonin, urine 5-HIAA, gastrin and VIP) and histology of a suspected NEN is, therefore, critical for both confirmation of the diagnosis and classification as an NET or NEC. Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. As the incidence of NENs is on the rise in the United States and several other countries, physicians are more likely to see these cases, and their better understanding may support earlier diagnosis and tailoring treatment to the patient. We have compiled clinically significant evidence for NENs, including relevant changes to clinical practice that have greatly updated our diagnostic and therapeutic approach for NEN patients. [ABSTRACT FROM AUTHOR]

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small cell lung cancer, a far more common G3 neuroendocrine neoplasm, although emerging molecular and clinical data increasingly question this approach. In this article, we will briefly summarize epidemiology and prognosis of gastroenteropancreatic neuroendocrine carcinomas to emphasize the very low incidence, aggressive nature, and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background compared with small cell lung cancer, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors), and additional treatment strategies targeting other tumor vulnerabilities (ie, Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient's care and prognosis. [ABSTRACT FROM AUTHOR]

Key molecular alterations (MA) of neuroendocrine neoplasm (NEN) of various grade/primaries have been described but the applicability of molecular profiling (MP) for precision medicine in NEN remains to be demonstrated. We conducted a retrospective study of all patients with metastatic NEN who had MP on tumour tissue at Gustave Roussy. The primary objective was to assess the clinical applicability of MP by evaluating the growth modulator index (GMI) as the primary end-point. MPs were obtained in 114 out of 156 eligible patients, including 12% NET-G1, 42% NET-G2, 13% NET-G3 and 35% neuroendocrine carcinoma (NEC). Primary sites were lung/thymus (40%), pancreas (19%), gastro-intestinal (16%), head&neck (10%), unknown (10%) and others (10%) with synchronous metastases in 61% of the patients. Most frequent MA were: MEN1 (25%), PTEN (13%), TP53 (11%) and TSC2 (9%), in neuroendocrine tumour (NET), and TP53 (50%) and RB1 (18%) in NEC. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) classification of these MA were: I(5%), III(20%), IV(23%), X(27%); a putative actionable MA was identified in 48% patients. Median TMB was 5.7 Mut/Mb, with 3 TMB > 10 and 1 MSI NET. No MA was found in 26% patients. Molecularly matched treatment was administered to 19 patients (4 NEC, 15 NET): immunotherapy (n = 3), tipifarnib (n = 1), NOTCHi (n = 1), EGFRi (n = 2), HER2i (n = 1) and everolimus (n = 11). Overall, 67% of patients had a clinical benefit defined as a GMI over 1.3 with a 78% disease control rate. We report 48% of NEN with a putative actionable MA of which 35% received molecularly matched treatment, with a clinical benefit in 67% of the cases. • Molecular alterations of NEN of various grade/primaries have been described. • Applicability of molecular profiling in NEN remains to be demonstrated. • We describe the largest cohort of metastatic NENs molecularly characterised. • We report the clinical benefit obtained in NENs with molecular profiling. • Our results put in a routine perspective the impact of precision medicine in NENs. [ABSTRACT FROM AUTHOR]

Abstract Background Neuroendocrine carcinomas of the gastrointestinal tract (GI‐NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI‐NECs. Methods Comprehensive genomic analysis using whole‐exome sequencing was performed on 143 formalin‐fixed, paraffin‐embedded samples of surgically resected GI‐NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. Results In total, 143 GI‐NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty‐three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI‐NECs showed distinct genetic alterations from their lung counterparts and non‐neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low‐density lipoprotein receptor‐related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT‐β‐catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI‐NECs harbored putative clinically relevant alterations, and non‐gastric location and RB1 bi‐allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI‐NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole‐genome doubling (WGD) and post‐WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb‐b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. Conclusions GI‐NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI‐NECs.

Neuroendocrine tumors are a spectrum of rare and highly heterogeneous neoplasms with distinct functional and biological behavior in relation to location, tumor size, and histological differentiation. Neuroendocrine tumors arise from the neuroendocrine cells of the diffuse neuroendocrine system located in almost every organ. Neuroendocrine tumors in the head and neck district are usually reported in sinonasal cavities and larynx. We present the case of a nasopharyngeal small-cell neuroendocrine carcinoma, which, as far as we know, is the 16th case reported in literature. [ABSTRACT FROM AUTHOR]

Primary hepatic neuroendocrine carcinomas (PHNECs) are extremely rare, with only about 90 cases having been reported in the English-language literature. Among all neuroendocrine neoplasms, primary hepatic neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are extremely rare, accounting for 0.3% of NETs and 0.28–0.46% of malignant liver tumors. Additionally, primary hepatic NECs occur infrequently. The clinical diagnosis of primary hepatic NEC remains challenging because of its rarity and the lack of information about its characteristic appearance on images. Consequently, pathological examination through the performance of a preoperative liver tumor biopsy is essential for diagnosis. Due to the lack of availability of substantial high-quality data, there is no standard therapy for primary hepatic NEC. We present the first case of PHNEC metastasized to the mesentery reported in the English-language literature. [ABSTRACT FROM AUTHOR]

Summary: In the last decade, a number of genetic alterations in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have been identified. In addition, differences in tumor morphology as well as proliferation index (Ki-67) or number of mitoses have led to changes in the classification of these neoplasms. According to the new World Health Organization (WHO) classification, GEP-NENs are now divided into two genetically and prognostically different categories: (i) well-differentiated neuroendocrine tumors (NET) subdivided into low (G1), intermediate (2) and high (G3) grade tumors, and (ii) poorly differentiated neuroendocrine carcinomas (NEC). In addition, a group of mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN) has been defined. This review focuses on the clinical, morphological, immunohistochemical and molecular findings of the GEP-NENs and their key diagnostic features that can help the pathologist to differentiate between tumors in this heterogeneous group. In challenging cases, additional immunohistochemical and/or molecular analysis can be helpful to determine the correct diagnosis and proper treatment for the patient. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine neoplasms are increasing in incidence at a remarkable rate meaning more providers are encountering them in both adult and pediatric patients. This classification of neoplasm encompasses a wide range of different malignancies with a variety of symptoms at presentation and each treated differently. Additionally, over the past few years there has been a change in classification of these neoplasms and a variety of changes and advances in how they are treated. Given this and their rarity in pediatric patients, healthcare providers may not be familiar with these changes. Our goal with this review was to provide an overview of all the most commonly encountered forms of neuroendocrine neoplasms in pediatric patients with up to date recommendations so any healthcare provider can quickly and accurately acclimate themselves. Neuroendocrine neoplasms (NENs) encompass a variety of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) which can arise anywhere in the body. While relatively rare in the pediatric population, the incidence of NENs has increased in the past few decades. These neoplasms can be devastating if not diagnosed and treated early, however, symptoms are variable and can be indolent for many years. There is a reported median of 10 years from the appearance of the first symptoms to time of diagnosis. Considering some of these neoplasms have a mortality rate as high as 90%, it is crucial healthcare providers are aware of NENs and remain vigilant. With better provider education and easily accessible resources for information about these neoplasms, awareness can be improved leading to earlier disease recognition and diagnosis. This manuscript aims to provide an overview of both the most common NENs as well as the rarer NENs with high lethality in the pediatric population. This review provides up to date evidence and recommendations, encompassing recent changes in classification and advances in treatment modalities, including recently completed and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumours can originate from any part of the body. The most common site in the head and neck is the larynx, accounts for less than 0.6%. The neuroendocrine carcinomas (NECs) of the larynx are rare tumours with high incidence of widespread metastases and poor prognosis. Here we report a 50-year-old male with localised primary moderately differentiated NEC of the larynx. He was treated with surgery followed by adjuvant chemotherapy and concurrent chemoradiation. He is free of his disease and is doing well. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine tumors (NETs) are epithelial neoplasms that originate from the endocrine cells, contain cytoplasmic granules, and secrete a variety of biogenic amines, which are responsible for a variety of signs and symptoms produced by these tumors. Endocrine cells are interspersed within the mucosa of the gastrointestinal tract (GIT) and are also present in a variety of other viscera such as pancreas, adrenal gland, lung, and thyroid. The present study included forty cases of NETs of the GIT (excluding pancreas) reported in the Department of Pathology at Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Kashmir. The objectives of this study were to study the histopathological spectrum of NETs of the GIT and to evaluate the immunohistochemical (IHC) expression of chromogranin, synaptophysin (SYP), neuron-specific enolase, and Ki-67 (MIB) in these tumors. Materials and Methods: The study was conducted at the SKIMS, Srinagar, Kashmir, in the Department of Pathology. It was a prospective study for a period of 1½ years starting from July 2015 to December 2016 and retrospective study for 3½ years from January 2012 to June 2015. The study included all cases of NETs of GIT with or without nodal metastasis. Results: Most of the tumors were well-differentiated NETs (45% G1 and 25% G2). Stomach was the most common site (27.5%) followed by duodenum (25%). Regional lymph node involvement was present in 25% of the cases. Liver was the most common site for distant metastasis. There was a slight female predominance (57.3%). On IHC, SYP, chromogranin-A, and neuron-specific enolase were positive in 100%, 77.5%, and 85% of cases, respectively. Ki-67/MIB-1 index was used to grade the neuroendocrine neoplasms and 45% were graded as G1 NETs, 25% as G2 NETs, and 30% as NEC. Conclusion: Lately, there has been a surge in the number of cases being diagnosed as NETs most probably due to advancement in various diagnostic modalities and increasing knowledge about these tumors which have helped in diagnosing more of these tumors early and correctly.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs—both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs)—have appreciably evolved. Diagnosis of NEN mostly follows a suspicion from clinical features or incidental imaging findings. Hormonal or non-hormonal biomarkers (like serum serotonin, urine 5-HIAA, gastrin and VIP) and histology of a suspected NEN is, therefore, critical for both confirmation of the diagnosis and classification as an NET or NEC. Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. As the incidence of NENs is on the rise in the United States and several other countries, physicians are more likely to see these cases, and their better understanding may support earlier diagnosis and tailoring treatment to the patient. We have compiled clinically significant evidence for NENs, including relevant changes to clinical practice that have greatly updated our diagnostic and therapeutic approach for NEN patients.

Clinical Issue: After the first description of the "carcinoid tumors" by the pathologist Siegfried Oberndorfer in Munich, the classification system of neuroendocrine neoplasms (NENs) is still a challenge and an evolving concept., Methodical Innovations: The new WHO classification system proposed a framework for universal classification., Achievements: The new WHO classification system recognizes two distinct families distinguished by genetic, morphology and clinical behaviour: Well differentiated NENs are defined as neuroendocrine tumor (NET G1, G2, G3), while poorly differentiated ones are defined as neuroendocrine carcinoma (NEC, G3) and further subdivided into small and large cell carcinoma. All NENs are characterized by the expression of synaptophysin and chromogranin A, Ki-67 and morphology., Molecular Pathology: The morphological NEN dichotomy is supported by genetic alterations. NECs show TP53 and RB1 alterations that are absent in NETs and are therefore useful for differentiating between NETs and NECs., Practical Recommendations: All NENs are divided into well-differentiated neuroendocrine tumor (NET G1, G2, G3) or poorly differentiated neuroendocrine carcinoma (NEC, G3). They are categorized by morphology, mitotic count and immunohistochemistry with synaptophysin, chromogranin and Ki-67., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Oncolytic viruses have made a significant inroad in cancer drug development. Numerous clinical trials are currently investigating oncolytic viruses both as single agents or in combination with various immunomodulators. Oncolytic viruses (OV) are an integral pillar of immuno-oncology and hold potential for not only delivering durable anti-tumor responses but also converting “cold” tumors to “hot” tumors. In this review we will discuss one such promising oncolytic virus called Seneca Valley Virus (SVV-001) and its therapeutic implications. SVV development has seen seismic evolution over the past decade and now boasts of being the only OV with a practically applicable biomarker for viral tropism. We discuss relevant preclinical and clinical data involving SVV and how bio-selecting for TEM8/ANTXR1, a negative tumor prognosticator can lead to first of its kind biomarker driven oncolytic viral cancer therapy.

Neuroendocrine carcinomas are very aggressive tumors with few treatment options. DLL3 seems to be an optimal target for therapeutic intervention, as it is expressed mainly on the membrane of tumor cells with neuroendocrine origin. In this article, we outline the preclinical and clinical studies published in the last years on DLL3 in neuroendocrine neoplasm, above all of lung origin. Furthermore, we review the current literature on the interaction between DLL3 and the tumor microenvironment. Several DLL3-targeting strategies have been proposed in the last years with mixed results. Understanding the influence of DLL3 on the tumor (immune) microenvironment and developing adoptive therapies directed against this optimal target might represent the key strategy. Building on the clinical data obtained so far, future trials on in vivo diagnostic tools for predictive purpose and new specific therapies are needed. [ABSTRACT FROM AUTHOR]

The neuroendocrine carcinomas (NECs) of the head and neck are rare. The purpose of this article is to explore the diagnosis and treatment of NECs in the ear and larynx. We report a case of a patient with NECs found in the ear and throat simultaneously, and the relevant literatures are reviewed. It is difficult to identify which is the original site. There is no specific clinical manifestation of NECs in the ear and throat, and carcinoid syndrome is a rare situation. Surgery is still the preferred treatment for this disease. For patients with metastasis, radiotherapy and/or chemotherapy are required. [ABSTRACT FROM AUTHOR]

Purpose: Neuroendocrine neoplasms (NENs) of the gallbladder are very rare. As a result, the classification of pathologic specimens from gallbladder NENs, currently classified as gallbladder neuroendocrine tumors (GB-NETs) and carcinomas (GB-NECs), is inconsistent and makes nomenclature, classification, and management difficult. Our study aims to evaluate the epidemiological trend, tumor biology, and outcomes of GB-NET and GB-NEC over the last 5 decades. Methods: This is a retrospective analysis of the SEER database from 1973 to 2016. The epidemiological trend was analyzed using the age-adjusted Joinpoint regression analysis. Survival was assessed with Kaplan–Meier analysis and Cox regression was used to assess predictors of poor survival. Results: A total of 482 patients with GB-NEN were identified. Mean age at diagnosis was 65.2 ± 14.3 years. Females outnumbered males (65.6% vs. 34.4%). The Joinpoint nationwide trend analysis showed a 7% increase per year from 1973 to 2016. The mean survival time after diagnosis of GB-NEN was 37.11 ± 55.3 months. The most common pattern of nodal distribution was N0 (50.2%) followed by N1 (30.9%) and N2 (19.2%). Advanced tumor spread (into the liver, regional, and distant metastasis) was seen in 60.3% of patients. Patients who underwent surgery had a significant survival advantage (111.0 ± 8.3 vs. 8.3 ± 1.2 months, p < 0.01). Cox regression analysis showed advanced age (p < 0.01), tumor stage (P < 0.01), tumor extension (p < 0.01), and histopathologic grade (p < 0.01) were associated with higher mortality. Conclusion: Gallbladder NENs are a rare histopathological variant of gallbladder cancer that is showing a rising incidence in the USA. In addition to tumor staging, surgical resection significantly impacts patient survival, when patients are able to undergo surgery irrespective of tumor staging. Advanced age, tumor extension, and histopathological grade of the tumor were associated with higher mortality. [ABSTRACT FROM AUTHOR]

Background: Colonic neuroendocrine carcinomas (co-NECs) are heterogeneous and aggressive, especially with regard to metastasis. Whether co-NECs on the right and left sides of the colon have different characteristics from colon adenocarcinoma is unknown. Methods: The co-NEC patients were selected from the 2010–2017 Surveillance, Epidemiology, and End Results Program (SEER) database. The right and left sides of the colon were separated by the splenic flexure. Coarsened exact matching (CEM) was performed to adjust for relevant factors before regression models were constructed. Results: A total of 669 pathologically diagnosed co-NEC patients with sufficient baseline data were identified from the SEER database. A total of 80.72% of the patients had co-NEC that originated from the right side of the colon, and their mean overall survival (mOS) was similar to that of the patients with left-sided co-NECs (right versus left: 22.30 m versus 22.55 m). A total of 44.84% of the patients were diagnosed with liver metastasis (46.68% right side versus 37.98% left side). In patients with liver metastasis, those with right-sided co-NECs had better survival than those with left-sided co-NECs (mOS right versus left: 15.37 m versus 9.62 m; adjusted hazard ratio (HR) = 0.69, 95% confidence interval (CI): 0.49–0.98, p = 0.035). To further investigate the survival benefits of primary site resection, we separated the patients who had liver metastasis according to the primary site and performed CEM to balance the groups (no patients underwent liver metastasis resection or intervention). The results suggested that primary surgery could benefit patients with both left- and right-sided co-NECs (adjusted HR = 0.50, 95% CI: 0.33–0.77, p = 0.001 on the right side; HR = 0.38, 95% CI: 0.16–0.89, p = 0.026 on the left side). Conclusions: Co-NECs frequently originate on the right side and commonly develop liver metastasis. Right-sided co-NECs are associated with better survival than left-sided co-NECs after liver metastasis has occurred. Primary site resection is associated with prolonged survival in co-NEC patients with liver metastasis, regardless of the side from which the co-NEC has originated. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumours, which can be classified into neuroendocrine tumours (NETs), neuroendocrine carcinomas (NECs) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). To date, there is no consensus regarding the optimal therapy, which usually depends on the primary location and classification, according to morphological features of differentiation and proliferation rates. Nevertheless, multidisciplinary strategies combining medical treatments and locoregional strategies have yielded better efficacy results. Here, we report the case of a patient diagnosed with a nonfunctional rectal NECs with metastatic widespread to pelvic lymph nodes and bilateral lung metastases. The patient received three cycles of platinumetoposide, concomitantly with palliative radiotherapy. Although CT scan after three cycles showed a significant partial response, there was an early fatal progression only 3 months after having stopped systemic therapy. As formerly described in the literature, this case highlights the aggressive behaviour of NECs, rare tumours that often present in advanced stages at diagnosis. Lately, new insights into the molecular biology of NECs have unveiled the possibility of using novel drugs, such as targeted agents or immunotherapy, in molecularly selected subgroups of patients. In this review, we discuss the current management of this rare entity and provide an overview of the most relevant molecular findings, whilst illustrating the potential value that prescreening panels can offer, searching for actionable targets (MSI/dMMR, PD-L1, BRAFv600E) to guide therapy with promising agents that could fill a void in this disease.

Abstract Background High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. Method Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative ( 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%). Results In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

Neuroendocrine neoplasms (NENs) encompass a variety of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) which can arise anywhere in the body. While relatively rare in the pediatric population, the incidence of NENs has increased in the past few decades. These neoplasms can be devastating if not diagnosed and treated early, however, symptoms are variable and can be indolent for many years. There is a reported median of 10 years from the appearance of the first symptoms to time of diagnosis. Considering some of these neoplasms have a mortality rate as high as 90%, it is crucial healthcare providers are aware of NENs and remain vigilant. With better provider education and easily accessible resources for information about these neoplasms, awareness can be improved leading to earlier disease recognition and diagnosis. This manuscript aims to provide an overview of both the most common NENs as well as the rarer NENs with high lethality in the pediatric population. This review provides up to date evidence and recommendations, encompassing recent changes in classification and advances in treatment modalities, including recently completed and ongoing clinical trials.

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are classified according to morphology as well-differentiated neuroendocrine tumours (NETs) G3 or poorly differentiated neuroendocrine carcinomas (NECs). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. A total of 213 patients with high-grade GEP-NEN (Ki-67 >20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells, and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67 <55% (NEC < 55) in 29.6%, and NEC with a Ki-67 ≥55% (NEC ≥ 55) in 56.6%. Only in 1.5%, the morphology was ambiguous. Of 164 patients receiving first-line chemotherapy, 88% received platinum/etoposide treatment. Response rate was higher for NEC ≥ 55 (44%) than that of NEC < 55 (25%) and NET G3 (24%) (p = 0.025 and p = 0.026). Median progression-free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC < 55 and NEC ≥ 55 (p = 0.004 and 0.003). Specific morphological criteria can separate NET G3 from NECs and show prognostic significance. High-grade GEP-NEN patients stratified by morphology and proliferation rate demonstrate significant differences in response to chemotherapy and survival. [ABSTRACT FROM AUTHOR]

Background: Galectin-1 (Gal-1) plays major roles in cancer by modulating different processes leading to tumor development and progression. In the last years, it has been suggested as a promising target for anticancer therapy. Recently, aflibercept has shown high affinity for Gal-1. Here, we investigated how aflibercept could exert its antitumor activity via Gal-1-driven pathways in neuroendocrine carcinomas (NECs). Methods and Results: NEC tumor xenografts were used to assess the effect of aflibercept on Gal-1 functions. Aflibercept induced a significant reduction of Gal-1 at epithelial, stromal, and extracellular localizations in lung NEC, whereas this was not observed in colon NECs, which displayed low expression of Gal-1. Additionally, aflibercept significantly reduced p-VEGFR2 protein, extracellular matrix remodeling, epithelial-mesenchymal transition, and activation of cancer-associated fibroblast hampering cell invasion in lung NEC but not in colon NEC. Gal-1 screening in human NECs confirmed that pulmonary and pancreatic tumors displayed higher levels of Gal-1 than colon NECs, becoming good candidates to benefit from aflibercept treatment. Conclusions: The lack of validated predictive markers of aflibercept is a weakness for guaranteeing the best treatment management with this drug. This work provides new mechanistic insight of aflibercept depending on Gal-1. Thus, in tumors overexpressing Gal-1, aflibercept has not only an antiangiogenic effect but also prevents Gal-1-mediated tumor-stroma cross talk. The stronger aflibercept effect in tumors with high levels of Gal-1 points out this protein as a molecular marker to predict the efficacy of this agent not only for NECs but also for other tumors with high levels of this protein. [ABSTRACT FROM AUTHOR]

Mixed hepatocellular carcinoma-neuroendocrine carcinomas (HCC-NECs)11 HCC-NECs: hepatocellular carcinoma-neuroendocrine carcinomas. are rare, and they usually carry a poor prognosis. We report a fascinating case of mixed HCC-NEC — the neuroendocrine component of the tumor was diagnosed retrospectively after discovery of the metastatic neuroendocrine carcinoma (NEC).22 NEC: neuroendocrine carcinoma. A 50-year-old man with cirrhosis underwent resection of a 2.7 cm hepatocellular carcinoma (HCC)33 HCC: hepatocellular carcinoma. at the segment II of the liver. Thirteen months after the surgery he had local recurrence in the liver that was treated with radio-embolization. Eighteen months after the initial diagnosis, he was found to have metastatic NEC in the left shoulder. Later, re-evaluation of the previously resected liver tumor revealed a small focus of tumor cells with neuroendocrine morphology within the tumor, which were negative for HepPar1 and positive for synaptophysin, whereas the majority of the tumor cells were positive for HepPar1 and negative for synaptophysin that reclassified the liver tumor as a combined type of mixed HCC-NEC tumor. Upon discovery of the metastatic NEC, the patient was treated with eight cycles of cisplatin and etoposide with a partial response. Nonetheless, his disease progressed two months after finishing chemotherapy, and he was treated with nivolumab for two cycles. In addition, he received palliative radiation to different skeletal metastases. The patient died of sepsis thirty-three months after the initial diagnosis of liver tumor. In conclusion, mixed HCC-NECs are rare and aggressive— an accurate diagnosis may require a high degree of clinical suspicion and re-evaluation of the pathological specimen, especially when one of the components is scarce. Strategic use of multiple modalities of treatment may prolong the life of patients with this type of aggressive tumor.

Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy. Objectives: We aimed to evaluate the effect of neoadjuvant +/– adjuvant and adjuvant therapy in this indication. Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity. Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/– adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death. Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

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Background: High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%.Method: Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier's method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5-30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1-30%), and abnormal when negative (0%) or strongly positive (> 30%).Results: In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression.Conclusion: Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine carcinoma (NEC) is a rare and very aggressive tumor. It has been greatly understudied, and very little is known about optimal treatment strategy for patients with this disease. The purpose of this study was to evaluate in vivo whether anti-vascular endothelial growth factor (VEGF) drugs could be a therapeutic alternative for these tumors with a poor prognosis. Methods: We have developed 2 xenograft models using either human cell line derived from lung (H460) or from colon (COLO320) NEC to assess the effect of 2 antiangiogenic drugs, aflibercept and bevacizumab, on tumor growth and their pathological characteristics. Additionally, tumors were subjected to immunohistochemistry staining and proteins were measured with Western blot and ELISA. Results: Both aflibercept and bevacizumab showed significant antitumor activity (p < 0.001). In the H460 model, aflibercept resulted in 94% tumor growth inhibition (TGI) and bevacizumab treatment resulted in 72.2% TGI. Similarly, in the COLO320 model, aflibercept and bevacizumab resulted in 89.3 and 84% TGI, respectively. Moreover, antitumor activity occurs early after treatment initiation. Using Tumor Control Index score, which address the kinetics of tumor growth in a way comparable to the methods used in human clinical studies, we confirmed that both drugs inhibit significantly tumor growth. When tumor stabilization was evaluated, aflibercept shows higher ability to stabilize NEC tumors than bevacizumab. Conclusion: Results derived from this study strongly support anti-VEGF therapies, especially aflibercept, as a novel therapeutic option in NECs. Further studies are necessary, but our observations encourage the evaluation of antiangiogenics in clinical trials combined with standard chemotherapy. [ABSTRACT FROM AUTHOR]