Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms.

BACKGROUND: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs. METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored. RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively). CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.

Advancements in medical treatment for pancreatic neuroendocrine tumors: A beacon of hope.

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors (pan-NETs), emphasizing tailored approaches for specific subtypes. Cytoreductive surgery and somatostatin analogs (SSAs) play pivotal roles in managing tumors, while palliative options such as molecular targeted therapy, peptide receptor radionuclide therapy, and chemotherapy are reserved for SSA-refractory patients. Gastrinomas, insulinomas, glucagonomas, carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies. Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research. This review underscores the evolving landscape of pan-NET treatment, offering renewed hope and improved outcomes for patients facing this complex disease.

[Efficacy analysis of 7 cases of mixed neuroendocrine-nonneuroendocrine neoplasm of the duodenal papilla].

The clinical data of 7 patients diagnosed with mixed neuroendocrine-nonneuroendocrine neoplasm were analyzed in the Department of Hepatobiliary Surgery of Hunan Provincial People's Hospital from January 2016 to December 2022. Among the 7 patients, 5 were male and 2 were female, with an average age of 59.3 years. Its clinical characteristics are similar to malignant ampulla tumors, and it is difficult to differentiate them. The preoperative puncture biopsy positivity rate is low, making it difficult to diagnose preoperatively, and the prognosis is worse.Comprehensive treatment including surgery, chemotherapy, and radiotherapy can be the preferred treatment option for this disease.

Gastric neuroendocrine neoplasms.

Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger-Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients' gNETs.

Liver-Directed Locoregional Therapies for Neuroendocrine Liver Metastases: Recent Advances and Management.

Neuroendocrine tumors (NETs) are a heterogeneous class of cancers, predominately occurring in the gastroenteropancreatic system, which pose a growing health concern with a significant rise in incidence over the past four decades. Emerging from neuroendocrine cells, these tumors often elicit paraneoplastic syndromes such as carcinoid syndrome, which can manifest as a constellation of symptoms significantly impacting patients' quality of life. The prognosis of NETs is influenced by their tendency for metastasis, especially in cases involving the liver, where the estimated 5-year survival is between 20 and 40%. Although surgical resection remains the preferred curative option, challenges emerge in cases of neuroendocrine tumors with liver metastasis (NELM) with multifocal lobar involvement, and many patients may not meet the criteria for surgery. Thus, minimally invasive and non-surgical treatments, such as locoregional therapies, have surfaced. Overall, these approaches aim to prioritize symptom relief and aid in overall tumor control. This review examines locoregional therapies, encompassing catheter-driven procedures, ablative techniques, and radioembolization therapies. These interventions play a pivotal role in enhancing progression-free survival and managing hormonal symptoms, contributing to the dynamic landscape of evolving NELM treatment. This review meticulously explores each modality, presenting the current state of the literature on their utilization and efficacy in addressing NELM.

Neuroendocrine Breast Tumors: Could Multigene Assays Help in Guiding Treatment Decisions? Case Presentation.

BACKGROUND/AIM: Breast cancer remains the most prevalent type of cancer among women worldwide, and it remains the primary cause of cancer-related deaths in this demographic. Neuroendocrine breast cancer (NBC), an uncommon subtype comprising less than 1% of cases, typically occurs in older women and displays as a slow-growing, low-grade condition. NBC exhibits distinct histological patterns and immunohistochemical markers. Given the limited data on NBC, assays are required that will provide information on molecular profiling and assist in clinical decision making. The aim of the study was to investigate whether a modern Multigene Assay (MGA) could assist on treatment planning of NBC patients. CASE REPORT: A cohort of four patients was analyzed using a MGA. The presented cases featured young, pre-menopausal women with clear NBC, lacking family history. All were lymph node-negative, with robust expression of neuroendocrine markers. Despite high hormone receptor expression, all tumors were poorly differentiated with elevated Ki67 levels. Oncotype DX analysis indicated a need for chemotherapy in three cases and not in one. This underscores the heterogeneity within NBC, emphasizing the importance of personalized treatment decisions. CONCLUSION: While NBC is rare and lacks extensive studies, the use of multigene assays like Oncotype DX may play a pivotal role in treatment planning, especially in cases with varying histological parameters.

Efficacy and safety of neoadjuvant therapy in gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

OBJECTIVE: To determine the effectiveness and safety of neoadjuvant therapy in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and provide evidence-based suggestions for clinical treatment. METHODS: The Cochrane Library, Embase, PubMed, and Web of Science were searched for articles published that analyzed the effectiveness and safety of GEP-NEN-targeted neoadjuvant therapy before March 2023. A confidence interval (CI) of 95%, a subgroup analysis, heterogeneity, and effect size (ES) were analyzed, and a meta-analysis of the literature was performed using the Stata BE17 software. RESULTS: A total of 417 patients from 13 studies were included in this meta-analysis. The primary variables comprised the objective response rate (ORR), disease control rate (DCR), surgical resection rate, and R0 resection rate with ES values of 0.42 (95% CI: 0.25-0.60), 0.96 (95% CI: 0.93-0.99), 0.67 (95% CI: 0.50-0.84), and 0.60 (95% CI: 0.54-0.67), respectively. The secondary variables were the incidence rates of treatment-related adverse events (TRAEs), Grade 3 or higher TRAEs, and surgical complications with ES values of 0.29 (95% CI: -0.03-0.21), 0.13 (95% CI: -0.07-0.33), and 0.35 (95% CI: 0.27-0.44), respectively. CONCLUSION: Neoadjuvant therapy is an effective and safe treatment method for GEP-NENs. However, further studies are required to determine the optimal regimen for this therapy in these tumors.

Multimodal management of foregut neuroendocrine neoplasms.

The foregut, which includes the esophagus, stomach and duodenum, represents one of the most common sites for neuroendocrine neoplasms. These are highly heterogenous with different risk of progression depending on location, cell-type of origin, size, grade and other factors. Various endoscopic and imaging modalities exist to inform therapeutic decision-making, which may be in the form of surgical or endoscopic resection and medical therapy depending on the extent of the disease after diagnostic evaluation. This narrative review aims to explore the literature on the multimodal management of such foregut neuroendocrine neoplasms.

Neuroendocrine neoplasms: Consensus on a patient care pathway.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

[Ectopic acromegaly due to bronchial neuroendocrine tumors: the first description in Russia of three clinical cases].

 Acromegaly is a neuroendocrine disorder caused by excessive production of growth hormone (GH). In the majority of cases the cause of acromegaly is a pituitary tumor producing GH. Cases of ectopic acromegaly are much rarer. Ectopic acromegaly occurs in cases of tumors which produce growth hormone-releasing hormone (GHRH) or extrapituitary tumors which produce GH. The main sources of excessive GHRH production are neuroendocrine tumors (NETs) of the lung or pancreas. Treatment of ectopic acromegaly consists of surgical removal of the source of GHRH hyperproduction and in cases where surgery is not an option, somatostatin analogues, pegvisomant, chemotherapy, immunotherapy or radiation therapy are used.In this article three cases of ectopic acromegaly due to GHRH-producing lung NETs are presented, each of them being notable for a number of features. In the first two cases, clinical symptoms were mild, besides in the second case ectopic acromegaly was accompanied by primary hyperparathyroidism. In the third case ectopic acromegaly was accompanied by pituitary macroadenoma, and after surgical removal of the lung NET remission of acromegaly was not achieved. In all three cases, lung NETs were detected incidentally on radiologic chest screening for other conditions.

Neuroendocrine neoplasms of the gallbladder: A single institute analysis of outcomes and prognostic factors.

INTRODUCTION: Neuroendocrine neoplasms (NENs) are classified as neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine and nonneuroendocrine neoplasms (MiNENs) according to World Health Organization classification. We present our experience of NENs of the gallbladder (GB) from a high-volume cancer hospital. MATERIALS AND METHODS: The present study is a retrospective analysis of all patients with GB NENs who presented between January 2015 and June 2023. The patient details and treatment received with follow-up were noted. The primary endpoint was overall survival (OS). RESULTS: A total of 147 patients were included in the study. The median age was 52 (27-81) years. There was a female predominance (70.7%). NEC was the most common subtype (84.4%) followed by MiNEN (12.9%) and NET (2.7%). The most common stage at presentation was metastatic (70.7%) followed by locally advanced (21.8%), and early disease (7.5%). The median follow-up was 9.92 (1.77-76.06) months. Median OS was 6.14 (3.93-8.35) months. Median OS in patients who received multimodality treatment was 20.20 (17.99-22.41) months versus 4.00 (2.91-5.10) months in those who did not receive it. CONCLUSION: GB NENs are rare, but aggressive tumors with NEC being the most common type. Multimodality treatment yields favorable outcomes. However, the development of better systemic therapy is needed to help improve survival further.

Virtual Care for Patients with Advanced Well Differentiated Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET).

INTRODUCTION: The COVID-19 pandemic resulted in an unprecedent shift towards virtual cancer care, including the care of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of this study was to evaluate the use of virtual care for GEP-NETs during the COVID-19 pandemic at a high-volume academic cancer center. METHODS: This retrospective, observational study performed at the Ottawa Hospital Cancer Center in Canada evaluated adult patients with GEP-NETs seen in consultation by medical oncology between 1 June 2019 and 31 December 2022. Demographic, clinicopathologic, cancer treatment and visit data were collected. Univariable and multivariable analyses assessed the relationship between patient characteristics and virtual care use. RESULTS: A total of 103 patients with well-differentiated GEP-NETS were included. Overall, 18/103 (17.5%) consults and 594/781 (76.1%) follow-ups were performed virtually. All consultation visits returned to in-person assessment by 2022, while 67.0% and 41.4% follow-ups remained virtual in 2022 and 2023, respectively. The year of follow-up, sex, employment and Charlston comorbidity index were associated with virtual follow-up use in the multivariable analysis. DISCUSSION: Virtual care remained a predominant method of GEP-NET patient assessment in the peri-pandemic period. These results highlight an opportunity to improve access to subspecialty neuroendocrine cancer care through the continued use of virtual care.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

BACKGRUOUND: Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. METHODS: A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. RESULTS: Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. CONCLUSION: The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

A nomogram incorporating treatment data for predicting overall survival in gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

BACKGROUND: Over the last few decades, the annual global incidence of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) has steadily increased. Because of the complex and inconsistent treatment of GEP-NETs, the prognosis of patients with GEP-NETs is still difficult to assess. The study aimed to construct and validate the nomograms included treatment data for prediction overall survival (OS) in GEP-NETs patients. METHODS: GEP-NETs patients determined from the Surveillance, Epidemiology, and End Results (SEER)-13 registry database (1992-2018) and with additional treatment data from the SEER-18 registry database (1975-2016). In order to select independent prognostic factors that contribute significantly to patient survival and can be included in the nomogram, multivariate Cox regression analysis was performed using the minimum value of Akaike information criterion (AIC) and we analyzed the relationship of variables with OS by calculating hazard ratios (HRs) and 95% CIs. In addition, we also comprehensively compared the nomogram using to predict OS with the current 7th American Joint Committee on Cancer (AJCC) staging system. RESULTS: From 2004 to 2015, a total of 42 662 patients at diagnosis years with GEP-NETs were determined from the SEER database. The results indicated that the increasing incidence of GEP-NETs per year and the highest incidence is in patients aged 50-54. After removing cases lacking adequate clinicopathologic characteristics, the remaining eligible patients ( n =7564) were randomly divided into training (3782 patients) and testing sets (3782 patients). In the univariate analysis, sex, age, race, tumour location, SEER historic stage, pathology type, TNM, stage, surgery, radiation, chemotherapy, and CS tumour size were found to be significantly related to OS. Ultimately, the key factors for predicting OS were determined, involving sex, age, race, tumour location, SEER historic stage, M, N, grade, surgery, radiation, and chemotherapy. For internal validation, the C-index of the nomogram used to estimate OS in the training set was 0.816 (0.804-0.828). For external validation, the concordance index (C-index) of the nomogram used to predict OS was 0.822 (0.812-0.832). In the training and testing sets, our nomogram produced minimum AIC values and C-index of OS compared with AJCC stage. Decision curve analysis (DCA) indicated that the nomogram was better than the AJCC staging system because more clinical net benefits were obtained within a wider threshold probability range. CONCLUSION: A nomogram combined treatment data may be better discrimination in predicting overall survival than AJCC staging system. The authors highly recommend to use their nomogram to evaluate individual risks based on different clinical features of GEP-NETs, which can improve the diagnosis and treatment outcomes of GEP-NETs patients and improve their quality of life.

Current and emerging strategies for the management of advanced/metastatic lung neuroendocrine tumors.

Pulmonary neuroendocrine tumors represent a spectrum of disease ranging from typical carcinoid tumors to small cell lung cancers. The incidence of low-grade pulmonary NETs has been increasing, leading to improved awareness and the need for more treatment options for this rare cancer. Somatostatin analogs continue to be the backbone of therapy and may be followed or accompanied by targeted therapy, chemotherapy, and immune therapy. The recent addition of peptide receptor radionuclide therapy (PRRT) to the treatment armamentarium of NETs has led to the development of targeted alpha therapy to overcome PRRT resistance and minimize off-target adverse effects. Herein, we aim to highlight current treatment options for patients with advanced low grade pulmonary NETs along with emerging therapies, sequencing of therapies, upcoming clinical trials, and the importance of a multidisciplinary team to improve patient outcomes.

Making progress against rare cancers: A case study on neuroendocrine tumors.

In April 2023, the National Cancer Institute offered a roadmap for cancer research to achieve Cancer Moonshot goals. To reach these goals requires making progress for all cancers, not just those that are most common. Achieving progress against rare cancers, as well as common cancers, requires involvement of large clinical research networks. In 2020, the Patient-Centered Outcomes Research Institute (PCORI) launched an initiative on Conducting Rare Disease Research using PCORnet, the National Patient-Centered Clinical Research Network. The purpose of this commentary is to introduce the broader community of cancer researchers to the PCORnet NET-PRO study (comparing the effects of different treatment approaches for neuroendocrine tumors on patient-reported outcomes) thereby demonstrating how researchers can use the PCORnet infrastructure to conduct large-scale patient-centered studies of rare cancers.