Types Of Neuroendocrine Tumors Research Articles

Conditional Activation of c-MYC in Distinct Catecholaminergic Cells Drives Development of Neuroblastoma or Somatostatinoma.

c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC-driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. Here, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase (Th) promoter led to a preponderance of PDX1+ somatostatinoma, a type of pancreatic neuroendocrine tumor (PNET). However, c-MYC activation via an improved Cre recombinase driven by a dopamine β-hydroxylase (Dbh) promoter resulted in neuroblastoma development. The c-MYC murine neuroblastoma tumors recapitulated the pathologic and genetic features of human neuroblastoma and responded to anti-GD2 immunotherapy and DFMO, an FDA-approved inhibitor targeting the MYC transcriptional target ODC1. Thus, c-MYC overexpression results in different but related tumor types depending on the targeted cell. The GEMMs represent valuable tools for testing immunotherapies and targeted therapies for these diseases.

RepID as a potential biomarker and therapeutic target for lung neuroendocrine tumor

Neuroendocrine tumor (NET) is a rare malignant tumor, notably small cell lung cancer (SCLC), a type of lung neuroendocrine tumor, which has a survival rate of less than 7%. Although various biomarkers including CHGA (Chromogranin A), INSM1 (Insulinoma-associated protein 1), and SYP (Synaptophysin) are extensively used for the diagnostic testing of NET, their diverse specificities and sensitivities are acknowledged as limitations. Here, we demonstrate that RepID (Replication initiation determinant protein), a component of CRL4 (Cullin-RING ubiquitin E3 ligase 4), holds promise as a biomarker for identifying NET and SCLC. Analysis of the Cancer Cell Line Encyclopedia (CCLE) via the CellMinerCDB portal reveals a high correlation between RepID transcript levels and mRNA expression of NE signature genes. Additionally, RepID protein is highly expressed in SCLC patient tissues and a subset of SCLC cell lines. Viability analysis following treatment with pevonedistat and SZL-P1-41 in SCLC cell lines and human SCLC-organoid models indicates that RepID expression determines the sensitivity to CRL-targeting anti-cancer drugs. These findings suggest that RepID represents a novel biomarker for NET and SCLC, and insights from RepID research in these cancers could lead to innovative therapeutic strategies.

An automated pheochromocytoma and paraganglioma lesion segmentation AI-model at whole-body 68Ga- DOTATATE PET/CT.

Somatostatin receptor (SSR) targeting radiotracer 68Ga-DOTATATE is used for Positron Emission Tomography (PET)/Computed Tomography (CT) imaging to assess patients with Pheochromocytoma and paraganglioma (PPGL), rare types of Neuroendocrine tumor (NET) which can metastasize thereby becoming difficult to quantify. The goal of this study is to develop an artificial intelligence (AI) model for automated lesion segmentation on whole-body 3D DOTATATE-PET/CT and to automate the tumor burden calculation. 132 68Ga-DOTATATE PET/CT scans from 38 patients with metastatic and inoperable PPGL, were split into 70, and 62 scans, from 20, and 18 patients for training, and test sets, respectively. The training set was further divided into patient-stratified 5 folds for cross-validation. 3D-full resolution nnUNet configuration was trained with 5-fold cross-validation. The model's detection performance was evaluated at both scan and lesion levels for the PPGL test set and two other clinical cohorts with NET (n = 9) and olfactory neuroblastoma (ONB, n = 5). Additionally, quantitative statistical analysis of PET parameters including SUVmax, total lesion uptake (TLU), and total tumor volume (TTV), was conducted. The nnUNet AI model achieved an average 5-fold validation dice similarity coefficient of 0.84 at the scan level. The model achieved dice similarity coefficients (DSC) of 0.88, 0.6, and 0.67 at the scan level, the sensitivity of 86%, 61.13%, and 61.64%, and a positive predictive value of 89%, 74%, and 86.54% at the lesion level for the PPGL test, NET and ONB cohorts, respectively. For PPGL cohorts, smaller lesions with low uptake were missed by the AI model (p < 0.001). Anatomical region-based failure analysis showed most of the false negative and false positive lesions within the liver for all the cohorts, mainly due to the high physiologic liver background activity and image noise on 68Ga- DOTATATE PET scans. The developed deep learning-based AI model showed reliable performance for automated segmentation of metastatic PPGL lesions on whole-body 68Ga-DOTATATE-PET/CT images, which may be beneficial for tumor burden estimation for objective evaluation during therapy follow-up. https://www. gov/study/NCT03206060 , https://www. gov/study/NCT04086485 , https://www. gov/study/NCT05012098 .

Somatostatin receptors in pituitary somatotroph adenomas as predictors of response to somatostatin receptor ligands: A pathologist's perspective.

There are five subtypes of somatostatin receptors (SST1-5), which are expressed in several types of solid neoplasms, neuroendocrine tumors, and pituitary adenomas. Most commonly, SST2 and SST5, are of interest regarding diagnostic, treatment, and prognostic purposes. In this article the basic biological characteristics of SST are briefly reviewed, and focus given to the immunohistochemical evaluation of SST2 and SST5 in growth hormone (GH)-secreting pituitary tumors, and their quantification as predictors of response to treatment with somatostatin receptor ligands (SRL), the mainstay of the pharmacological therapy available for these tumors. Although many different scoring systems for SST2 immunohistochemistry showing correlation with SRL response have been reported, among which the immunoreactivity score (IRS) has been the most consistently used, a universally validated immunohistochemical technique and scoring scheme is lacking. Efforts should be made on collaborative multicenter studies aiming at validating homogeneous immunostaining protocols and a scoring system for SST2 and SST5 expression, to help clinicians to define the optimal therapeutic strategy for the patients with somatotroph tumors.

Updated Morphological and Immunohistochemical Profile of Neuroendocrine Tumors Developing in Ovarian Teratomas: A Large Series of a Rare and Heterogeneous Disease.

Ovarian neuroendocrine tumors are rare and often arise within mature teratoma of the ovary. No recent re-evaluation of the immunophenotype of these tumors with the new markers available in the field of neuroendocrine neoplasms has been performed. The objectives were to describe the morphologic and immunohistochemical characteristics of neuroendocrine tumors (NETs) arising from ovarian teratomas, to correlate them with the type of teratomatous epithelial components present and to evaluate their proliferative activity using the WHO recommendations for gastroenteropancreatic NETs. This is a bi-centric retrospective study using a panel of markers (chromogranin-A, chromogranin-B, synaptophysin, CDX2, SATB2, TTF1, PAX8, islet-1, serotonin and calcitonin) and Ki-67 proliferation index. The 34 NETs studied were unilateral and presented when it's done four distinct immunophenotypic profiles: 8 NETs expressed serotonin and CDX2 (small intestinal profile), 12 SATB2 (colorectal profile), one TTF1 (thoracic profile) and 4 "null" tumors expressed none of the above markers. The Ki-67 index ranged from 0 to 19.82% (median: 1.51%). 28 tumors were grade 1 (85%), 5 tumors were grade 2 (15%). They were associated with squamous (n = 26), respiratory (n = 23), thyroid (n = 10) and gastrointestinal (n = 5) components. The main type of NET is intestinal phenotype, but rarely accompanied with digestive tissue. This suggests that the cell of origin may be a neuroendocrine precursor present in the teratoma, and confirms that primary NETs arising in ovarian teratomas should not be classified or named according to the type of the surrounding teratoma tissue.

An Uncommon Culprit: Pancreatic Neuroendocrine Tumor in a Patient with Uncontrolled Diabetes

Pancreatic Neuro Endocrine Tumors (NETs) are rare neoplasms that originate from the endocrine tissues of the pancreas, accounting for only 1-2% of pancreatic tumors. Despite their low incidence, these tumors present with a wide range of symptoms and have the ability to secrete hormones, posing significant challenges for their diagnosis and treatment. There are two distinct types of pancreatic NETs: functioning and nonfunctioning. Functioning tumors are characterized by hormone-related clinical syndromes, while nonfunctioning tumors are often found incidentally. The pathogenesis of pancreatic NETs involves both sporadic and hereditary factors, including syndromes such as MEN1, VHL, and NF1. Typically, these tumors are diagnosed in individuals between the ages of 40 and 60, and their effective management requires a multidisciplinary approach. Diagnostic imaging techniques, such as CT and EUS, play a crucial role in accurate diagnosis, while PET scans aid in staging and treatment planning. Histological analysis is essential for determining the tumor grade and predicting prognosis. Treatment strategies are tailored to the tumor's characteristics and the patient's overall health. These may include the use of somatostatin analogs, such as Lanreotide and Octreotide, to control hormone secretion and inhibit tumor growth, as well as systemic therapies like everolimus, sunitinib, and PRRT for metastatic disease. This case report describes the clinical course of a 66-year-old male with a well-differentiated pancreatic NET who initially presented with persistent hyperglycemia. Further investigations revealed a sizable pancreatic mass and liver metastases. Diagnostic evaluation confirmed a grade 1 Neuro Endocrine Tumor, and the patient was started on treatment with Lanreotide. However, his management was complicated by the development of hepatic encephalopathy, which necessitated treatment with lactulose and rifaximin. This case highlights the importance of considering pancreatic NETs in cases of atypical diabetes presentations and emphasizes the need for a multidisciplinary team to provide optimal care. Given the complex nature of pancreatic NETs, a comprehensive diagnostic workup and personalized treatment approach are essential for improving patient outcomes.

Hypoglycemia in a non - diabetic patient: a case report

Non diabetic hypoglycemia (or endogenous hypoglycemia) is an uncommon clinical problem, their study and treatment are a complex process. Under normal physiologic conditions, counterregulatory mechanisms prevent hypoglycemia. The use (involuntary or prescribed) of drugs associated with hypoglycemia (meglitinides, sulfonylureas and insulin) must always be ruled out. In healthy patients the main cause is an insulinoma (a type of neuroendocrine pancreatic tumor) and demands multidisciplinary management. The key for the diagnosis of insulinoma is the Whipple's triad described in 1930 by Allen Whipple (an American surgeon); symptoms occur during fasting or exercise, and are weird after eating. Surgical treatment is usually the only curative option. We aim to improve the diagnosis approach and our comprehension about these rare cases in clinical practice. Below we present a clinical case of a 51-year-old female patient with no history of diabetes admitted to our institution due to persistent hypoglycemia.

Abstract Mo016: Atrial Fibrillation Outcomes in Carcinoid Tumor: A National Inpatient Sample (NIS) Study (2018-2020)

Background: Carcinoid Tumor (CT) is a rare type of neuroendocrine tumor with a slow-growing nature. CT can affect different parts of the body, but it most commonly affects the gastrointestinal tract or the lungs. The average age of onset is in the early 60s, affecting around 1.5-1.9 people per 100,000 population. Atrial fibrillation (AF) has been associated with CT, however there is limited data about the outcomes associated with AF in the CT population. We aim to assess the impact of AF on mortality and complications in this population. Methods: The National Inpatient Sample database from 2018 to 2020 was analyzed to identify adult hospitalizations (age &gt; 18) with a diagnosis of CT using appropriate ICD 10 codes. This population was stratified based on concomitant AF. Demographics and complication rates including venous thromboembolic diseases (VTE), acute heart failure (AHF) and acute ischemic stroke (AIS) were studied in these cohorts using a chi-square test for categorical and a t-test for continuous variables. Multivariate regression analysis was further performed to study the impact of AF on complications and mortality after adjusting for relevant confounders. Results: A total of 70504 adult hospitalizations with CT were identified of which 12.71% (N=8964) had AF. 54% of CT admissions were females and the mean age was 64 years. Hospitalizations with CT and AF had a higher rate of VTE, AHF and AIS (Table 1). Multivariate regression analysis revealed higher odds of AHF and AIS with AF in the subpopulation of adults with CT, while the odds of VTE were statistically insignificant. The odds of mortality with AF were also significantly higher in this subpopulation (Table 2). Conclusion: Our study concludes that atrial fibrillation portends a worse prognosis in hospitalizations with Carcinoid Tumor. It also shows a higher rate of AHF and AIS in this subgroup with statistically significant odds. Further studies should be done to study the impact of atrial fibrillation in Carcinoid Tumor patients and treatment guidelines for better management of atrial fibrillation in this vulnerable cohort should be formulated to improve patient outcomes.

Insulinoma- Rare pancreatic tumor

Insulinoma is hormone producing neuroendocrine pancreatic tumor. Insulinoma is a type of functional neuroendocrine tumor characterized by hypersecretion of insulin, causing hypoglycemia. It typically presents as a solitary benign tumor but can be associated with multiple endocrine neoplasia type 1 (MEN1). Patients with insulinoma have hypoglycemic episodes, more characteristically as fasting hypoglycemia.46 yrs. old male having recurrent episode of Syncopal attack, sweating, excessive thrust, and weakness last 3 to 4 yrs. His blood sugar level was always below normal range at time of attack. No H/O diabetes, Hyper tension or any other chronic illness.On detail examination and investigation, we found that his blood sugar level fall 01 hrs. After food intake and blood sugar fasting and post prandial (F=46 mg/dl &amp; PP= 180 mg/dl) is impaired. C Peptide level, serum insulin level is high. MRI shows growth near head of pancreas.Partial pancreatectomy done and sample send for histopathological examination which shows well differentiated pancreatic neuroendocrine tumor with no lymph node involvement and congested spleen.The Whipple triad, named after the American surgeon Allen O. Whipple (1881-1963), is the diagnostic hallmark establishing the existence of a hypoglycemic disorder and has the following 3 features: (1) symptoms, signs, or both consistent with hypoglycemia; (2) low plasma glucose measured at the time of the symptoms and signs; and (3) relief of symptoms and signs when the glucose is raised to a normal level (2, 3). Insulinoma is usually diagnosed by biochemical testing. Surgical resection is the preferred treatment choice.

Exploring the multifaceted antitumor activity of axitinib in lung carcinoids.

Lung carcinoids (LCs) are a type of neuroendocrine tumor (NET) that originate in the bronchopulmonary tract. LCs account for 20-25% of all NETs and approximately 1-2% of lung cancers. Given the highly vascularized nature of NETs and their tendency to overexpress vascular growth factor receptors (VEGFR), inhibiting angiogenesis appears as a potential therapeutic target in slowing down tumor growth and spread. This study evaluated the long-term antitumor activity and related mechanisms of axitinib (AXI), a VEGFR-targeting drug, in LC cell lines. Three LC cell lines (NCI-H727, UMC-11 and NCI-H835) were incubated with their respective EC50 AXI concentrations for 6 days. At the end of the incubation, FACS experiments and Western blot analyses were performed to examine changes in the cell cycle and the activation of apoptosis. Microscopy analyses were added to describe the mechanisms of senescence and mitotic catastrophe when present. The primary effect of AXI on LC cell lines is to arrest tumor growth through an indirect DNA damage. Notably, AXI triggers this response in diverse manners among the cell lines, such as inducing senescence or mitotic catastrophe. The drug seems to lose its efficacy when the DNA damage is mitigated, as observed in NCI-H835 cells. The ability of AXI to affect cell viability and proliferation in LC tumor cells highlights its potential as a therapeutic agent. The role of DNA damage and the consequent activation of senescence seem to be a prerequisite for AXI to exert its function.

Pituitary Crooke cell neuroendocrine tumor of adrenocorticotropic hormone differentiation-specific transcription factor lineage: a clinicopathological analysis of six cases

Objective: To investigate the clinicopathological features of Crooke cell tumor of adrenocorticotropic hormone differentiation specific transcription factor (TPIT, also known as transcription factor 19, TBX19) lineage neuroendocrine tumors. Methods: Six cases of Crooke cell tumor diagnosed at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China from October 2019 to October 2023 were collected. The clinical and pathological features of these cases were analyzed. Results: Among the six cases, one was male and five were female, with ages ranging from 26 to 75 years, and an average age of 44 years. All tumors occurred within the sella turcica. Clinical presentations included visual impairment in two cases, menstrual disorders in one case, Cushing's syndrome in one case, headache in one case, and one asymptomatic case discovered during a physical examination. Preoperative serum analyses revealed elevated levels of cortisol and adrenocorticotropic hormones in two cases, elevated cortisol in two cases, elevated adrenocorticotropic hormone in one case, and one case with a mild increase in prolactin due to the pituitary stalk effect. Magnetic resonance imaging revealed uneven enhancement of masses with maximum diameters ranging from 1.7 to 3.2 cm, all identified as macroadenomas. Microscopically, tumor cells exhibited irregular polygonal shapes, solid sheets, or pseudo-papillary arrangements around blood vessels. The cell nuclei were eccentric or centrally located, varying in size, with abundant cytoplasm. Some tumor cells showed perinuclear halo. Immunohistochemistry demonstrated diffuse strong positivity for TPIT in five cases, focal weak positivity for TPIT in one case, diffuse strong positivity for adrenocorticotropic hormone in all cases, and faint staining around the nuclei in a few cells. CK8/18 showed a strong positive ring pattern in more than 50% of tumor cells, focal weak positive expression of p53, and the Ki-67 positive index ranged 1%-5%. Periodic acid-Schiff staining revealed positive cytoplasm and negative perinuclear areas. Conclusions: Crooke cell tumor is a rare type of pituitary neuroendocrine tumors. Its pathological characteristics include a distinctive perinuclear clear zone and immunohistochemical markers, such as CK8/18 exhibiting a ring or halo pattern. This entity represents a high-risk subtype among pituitary neuroendocrine tumors, displaying a high risk of invasion and a propensity for recurrence. Accurate diagnosis is crucial for the postoperative follow-up and multimodal treatment planning.

Primary mediastinal small cell neuroendocrine carcinoma in a young man: a rare case report

A mediastinal small cell neuroendocrine carcinoma (MSCNEC) is a rare form of neuroendocrine tumor (NET). Due to its aggressive nature, it often recurs after treatment and has a high tendency to metastasize or spread to other parts of the body, such as the lymph nodes, lungs, liver, bones, or brain. Because of its rarity and aggressive behavior, managing MSCNEC can be challenging. However, the prognosis for this type of cancer is generally poorer compared to some other types of NETs, highlighting the need for early detection and aggressive treatment strategies. Here, we report a case of a 28-year-old nonsmoker man with small cell carcinoma of the lung presenting as a mediastinal mass with superior vena cava syndrome.

The Clinicopathological Significance of Tumor Cell Subtyping in Appendiceal Neuroendocrine Tumors: A Series of 135 Tumors

Appendiceal neuroendocrine tumors (NETs) are common and often are identified as incidental lesions at the time of appendectomy. The guidelines for management are based on tumor size, degree of invasion, and the Ki67 proliferation index. Most small bowel NETs are composed of serotonin-producing EC-cells, but there are multiple other neuroendocrine cell types. In the rectum, there are L-cell tumors that express peptide YY (PYY), glucagon-like peptides (GLPs), and pancreatic polypeptide (PP); they are thought to have a better prognosis than serotonin-producing tumors. We investigated whether the appendix has distinct neuroendocrine tumor types based on cell type and whether that distinction has clinical significance. We collected 135 appendiceal NETs from the pathology archives of UHN Toronto and UHCMC (Cleveland). We analyzed the expression of biomarkers including CDX2, SATB2, PSAP, serotonin, glucagon (that detects GLPs), PYY, and pancreatic polypeptide (PP) and correlated the results with clinicopathologic parameters. Immunohistochemistry identified three types of appendiceal NETs. There were 75 (56%) classified as EC-cell tumors and 37 (27%) classified as L-cell tumors; the remaining 23 (17%) expressed serotonin and one of the L-cell biomarkers and were classified as mixed. EC-cell tumors were significantly larger with more extensive invasion involving the muscularis propria, subserosa, and mesoappendix compared with L-cell tumors. Mixed tumors were intermediate in all of these parameters. Both EC-cell and mixed tumors had lymphatic and/or vascular invasion while L-cell tumors had none. Unlike EC-cell NETs, L-cell tumors were not associated with lymph node metastasis. Tumor type correlated with pT stage and the only patient with distant metastatic disease in this series had an EC-cell tumor. Our study confirms that appendiceal NETs are not a homogeneous tumor population. There are at least three types of appendiceal NET, including EC-cell, L-cell, and mixed tumors. This information is important for surveillance of patients, as monitoring urinary 5HIAA levels is only appropriate for patients with serotonin-producing tumors, whereas measurement of GLPs and/or PP is more appropriate for patients with L-cell tumors. Our data also show that tumor type is of significance with EC-cell tumors exhibiting the most aggressive behavior.

Demographic and socioeconomic analysis of patients with glucagonoma: Insights from the National Cancer Database.

e16319 Background: Glucagonoma is a rare glucagon-producing alpha islet cell tumor primarily of the pancreas, and a type of pancreatic neuroendocrine tumor. These types of cancers have a 10-year survival rate of about 38%. Metastasis may be found in approximately 50% of glucagonoma cases. As a result of the low incidence of glucagonoma, analysis of the diagnostic patterns may provide more insight into the disease’s epidemiology. This study analyzed the National Cancer Database (NCDB) to examine demographic factors of individuals diagnosed with glucagonoma. Methods: ICD-8152-3 Data from the NCDB between 2004-2020 was gathered to perform a retrospective cohort analysis on patients diagnosed with glucagonoma (N = 88). Descriptive statistics were used to investigate demographic factors such as age, sex, race, Hispanic status, years of education, insurance, facility type, distance from facility, and Charlson-Deyo score. Regression analysis was utilized to evaluate incidence trends. Results: We found that patients had an average age of 61 years (SD = 13, range = 23-90), with an average tumor size of 53 mm (SD = 39, range = 12-140), and the majority were male (61%) and White (90%). The majority of patients (97%) did not receive palliative care, with surgery (57%) and chemotherapy (28%) being the primary treatments. Post-surgery, 90% had no residual tumor, and survival rates were 98% after thirty days and 96% after ninety days. Most were treated in academic/research facilities (43%) and had private insurance (59%) or Medicare (34%). The largest median household income quartile of these patients was $74,063 or more (39%).The study noted a 2-year survival rate of 74%, a 5-year rate of 54%, and a 10-year rate of 31%, with a mean survival of 89.3 months. The primary disease sites were the tail of the pancreas (32%) and pancreas, NOS (22%). The distribution across NCDB Analytic Stage Groups was 19% for Stage I, 11% for Stage II, 2% for Stage III, and 23% for Stage IV. Conclusions: This study represents the first analysis of glucagonoma patients using the National Cancer Database, filling a gap in our understanding of the disease. The findings indicate that the majority of glucagonoma patients were non-Hispanic, White, and had tumors primarily located in the tail of the pancreas, aligning with earlier case report descriptions. Socioeconomically, patients most likely had earnings above the median income quartile, resided in densely populated metropolitan areas, and received treatment in academic facilities. Further investigation is necessary to have a more thorough grasp of the impact of demographic and socioeconomic characteristics on glucagonoma patients' diagnosis, course of treatment, and overall survival rates.

SLC7A11 promotes EMT and metastasis in invasive pituitary neuroendocrine tumors by activating the PI3K/AKT signaling pathway.

Invasive pituitary neuroendocrine tumors (PitNETs) are the most prevalent types of intracranial and neuroendocrine tumors. Their aggressive growth and difficulty in complete resection result in a high recurrence rate. Cystine transporter solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers, which contributes to tumor growth, progression, and metastasis by promoting cystine uptake and glutathione biosynthesis. We identified SLC7A11 as an invasive biomarker based on three Gene Expression Omnibus cohorts. This study aimed to investigate the role of SLC7A11 in invasive PitNETs. Cell proliferation was assessed using CCK-8 and colony formation assays, while cell apoptosis was estimated with flow cytometry. Wound healing assays and transwell assays were utilized to evaluate migration and invasion ability. Our findings demonstrated that SLC7A11 was markedly upregulated in invasive PitNETs, and was associated with the invasiveness of PitNETs. Knockdown of SLC7A11 could largely suppress tumor cell proliferation, migration, and invasion, while inducing apoptosis. Furthermore, SLC7A11 depletion was implicated in regulating epithelial-mesenchymal transition and inactivating the PI3K/AKT signaling pathway. These insights suggest SLC7A11 as a potential therapeutic target for invasive PitNETs.

Anlotinib for Metastatic Progressed Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data.

Pheochromocytomas (PCC) and paragangliomas (PGL) (collectively PPGL) are a type of rare hypervascular neuroendocrine tumors that are very challenging to treat. This study aimed to determine the efficacy and safety of the multi-tyrosine kinase inhibitor anlotinib for the treatment of locally advanced or metastatic (LA/M) PPGL. A total of 37 eligible patients with unresectable or progressive LA/M PPGL were enrolled. Of them, 27 patients received anlotinib alone (n = 19) or in combination (n = 8) with radionuclide therapies, including peptide receptor radionuclide therapy (PRRT) and iodine 131 meta-iodobenzylguanidine (131I-MIBG). The primary endpoints included objective response rate (ORR), defined as partial response (PR) or complete response (CR), and disease-control rate, defined as PR, CR, or stable disease (SD). The secondary endpoints were progression-free survival (PFS), duration of response, and drug safety. In the efficacy evaluation for all 27 patients, the ORR was 44.44% (95% CI: 24.4%-64.5%) and disease-control rate was 96.29% (95% CI: 88.7%-100%). Twelve cases (44.44%) achieved PR, 14 (51.85%) SD. The median PFS was 25.2 months (95% CI: 17.2 months to not reached). PFS was shorter in the anlotinib monotherapy group than in the group receiving anlotinib in combination with radionuclide therapy (P = .2). There were no serious treatment-related AEs. Anlotinib monotherapy or in combination with radionuclide therapies shows promising efficacy and safety for the treatment of LA/M PCC and PGL. Multi-tyrosine kinase inhibitors might represent a novel therapeutic strategy for patients with PPGL; however, large-scale prospective randomized, blinded, controlled clinical research studies are required.

Lysine Methyltransferase 5A Promotes the Progression of Growth Hormone Pituitary Neuroendocrine Tumors through the Wnt/β-Catenin Signaling Pathway

Introduction: Growth hormone (GH) secreting pituitary adenoma is considered one of the most harmful types of Pituitary Neuroendocrine Tumors (PitNETs). Our previous research has found that high expression of Lysine methyltransferase 5A (KMT5A) is closely related to the proliferation of PitNETs. The aim of this study was to investigate the role and molecular mechanism of KMT5A in the progression of GH PitNETs. Methods: Immunohistochemistry, qRT-PCR, and Western blot (WB) were used to assess the expression levels of KMT5A in human normal pituitary and GH PitNETs, as well as in rat normal pituitary and GH3 cells. Additionally, we utilized RNA interference technology and treatment with a selective KMT5A inhibitor to decrease the expression of KMT5A in GH3 cells. CCK-8, EdU, flow cytometry (FCM), clone formation, and WB assay were further employed to evaluate the impact of KMT5A on the proliferation of GH3 cells in vitro. A xenograft model was established to evaluate the role of KMT5A in GH PitNETs progression in vivo. Results: KMT5A was highly expressed in GH PitNETs and GH3 cells. Moreover, the reduction of KMT5A expression led to inhibited growth of GH PitNETs and increased apoptosis of tumor cells, as indicated by the findings from CCK-8, EdU, clone formation, and FCM assays. Additionally, WB analysis identified the Wnt/β-catenin signaling pathway as a potential mechanism through which KMT5A promotes GH PitNETs progression. Conclusion: Our research suggests that KMT5A may facilitate the progression of GH PitNETs via the Wnt/β-catenin signaling pathway. Therefore, KMT5A may serve as a potential therapeutic target and molecular biomarker for GH PitNETs.

Surgical approaches in pituitary neuroendocrine tumors

Introduction. Pituitary neuroendocrine tumors account for 3.9-7.4/100.000 of central nervous system tumors in the Western world. They are particularly noteworthy, comprising 10-15% of all cases, with a higher prevalence in the 75-79 age group. In the Republic of Moldova, these tumors account for 34% of cases in postmortem examinations while remain an actual theme of discussion in the ENDO WHO congress and are regarded as a factor, which may influence the quality of life (QOL). Material and methods. We have critically revised 66 literary sources, which were selected using the PubMed library after introducing the keywords “pituitary adenoma surgical approach”. Results. The main surgical approaches were the transsphenoidal (transnasal, sublabial and endonasal) and transcranial (subfrontal unilateral/bilateral, fronto-lateral, fronto-temporal and median basilar) while the additional surgical approaches were designed for complicated and unusual pituitary neuroendocrine tumors and included combined versions, multiple surgeries or extended approaches. Numerous factors were influential for the selection of a surgical approach concerning the pituitary neuroendocrine tumors. They are not sensible for a type of pituitary neuroendocrine tumor according to the WHO classification while the size of a tumor may dictate its surgical approach. Conclusion. Each surgical intervention requires a personalized approach and the critical thinking of the surgical team but most of them can be systematically considered before confronting the tumor in an intraoperatory environment because most of the preoperatory investigations are proven unreliable. There is no established superior surgical approach for each surgical intervention.

Abstract 3148: ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers

Abstract Lung cancer has the highest rates of incidence (2.1 million cases/year) and mortality (1.8 million deaths/year) among all cancers worldwide. Approximately 15% of lung cancers are small cell lung cancer (SCLC). SCLC is typically diagnosed at late stages, with approximately 70% of patients having extensive stage disease at time of diagnosis. Unfortunately, these patients have a dismal 5-year survival rate of approximately 3%. In contrast to non-small cell lung cancer (NSCLC), there has been little advancement in the treatment of SCLC, with no biomarker directed therapies available for patients. SEZ6 is overexpressed in most SCLC’s and other neuroendocrine tumor types. This overexpression and limited normal tissue expression suggest SEZ6 would be a good target for the development of an antibody drug conjugate (ADC). Validation of SEZ6 as an ADC target was supported by signs of clinical activity for ABBV-011, a SEZ6-targeting calicheamicin ADC. Preclinical and clinical data suggest an increased therapeutic index for Top1i ADCs relative to calicheamicin ADCs. Furthermore, Top1i inhibition is an effective mechanism of action in SCLC with topotecan approved in 2L, although significant toxicity limits broad utility. As such, we hypothesized that a SEZ6-Top1i ADC would enable effective Top1 inhibition in tumor cells and reduce toxicity relative to ABBV-011 or systemic chemotherapy, driving increased therapeutic benefit. ABBV-706 is an ADC comprised of the same SEZ6 targeting antibody as ABBV-011 conjugated to AbbVie’s topoisomerase-1 (Top1) inhibitor. ABBV-706 is a potent anti-proliferative agent in SEZ6 positive SCLC cell lines, with sub- to low-nanomolar activity. SEZ6 dependence was demonstrated by the correlation of SEZ6 mRNA expression to ABBV-706 growth inhibition. On-target Top1i activity was confirmed in cells treated with ABBV-706 as measured by dose-dependent induction of γ-H2AX, a marker of DNA damage, and G2/M arrest. ABBV-706 possessed superior anti-tumor activity compared to ABBV-011 in a panel of SCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models with a range of SEZ6 expression levels. In addition, ABBV-706 had activity in the setting of resistance to cisplatin/etoposide (1L SoC in SCLC), in combination with cisplatin, and in SEZ6-expressing neuroendocrine liver and cervical PDX models. ABBV-706 has favorable pharmacokinetics and is well-tolerated in cynomolgus monkeys with bone marrow and gastrointestinal tract toxicities common to other Top1 inhibitors. ABBV-706 shows promise as an agent for the treatment of SCLC and other difficult to treat SEZ6 expressing neuroendocrine tumors. ABBV-706 has completed dose escalation, and dose expansion is currently ongoing in a Phase 1 FIH clinical study (NCT05599984). Citation Format: Emily J. Faivre, Marybeth A. Pysz, Eoghainín Ó hAinmhire, Laura Kreckler, Kelly Doyle, Aloma D'Souza, Zhiyong Ding, Trusha Sondkar, Dolonchampa Maji, Fan Zhao, Andrew Phillips. ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3148.

Lung NETs and GEPNETs: One Cancer with Different Origins or Two Distinct Cancers?

Lung neuroendocrine tumors (LNETs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are two distinct types of neuroendocrine tumors (NETs) that have traditionally been treated as a single entity despite originating from different sources. Although they share certain phenotypic characteristics and the expression of neuroendocrine markers, they exhibit differences in their microenvironment, molecular mutations, and responses to various therapeutic regimens. Recent research has explored the genetic alterations in these tumors, revealing dissimilarities in the frequently mutated genes, the role of EGFR in carcinogenesis, the presence of transcription factors, and the immunogenicity of the tumor and its microenvironment. Spread Through Air Spaces (STAS), a phenomenon unique to lung carcinomas, appears to play a crucial role in LNET prognosis. These distinctions are also evident in the cascade response of lung and GI tract neuroendocrine tumors to somatostatin analogs, Peptide Receptor Radionuclide Therapy (PRRT), chemotherapy, and immunotherapy. Identifying similarities and differences between the two groups may improve our understanding of the underlying mechanisms and facilitate the development of more effective treatment strategies.