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.

Gallbladder carcinoid in a cat.

Carcinoids are rare tumors that originate from neuroendocrine system cells. There has apparently only been 1 report in the veterinary medical literature of a cat with a gallbladder carcinoid, with no long-term follow-up information available from that case. Furthermore, apparently only 9 dogs with gallbladder carcinoids have been reported, again with no long-term follow-up. This case report describes the clinical presentation, surgical appearance, histopathologic and immunohistochemical findings, postoperative adjuvant chemotherapy treatment, and long-term outcome of a domestic longhair cat with a gallbladder carcinoid. The diagnosis of a gallbladder carcinoid in the present case was based on histologic and immunohistochemical findings. Clinical signs of a gallbladder carcinoid are nonspecific and ultrasonographic findings may not be definitive; however, it should be considered as a potential differential diagnosis in cats with lesions of the gallbladder or in the region of the gallbladder. The prognosis is poor, with a potentially high metastatic rate. In the present case, metastasis occurred 7 mo postoperatively despite adjuvant therapy, and the survival time was only 10 mo from the time of diagnosis. Key clinical message: This case report describes the clinical presentation, surgical appearance, histopathologic and immunohistochemical findings, postoperative adjuvant treatment, and long-term outcome of a cat with a gallbladder carcinoid, which should be considered as a potential differential diagnosis in cats with lesions of the gallbladder or in the region of the gallbladder.

Carcinoïde de la vésicule biliaire chez un chat. Les carcinoïdes sont des tumeurs rares qui prennent leur origine des cellules du système neuroendocrinien. Dans la littérature médicale vétérinaire il n'y aurait qu'un seul cas rapporté d'un chat avec un carcinoïde de la vésicule biliaire, sans aucune information de suivi à long terme disponible pour ce chat. Également, il y aurait 9 cas rapportés de chiens avec des carcinoïdes de la vésicule biliaire, mais encore là aucun suivi à long terme. Le cas présenté ici décrit la présentation clinique, l'apparence chirurgicale, les trouvailles histopathologiques et immunohistochimiques, le traitement post-opératoire par chimiothérapie adjuvante, et le devenir à long terme d'un chat domestique à poil court avec un carcinoïde de la vésicule biliaire. Dans le cas présent, le diagnostic de carcinoïde de la vésicule biliaire était basé sur les trouvailles histologiques et immunohistochimiques. Les signes cliniques d'un carcinoïde de la vésicule biliaire sont non-spécifiques et les trouvailles échographiques pourraient ne pas être concluantes; toutefois, il devrait être considéré comme un diagnostic différentiel possible chez des chats avec des lésions à la vésicule biliaire ou dans la région de la vésicule biliaire. Le pronostic est mauvais, avec un risque élevé de métastases. Dans le cas présent, des métastases sont apparues 7 mo post-chirurgie malgré une chimiothérapie adjuvante, et le temps de survie a été de 10 mo à compter du moment du diagnostic.Message clinique clé:Ce rapport de cas décrit la présentation clinique, l'apparence chirurgicale, les trouvaille histologiques et immunohistochimiques, la thérapie adjuvante postopératoire, et le résultat à long-terme pour un chat avec un carcinoïde de la vésicule biliaire, qui devrait être considéré comme un diagnostic différentiel potentiel chez les chats avec des lésions à la vésicule biliaire ou dans la région de la vésicule biliaire.(Traduit par Dr Serge Messier).

Prognostic thresholds of fluorine-18 fluorodeoxyglucose-positron emission tomography mean and maximum standardized uptake values for survival and nodal involvement in lung neuroendocrine neoplasms.

OBJECTIVES: The mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose-positron emission tomography are prognostic biomarkers for survival and nodal involvement in non-small-cell lung cancer but their prognostic value in lung neuroendocrine neoplasms (NENs) remains unexplored. In this study, we aimed to examine whether they are also prognostic biomarkers for survival and nodal involvement in lung NENs. METHODS: We retrospectively studied patients with typical carcinoid, atypical carcinoid or large cell neuroendocrine carcinoma who had been radically resected at our institution between 2008 and 2020. We measured SUVmean and SUVmax on all primary tumours and lymph nodes that were clinically and/or pathologically involved. We dichotomized the patients into groups of high or low SUVmean and SUVmax of the primary tumour using time-dependent receiver operating characteristic curves and compared their overall survival using Kaplan-Meier curves and Cox models. Lastly, we predicted the patients' pathological nodal status with SUVmean and SUVmax of the lymph nodes using binomial logistic models. RESULTS: The study included 245 patients. Patients died earlier if their SUVmean of the primary tumour exceeded 3.9 [hazard ratio 1.97, 95% confidence interval (CI) 1.27-3.04, P = 0.002] or SUVmax exceeded 5.3 (hazard ratio 1.85, 95% CI 1.20-2.87, P = 0.006). Likewise, patients had a higher risk of pathological nodal involvement if their SUVmean of the lymph nodes exceeded 3.3 (odds ratio 10.00, 95% CI 2.59-51.01, P = 0.002) or SUVmax exceeded 4.2 (odds ratio 4.00, 95% CI 1.20-14.65, P = 0.028). CONCLUSIONS: The fluorine-18 fluorodeoxyglucose-positron emission tomography SUVmean and SUVmax are strong prognostic biomarkers for survival and nodal involvement in lung NENs and could be important guides for making treatment decisions.

Hydrophilic molecularly imprinted resin-hexagonal boron nitride composite as a new adsorbent for selective extraction and determination of a carcinoid tumor biomarker in urine.

BACKGROUND: The detection of disease biomarkers in biological samples plays an important role in early diagnosis and treatment of carcinoid tumor. However, due to the complexity of biological samples and the extremely low concentration of disease biomarkers, sample pretreatment is still the bottleneck of achieving accurate quantitative determination. In this work, new hydrophilic molecularly imprinted resin-hexagonal boron nitride (HMIR-h-BN) composites were developed and used as a new solid phase extraction (SPE) adsorbent for selective detection of 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of carcinoid tumor, in urine. RESULTS: Twenty-two types of HMIR-h-BN were successfully synthesized through growing hydrophilic molecularly imprinted resin on surface of activated two-dimensional h-BN nanosheets, and preparation parameters affecting the adsorption performance of HMIR-h-BN were investigated and optimized through adsorption experiments. HMIR-h-BN #19 (the ratio of resorcinol to hexamethylenetetramine: 6:3; the dosage of h-BN: 300 mg; the dosage of dummy template: 0.12 mmol; the imprinting time: 4 h) has demonstrated to be the optimal material for efficient separation and extraction of 5-HIAA. Combined with HPLC-UV, the limit of detection and the limit of quantification of 5-HIAA in real urine samples were 9.4 ng mL-1 and 31.3 ng mL-1, respectively, the coefficient of determination (R2) was 0.9996 in the linear range of 0.1-300 µg mL-1 and the relative recoveries ranged from 86.9 % to 97.7 % with RSD ≤5.1 %. Moreover, after being processed by HMIR-h-BN-SPE, there are no interferences from other peaks at the peak position of 5-HIAA. SIGNIFICANCE: The HMIR-h-BN composite has been demonstrated to be capable of selective extraction of 5-HIAA from urine samples and have a significant purification effect. Based on the established HMIR-h-BN-SPE-HPLC-UV method, accurate quantitative determination of 5-HIAA in urine samples was achieved, which is expected to be applied in the early diagnostic of carcinoid tumor.

Pulmonary Mucoepidermoid Carcinoma Mimicking Carcinoid Lung on 18 F-FDG and 68 Ga-DOTANOC PET/CT.

ABSTRACT: Pulmonary mucoepidermoid carcinoma (PMEC) is a rare pulmonary neoplasm. Although 18 F-FDG PET/CT has been shown to present with increased metabolic activity in PMEC, literature does not report increased somatostatin receptor expression in these tumors. We present the case of a 15-year-old boy where PMEC mimicked a typical carcinoid of the lung on DOTANOC PET/CT by showing significant uptake on 68 Ga-DOTANOC.

Comparison of Octreotide and Vasopressors as First-Line Treatment for Intraoperative Carcinoid Crisis.

BACKGROUND: Intraoperative carcinoid crisis is typically sudden onset of profound hypotension during operations on patients with neuroendocrine tumors. The crisis was thought to be due to massive release of hormones, and perioperative octreotide was recommended as a prophylaxis against the crisis and as first-line treatment. Recent studies show that octreotide does not prevent the crisis and that no massive release of hormones occurs. Therefore, the authors hypothesized that octreotide is not effective for treating the crisis. METHODS: A prospective carcinoid anesthesia database was analyzed for occurrences of crisis. Outcomes were compared between protocols when first-line therapy was bolus octreotide and when it was vasopressors without octreotide. Significance was determined by Student's t test, the Mann-Whitney U test, and Fisher's exact test. RESULTS: Among operations performed with octreotide as first-line treatment (n = 150), crisis occurred for 45 (30 %) patients, the median crisis duration was 6 min, 12 (27 %) patients had crises longer than 10 min, 42 patients (93 %) required subsequent vasopressor administration to resolve the crisis, and 3 (2 %) operations were aborted. Among operations performed with vasopressors as the first-line treatment (n = 195), crisis occurred for 49 (25 %) patients (p = 0.31), the median crisis duration was 3 min (p < 0.001), and no crisis lasted longer than 10 min (p = 0.001). Patients treated with vasopressors were less likely to have multiple crises and had a shorter total time in crisis, a shorter anesthesia time, and no aborted operations (p < 0.05 for all). CONCLUSIONS: First-line octreotide was ineffective treatment for carcinoid crisis, with patients requiring vasopressors to resolve the crisis, and many crises lasting longer than 10 min. First-line vasopressor treatment resulted in significantly shorter crisis durations, fewer crises and aborted operations, and shorter anesthesia times. Vasopressors should be used as first-line treatment for intraoperative crisis, and treatment guidelines should be changed.

Neuroendocrine neoplasms of the ovary: a review of 63 cases.

OBJECTIVE: To describe the clinicopathological characteristics and survival outcomes of ovarian neuroendocrine neoplasms from a curated registry. METHODS: This is a retrospective cross-sectional study of patients in our registry with confirmed ovarian neuroendocrine neoplasms. We excluded patients with small cell carcinoma not otherwise specified, small cell hypercalcemic type, and those with neuroendocrine 'features' or 'differentiation.' Clinicopathological characteristics were described in two separate groups: patients with carcinoid tumors and patients with neuroendocrine carcinomas. Progression-free and overall survival were estimated with the Kaplan-Meier product-limit estimator in these two groups, and multivariable analysis was done to identify predictors of survival for neuroendocrine carcinomas only. RESULTS: A total of 63 patients met inclusion criteria, 13 (21%) with carcinoid tumors and 50 (79%) with neuroendocrine carcinomas. In the carcinoid tumor group, one patient (8%) was misdiagnosed. Two patients (15%) had a recurrence and the 5-year overall survival rate was 80% (95% CI 45% to 100%), with a lower bound of the median survival of 4.8 years (95% CI). In the neuroendocrine carcinoma group, 23 patients (46%) were misdiagnosed, 16 of whom (69%) received therapy with the presumption of a non-neuroendocrine carcinoma diagnosis. Thirty patients (60%) had a recurrence, and the 5-year overall survival rate was 24% (10%, 38%), with a median survival of 1.6 years (1.3, 3.3). Patients with carcinomas stage III or IV had an increased risk of progression/recurrence (HR=5.6; 95% CI 1.9 to 17.0) and death (HR=8.1; 95% CI 2.2 to 29.7) compared with those with stage I or II. Pure histology was associated with an increased risk of progression/recurrence (HR=2.3; 95% CI 1.0 to 5.2) compared with admixed histology. CONCLUSION: Most patients had neuroendocrine carcinomas, which were associated with a higher recurrence rate and worse survival than carcinoid tumors. A high proportion of patients in both groups were initially misdiagnosed, and a new association with endometrial hyperplasia was observed. Neuroendocrine admixed histology is associated with a higher risk of progression.

A Diagnostic Dilemma: Metastatic Neuroendocrine Tumor Mimicking Hepatocellular Carcinoma.

Carcinoid syndrome arises from neuroendocrine tumors, characterized by the presence of neurosecretory granules. The diagnosis of carcinoid syndrome involves biochemical testing and various imaging techniques. We report the case of a 62-year-old man with Parkinson's Disease who was found to have new-onset cirrhosis and multiple hepatic lesions with necrosis on CT imaging. These findings were concerning for metastatic malignancy of unknown primary origin. Subsequent MRI characterization of the liver lesions indicated hepatocellular carcinoma as the most likely diagnosis. However, a transthoracic echocardiogram, performed for anasarca and dyspnea on exertion, revealed a thickened tricuspid leaflet, highly suspicious for carcinoid valvulitis. A biopsy of one of the hepatic lesions was consistent with neuroendocrine tumor, confirming the diagnosis of carcinoid syndrome. This case highlights the limitations of diagnostic imaging approaches in distinguishing hepatocellular carcinoma from neuroendocrine tumors.

An in-silico analysis reveals further evidence of an aggressive subset of lung carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin.

The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.

Performance of capsule endoscopy for the detection of small intestinal neuroendocrine tumors in familial carcinoid: a prospective single-site study.

BACKGROUND AND AIMS: Small-bowel neuroendocrine tumors (NETs) are slow growing, clinically silent tumors whose prognosis depends on disease stage. Members of kindreds with a familial form of small intestinal NETs (SI-NETs) represent a high-risk population for whom early detection improves disease outcome. Our aim was to determine the utility of small-bowel capsule endoscopy (SB-CE) for screening high-risk asymptomatic relatives from kindreds with familial carcinoid. METHODS: One hundred seventy-four asymptomatic subjects with a family history (≥2 family members) of SI-NETs were screened under Protocol NCT00646022, Natural History of Familial Carcinoid Tumor at the National Institutes of Health. All patients were imaged with SB-CE and 18fluoro-dihydroxphenylalanine (18F-DOPA) positron emission tomography (PET)/CT, and results were independently analyzed. Patients with a positive imaging study underwent surgical exploration. RESULTS: Thirty-five of 174 asymptomatic subjects screened for SI-NETs were positive on either SB-CE or 18F-DOPA PET. Thirty-two of 35 patients with a positive study were confirmed at surgery. SB-CE was positive in 28 of 32 patients with confirmed tumors for a per-patient sensitivity of 87.5%. SB-CE had a specificity of 97.3% and a negative predictive value of 96.5%. The average tumor number and size were 7.7 and 5.0 mm, respectively, and 81.2% of patients had multiple tumors. 18F-DOPA PET/CT had a similar sensitivity of 84% versus surgery. CONCLUSIONS: SB-CE is a sensitive and specific method comparable with 18F-DOPA PET/CT for screening high-risk patients with familial SI-NET. (Clinical trial registration number: NCT00646022.).

Smart dual imprinted Origami 3D-ePAD for selective and simultaneous analysis of vanillylmandelic acid and 5-hydroxyindole-3-acetic acid carcinoid cancer biomarkers using graphene quantum dots coated with dual molecularly imprinted polymers.

Measuring the levels of the biomarkers vanillylmandelic acid (VMA) and 5-Hydroxyindole-3-acetic acid (5-HIAA) is a valuable tool for clinical diagnosis not only of neuroblastoma or carcinoid syndrome, but also of essential hypertension, depression, migraine, and Tourette's syndrome. Herein, we explore using graphene quantum dots (GQDs) coated with molecularly imprinted polymer (MIP) as novel dual-imprinted sensors for selective and simultaneous determination of VMA and 5-HIAA in urine and plasma samples. The dual-MIP was successfully coated on the GQDs core via co-polymerization of (3-aminopropyl) triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS), acting as functional and cross-linking monomers, respectively. In addition, we successfully created the dual imprinted VMA and 5-HIAA shell on the GQDs' core via a one-pot synthesis. We fabricated a facile and ready-to-use Origami three-dimensional electrochemical paper-based analytical device (Origami 3D-ePAD) for simultaneous determination of VMA and 5-HIAA using a GQDs@dual-MIP modified graphene electrode (GQDs@dual-MIP/SPGE). The Origami 3D-ePAD was designed to form a voltammetric cell on a three-layer foldable sheet with several advantages. For example, they were quickly assembled and enhanced the device's physical durability with the hydrophobic backup sheet. The developed dual imprinted Origami 3D-ePAD leads to substantially enhanced sensitivity and selectivity to electrochemical signal amplification generated from increasing the electrode-specific surface area, electrocatalytic activity, and the large numbers of dual imprinted sites for VMA and 5-HIAA detection. The synthetic recognition sites are highly selective for 5-HIAA and VMA molecules with an imprinting factor of 8.46 and 7.10, respectively. Quantitative analysis relying on square wave voltammetry reveals excellent linear dynamic ranges of around 0.001-25 µM, with detection limits of 0.023 nM for 5-HIAA and 0.047 nM for VMA (3Sb, n = 3). The Origami 3D-ePAD provides high accuracy and precision (i.e., recovery values of 5-HIAA ranged from 82.98 to 98.40 %, and VMA ranged from 83.28 to 104.39 %), and RSD less than 4.37 %) in urine and plasma samples without any evidence of interference. Hence, it is well suited as a facile and ready-to-use disposable device for point-of-care testing. It is straightforward, cost-effective, reproducible, and stable. Furthermore, it allows for rapid analysis (analysis time ∼20s) useful in medical diagnosis and other relevant fields.

Midgut neuroendocrine tumor patients have a depleted gut microbiome with a discriminative signature.

RATIONALE: When compared to other types of cancer, the prevalence of midgut neuroendocrine tumors (NET) has disproportionally increased over the past decades. To date, there has been very little progress in discovering (epi)genetic drivers and treatment options for these tumors. Recent microbiome research has revealed that enteroendocrine cells communicate with the intestinal microbiome and has provided novel treatment targets for various other cancer types. Hence, our aim was to analyze the role of the gut microbiome in midgut NET patients. METHODS: Fecal samples, prospectively collected from patients and control subjects, were analyzed with next generation 16S sequencing. Patients with neuroendocrine carcinomas and recent antibiotics use were excluded. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between groups within the patient cohort. RESULTS: 87 midgut NET patients and 95 controls were included. Midgut NET patients had a less rich and diverse gut microbiome than controls (p < 0.001). Moreover, we identified 31 differentially abundant species and a gut microbial signature consisting of 17 species that was predictive of midgut NET presence with an area under the receiver operating characteristic curve of 0.863. Gut microbial composition was not directly associated with the presence of the carcinoid syndrome, tumor grade or multifocality. Nonetheless, we did observe a potential link between microbial diversity and the presence of carcinoid syndrome symptoms within the subset of patients with elevated 5-hydroxyindolacetic acid levels. CONCLUSION: Midgut NET patients have an altered gut microbiome which suggests a role in NET development and could provide novel targets for microbiome-based diagnostics and therapeutics.

ETV6::NTRK3 gene fusion in a patient with metastatic lung atypical carcinoid successfully treated with repotrectinib: A case report.

INTRODUCTION: Chromosomal rearrangements involving the neurotrophin kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 with different fusion partners occur in non-small cell lung cancers (NSCLCs) and other solid tumors. Novel NTRK rearrangement-related tumors are still being discovered. METHODS: Herin, we describe a male patient with a mass in the left upper lobe that was biopsied by bronchoscopy. This case was diagnosed with stage Ⅳ lung atypical carcinoid (AC) harboring the ETV6::NTRK3 gene fusion. RESULTS: He received 1st line treatment with everolimus lasting for 4 months. After chemotherapy failure, he received 3rd treatment with VC004 in a phase 1/2 study and achieved stable disease, but he stopped taking it due to intolerance. He subsequently received repotrectinib treatment and achieved a partial response of more than ten months. CONCLUSIONS: To the best of our knowledge, we reported the first case demonstrating anti-tumor activity of repotrectinib in a patient with AC carring an ETV6-NTRK3 gene fusion, indicating that repotrectinib may be an efficient therapeutic option for tumors with NTRK gene rearrangements.

Real-World comprehensive genomic profiling data for diagnostic clarity in pulmonary Large-Cell neuroendocrine carcinoma.

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon subtype of lung cancer believed to represent a spectrum of tumors sharing characteristics of both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Other groups have proposed genomic LCNEC subtypes, including small cell-like, non-small cell-like, and carcinoid-like subtypes. The primary goal of this study was to better define the NSCLC-like subtype with comprehensive genomic profiling (CGP). METHODS: An institutional database was queried to identify tissue specimens (TBx, N = 1,426) and liquid biopsies (LBx, N = 39) submitted for CGP during routine clinical care (8/2014 - 7/2023) with a disease ontology of LCNEC. TBx were profiled with FoundationOne® (F1) or F1CDx, using hybrid-capture technology to detect genomic alterations (GAs). RESULTS: 1,426 LCNEC samples were genomically profiled. The presence of RB1 and TP53 genomic alterations (GAs) were used to define a SCLC-like subtype (n = 557). A carcinoid-like group was defined by the presence of MEN1 mutation in the absence of TP53 GAs (n = 25). The remaining 844 samples were compared to the SCLC-like group and GAs enriched relative to the SCLC-like samples with a false discovery rate (FDR) < 0.0001 were used to define a NSCLC-like group. These NSCLC-like subtype-defining GAs included SMARCA4, KRAS, FGF3/4/19, STK11, CDKN2A/B, MTAP, and CCND1. Under this schema, 530 samples were classified as NSCLC-like and 314 remained unclassified. CONCLUSIONS: Large-scale CGP can better characterize biologically distinct molecular subtypes in LCNEC. Further studies to define how these molecular subtypes may help inform treatment decisions in this complex and challenging malignancy are warranted.

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery.

BACKGROUND: Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. METHODS: We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. RESULTS: The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. CONCLUSIONS: These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

Preliminary analysis of immune-related markers in thymic carcinoid.

The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects.