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Endoscopic Submucosal Dissection (ESD) has been reported as a feasible and effective treatment for Rectal Neuroendocrine Tumours (R-NETs). However, most of the experience on the topic comes from retrospective tertiary centre from Eastern Asia. Data on ESD for R-NETs in Western centres are lacking. This is a retrospective study, including patients who underwent endoscopic resection of R-NETS by ESD between 2015 and 2020 in Western Centres. Important clinical variables such as demographic, size of R-NETs, histological type, presence of lymphovascular invasion or distant metastasis, completeness of the endoscopic resection, recurrence, and procedure related complications were recorded. 40 ESD procedure on R-NETs from 39 patients from 8 centres were included. Mean R-NETs size was 10.3 mm (SD 4.01). Endoscopic en-bloc resection was achieved in 39/40 ESD (97.5 %), R0 margin resection was obtained in 87.5 % (35/40) of the procedures, one patient was referred to surgery for lymphovascular invasion, two procedures (5 %) reported significant episodes of bleeding, whereas a perforation occurred in one case (1/40, 2.5 %) managed endoscopically. Recurrence occurred in 1 patient (2.5 %). ESD is an effective and safe treatment for R-NETs in western centres. [ABSTRACT FROM AUTHOR]

Insulinoma-associated protein 1 (INSM1) is an immunohistochemical marker commonly used to confirm cytomorphological concordant neuroendocrine tumors/carcinomas (NETs/NECs), demonstrating high utility in small samples. Previous reports have suggested comparable INSM1 staining in CytoLyt-fixed cell blocks and formalin-fixed surgical pathology specimens. This study aimed to assess INSM1 immunoreactivity using both fixation methods and investigate potential factors contributing to its variable expression. A retrospective query was performed (03/31/21-05/31/22) for NET/NEC cases that had both formalin- and CytoLyt-fixed cell blocks. We collected clinical data and reporting of immunostains for each case. INSM1 staining was evaluated in both fixation methods, and reported as positive, negative, or equivocal. Equivocal INSM1 staining was further scored as a percentage of 1%-100% and intensity of weak (faint staining), moderate (darker staining), and strong (dense staining). Our search identified 20 cases from diverse body sites, including mediastinal lymph nodes (40%), pancreas (35%), lung (20%), and porta hepatis lymph nodes (5%). All cases exhibited a widespread positivity (over 90%) in formalin-fixed cell blocks. In contrast, CytoLyt fixed cells showed a negative stain in 65% of cases and 30% exhibited an equivocal positivity. While INSM1 is previously reported as a sensitive (75%-100%) and specific (82.7%-100%) marker for NET/NECs, our study found a reduced immunohistochemical staining in CytoLyt-fixed cell blocks. Consequently, false negative INSM1 immunohistochemical results in CytoLyt-fixed cell block material may pose a pitfall in the diagnosis of NET/NEC. • Formalin-fixed cell blocks consistently exhibited strong positivity for insulinoma-associated protein 1 (INSM1), while CytoLyt-fixed cell blocks showed significant variability, with 65% negative and 30% equivocal staining. • Differences in INSM1 staining patterns were consistent across diverse anatomical locations and tumor types. • CytoLyt-fixed cell blocks may pose diagnostic challenges for neuroendocrine tumors due to inconsistent INSM1 staining. [ABSTRACT FROM AUTHOR]

Craniopharyngiomas arise from the Rathke pouch and account for 1.2%–18.4% of pediatric primary brain tumors. Despite relatively good survival outcomes, patients face long-term morbidity from recurrences, visual impairment, and endocrinopathies, which reduce quality of life. We examined the management of pediatric craniopharyngiomas, their recurrences, and subsequent neuroendocrine sequelae in a tertiary center in South-East Asia. A retrospective cohort of 12 paediatric patients (aged ≤18 years) with histologically confirmed diagnosis of craniopharyngioma treated from January 2002 to June 2017 was conducted. Data collected included demographics, clinical presentation, imaging data, treatment details, postoperative sequelae, and outcomes on mortality and recurrence. Survival analysis was conducted using Cox-proportional hazards model. The median follow-up time was 6.60 years (1.9–11.5 years). The mean age was 7.6 years (standard deviation 4.8) and 7 patients (58.3%) were male. The most common presenting symptoms were raised intracranial pressure (7, 58.3%), visual deficits (6, 50.0%), and preoperative endocrine abnormalities (2, 16.7%). Five patients underwent gross total resection (41.7%), and 7 underwent subtotal resection (58.3%). Overall survival was 75.0% (9 patients), and recurrence was 58.0% (7 patients). Median time-to-recurrence was 5.87 months (0.23–33.7, interquartile range 15.8), and median progression-free survival was 4.16 years (0.18–10.1, interquartile range 5.29). Long-term management of pediatric craniopharyngioma remains difficult, with multiple recurrences and long-term neuroendocrine sequelae impairing quality of life for patients. Further research into management of recurrences and neuroendocrine sequelae, as well as novel therapies to improve outcomes in these patients, may be warranted. [ABSTRACT FROM AUTHOR]

Acrolein and trichloroethylene (TCE) are priority hazardous air pollutants due to environmental prevalence and adverse health effects; however, neuroendocrine stress-related systemic effects are not characterized. Comparing acrolein, an airway irritant, and TCE with low irritancy, we hypothesized that airway injury would be linked to neuroendocrine-mediated systemic alterations. Male and female Wistar-Kyoto rats were exposed nose-only to air, acrolein or TCE in incremental concentrations over 30 min, followed by 3.5-hr exposure to the highest concentration (acrolein - 0.0, 0.1, 0.316, 1, 3.16 ppm; TCE - 0.0, 3.16, 10, 31.6, 100 ppm). Real-time head-out plethysmography revealed acrolein decreased minute volume and increased inspiratory-time (males>females), while TCE reduced tidal-volume. Acrolein, but not TCE, inhalation increased nasal-lavage-fluid protein, lactate-dehydrogenase activity, and inflammatory cell influx (males>females). Neither acrolein nor TCE increased bronchoalveolar-lavage-fluid injury markers, although macrophages and neutrophils increased in acrolein-exposed males and females. Systemic neuroendocrine stress response assessment indicated acrolein, but not TCE, increased circulating adrenocorticotrophic hormone, and consequently corticosterone, and caused lymphopenia, but only in males. Acrolein also reduced circulating thyroid-stimulating hormone, prolactin, and testosterone in males. In conclusion, acute acrolein inhalation resulted in sex-specific upper respiratory irritation/inflammation and systemic neuroendocrine alterations linked to hypothalamic-pituitary-adrenal axes activation, which is critical in mediating extra-respiratory effects. • Acrolein but not TCE elicits acute respiratory irritancy and systemic stress. • Acrolein-induced respiratory injury prompts sex-specific SAM/HPA axes activation. • Acute acrolein inhalation increases HPA and decreases HPT and HPG neurohormones. • Integrating neuroendocrine assessment could inform etiology of HAPs stress effects. [ABSTRACT FROM AUTHOR]

We often associate nasal olfaction with desirable sensations, but the nose and paranasal sinuses also have an important role in filtration, detection and inactivation of particulate, chemical and biological irritants or toxins. The delicate mucosal lining of the sinonasal tract can be damaged by these external insults, and mutations affecting its diverse cellular components can result in an abundance of histological tumour types. While these are too numerous to catalogue in this short article, we have chosen a "fragrant pot pourri" of tumour types that have caused these authors diagnostic difficulties in the past and should therefore be of interest to the specialist trainee and jobbing histopathologist. While most are rarely encountered in general diagnostic practice, they can all initially present with non-specific symptoms, and feasibly reach the microscope of a general histopathologist as a seemingly innocuous nasal polyp. We highlight potential diagnostic pitfalls of this group of "sinonasal stinkers" in the hope of clarifying diagnostic terminology and highlighting some of the unique anatomical, morphological, molecular and biological characteristics of these lesions at this site. [ABSTRACT FROM AUTHOR]

B7-H3 is overexpressed by the majority of advanced prostate cancers, with its expression associating with alterations of DNA damage repair genes, such as BRCA2 and ATM , but not MMR protein loss. B7-H3 expression is a therapeutic vulnerability for a B7-H3–targeting antibody-drug conjugate with a topoisomerase-1 payload. B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development of and patient selection for B7-H3 targeted therapies. To characterise B7-H3 expression in same-patient hormone-sensitive (HSPC) and castration-resistant (CRPC) PC biopsies, associating this with PC genomics, and to evaluate the antitumour activity of an anti–B7-H3 antibody-drug conjugate (ADC) in human CRPC in vitro and in vivo. We performed immunohistochemistry and next-generation sequencing on a cohort of 98 clinically annotated CRPC biopsies, including 72 patients who also had HSPC biopsies for analyses. We analysed two CRPC transcriptome and exome datasets, and PC scRNASeq datasets. PC organoids (patient-derived xenograft [PDX]-derived organoids [PDX-Os]) were derived from PDXs generated from human CRPC biopsies. We evaluated B7-H3 mRNA expression in relation to a panel of 770 immune-related genes, compared B7-H3 protein expression between same-patient HSPC and CRPC biopsies, determined associations with PC genomic alterations, and evaluated the antitumour activity of DS-7300a, a topoisomerase-1 inhibitor payload anti–B7-H3 ADC, in human PC cell lines, organoids (PDX-Os), and xenografts (PDXs) of different histologies, B7-H3 expressions, and genomics. B7-H3 was among the most highly expressed immunomodulatory genes in CRPCs. Most CRPCs (93%) expressed B7-H3, and in patients who developed CRPC, B7-H3 expression was frequently expressed at the time of HSPC diagnosis (97%). Conversion from B7-H3 positive to negative, or vice versa, during progression from HSPC to CRPC was uncommon. CRPC with neuroendocrine features were more likely to be B7-H3 negative (28%) than adenocarcinomas. B7-H3 is overexpressed in tumours with defective DNA repair gene (ATM and BRCA2) alterations and is associated with ERG expression, androgen receptor (AR) expression, and AR activity signature. DS7300a had antitumour activity against B7-H3 expressing human PC models including cell lines, PDX-Os, and PDXs of adenocarcinoma and neuroendocrine histology. The frequent overexpression of B7-H3 in CRPC compared with normal tissue and other B7 family members implicates it as a highly relevant therapeutic target in these diseases. Mechanisms driving differences in B7-H3 expression across genomic subsets warrant investigation for understanding the role of B7-H3 in cancer growth and for the clinical development of B7-H3 targeted therapies. B7-H3, a protein expressed on the surface of the most lethal prostate cancers, in particular those with specific mutations, can be targeted using drugs that bind B7-H3. These findings are relevant for the development of such drugs and for deciding which patients to treat with these new drugs. [ABSTRACT FROM AUTHOR]

Primary neuroendocrine tumours of the thymus (NETTs) are exceedingly rare tumours, usually presenting around mid-life, which have a propensity towards males and smokers. They are seen more often in those with MEN-1, but multiple different genetic mutations have been found to be involved in the tumorigenesis of NETTs. Histologically, NETTs are classified according to number of mitoses, the presence of necrosis, and the presence or absence of small cell features. NETTs display a wide spectrum of behavior, and they can be incidentally found on chest imaging, on screening in MEN-1, or present with symptoms of local compression. Advanced disease and paraneoplastic syndromes are common. CT-, PET/CT-, MRI-scans, and somatostatin receptor scintigraphy are the imaging modalities of choice both for the initial assessment as well as for monitoring after treatment. For patients with localized disease, complete surgical resection with lymphadenectomy provides the best chance of long-term, disease-free survival, and can be achieved through either an open or thoracoscopic approach. While chemotherapy-regimens based on platinum, taxane, and temozolomide are used most often, the optimum chemotherapy regimen in the adjuvant and palliative settings remains unclear, as does the role of radiotherapy. Ongoing research on the most effective use of somatostatin analogues, peptide receptor radionuclide therapy (PPRT), kinase inhibitors and immunotherapy in patients with other types of advanced neuroendocrine tumours may lead to further treatment options for NETTs in the future. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine neoplasm of the skin. Immunosuppression, ultraviolet radiation and the integration of Merkel cell polyomavirus (MCPyV) have all been shown to be involved in the pathogenesis of this malignancy. We performed whole genome sequencing on two MCPyV-negative cases of MCC that demonstrated very different clinical presentations and outcomes, and mutational profiles. The first case exhibited a highly aggressive clinical course, absence of UV-signature mutations and a low tumor mutational burden. A rearrangement in the tumor suppressor gene SUFU was identified, a likely driver and potential target of the Hedgehog signaling pathway. Meanwhile, the second case exhibited a less aggressive behavior, harbored UV-signature mutations, and a high mutational burden including mutations in TP53 and RB1. [ABSTRACT FROM AUTHOR]

Autoimmune atrophic gastritis (AAG) is a frequently underdiagnosed disease due to its broad-spectrum clinical presentation. The diagnosis is based on histological confirmation of corpus-restricted metaplastic chronic atrophic gastritis. To thoroughly describe the histological features of a European cohort of AAG patients. Clinical and pathological data of 57 out of 676 patients diagnosed with AAG were reviewed. Thirty-nine patients were female and eighteen were male. The mean age was 62 years. Antibodies were identified in 32/42 patients (76 %). Vitamin B12 levels were low (< 200 pg/mL) in 37/54 patients (69 %). Serum gastrin levels was elevated (> 115 pg/mL) in all cases tested. Associated autoimmune/inflammatory conditions were identified in 20/57 patients (35 %). Histologically, deep chronic inflammation was present in 46/57 (81 %) patients. Complete destruction of oxyntic glands was observed in 45/57 (79 %) patients. Pyloric metaplasia was present in 54/57 (95 %) patients, intestinal metaplasia in 51/57 (89 %) patients, and pancreatic metaplasia in 20/57 (35 %) patients. Among ECL cell proliferation, linear hyperplasia was present in all 57/57 patients, micronodular hyperplasia in 55/57 patients, and adenomatoid hyperplasia in 10/57 patients. ECL cell dysplasia was identified in 5/57 patients, and neuroendocrine microtumor in 4/57 patients. The diagnosing of AAG remains challenging due to the greater variability in symptoms than previously recognized. It is important to consider chronic AAG, especially with other concurrent autoimmune conditions. The importance of accurate diagnosis and surveillance is based on the potential development of type 1 gastric neuroendocrine tumor and increased risk of gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

The frequency of detection and concentrations of bifenthrin, a pyrethroid insecticide, in the waterways inhabited by the endangered species, steelhead trout (Oncorhynchus mykiss), has become a significant concern for regulatory agencies. Endocrine disruption has been observed with estrogenic and anti-estrogenic responses in fish species at different life stages. Since several studies have indicated alterations in dopaminergic signaling associated with endocrine responses, juvenile steelhead were exposed to environmentally relevant concentrations of 60 or 120 ng/L bifenthrin for two weeks. Fish brains were assessed for dopamine levels and the expression of genes involved in dopaminergic and estrogenic processes, such as catechol- o -methyltransferase (comt) and monoamine oxidase (mao). Vitellogenin (vtg) and estrogenic receptors (ERα1 , ERβ1 , and ERβ2) were also evaluated in livers of the animals. Dopamine concentrations were significantly higher in fish brains following bifenthrin exposure. Consistent with a reduction in dopamine clearance, there was a significant decrease in the mRNA expression of comt with increased bifenthrin concentration. Hepatic expression of ERα1 and ERβ2 mRNA was significantly decreased with increased bifenthrin concentration. These data support the possible mechanism of bifenthrin altering the dopaminergic pathway at low ng/L concentrations, in juvenile steelhead, which could interfere with endocrine feedback loops. These findings support the need for and importance of identifying species and life stage differences in pesticide modes of action to reduce uncertainties in risk assessments. [Display omitted] • Bifenthrin induces anti-estrogenic response to juvenile steelhead at ng/L dose. • Increased dopamine levels in brains of bifenthrin-exposed steelhead. • Decreased estrogen receptor expression with increased bifenthrin exposure. • Dopaminergic pathway altered in bifenthrin-exposed juvenile steelhead. [ABSTRACT FROM AUTHOR]

Recommendations for resection technique of duodenal neuroendocrine neoplasms (D-NEN) with a size between 10 and 20 mm are lacking. The primary aim was to compare overall survival (OS) and progression-free survival (PFS) after endoscopic resection (ER) with surgical resection (SR). The secondary aim was to assess the incidence and clinical variables correlated with OS. Data of patients with D-NENs between 2008 and 2018 were extracted from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank. A total of 259 patients were identified, of which 138 were included: 98 (68 %) underwent ER and 44 patients (32 %) underwent SR. Of these, 38 patients had D-NENs sized between 10 and 20 mm. ER Patients were more frequently male and had a lower T-stage and tumour size than SR patients (all P < 0.05). Positive resection margins were observed more frequently after ER compared to SR (71 % vs 15 %, P < 0.005). No patients with tumours between 10 and 20 mm died after ER or SR (median follow-up 71.8 vs. 52.0 months). PFS rates were not significantly different after ER compared to SR (P = 0.672). Recurrence rates were 13 % for ER and 7 % for SR (P = 0.604). Between 2008 and 2018, the incidence increased from 0.06 to 0.11 per 100,000 patients per year. OS after ER or SR did not differ for D-NEN between 10 and 20 mm. Recurrence and PFS rates were not significantly different. These results suggest that D-NENs sized between 10 and 20 mm could potentially be treated first with ER. Future studies are needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Teratoid hepatoblastoma is an uncommon but well-recognized variant of mixed hepatoblastoma. A one-year female child presented with palpable and progressively increasing right abdominal mass for 3 months. The contrast-enhancing computed tomography (CECT) abdomen revealed a large heterogeneous hepatic mass measuring 12 × 6.6 × 6 cm. Histopathological examination of the resected specimen showed a mixed hepatoblastoma (epithelial and mesenchymal) with teratoid features and multi-lineage differentiation (all three germ cell layers). A focus showed embryonal rhabdomyosarcomatous element. Teratoid hepatoblastoma can show a wide range of heterologous differentiation that may pose a significant diagnostic dilemma. S uch a broad spectrum has not been described in the literature previously. An appropriate immunohistochemical panel may be needed to identify and delineate the various heterologous differentiation to clinch the correct diagnosis. Secondary somatic malignancy such as rhabdomyosarcoma can develop in a teratomatous element. [ABSTRACT FROM AUTHOR]

Introduction : There is a paucity of effective treatment options for advanced pancreatic neuroendocrine tumors (pNETs). Genome-wide analyses may allow for potential drugs to be identified based on differentially expressed genes (DEGs). Methods: Oligo microarray data of RNA expression profiling of pNETs and normal pancreas tissues were downloaded from the Gene Expression Omnibus. Functional and pathway enrichment information of the DEGs was obtained using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Corresponding homologous proteins were analyzed and potential therapeutic drugs for pNETs were identified using the Connectivity Map and Drug-Gene Interaction Database. Results: Assessment of raw data from 12,610 pNET genes demonstrated that 1082 and 380 genes were upregulated and downregulated, respectively, compared with normal pancreas tissue. Upregulated pathways were associated with nitrogen metabolism (i.e., GABAergic synapse, and graft-versus-host disease), whereas downregulated pathways included C-type leptin receptor signaling pathway, pertussis and AMPK signaling pathway. In particular, the protein–protein interaction analysis revealed 10 upregulated hub genes (DYNLL1, GNB5, GNB2, GNG4, GNAI2, GNAI1, HIST2H2BE, NUP107, NUP133, and SNAP25) and 10 downregulated hub genes (CXCL8, F2, CXCL2, GCG, SST, INS, GALR3, CCL20, ADRA2B, and CXCL6). Using the Drug-Gene Interaction Database, candidate drugs for pNETs treatment included 3 EGFR inhibitors (canertinib, erlotinib, WZ-4–145), as well as other cell-signaling pathway inhibitors such as AG-592, acarbose, lonidamine, azacytidine, rottlerin, and HU-211. Conclusion: Using available genetic atlas data, potential drug candidates for treatment of pNETs were identified based on differentially expressed genes. These results may help focus efforts on identifying targeted agents with therapeutic efficacy to treat patients with pNETs. [ABSTRACT FROM AUTHOR]

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs. [Display omitted] • A positive selection genome-wide CRISPR-Cas9 screen identifies POU2F3 regulators • The mSWI/SNF complex maintains POU2F3 and its oncogenic program • Neuroendocrine (NE) status demarcates two subclasses of POU2F3+ SCLC • Non-NE POU2F3+ SCLCs are highly sensitive to SMARCA4/2 inhibitors and BRD9 degraders Duplaquet et al. use positive-selection CRISPR screening to identify that mSWI/SNF chromatin remodeler complexes regulate POU2F3 and its oncogenic program in SCLC and are required for POU2F3+ SCLC survival. Clinical-grade SMARCA4/2 inhibitors or BRD9 degraders demonstrate efficacy in POU2F3+ patient-derived and cell line xenograft models. [ABSTRACT FROM AUTHOR]

High-grade neuroendocrine cancers (NEC) of the head and neck (HN) are rare and aggressive, accounting for ≤1 % of all HN cancers, with a 5-year overall survival (OS) of ≤20 %. This case series examines clinical characteristics, treatments, and outcomes of patients diagnosed at a regional UK HN cancer centre over the last 23 years. A retrospective review of medical records was conducted for all patients diagnosed with NEC HN from 1st January 2000 until 1st March 2023 at Velindre Cancer Centre. During the study period, 19 cases of NEC HN were identified, primarily affecting males (n = 15, 79 %). Median age of 67 years (range: 44–86). At diagnosis, 32 % of patients (n = 6) were smokers. The most common primary tumour sites were larynx (n = 5, 26.3 %) and sinonasal (n = 5, 26.3 %). Most patients presented with advanced loco-regional disease or distant metastasis, with stage IVA (n = 6, 32 %) and stage IVC (n = 6, 32 %) being the most common. The key pathology marker was synaptophysin, present in 100 % of the tested patients (n = 15). In the study, of the 12 patients with non-metastatic disease, 10 received a combination of treatments that included radiotherapy (RT). Some of these patients also received chemotherapy (CT) at the same time as their radiotherapy. Surgery alone was used in two patients with stage II disease. Seven subjects had complete responses, and one achieved a partial response. Among the seven metastatic patients, three received CT, and one underwent palliative RT, all achieving a partial response. In all cases, the CT used was carboplatin and etoposide. After a median follow-up of 11 months (range: 1–96), the median OS was 27 months for the overall population, 51 months for those treated radically, and three months for metastatic patients with palliative treatment. The 1-year OS for all patients was 54.3 %, the 2-year OS was 46.5 %, and the 5-year OS was 23.3 %. Among patients treated radically, these rates were 65.3 %, 52.2 %, and 26.1 %, respectively. For patients treated palliatively, the 1-year OS was 33.3 %. This case series contributes preliminary observations on the characteristics and management of non-metastatic NEC HN, suggesting potential benefits from multimodality treatment strategies. Given the small cohort size, these observations should be interpreted cautiously and seen as a foundation for further research. [ABSTRACT FROM AUTHOR]

The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity—evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment. [Display omitted] • Rb1/Trp53/Myc alterations promote high-grade metastatic NEUROD1+ ONB • Mouse and human ONBs exhibit transcriptional similarity to neuroendocrine tumors • ONB harbors intratumoral cell fate heterogeneity and lineage plasticity • ASCL1 suppresses non-neuronal lineages including POU2F3+ microvillar-like states Finlay et al. generate mouse models of olfactory neuroblastoma (ONB) that demonstrate striking similarities to human ONB and other neuroendocrine tumors, including expression of lineage-related oncogenes ASCL1 , NEUROD1 , and POU2F3 , an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity and plasticity, and shared expression of therapeutic targets. [ABSTRACT FROM AUTHOR]

Atrazine (ATR) is one of the most widely utilized herbicides globally and is prevalent in the environment due to its extensive use and long half-life. It can infiltrate the human body through drinking water, ingestion, and dermal contact, and has been recognized as an environmental endocrine disruptor. This study aims to comprehensively outline the detrimental impacts of ATR on the endocrine system. Previous research indicates that ATR is harmful to various bodily systems, including the reproductive system, nervous system, adrenal glands, and thyroi d gland. The toxic effects of ATR on the endocrine system and its underlying molecular mechanisms are summarized as follows: influencing the expression of kisspeptin in the HPG axis, consequently affecting steroid synthesis; disrupting DNA synthesis and meiosis, as well as modifying DNA methylation levels, leading to reproductive and developmental toxicity; impacting dopamine by altering Nurr1, VMAT2, and DAT expression, consequently affecting dopamine synthesis and transporter expression, and influencing other neurotransmitters, resulting in neurotoxicity; and changing adipose tissue synthesis and metabolism by reducing basal metabolism, impairing cellular oxidative phosphorylation, and inducing insulin resistance. Additionally, a compilation of natural products used to mitigate the toxic effects of ATR has been provided, encompassing melatonin, curcumin, quercetin, lycopene, flavonoids, vitamin C, vitamin E, and other natural remedies. It is important to note that existing research predominantly relies on in vitro and ex vivo experiments, with limited population-based empirical evidence available. • Described the various toxicities produced by ATR on the endocrine system. • Reviewed the mechanisms of ATR toxicity on reproductive endocrine and neuroendocrine production. • Mechanisms by which ATR affects the neuroendocrine axis. • ATR affects lipid metabolism. [ABSTRACT FROM AUTHOR]

Up to 14% of bladder urothelial carcinoma has variant histology (VH), which is associated with a higher incidence of occult regional lymph node metastasis. Neoadjuvant chemotherapy (NAC) is the gold-standard for resectable cT2-4 disease as it achieves pathologic complete response (pCR) in select patients at the time of radical cystectomy (RC). A landmar k tr ial demonstrated chemosensitivity and pT0 status in the setting of VH. pT0N + pathology in patients undergoing subsequent RC has prompted concerns about post-chemotherapy bladder preservation. We investigate how VH impacts pathologic primary site and nodal downstaging post-NAC. We queried the National Cancer Database for cT2-4N0M0 patients who underwent NAC and RC between 2004 and 2016. These patients were stratified into pure urothelial cell carcinoma (UCC) and VH. The rate of downstaging to =pT1 was analyzed, along with pN + status. Overall survival was analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards regression model. Multivariable models were adjusted for demographic and clinicopathologic variables. Of 5,335 patients, 92.1% were UCC and 7.9% VH. UCC was associated with better unadjusted survival and lower adjusted odds of being pN + (aOR = 0.60, P < .001). Squamous cell, glandular, and sarcomatoid histologies were significantly associated with decreased adjusted odds of any pT downstage. Neuroendocrine histology (NE) trended towards increased adjusted odds of downstage to pT0N0. Patients with VH were more likely to harbor occult regional lymph node metastasis in the setting of intravesical pCR. NE had the highest pT0N0 rate, with potential implications on post-NAC bladder preservation. These findings reinforce the role of RC after NAC especially for VH. [ABSTRACT FROM AUTHOR]

As the use of cross-sectional imaging has become more frequent, there has been an increase in the diagnosis of cystic neoplasms and small non-functioning neuroendocrine neoplasms within the pancreas. Investigation and follow-up of cystic lesions of the pancreas requires a multimodal approach, of which endoscopic ultrasound with biopsy is becoming an increasingly important component. The main premalignant cystic neoplasms of the pancreas are mucinous-type tumours, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Main-duct IPMN should be resected due to the high incidence of underlying malignancy; however, a selective approach to intervention for side-branch IPMN should be taken (dependent on the presence of symptoms, tumour markers and tumour characteristics). Pancreatic neuroendocrine neoplasms (PanNENs) can also present as cystic lesions in approximately 18% of cases. Biochemically confirmed functional PanNEN and non-secreting PanNENs larger than 2 cm in size should be evaluated for surgery. [ABSTRACT FROM AUTHOR]

• Substance use disorders vulnerability is rooted in neurobiological developmental pathways. • Insecure attachment and trauma are greater risk factors for developing substance use disorders. • Vulnerability to substance use disorders involve genetic, epigenetic and neuroendocrine changes. • Parenting represents a therapeutic target for prevention of addiction. This review aims to elucidate environmental and genetic factors, as well as their epigenetic and neuroendocrine moderators, that may underlie the association between early childhood experiences and Substance Use Disorders (SUD), through the lens of parental attachment. Here we review those attachment-related studies that examined the monoaminergic systems, the hypothalamic pituitary adrenal stress response system, the oxytoninergic system, and the endogenous opioid system from a genetic, epigenetic, and neuroendocrine perspective. Overall, the selected studies point to a moderating effect of insecure attachment between genetic vulnerability and SUD, reasonably through epigenetic modifications. Preliminary evidence suggests that vulnerability to SUDs is related with hypo-methylation (e.g. hyper-expression) of high-risk polymorphisms on the monoaminergic and hypothalamic pituitary adrenal system and hyper-methylation (e.g. hypo-expressions) of protective polymorphisms on the opioid and oxytocin system. These epigenetic modifications may induce a cascade of neuroendocrine changes contributing to the subclinical and behavioural manifestations that precede the clinical onset of SUD. Protective and supportive parenting could hence represent a key therapeutic target to prevent addiction and moderate insecure attachment. [ABSTRACT FROM AUTHOR]

Locally advanced rectal neuroendocrine neoplasms (NENs) are rare, and the therapeutic effects of surgery in improving the prognosis have been questioned in previous reports. The research included 58 consecutive patients with locally advanced rectal NENs from three Chinese medical centers between 2000 and 2020. All have received radical surgical treatment. The clinicopathological and survival data were collected. Kaplan-Meier methods and a Cox proportional hazards regression model were used to evaluate the prognosis and identify independent prognostic factors. All patients were followed up for a median period of 36 (2–125) months. Of the 58 patients, 13 (22.4%) had G1 neuroendocrine tumors (NETs), 15 (25.9%) had G2 NETs, 6 (10.3%) had G3 NETs, and the remaining 24 (41.4%) patients had G3 neuroendocrine carcinomas (NECs). The 1-year and 3-year disease-free survival (DFS) rates were 64.5% and 48.8%, respectively. The 1-year and 3-year overall survival (OS) rates were 90.5% and 75.4%, respectively. Univariate analysis demonstrated that tumor differentiation (p = 0.002), gross morphology (p = 0.009), T stage (p = 0.024), and extramural vascular invasion (p = 0.009) were associated with the OS. The subsequent multivariate analysis confirmed that tumor differentiation [hazard ratio (HR) = 6.002, 95% confidence interval (CI): 1.210–29.767, p = 0.028] and gross morphology (HR = 3.438, 95% CI: 1.038–11.382, p = 0.043) were independent prognostic factors affecting the clinical outcomes. Rectal NENs are a heterogeneous group of diseases. The survival benefits obtained from surgery vary widely based on the tumor clinicopathological features. Patients with G3 NECs and ulcerative mass are at high risks of poor prognosis. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to analyze whether primary tumor resection (PTR) among patients with stage IV gastrointestinal neuroendocrine tumor (GI-NET) and unresected metastases was associated with improved outcomes. Methods: Patients diagnosed with stage IV GI-NETs were identified in the linked SEER-Medicare database from 2004 to 2015. Overall survival (OS) of patients who did versus did not undergo PTR was examined using bivariate and multivariable cox regression analysis as well as propensity score matching (PSM). Results: Among 2219 patients with metastatic GI-NETs, 632 (28.5%) underwent PTR, whereas 1587 (71.5%) did not. The majority of individuals had a NET in the pancreas (n = 969, 43.6%); the most common site of metastatic disease was the liver (n = 1064, 47.9%). Patients with stage IV small intestinal NETs most frequently underwent PTR (62.6%) followed by individuals with colon NETs (56.5%). After adjusting for all competing factors, PTR remained independently associated with improved OS (HR = 0.65, 95% CI: 0.56–0.76). Following PSM (n = 236 per group), patients who underwent PTR had improved OS (median OS: 1.3 years vs 0.8 years, p = 0.016). While PTR of NETs originating from stomach, small intestine, colon, and pancreas was associated with improved OS, PTR of rectal NET did not yield a survival benefit. Conclusion: Primary GI-NET resection was associated with a survival benefit among individuals presenting with metastatic GI-NET with unresected metastases. Resection of primary GI-NET among patients with stage IV disease and unresected metastases should only be performed in selected cases following multi-disciplinary evaluation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sleep disruption may be a mechanism by which early adversity impacts long-term mental and physical health. • Early adversity and sleep disruption share similar neural, neuroendocrine, and neuroimmune mechanisms. • Researchers should pay attention to the sleep disruptions that occur at periods of developmental transition. • Interventions can test the role of sleep as well as potentially mitigate the long-term impact of early adversity. Sleep disturbance may be a central, yet underappreciated mechanism by which early adversity has a long-term impact upon mental and physical health. The fundamental regulatory processes shaped by early adversity – neural, neuroendocrine, and immune – are also central to sleep. Sleep problems, in turn, lead to a similar constellation of chronic health problems that have been linked to early adversity. We bring together work from the fields of early adversity and sleep in order to suggest a model by which sleep disturbance plays a critical role in the far-reaching impacts of early adversity on health. Future research should employ more longitudinal designs and pay particular attention to the impact of developmental periods such as adolescence and midlife when maturational and environmental factors conspire to create a unique time of sleep disturbance. We also suggesting that intervening to minimize sleep disturbance may be a promising means by which to test the model, as well as potentially blunt the long-term impact of early adversity on health. [ABSTRACT FROM AUTHOR]

There is an absence of mechanism-driven interventions equipped to reduce the large mental health disparities that exist for preadolescent youth living in poverty. Building a Strong Identity and Coping Skills (BaSICS) is a preventive intervention designed to target multiple aspects of poverty-related stress adaptation, including altered neuroendocrine function. The purpose of the current study was to examine whether pre-post shifts in preadolescent hypothalamic-pituitary-adrenal (HPA) activation could longitudinally predict internalizing outcomes and to determine whether BaSICS could buffer such HPA-related risk for psychopathology. Low-income youth (n = 112) ages 11–12 years were randomized to the 16-session intervention or assessment-only control (53% intervention; 54% female; 40% Hispanic, 63% Black, 20% White). Youth completed questionnaires and the Trier Social Stress Test, and provided cortisol via saliva at six timepoints during the 90-minute assessment. Adjusting for pre-intervention Cortisol Area Under the Curve–Ground (CAUCg) scores and internalizing problems, post-intervention CAUCg and intervention main and interactive effects were modeled as predictors of internalizing outcomes across post-intervention, 6-month, and 12-month follow-up assessments using multilevel regression methods. A significant post-intervention CAUCg by intervention interaction emerged (B =1.198, SE =0.433, p =.006). For control youth, baseline-adjusted decreases in cortisol output were associated with increases in internalizing problems that remained stably elevated across follow-up assessments. For BaSICS youth, however, internalizing problems decreased and remained stably low following program delivery, irrespective of post-intervention increases or decreases in cortisol output. Findings illustrate how BaSICS may buffer against HPA-related risk for internalizing psychopathology and provide support for interventions targeting biological mechanisms of risk for low-income preadolescents. • BaSICS is a coping skills intervention targeting poverty-related stress adaptation. • Mechanisms of stress adaptation include altered neuroendocrine function (e.g., HPA). • A significant post-intervention CAUCg by intervention interaction emerged. • BaSICS may buffer risk for internalizing problems via normalization of HPA rhythms. • Interventions targeting biological risk mechanisms for low-income youth are needed. [ABSTRACT FROM AUTHOR]

Neuropeptide FF (NPFF) is an octapeptide that regulates various cellular processes, especially pain perception. Recently, there has been a growing interest in understanding the modulation of NPFF in neuroendocrine inflammation. This review aims to provide a thorough overview of the regulation of NPFF in macrophage-mediated biological processes. We delve into the impact of NPFF on macrophage polarization, self-renewal modulation, and the promotion of mitophagy, facilitating the transition from thermogenic fat to fat-storing adipose tissue. Additionally, we explore the NPFF-dependent regulation of the inflammatory response mediated by macrophages, its impact on the differentiation of macrophages, and its capacity to induce alterations in the transcriptome of macrophages. We also address the potential of NPFF as a therapeutic molecule in the field of neuroendocrine inflammation. Overall, our work offers an understanding of the influence of NPFF on macrophage, facilitating the exploration of its pharmacological significance in future studies. • NPFF changes the transcriptome of macrophages. • NPFF affects the polarization of macrophages and the self-renewal of macrophages. • NPFF regulates the macrophage-mediated inflammatory response. • NPFF alters macrophage differentiation. [ABSTRACT FROM AUTHOR]

Antidepressants are high-volume pharmaceuticals that accumulate to concentrations in the μg·L−1 range in surface waters. The release of peptide hormones via neurosecretory cells appears as a natural target for antidepressants. Here I review research that suggests that antidepressants indeed disrupt endocrine signalling in crustaceans, by acting on the synthesis and release of neurohormones, such as crustacean hyperglycaemic hormone, moult inhibiting hormone and pigment dispersing hormone in decapods, as well as methyl farnesoate in Daphnids. Hence, antidepressants can affect hormonal regulation of physiological functions: increase in energy metabolism and activity, lowered ecdysteroid levels, potentially disrupting moult and somatic growth, reducing colour change capacity and compromising camouflage, as well as induction of male sex determination. Several studies further suggest effects of antidepressants on crustacean reproduction, but the hormonal regulation of these effects remains elusive. All things considered, a body of evidence strongly suggests that antidepressants are endocrine disrupting compounds in crustaceans. [ABSTRACT FROM AUTHOR]

The correlation between the endocrine system and bipolar disorder(BD) has been well recognized, yet the influence of neuroendocrine hormones on readmission risk post-hospitalization for BD remains largely unexplored. This retrospective cohort study was to scrutinize the impact of neuroendocrine functionality on the readmission of patients with BD post-hospitalization for mental disorders. The dataset was derived from the electronic medical records of the First Affiliated Hospital of Jinan University in Guangzhou, China. Both univariate and multivariate logistic regression analysis were conducted on all patients hospitalized for BD, and from 1 January 2017 to October 2022. Of the 1110 eligible patients, 83 and 141 patients experienced psychiatric readmissions within 90 and 180 days post-discharge, respectively. Multivariate analysis revealed that high serum TSH levels (aOR = 1.079; 95%CI = 1.003–1.160) and thyroid disease comorbidities (aOR = 2.899; 95%CI = 1.303–6.452) were independently correlated with the risk of 90-day readmission; while increased serum TSH levels (aOR = 1.179; 95%CI = 1.081–1.287) represented a risk factor for 180-day readmission. These results indicate that high serum TSH levels and thyroid disease comorbidities may contribute to an elevated readmission risk in patients with BD following hospitalization. Routinely evaluating and intervening in thyroid function is crucial in the treatment of BD, as it may aid in preventing re-hospitalization. • Serum TSH level predicts BD patient readmission risk. • Thyroid comorbidity correlates with BD readmission. • High past hospitalizations independently elevate BD readmission risk. [ABSTRACT FROM AUTHOR]

Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600E BRAF- mutated (BRAF mt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAF mt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier and log-rank tests. Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21–3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35–3.85, p = 0.001). Among BRAF mt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies. • Neuroendocrine differentiation is associated with worse prognosis in several cancers. • Neuroendocrine differentiation is associated with secondary therapy resistance. • V600E BRAF colorectal cancers show high prevalence of neuroendocrine differentiation. • Synaptophysin-positive tumours are characterized by worse PFS and OS. [ABSTRACT FROM AUTHOR]

• MeA treatment with naloxone potentiated the autonomic responses elicited by RS. • MeA treatment with naloxone increased the corticosterone levels during RS. • κ-opioid receptors antagonism into MeA increases tachycardiac response induced by RS. • κ-opioid receptors antagonism into MeA also increases the corticosterone levels during RS. The medial amygdaloid nucleus (MeA) is a key neural structure in triggering physiologic and behavioral control during aversive situations. However, MeA role during stress exposure has not yet been fully elucidated. Thus, in the present study, we investigated the involvement of the MeA opioid neurotransmission in the modulation of autonomic, neuroendocrine and behavioral responses evoked by acute restraint stress (RS). The bilateral microinjection of naloxone (non-selective opioid antagonist) into the MeA potentiated RS-evoked autonomic responses and increased plasma corticosterone levels, in a dose-dependent manner. However, no effects were observed in RS-evoked increases on plasma oxytocin levels and anxiogenic-like behavior. Similar to naloxone, MeA pretreatment with the selective κ-opioid antagonist (nor-BNI) also enhanced heart rate and corticosterone increases induced by RS, whereas treatment with selective µ- or δ-opioid antagonists did not affect the physiologic and behavioral responses caused by RS. The present results showed MeA κ-opioid receptors modulate heart rate and corticosterone increases evoked by acute RS, reinforcing the idea of an inhibitory role exerted by MeA during aversive situations. [ABSTRACT FROM AUTHOR]

Background: Rectal neuroendocrine tumors comprise 20% of neuroendocrine tumors in the alimentary tract, but there is controversy surrounding the optimal management of this disease. The purpose of this study is to better define treatment for patients with rectal neuroendocrine tumors. Methods: Using the National Cancer Database, we analyzed patients with rectal neuroendocrine tumors between 2004 and 2015. Patients with metastatic disease and missing treatment data were excluded. We examined overall survival stratified by tumor size, treatment type, and presence of positive lymph nodes using Kaplan-Meier analysis with log-rank test. Cox proportional hazard regression model was performed to identify factors associated with overall survival. Results: In total, 17,448 patients with rectal neuroendocrine tumors were identified; 16,531 of these patients met inclusion criteria. The majority of patients had tumors ≤ 10 mm (9216 patients, 79.8%), and approximately 90% underwent local excision. The probability of 5-year overall survival was significantly higher for patients with smaller tumors (≤ 10 mm: 94.1% 11–20 mm: 85.7%, > 20 mm: 71.8%; p < 0.001) and those with no positive lymph nodes (91.4% versus 53.3%, p < 0.001). The probability of 5-year overall survival differed based on treatment modality (local excision: 93.6%, radical resection: 79.1%, observation alone: 77.1%; p < 0.001). On multivariable Cox regression, when compared to local excision, radical resection was not associated with a difference in overall survival but observation alone was associated with significantly worse OS (HR = 2.750, p < 0.001). Conclusions: There is a significant difference in overall survival between patients who underwent local excision versus observation alone. Excision of the tumor should be offered to all patients with rectal neuroendocrine tumors who are appropriate surgical candidates, regardless of the tumor size. [ABSTRACT FROM AUTHOR]

• Merkel cell carcinoma (MCC) often presents with regional lymph node involvement. • Indications for regional lymph node radiotherapy (rLN-RT) aren't well established. • rLN-RT reduced regional and distant relapse and improved disease-specific survival. • Adjuvant nodal radiation therapy (AnRT) improved all outcome-related endpoints. • Patients with ENE, ≥2 positive nodes, or bulky nodes benefited the most from AnRT. One-third of patients with Merkel cell carcinoma (MCC) present with locally advanced disease involving the regional lymph nodes, but indications for regional lymph node radiation therapy (rLN-RT) are not well established. 72 patients with locally advanced MCC were retrospectively reviewed. Regional lymph nodes were addressed with observation, lymph node dissection (LND) alone, definitive nodal radiotherapy (DnRT), or LND plus adjuvant nodal radiotherapy (AnRT). Cox regression was used to compare treatment modalities in terms of regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS) and disease-specific survival (DSS). rLN-RT, including both DnRT and AnRT, improved RRFS (Hazard ratio (HR): 0.07, 95% confidence interval (CI): 0.01–0.40, p = 0.003), DRFS (HR: 0.28, CI: 0.11–0.76, p = 0.01), DFS (HR: 0.23, CI: 0.09–0.58, p = 0.002), and DSS (HR: 0.23, CI: 0.06–0.90, p = 0.03). AnRT improved DFS and DSS in high-risk subgroups (e.g., extranodal extension (ENE), ≥ 2 positive lymph nodes, or bulkier lymph nodes). The benefit of AnRT increased with higher disease burden. After controlling for these adverse factors, AnRT significantly improved RRFS (HR: 0.04, CI: 0.01–0.37, p = 0.004), DRFS (HR: 0.14, CI: 0.04–0.50, p = 0.003), DFS (HR: 0.09, CI: 0.02–0.33, p < 0.001), and DSS (HR: 0.21, CI: 0.05–0.89, p = 0.03). rLN-RT, including both DnRT and AnRT, reduces relapse and death from MCC in patients with node-positive disease. AnRT is particularly beneficial for patients with ENE, multiple involved lymph nodes, or larger nodal foci of disease. These results argue for more liberal use of nodal RT for MCC patients who present with node-positive disease. [ABSTRACT FROM AUTHOR]

Background: Surgical resection for asymptomatic, localized, well-differentiated pancreatic neuroendocrine tumors (PNETs) is common yet controversial. Studies using overall survival as an endpoint have shown a benefit for resection; however, these results may be due to treatment selection bias. We assessed the impact of surgery on both overall (OS) and cancer-specific survival (CSS) for asymptomatic patients with stage I PNETs (AJCC 8th edition).Methods: Using SEER data, we identified 709 patients from 2007 to 2015 with well- and moderately differentiated stage I PNETs. We performed Kaplan-Meier survival estimates and adjusted Cox regression for OS and CSS.Results: Among 709 patients, 628 (88.6%) underwent surgery. There were 37 overall deaths and 11 cancer-specific deaths. All cancer-specific deaths occurred within 3 years of diagnosis. Five-year OS and CSS rates were 89% and 98%, respectively, for the population. Five-year OS rates were 56% in the non-surgical cohort versus 92% in the surgical cohort (log rank, p < 0.001). However, the 5-year CSS rates were similar; 94% in the non-surgical group and 98% in the surgical group (log rank, p  = 0.207). On multivariable analysis, surgery predicted improved OS but not CSS.Conclusion: Although OS is superior in surgically treated stage I PNETs, CSS is not improved, implying treatment selection bias towards surgery being performed in healthier patients. These data suggest that overall survival is a problematic endpoint for the study of asymptomatic, stage I PNETs. Surgery should be individualized for this cohort of patients as the primary cause of death is non-cancer related. [ABSTRACT FROM AUTHOR]

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity. [ABSTRACT FROM AUTHOR]

• PART 2: Biological Mechanisms. • Birth prior to full term (preterm/early term) is a substantial public health issue. • Biological mechanisms link psychosocial exposures to birth outcomes. • Key biomechanisms: Neuroendocrine, inflammation, gene expression, aging, and microbiome. • Moderating and mediating effects are observed in relation to race and ethnicity. • An integrated approach addressing both behavior and biology is needed. As reviewed in Part 1 of this two part review, birth prior to full term is a substantial public health issue. In the US, ˜400,000 babies per year are born preterm (< 37 weeks), while>1 million are early term (37–386/7 weeks) and remarkable racial disparities in shortened gestation are observed among African Americans as compared to Whites. Biomechanisms linking stressor exposures with birth outcomes are increasingly being explicated. The current paper reviews the mechanistic role of maternal biological functioning in the link between behavioral exposures and birth outcomes. These include the inter-related roles of neuroendocrine function, inflammatory regulation, biological aging, and the microbiome. An integrative approach which addresses both behavioral and biological factors within the same study, carefully considers the role of race/ethnicity, and rigorously defines birth outcomes (e.g., spontaneous versus medically-indicated and inclusive of early term birth) is needed to move research in this field toward better mechanistic understanding and clinical application. [ABSTRACT FROM AUTHOR]

Bladder paragangliomas are rare tumors, with no prospective studies or guidelines on the management of this disease. We present a case series of 6 patients managed with bladder preservation over a median follow-up period of 124 months. We also present a review of the recent literature on bladder paragangliomas. We aim to provide a timely synthesis of the recent evidence on bladder paragangliomas as changing paradigms necessitate individualized treatment. [ABSTRACT FROM AUTHOR]

Colostrum feeding is vital for the development of the immune system and gastrointestinal tract in neonatal calves; however, it is currently unknown whether different colostrum feeding strategies affect their neuroendocrine system and potentially the gut–brain axis. The present study investigated the effect of 3 different colostrum feeding regimens on the expression of neuroendocrine genes in adrenal glands and gastrointestinal tissues and on the abundance of intestinal commensal bacteria. Holstein bull calves were fed colostrum immediately after birth and randomly assigned to 3 groups: whole milk (n = 8), mixture of 50% colostrum and 50% whole milk (n = 8), and colostrum (CF; n = 8) for 72 h with 12-h intervals. Adrenal glands, ileum, and colon tissues were collected at 75 h and were subjected to the expression of 11 targeted neuroendocrine genes and the abundance of tissue mucosa-associated bacteria measurement using quantitative real-time PCR and quantitative PCR, respectively. The expressions of all targeted genes were detected, and the expression of α-adrenergic receptor (ADRA1A) gene was affected by CF in adrenal glands and gut tissues. In addition, CF upregulated the expression of HTR4 (serotonin receptor) and SLC4A4 (serotonin transporter) genes in the ileum and increased the abundance of active Lactobacillus spp. and Escherichia coli (as detected at RNA level) associated with ileum and colon tissue. Furthermore, there were positive correlations between the abundance of active Lactobacillus spp. and E. coli with expression of HTR2B and HTR4 genes in the colon, suggesting that extended colostrum feeding strategies may affect the interaction between gut microbiota and host endocrine functions in neonatal calves. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (pNETs) are known to frequently metastasize to the liver and lymphatics; however, metastasis to the spine is exceedingly rare. We report the first case of an intradural, extramedullary pNET metastasis to the upper cervical spine. A 75-year-old Hispanic male patient with history of stage IV pNET with metastasis to the liver and lymph nodes and new-onset lymphadenopathy seen on CT of the chest was found on positron emission tomography scan to have a lesion in the cervical spine. The patient was neurologically intact on physical examination, yet given the patient's medical history, magnetic resonance imaging of the cervical spine was performed, revealing a right-sided intradural, extramedullary mass at the C1–C2 level with associated mass effect on the spinal cord, likely representing a schwannoma. Due to the tumor size, mass effect, and the need for definitive tissue diagnosis, a partial C1–C2 laminectomy with intradural resection of the tumor was performed. The histology was consistent with the patient's known pNET. As treatment for pNETs has evolved, there has been a surge in unique presentations of systemic well-differentiated pNETs being reported. It is vital that patients diagnosed with pNET be monitored for metastases, and when discovered, treated promptly. [ABSTRACT FROM AUTHOR]

We used 1.5T magnetic resonance imaging (MRI) to investigate the role of semiquantitative parameters related to dynamic contrast-enhanced (DCE)-MRI and the apparent diffusion coefficient (ADC) of diffusion-weighted imaging (DWI) in predicting and monitoring the efficacy of concurrent radiotherapy and chemotherapy for laryngeal cancer. The data from 58 patients with newly diagnosed laryngeal cancer who had been treated at our hospital from August 2016 to March 2018 were collected. The 58 patients included 56 men and 2 women, with a median age of 57 years. The pathologic examination of the biopsy specimens revealed squamous cell carcinoma. The time signal curve (TIC) of the tumor and related semiquantitative parameters was measured before, during (radiation dose, 50 Gy), and at the end of treatment (monitoring value after treatment). The results revealed that the TIC types and DCE-MRI–related semiquantitative parameters can predict the efficacy of concurrent chemoradiotherapy for laryngeal and hypopharyngeal cancer. Of the semiquantitative parameters, the signal enhancement ratio at 56 seconds had the greatest predictive value. Patients with TIC type I before treatment had a better prognosis than those with TIC type III. The pre-ADC value was not enough to predict the efficacy. The ADC value, DCE-MRI–related semiquantitative parameters, and their change before treatment had a certain effect in monitoring the changes in water molecule diffusion movement and hemodynamic changes after tumor treatment. However, these were not enough to predict the efficacy. [ABSTRACT FROM AUTHOR]

Purpose: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort.Materials and Methods: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like.Results: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery.Conclusions: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients. [ABSTRACT FROM AUTHOR]

There are few effective biomarkers for neuroendocrine tumors. Precision oncology strategies have provided liquid biopsies for real-time and tailored decision-making. This has led to the development of the first neuroendocrine tumor liquid biopsy (the NETest). The NETest represents a transcriptomic signature of neuroendocrine tumor (NETs) that captures tumor biology and disease activity. The data have direct clinical application in terms of identifying residual disease, disease progress and the efficacy of treatment. In this overview we assess the available published information on the metrics and clinical efficacy of the NETest. Published data on the NETest have been collated and analyzed to understand the clinical application of this multianalyte biomarker in NETs. NETest assay has been validated as a standardized and reproducible clinical laboratory measurement. It is not affected by demographic characteristics, or acid suppressive medication. Clinical utility of the NETest has been documented in gastroenteropancreatic, bronchopulmonary NETs, in paragangliomas and pheochromocytomas. The test facilitates accurate diagnosis of a NET disease, and real-time monitoring of the disease status (stable/progressive disease). It predicts aggressive tumor behavior, identifies operative tumor resection, and efficacy of the medical treatment (e.g. somatostatin analogues), or peptide receptor radionuclide therapy (PRRT). NETest metrics and clinical applications out-perform standard biomarkers like chromogranin A. The NETest exhibits clinically competent metrics as an effective biomarker for neuroendocrine tumors. Measurement of NET transcripts in blood is a significant advance in neuroendocrine tumor management and demonstrates that blood provides a viable source to identify and monitor tumor status. [ABSTRACT FROM AUTHOR]

Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity. This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7–30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%. Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5–43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14–23), 17 (13–22), and 51 (33–60) months. The most common grade III–IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%). The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease. NCT01678664 (clinicaltrials.gov). • Hepatic arterial embolisation therapy (HAET) is the main treatment of neuroendocrine liver metastases. • This phase II study tested the combination of both treatments. • Everolimus can be safely administered after HAET. • The primary end-point (hepatic progression-free survival at 24 months of 50%) was not reached. • HAET allows high liver objective response rate, and everolimus controls the extrahepatic disease. [ABSTRACT FROM AUTHOR]

Factors associated with rectal NENs prognosis are poorly investigated. To evaluate the prognostic role of the ENETs staging and grading systems in rectal NENs. Tertiary referral, multicenter, retrospective study. Factors associated with OS and PFS were investigated by Cox-regression analysis, with best size cut-offs calculated by ROC analysis. Of 100 patients (mean age 55, 45% male, mean size 16.2 mm) 62, 5, 10 and 23 were TNM stage 1 to 4, and 63, 15 and 22 were G1, G2 and G3. Primary treatment was endoscopic snare resection in 62%, endoscopic mucosal resection/endoscopic submucosal dissection in 10%, surgery in 20% and medical treatment in 8%. The best size cut-offs to predict OS and PFS were 10 and 12 mm. During a mean follow-up of 40.7 months 12% died and 26% progressed. The 5-year OS and PFS were 79.5% and 65.2%. Stage IV and G3 were associated with worse OS (HR 8.16; p = 0.002; HR 15.57; p = 0.0004) and PFS (HR 14.26 p < 0.0001; HR 6.42; p = 0.0007). Both staging and grading accurately predict rectal NENs prognosis. Size alone has limited accuracy as 26% of patients with stage IV and 16% with G3 have a primary tumour≤10 mm. [ABSTRACT FROM AUTHOR]

Nervous system processes, including cognition and affective state, fundamentally rely on mitochondria. Impaired mitochondrial function is evident in major depressive disorder (MDD), reflecting cumulative detrimental influences of both extrinsic and intrinsic stressors, genetic predisposition, and mutation. Glucocorticoid 'stress' pathways converge on mitochondria; oxidative and nitrosative stresses in MDD are largely mitochondrial in origin; both initiate cascades promoting mitochondrial DNA (mtDNA) damage with disruptions to mitochondrial biogenesis and tryptophan catabolism. Mitochondrial dysfunction facilitates proinflammatory dysbiosis while directly triggering immuno-inflammatory activation via released mtDNA, mitochondrial lipids and mitochondria associated membranes (MAMs), further disrupting mitochondrial function and mitochondrial quality control, promoting the accumulation of abnormal mitochondria (confirmed in autopsy studies). Established and putative mechanisms highlight a mitochondrial nexus within the psycho-immune neuroendocrine (PINE) network implicated in MDD. Whether lowering neuronal resilience and thresholds for disease, or linking mechanistic nodes within the MDD pathogenic network, impaired mitochondrial function emerges as an important risk, a functional biomarker, providing a therapeutic target in MDD. Several treatment modalities have been demonstrated to reset mitochondrial function, which could benefit those with MDD. [Display omitted] • Stress increases cerebral energy demands and impairs mitochondrial function. • Impaired mitochondrial structure and respiration, decrease energy generation. • Deficits in energy production affect the Psycho-Immune Neuroendocrine Network. • Mediators released from mitochondria, lower neurotransmitter and adipokine levels. • Treatment modalities can initiate mitochondrial plasticity to reset mitochondrial function. [ABSTRACT FROM AUTHOR]

• IHC reveals ASCL1 as the most prevalent subtype in SCLC; YAP1 is rare. • IHC for SCLC subtyping reveals frequent subtype co-expression and temporal changes post-treatment. • Transformed SCLC associated with reduced progression-free survival post-chemoimmunotherapy. Molecular subtyping of small cell lung cancer (SCLC) tumors based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) using immunohistochemical (IHC) staining has recently emerged as a proposed approach. This study was aimed to examine this subtyping method in Asian patients with SCLC and investigate its correlation with treatment efficacy. Seventy-two tumor samples from patients with SCLC, including de novo cases and those transformed from EGFR -mutant tumors, were analyzed. IHC staining was used to measure the expression of the four transcription factors and conventional SCLC markers. Subtypes were defined based on relative expression levels. The treatment response and outcome of patients receiving immune checkpoint inhibitors and chemotherapy were also reviewed. ASCL1 was the most common subtype, observed in 55.2 % of the samples, followed by NEUROD1 (26.9 %) and POU2F3 (9 %). No tumor exhibited predominant YAP1 positivity, while 41.8 % of the samples demonstrated positivity for two subtype markers. Approximately 50 % of the patients experienced a subtype switch after disease progression. Patients with the ASCL1/NEUROD1 (SCLC-A/N) subtype had similar progression-free survival (PFS) compared to non-SCLC-A/N patients after treatment with immune checkpoint inhibitors plus chemotherapy. Transformed SCLC patients had significantly worse PFS than de novo SCLC patients after chemoimmunotherapy. (2.1 vs. 5.4 months, P = 0.023) This study revealed the challenges associated with using IHC alone for molecular subtyping, highlighting the frequent co-expression of subtypes and temporal changes following treatment. Further research is warranted to explore the prognostic and therapeutic implications of IHC subtyping in patients with SCLC. [ABSTRACT FROM AUTHOR]

Interpersonal touch is an essential aspect of human interaction that has the ability to regulate physiological stress responses. Prolonged exposure to stress can have cumulative multiphysiological effects; for example, allostatic load. Despite the increased susceptibility of social isolation for older adults, there is a paucity of research on the efficacy of touch in regulating stress responses among this population. It is also unknown whether touch confers benefits regardless of the person with whom it is shared. This study investigates the difference in physiological stress based on the frequency of touch (hugs, holding, or other close physical contact) shared with romantic partners as compared to other close adults (family, friends, and neighbours) in an older adult population. Data were analysed from 1419 respondents (aged 57–85 years) of the National Social Life, Health, and Aging Project (NSHAP) in 2005–2006. Principal components analysis determined whether the eight markers of allostatic load measured in the NSHAP function as a singular system or as distinct components. Analyses revealed three components of allostatic load: metabolic, cardiovascular, and neuroendocrine health. The results of multiple regression revealed that a higher frequency of interpersonal touch shared with romantic partners was associated with better neuroendocrine health (β = 0.13, p = 0.004) following adjustment for a variety of covariates (but not with better metabolic or cardiovascular health), with no associations apparent for touch from other close adults. These findings highlight the importance of promoting interpersonal touch with romantic partners for older adults' neuroendocrine health. • Principal component analysis revealed three loadings for allostatic load markers: metabolic, cardiovascular, and neuroendocrine health. • Frequent partner touch is associated with better neuroendocrine health in older adults as compared to less frequent partner touch. • Frequency of touch with other close adults is not associated with improved health. [ABSTRACT FROM AUTHOR]

Trans -differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans -differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states. [Display omitted] • PARCB temporal model profiling informs key aspects of SCNPC trans -differentiation • Trans -differentiation trajectory resembles a common developmental arc-like pattern • ASCL1 and ASCL2 mark distinct bifurcating SCNPC trans -differentiation trajectories • TFAP4 as a common regulator of ASCL1/2 implicated in SCNPC trans -differentiation Chen et al. use temporal profiling of a small cell neuroendocrine prostate cancer model to inform anti-androgen therapy-induced trans -differentiation. An arc-like trajectory common to developmental biology is observed, and a bifurcation marked by ASCL1 and ASCL2, with parallels to SCLC. TFAP4 is identified as a common regulator of ASCL1 and ASCL2. [ABSTRACT FROM AUTHOR]

The pituitary is the master neuroendocrine gland, which regulates body homeostasis. It consists of the anterior pituitary/adenohypophysis harboring hormones producing cells and the posterior pituitary/neurohypophysis, which relays the passage of hormones from the brain to the periphery. It is accepted that the adenohypophysis originates from the oral ectoderm (Rathke's pouch), whereas the neural ectoderm contributes to the neurohypophysis. Single-cell transcriptomics of the zebrafish pituitary showed that cyp26b1 -positive astroglial pituicytes of the neurohypophysis and prop1 -positive adenohypophyseal progenitors expressed common markers implying lineage relatedness. Genetic tracing identifies that, in contrast to the prevailing dogma, neural plate precursors of zebrafish (her4.3 +) and mouse (Sox1+) contribute to both neurohypophyseal and a subset of adenohypophyseal cells. Pituicyte-derived retinoic-acid-degrading enzyme Cyp26b1 fine-tunes differentiation of prop1+ progenitors into hormone-producing cells. These results challenge the notion that adenohypophyseal cells are exclusively derived from non-neural ectoderm and demonstrate that crosstalk between neuro- and adeno-hypophyseal cells affects differentiation of pituitary cells. [Display omitted] • Pituicytes, the resident neurohypophyseal astroglia, are conserved among vertebrates • Pituicytes and adenohypophyseal progenitors are closely related cell types • Neuroectodermal cells contribute to both neurohypophyseal and subsets of adenohypophyseal cells • Pituicyte-derived Cyp26b1 limits transition of Prop1+ progenitors into endocrine cells The adenohypophysis and neurohypophysis that constitute the pituitary gland are derived from the pre-placodal ectoderm and the neuro-ectoderm, respectively. However, Chen et al. demonstrate that subsets of adenohypophyseal cells are derived from the neuroectoderm of zebrafish and mouse, and that neuroectoderm-derived astroglial pituicytes refine differentiation of adenohypophyseal progenitors. [ABSTRACT FROM AUTHOR]

Ectopic hormone production may be present in neuroendocrine and non-endocrine neoplasms. Ectopic sources of growth hormone, adrenocorticotropin (ACTH), or their releasing factors are uncommon but clinically relevant. Ectopic ACTH tumors have been studied more than the rest, but there are still no comprehensive multidisciplinary guidelines that include all the pitfalls in the diagnosis and management of ectopic hormonal syndromes and the neoplasms associated with ectopic Cushing or acromegaly. The frequency of neuroendocrine neoplasms and other neoplasms with neuroendocrine differentiation has been increasing in recent decades. The review of the available data on these tumors, their classification, and improvements in diagnostic and therapeutic procedures is important to understand the relevance of ectopic Cushing's syndrome and acromegaly in clinical practice. [Display omitted] [ABSTRACT FROM AUTHOR]

Insulinoma-associated protein 1 (INSM1) is an immunohistochemical marker for neuroendocrine differentiation with potentially superior sensitivity and specificity. INSM1 performance in pulmonary cytology cell block material (CB) has not been well established, and large series demonstrating its performance have been few. Typical and atypical carcinoid, small cell lung carcinoma, and large cell neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma CBs and 563 surgical specimens comprising 17 typical carcinoid, 14 atypical carcinoid, 8 small cell lung carcinoma, 10 large cell neuroendocrine carcinoma, 58 squamous cell carcinoma, 415 adenocarcinoma, and 17 large cell carcinoma cases and 24 other tumor types were immunostained with INSM1, CD56, synaptophysin, and chromogranin A. The INSM1 sensitivity, specificity, positive predictive value, and negative predictive value were 92.3%, 100%, 78.9%, and 99% in the CBs and 89.8%, 98.1%, 81.5%, and 99% in the surgical specimens, respectively, with 86.2% concordance. The sensitivity, specificity, positive predictive value, and negative predictive value for the other neuroendocrine markers were 97.4%, 93.3%, 97.4%, and 93.3% in the CBs and 93.9%, 93.6%, 58.2%, and 99.4% in the surgical specimens for CD56; 89.7%, 100%, 100%, and 75% in the CBs and 93.4%, 91.2%, 50.5%, and 99.4% in the surgical specimens for synaptophysin; 66.7%, 100%, 100%, and 53.6% in the CBs and 75.5%, 98.6%, 84.1%, and 97.7% in the surgical specimens for chromogranin A, respectively. Finally, INSM1, together with CD56, maximized the sensitivity to 100% with 93.3% specificity in the CBs. The results from our study have further established the high sensitivity and specificity of INSM1 in the largest pulmonary cytologic and surgical cohorts to date. INSM1 either matched or outperformed the performance of existing neuroendocrine markers, and its combination with CD56 appeared to maximize test performance. [ABSTRACT FROM AUTHOR]