Search Results (133)

Background and Objective: Insulinoma-associated protein 1 (INSM1) is a novel immunohistochemical marker with potential utility in identifying neuroendocrine differentiation in lung cancer. Unlike conventional neuroendocrine (NE) markers, INSM1 can potentially serve as a standalone diagnostic biomarker. This study presents the first meta-analysis assessing the diagnostic accuracy of using INSM1 to distinguish LCNEC and SCLC from other lung cancer subtypes, addressing the variability across individual studies. Methods: A systematic review and meta-analysis were conducted to comprehensively evaluate the diagnostic performance of INSM1 in the pathological classification of lung cancer. The online databases PubMed, Web of Science, and Embase were systematically searched for data collection. Studies reporting the sensitivity and specificity of INSM1 in diagnosing LCNEC and SCLC were included. Pooled estimates were calculated using two models: the NSCLC model, which distinguishes LCNEC from other non-small cell lung cancers (NSCLCs), and the lung cancer model, which differentiates both LCNEC and SCLC from non-neuroendocrine (non-NE) lung cancer. Results: Fourteen studies comprising 3,218 specimens were included in this systematic review and meta-analysis. In the NSCLC model, INSM1 demonstrated a pooled sensitivity of 0.67 (95% CI: 0.61–0.73) and specificity of 0.97 (95% CI: 0.96–0.98), with an area under the curve (AUC) of 0.943. In the lung cancer model, the pooled sensitivity and specificity were 0.86 (95% CI: 0.84–0.88) and 0.97 (95% CI: 0.96–0.98), respectively, with an AUC of 0.974. Conclusions: INSM1 demonstrated excellent diagnostic accuracy and consistently high specificity for pulmonary neuroendocrine carcinomas, supporting its utility as a reliable standalone immunohistochemical marker with the potential to replace conventional NE markers in the pathological diagnosis of LCNEC and SCLC. Full article

Health outcomes for people with HIV (PWH) have improved significantly with combination antiretroviral therapy (ART), yet the risk of lung cancer remains elevated. While a single case cannot establish causality, we describe here an investigation of a 74-year-old male PWH with de novo high-grade neuroendocrine small cell lung carcinoma. To investigate the potential contribution of HIV to cancer development, we performed HIV integration site sequencing on blood, tumor, and non-tumor tissue samples from the patient. We analyzed integration site distribution, clonal expansion, and associated gene disruption. Phosphatase and Tensin Homolog (PTEN) expression was evaluated using immunofluorescence and microscopy. A total of 174 unique HIV integration sites were identified, with 29.9% (52/174) located in clonally expanded cells. The most frequent integration site in clonally expanded cells was within the PTEN gene, representing 4.2% to 16.7% of all HIV-infected cells across samples. PTEN expression was markedly reduced in tumor regions relative to non-tumor tissue. Areas positive for HIV p24 antigen showed minimal PTEN expression. These findings suggest that HIV integration into the PTEN gene, coupled with clonal expansion of HIV-infected cells, may impair anti-tumor immune responses and promote cancer progression in PWH. Full article

Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by rapid growth and early metastases. As a neuroendocrine tumour, SCLC is especially notorious for various paraneoplastic syndromes, one of which is a rare neurological syndrome called paraneoplastic limbic encephalitis (PLE) that manifests with amnestic cognitive impairment and seizures. Here, we describe a case of a 53-year-old female who presented with neuropsychiatric symptoms of delusions, hallucinations, and cognitive impairment that started months prior to being diagnosed with extensive-stage SCLC. With no previous neuropsychiatric history, this raised the question of whether her presentation was related to PLE rather than a primary psychiatric condition, as initially diagnosed. Her symptoms improved with chemotherapy and radiation treatment of the underlying cancer, favouring a paraneoplastic etiology. Overall, this case underscores the importance of considering paraneoplastic syndromes in patients presenting with new neuropsychiatric symptoms, as early recognition and treatment can improve prognosis. Full article

Background: Poorly differentiated neuroendocrine tumors of the pancreas (pd-PNETs) are very rare tumors. Differentiating primary pd-PNET from neuroendocrine carcinomas, which metastasize to the pancreas, can be difficult. We will refer to any neuroendocrine carcinoma with pancreatic metastasis as secondary pd-PNETs. This study evaluates the differences in incidence, clinical picture, outcomes, and treatment between primary and secondary pd-PNETs. Methods: A comprehensive search of the pd-PNET database was performed to gather data on incidence, race, age, gender, clinical picture, and outcomes for primary and secondary pd-PNETs. The emphasis was on small-cell lung cancer (SCLC) and Merkel cell carcinoma (MCC) due to their associations with secondary pd-PNET. Additional data from the PubMed database were analyzed, and 12 case reports of primary pd-PNETs were added for clinical characteristic analysis. Results: Primary and secondary pd-PNETs exhibit highly similar profiles in terms of age, gender, race, and clinical features. However, treatment strategies are significantly different. Primary pd-PNETs are managed with tumor resection and platinum-based chemotherapy. Primary tumors usually have poor prognosis, with a median survival of 12 months. Treatment for secondary pd-PNETs varies based on the primary tumor. The treatment strategy for metastatic MCC was changed to immune checkpoint inhibitors (ICIs), and survival improved. Tarlatamab also recently showed a good response in the management of SCLC. These findings highlight the need for accurate and timely diagnosis to provide correct treatment. Conclusions: Patients with primary and secondary pd-PNETs exhibit similar clinical presentations and epidemiological characteristics. However, when a poorly differentiated neuroendocrine pancreatic mass is identified, it is critical to exclude MCC or small-cell lung carcinoma metastasis, as treatments may be different and prognosis may also be different. Full article

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression, high metastatic potential, and limited therapeutic options. Lysine-specific demethylase 1 (LSD1) has been identified as a promising epigenetic target in SCLC. RG6016 (ORY-1001) is a selective LSD1 inhibitor currently under clinical investigation for its antitumor activity. In this study, publicly available RNA-Seq datasets from SCLC patient-derived xenograft (PDX) models treated with RG6016 were reanalyzed using bioinformatic approaches. Differential gene expression analysis was conducted to identify genes responsive to LSD1 inhibition. Candidate genes showing significant downregulation were further evaluated by molecular docking to assess their potential interaction with RG6016. The analysis identified a set of differentially expressed genes following RG6016 treatment, including notable downregulation of MYC, UCHL1, and TSPAN8. In silico molecular docking revealed favorable docking poses between RG6016 and the proteins encoded by these genes, suggesting potential direct or indirect targeting. These findings support a broader mechanism of action for RG6016 beyond its known interaction with LSD1. This study demonstrates that RG6016 may exert its antitumor effects through the modulation of additional molecular targets such as MYC, UCHL1, and TSPAN8 in SCLC. The combined bioinformatic and molecular docking analyses provide new insights into the potential multi-target profile of RG6016 and indicate the need for further experimental validation. Full article

Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies that consist of two major subtypes: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Glucagon-like peptide-1 receptor agonists (GLP-1Ra) have demonstrated favorable results in preclinical studies, but their impact on NEN outcomes remains unexplored. Methods: Using the TriNetX US Research Network, we identified adult patients with NEN and either diabetes or obesity. After 1:1 propensity score matching based on demographics, comorbidities, procedures, and medication use, we compared survival outcomes between patients who received GLP-1Ra after NEN diagnosis and those who did not. Results: Among 32,464 eligible patients, 3139 received GLP-1Ra and 29,325 did not. After propensity matching, each cohort included 3043 patients with well-balanced baseline characteristics. During follow-up periods extending up to 15 years, all-cause mortality occurred in 356 (11.7%) GLP-1Ra users versus 753 (24.7%) non-users, representing a 13.0% absolute risk reduction (p < 0.001). GLP-1Ra use was associated with significantly improved survival (HR = 0.56, 95%CI = 0.49–0.63, p < 0.001). Both well-differentiated (HR = 0.52) and poorly differentiated tumors (HR = 0.56) showed significant improvement. Among primary sites, lung NENs demonstrated the most pronounced benefit (HR = 0.42). Tirzepatide showed the strongest association with reduced mortality (HR = 0.16), followed by semaglutide (HR = 0.27) and dulaglutide (HR = 0.52). Results: In this large propensity-matched study, GLP-1Ra use was associated with a 44.3% reduction in mortality risk among NEN patients with diabetes or obesity. The magnitude of the observed benefit suggests a potential role for GLP-1Ra as adjunctive therapy in this patient population. Prospective clinical trials are warranted to confirm these findings and explore underlying mechanisms. Full article

Neuroendocrine neoplasms (NENs) comprise a group of tumours that can develop in various internal organs, but in this review, we will describe only those arising in the lungs, thyroid, and thymus. Pulmonary neuroendocrine neoplasms (pulmonary NENs) account for approximately 25% of all lung cancers. They are classified into four groups of tumours: typical carcinoids (TCs), atypical carcinoids (ACs), small cell lung carcinoma, and large cell lung carcinoma. This review focuses on TC and AC. The treatment consists mainly of radiotherapy, chemotherapy, and surgical resection, but novel drugs like atezolizumab are also utilised. The most common neuroendocrine neoplasm of the thyroid gland is medullary thyroid carcinoma (MTC), which commonly possesses RET protooncogene mutations. MTC is treated by a total thyroidectomy. Recently, tyrosine kinase inhibitors (TKIs) have emerged as an effective treatment option for patients with advanced MTC. Neuroendocrine tumours of the thymus (NETTs) are also being treated with a radical surgery. Full article

Background/Objectives: Lung neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors requiring accurate differentiation from non-small cell lung cancer (NSCLC) for effective treatment. Conventional computed tomography (CT) lacks pathognomonic features to distinguish these subtypes. Radiomics, which extracts quantitative imaging features, offers a potential solution. Methods: This retrospective multicenter study included 301 patients with histologically confirmed lung cancer who underwent native CT scans. The dataset comprised 150 NSCLC cases (75 adenocarcinomas, 75 squamous cell carcinomas) and 151 NENs (75 SCLC, 60 carcinoids, 16 large cell neuroendocrine carcinomas). Tumors were manually segmented, and 107 radiomics features were extracted. Dimensionality reduction and feature selection were performed using Pearson correlation analysis and LASSO regression. Decision tree and random forest classifiers were trained and evaluated using a 70:30 training–testing split. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1-score. Results: The model differentiating NENs from NSCLC achieved an AUC of 0.988 on the test set, with an accuracy of 97.8%. The model distinguishing SCLC from other NENs attained an AUC of 0.860 and an accuracy of 82.6%. First-order and textural radiomics features were key discriminators. Conclusions: Radiomics-based machine learning models demonstrated high diagnostic accuracy in differentiating lung NENs from NSCLC and in subclassifying NENs. These findings highlight the potential of radiomics as a non-invasive, quantitative tool for lung cancer diagnosis, warranting further validation in larger multicenter studies. Full article

Background/Objectives: Neuroendocrine tumors (NETs) can arise in any organ and are most commonly found in the lungs and gastroenteropancreatic (GEP) system. GEP-NETs represent a small percentage of gastrointestinal cancers, and therefore, the standard treatment is not well-defined, especially for advanced disease. Our objective is to review GI NETs among veterans and analyze their therapeutic outcomes. Methods: A total of 61 GI NET cases were identified from our institution from 2019–2024. In total, twenty-seven review papers, ten population-based/multicenter/outcome studies, six case reports, and one case series were reviewed for the literature review. Results: The incidence of GI NETs at our institution was higher than the known epidemiology of GI NETs. Small intestine NETs were one of the most common sites of GEP-NETs at our institution, with only one of nineteen cases being grade 3 poorly differentiated neuroendocrine carcinoma. All cases of colonic and rectal NETs had good clinical outcomes consistent with findings from the literature. Most of the gastric NETs were type 1 and had benign courses of disease, except for one case with an intermediate grade and metastatic liver lesions. One case of esophageal neuroendocrine carcinoma (E-NEC) showed a complete response to chemotherapy despite a significant tumor burden on presentation and high-grade pathology, while another case of ENEC had recurrent disease despite systemic therapy. Conclusions: While the role of surgery or endoscopic resection is limited to localized tumors, combined treatment with chemoradiation can significantly improve patient outcomes, especially in high-grade, poorly differentiated tumors. Further studies are needed to establish systemic (i.e., chemotherapy and radiation) treatment strategies for poorly differentiated GI NETs. Full article

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor. Lung cancer patients with ALK and EML4 fusions respond significantly to ALK inhibitors. The EML4-ALK fusion gene mutation is the result of an inversion of chromosome 2, which juxtaposes the 5 end of the EML4 gene with the 3 end of the ALK gene. In SCLC, the frequency of fusion genes is very low, and to the best of our knowledge, only four cases of ALK fusion gene mutations in SCLC have been reported. In this report, we describe the treatment of a 74-year-old female patient with SCLC who developed recurrence of hilar lymph node metastasis three years after surgical resection. Postoperative NGS showed that this patient is a SCLC patient harboring a rare EML4-ALK fusion mutation, and a satisfactory 43-month overall survival (OS) was achieved after treatment with ensartinib targeting the EML4-ALK fusion gene mutation. The ALK-TKI may be a new treatment option for these patients. This article provides a therapeutic reference. Full article

Objectives: While the treatment of non-small-cell lung carcinoma has improved rapidly, the treatment of pulmonary large-cell neuroendocrine carcinoma (LCNEC) remains underdeveloped. The use of immunohistochemistry allows for accurate risk stratification. With our study, we investigated the outcome of patients with pulmonary LCNEC and analyzed whether CK7 correlates with long-term survival. Methods: We retrospectively collected the monocentric data of patients which underwent anatomical resection for lung cancer between January 2012 and December 2020. Patients that did not show pulmonary LCNEC or adenocarcinoma, had a positive resection margin, or underwent neoadjuvant therapy were excluded. The long-term survival rate of the LCNEC and adenocarcinoma groups were compared before and after propensity score matching. Furthermore, we performed survival analyses for a subgroup of LCNEC distinguished by CK7 expression, followed by Cox regression analyses. Results: A total of 466 patients were integrated for further analysis. The mean age was 65.3 ± 9.6 years. There were no significant differences between both groups regarding age, gender, or comorbidities. In terms of the UICC stage, the groups were equally distributed. Mean survival in the LCNEC group was significantly worse than in the adenocarcinoma group (LCENC: 36.4 ± 7.5 months; adenocarcinoma: 80.7 ± 8.1 months; p-value = 0.001). The mean survival rate was 19.23 ± 4.8 months in the CK7 expression group and 57.01 ± 8.5 months in the group without expression, which reached statistical significance (p-value = 0.019). Conclusions: Our study suggests that pulmonary LCNEC has a significantly worse prognosis than pulmonary adenocarcinoma. CK7 expression seems to be correlated with a worse outcome for the long-term survival rate of patients suffering from highly malignant pulmonary LCNEC. Full article

Lung cancer is the leading cause of cancer-related deaths worldwide, highlighting a major clinical challenge. Lung cancer is broadly classified into two histologically distinct subtypes, termed small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Identification of various oncogenic drivers of NSCLC has facilitated the development of targeted therapies that have dramatically improved patient outcomes. However, acquired resistance to these targeted therapies is common, which ultimately results in patient relapse. Several on-target and off-target resistance mechanisms have been described for targeted therapies in NSCLC. One common off-target mechanism of resistance to these therapies is histological transformation of the initial NSCLC into SCLC, a highly aggressive form of lung cancer that exhibits neuroendocrine histology. This mechanism of resistance presents a significant clinical challenge, since there are very few treatments available for these relapsed patients. Although the phenomenon of NSCLC-to-SCLC transformation was described almost 20 years ago, only recently have we begun to understand the mechanisms underlying this therapy-driven response. These recent discoveries will be key to identifying novel biomarkers and therapeutic strategies to improve outcomes of patients that undergo NSCLC-to-SCLC transformation. Here, we highlight these recent advances and discuss the potential therapeutic strategies that they have uncovered to target this mechanism of resistance. Full article

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum–etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes. Full article

Background: Pancreatic cancer is among the malignancies with the poorest prognosis, largely due to its aggressive nature and resistance to conventional therapies. Case Summary: This report describes the case of a 69-year-old male patient with stage IV primary lung adenocarcinoma presenting with high levels of programmed death-ligand 1 (PD-L1). Simultaneously, abdominal computed tomography (CT) showed a dilated pancreatic duct at the level of the pancreatic head and a hypodense lesion in the uncinate process involving the superior mesenteric artery. Fine-needle aspiration (FNA) of the pancreatic lesions was negative. After three cycles of chemoimmunotherapy, positron emission tomography–computed tomography (PET-CT) showed complete remission of the lung nodules, lymphadenopathy, and pleural thickening, as well as a decrease in the size of the pancreatic lesion. After another six months, a PET-CT scan showed a focal increased uptake in the pancreatic mass in the same location, indicating disease progression. A core biopsy of the pancreatic tumor showed atypical spindle cell morphology with positive staining for vimentin, characteristic of mesenchymal differentiation with no apparent epithelial features. Comprehensive molecular profiling through Caris Molecular Intelligence^® revealed four genes with actionable mutations in the pancreatic tissue, including KRAS (p.G12D) and TP53 (p.R175H). These molecular findings suggested the diagnoses of sarcomatoid carcinoma and conventional pancreatic ductal adenocarcinoma with epithelial–mesenchymal transition. Primary mesenchymal tumors and neuroendocrine neoplasms were excluded because immunohistochemistry was negative for anaplastic lymphoma kinase (ALK), smooth muscle actin (SMA), desmin, CD34, signal transducer and activator of transcription 6 (STAT6), S100, HMB45, CD117, discovered on GIST-1 (DOG1), CD56, progesterone, and synaptophysin. However, despite multiple rounds of systemic chemotherapy, immunotherapy, and radiation, his pancreatic disease rapidly deteriorated and metastasized to the liver and bone. Conclusions: Despite multiple lines of treatment, the patient’s condition worsened and he succumbed to his pancreatic malignancy. This study highlights the clinical characteristics, diagnosis, and treatment of rare pancreatic cancer, emphasizing the importance of molecular testing and histopathological biomarkers in personalizing treatment. It also provides insights into promising therapeutic approaches for similar cases with an unusual presentation. Full article