Small Cell Carcinoma Research Articles

Abstract 4590: Clinicopathological analysis of pulmonary high-grade neuroendocrine carcinoma with high expression of hepatocyte nuclear factor 4 alpha

Abstract Pulmonary high-grade neuroendocrine carcinomas (HGNECs), including small cell carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs), are highly aggressive and have a poor prognosis. The molecular subtyping of HGNECs has recently attracted attention, and Wang et al. recently proposed a cross-tissue classification framework of NECs, including the hepatocellular nuclear factor 4 alpha (HNF4A) subtype [Cancer Cell, 2024]. HNF4α, a transcription factor associated with gastrointestinal differentiation, and TTF-1 are mutually and exclusively expressed in lung adenocarcinomas; however, the characteristics of HNF4α-high HGNECs and TTF-1-high HGNECs have yet to be compared. We immunohistochemically examined the characteristics of HNF4α-high HGNECs in 83 surgically resected specimens (37 SCLCs and 46 LCNECs) and revealed that HNF4α-high and TTF-1-high HGNECs accounted for 15% (12/83) and 47% (39/83), respectively. Regarding morphology of HNF4α-high HGNECs, HNF4α-high SCLCs had a slightly more abundant cytoplasm and more obscured nuclear molding than HNF4α-low SCLCs, while HNF4α-high LCNECs were characterized by a coarse nuclear chromatin pattern and prominent nuclear atypia. The cytomorphological score referred to the previous study [Jimbo, Am J Surg Pathol. 2024] was significantly higher for HNF4α-high HGNECs than for HNF4α-low HGNECs (p<0.01). In SCLCs, HNF4α-high cases (n=3) and TTF-1-high cases (n=20) were almost confined to the neuroendocrine phenotype with high ASCL1 expression, and the expressions of HNF4α, TTF-1, and POU2F3 were mutually exclusive. Similar results were obtained for LCNECs; however, some HNF4α-high cases were positive for TTF-1 or YAP1, possibly due to the heterogeneity of LCNECs. Therefore, we investigated the heterogeneity of LCNECs and performed a spatial transcriptome analysis of one HNF4α-high LCNEC case, which revealed a mutually exclusive mixture of different subgroups characterized by HNF4A and TTF-1 expression. A whole-genome analysis of 10 LCNECs showed that NFE2L2/KEAP1 mutations were characteristic of HNF4α-positive LCNECs. A prognostic analysis revealed a significantly poorer prognosis in HNF4α-high LCNECs compared to HNF4α-low LCNECs (p<0.01). A cell line analysis showed that TTF-1-high-expressing (H446/Lu139/H889/H510A) and HNF4α-high-expressing (VMRC-LCD) lines were consistent with ASCL1-high-expressing lines. HNF4α knockdown/knock-in experiments in VMRC-LCD and SBC5 (HNF4α-negative) revealed that HNF4α promoted cell proliferation by inhibiting apoptosis. HNF4α subtype HGNECs are a unique subtype, belonging to a neuroendocrine phenotype with high ASCL1 expression and showing mutual exclusivity with the TTF-1/POU2F3 subtypes. NFE2L2/KEAP1 mutations and HNF4α itself are potential therapeutic targets for this subtype. Citation Format: Kei Asayama, Ryota Matsuoka, Aya Shiba, Daisuke Matsubara. Clinicopathological analysis of pulmonary high-grade neuroendocrine carcinoma with high expression of hepatocyte nuclear factor 4 alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4590.

Abstract 7250: Extracellular acidity in the TME interferes with the IFN-γ induction of the immunoproteasome

Abstract The immunoproteasome (IP) is a component of the MHC class I presentation pathway (MHC1PP) that is induced by IFN-γ, functions to augment the immunogenicity of cancer cells by generating optimal tumor antigens from polypeptide precursors, and is correlated with favorable responses to immunotherapy. Understanding tumor intrinsic factors that regulate the IP in cancer is essential for addressing immunologically cold tumors which respond poorly to immunotherapy. Extracellular acidity (pH 6.5) is a hallmark of solid tumors and despite being shown to impair CD8+ anti-tumor immunity, remains understudied as a driver of immune-evasion in cancer. Here, we present data that extracellular acidity in vitro can restrict the induction of the catalytically active subunits of the IP, in particular 20s proteasome subunit beta type 9 (β1i) and 20s proteasome subunit beta type 10 (β2i). Various human and murine cancer cell lines (Human: pancreatic ductal adenocarcinoma PANC1, hepatocellular carcinoma HEPG2, non small cell carcinoma A549; Murine: non small cell carcinoma LLC) were cultured in control media (DMEM pH 7.4) versus acidic media (DMEM pH 6.5) and stimulated with IFN-γ to induce the IP. Cell lysates were assessed by Western blot and demonstrated a sharp reduction in the protein induction of β1i and β2i, which are both required for the formation of the mature IP, under acidic conditions compared to controls. RT-PCR analysis of A549 cells indicates that these proteins are blocked transcriptionally as well as translationally. Mechanistically, we demonstrate via Western blot that activation of signal transducer and activator of transcription 1 (STAT1), the critical transcription factor required for IFN-γ induction of the IP, is delayed in acidic conditions compared to controls. We further show that signal transducer and activator of transcription 3 (STAT3), a pro-tumorigenic transcription factor and antagonist of STAT1 transcriptional activity, is activated under acidic conditions in A549 cells and furthermore IFN-γ enhances this STAT3 activation but only under acidic conditions. Functionally, we show via flow cytometry that downstream of the blockade in IP subunit induction that occurs under acidic conditions, surface MHC I expression is diminished. Overall, these studies indicate extracellular acidity in the TME restricts the induction of IP components potentially through a STAT3 dependent mechanism, suggesting that targeting STAT3 activation in acidic tumors may improve tumor immunogenicity and responses to immunotherapy. Citation Format: Matthew G. Smith, Alexis Ramos, Heena Panchal, Adam Mailloux. Extracellular acidity in the TME interferes with the IFN-γ induction of the immunoproteasome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7250.

Abstract 2263: DNA methylation-estimated C-reactive protein levels and lung cancer risk and mortality in individuals with a heavy smoking history

Abstract Inflammation, a hallmark of cancer and chronic disease, is an established risk factor for lung cancer and is also associated with worse survival in lung cancer cases. C-reactive protein (CRP) is one circulating biomarker of inflammation that has been shown to be associated with DNA methylation (DNAm) in epigenome-wide association studies (EWAS). Several epigenetic CRP scores have been proposed using results from these studies, offering the unique opportunity to approximate CRP in studies without directly measured CRP. A validated DNAm CRP score was recently published by Hillary et al., which explains 18% of CRP variation beyond age, sex, and CRP-based genotype. This score, mCRP, includes 1,468 CpGs obtained from elastic net regression on EWAS results for measured CRP in a training set of nearly 18k individuals. Using an additive linear combination of the published CpGs and EWAS regression weights, we estimated pre-diagnosis mCRP in individuals with a heavy smoking history from the β-Carotene and Retinol Efficacy Trial (CARET) and assessed associations with both lung cancer risk and mortality for all cases and by histotype. Analytic samples included: 316 lung cancer case-control pairs through 2005, matched on age (±5 years), sex, race and ethnicity, enrollment year (±2 years), smoking status (ever/never), asbestos exposure, and follow-up time, (mean 57 pack years, range 11-185) for risk; and 372 lung cancer cases diagnosed through 2013 (mean 59 pack years, range 20-162) for mortality. DNAm data was assayed on the Illumina EPIC array in blood collected on average 4.3 years before diagnosis in cases for risk and 4.9 years for mortality. Conditional logistic regression models adjusted for age and pack years revealed no strong evidence of increased lung cancer risk with increasing mCRP. Cox proportional hazards models adjusted for age, sex, smoking status (current/former), pack years, and time from blood draw to diagnosis with stage as a stratification variable (early I/II, advanced III/IV, unknown) showed a greater hazard of death per standard deviation increase in mCRP among all lung cancer cases (Hazard Ratio (HR) 1.13, CI: 1.02-1.25), adenocarcinoma (HR 1.21, CI: 1.02-1.43), and small cell carcinoma (SCLC; HR 1.33, CI: 1.06-1.68). No associations were observed for squamous cell carcinoma, and results were similar for lung cancer-specific mortality among each case group. While these results do not provide support that pre-diagnosis mCRP is associated with lung cancer risk in individuals with a heavy smoking history, we observed that greater pre-diagnosis mCRP may be an indicator of mortality in members of this population. This work highlights the possible importance of pre-diagnosis inflammation via mCRP and mortality in heavy smokers who later develop lung cancer, particularly adenocarcinoma and SCLC. Citation Format: Laurie Grieshober, Stefan Graw, Matt J. Barnett, Gary E. Goodman, Chu Chen, Devin C. Koestler, Carmen J. Marsit, Jennifer A. Doherty. DNA methylation-estimated C-reactive protein levels and lung cancer risk and mortality in individuals with a heavy smoking history [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2263.

Abstract 1911: Platform agnostic lung cancer plasma signature identified using multidimensional proteomics and explainable machine learning

Introduction: Lung cancer is the leading cause of cancer mortality worldwide with 70% diagnosed at the late stage. Low-dose CT (LDCT) is available for screening but its uptake remains low. A blood test providing a molecular signature that identifies those at highest risk of lung cancer can integrate with existing screening pathways to increase uptake and enable earlier detection. The blood proteome harbors promising information for minimally invasive biomarker discovery especially for early stage and low tumor-burden lung cancer with limited circulating tumor DNAs. Methods: We combined data-independent acquisition mass spectrometry (MS) as an unbiased approach with a targeted proximity extension assay (PEA, Olink) for biomarker discovery in 614 patients: 490 lung cancer (180 stage I/II, 310 stage III/IV, all major histologies) and 124 matched control (from a LDCT screening program) plasma samples collected under standardized protocol (PMCC, Toronto, 2008-2019). To identify a lung cancer molecular signature, we used a 80/20% discovery/holdout testing approach and incorporated explainability in a tailored machine learning (ML) platform (iScience, 2023) to provide ranking and rationale for feature selection decision making. Finally, aptamer based proteomic profiling (SomaScan) validated a focused molecular signature panel. Results: In total 5,403 distinct protein groups were identified, 3,655 by MS, 2,884 by PEA, with 1,136 overlapping. Both approaches identified proteins significantly enriched for inflammation, chemotaxis/migration, humoral immune response, and complement activation in lung cancer. MS identified additional proteins distinctly enriched for epithelial cell migration and ROS metabolism. ML directed feature selection identified focused panels of 17 and 20 proteins from MS and PEA datasets, each achieving 92% and 98% area under the ROC curve (AUC) respectively in hold-out validation, demonstrating sensitivity/specificity for overall lung cancer detection at 88/90% and 94/90% using ≤20 biomarkers. Importantly, each panel accurately detects early stage, late stage, small cell, adenocarcinoma, and squamous cell carcinoma of the lung, with AUCs of 88%-98% (MS) and 95%-99% (PEA) for each subtype. Further evaluation of the signatures using an aptamer platform confirmed a biomarker panel with strong concordance across the three distinct proteomic approaches, creating a platform agnostic lung cancer plasma signature for disease detection. Conclusion: We identified a platform agnostic plasma molecular signature for lung cancer using three distinct proteomic approaches and explainable ML. This molecular signature can be highly scalable across different protein detection platforms, with prospective studies underway to assess its impact enhancing existing screening programs, enabling earlier detection, and improving survivorship. Citation Format: Peter Jianrui Liu, Harriet R. Ferguson, Luke Hankey, Honglei Huang, Junetha Syed, Iliyana Kaneva, Ella Mi, Daniel A. Szulc, Luna Jia Zhan, Devalben Patel, Ming-Sound Tsao, Roman Fischer, Benedikt M. Kessler, Geoffrey Liu, Nikola I. Gushterov, Andreas J. Halner. Platform agnostic lung cancer plasma signature identified using multidimensional proteomics and explainable machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1911.

Harnessing single-cell and multi-omics insights: STING pathway-based predictive signature for immunotherapy response in lung adenocarcinoma

BackgroundLung adenocarcinoma is the most prevalent type of small-cell carcinoma, with a poor prognosis. For advanced-stage patients, the efficacy of immunotherapy is suboptimal. The STING signaling pathway plays a pivotal role in the immunotherapy of lung adenocarcinoma; therefore, further investigation into the relationship between the STING pathway and lung adenocarcinoma is warranted.MethodsWe conducted a comprehensive analysis integrating single-cell RNA sequencing (scRNA-seq) data with bulk transcriptomic profiles from public databases (GEO, TCGA). STING pathway-related genes were identified through Genecard database. Advanced bioinformatics analyses using R packages (Seurat, CellChat) revealed transcriptomic heterogeneity, intercellular communication networks, and immune landscape characteristics. We developed a STING pathway-related signature (STINGsig) using 101 machine learning frameworks. The functional significance of ERRFI1, a key component of STINGsig, was validated through mouse models and multicolor flow cytometry, particularly examining its role in enhancing antitumor immunity and potential synergy with α-PD1 therapy.ResultsOur single-cell analysis identified and characterized 15 distinct cell populations, including epithelial cells, macrophages, fibroblasts, T cells, B cells, and endothelial cells, each with unique marker gene profiles. STING pathway activity scoring revealed elevated activation in neutrophils, epithelial cells, B cells, and T cells, contrasting with lower activity in inflammatory macrophages. Cell-cell communication analysis demonstrated enhanced interaction networks in high-STING-score cells, particularly evident in fibroblasts and endothelial cells. The developed STINGsig showed robust prognostic value and revealed distinct immune microenvironment characteristics between risk groups. Notably, ERRFI1 knockdown experiments confirmed its significant role in modulating antitumor immunity and enhancing α-PD1 therapy response.ConclusionThe STING-related pathway exhibited distinct expression levels across 15 cell populations, with high-score cells showing enhanced tumor-promoting pathways, active immune interactions, and enrichment in fibroblasts and IFI27+ inflammatory macrophages. In contrast, low-score cells were associated with epithelial phenotypes and reduced immune activity. We developed a robust STING pathway-related signature (STINGsig), which identified key prognostic genes and was linked to the immune microenvironment. Through in vivo experiments, we confirmed that knockdown of ERRFI1, a critical gene within the STINGsig, significantly enhances antitumor immunity and synergizes with α-PD1 therapy in a lung cancer model, underscoring its therapeutic potential in modulating immune responses.

A Case of Small Cell Carcinoma of Bladder With Significant Tumor Reduction Following Combination Chemotherapy and Radiation Therapy

A Case of Small Cell Carcinoma of Bladder With Significant Tumor Reduction Following Combination Chemotherapy and Radiation Therapy

Clinicopathological characteristics,prognosis and related factors of lung cancer arising in the native lung following single lung transplantation

Objective: To explore the clinicopathological characteristics and prognosis of lung cancer arising in the native lung after single lung transplantation for end-stage lung disease. Methods: We conducted a respective analysis of the clinical, pathological, and follow-up data of 12 recipients who developed lung cancer in the native lung after single-lung transplantation at China-Japan Friendship Hospital from September 2017 to June 2021, among a total of 247 single-lung transplantations performed during this period. Eleven were male and 1 was female, with ages ranging from 46-67 (59.25±5.75) years. Results: Of the 12 recipients, 11 had a smoking history before transplantation. The underlying diagnosis of lung diseases before transplantation included 8 cases of idiopathic pulmonary fibrosis, 3 cases of connective tissue disease-associated interstitial lung disease, and 1 case of chronic obstructive pulmonary disease. The time interval from transplantation to the development of lung cancer in the native lung was 3 to 53 months, with an average of (30.0±16.2) months. Eleven patients had elevated levels of serum tumor markers at the time of lung cancer diagnosis. CT/PET-CT showed new nodules or FDG avidity in the native lung. The histological types of lung cancer in the 12 cases included 1 case of small cell carcinoma and 11 cases of non-small cell lung cancer (7 cases of squamous cell carcinoma, 3 cases of adenocarcinoma, and 1 case of SMARCA4-deficient undifferentiated carcinoma). There were 8 cases in clinical stage Ⅳ, 1 case in stage Ⅲ, and 3 cases in stageⅠ. Three patients in stage Ⅰ and one patient in stage Ⅲ underwent surgical treatment, while patients in stage Ⅳ were treated with radiotherapy, chemotherapy, and palliative care. At the end of this study, 10 patients had died, 1 patient survived, and 1 patient was lost to follow-up. The median survival time was 7 months (ranging from 2 to 47 months), and the 1-year cumulative survival rate was 9.2%. Conclusions: The risk of developing lung cancer in the native lung after single lung transplantation is increased. The prognosis is very poor. Most of the histological types are squamous cell carcinoma. Close monitoring of high-risk populations after transplantation for early tumor detection may prolong survival time.

Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type

PurposeSmall cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal cancer lacking effective treatment. Its genomic mutations and tumor microenvironment need further exploration.MethodsWe performed whole-exome sequencing or gene panel test to explore the SMARCA4 mutation spectrum in SCCOHT (15 samples). Single-cell RNA sequencing was conducted on one primary lesion with matched normal ovarian tissue and one recurrent lesion to investigate the intra-tumoral heterogeneity and immune microenvironment. Multiplex immunofluorescence staining validated T cell infiltration and PD-1 expression.Results13/15 (86.7%) patients harbored SMARCA4 mutations. The loss of heterozygosity (LOH) occurred in 10/15 (66.7%) patients. Cancer cells and immune cells were observed in SCCOHT tumors. Cancer cells were further divided into seven subtypes and one from recurrent lesion exhibited the highest stemness accompanied by high expression of genes related to cell mitosis (AURKB, CHEK2, CCNB1, WEE1), DNA repair (BRCA1, RAD51) and epigenetic (EZH2, DNMT1). Immune cells mainly included macrophages and T cells. Lipid-associated tumor-associated macrophages (TAMs) was mainly in primary lesion while inflammatory cytokine-enriched TAMs in recurrent lesion. CD4+/ CD8+ T cell infiltration was observed in SCCOHT tumor and a certain proportion of T cells expressed PD-1.ConclusionsSCCOHT exhibits universal SMARCA4 LOH and significant intra-tumoral heterogeneity, suggesting potential therapeutic targets, including CHEK2, CCNB1, and WEE1. Exhausted T cells and distinct TAM subsets infiltrate tumors. Targeting macrophage polarization or cytokine signaling may also be promising. These findings provide insights for developing novel therapies to improve outcomes in SCCOHT.Clinical trial numberNot applicable.

Molecular pathology in non-small-cell lung cancer: current and emerging biomarkers

In the classification of lung cancer, the basic division into small cell and non-small cell carcinomas continues to apply. Despite the same histological subtyping, it is known that there are defined genetic changes in the tumor cells that significantly determine tumor growth as "drivers", so that their blockade can significantly influence the clinical course. Thus, in the last 10years, the treatment of lung cancer has been increasingly supplemented by the establishment of tumor-specific targeted drugs and immunomodulatory approaches. This development has led to increasingly differentiated and individualized approaches to treatment. Pathology and especially molecular pathological diagnostics play acentral role here, as an increasing number of biomarkers must be examined.

Clinicopathologic features of histologic transformation in lung adenocarcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitors.

Clinicopathologic features of histologic transformation in lung adenocarcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitors.

Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared With Urothelial Carcinoma and Small Cell Lung Carcinoma.

Small cell bladder cancer (SCBC) is a rare histologic variant of bladder cancer with an aggressive disease course and poor outcomes. Given its uncommon nature, there is a paucity of high-quality data characterizing genomic drivers of this disease, and most patients are treated with approaches mirroring small cell lung cancer (SCLC). Leveraging the Tempus Lens deidentified clinically annotated genomic data set, we sought to evaluate the mutational landscape of SCBC relative to urothelial carcinoma (UC) and SCLC. Somatic pathogenic genomic alterations in patients with SCBC, UC, and SCLC of any stage who underwent blood- or tissue-based genomic profiling through the Tempus assay were cataloged. Baseline clinical and demographic features were compared across histologic groups. Alterations were collated and summarized using descriptive statistics. Pairwise comparisons were performed to assess differences in mutation frequency across pathologic cohorts. In total, 149 SCBC, 4,350 UC, and 1,697 SCLC patients were included in the study. The most common genomic alterations in SCBC were in TP53 (87%), TERT (75%), and RB1 (70%). Among SCBC patients with TP53 mutations, RB1 comutations were observed in 77% of patients. Compared with UC, SCBC patients were significantly enriched for TP53, RB1, KMT2D, and KDM6A mutations. Compared with SCLC, SCBC patients were enriched for TERT, ARID1A, and CREBBP mutations, among others (P < .05). Multiple clinically targetable mutations were observed in SCBC, including PIK3CA (19%), ERBB2/3 (13%), and ALK (10%). Limitations of this study include its retrospective nature. This study represents one of the most extensive efforts to characterize SCBC to date, providing a novel understanding of the genomic alterations underlying the disease and revealing actionable mutations that could serve as potential targets for improved clinical outcomes.

Clinical features and prognosis of small cell carcinoma of the bladder: a single center retrospective analysis.

Small cell carcinoma of the bladder (SCCB) is a rare and aggressive subtype, usually diagnosed at advanced stages. Due to its rarity, the clinical features, prognostic factors, and treatment strategies are not well defined, and data on long-term outcomes are limited. This study aims to analyze the clinical characteristics, treatment options, and prognostic factors of SCCB to enhance clinical understanding and guide practice. A retrospective analysis of 41 SCCB cases treated at Changhai Hospital between 2006 and 2023 was conducted. Clinical, pathological, and treatment data were collected. The median follow-up duration was calculated as 41.0 months [95% confidence interval (CI): 31.3-50.7] using the reverse Kaplan-Meier method. Overall survival (OS) rates were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were used to identify prognostic factors. The median age was 71 years (range, 41-89 years). Pure SCCB accounted for 56.1% of cases, and 48.78% of tumors were located on the lateral bladder wall. Tumors ≥4 cm were found in 56.10% of cases. According to the tumor-node-metastasis (TNM) classification, 63.41% of patients underwent radical cystectomy, and 34.14% had lymph node or distant metastasis. None of the patients received neoadjuvant chemotherapy (NACT), while 41.03% underwent adjuvant chemotherapy post-surgery. The median OS was 30 months, with 1- and 3-year OS rates of 74.8% and 41.4%, respectively. Univariate analysis showed that T stage (P=0.002), lymph node metastasis (P<0.001), and distant metastasis (P<0.001) were associated with poor prognosis. Multivariate analysis confirmed T stage (P=0.04) and distant metastasis (P<0.001) as independent prognostic factors. SCCB is often diagnosed at a late stage with gross hematuria as the most common symptom, Neoadjuvant therapy and immunotherapy can extend OS. T stage and distant metastasis are critical prognostic factors. Early diagnosis and intervention are crucial for improving outcomes.

Sex specific familial risk in lung cancer through changing histologies in Sweden.

Familial clustering of lung cancer (LC) is related to shared smoking habits but the contribution of other potential factors such as sex or histology is not well known, and these are the subjects of the present study in Sweden. Family relationships (from Multigeneration register) and diagnosed cancers (from Cancer registry) were obtained from the national registers from 1961 to 2021. The overall familial risk for LC was constant from the 1990s but the male familial risk decreased while the female familial risk doubled at the same time when female incidence doubled. The female familial risk for mother-daughter pairs was higher (SIR = 2.2 [2.0-2.3], N = 716) than for father-son pairs (SIR = 1.6 [1.5-1.8], N = 962). The histology-specific familial risks for adenocarcinoma, squamous cell carcinoma, small cell and large cell carcinoma were highest for concordant histology but also present for discordant histology. The number of family members diagnosed with LC was a strong determinant of familial risk. The novel results showed that familial risk of LC depends on the background incidence of LC and is higher for women compared to men. We demonstrated further an increased familial risk for each of the four histological types of LC which was higher for concordant than discordant histologies but was even detected between discordant histologies suggesting that LC histology is not a genetic trait.

Clinical Significance of Different Histology and High-Risk HPV Types in Neuroendocrine Carcinomas of the Cervix.

This study aimed to investigate the impact of different histologic and high-risk (HR) human papillomavirus (HPV) types on the clinicopathologic characteristics and survival of patients with neuroendocrine carcinoma of the cervix (NEC). We retrospectively reviewed the medical records of patients with NEC diagnosed and treated at the Seoul National University Hospital between January 2000 and December 2021. Two pathologists specializing in gynecologic oncology thoroughly examined the slides. To determine the type of HPV infection, microarray analysis and next-generation sequencing were conducted. In addition, the impact of several variables on progressoin-free survival (PFS) and overall survival (OS) was investigated. In total, 47 patients with NEC were included in this analysis. Small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) were identified in 36 (76.6%) and 11 (23.4%) patients, respectively. Whereas 31 (66.0%) patients had a pure NEC, 16 (34.0%) were diagnosed with a mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN). Of the 32 NEC patients whose HPV infection status was confirmed, HR-HPV infection was found in 30 of them (93.8%). Nineteen patients were infected with HPV 18. Between patients infected with HPV 16 or 18 and HR-HPV other than 16 or 18, there was no significant difference in most clinicopathologic characteristics such as histology (P=0.311). However, HR-HPV type other than 16 or 18 was associated with pelvic lymph node metastasis (P=0.044) and advanced stage (P=0.035). In the Kaplan-Meier analysis and the Cox regression analyses, no significant difference in PFS and OS was observed between LCNEC and SCNEC, pure NEC and MiNEN, and HPV 16 or 18 and HR-HPV other than 16 or 18. High-risk HPV infection, especially from HPV 18, might play a role and impact on NEC pathogenesis. In this study, we did not find evidence that diverse histology and HR-HPV types affect PFS and OS.

A phase II study of lurbinectedin with or without avelumab in small cell carcinoma of the bladder (laser)-design and rationale.

Small cell carcinoma of the bladder is a rare, aggressive malignancy accounting for less than 1% of all bladder malignancies. Treatment regimens are drawn from the small cell lung cancer (SCLC) literature, with platinum and etoposide commonly used in the first-line setting. Unfortunately, responses are generally short-lived, and most patients relapse. There is little evidence to guide selection of later lines of therapy. Lurbinectedin is an alkylating agent with accelerated US FDA approval for use in patients with SCLC. Immune checkpoint inhibitors have also been approved for SCLC, improving survival when added to chemotherapy. This article describes the design and rationale behind LASER, an open-label phase II trial of lurbinectedin with or without avelumab.Clinical trial registration: NCT06228066 (ClinicalTrial.gov).

The synergistic antitumour effect of Carrimycin combined with 5-fluorouracil on colorectal cancer

5-Fluorouracil (5-FU)-based chemotherapy often leads to drug resistance and adverse reactions in individuals with colorectal cancer (CRC). Carrimycin (CAM), a drug with notable antitumour effects across various tumour types, including hepatocellular carcinoma, glioblastoma, and small-cell lung carcinoma, offers an alternative owing to its limited side effects. Combination therapy is a common strategy to mitigate the negative effects of 5-FU and enhance its therapeutic efficacy. This study aimed to investigate the potential synergistic antitumour effects of CAM and 5-FU on HCT-15 and HT-29 CRC cell lines. Using computational analysis, we identified and quantified the synergistic effects of CAM and 5-FU. The combination therapy significantly outperformed 5-FU alone in inhibiting cell proliferation, colony formation, cell cycle progression, and migration. Additionally, it markedly increased the levels of reactive oxygen species and induced DNA damage. Furthermore, RNA-seq analysis revealed that the JNK and p38 MAPK signalling pathways were activated by this combination. In addition, the synergistic effects of the combination therapy were validated in a mouse subcutaneous tumour graft model. In conclusion, CAM enhances the sensitivity of CRC cells to 5-FU both in vitro and in vivo, suggesting its potential as a promising candidate for combination cancer therapy.

Machine learning prediction of overall survival in prostate adenocarcinoma using ensemble techniques.

Machine learning prediction of overall survival in prostate adenocarcinoma using ensemble techniques.

Favorable trends in lung cancer incidence with unfavorable survival prognosis: A spatiotemporal analysis by histology in Córdoba, Argentina.

Favorable trends in lung cancer incidence with unfavorable survival prognosis: A spatiotemporal analysis by histology in Córdoba, Argentina.

Oopherectomy in a Child to Reduce Cancer Risk: Oncogenetic, Ethical, andLegal Considerations.

In the following case, we will discuss the clinical, ethical, and legal intricacies associated with the management of a young child with a hereditary cancer predisposition syndrome. Patients with germline pathogenic variants in SMARCA4 are at an increased risk for development of small cell carcinoma of the ovary-hypercalcemic type, malignant rhabdoid tumors, and some lung cancers. This case highlights the complexity of a case wherein a mother is found to have this genetic syndrome, and further testing reveals her daughter to have the same pathogenic variant. Through this case, we explore the oncologic, genetic, legal, and ethical considerations at play when making an irreversible decision for a child that affects her current and future medical and reproductive capacities. To do so would mitigate the risk of future malignancy, adding a layer of legal and ethical complexity. Although each contributor individually concludes that surgery in this case should be delayed, this case demonstrates the need for an individualized approach that considers medical evidence, patient and family interests, and child welfare.

INSIGHTS INTO PRIMARY BREAST ENDOCRINE CARCINOMA: A CASE STUDY

A 75-year-old woman with a medical history of hypothyroidism presented to the triple-assessment breast clinic with a 2-week history of a right-sided breast lump, no history of pain or nipple discharge, and no significant family history of breast cancer. Her clinical examination revealed 4 x 4 cm of hard, nonmobile right upper outer quadrant (10 o'clock) breast mass with multiple enlarged right axillary lymph nodes. No evidence of skin or underlying muscle involvement. No nipple discharge was noted. Her radiological assessment with mammogram and ultrasound showed two suspicious masses occupying the right upper outer and central outer breast, one at 9 o'clock and the second at 11-12 o'clock (the largest), with suspicious pleomorphic microcalcification in the mammogram. Multiple significant axillary lymphadenopathies are also detected. An ultrasound-guided core biopsy was performed, and the histopathology was in favor of a triple negative neuroendocrine carcinoma in keeping with small cell carcinoma with axillary metastasis. An extensive workup was done for the patient to detect distant metastasis (PET/CT scan) versus other primary tumors. Her PET scan demonstrated a multicenteric breast tumor with uptake in the splenic flexure; therefore, gastrocolposcopy was performed and showed adenoma with low-grade dysplasia on final histopathology. The tumor was staged as cT2N2M0. The patient started on neoadjuvant chemotherapy, and on further follow-up, the tumor size had regressed completely, and the patient will be scheduled for surgery upon finishing her chemotherapy.