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Background: Usage of immune checkpoint inhibitors (ICIs) has prolonged the overall survival (OS) of patients with extensive‐stage small‐cell lung cancer (ES‐SCLC). In clinical trials, males accounted for a large proportion, leading to the uncertainty of its efficacy in female patients. We therefore conducted this study to explore the efficacy and safety of using ICIs in female patients with ES‐SCLC. Methods: We retrospectively enrolled female SCLC patients and subdivided them into two groups. Group A (n = 40) was defined as ES‐SCLC patients who received first‐line standard chemotherapy with or without ICIs. Group B (n = 47) included relapsed SCLC patients who were administered with second‐line therapies. Kaplan–Meier methodology was used to calculate survival analysis. Chi‐squared tests were used to analyze the incidence of adverse events (AEs). Results: Median progression‐free survival (PFS) and median OS favored the ICI‐contained cohorts (Group A PFS: 8.3 vs. 6.1 months; OS: not reached vs. 11.3 months; Group B PFS: 15.1 vs. 3.3 months; OS: 35.3 vs. 8.3 months), especially in those patients who received second‐line immunotherapies. Patients who received immunotherapy had a slightly higher incidence rate of grade ≥3 AEs (Group A: 71.4% vs. 46.2%; Group B: 44.5% vs. 13.2%). Those who developed grade ≥3 AEs in first‐line ICIs cohort had a more favorable survival (PFS: 8.3 vs. 3.2 months; OS: not reached vs. 5.1 months). Conclusions: Our study suggested that female ES‐SCLC patients treated with immunotherapy tended to achieve a relatively longer survival. The incidence of AEs (grade ≥3) was higher in women patients receiving ICIs, which requires monitoring more closely. [ABSTRACT FROM AUTHOR]

This article presents several cases of rare tumors and their clinical and pathological characteristics. The first case discusses a highly aggressive tumor called sinonasal teratocarcinosarcoma, which can be difficult to diagnose due to its morphological heterogeneity. The second case focuses on oncocytic lesions in the salivary glands, highlighting the challenges in distinguishing them from other conditions. The third case examines papillary thyroid carcinoma arising within a branchial cleft cyst, emphasizing the need for further investigation. The fourth case explores an unusual presentation of hepatocellular carcinoma as an intraoral mass. Additionally, the article discusses IgG4-related disease in the head and neck region, emphasizing the importance of accurate diagnosis based on histological features, radiology, and serum IgG4 levels. [Extracted from the article]

Human papillomavirus (HPV) is a major cause of cervical cancer. As the natural history of HPV‐associated cervical lesions is HPV genotype‐dependent, it is important to understand the characteristics of these genotypes and to manage them accordingly. Among high‐risk HPVs, HPV16 and 18 are particularly aggressive, together accounting for 70% of HPV genotypes detected in cervical cancer. Other than HPV16 and 18, HPV31, 33, 35, 45, 52, and 58 are also at a high risk of progression to cervical intraepithelial neoplasia (CIN)3 or higher. Recent studies have shown that the natural history of HPV16, 18, 52, and 58, which are frequently detected in Japan, depends on the HPV genotype. For example, HPV16 tends to progress in a stepwise fashion from CIN1 to CIN3, while HPV52 and 58 are more likely to persist in the CIN1 to CIN2 state. Among the high‐risk HPVs, HPV18 has some peculiar characteristics different from those of other high‐risk HPV types; the detection rate in precancerous lesions is much lower than those of other high‐risk HPVs, and it is frequently detected in highly malignant adenocarcinoma and small cell carcinoma. Recent findings demonstrate that HPV18 may be characterized by latent infection and carcinogenesis in stem cell‐like cells. In this context, this review outlines the natural history of HPV‐infected cervical lesions and the characteristics of each HPV genotype. [ABSTRACT FROM AUTHOR]

A study published in Clinical & Translational Medicine suggests that the antiviral drug oseltamivir (Tamiflu) may have potential as a treatment for hearing loss. The researchers found that oseltamivir protected against hair cell loss in mouse cochlear explants caused by the chemotherapy drug cisplatin, without affecting cisplatin's ability to kill tumors. In mouse models, oseltamivir also protected against cisplatin-induced hearing loss and outer hair cell loss. Furthermore, oral oseltamivir therapy showed promise in protecting against noise-induced hearing loss. The study suggests that oseltamivir could be a promising candidate for treating hearing loss caused by chemotherapy and noise exposure. [Extracted from the article]

Background: Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin‐2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored. Methods: We retrospectively analyzed 191 patients with SCLC (72 with limited‐stage [LD] and 119 with extensive‐stage) treated using platinum‐based chemotherapy. Lipocalin‐2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin‐2 and neutrophil‐to‐lymphocyte ratio (NLR) were determined using time‐dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia. Results: In LD‐SCLC, high lipocalin‐2 expression was associated with worse progression‐free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin‐2 expression. Patients were stratified into three prognostic groups by combining lipocalin‐2 with NLR: low lipocalin‐2/low NLR, high lipocalin‐2/low NLR or low lipocalin‐2/high NLR, and high lipocalin‐2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin‐2 with the pectoralis muscle index. High lipocalin‐2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin‐2 in extensive‐stage SCLC. Conclusions: High lipocalin‐2 expression is potentially associated with poorer survival in LD‐SCLC. Combining lipocalin‐2 with other inflammation‐related markers could improve prognostic stratification. [ABSTRACT FROM AUTHOR]

Background and Aims: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum‐containing therapy. Methods: Multicentre real‐world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three‐weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). Results: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second‐ (83%, 38/46) or subsequent‐ (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high‐grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six‐month OS was 44% (95% confidence interval (CI): 29.0–57.1). Twelve‐month OS was 15% (95% CI: 6.5–26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8–2.9) and OS was 4.5 months (95% CI: 3.5–7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0–17.2). Individuals with a longer chemotherapy‐free interval prior to lurbinectedin had longer PFS and OS. Conclusion: This real‐world national experience of lurbinectedin post‐platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials. [ABSTRACT FROM AUTHOR]

This document provides information on the diagnosis and characteristics of NUT carcinoma, a rare and aggressive form of cancer. It emphasizes the importance of accurate diagnosis through immunohistochemistry and molecular testing, as well as the potential diagnostic pitfalls and differential diagnoses. The document also mentions ongoing clinical trials investigating the efficacy of BET protein inhibitors in treating NUT carcinoma. It concludes by highlighting the challenges in diagnosing NUT carcinoma and the need for caution in interpreting cytology specimens. [Extracted from the article]

Background: Growing evidence has shown that atopic dermatitis (AD) may decrease lung cancer (LC) risk. However, the causality between the two diseases is inconsistent and controversial. Therefore, we explored the causal relationship between AD and different histological subtypes of LC by using the Mendelian randomization (MR) method. Materials and methods: We conducted the MR study based on summary statistics from the genome‐wide association studies (GWAS) of AD (10,788 cases and 30,047 controls) and LC (29,266 cases and 56,450 controls). Instrumental variables (IVs) were obtained after removing SNPs associated with potential confounders. We employed inverse‐variance weighted (IVW), MR‐Egger, and weighted median methods to pool estimates, and performed a comprehensive sensitivity analysis. Results: The results of the IVW method suggested that AD may decrease the risk of developing lung adenocarcinoma (LUAD) (OR = 0.91, 95% CI: 0.85‐0.97, P = 0.007). Moreover, no causality was identified between AD and overall LC (OR = 0.96, 95% CI: 0.91–1.01, P = 0.101), lung squamous cell carcinoma (LUSC) (OR = 1.04, 95% CI: 0.96–1.036, P = 0.324), and small cell lung carcinoma (SCLC) (OR = 0.95, 95% CI: 0.82–1.10, P = 0.512). A comprehensive sensitivity test showed the robustness of our results. Conclusion: The present study indicates that AD may decrease the risk of LUAD in the European population, which needs additional investigations to identify the potential molecular mechanisms. [ABSTRACT FROM AUTHOR]

Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence‐based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (n = 18), HPV integration (n = 18), and transcriptomic sequencing (n = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non‐negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (n = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of PIK3CA and TP53 alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or 'desert' infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high‐level expression of genes related to the MHC‐II complex (CD74) and IFN‐α/β (SCCC‐I), and two neuroendocrine subtypes with high‐level expression of ASCL1 or NEUROD1, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more TP53 mutations and SCCC‐I had more PIK3CA mutations. Multiplex immunofluorescence validated these subtypes and SCCC‐I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

A 69‐year‐old ex‐smoker Japanese man presented with a left mediastinal lymph node and left upper lobe tumour. Bronchoscopic biopsy specimens from the enlarged left mediastinal lymph node and left upper lobe tumour revealed small cell lung carcinoma (SCLC). He was treated with first‐line chemotherapy with carboplatin, etoposide, and atezolizumab for four courses and subsequent atezolizumab maintenance therapy. However, his left upper lobe lung tumour only increased in size, and left upper lobectomy revealed combined SCLC (adenocarcinoma and chondrosarcoma‐like features). Four months after lobectomy, liver metastasis of chondrosarcoma‐like features (similar to pathological findings of the left upper lobe tumour) were observed. Combined SCLC, including sarcomatous components, is rare and poorly responds to chemotherapy. The metastases of combined SCLC in this patient were of only one type of histological component, making diagnosis and treatment difficult. If treatment for SCLC responds inadequately, considering combined SCLC and actively re‐examining histological diagnosis is necessary. [ABSTRACT FROM AUTHOR]

Objective: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm that predominantly affects elderly and immunocompromised patients. Merkel cell polyoma virus (MCPyV) is clonally integrated into the majority of MCCs and has been linked to patient outcomes, playing a central role in the pathogenesis of the disease. We aimed to assess the utility of MCPyV immunohistochemistry (IHC) in the diagnosis of MCC in cytology cell block specimens and correlating with clinicopathologic features. Methods: Fifty‐three cytology samples of MCC with sufficient cell block material were stained for MCPyV by IHC and scored semi‐quantitatively in extent and intensity. Morphologic mimics of MCC including small cell lung carcinoma (n = 10), non‐Hodgkin lymphoma (n = 10), basaloid squamous cell carcinoma (n = 6) and other neuroendocrine carcinomas (n = 8) were stained in parallel. Positive staining was defined as >1% of the tumour cells showing at least moderate staining intensity. Results: The cytologic features of MCC were characterized by high nuclear‐cytoplasmic ratios, hyperchromatic nuclei with 'salt and pepper' chromatin, and nuclear moulding. MCPyV was detected in 24 of 53 cases (45%). Staining was strong and diffuse in roughly half of the positive samples. Of the morphologic mimics, one follicular lymphoma showed strong and diffuse staining. In contrast to prior studies, we saw no association between MCPyV status and patient outcomes. Conclusion: Merkel cell polyoma virus IHC is highly specific (97%) for the diagnosis of MCC in our cohort, and can serve as a useful diagnostic tool for distinguishing MCC for morphologic mimics. [ABSTRACT FROM AUTHOR]

Tracheomediastinal fistula is a rare but life‐threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features. [ABSTRACT FROM AUTHOR]

Background: Consolidative thoracic radiotherapy (cTRT) has previously shown benefit to patients with extensive stage small cell lung cancer (ES‐SCLC) who respond to chemotherapy. However, the optimum dose of cTRT is unknown. The purpose of this randomized trial is to compare the efficacy of 45 Gy in 15 fractions with 30 Gy in 10 fractions cTRT in ES‐SCLC. Methods: This phase III, multicenter, randomized trial is designed to evaluate the safety and efficacy of different cTRT dose in ES‐SCLC. Eligible patients with pathologically confirmed ES‐SCLC who responded to 4–6 cycles of etoposide plus cisplatin (EP) or carboplatin (EC) chemotherapy were randomized 1:1 to receive either 30 Gy in 10 fractions (standard dose) or 45 Gy in 15 fractions (high dose) cTRT. The primary endpoint is 2‐year overall survival (OS). Secondary endpoints include 2‐year progression‐free survival (PFS), 2‐year local control (LC) and treatment related toxicity as measured by adverse events according to the Common Terminology Criteria for Adverse Events (version 4.0). Discussion: The present study is the first randomized phase III trial designed to evaluate the efficacy of higher versus lower dose cTRT in ES‐SCLC, providing evidence for future clinical practice in prolonging survival of patients with ES‐SCLC. [ABSTRACT FROM AUTHOR]

This case report expands the reported range of clinical presentations of CV2/CRMP5 antibody‐related syndromes with two novel findings (manic psychosis and psychogenic polydipsia). A systematic literature review highlights a potentially higher incidence of psychosis than previously reported, clinical features that should prompt antibody testing, and the potential for treatment response. [ABSTRACT FROM AUTHOR]

Small cell lung carcinoma (SCLC) is a high-grade neuroendocrine carcinoma that is often found in smokers and has a poor prognosis. Previous histological subclassifications of SCLC, such as oat cell and intermediate cell types, have been phased out due to their lack of reproducibility and clinical significance. However, recent studies have highlighted the importance of molecular profiling and the expression of certain transcription regulators, such as POU2F3, in refining the diagnosis of SCLC. This article presents a case study of a patient with SCLC exhibiting two distinct components with variable POU2F3 expression, which correlates with the previously obsolete classifications of oat cell and intermediate cell types. The findings suggest the potential resurgence and relevance of these older classifications in light of modern molecular diagnostic technologies. [Extracted from the article]

Background: Brain metastases (BMs) are common in small cell lung cancer (SCLC), and the efficacy of immune checkpoint inhibitors (ICIs) in these patients is uncertain. In this study we aimed to develop and validate a radiomics nomogram based on magnetic resonance imaging (MRI) for intracranial efficacy prediction of ICIs in patients with BMs from SCLC. Methods: The training and validation cohorts consisted of 101 patients from two centers. The interclass correlation coefficient (ICC), logistic univariate regression analysis, and random forest were applied to select the radiomic features, generating the radiomics score (Rad‐score) through the formula. Using multivariable logistic regression analysis, a nomogram was created by the combined model. The discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. Kaplan–Meier curves were plotted based on the nomogram scores. Results: Ten radiomic features were selected for calculating the Rad‐score as they could differentiate the intracranial efficacy in the training (area under the curve [AUC], 0.759) and the validation cohort (AUC, 0.667). A nomogram was created by combining Rad‐score, treatment lines, and neutrophil‐to‐lymphocyte ratio (NLR). The training cohort obtained an AUC of 0.878 for the combined model, verified in the validation cohort (AUC = 0.875). Kaplan–Meier analyses showed the nomogram was associated with progression‐free survival (PFS) (p = 0.0152) and intracranial progression‐free survival (iPFS) (p = 0.0052) but not overall survival (OS) (p = 0.4894). Conclusion: A radiomics nomogram model for predicting the intracranial efficacy of ICIs in SCLC patients with BMs can provide suggestions for exploring individual‐based treatments for patients. [ABSTRACT FROM AUTHOR]

With the promise of a potentially single‐dose curative regimen, CAR‐T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with 6 approved products in the USA. However, there are no approved CAR‐T cell therapies for solid tumors. Herein, we report the clinical pharmacology profile of AMG 119, the first CAR‐T cell therapy targeting delta‐like ligand 3 (DLL3), in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC). AMG 119 demonstrated robust cellular expansion with long‐lasting cell persistence and a favorable exposure–response relationship. AMG 119 has been demonstrated to be clinically safe and well tolerated at the doses tested, with no dose‐limiting toxicities (DLTs) reported. This is the first publication of the clinical pharmacology profile of a CAR‐T cell therapy in SCLC, with encouraging cellular kinetics data supporting the potential for CAR‐T cell therapy in solid tumor space. [ABSTRACT FROM AUTHOR]

Background: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1–0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. Aims: We conducted a retrospective cohort study comparing the outcomes of extensive‐stage (ES) SCLC and EPSCC. Methods: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression‐free survival (PFS) and overall response rates (ORRs). Results: Three hundred and eighty‐four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5–1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58–1.46, P = 0.74) and ORR were 73% versus 68%. Conclusions: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma represents a diverse group of tumours with distinct histologic subtypes, each exhibiting unique cytomorphologic features, architectural growth patterns, and/or well‐developed aberrant differentiation. In fact, there are more than 13 subtypes of urothelial carcinoma recognized in the 2022 WHO classification of tumours in the urinary tract. The identification of these subtypes is crucial for an accurate diagnosis of urothelial carcinoma, and many have important clinical implications. Variant/divergent features may coexist with conventional high‐grade urothelial carcinoma (HGUC) or present with 100% variant morphology. In urinary tract cytology (UTC), urothelial carcinoma can display divergent differentiation, such as squamous, glandular, or small cell carcinoma differentiation. The use of cell block preparations and immunohistochemistry with available residual urine can enhance diagnostic accuracy. On the other hand, identifying urothelial carcinoma variants, including nested, micropapillary, and plasmacytoid subtypes, poses significant challenges in UTC. Many cases of these variants are only detected retrospectively after variant histology has been established from resection specimens. Moreover, some variants exhibit features inconsistent with the diagnostic criteria for HGUC according to the Paris System for Reporting Urinary Tract Cytology. Nevertheless, the rarity of pure variant morphology and the occurrence of some false negatives for these variant cases are essential to maintain the specificity of UTC overall. This review covers the histology, cytomorphology, and important clinical aspects observed in urothelial carcinoma exhibiting divergent differentiation and various urothelial carcinoma variants detected in UTC. [ABSTRACT FROM AUTHOR]

Objective: This study assessed the outcomes of elderly patients with limited‐stage small cell lung cancer (LS‐SCLC), which may be linked to the timing of thoracic radiotherapy (TRT) following chemotherapy. Methods: Elderly patients (n = 78) with LS‐SCLC were divided into three groups depending on the timing of radiotherapy. The patients in the TRT group were stratified into early (TRT after 1–2 cycles of chemotherapy, n = 29), medium‐term (TRT after 3–4 cycles of chemotherapy, n = 33), and late (TRT after 5–6 cycles of chemotherapy, n = 16) TRT groups. The overall survival (OS) and progression‐free survival (PFS) were assessed and compared. Results: The medium‐term TRT group demonstrated significantly longer mPFS (20.12 months) and better mOS (35.97 months) than those in the other groups (PFS: P = 0.021;OS: P = 0.035). A pairwise comparison of the three groups revealed that those who received medium‐term TRT exhibited significantly improved PFS than the early (mPFS: 20.12 vs. 10.36 mouths, P = 0.018) and late (mPFS: 20.12 vs. 9.17 months, P = 0.016) TRT. The medium‐term TRT group demonstrated significantly improved OS than the early TRT (mOS: 35.97 vs. 25.22 months, P = 0.007) but not in comparison with the late TRT (mOS: 35.97 vs. 21.63 months, P = 0.100). Conclusion: In elderly patients with LS‐SCLC, the addition of TRT after 3–4 cycles of chemotherapy appears to be a viable and potentially beneficial treatment approach. [ABSTRACT FROM AUTHOR]

Background: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)‐SCLC, to assess whether conventional NE markers are predictive of ICIs. Methods: Patients with untreated ED‐SCLC who received first‐line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first‐line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI‐chemo group) and with chemotherapy alone (chemo group). Results: A total of 227 patients were included in the ICI‐chemo and chemo groups, respectively. The progression‐free survival (PFS) tended to be better in patients in the ICI‐chemo group than those treated with chemotherapy alone in patients with NE marker‐positive SCLC. In particular, it was statistically significant in patients with chromogranin A‐positive SCLC (p = 0.036). In patients with NE marker‐negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Conclusion: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker‐negative SCLC. [ABSTRACT FROM AUTHOR]

Introduction: The outcomes of palliative radiation therapy (RT) for neuroendocrine neoplasms (NEN) are seldom reported. We investigated outcomes following palliative radiotherapy in a cohort of patients with NENs. We hypothesised that well‐differentiated NEN will be less likely to have a clinical response than poorly differentiated NEN. Methods: Patients who received at least one course of palliative RT were identified using the New Zealand NETwork! Registry. Patients with Merkel cell carcinoma, pulmonary small cell carcinoma or asymptomatic patients were excluded. Clinical response to RT within 90 days and overall survival were analysed alongside clinical variables (fractionation, RT site, tumour differentiation and tumour primary site). Results: The cohort comprised 79 patients, with 147 courses of palliative RT delivered. Clinical response was measurable for 100 courses, with clinical response rate of 76%. A course delivered to a well‐differentiated NEN was associated with 2.02‐fold (95% CI 0.67, 6.12; P = 0.21) increase in odds of a clinical response compared to a poorly differentiated NEN. Median overall survival from the first fraction of RT was 94 days (95% CI 80, 138 days). Overall survival was higher in well‐differentiated NEN than in poorly differentiated NEN (HR 0.2, 95% CI 0.10–0.40, P‐value < 0.001); 30‐day mortality was 7%. There were significantly reduced odds of clinical response for non‐bone sites, and for courses >10 fractions compared to a single fraction. Conclusion: Palliative RT is an appropriate option for management of symptoms in patients with both well‐ and poorly differentiated metastatic NEN. [ABSTRACT FROM AUTHOR]

Aims: Small cell lung carcinoma (SCLC) can be classified into transcription factor‐based subtypes (ASCL1, NeuroD1, POU2F3). While in‐vitro studies suggest intratumoral heterogeneity in the expression of these markers, how SCLC subtypes vary over time and among locations in patients remains unclear. Methods and results: We searched a consecutive series of patients at our institution in 2006–22 for those with greater than one available formalin‐fixed paraffin‐embedded SCLC sample in multiple sites and/or time‐points. Immunohistochemistry for ASCL1, NeuroD1 and POU2F3 was performed and evaluated using H‐scores, with subtype assigned based on the positive marker (H‐score threshold >10) with the highest H‐score. The 179 samples (75, lung; 51, lymph nodes; 53, non‐nodal metastases) from 84 patients (74 with two, 10 with more than two samples) included 98 (54.7%) ASCL1‐dominant, 47 (26.3%) NeuroD1‐dominant, 15 (8.4%) POU2F3‐dominant, 17 (9.5%) triple‐negative and two (1.1%) ASCL1/NeuroD1 co‐dominant samples. NeuroD1‐dominant subtype was enriched in non‐lung locations. Subtype concordance from pairwise comparison was 71.4% overall and 89.7% after accounting for ASCL1/NeuroD1‐dual expressors and technical factors including <500 cells/slide, H‐score thresholds and sample decalcification. No significant difference in subtype concordance was noted with a longer time lapse or with extrathoracic versus intrathoracic samples in this cohort. Conclusions: After accounting for technical factors, transcription factor‐based subtyping was discordant among multiple SCLC samples in ~10% of patients, regardless of sample locations and time lapse. Our findings highlighted the spatiotemporal heterogeneity of SCLC in clinical samples and potential challenges, including technical and biological factors, that might limit concordance in SCLC transcription factor‐based subtyping. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is a neuroendocrine tumor with poor prognosis. Neuroendocrine tumors possess characteristics of both nerve cells and hormone‐secreting cells; therefore, targeting the neuronal properties of these tumors may lead to the development of new therapeutic options. Among the endogenous signaling pathways in the nervous system, targeting the glutamate pathway may be a useful strategy for glioblastoma treatment. Perampanel, an antagonist of the synaptic glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR), has been reported to be effective in patients with glioblastoma. In this study, we aimed to investigate the antitumor effects of AMPAR antagonists in human SCLC cell lines. Methods: We performed to examine the expression of AMPAR using Western blot and immunohistochemical analysis. The antitumor effects of AMPAR antagonists on human SCLC cell lines were investigated in vitro and in vivo. We also analyzed the signaling pathway of AMPAR antagonists in SCLC cell lines. Statistical analysis was performed by the GraphPad Prism 6 software. Results: We first examined the expression of endogenous AMPAR in six human SCLC cell lines, detecting AMPAR proteins in all of them. Next, we tested the anti−proliferative effect of two AMPAR antagonists, talampanel and cyanquixaline, using SCLC cells in vitro and in vivo. Both AMPAR antagonists inhibited cell proliferation and mitogen‐activated protein kinase (MAPK) phosphorylation in SCLC cells in vitro. Further, we observed reduced proliferation of implanted cell lines in an in vivo setting, assessed by Ki‐67 immunohistochemistry. Additionally, using immunohistochemical analysis we confirmed AMPAR protein expression in human SCLC samples. Conclusion: AMPAR may be a potential therapeutic target for SCLC. [ABSTRACT FROM AUTHOR]

Objectives: Pulmonary embolism (PE) is a life‐threatening complication that can occur in patients with lung cancer. In this study, we aimed to identify risk factors and examine the clinical characteristics of advanced lung cancer patients with PE. Methods: We conducted a retrospective review of patients admitted to our two hospitals between January 2020 and June 2022. The case group consisted of patients with lung cancer and PE, and a closely matched control group was included to identify risk factors. Statistical analysis was conducted using R language. Results: A total of 4957 patients were reviewed, and 162 patients (comprising 54 cases and 108 controls) were included in this study. The prevalence of lung cancer with PE in the study population was 1.08%. The majority of patients were male, and the most common histological subtype was adenocarcinoma (67%), followed by squamous cell carcinoma, small cell carcinoma, and poorly differentiated non‐small cell lung cancer. The majority of patients had a high performance status (PS) score, with 50% experiencing respiratory failure (mainly hypoxia) and 33% with deep vein thrombosis (DVT). Forty‐eight percent of patients were diagnosed with concurrent PE. Further analysis showed that PE was an independent predictor of poor survival, and a PS score of >1 was an independent risk factor for PE in patients with lung cancer. Conclusion: Our study provides valuable insights into the epidemiology and prognosis of PE in lung cancer patients and suggests that a poor ECOG PS, which has not been previously reported, is an independent risk factor for PE. [ABSTRACT FROM AUTHOR]

Background: Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novoSMARCA4 exon 14 deletion. Methods: The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel‐ and capillary electrophoresis and nanopore sequencing. Results: The deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in‐frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic. Conclusion: We propose to include RNA analysis in classification of single‐exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines. [ABSTRACT FROM AUTHOR]

Alveolar macrophages (AMs) are resident macrophages in the lungs; however, whether the number of AMs plays a role in the lung neuroendocrine tumor (NET) prognosis remains unclear. We counted the number of AMs located around the tumor (peritumoral alveolar macrophages [pAMs]) and the number of AMs located apart from the tumor (distant macrophages; dAMs). In 73 cases of neuroendocrine carcinoma (NEC: small cell lung carcinoma and large cell neuroendocrine carcinoma), the group that contained higher pAMs (≥86/μm2) revealed shorter recurrent‐free survival (RFS) than those with lower pAMs (<86/μm2) (p = 0.005). Bivariate analysis showed that the number of pAMs was an independent predictor of a poor RFS. In contrast, in the carcinoid tumor cohort (n = 29), there was no statistically significant correlation between the two groups with high and low numbers of pAMs in RFS (p = 0.113). Furthermore, we examined the correlation between genomic alterations and the number of pAMs in NEC, but no significant correlation was observed. In conclusion, the number of pAMs is a prognostic factor for NEC in the lung and pAMs may contribute to tumor progression within the peritumoral microenvironment. [ABSTRACT FROM AUTHOR]

Introduction: Combined treatment using anti‐programmed death‐ligand 1 antibody (anti‐PD‐L1) and platinum‐etoposide is the current standard first‐line treatment for patients with extensive‐stage (ES) small cell lung cancer (SCLC). However, the best treatment for relapsed ES‐SCLC after the first‐line treatment remains unclear. There are some approved chemotherapeutic agents that can be used against ES‐SCLC, and treatment with irinotecan is well established as both a monotherapy and a combined therapy, in combination with platinum. Therefore, we conduct a phase II study with irinotecan in the second‐ or later‐line setting for patients with ES‐SCLC who have been previously treated with combined treatment. Methods: Our study will enroll total 30 patients who are diagnosed with ES‐SCLC and have experienced disease progression after the combined treatment. Patients will receive irinotecan on days 1, 8, and 15, which will be repeated every 4 weeks. Doses of irinotecan (100/80/60 mg/m2) will be determined according to the type of UGT1A1 gene polymorphism, and the treatment will be discontinued following disease progression, intolerance, withdrawal of patient consent, and based on the investigator's decision. The primary endpoint of the study is the response rate, and the secondary endpoints are overall survival, progression‐free survival, and safety. Discussion: Since the present first‐line treatment has been changed to the combined treatment, the second‐ or later‐line treatment should be re‐evaluated for patients with relapsed SCLC. Irinotecan is a major chemotherapeutic agent used for SCLC. This study demonstrates and re‐evaluates the clinical benefits of irinotecan after combined treatment with anti‐PD‐L1 and platinum‐etoposide for patients with ES‐SCLC. Registration details: This study was registered in the Japan Registry of Clinical Trials (no. jRCT s071210090) on November 4, 2021. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is highly aggressive with limited therapeutic options and a poor prognosis. Moreover, noninvasive biomarker tools for detecting disease and monitoring treatment response are lacking. To address this, we evaluated serum biomarkers of extracellular matrix proteins not previously explored in SCLC. Methods: We measured biomarkers in the serum of 16 patients with SCLC before and after chemotherapy as well as in the serum of 11 healthy individuals. Results: Our findings demonstrated that SCLC serum had higher levels of collagen type I degradation, collagen type III formation, and collagen type XI formation than healthy controls. In addition, we observed higher levels of type XIX and XXII collagens, fibrinogen, and von Willebrand factor A formation in SCLC serum. The formation of type I collagen did not exhibit any discernible variation. However, we observed a decrease in the degradation of type I collagen following chemotherapy. Conclusion: Overall, our findings revealed elevated levels of collagen and blood‐clotting markers in the serum of SCLC patients, indicating the potential of ECM proteins as noninvasive biomarkers for SCLC. [ABSTRACT FROM AUTHOR]

A 67‐year‐old male patient presented with extensive‐stage small cell lung cancer with the primary lesion located in the right upper lung, accompanied by multiple metastases to the pleura and abdominal cavity with enlarged mediastinal lymph nodes. A combination therapy approach was used to target the patient's multiple systemic metastases after localized radiotherapy. The approach involved adoptive transfer of programmed death ligand 1 (PD‐L1) enhanced exogenous natural killer (NK) cells, along with antiangiogenic treatment. Allogeneic cord blood NK cells were infused back into the patient over two consecutive days. On the first day, the treatment was followed by a dose of 1200 mg of atezolizumab. Subsequently, the patient received a daily dose of 10 mg of anlotinib administered orally for 14 days. This was followed by a 7‐day break, and each cycle lasted 21 days. After delivering localized radiation to the primary lesion in the right lung and metastatic mediastinal lymph nodes, complete remission was achieved in the local lesion, effectively avoiding the risk of superior vena cava syndrome. Following six cycles of combined therapy, most of the metastatic lesions had disappeared, and the remaining metastatic lesions had significantly reduced in size. The recent therapeutic effect resulted in partial remission. The combination therapy of immune checkpoint inhibitor PD‐L1‐enhanced exogenous adoptive transfer NK cells, along with antiangiogenic targeted treatment, demonstrated a satisfactory short‐term effect, with disappearance of most of the metastases and noticeable shrinkage in the remaining metastatic lesions. [ABSTRACT FROM AUTHOR]

This article discusses a case of large cell neuroendocrine carcinoma (LCNEC) in the sigmoid colon. LCNEC is a type of aggressive neuroendocrine carcinoma characterized by severe atypia and rapid mitotic activity. In this case, approximately half of the tumor showed a discohesive growth pattern resembling undifferentiated carcinoma (UC). The patient experienced a highly unfavorable clinical course, highlighting the importance of recognizing this pattern for accurate diagnosis and prognosis. Further research is needed to understand the genetic changes and prognostic impact of LCNEC with a discohesive growth pattern. [Extracted from the article]

Background: Extrapulmonary small cell cancer (EPSCC) is a rare malignancy with an incidence of approximately 0.1%–0.4% of all cancers. Treatment of this disease is often based on small cell lung cancer. Aims: We aimed to investigate real‐world clinical outcomes of patients with extensive‐stage (ES) ESPCC. Methods: Patients diagnosed with ES EPSCC between 2010 and 2020 from multiple centres in New South Wales were identified. Patient, disease and treatment characteristics were collected and presented using descriptive statistics. Survival was analysed using the Kaplan–Meier method. Univariate and multivariate Cox regression hazard models were used to identify potential prognostic factors. Results: Sixty eligible ES EPSCC patients were identified, including 65% male and 35% female. The mean age was 69 years (range 37–88). Forty‐five per cent were never smokers, 42% ex‐smokers and 13% current smokers, and 17% of patients had limited‐stage disease prior to development of ES disease. The most common primary sites were genitourinary (42%; mainly prostate (n = 14) and bladder (n = 10)), gastrointestinal (28%; mainly oesophagus (n = 5) and colon (n = 4)) and unknown primary (22%). Treatments received included palliative chemotherapy (67%), palliative radiotherapy (53%), palliative surgery (13%) and best supportive care alone (13%). The median overall survival (OS) was 8.0 months. The median progression‐free survival was 5.4 months, and response rate to first‐line chemotherapy was 65%. Platinum‐based chemotherapy was prognostic of longer OS (HR 0.27, CI 0.12–0.60, P = 0.001). Conclusions: Patients with ES EPSCC had good response to palliative chemotherapy, but OS remained poor. Further research is required to improve the prognosis in this population. [ABSTRACT FROM AUTHOR]

Small‐cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that is prone to spread extensively. Compared to non‐small‐cell lung cancer (NSCLC), SCLC treatment progresses slowly. Although SCLC is highly sensitive to chemotherapy during the initial treatment, most patients still experience resistance and recurrence after receiving chemotherapy. A meta‐analysis demonstrated that thoracic radiotherapy (TRT) improves overall survival in SCLC. The results of the CALGB and CONVERT trials provide evidence for the efficacy of once‐daily high‐dose TRT. TRT at 60 Gy administered twice daily significantly improved survival without increasing toxicity. The long‐standing debate over the optimal timing of radiotherapy has not been fully resolved. SBRT has excellent local control rates and is a safe and effective treatment option for patients with stage I or II SCLC. Prophylactic cranial irradiation (PCI) is used to reduce treatment‐related neurotoxicity to the extent that there has been a recent discussion on whether magnetic resonance imaging (MRI) monitoring can replace PCI. Radiotherapy combined with immunotherapy significantly improves the survival rate of patients with NSCLC; however, its clinical effectiveness has not been systematically explored in patients with SCLC. Therefore, we summarize the evolving therapeutic strategies, (TRT for limited stage‐SCLC and consolidative TRT for extensive stage‐SCLC) and improved radiotherapy techniques (role of SBRT in stage I or II node‐negative SCLC, progress of PCI, and stereotactic radiosurgery), and discuss the possibilities and prospects of radiotherapy combined with immunotherapy for SCLC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the relationship between immune response adverse events (irAEs) and treatment efficacy in patients with extensive disease small cell lung cancer (ED-SCLC). Methods: We retrospectively evaluated the clinical effects in 40 ED-SCLC patients who had received immune-checkpoint inhibitors (ICIs), platinum agents, and etoposide between September 2019 and September 2021. We identified and compared patients belonging to two groups: irAE and non-irAE. Results: Fifteen patients experienced irAEs, and 25 did not. The median progressionfree survival in patients with irAE was longer than that in patients without irAE (12.6 months [95% CI: 6.3–19.3 months] vs. 7.2 months [95% CI: 5.8–7.9 months], p = 0.0108). However, the median overall survival (OS) was similar between irAE and non-irAE groups (27.6 months [95% CI: 15.4–NA] vs. 24.9 months [95% CI: 13.7– NA], p = 0.268). Seven (46.7%) in the irAE group and 20 (80%) in the non-irAE group received sequential therapy. The median OS was prolonged in patients who received first- and second-line therapy than in those who received first-line therapy alone (27.6 months [95% CI: 19.2–NA] vs. 6.6 months [95% CI: 0.3–NA], p = 0.053). Grade ≧ 3 irAEs occurred in five (12.5%) patients. Among them, grade 5 irAEs were observed in two patients, including exacerbation of polymyositis and pulmonary arterial embolism. Conclusion: In this study, the development of irAEs did not affect OS in patients with ED-SCLC who received platinum-based agents, etoposide, or ICI therapy. We determined that managing irAEs and administering first- and second-line therapies could contribute to prolonged OS. [ABSTRACT FROM AUTHOR]

Several transcription factors in small cell lung cancer (SCLC), including achaete‐scute homolog 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), contribute to rapid tumor growth and early metastatic dissemination. Recent studies suggested that these molecular subtypes represent neuroendocrine differentiation in dynamic SCLC evolution. In the present case, a 62‐year‐old man was diagnosed with limited disease SCLC originating from the right upper lobe. Biopsy specimens were positive for ASCL1 but negative for NEUROD1. Six months after concurrent chemoradiotherapy and prophylactic cranial irradiation, the primary tumor had regrown and salvage surgery was performed. The pathological diagnosis was recurred SCLC, and postoperative histopathology was positive for both ASCL1 and NEUROD1. The patient was subsequently followed up; however, he had multiple bone metastases 9 months after surgery. It was speculated that the shift to NEUROD1‐high expression in tumor cells surviving concurrent chemoradiation therapy may be related to the poor outcome after combined modality treatment. [ABSTRACT FROM AUTHOR]

Primary breast neuroendocrine (NE) neoplasms are uncommon, and definitions harbor controversy. We retrospectively collected 73 triple‐negative breast cancers (TNBC) and evaluated NE biomarker expression along with p53 aberrant staining (which correlates with TP53 gene mutation) and Rb protein loss by immunohistochemistry. In the study cohort, we found 11 (15%) cases of TNBC with neuroendocrine differentiation (TNBC‐NED) showing positivity for one or more NE markers (synaptophysin/chromogranin/insulinoma‐associated protein 1 [INSM1]). We also identified one separate small cell neuroendocrine carcinoma. Histologic types for these 11 TNBC‐NED cases were as follows: 8 invasive ductal carcinoma (IDC) not otherwise specified (NOS), 2 IDC with apocrine features, 1 IDC with solid papillary features. INSM1 had the highest positivity and was seen in all 11 carcinomas. Seven (64%) cases showed p53 aberrant staining, 6 (55%) had Rb protein loss, while 6 (55%) had p53/Rb co‐aberrant staining/protein loss. TNBC‐NED was associated with Rb protein loss (p < 0.001), as well as p53/Rb co‐aberrant staining/protein loss (p < 0.001). In 61 cases negative for NE markers, 37 (61%) showed p53 aberrant staining, while 5 (8%) had Rb protein loss. We also analyzed genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) PanCancer Atlas of 171 basal/TNBC patients. Transcriptomic analysis revealed mRNA expression of RB1 to be correlated negatively with SYN1 mRNA expression (p = 0.0400) and INSM1 mRNA expression (p = 0.0106) in this cohort. We would like to highlight the importance of these findings. TNBC‐NED is currently diagnosed as TNBC, and although it overlaps morphologically with TNBC without NED, the unique p53/Rb signature highlights a genetic overlap with NE carcinomas of the breast. [ABSTRACT FROM AUTHOR]

Aims: Small cell bladder carcinoma (SCBC) is a rare, divergent form of urothelial carcinoma (UC). We aimed to determine whether pure (n = 16) and mixed (SCBC and UC; n = 30) tumours differed in pathology, gene expression characteristics, genetic alterations, and clinical outcomes. Methods and results: Forty (87%) patients received first‐line chemotherapy. Twenty‐nine patients had no metastatic disease at diagnosis and underwent radical cystectomy. There were no differences in age, sex, race distribution, tumour size, stage at presentation, therapy response with pathological downstaging to ≤ypT1N0, or overall or progression‐free survival (PFS) between pure and mixed tumours. There was a longer PFS among downstaged chemotherapy‐responding tumours ≤ypT2N0M0 than among unresponsive tumours ≥ypT2 ≥ yN1M1 (P = 0.001). Patients who achieved pathological downstaging with neoadjuvant chemotherapy (n = 10) were stage cT2N0M0 at the time of diagnosis and were alive at the last follow‐up (median 37 months), while 46% of patients who failed to achieve pathological downstaging were alive at the last follow‐up (median 38 months; P = 0.008). RNA sequencing showed that the UC of mixed SCBC had similar neural expression signatures to pure SCBC. DNA sequencing revealed alterations in TERT (83%), P53 (56%), ARID1A (28%), RB1 (22%), and BRCA2 (11%). Immunohistochemistry for RB1 showed loss of expression in 18/19 (95%) patients, suggesting frequent pathway downregulation despite a low prevalence of RB1 mutation. Conclusion: Patients with pure and mixed SCBC have similar outcomes and these outcomes are determined by the pathological stage at RC and are best among patients who have pathological downstaging after NAC. [ABSTRACT FROM AUTHOR]

Background: To review the outcomes of surgically resected lung neuroendocrine neoplasms (LNEN) at a tertiary referral centre and to validate a previously published LNEN‐specific staging system (NETL). Methods: All patients who were identified on histopathology to have LNEN were included. Pre‐, intra‐ and post‐operative outcomes were collected, including long‐term survival. Patients were staged by both the TNM (seventh and eighth edition) and NETL staging (seventh and eighth edition definitions). Kaplan–Meier (KM) survival analysis was performed according to histopathology and stage, along with uni‐ and multivariate analyses. Result: A total of 132 patients were included in the study, with a median age of 65 years; 55% were female. Typical carcinoid (TC) was the most common pathology (53.4%) followed by large cell neuroendocrine carcinoma (LCNEC – 23.5%), atypical carcinoid (AC – 20.5%) and small cell carcinoma (3.0%). The most common operation performed was a lobectomy (55.3%). Overall survival at 5 years was 80% (100% TC, 78.2% AC, LCNEC 40.9%) and 5‐year disease free survival was 76.8% (TC 94.3%, AC 56.8%, LCNEC 56.4%). KM curves showed a trend towards NETL performing better than TNM, however, in multivariate analysis only the histological subtype was found to be significant in our study. Conclusion: This is the largest known Australian series of LNEN to date, showing survival comparable to international outcomes. We have demonstrated large variations in outcome, driven by histological grade. The TNM system does not correlate with survival and we have not been able to show that currently proposed NETL staging is superior. [ABSTRACT FROM AUTHOR]

Objective: The role of prophylactic cranial irradiation (PCI) in treating extensive‐stage small‐cell lung cancer (ES‐SCLC) has been controversial. This study aimed to comprehensively analyze the efficacy of PCI for the treatment of ES‐SCLC under active brain magnetic resonance imaging (MRI) surveillance. Methods: Patients with ES‐SCLC with no brain metastases (BM) confirmed by MRI at the time of diagnosis who responded well to first‐line chemoimmunotherapy at three general hospitals were retrospectively included. Overall survival (OS), progression‐free survival (PFS), and cumulative incidence of BM were compared between patients who underwent PCI and those who did not. Results: In total, 66 consecutive patients treated between March 2019 and December 2021 were included in our dataset. Seventeen patients underwent PCI (PCI group) and 49 patients did not (non‐PCI group). In comparison with the non‐PCI group, PCI did not provide OS (median OS: 18.53 vs. 17.35 months, p = 0.28) or PFS (median PFS: 8.61 vs. 7.56 months, p = 0.41) benefits. When death was counted as a competing risk, the difference in the cumulative incidence rate of BM was not statistically significant (1‐year: 12.79% vs. 38.09%; p = 0.14). Conclusion: Compared to active MRI surveillance, first‐line chemoimmunotherapy followed by PCI did not improve the prognosis of patients with ES‐SCLC. Further studies are warranted to evaluate the therapeutic effects of PCI following chemoimmunotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Our research aimed to evaluate the effectiveness of first‐line immune checkpoint inhibitors (ICIs) with etoposide and platinum (EP) for extensive‐stage small cell lung cancer (ES‐SCLC) and identify prognostic factors, as real‐world outcomes and the inconsistency of PD‐1 and PD‐L1 inhibitors are uncertain. Methods: We selected ES‐SCLC patients in three centers and conducted a propensity score‐matched analysis. The Kaplan–Meier method and Cox proportional hazards regression were conducted to compare the survival outcomes. We also performed univariate and multivariate Cox regression analyses to investigate predictors. Results: Among 236 patients included, 83 pairs of cases were matched. The EP plus ICIs cohort had a longer median overall survival (OS) (17.3 months) than the EP cohort (13.4 months) (hazard ratio [HR], 0.61 [0.45, 0.83]; p = 0.001). The median progression‐free survival (PFS) was also longer in the EP plus ICIs cohort (8.3 months) than in the EP cohort (5.9 months) (HR, 0.44 [0.32, 0.60]; p < 0.001). The EP plus ICIs group had a higher objective response rate (ORR) (EP: 62.3%, EP + ICIs: 84.3%, p < 0.001). Multivariate analysis presented that liver metastases (HR, 2.08; p = 0.018) and lymphocyte–monocyte ratio (LMR) (HR, 0.54; p = 0.049) were independent prognostic factors for OS, and performance status (PS) (HR, 2.11; p = 0.015), liver metastases (HR, 2.64; p = 0.002), and neutrophil‐lymphocyte ratio (NLR) (HR, 0.45; p = 0.028) were for PFS in patients with chemo‐immunotherapy. Conclusion: Our real‐world data demonstrated that ICIs with chemotherapy as the first‐line setting for ES‐SCLC are effective and safe. PS, liver metastases, and inflammatory markers could serve as valuable risk factors. [ABSTRACT FROM AUTHOR]

Background: Amrubicin (AMR) has become the standard of care for post‐relapse small cell lung cancer (SCLC). It has also been reported to achieve long‐term disease control in patients with good treatment response. However, the optimal patient population for whom AMR is effective and the factors associated with long‐term disease control are yet to be identified. The aim of the study was to identify the clinical characteristics and factors associated with long‐term disease control in patients with recurrent SCLC who would benefit from AMR therapy. Methods: The clinical records of 33 patients diagnosed with recurrent SCLC and treated with AMR were retrospectively reviewed. Clinical information was compared between patients who achieved disease control (effective group) and who developed disease progression (noneffective group) on the first efficacy assessment after AMR and between patients who continued AMR for more than seven cycles (maintenance group) and those who terminated treatment after 1–6 cycles (discontinuation group). Results: The noneffective group included significantly more patients with AMR dose reductions after the second cycle (p = 0.006). AMR dose reduction was an independent risk factor for disease progression. The maintenance group had significantly lower pretreatment lactate dehydrogenase (LDH) levels than the discontinuation group (p = 0.046). A high LDH level was an independent risk factor for short AMR discontinuation. Overall survival was significantly longer in the effective group than in the noneffective group (p < 0.001). Conclusions: In AMR therapy for patients with relapsed SCLC, continuation of AMR without dose reduction after the second cycle may contribute to disease control and prolonged survival. [ABSTRACT FROM AUTHOR]

Background: To investigate whether whole‐brain radiotherapy (WBRT) decreases lymphocyte counts and evaluate the impact of treatment‐related lymphopenia on survival in patients with brain metastasis. Methods: Medical records from 60 small‐cell lung cancer patients treated with WBRT from January 2010 to December 2018 were included in the study. Total lymphocyte count (TLC) was obtained pre and post treatment (within 1 month). We performed linear and logistic regression analyses to identify predictors of lymphopenia. The association between lymphopenia and survival was analyzed using Cox regression analysis. Results: Thirty‐nine patients (65%) developed treatment‐related lymphopenia. The median TLC decrease was −374 cells/μL (interquartile range −50 to −722, p < 0.001). Baseline lymphocyte count was a significant predictor of TLC difference and percentage change in TLC. Logistic regression analysis found male sex (odds ratio [OR] 0.11, 95% confidence interval [CI] 0.00–0.79, p = 0.033) and higher baseline lymphocyte count (OR 0.91, 95% CI 0.82–0.99, p = 0.005) were associated with a lower risk of developing ≥grade 2 treatment‐related lymphopenia. Cox regression analysis showed that age at brain metastasis (hazard ratio [HR] 1.03, 95% CI 1.01–1.05, p = 0.013), ≥grade 2 treatment‐related lymphopenia, and percentage change in TLC (per 10%, HR 0.94, 95% CI 0.89–0.99, p = 0.032) were prognostic factors of survival. Conclusions: WBRT decreases TLC and the magnitude of treatment‐related lymphopenia is an independent predictor of survival in small‐cell lung cancer patients. [ABSTRACT FROM AUTHOR]

One year following bladder cancer surgery, a 65‐year‐old man had computed tomography (CT) that revealed bilateral pulmonary nodules. Pulmonary wedge resections were performed after the nodules were found to grow in follow‐up. Unusually, we found that these two lesions were not homologous, nor were they metastases from prior bladder cancer, and therefore, synchronous double primary lung cancer (sDPLC) was diagnosed. The immunohistochemical findings excluded the possibility of bladder cancer metastasis, but could not determine whether they were from the same source. Next generation sequencing (NGS) supported the diagnosis sDPLC because they amply demonstrated the two sources' distinct origins. Finally, after discussion with pathologists, this patient was diagnosed as small cell lung carcinoma (SCLC) and received postoperative EP chemotherapy. We also documented a few rather uncommon alterations that might serve as a foundation for further investigation. This case suggests that in addition to immunohistochemical, NGS is also helpful to clarify the etiology and refine the pathological classification of tumors, which has guiding significance for the establishment of precise diagnosis and optimal treatment. [ABSTRACT FROM AUTHOR]

Aims: Subtypes of small cell lung carcinoma (SCLC) are defined by the expression of ASCL1, NEUROD1, and POU2F3 markers. The aim of our study was to explore the extent to which the intratumoral heterogeneity of ASCL1, NEUROD1, and POU2F3 may lead to discrepancies in expression of these markers in surgical samples and their matched tissue microarray (TMA) and lymph node (LN) metastatic sites. Methods and results: The cohort included 77 patients with SCLC. Immunohistochemical examinations were performed on whole slides of the primary tumour, paired TMAs, and metastatic LN sites. Samples with H‐scores >50 were considered positive. Based on the ASCL1, NEUROD1, and POU2F3 staining pattern, we grouped the tumours as follows: ASCL1‐dominant (SCLC‐A), NEUROD1‐dominant (SCLC‐N), ASCL1/NEUROD1 double‐negative with POU2F3 expression (SCLC‐P), and negative for all three markers (SCLC‐I). In whole slides, 40 SCLC‐A (52%), 20 SCLC‐N (26%), 15 SCLC‐P (20%), and two SCLC‐I (3%) tumours were identified. Comparisons of TMAs or LN metastatic sites and corresponding surgical specimens showed that positivity for ASCL1, NEUROD1, and POU2F3 in TMAs (all P < 0.0001) or LN metastatic sites (ASCL1, P = 0.0047; NEUROD1, P = 0.0069; POU2F3, P < 0.0001) correlated significantly with that of corresponding surgical specimens. Conclusion: The positivity for these markers in TMAs and LN metastatic sites was significantly correlated with that of corresponding surgical specimens, indicating that biopsy specimens could be used to identify molecular subtypes of SCLC in patients. [ABSTRACT FROM AUTHOR]

Ciliated muconodular papillary tumor/bronchiolar adenoma (CMPT/BA) is a recently introduced benign lung tumor. It remains unclear whether CMPT/BA is associated with a specific type of lung cancer (LC). We studied the clinicopathological characteristics and genetic profiles of the coexisting primary LC and CMPT/BA (LCCM) cases. We identified eight LCCM (0.4%) from the resected Stage 0–III primary LC (n = 1945). The LCCM cohort was male‐dominant (n = 8), elderly (median 72 years old), and most were smokers (n = 6). In addition to the adenocarcinoma (n = 8), we detected two squamous cell carcinomas and one small cell carcinoma—in some cases, multiple cancer. The target sequence/whole exome sequence (WES) revealed no shared mutations between CMPT/BA and LC. One exceptional case was invasive mucinous adenocarcinoma harboring an HRAS mutation (I46N, c.137T>A), but it was likely to be a single nucleotide polymorphism based on variant allele frequency (VAF). Other driver mutations in LC included EGFR (InDel, n = 2), BRAF(V600E) (n = 1), KRAS (n = 2), GNAS (n = 1), and TP53 (n = 2). BRAF(V600E) was the most frequent mutation in CMPT/BA (60%). In contrast, LC showed no specific trend in driver gene mutations. In conclusion, our study revealed differences in the gene mutation profiles of CMPT/BA and LC in coexisting cases, suggesting mostly independent clonal tumorigenesis of CMPT/BA from LC. [ABSTRACT FROM AUTHOR]

Primary tracheal small‐cell carcinoma is rare, and is often treated using small‐cell lung cancer guidelines given that no standard treatment has been established for it. We report a patient in whom nodules appeared in the trachea and left main bronchus 11 months after surgery for pulmonary large‐cell neuroendocrine carcinoma; a biopsy revealed small‐cell carcinoma. Given the absence of malignant lesions elsewhere in the body, the lesions were diagnosed as primary tracheal small‐cell carcinoma. Respiratory failure progressed rapidly owing to airway stenosis caused by the growing lesion, and the patient required nasal high‐flow therapy. However, the lesions shrank a few days after commencing first‐line chemotherapy, and his respiratory failure resolved. Accelerated hyperfractionated radiotherapy was administered in conjunction with the third course of chemotherapy, and the patient ultimately achieved a complete response. Although the lesions were initially suspected of being postoperative recurrence of pulmonary large‐cell neuroendocrine carcinoma, the fact that the biopsy revealed them to be primary tracheal small‐cell carcinoma indicates that intra‐airway nodules that appear after lung cancer surgery may possibly be primary tracheal tumors. [ABSTRACT FROM AUTHOR]

Background: Neurogenic differentiation factor 1 (NEUROD1) is frequently overexpressed in small‐cell lung cancer (SCLC). NEUROD1 plays an important role in promoting malignant behavior and survival. Methods: In this study, we evaluated the association between putative functional polymorphisms in 45 NEUROD1 target genes and chemotherapy response and survival outcomes in 261 patients with SCLC. Among the 100 single nucleotide polymorphisms (SNPs) studied, two were significantly associated with both chemotherapy response and overall survival (OS) of patients with SCLC. Results: The SNP rs3806915C>A in semaphorin 6A (SEMA6A) gene was significantly associated with better chemotherapy response and OS (p = 0.04 and p = 0.04, respectively). The SNP rs11265375C>T in nescient helix–loop helix 1 (NHLH1) gene was also associated with better chemotherapy response and OS (p = 0.04 and p = 0.02, respectively). Luciferase assay showed a significantly higher promoter activity of SEMA6A with the rs3806915 A allele than C allele in H446 lung cancer cells (p = 4 × 10−6). The promoter activity of NHLH1 showed a significantly higher with the rs11265375 T allele than C allele (p = 0.001). Conclusion: These results suggest that SEMA6A rs3806915C>A and NHLH1 rs11265375C>T polymorphisms affect the promoter activity and expression of the genes, which may affect the survival outcome of patients with SCLC. [ABSTRACT FROM AUTHOR]

Poorly differentiated extrapulmonary neuroendocrine carcinomas (EP NECs) are aggressive cancers characterized by a high Ki‐67 index, rapid tumor growth and poor survival, and are subdivided into small and large cell carcinoma. For small cell carcinoma of the lung, a pulmonary NEC, the combination of cytotoxic chemotherapy (CTX) and a checkpoint inhibitor (CPI) is considered standard therapy and superior to CTX alone. EP NECs are typically treated with platinum‐based regimens, some clinicians have adopted the addition of a CPI to CTX based on data from trials in patients with small cell carcinoma of the lung. In this retrospective study of EP NECs, we report 38 patients treated with standard first‐line CTX and 19 patients treated with CTX plus CPI. We did not observe any additional benefit of adding CPI to CTX in this cohort. [ABSTRACT FROM AUTHOR]

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration‐resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican‐3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3‐targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor‐specific expression. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: The addition of immune checkpoint inhibitors (ICIs) to chemotherapy is the new standard of care in the first‐line treatment of small cell lung cancer (SCLC). However, although the concomitant use of immunotherapy and chemotherapy can increase the antitumor efficacy, it can also increase toxicity. The present study evaluated the tolerability of immune‐based combinations in the first‐line treatment of SCLC. Methods: Relevant trials were identified by searching electronic databases and conference meetings. Seven phase II and III randomized controlled trials and 3766 SCLC patients were included in the meta‐analysis (immune‐based combinations = 2133; chemotherapy = 1633). Outcomes of interest included treatment‐related adverse events (TRAEs) and the rate of discontinuation due to TRAEs. Results: Immune‐based combination treatment was associated with a higher risk of grade 3–5 TRAEs (odds ratio [OR], 1.16; 95% confidence interval [CI]: 1.01–1.35). Immune‐based combinations were associated with a higher risk of TRAEs leading to discontinuation (OR, 2.30; 95% CI: 1.17–4.54). No differences were observed in grade 5 TRAEs (OR, 1.56; 95% CI: 0.93–2.63). Conclusion: This meta‐analysis indicates that the addition of immunotherapy to chemotherapy in SCLC patients is associated with a higher risk of toxicity and probably of treatment discontinuation. Tools for identifying SCLC patients that would not benefit from immune‐based therapy are urgently needed. [ABSTRACT FROM AUTHOR]