Search

Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively cold immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases.

Introduction: Patients with extensive-stage small cell lung cancer (ES-SCLC) have a poor Q6 prognosis and there is no standard protocol for maintenance treatment. Anlotinib as a third-line or beyond therapy for ES-SCLC was proved to be effective. Methods: We retrospectively screened of patients with ES-SCLC who started receiving anlotinib as first-line or second-line therapy at the Second Affiliated Hospital of Chongqing Medical University from November 2018 to December 2022. 30 patients treated with anlotinib based combination therapy and subsequent maintenance therapy were included. The primary study endpoint was progression-free survival (PFS) and the secondary study endpoints were overall survival (OS), clinical response and adverse events (AEs). Results and discussion: In 30 ES-SCLC patients, the median PFS and OS were 7.2 months and 17.6 months respectively. The ORR and DCR were 50.0% (15/30) and 86.7% (26/30) respectively. The median PFS was 8.2 months and 5.6 months for patients who received synchronized immunotherapy or chemotherapy. The median OS was 20.1 months and 15.1 months for patients who received synchronized immunotherapy or chemotherapy. The median time to intracranial progression (TTP) was 7.2 months for patients who were without brain metastases before receiving anlotinib. No unexpected AEs were reported. Grade 3-4 adverse events were reported in 10 patients (33.3%). No treatment-related deaths occurred during this study. Our study has indicated the good efficacy and safety about the application of anlotinib in the maintenance therapy in the first-line or second-line treatment of ES-SCLC and it can also achieve good intracranial control. [ABSTRACT FROM AUTHOR]

Objective: The main objective of this study was to explore and identify new genetic targets in small-cell lung cancer (SCLC) through transcriptomics analysis and Mendelian randomization (MR) analysis, which will help in the subsequent development of new therapeutic interventions. Methods: In this study, we extracted the SCLC dataset from the Gene Expression Omnibus (GEO) database, processed the data, and screened out differentially expressed genes (DEGs) using R software. Based on expression quantitative trait loci data and the genome-wide association study data of SCLC, MR analysis was used to screen the genes closely related to SCLC disease, which intersect with DEGs to obtain co-expressed genes (CEGs), and the biological functions and pathways of CEGs were further explored by enrichment analysis. In addition, the CIBERSORT algorithm was applied to assess the level of immune cell infiltration in SCLC and to analyze the correlation between CEGs and immune cells. Meanwhile, we performed a survival analysis on these five CEGs using an independent cohort of SCLC patients. Finally, the results for the target genes were validated. Results: In this study, 857 DEGs were identified, including 443 up-regulated and 414 down-regulated genes, and 5 CEGs (PSAT1, PSRC1, COLEC12, PLLP, HP) that were significantly associated with SCLC were identified through further intersecting. The results of enrichment analyses indicated that CEGs play important roles in several key functions and pathways. Immune-cell-related analysis revealed the unique distribution of immune cell infiltration in SCLC and the mechanism of immune cell regulation by CEGs. Survival analysis results indicated that PSRC1 was significantly correlated with the overall survival of SCLC, and the survival rate of the high-expression group was markedly lower than that of the low-expression group. Finally, the consistency of the results between the validation group analyses and MR analysis confirmed that the results of this study is reliable. Conclusion: The CEGs and their associated functions and pathways screened in this study may be potential targets of therapeutic intervention in SCLC by targeting specific molecular pathways. [ABSTRACT FROM AUTHOR]

Introduction: Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, contributing to its aggressive progression and therapy resistance. Autophagy, a conserved cellular process, is implicated in many cancers, but its role in SCLC remains unclear. Methods: Using a genetically engineered mouse model (Rb1fl/fl ; Trp53fl/fl ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to investigate its effects on SCLC biology. Additional in vitro experiments were conducted to modulate autophagic flux in NE and non-NE SCLC cell lines. Results: Tumor subpopulations with high autophagic flux displayed increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics. Conversely, low-autophagic flux subpopulations exhibited immune-related signals and non-NE traits. In vitro , increasing autophagy induced NE features in non-NE cell lines, while autophagy inhibition in NE cell lines promoted non-NE characteristics. Discussion: This study provides a novel model for investigating autophagy in vivo and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights. [ABSTRACT FROM AUTHOR]

Topoisomerase II inhibitors, particularly etoposide, have long been integral to the treatment of lung cancer, especially small cell lung cancer. This review comprehensively examines the mechanisms of action of etoposide, its clinical efficacy, and its role in current lung cancer treatment regimens. Etoposide exerts its anticancer effects by inducing DNA strand breaks through the inhibition of topoisomerase II, leading to cancer cell apoptosis. Despite their widespread use, challenges such as drug resistance, toxicity, and limited efficacy in non-small cell lung cancer have spurred ongoing research on combination therapies and novel drug formulations. Emerging therapeutic strategies include the integration of etoposide with immunotherapy, targeted therapies, and novel drug delivery systems aimed at enhancing the therapeutic window and overcoming drug resistance. This article aims to inform the development of more effective treatment strategies by providing a critical overview of the clinical applications of etoposide and exploring future directions for lung cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Whether the intake of whole grain foods can protect against lung cancer is a long-standing question of considerable public health import, but the epidemiologic evidence has been limited. Therefore we aim to investigate the relationship between whole grain food consumption and lung cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Methods: Diet was assessed with a self-administered Diet History Questionnaire (DHQ) at baseline. All incident lung cancer cases were pathologically verified. Hazard ratios and 95% confidence intervals for lung cancer risk associated with whole grain food consumption were estimated by Cox proportional hazards regression. Results: During a median follow-up of 12.2 years, a total of 1,706 incident lung cancer events occurred, including 1,473 (86.3%) cases of non-small cell lung cancer (NSCLC) and 233 (13.7%) of small cell lung cancer (SCLC). After multivariate adjustment, comparing the highest quarter of consumption of whole grain foods to the lowest quarter, a 16% lower rate (HR 0.84, 95% CI 0.73–0.98) of lung cancer risks and a 17% lower rate (HR 0.83, 95% CI 0.69–0.98) for NSCLC were found, but no significant difference was shown for SCLC (HR 0.95, 95% CI 0.63–1.44). These results were consistently observed after a large range of subgroup and sensitivity analyses. A linear dose-response pattern was shown for lung cancer, NSCLC, and SCLC (P for non-linearity > 0.05). Conclusions: In this large prospective cohort study, whole grain food consumption was associated with reduced lung cancer and NSCLC. Our findings suggest a potential protective role of whole grain foods against lung cancer. [ABSTRACT FROM AUTHOR]

Background: As in numerous cancers, the connection between the Ki-67 proliferation index and response to treatment in cellular breakdown in the lungs is underlined. The purpose of this study was to investigate the connection between the Ki-67 proliferation index and radiotherapy's therapeutic and survival effects in small cell lung cancer. Methods: The limited-stage small cell lung cancer patients in our hospital were retrospectively reviewed. Patients receiving standard chemoradiotherapy were included in the study. Age, sex, cancer stage, comorbidities, response to treatment, and survival time were recorded. Bronchoscopic or transthoracic lung biopsy specimens which were taken at the time of diagnosis were stained with the Ki-67 immunohistochemical stain. Survival of patients and treatment response were compared statistically with the Ki-67 values. Results: The Ki-67 proliferation index (62.29 ± 7.52) was lower in patients with partial response than in patients with complete response (77.08 ± 2.84) (p < 0.001). When the correlation between survival time and Ki-67 was examined, there was a positive correlation between the Ki-67 and survival time (p: 0.019; r: 0.426). The patients were divided into two groups: Ki-67 < 68.70 and Ki-67 ≥ 68.70. In patients with Ki-67 ≥ 68.70, the survival rate was better than that of patients with Ki-67 < 68.70 (p: 0.012). In Cox regression analysis, Ki-67 PI < 68.7 was found that increased mortality by 2742 times independently. Conclusions: Patients with a high Ki-67 had a better survival effect than those with low Ki-67, and patients with complete responses had a higher Ki-67 value. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions This study aims to explore the value of habitat‐based magnetic resonance imaging (MRI) radiomics for predicting the origin of brain metastasis (BM).To investigate whether habitat‐based radiomics can identify the metastatic tumor type of BM and whether an imaging‐based model that integrates the volume of peritumoral edema (VPE) can enhance predictive performance.A primary cohort was developed with 384 patients from two centers, which comprises 734 BM lesions. An independent cohort was developed with 28 patients from a third center, which comprises 70 BM lesions. All patients underwent T1‐weighted contrast‐enhanced (T1CE) and T2‐weighted (T2W) MRI scans before treatment. Radiomics features were extracted from tumor active area (TAA) and peritumoral edema area (PEA) selected using the least absolute shrinkage and selection operator (LASSO) to construct radiomics signatures (Rads). The Rads were further integrated with VPE to build combined models for predicting the metastatic type of BM. Performance of the models were assessed through receiver operating characteristic (ROC) curve analysis.Rads derived from TAA and PEA both showed predictive power for identifying the origin of BM. The developed combined models generated the best performance in the training (AUCs, lung cancer [LC]/non‐lung cancer [NLC] vs. small cell lung cancer [SCLC]/non‐small cell lung cancer [NSCLC] vs. breast cancer [BC]/gastrointestinal cancer [GIC], 0.870 vs. 0.946 vs. 0.886), internal validation (area under the receiver operating characteristic curves [AUCs], LC/NLC vs. SCLC/NSCLC vs. BC/GIC, 0.786 vs. 0.863 vs. 0.836) and external validation (AUCs, LC /NLC vs. SCLC/NSCLC vs. BC/GIC, 0.805 vs. 0.877 vs. 0.774) cohort.The developed habitat‐based radiomics models can effectively identify the metastatic tumor type of BM and may be considered as a potential preoperative basis for timely treatment planning. [ABSTRACT FROM AUTHOR]

Background: Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP. Methods: Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21–28 days at a dose of area under the curve 4–6 on day 1 and etoposide at a dose of 80–100 mg/m2 on days 1–3. Results: Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0–9.6%, p = 0.038). The objective response rate was 83.9% (95% CI: 82.5–85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7–6.8) months and 14.0 (95% CI: 7.6–27.6) months, respectively. The 1-year survival rate was 61% (95% CI 41–76). Conclusions: The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP. [ABSTRACT FROM AUTHOR]

Primary small cell neuroendocrine carcinoma of the prostate is extremely rare, highly aggressive, and has a very poor prognosis, with an overall survival typically not exceeding one year. Standard treatment is generally based on the regimen for small cell lung cancer (SCLC), with guidelines recommending etoposide combined with cisplatin (EP regimen) as the first-line treatment. However, their therapeutic effects are limited. For primary small cell neuroendocrine carcinoma of the prostate that has failed the EP regimen treatment, there is currently a lack of relevant treatment methods. Here, we report a case of small cell neuroendocrine carcinoma of the prostate with multiple metastases, whose disease rapidly progressed despite receiving EP and second-line systemic chemotherapy. The patient was then administered a combination of anlotinib and tislelizumab. After treatment, the patient's symptoms were controlled, tumor marker levels decreased, and imaging showed significant improvement. The patient had a progression-free survival time of more than 22 months and continued to receive treatment. This is the first report of the use of anlotinib combined with tislelizumab for the treatment of primary small cell neuroendocrine carcinoma of the prostate, providing a new therapeutic option for patients with this disease. [ABSTRACT FROM AUTHOR]

Background/Objectives: ACEIs protect against radiation pneumonitis by reducing angiotensin II production, oxidative stress, and inflammation. This study highlights the significance of concurrent angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use in radiotherapy by evaluating its impact on radiotherapy-related side effects and survival outcomes, addressing the gap in existing research and providing insights to guide clinical practice in oncology. Methods: The literature was retrieved from the MEDLINE, EMBASE, Web of Science, and Scopus databases from January 2000 to October 2024. Studies on adults (≥18 years) with histologically confirmed cancer, receiving ACEIs or ARBs during radiotherapy, were included. Radiotherapy-related side effects and clinical outcomes were analysed using odds ratios (ORs) and 95% confidence intervals (95%CIs), comparing ACEI/ARB users to non-users. Differences in the median survival time, recurrence, and death rates were also calculated. Results: Sixteen studies (14 cohort studies and two randomised trials) were included. ACEI users exhibited a 50% reduction in the risk of ≥grade 2 radiation pneumonitis (OR: 0.50, 95%CI: 0.32–0.77) in lung cancer and significant reductions in the odds of proctitis (80%, OR: 0.20, 95%CI: 0.12–0.33), haematuria (75%, OR: 0.25, 95%CI: 0.16–0.41), and rectal bleeding (61%, OR: 0.39, 95%CI: 0.30–0.51) in prostate cancer. ACEI/ARB users showed reduced symptomatic radiation necrosis in brain metastases and better 6-month functional independence in supratentorial glioblastoma. Among six studies reporting survival, ACEI/ARB users had longer median survival in early-stage non-small-cell lung cancer and glioblastoma but shorter survival in small cell lung cancer and brain metastases. ARB users had inconsistent survival rates for lung cancer. The varying survival outcomes suggest that ACEIs/ARBs have different effects depending on the cancer type and stage, potentially influenced by cancer-specific factors, treatment protocols, or disease progression. Conclusions: ACEI use is associated with a reduction in radiation pneumonitis, but evidence for other radiotherapy-related toxicity and survival outcomes remains inconsistent across cancer types and severities. Further research should carefully control for confounders. [ABSTRACT FROM AUTHOR]

Background Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer and prostate cancer. We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the American Association for Cancer Research Genomics, Evidence, Neoplasia, Information, Exchange database. Methods FOXA1 alterations were characterized across more than 87 000 samples from more than 30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the Memorial Sloan Kettering - Metastatic Events and Tropisms (MSK-MET) cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models. Results FOXA1 was altered in 1869 (2.1%) samples, with distinct patterns across different cancers: prostate cancer enriched with indel-inframe alterations, breast cancer with missense mutations, and lung cancers with copy number amplifications. Of 74 715 samples with FOXA1 copy number profiles, amplification was detected in 834 (1.1%). Amplification was most common in non–small cell lung cancer (NSCLC; 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by breast cancer (2% primary; 1.6% metastatic) and prostate cancer (2.2% primary; 1.6% metastatic). Copy number amplifications were associated with decreased overall survival in NSCLC (HR = 1.45, 95% confidence interval [CI] = 1.06 to 1.99; P  = .02), breast cancer (HR = 3.04, 95% CI = 1.89 to 4.89; P  = 4e−6), and prostate cancer (HR = 1.94, 95% CI = 1.03 to 3.68; P  = .04). Amplifications were associated with widespread metastases in NSCLC, breast cancer, and prostate cancer. Conclusions FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is the most aggressive neuroendocrine lung cancer, with a dismal 5‐year survival rate. No reliable biomarkers or imaging are available for early SCLC detection. In a search for a specific marker of SCLC, this study identified that hepatocyte cell adhesion molecule 2 (HEPACAM2), a member of the immunoglobulin‐like superfamily, is highly and specifically expressed in SCLC. Methods: This study investigated HEPACAM2 expression in patients with SCLC via RNA sequencing and evaluated its relationship to progression‐free survival (PFS) and overall survival (OS). Immunofluorescence microscopy was used to assess the cellular location of HEPACAM2 and to conduct in vitro and in vivo studies to understand its expression and functional significance. These findings were integrated with databases of patients with SCLC. Results: HEPACAM2 is highly expressed and specific to SCLC. HEPACAM2 levels are inversely correlated with PFS and OS in patients with SCLC and are expressed at all stages. Moreover, HEPACAM2 messenger RNA and its peptides can be detected in the secretomes in cell lines. Positively correlated with ASCL1 expression in SCLC tumors, HEPACAM2 is localized primarily to the plasma membrane and linked to extracellular matrix signaling and cellular migration. A loss of HEPACAM2 in SCLC cells attenuated ASCL1 and MYC expression. Consistent with clinical data, in vitro and in vivo studies suggested that HEPACAM2 promotes cancer cell growth. Conclusions: With its remarkable specificity, high expression, presence in early disease, and extracellular secretion, HEPACAM2 could be a potential diagnostic cell surface biomarker for early SCLC detection. These findings warrant further investigation into its role in the pathobiology of SCLC. Hepatocyte cell adhesion molecule 2 (HEPACAM2) shows great promise as a diagnostic biomarker for small cell lung cancer (SCLC) due to its high specificity, strong expression in SCLC tissues, and extracellular secretion, which make it an ideal candidate for early detection. As a cell surface protein, HEPACAM2 offers the potential for minimally invasive diagnostic approaches to improve SCLC screening and early intervention strategies. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the malignant tumors with high morbidity and mortality worldwide. Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that is closely associated with tobacco exposure, accounting for 13% to 15% of all lung cancer cases. It is characterized by a high proliferation rate and exceptional metastatic capacity. At the time of diagnosis, approximately 70% of the patients have metastasized and are classified as extensive-stage small cell lung cancer (ES-SCLC). From 1980 to 2018, chemotherapy and radiotherapy were the main treatment strategies for SCLC. Etoposide combined with platinum has remained the standard first-line treatment for ES-SCLC. Although SCLC is very sensitive to initial treatment, the majority of patients have disease progression within 6 months, and treatment options after recurrence are very limited, and the median survival time is only about 8-10 months. The advent of immune checkpoint inhibitors (ICIs), particularly programmed death-ligand 1 (PD-L1) and programmed death -1 (PD-1) inhibitors, has brought new hope to patients with SCLC. PD-1/PD-L1 plus chemotherapy have significantly prolonged overall survival of patients with ES-SCLC, which has become the new standard of first-line treatment for ES-SCLC. Currently, a raised number of immune checkpoint inhibitors (ICIs) have been approved in China for the treatment of SCLC, providing more treatment options for SCLC patients. To further standardize the clinical practice of SCLC immunotherapy, the "Expert consensus on immunotherapy for SCLC (2025 edition)" has been developed based on domestic and international guidelines, consensus, and relevant medical evidence, aiming to provide reference and guidance for domestic clinicians. [ABSTRACT FROM AUTHOR]

Introduction: Platinum rechallenge is recommended for patients with small cell lung cancer (SCLC) who relapse ≥90 days after completing first-line chemotherapy, although it may not always be the most suitable option. Areas covered: Articles for review were identified via PubMed and ClinicalTrials.gov searches, supplemented with non-indexed publications (e.g. conference abstracts) known to the manufacturer. We examined evidence for platinum re-exposure in patients with sensitive relapsed SCLC, and present lurbinectedin as a potential alternative. The complementary mechanisms of action of lurbinectedin and platinum, owing to opposite sensitivity of SCLC cells, may resensitize tumor cells to platinum. As efficacy outcomes with lurbinectedin are equivalent or better than those with platinum rechallenge and its hematological safety profile is more favorable, achieving maximum dose intensity is more likely. The simpler dosing schedule of lurbinectedin (1 vs 3 days) and lack of need for granulocyte colony-stimulating factor primary prophylaxis lessens treatment burden. Expert opinion: Incorporation of lurbinectedin into therapeutic algorithms for relapsed SCLC has challenged long-established treatment paradigms. Initial evidence indicates that using lurbinectedin after failure of first-line platinum may prolong the platinum-free interval and reserve platinum for later use. Current evidence supports lurbinectedin as a second-line option in patients with sensitive relapsed SCLC. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugate (ADC) therapy has transformed treatment for several solid tumors, including small cell lung cancer (SCLC). However, significant challenges remain, including systemic toxicity, acquired resistance, and the lack of reliable biomarkers for patient selection. To enhance the effectiveness of ADC therapies in SCLC, we focused on target selection in this study by investigating the expression of ADC targets - SEZ6, DLL3, CD276, and TACSTD2 - in cell lines and patient samples. SEZ6 expression was significantly elevated in various SCLC transcriptional subtypes, particularly ASCL1, and exhibited gender-specific differences, being lower in women. DLL3 was primarily observed in the ASCL1 subtype, while CD276 showed high expression in non-neuroendocrine subtypes. TACSTD2 levels were generally low and attenuated in lymph nodes and brain metastases compared to primary tumors. Our findings underscore the importance of understanding target expression patterns to optimize ADC therapy and advance precision medicine in SCLC treatment. [ABSTRACT FROM AUTHOR]

Various therapeutic strategies have been developed to treat Pancreatic Cancer (PaCa). Unfortunately, most efforts have proved unfruitful, as the poor prognosis observed in this disease has only attained little improvement in the past 40 years. Recently, deeper understanding of the immune system and its interaction with malignant tumors have allowed significant advances in immunotherapy. Consistent with this, some of the most promising approaches are those that involve T-cell redirection to the tumor site, such as bispecific T-cell engagers (BiTEs). These recombinant antibodies bridge cytotoxic T-cells to tumor cells, inducing target cell-dependent polyclonal T-cell activation/proliferation, which in turn results in elimination of bound tumor cells. Blinatumomab, an anti-CD19 BiTE, received FDA approval in 2014 for Precursor B-cell Acute Lymphoblastic Leukemia. In the past decade, it has demonstrated impressive clinical benefit in patients with B-cell leukemias; and other T-cell engagers have been FDA-approved for hematological malignancies and other diseases, yet limited effect has been observed with other BiTEs against solid cancers, including PaCa. Nevertheless, on May 2024, Tarlatamab, an anti-DLL3 BiTE was approved by the FDA for extensive small cell lung cancer, becoming the first BiTE for solid tumors. In this review, the generation of BiTEs, therapeutic features, manufacturing issues as well as the remaining challenges and novel strategies of BiTE therapy in the context of PaCa, including the lessons we can learn from the use of BiTEs on other types of cancer will be explored. [ABSTRACT FROM AUTHOR]

Background: Lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is the most prevalent cancer globally and remains the leading cause of cancer-related mortality. Epidermal growth factor receptor (EGFR) mutations, frequently observed in female NSCLC patients, have revolutionized treatment strategies with the advent of tyrosine kinase inhibitors (TKIs). These therapies significantly improve survival and are considered the standard of care for patients harboring EGFR mutations. However, most patients eventually develop resistance to EGFR-TKIs, leading to disease progression. Resistance mechanisms are classified as either EGFR-dependent or EGFR-independent, the latter involving bypass pathway activation, including dysregulation of downstream signaling cascades. EGFR-independent resistance often renders all EGFR-TKIs ineffective, necessitating further investigation into resistance mechanisms. Case summary: We report the case of a 63-year-old Chinese woman diagnosed with synchronous lung adenocarcinoma harboring an EGFR exon 21 far-loop insertion mutation and clear cell renal cell carcinoma (ccRCC). A multidisciplinary team recommended systemic therapy for the lung adenocarcinoma and clinical observation for ccRCC. First-line treatment with bevacizumab plus pemetrexed-carboplatin achieved a progression-free survival (PFS) of 7 months. Second-line treatment with sintilimab and nedaplatin resulted in a PFS of 4.9 months. Third-line therapy with sintilimab and anlotinib proved ineffective. In the fourth line, the patient received furmonertinib, a third-generation EGFR-TKI, based on the FAVOUR trial. This treatment achieved durable disease control with excellent tolerability, yielding a PFS of 27 months and ongoing clinical benefit. Conclusion: This case demonstrates that furmonertinib can provide significant clinical benefit to NSCLC patients with complex resistance mechanisms, including those involving the PIK3CA/mTOR pathway. These findings support its potential to overcome EGFR-TKI resistance and warrant further investigation in similar clinical contexts. [ABSTRACT FROM AUTHOR]

Objective: Small cell lung cancer (SCLC) is commonly recognized as the most fatal lung cancer type. Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers, their benefits are limited to a minority of patients with SCLC. In the present study, novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated. Methods: We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC. The functional role of the key gene identified in SCLC was determined both in vitro and in vivo. Results: A significant correlation was observed between patient survival and CD56dim natural killer (NK) cell proportion. Furthermore, we noted that the hub gene ubiquitin-specific protease 1 (USP1) is closely correlated with both CD56dim NK cells and overall survival in SCLC. Bioinformatics analysis revealed that USP1 is upregulated in SCLC. In addition, gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses. By co-cultivating NK-92 cells with SCLC cells, we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition. Furthermore, using a nude-mice xenograft tumor model, we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers. Conclusions: Our study findings highlight the importance of NK cells in regulating SCLC. USP1 overexpression can inhibit NK cell-mediated immunity; therefore, USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy. [ABSTRACT FROM AUTHOR]

Objectives: The ETER701 trial demonstrated that benmelstobart combined with anlotinib and etoposide-carboplatin (EC) significantly extends survival in patients with extensive-stage small cell lung cancer (ES-SCLC), setting a new record for median overall survival. In contrast, anlotinib plus EC only significantly prolongs progression-free survival. However, there is currently no evidence evaluating the cost-effectiveness of these regimens as first-line treatments. Therefore, this study assesses the cost-effectiveness of these three first-line treatment options from the perspective of the Chinese healthcare system. Methods: A time-varying Markov model was constructed to simulate the disease progression of a 62-year-old patient with ES-SCLC, assessing direct medical costs, health benefits, and incremental cost-effectiveness ratios (ICER). Both flexible and standard parametric models were included to fit and extrapolate survival data. The probabilities, costs, and health utilities required for the model were sourced from literature, databases, and expert consultations. Additionally, sensitivity and scenario analyses were conducted to explore the impact of various parameters on model uncertainty. Results: Compared to EC alone, the combination of benmelstobart, anlotinib, and EC added $80,879.12 in cost for 0.7288 quality-adjusted life years (QALYs), an ICER of $110,970.19/QALY. Anlotinib plus EC added $4,107.86for 0.1951 QALYs, an ICER of $21,056.19/QALY. At a $37,598/QALY threshold, the cost-effectiveness probability for benmelstobart combination is 0%, and for anlotinib combination is 80.42%. A 73.79% price cut for benmelstobart is needed for cost-effectiveness. Conclusions: In China, benmelstobart combined with anlotinib and EC is not a cost-effective first-line treatment for ES-SCLC; however, reducing the price of benmelstobart by 73.79% could make this regimen cost-effective. In contrast, anlotinib combined with EC may represent a more cost-effective first-line treatment option. [ABSTRACT FROM AUTHOR]

The Phase 3 RATIONALE-312 trial (NCT04005716) showed that tislelizumab plus chemotherapy led to a noteworthy enhancement resulted in a significant improvement in overall survival among patients diagnosed with extensive-stage small-cell lung cancer (ES-SCLC) compared to chemotherapy alone. The treatment also had an acceptable level of safety. Nevertheless, the debate over the efficacy of implementing several treatment plans in competition continues due to the significant expenses involved. Therefore, we aimed to evaluate the potential efficacy and cost of tislelizumab treatment as a first-line treatment for the ES-SCLC patient population in China. The study assessed primary health outcomes by measuring life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). This was done using a Markov model considering three health states with a 15-year horizon. To assess its model resilience, we conducted one-way sensitivity analyses with probability. In addition, subgroup analyses of some pre-specified patients was performed. Compared to chemotherapy alone, tislelizumab plus chemotherapy resulted in an additional 0.34 ($8,028) QALYs, leading to an ICER of $23,553 per QALY for the overall patient population. The ICER was lower than the assumed willingness-to-pay threshold of $35,367 per QALY. Approximately 60% of simulations suggested that tislelizumab in combination with chemotherapy was cost-effective, while 40% suggested that chemotherapy alone was cost-effective. The subsequent sensitivity analyses revealed that the health utility value associated with the disease progression parameter had the greatest influence on ICER. Tislelizumab plus chemotherapy was a preferable treatment option for regimens for patients with ES-SCLC in China. This finding is important in guiding the Chinese healthcare system. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the prognostic role of pretreatment albumin-bilirubin (ALBI) grade in lung cancer patients. Methods: The PubMed, EMBASE, Web of Science and CNKI databases were searched up to April 20, 2024. Primary outcomes included the overall survival (OS), progression-free survival (PFS) and cancer-specific survival (CSS). Hazard ratios (HRs) with 95% confidence intervals (CIs) were combined and subgroup analysis based on the type of lung cancer [non-small cell lung cancer (NSCLC) vs. small cell lung cancer (SCLC)] and treatment [surgery vs. immune checkpoint inhibitors (ICIs) vs. chemotherapy] was conducted. Results: Eight studies with 2,057 patients were included. Pooled results indicated that elevated pretreatment ALBI grade was significantly related to poor OS (HR = 2.50, 95% CI: 2.03–3.09, P<0.001), PFS (HR = 1.91, 95% CI: 1.56–2.33, P<0.001) and CSS (HR = 1.90, 95% CI: 1.11–3.11, P = 0.018). Subgroup analysis for OS based on the pathological type and primary treatment manifested similar results. Conclusion: Pretreatment ALBI grade is associated with prognosis in lung cancer and patients with elevated ALBI grade are more likely to experience worse survival. [ABSTRACT FROM AUTHOR]

ABSTRACT Histologic transformation from non‐small cell to small cell lung cancer (SCLC) is a resistance mechanism to immune checkpoint inhibitors. We report herein a case of lung adenocarcinoma who developed liver and brain metastases during adjuvant atezolizumab therapy. The patient underwent a craniotomy to resect a brain metastasis, which was pathologically diagnosed as SCLC. He subsequently received platinum‐based chemotherapy with durvalumab, resulting in sustained regression of the liver metastases. This case demonstrates a metastatic brain tumor‐acquired resistance to atezolizumab through histologic transformation from adenocarcinoma to SCLC. Therefore, rebiopsy is needed if recurrent disease appears during immune checkpoint inhibitor treatment in patients with non‐small cell lung cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Materials and Methods Results Conclusion Small cell lung cancer (SCLC) is known for its high proliferative rate and poor prognosis. Although Delta‐like ligand 3 (DLL3) is specifically expressed on the surface of SCLC, the association of DLL3 with prognosis in SCLC remains uncertain. Hence, we aimed to evaluate prognostic role of DLL3 in extensive stage of SCLC treated with first‐line chemotherapy.A total of 54 patients with extensive stage of SCLC (ES‐SCLC) who were treated with first‐line chemotherapy were included for our analysis. In addition, tissue specimen should be available for immuno‐histochemical staining for DLL3, and their clinico‐pathologic data, including progression‐free survival (PFS) and overall survival (OS), were obtained. DLL3 expression and the percentage of tumor cells with DLL3 positive among total cancer cells were analyzed microscopically and DLL3 high and DLL3 low were defined as the percentage of DLL3 positive tumor cells versus total cancer cells ≧ 75% and < 75%, respectively.DLL3 expression was not associated with any of the clinico‐pathological characteristics such as age at diagnosis, sex, response to first‐line chemotherapy, second‐line chemotherapy (Yes or No), and number of metastatic sites. However, response to first‐line chemotherapy and number of metastatic sites were correlated to PFS, while DLL3 expression and number of metastatic sites were correlated to OS.DLL3 was highly expressed in SCLC, and not associated with any clinico‐pathological characteristics. In survival outcome, DLL3 was correlated with worse OS, which suggests the prognostic role of DLL3 in ES‐SCLC. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is a highly fatal malignancy, the complex tumor microenvironment (TME) is a critical factor affecting SCLC progression. Cancer-associated fibroblasts (CAFs) are crucial components of TME, yet their role in SCLC and the underlying mechanisms during their interaction with SCLC cells remain to be determined. Methods: Microenvironmental cell components were estimated using transcriptome data from SCLC tissue available in public databases, analyzed with bioinformatic algorithms. A co-culture system comprising MRC5 fibroblasts and SCLC cell lines was constructed. RNA sequencing (RNA-seq) was performed on co-cultured and separately cultured MRC5 and H196 cells to identify differentially expressed genes (DEGs) and enriched signaling pathways. Glycolysis and STING signaling in SCLC cells were assessed using glucose uptake assays, qRT-PCR, and Western blot analysis. Immunohistochemical staining of SCLC tissue arrays quantified α-SMA, HLA-DRA and CD8 expression. Results: Non-neuroendocrine (non-NE) SCLC-derived CAFs exhibited more abundance and DEGs than NE SCLC-derived CAFs did, which interact with non-NE SCLC cells can induce the enrichment of glycolysis-related genes, increasement of glucose uptake, upregulation of glycolytic signaling proteins in non-NE SCLC cells and accumulation of lactate in the extracellular environment, confirming CAF-mediated glycolysis promotion. Additionally, glycolysis-induced ATP production activated STING signaling in non-NE SCLC cells, which upregulated T cell chemo-attractants. However, CAF abundance did not correlate with CD8 + T cell numbers in SCLC tissues. Additionally, non-NE SCLC cell-educated CAFs exhibited features of antigen-presenting CAFs (apCAFs), as indicated by the expression of major histocompatibility complex (MHC) molecules. Co-localization of HLA-DRA and α-SMA signals in SCLC tissues confirmed apCAF presence. The apCAFs and CD8 + T cells were co-located in the SCLC stroma, and there was a positive correlation between CAFs and regulatory T cell (Treg) abundance. Conclusion: Our findings suggest that crosstalk between CAFs and non-NE SCLC cells promotes glycolysis in non-NE SCLC cells, thereby increase T cell chemo-attractant expression via activating STING signaling. On the other hand, it promotes the presence of apCAFs, which probably contributes to CD8 + T cell trapping and Treg differentiation. This study emphasizes the pro-tumor function of CAFs in SCLC by promoting glycolysis and impairing T cell function, providing direction for the development of novel therapeutic approaches targeting CAF in SCLC. [ABSTRACT FROM AUTHOR]

Background: The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs). Materials and methods: Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model’s performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Result: Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p < 0.05). In the meantime, PNI was considerably lower in the PD group than in the PR group (both p < 0.01). Kaplan-Meier curves demonstrated that patients with a low SII-PNI had prolonged progression-free survival (PFS) and overall survival (OS) compared to those with a high SII-PNI (all p < 0.01). Multivariate Cox analysis showed that PS = 1, bone metastasis, brain metastasis, and SII-PNI = 1,2 after four treatment cycles were independent risk factors for shorter OS and were included in the nomogram model. The ROC curves, C-index, and DCA curves confirm that the SII-PNI scores-based nomograms have strong predictive accuracy for OS. Conclusion: There was a significant correlation between pre- and post-treatment SII-PNI and treatment effect in ES-SCLC. The SII-PNI score after four treatment cycles is a useful prognostic indicator for ES-SCLC patients receiving chemotherapy combined with immune checkpoint inhibitors (ICIs). [ABSTRACT FROM AUTHOR]

What is this summary about? This is a summary of a phase 2 clinical study called DeLLphi-301. The study looked at how effective and safe a medicine called tarlatamab was in participants with small cell lung cancer (SCLC). Participants previously received at least two other treatments for their SCLC. Tarlatamab is a new medicine that locates a protein called DLL3 on the cancer, which allows T cells to attack the cancer. T cells belong to the body's natural defense system known as the immune system. The DeLLphi-301 study separated participants into two groups to receive tarlatamab 10 mg or 100 mg to determine which dose best shrank SCLC with minimal side effects. All participants received a small first dose (1 mg tarlatamab) to decrease the risk of an immune system reaction called cytokine release syndrome (CRS). Tarlatamab was given through the participant's vein once every 2 weeks. This method of administration is known as intravenous (IV) infusion. What were the results of the DeLLphi-301 study? In the group given 10 mg tarlatamab, 40% of participants responded to treatment (cancer shrank). In the group given 100 mg tarlatamab, 32% of participants responded to treatment (cancer shrank). After taking tarlatamab at either dose, 59% of participants lived for at least 6 months without their cancer growing or getting worse. The most common side effect was CRS, which occurred in 51% of participants in the group given 10 mg tarlatamab and 61% of participants in the group given 100 mg tarlatamab. Other common side effects were decreased appetite, fever, constipation, and anemia. Some participants had a type of immune reaction called immune effector cell–associated neurotoxicity syndrome (ICANS). A small number of participants (3%) stopped taking tarlatamab because of side effects related to tarlatamab. What do the results from the DeLLphi-301 study mean? The study found that tarlatamab given every 2 weeks shrank SCLC in participants with SCLC who received previous treatments. Participants given the 10 mg tarlatamab dose had fewer side effects than those given the 100 mg tarlatamab dose. Clinical Trial Registration:NCT05740566 (DeLLphi-304) (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) is one of the most common neoplastic diseases and a leading cause of death in Saudi Arabia. Its incidence in Saudi Arabia has increased by more than 3% within two decades. Our study aimed to describe the epidemiological and genetic landscapes of LC in Al-Madinah city in Saudi Arabia. Methods: A retrospective analysis was conducted on the medical records of 65 patients diagnosed with lung cancer between 2015 and 2021 at a single medical oncology center in Al-Madinah city of Saudi Arabia. Results: The mean patients' age was 59.2 years, with 50 (76.9%) males and 15 (23.1%) females; 37 (57%) smokers, and 28 (43%) non-smokers. The number of cases per year has increased gradually over six years from 2015 (n = 3) to 2020 (n = 13). The most prevalent histopathological diagnosis was non-small cell lung cancer (NSCLC) (n = 58, 89%) followed by small cell lung cancer (SCLC) (n = 5, 7.8%). NSCLC was frequently more common in smokers while squamous cell carcinoma was more frequent in non-smokers. Around 89% (n = 58) of the cases were diagnosed in late stage IV and the most common metastatic sites were to pleura and lymph nodes (n = 32, 49.2%). Program Death Legend-1 (PDL-1) was fairly expressed in 7/10 (70%) patients. Epidermal Growth Factor Receptor (EGFR) was mutated in 5/17 (29%) patients. Other mutations detected include Anaplastic Lymphoma Kinase (ALK) and phosphatidylinositol 3-kinase (PIK3C) mutations in two patients. Conclusions: Our study revealed that lung cancer is a significant burden in Al-Madinah city of Saudi Arabia. If the risk factors are not controlled, the number of cases may increase considerably. Health education about the risk factors and cancer prevention helps in early lung cancer detection. [ABSTRACT FROM AUTHOR]

Background: The therapeutic advantage of radiotherapy (RT) as an adjunct to first-line immunotherapy and chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC) remains unclear. This study aimed to elucidate the value of RT based on the first failure pattern of ES-SCLC. Methods: In this study, we retrospectively analyzed ES-SCLC patients treated with first-line chemotherapy and immune checkpoint inhibitors (ICIs) at Shanghai Chest Hospital from August 2018 to October 2023. Our study recorded the first failure pattern in ES-SCLC, analyzed the main sites of disease progression, explored factors that may affect prognosis and estimated the value of RT in extending patient survival in the immunotherapy era. Key endpoints included the first failure pattern, progression-free survival (PFS) and overall survival (OS). Results: Among 344 patients, 70 (20%) had local failure, 105 (31%) had distant failure, 69 (20%) experienced both types of failure, and 100 (29%) showed no disease progression. Disease progression occurred in 244 patients (71%). They were divided into two groups: 183 without pre-progression RT and 61 with pre-progression RT. In the non-pre-progression RT group, 55 patients (30%) had local failure, 72 patients (39%) had distant failure, and 56 patients (31%) had both. In the pre-progression RT group, 15 patients (25%) had local failure, 33 patients (54%) had distant failure, and 13 patients (21%) had both. Univariate and multivariate analyses identified RT as an independent prognostic factor for improved OS (P < 0.05). Subgroup analysis further confirmed these findings. Pre-progression RT was associated with superior PFS (P < 0.05). The median overall survival (mOS) was 20.1 months (95% confidence interval [CI]: 15.5–24.7 months) in the pre-progression RT group, compared to 13.4 months (95% CI: 13.4–19.2 months) in the non-pre-progression RT group. Conclusion: RT improved OS in these patients, and pre-progression RT improved PFS further. Pre-progression RT shows a trend toward OS benefit. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is associated with tumour growth, infiltration, and metastasis. This study aimed to detect the mechanisms of angiogenesis-related genes (ARGs) in multiple myeloma (MM) and to construct a new prognostic model. Methods: MM research foundation (MMRF)-CoMMpass cohort, GSE47552, GSE57317, and ARGs were sourced from public databases. Differentially expressed genes (DEGs) in the tumour and control cohorts in GSE47552 were determined through differential expression analysis and were enriched with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Weighted gene coexpression network analysis (WGCNA) was applied to derive modules linked to the ARG scores and obtain module genes in GSE47552. Differentially expressed ARGs (DE-ARGs) were selected for subsequent analyses by overlapping DEGs and module genes. Furthermore, prognostic genes were selected using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Depending on the prognostic genes, a risk model was constructed, and risk scores were determined. Moreover, MM samples from MMRF-CoMMpass were sorted into high- and low-risk teams on account of the median risk score. Additionally, correlations among clinical characteristics, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), immune analysis, immunotherapy predictions and the mRNA‒miRNA‒lncRNA network were carried out. Results: A total of 898 DEGs, 211 module genes, 24 DE-ARGs and three prognostic genes (AKAP12, C11orf80 and EMP1) were selected for this study. Enrichment analysis revealed that the DEGs were related to 86 GO terms, such as 'cytoplasmic translation', and 41 KEGG pathways, such as 'small cell lung cancer'. A prognostic gene-based risk model was created in MMRF-CoMMpass and confirmed with the GSE57317 dataset. Moreover, a nomogram was established on the basis of independent prognostic factors that have proven to be good predictors. In addition, the immune cell infiltration results suggested that memory B cells were enriched in the high-risk group and that immature B cells were enriched in the low-risk group. Finally, the mRNA‒miRNA‒lncRNA network demonstrated that hsa-miR-508-5p was tightly associated with EMP1 and AKAP12. RT‒qPCR was used to validate the expression of the genes associated with prognosis. Conclusion: A new prognostic model of MM associated with ARGs was created and validated, providing a new perspective for exploring the connection between ARGs and MM. [ABSTRACT FROM AUTHOR]

Background: The prognostic significance of Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) in Small Cell Lung Cancer (SCLC) patients receiving platinum-based chemotherapy is debated. Methods: This study aims to elucidate their roles in survival outcomes. A systematic search across PubMed, Embase, Web of Science, and Cochrane Library identified relevant studies. The Newcastle-Ottawa Scale (NOS) evaluated study quality. Meta-analysis was conducted using random-effects and fixed-effects models, supplemented by sensitivity analysis. Results: A total of 11 studies with 3,634 SCLC patients were included. Patients with high NLR had significantly decreased overall survival (OS) (HR = 1.39, 95% CI: 1.18–1.59, P < 0.001) and progression-free survival (PFS) (HR = 1.52, 95%CI: 1.27–1.78, P < 0.001). The OS was not statistically different between high and low PLR groups (HR = 1.13, 95%CI: 0.84–1.43, P = 0.265). Subgroup analysis revealed that OS in high NLR group was significantly lower across different strata, and OS in the high PLR group was significantly lower among patients with limited-stage SCLC (LS-SCLC) and populations with a PLR cutoff value < 160. Conclusions: High NLR is associated with poor OS and PFS in patients with SCLC receiving first-line platinum-based chemotherapy. PLR does not significantly impact OS, except in LS-SCLC patients and populations with a PLR cutoff value < 160. These findings require further validation from prospective studies. [ABSTRACT FROM AUTHOR]