Primary small cell carcinoma of the esophagus (SCCE) is an aggressive carcinoma with a rare incidence. Most patients were diagnosed with stage III-IV and have a poor prognosis. The poor therapeutic outcomes of SCCE reveal the need for more rational therapies.

We retrospectively reviewed 15,463 patients with esophageal carcinoma from January 2015 to December 2020. 235 (1.52%) patients were pathologically diagnosed with primary SCCE. Clinical characteristics and treatment information were extracted from medical records. All statistical analyses were performed with the SPSS software. Patients were divided into radiotherapy (RT) group and non-RT group. The chi-square test was conducted to analyze the difference in baseline characteristics and propensity score matching (PSM) was used to balance the patient characteristics. Univariate and multivariate analysis was used to identify independent prognostic factors and calculated the estimated hazard ratio (HR) and 95% confidence interval (CI). The Kaplan-Meier method was used to draw survival curves, calculate the median overall survival (OS), and compare prognosis between groups with the log-rank p test. The two-tailed p value less than 0.05 indicated a significant difference.

The median OS was 15.2 months (range:13.4-17.1 months). The addition of RT improved median OS from 14.3 months to 16.5 months, but the difference was not statistically significant (p = 0.657). After PSM, the median OS of the RT group was longer than the non-RT group (16.5 months vs. 11.5 months, p < 0.001). Multivariate analysis identified RT (HR: 0.711, 95%CI: 0.533-0.949, p = 0.020), surgery (HR: 0.490, 95%CI: 0.365-0.660, p < 0.001), and smoking history (HR: 1.335, 95%CI: 1.010-1.765, p = 0.042) as independent prognostic factors. Subgroup analysis showed that RT was not a prognostic factor in patients with surgery (p = 0.450), but could significantly improve OS in patients without surgery (HR: 0.585, 95%CI: 0.415-0.824, p = 0.002). Both middle and lower thoracic SCCE patients could benefit from the addition of RT. RT could improve OS regardless of Ki67 expression level. Subgroup analyses also indicated that stage IV, age ≥ 60, no smoking history, pure SCCE, Syn-positive, CgA-positive, CD56-positive patients could benefit from RT.

SCCE patients could benefit from RT, especially those without surgery. Further studies are required for confirmation of the conclusion.

Introduction: Nowadays the prognosis of extended stage (ES) small cell lung cancer (SCLC) patients is poor. However, a high response rate to first-line chemotherapy (CT) and the addition of immune checkpoint inhibitors (ICIs) have notably ameliorated the outcome of these patients. The aim of our study is to compare treatment-related adverse events (TRAEs) between ES- SCLC patients receiving first-line ICIs adding CT and those receiving only CT. Methods: All phase III clinical trials published between 15 June 2008, and 30 June 2024, likenessing ICIs adding systemic CT and only CT in treatment-naïve ES-SCLC patients were retrieved. Results: Twenty-six types of adverse events were included, grouped into ten categories, for a total of 43,391 observations (observations in immune group n = 22,643 and in placebo group n = 20,748) and 9831 events. Our analysis suggested a statistically significant increase in hematological events in patients receiving ICIs plus CT compared with CT alone. Conversely, blood pressure alterations such as hypertension were more frequent in patients treated with CT alone. Conclusions: Despite our analysis confirming the manageable safety profile of chemoimmunotherapy, this remains an issue to be further investigated.

Progression-free survival (PFS) and overall survival (OS) curves generally approximate first-order kinetics. On log-linear plots, convex curves with downward inflection (indicating late acceleration of progression/death) might arise from stopping effective therapies. We digitized published PFS/OS curves for etoposide/platinum-treated extensive small-cell lung cancer (SCLC) and other malignancies and replotted the curves log-linearly. Of 26 SCLC PFS curves, 21 (81%) were highly convex (with a marked late down-turn), and 26 (100%) were moderately or highly convex vs. 35/888 (4%) highly convex and 186 (21%) moderately/highly convex curves for other cancers (p < 0.0001). For SCLC, all 32 OS curves were moderately or highly convex vs. 87/363 (24%) that were moderately/highly convex for other cancers (p < 0.0001). The SCLC PFS curves had an initial downward inflection at a median of 3.1 months (around the completion of first-line chemotherapy), then a second inflection at 5.4 months, with further acceleration of progression. The median PFS half-life was 11.9 months while receiving treatment vs. 1.7 months after the second inflection point. Immunotherapy benefit appeared to be limited to 6-10% of the population. SCLC PFS/OS curves are more often convex than for other cancers, reflecting SCLC chemotherapy sensitivity but rapid progression following the completion of first-line chemotherapy. Effective maintenance strategies are needed.

Hundreds of cancer drugs are approved globally based on surrogate endpoint response rate (RR). However, the characteristics of RR-based approvals remain unknown.

In this retrospective study, all cancer drug-indication pairs approved based on RR in the United States and China up to December 2023 were analyzed.

A total of 249 RR-supported drug-indication pairs were identified in the United States and 98 in China. In the United States, 98 of the 249 (39.4%) indications were granted regular approval (RA), whereas in China, only 21 of 98 (21.4%) approvals followed this regulatory pathway, with the remainder receiving accelerated approval (AA). The conversion rate from AA to RA was significantly lower in China compared to the United States (13.3% vs. 28.1%, p < 0.001). The proportion of AA withdrawals was significantly lower in China compared to the United States (1.0% vs. 10.4%, p < 0.001). Among all indications, the median RR in China was 60.9% (IQR, 35.8%-75.0%), which was significantly higher than the 45.0% (IQR, 29.0%-61.0%) in the United States (p < 0.001). In China, 18 of the 98 (18.4%) had an RR less than 30%. In contrast, in the United States, 26.9% of the 249 had an RR less than 30%.

Compared to the United States, RR-supported approvals in China are characterized by higher RR values and a stricter RA pathway. Regulatory authorities in both countries may need to consider both the quantity and quality during cancer drug development based on surrogate endpoints.

Lung cancer is the deadliest cancer worldwide, exhibiting the highest incidence rate among all cancer types. Poor outcomes often characterize this cancer as it is commonly diagnosed in advanced stages due to its unspecific symptoms. After diagnosis, the therapeutic choice is a crucial stage that profoundly affects patients' survival. Treatment choices for lung cancer must be made carefully, acknowledging the histological type and genetic characteristics of the tumor. Non-small cell lung cancer, the most common and complex type, has a high mutational burden, making next-generation sequencing (NGS) essential for identifying specific mutations and guiding treatment. With several approved targeted therapies already available, this approach highlights the critical role of personalized medicine in lung cancer care. Despite the current therapeutic pipeline, research trying to develop new tailored drugs considering individual patient characteristics has evolved over the years. This article aims to outline the current therapeutic approach for each type of lung cancer and present the latest insights into emerging therapies, highlighting the role of personalized medicine in enhancing treatment outcomes and improving patients' quality of life.

Background: Small cell lung cancer (SCLC) is an aggressive cancer with rapid progression, limited treatment success, and high relapse rates. Chemotherapy and radiation are standard treatments but often result in chemoresistance. PD-L1 inhibitors have gained attention for their role in enhancing tumor immunity. Methods: This review summarizes clinical trials involving PD-L1 inhibitors, such as atezolizumab, durvalumab, pembrolizumab, and nivolumab, in SCLC treatment. Key trials include IMpower133, CASPIAN, KEYNOTE-604, and CheckMate 331, focusing on survival outcomes and treatment efficacy. Results: Studies such as IMpower133 and CASPIAN demonstrate improved overall survival when PD-L1 inhibitors were added to platinum-based chemotherapy. However, outcomes in trials such as KEYNOTE-604 and CheckMate 331 varied, showing the need for refined patient selection. Adverse events (AEs) associated with these treatments were also noted. PD-L1 inhibitors offer promise in SCLC treatment, but efficacy varies across trials and patient groups. Future research should focus on better patient selection and overcoming resistance mechanisms. Addressing immune-related AEs is essential for optimizing treatment strategies.

Metastatic anal squamous cell carcinoma (SCC) carries a poor prognosis and the evidence base for surgical resection of metastases remains limited. The aim of this study was to establish the survival outcomes for patients undergoing metastasectomy for anal SCC.

A systematic review was performed using the MEDLINE®, Embase®, Cochrane and PubMed® databases. Studies were considered for inclusion in the review if they involved patients aged >18 years with a diagnosis of stage IV anal SCC who underwent metastasectomy for liver and/or lung metastases. The primary outcome measure was overall survival. Secondary outcome measures were disease free survival, early morbidity according to the Clavien-Dindo classification and quality of life, measured using a validated scoring tool. Risk of bias was assessed with the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions) tool.

There were 10 studies with a total of 98 patients. There was heterogeneity in results reporting, with recurrence free survival the most reported outcome. For all studies reporting on liver metastasectomy, the one-year overall survival rate was 87%. In studies with adequate follow-up reported, the three and five-year overall survival rates were 53% and 38% respectively. Only one study reported on lung metastasectomy patients; the overall median survival was 24 months. None of the studies reported on quality of life measures. The ROBINS-I tool identified a critical risk of bias in six studies, a serious risk in one study and a moderate risk in three studies.

The evidence base for metastasectomy in metastatic anal SCC is limited. Further information is required to inform future treatment methods and use of a standardised outcomes reporting method is needed to support this.

Small-cell lung cancer accounts for about 15% of lung cancers with an extremely poor prognosis. The incorporation of immunotherapy to platinum-based chemotherapy offers sustained overall survival benefits and become the standard for the first-line setting of extensive-stage small-cell lung cancer. However, only a limited number of patients derive prolonged benefits. Although novel immunomodulatory agents and combination strategies are currently under investigation, identifying patients who are likely to obtain clinical benefits from this therapeutic approach is urgently needed. The modest therapeutic response to immunotherapy can be explained by various mechanisms. Traditional biomarkers do not guide immunotherapeutic decision-making in small-cell lung cancer. Notably, recent progress in the understanding of the molecular typing of small-cell lung cancer based on multi-omics data might bring new sights. This review summarizes the potential biomarkers for small-cell lung cancer immunotherapy based on clinical trials and preclinical studies. Moreover, important constraints in identifying biomarkers for small-cell lung cancer treatment are discussed.

BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive malignancy with poor prognosis. This study aimed to assess the efficacy of combining immunotherapy (IT) with Anlotinib in ES-SCLC patients.MethodsThis study was a multicenter retrospective cohort analysis. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models.ResultsA total of 147 patients were included in the analysis. The median overall survival (mOS) for the cohort was 15.5 months (95% CI: 13.9-17.1). Patients in the chemotherapy(CT) plus IT group had an mOS of 17.8 months, compared to 12.6 months in the CT-alone group (p = 0.055). When stratified into CT + IT + Anlotinib, CT + IT, and CT-alone groups, the mOS were 18.5, 16.3, and 12.6 months, respectively, with the CT + IT + Anlotinib group demonstrating significantly improved OS compared to CT-alone (p = 0.044). The ORR and DCR for the entire cohort were 71.4% and 85.7%, respectively. Subgroup analysis revealed ORRs of 74.1% (CT + IT + Anlotinib), 73.9% (CT + IT), and 70.1% (CT-alone), with corresponding DCRs of 92.6%, 91.3%, and 82.5%. Multivariate analysis revealed that radiotherapy (RT, p = 0.003) and IT (p = 0.021) were independent prognostic factors for OS, while liver metastasis (p = 0.023) and RT (p = 0.018) were associated with PFS. Patients receiving RT in combination with CT showed markedly improved OS (17.5 vs 12.5 months; p = 0.002) and PFS (7.3 vs 6.3 months; p = 0.004). The incidence of adverse events was comparable across all groups (p = 0.721).ConclusionThe combined application of Anlotinib with IT and the combination of CT with RT both significantly improved survival outcomes in patients with ES-SCLC while maintaining a favorable safety profile. These findings warrant further investigation in future studies.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a poor prognosis. Although the addition of immunotherapy to chemotherapy has modestly improved outcomes, most patients rapidly develop resistance. Resistance to immunotherapy can be broadly categorized into primary resistance and acquired resistance, as proposed by the Society for Immunotherapy of Cancer (SITC) consensus definition. Primary resistance occurs in the setting of failure to respond to immune checkpoint inhibitors (ICIs), while acquired resistance develops after initial response. The mechanisms of acquired and primary resistance to ICI are not well understood in SCLC, denoting an area of critical unmet need. Both intrinsic and extrinsic mechanisms play significant roles in immunotherapy resistance. Intrinsic mechanisms include defects in antigen presentation, mutations in key genes, reduced tumor immunogenicity, and epigenetic alterations. Extrinsic mechanisms involve the tumor microenvironment (TME), which is a complex interplay of both tumor- and immunosuppressive immune cells, vasculature, and microbiome. An understanding of these resistance mechanisms is crucial for developing novel therapeutic strategies to advance effective immunotherapy in patients with SCLC, a critical area of unmet need.

Small-cell lung cancer (SCLC) is a refractory cancer with rapid growth and high aggressiveness. Extensive-stage SCLC is initially sensitive to chemotherapy; however, drug resistance and recurrence occur rapidly, resulting in a poor survival outcome due to lack of subsequently efficient therapy. The emergence of immune checkpoint inhibitors (ICIs) generated a new landscape of SCLC treatment and significantly prolonged the survival of patients. However, the unselected immunotherapy restrains both beneficiary population and responsive period in SCLC compared to the other tumors. The complex tumor origin, high heterogeneity, and immunosuppressive microenvironment may disturb the value of conventional biomarkers in SCLC including programmed cell death 1 ligand 1 and tumor mutation burden. Transcriptional regulator-based subtypes of SCLC are current research hotspot, revealing that Y (I) subtype can benefit from ICIs. Additionally, molecules related to immune microenvironment, immunogenicity, epigenetics, and SCLC itself also indicated the therapeutic benefits of ICIs, becoming potential predictive biomarkers. In this review, we discussed the advances of biomarkers for prediction and prognosis of immunotherapy, promising directions in the future, and provide reference and options for precision immunotherapy and survival improvement in patients with SCLC.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant, and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. In this study, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role played by tumor-infiltrating immune cells in malignant transformation.

Using fresh and formalin-fixed paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME through IHC, multiparameter flow cytometry, and comparative transcriptomic studies.

Immunophenotyping confirmed increased immune cell infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high programmed cell death 1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression-free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST.

Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising TAM with high expression of PD-L1, which is associated with inferior outcomes. These findings suggest the clinical potential of immune-modulating therapeutics that can unleash an antitumor immune response.

Extensive small cell lung cancer (ES-SCLC) are currently managed using first-line chemotherapy options, including atezolizumab (Atezo) plus etoposide and carboplatin (CE) or durvalumab (Durva) plus etoposide with either cisplatin (PE) or carboplatin (CE). However, a definitive distinction in therapeutic effects between Atezo and Durva in these regimens remains unestablished.

We analyzed data from 100 patients diagnosed with ES-SCLC who received immune checkpoint inhibitors (ICIs) as first-line chemotherapy. Among them, 70 were administered Atezo + CE, 12 received Durva + PE, and 18 received Durva + CE. We assessed the efficacy of the two ICIs across various factors.

The progression-free survival (PFS) and overall survival (OS) did not significantly differ between Atezo + CE and Durva + CE/PE as first-line chemotherapy treatments for SCLC. We observed no significant differences in age, sex, performance status (PS), liver metastasis, bone metastasis, or platinum-based agent usage between the treatment cohorts. However, a marked improvement in PFS and OS was observed in the solitary patient with brain metastasis treated with Atezo + CE.

The primary distinction between these treatments was observed in the management of patients with brain metastasis. The literature lacks comparative studies on the effects of first-line ICI treatment on the central nervous system, rendering our findings significant in clinical practice. Despite the retrospective nature of this study and the potential for various biases, we recommend the preferential use of Atezo + CE in patients with brain metastasis to potentially enhance prognosis.

Small cell neuroendocrine cancers share biologic similarities across tissue types, including transient response to platinum-based chemotherapy with rapid progression of disease. We report a phase 1b study of pembrolizumab in combination with platinum-based chemotherapy in 15 patients with stage III-IV small cell bladder (cohort 1) or small cell/neuroendocrine prostate cancers (cohort 2). Overall response rate (ORR) is 43% with two-year overall survival (OS) rate of 86% (95% confidence interval [CI]: 0.63, 1.00) for cohort 1 and 57% (95% CI: 0.30, 1.00) for cohort 2. Treatment is tolerated well with grade 3 or higher adverse events occurring in 40% of patients with no deaths or treatment cessation secondary to toxicity. Single-cell and T cell receptor sequencing of serial peripheral blood samples reveals clonal expansion of diverse T cell repertoire correlating with progression-free survival. Our results demonstrate promising efficacy and safety of this treatment combination and support future investigation of this biomarker. This study was registered at ClinicalTrials.gov (NCT03582475).

Lung cancer, both non-small cell and small cell, harbors a high propensity for spreading to the central nervous system. Radiation therapy remains the backbone of the management of brain metastases. Recent advances in stereotactic radiosurgery have expanded its indications and ongoing studies seek to elucidate optimal fractionation and coordination with systemic therapies, especially targeted inhibitors with intracranial efficacy. Efforts in whole-brain radiotherapy aim to preserve neurocognition and to investigate the need for prophylactic cranial irradiation. As novel combinatorial strategies are tested and prognostic/predictive biomarkers are identified and tested, the management of brain metastases in lung cancer will become increasingly personalized to optimally balance intracranial efficacy with preserving neurocognitive function and patient values.

This study aimed to systematically analyze the efficacy and toxicity of lurbinectedin as a second-line or subsequent treatment for extensive-stage small cell lung cancer (ES-SCLC).

Candidate studies were identified in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases up to 1 May 2024. Objective remission rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted, respectively. The efficacy and toxicity of lurbinectedin in ES-SCLC were analyzed by meta-analysis.

Six eligible prospective studies were included in this meta-analysis, including 536 patients with ES-SCLC who received second-line or subsequent treatment. In pooled analysis, the ORR of lurbinectedin was 35% (95% confidence interval [CI] 29-41), DCR was 67% (95%CI 58-76), DOR was 5.33 months (95%CI 4.51-6.16), PFS was 3.38 months (95%CI 2.59-4.17), and OS was 7.49 months (95%CI 5.11-9.87). The incidence of AEs and severe adverse events (SAEs) was 92% (95%CI 78-100) and 37% (95%CI 19-57), respectively. The most common AEs were leukopenia, neutropenia, anemia, and thrombocytopenia, with incidences of 81% (68-91), 74% (57-88), 73% (35-98) and 57% (46-68), respectively.

As a promising alternative for second-line treatment for ES-SCLC, lurbinectedin has a certain level of efficacy and a favorable safety profile. The integration of lurbinectedin with other therapeutic modalities presents an emerging area warranting further investigation.

Small-cell lung carcinoma (SCLC) is a high-grade neuroendocrine carcinoma of poor prognosis. Although immune checkpoint blockers have shown promising results in advanced SCLC, the tumor immune microenvironment (TME) remains poorly understood, with no validated prognostic or predictive biomarkers of efficacy.

This retrospective study included surgically samples from 48 SCLC patients between 2009 and 2018. We assessed the TME using two quantitative 7-plex immunofluorescence panels focusing on T and B cells, and compared it to NSCLC (N = 10). Molecular subtypes were determined by assessing the expression of ASCL1, NEUROD1 and YAP1 using immunohistochemistry.

Immune-hot SCLC were defined as those exhibiting the highest immune cell and immune-related marker densities. They were associated with longer overall survival, significantly more frequently detected at early stages, and exhibited high PD-L1 expression in immune cells, but were not associated with molecular subtypes. Compared to NSCLC, SCLC had significantly lower densities of CD20 + cells and higher density of PD1 + cells, with no significant differences in CD4 + , CD8 + and plasma cell densities. In univariate analysis, the highest OS was significantly associated with early stage (p < 0.001), low expression of NEUROD1 (p = 0.047), high PD1 + cell density (p < 0.001) and high PD-L1 immune cell expression (p = 0.04). Only stage and PD1 + cell density emerged as independent prognostic markers.

SCLC TME is highly heterogeneous. Immune-hot tumors were associated with OS but not with molecular classification. PD1 expression and PD-L1 expression by immune cells may thus serve as a prognostic marker.

Small cell lung cancer (SCLC) is a devastating malignancy characterized by rapid metastasis, drug resistance, and frequent recurrence. Owing to the paucity of existing therapeutic options, the prognosis of SCLC remains poor. Recently, the combination of immune checkpoint inhibitors and chemotherapy has resulted in modest improvements in treatment responses. In this review, we characterize the biological signature of SCLC and outline the obstacles to current treatment, including impaired antigen presentation and T cell infiltration. These obstacles may potentially be overcome by chimeric antigen receptor (CAR)-T cell therapy. For the first time, we summarize the available data and discuss the future prospects of CAR-T cell therapy for the treatment of SCLC. Given the high heterogeneity and immunosuppressive tumor microenvironment of SCLC, structural modifications of CAR-T cells and combination therapy may be required to elicit a successful antitumor response. Further research, including clinical trials, is needed to determine the suitability of CAR-T cell therapy as a treatment for SCLC.

Pancreatic neuroendocrine neoplasms (Pan-NEN) represent a group of highly heterogeneous cancers, characterized by complex and diverse biological behavior. The objective of this study was to systematically investigate the immunological features of the tumor microenvironment (TME) in Pan-NEN, aiming to identify prognostic biomarkers and explore the therapeutic potential of immunotherapy for Pan-NEN. Tumor and adjacent normal tissues were collected from 56 patients with Pan-NEN. Immunohistochemical analysis was conducted on tumor tissues using a panel of monoclonal antibodies targeting key immune markers. The expression levels of these markers were quantitatively assessed and correlated with clinicopathological features and overall survival. Low expression of CD3, CD8, CD4, CD68, CD163, Foxp3, CD56, CD69, GZMB, HLA-1, HLA-II, PD-1, and PD-L1 were observed in the majority of Pan-NEN patient samples. PD-1 expression was positively correlated with CD4 and Foxp3 expression, while PD-L1 expression was positively correlated with CD68, CD163, and Foxp3 expression; HLA-II expression was positively correlated with GZMB expression. Infiltration of lymphocytes (CD3 + or CD8+) and macrophages (CD68 + or CD163+) and expression of PD-1/PD-L1 were more pronounced in poorly differentiated neuroendocrine carcinoma (Pan-NEC) compared to well-differentiated neuroendocrine tumors (Pan-NET), while CD68 and PD-L1 correlated with advanced disease stage. Conversely, HLA-I antigen expression was commonly downregulated in Pan-NEC. Univariate Cox proportional hazard analysis demonstrated that tumor grade, stage; CD4+, CD68+, and CD163 + cell count; and expression of PD-1 and PD-L1 were significantly associated with poor survival outcomes, while the positive expression of HLA-I was correlated with a more favorable survival prognosis. Furthermore, multivariate Cox proportional hazard analyses revealed that tumor grade, stage, and PD-1 expression are independent prognostic factors. The immunological landscape of Pan-NEN offers potential prognostic value and therapeutic targets. The findings suggest that immunotherapy, particularly targeting the PD-1/PD-L1 pathway, may serve as a promising strategy for the treatment of Pan-NEN, especially for Pan-NEC patients.

Ovarian cancer is one of the most common malignancies in women. Tripartite motif-containing protein 22 (TRIM22) plays an important role in the initiation and progression of malignant tumors. Similarly, the transcription factor 4 (TCF4) is an essential factor involved in the initiation and progression of many tumors. However, it is still unclear whether TRIM22 can affect TCF4 in ovarian cancer. Therefore, this study aims to investigate the mechanism related to TRIM22 and TCF4 in ovarian cancer. TRIM22 protein and mRNA levels were analyzed in samples from clinical and cell lines. The effects of TRIM22 knockdown and overexpression on cell proliferation, colony formation, migration, invasion, and related biomarkers were evaluated. In addition, the role of ubiquitination-mediated degradation of TCF4 was investigated by qRT-PCR and Western blotting. The association between TRIM22 and TCF4 was evaluated by Western blotting, coimmunoprecipitation, proliferation, colony formation, invasion, migration, and related biomarkers. The results showed that the expression of TRIM22 was minimal in ovarian cancer tissues. Furthermore, upregulation of TRIM22 significantly inhibited ovarian cancer cell proliferation, colony formation, migration, and invasion. In addition, TRIM22 was observed to regulate the degradation of TCF4 through the ubiquitination pathway. TCF4 can reverse the effects of TRIM22 on proliferation, colony formation, migration, and invasion in ovarian cancer cells. TRIM22-mediated ubiquitination of TCF4 at K48 is facilitated by the RING domain. Implications: In conclusion, ubiquitination of TCF4 protein in ovarian cancer is regulated by TRIM22, which has the potential to limit the proliferation, migration, and invasion of ovarian cancer.

Patients with extensive-stage small cell lung cancer (ES-SCLC) experience significant therapeutic challenges and limited survival rates. This study aimed to investigate the efficacy of combining immunotherapy (IT) with chemotherapy (CT) for treating ES-SCLC and to explore the synergistic effect between radiotherapy (RT) and IT.

This retrospective analysis examined patients with ES-SCLC who received treatment at three centers. Furthermore, propensity score-matched (PSM) analysis was conducted. The Kaplan‒Meier method and Cox proportional hazards regression were used to compare the survival outcomes.

A total of 257 eligible patients with ES-SCLC were included in the analysis. Among all patients, the median overall survival (mOS) was 18.0 m in the chemoimmunotherapy (CT + IT) group and 15.7 m in the CT group (p = 0.208). The median real-world progression-free survival (mrwPFS) was 7.7 m and 6.8 m (p = 0.043) in the CT + IT and CT group, respectively. Moreover, the mOS was 22.0 m in the chemoradiotherapy (CT + RT) group and 13.6 m in the CT group (p < 0.001). The mrwPFS was 7.4 m and 6.0 m (p = 0.175) in the CT + RT group and CT group, respectively. The multivariate analyses revealed that sex, liver metastasis and RT were independent prognostic factors for OS (p < 0.05), while liver metastasis and IT were found to be independent predictive factors of real-world progression-free survival (rwPFS) (p < 0.05). After PSM, the mOS was 23.2 m in the CT + IT group and 13.0 m in the CT group (p = 0.008). The mrwPFS was 7.3 m and 6.2 m (p = 0.096) in the CT + IT group and the CT group, respectively. Moreover, the mOS was 21.4 m in the CT + RT group and 12.5 m in the CT group (p < 0.001). The mrwPFS was 7.3 m and 5.2 m (p = 0.220) in the CT + RT group and the CT group, respectively. Additionally, our study revealed that in the PD-1 group, RT significantly improved patient survival (36.0 m vs. 15.8 m, p = 0.041).

An increasing number of treatment options are being explored for ES-SCLC, and CT is the cornerstone of treatment for this disease. Combining CT with IT and RT has demonstrated remarkable efficacy and excellent safety profiles, and such treatments are worthy of further exploration.

Small cell lung cancer (SCLC) is a highly malignant and poor-prognosis cancer, with most cases diagnosed at the extensive stage (ES). Amidst a landscape marked by limited progress in treatment modalities for ES-SCLC over the past few decades, the integration of immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy has provided a milestone approach for improving prognosis, emerging as the new standard for initial therapy in ES-SCLC. However, only a minority of SCLC patients can benefit from ICIs, which frequently come with varying degrees of immune-related adverse events (irAEs). Therefore, it is crucial to investigate predictive biomarkers to screen potential beneficiaries of ICIs, mitigate the risk of side effects, and improve treatment precision. This review summarized potential biomarkers for predicting ICI response in ES-SCLC, with a primary focus on markers sourced from tumor tissue or peripheral blood samples. The former mainly included PD-L1 expression, tumor mutational burden (TMB), along with cellular or molecular components related to the tumor microenvironment (TME) and antigen presentation machinery (APM), molecular subtypes of SCLC, and inflammatory gene expression profiles. Circulating biomarkers predominantly comprised circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cytokines, plasma autoantibodies, inflammation-related parameters, and blood TMB. We synthesized and analyzed the research progress of these potential markers. Notably, investigations into PD-L1 expression and TMB have been the most extensive, exhibiting preliminary predictive efficacy in salvage immunotherapy; however, consistent conclusions have yet to be reached across studies. Additionally, novel predictive markers developed based on TME composition, APM, transcriptomic and genomic features provide promising tools for precision immunotherapy. Circulating biomarkers offer the advantages of convenience, non-invasiveness, and a comprehensive reflection of tumor molecular characteristics. They may serve as alternative options for predicting immunotherapy efficacy in SCLC. However, there is a scarcity of studies, and the significant heterogeneity in research findings warrants attention.

Immune checkpoint inhibitors (ICIs) had modest advances in the treatment of extensive-stage small cell lung cancer (ES-SCLC) in clinical trials, but there is a lack of biomarkers for prognosis in clinical practice.

We retrospectively collected data from ES-SCLC patients who received ICIs combined chemotherapy from two centers in China, integrated clinical and blood parameters, and constructed risk prognostication for immunochemotherapy. The population was divided into high- and low-risk groups, and the performance of the model was assessed separately in the training and validation cohorts.

Two hundred and twenty and 43 patients were included in the training and validation groups, respectively. The important predictors were screened including body mass index, liver metastases, coefficient variation of red blood cell distribution width, lactate dehydrogenase, albumin, and C-reactive protein. Predicting 1-year overall survival (OS), the AUC values under ROC for the model under training, internal validation, and external validation were 0.760, 0.732, and 0.722, respectively, and the calibration curve and clinical decision curve performed well. Applied the model to divide patients into low-risk and high-risk groups, and the median OS was 23.7 months and 9.1 months, and the median progression-free survival was 8.2 months and 4.8 months, respectively; furthermore, this ability to discriminate survival was also observed in the validation cohort.

We constructed a novel prognostic model for ES-SCLC to predict survival employing baseline tumor burden, nutritional and inflammatory parameters, it is easily measured to screen high-risk patient populations.

Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by early metastasis, rapid tumor growth and poor prognosis. In recent decades, the epidemiology, initiation and mutation characteristics of SCLC, as well as abnormal signaling pathways contributing to its progression, have been widely studied. Despite extensive investigation, fewer drugs have been approved for SCLC. Recent advancements in multi-omics studies have revealed diverse classifications of SCLC that are featured by distinct characteristics and therapeutic vulnerabilities. With the accumulation of SCLC samples, different subtypes of SCLC and specific treatments for these subtypes were further explored. The identification of different molecular subtypes has opened up novel avenues for the treatment of SCLC; however, the inconsistent and uncertain classification of SCLC has hindered the translation from basic research to clinical applications. Therefore, a comprehensives review is essential to conclude these emerging subtypes and related drugs targeting specific therapeutic vulnerabilities within abnormal signaling pathways. In this current review, we summarized the epidemiology, risk factors, mutation characteristics of and classification, related molecular pathways and treatments for SCLC. We hope that this review will facilitate the translation of molecular subtyping of SCLC from theory to clinical application.

Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody-drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes.

Patients with small cell lung cancer (SCLC) often respond to first-line chemoimmunotherapy. However, relapse is inevitable and is associated with a poor prognosis. Treatments for relapsed SCLC, such as lurbinectedin and topotecan, are limited by modest efficacy and significant hematologic adverse events, leaving a need for newer therapeutic agents or regimens. The combination of gemcitabine and nab-paclitaxel is active and safe in other types of malignancies, such as pancreatic cancer.

We conducted a phase II trial evaluating the efficacy and safety of gemcitabine and nab-paclitaxel in patients with relapsed/refractory SCLC. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with confirmed complete or partial response. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety.

Between October 2016 and May 2021, 32 patients were enrolled. Patients were followed for a median of 9.3 months (range 1.8-65.2). Median age was 65 years (range 48-81). Fifty percent of patients were female. Fifty-three percent of patients had platinum-resistant/refractory relapsed SCLC. The ORR was 28.1% (95% confidence interval [CI] 15.5-100%). Median PFS was 2.9 months (95% CI 2.4-3.6), and median OS was 9.3 months (95% CI 5.2-12.4). Seven patients (21.9%) developed grade 3 or 4 neutropenia.

Our study showed that the combination of gemcitabine and nab-paclitaxel led to encouraging outcomes in relapsed/refractory SCLC. Further studies are needed to compare this combination with other treatments used for relapsed SCLC, including lurbinectedin, temozolomide, and topotecan.

https://clinicaltrials.gov/study/NCT02769832?cond=NCT02769832&rank=1, identifier NCT02769832.

This retrospective study evaluates the efficacy of camrelizumab combined with anlotinib versus chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) undergoing second-line treatment.

Data were sourced from medical records at a Chinese medical facility, involving 34 patients diagnosed with ES-SCLC after failing first-line treatment. Patients were divided into two groups: one received camrelizumab (200 mg every 3 weeks) with anlotinib (12 mg daily for 14 days followed by a 7-day rest), while the other group received physician-chosen chemotherapy administered every 3 weeks. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and disease control rate (DCR).

The combination therapy group showed a significant improvement in PFS compared to the chemotherapy group (median PFS: 7 months vs. 3 months; hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.15-0.77; p<0.001). However, there was no statistically significant difference in OS between the groups (16.3 months vs. 17.3 months; p=0.82). The ORR was 52.9% in the combination therapy group versus 23.5% in the chemotherapy group (p=0.08), and the DCR was 82.4% compared to 58.8% (p=0.26). Grade 3 or higher adverse events were observed in 17.6% of the combination therapy group and 29.4% of the chemotherapy group.

The findings suggest that the combination of camrelizumab and anlotinib offers a superior anti-tumor response with a manageable safety profile in a second-line setting for ES-SCLC patients. This combination regimen may be a viable option for second-line ES-SCLC treatment.

Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need.

Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed.

42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups.

In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.

Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8 + T cell in SCCE for the first time.

Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density.

No patients had PD-L1 expressed in their tumor cells. PD-L1 + expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68 + monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression ( Ptrend <0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS.

Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.

Single-arm trials (SATs) and surrogate endpoints were adopted as pivotal evidence for accelerated approval of anticancer drugs for more than 30 years. However, concerns regarding clinical evidence quality in trials, particularly in the SATs of anticancer drugs have increasingly been raised. SAT may not always provide strong evidence due to the lack of control and endpoint of overall survival that is typically present in randomized controlled trials.

Clinical trial endpoint adjudication is a crucial factor in surrogate outcome measurement to ensure the data quality of the clinical trial of anticancer drugs. In this review, we systematically discuss the characteristics of adjudications in assessments in surrogate endpoint and safety outcome respectively, which are essential for ensuring reliable and transparent outcomes. Endpoint adjudication effectively reduces potential bias and mitigates variance that may be introduced by investigators when analyzing the medical records for the surrogate endpoints. We analyze the advantages and disadvantages of each type of adjudicator and provide a summary of the roles of adjudicators.

By suggestion of improving data reliability and transparency in pivotal trials, this review aims to supply a strategy for better clinical investigation for anticancer drugs, ultimately leading to better patient outcomes.

Undeniably, cancer immunotherapies have expanded the spectrum of cancer treatment, however, some patients do not respond to immunotherapies. This scenario is no different for lung cancer, whose two main types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), still pose a serious clinical challenge. Adoptive T-cell therapies (ATC), which primarily include cytokine-induced killer (CIK) cell therapy, chimeric antigen receptor T-cell (CAR T-cell) therapy and γδ-T-cell therapy, strengthen the patient's immune system in combating cancer. Combining ATC with immune checkpoint inhibitors (ICI) further enhances the effectiveness of this approach to eradicate cancer. With a particular emphasis on CIK cell therapy, which recently completed 30 years, we highlight the role of the PD-1/PD-L1 axis in NSCLC and SCLC. Besides, we provide insights into the potential synergies of PD-1/PD-L1 inhibitors with adoptive T-cell immunotherapy in reshaping the treatment paradigm for lung cancer.

Immune checkpoint blockade (ICB) with or without chemotherapy has a very modest benefit in patients with small cell lung cancer (SCLC). SCLC tumors are characterized by high tumor mutation burden (TMB) and low PD-L1 expression. Therefore, TMB and PD-L1 do not serve as biomarkers of ICB response in SCLC. CD38, a transmembrane glycoprotein, mediates immunosuppression in non-small cell lung cancer (NSCLC). In this brief report, we highlight the potential role of CD38 as a probable biomarker of immunotherapy response in SCLC.

We evaluated the role of CD38 as a determinant of tumor immune microenvironment in SCLC with bulk and single-cell transcriptomic analyses and protein assessments of clinical samples and preclinical models, including CD38 in vivo blockade.

In SCLC clinical samples, CD38 levels were significantly correlated with the gene expression of the immunosuppressive markers FOXP3, PD-1 and CTLA-4. CD38 expression was significantly enhanced after chemotherapy and ICB treatment in SCLC preclinical models and clinical samples. A combination of cisplatin/etoposide, ICB, and CD38 blockade delayed tumor growth compared to cisplatin/etoposide.

Our study provides a preliminary but important direction toward exploring CD38 as a potential biomarker of ICB response and CD38 blockade as a combination strategy for chemo-immunotherapy in SCLC.

This meta-analysis aimed to compare the efficacy of programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors in patients with extensive-stage small-cell lung cancer. The present meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant studies were identified through searches of databases including PubMed, Embase, and the Cochrane Library, as well as prominent oncology conferences. The search was conducted from the inception of the databases up to January 31, 2024. A total of 10 studies were included in this meta-analysis. Among these studies, six were randomized trials, while four were observational studies. The pooled meta-analysis showed that PD-1 and PD-L1 inhibitors are more effective in improving overall survival and progression-free survival compared to chemotherapy alone. However, when comparing PD-1 and PD-L1 inhibitors, there was no significant difference between the two groups regarding overall survival and progression-free survival. It is important to note that there is no head-to-head trial comparing these two interventions in patients with extensive-stage small-cell lung cancer. Therefore, future prospective trials are needed to define optimal therapeutic approaches in this patient population.

SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs.

Chemo-immunotherapy is the current standard of care for extensive-stage small cell lung cancer, but predictive biomarkers are lacking. In a recent article, the authors report the predictive role of programmed death ligand-1 expression and tissue tumor mutational burden on durvalumab ± tremelimumab + platinum-etoposide efficacy. See related article by Paz-Ares et al., p. 824.

Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC).

Patients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m2) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs).

Fifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months).

Pembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC.

ClinicalTrials.gov , NCT01840579.