Neoadjuvant camrelizumab (an anti-PD-1 antibody) plus chemotherapy or apatinib (a VEGFR-2 inhibitor) for initially unresectable stage II-III non-small-cell lung cancer: a multicentre, two-arm, phase 2 exploratory study.

This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II-III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2-4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3-48.1) in arm A and were 55.6% (95% CI 21.2-86.3) and 11.1% (95% CI 0.3-48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8-61.6) and 55.6% (95% CI 21.2-86.3). With a median follow-up of 22.4 months (95% CI 19.0-26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II-III NSCLC.

Real-world progression in the survival of de novo Metastatic prostate cancer over the past decade.

BACKGROUND: The impact of evolving treatment strategies for metastatic prostate cancer (mPCa) on real-world survival is not well understood. We analyzed changes in mPCa survival over the past decade and discussed the potential driving factors behind these changes. METHODS: Our study involved 43,228 mPCa patients (2004-2020) from the SEER database, divided into 4 diagnostic periods. We used a multivariate Cox proportional hazards model to evaluate diagnostic periods' influence on overall mortality (OM) and prostate cancer-specific mortality (PSM), and calculated relative median survival improvements between adjacent periods. Subgroup analyses based on age and distant metastasis sites were conducted. RESULTS: Patients diagnosed in 2016 to 2020 experienced significantly reduced mortality risk compared to those in 2004 to 2007 (HR 0.64 for OM, HR 0.62 for CSM, both P < 0.001). The study period witnessed an absolute improvement in median overall survival (OS) and prostate cancer-specific survival (PCSS), 17 months (54.8%) and 25 months (67.6%) respectively. The most rapid relative survival improvement occurred post-2016, with a 29.7% increase in median OS and a 37.8% increase in PCSS compared to 2012 to 2015. There was a significant reduction in mortality risk throughout the study period in both age groups (age <75 and ≥75), but absolute survival gains were smaller in the older group (24 months [68.6%] vs. 8 months [32%] for OS, 36 months [90.0%] vs. 11 months [33.3%] for PCSS), with lower relative survival improvements after 2016 (37.2% vs. 17.9% for OS, 49% vs. 22.2% for PCSS). All metastasis site subgroups (except M1a) exhibited a significant reduction in mortality risk (all P < 0.001). Absolute survival improvements were 58 months (134.9%) for M1a, 16 months (50.0%) for M1b, and 17 months (54.8%) for M1c. CONCLUSION: The survival of mPCa have significantly improved over the past decade, although the progress is slower in elderly patients. Investigating the underlying reasons for survival differences among various patient profiles can further refine mPCa treatment strategies.

Cuproptosis-related long noncoding RNAs predicts overall survival and reveal immune microenvironment of bladder cancer.

Background: Recently, a newly programmed cell death has been discovered, namely cuproptosis. It is considered a novel copper-dependent cell death model. Long non-coding RNA (lncRNA) influence the prognosis of bladder cancer. In this study, we established a scoring system based on 7 cuproptosis-related lncRNA to predict the prognosis and immune landscape of bladder cancer (BCa). Method: Gene expression and clinical data of 431 tissues were downloaded from The Cancer Genome Atlas (TCGA), including 19 normal samples and 419 cancer samples. All samples were randomly categorized into train and test cohorts. Cuproptosis-related lncRNA were distinguished. Then we conduct univariate COX and multivariate COX regression, paralleled with LASSO regression to cultivate a cuproptosis-related lncRNA risk model. Kaplan-Meier curves, scatter diagram, C-index, ROC curves, nomogram, PCA analysis and univariate and multivariate Cox regression were used to test the accuracy of risk model and to predict patient survival. Additional, gene mutation status between high- and low-risk groups was calculated.GO and KEGG were used to access the DEGs (different expression genes)-related pathway.The ssGSEA and ESTIMATE algorithms were used to assess the immune function in different tumor samples. Besides, patient's response to immunotherapy and drug susceptibility were also been estimated. Results: 7 cuproptosis-related lncRNA (LINC01184, LINC00513, LINC02443, SMARCA5-AS1, BDNF-AS, SOD2-OT1, HYI-AS1) were selected to construct the risk model in the train cohort. This model can well predict the overall survival (OS) in test group and entire cohort with different stage. Despite no significant different is observed in gene mutation between high- and low-risk group, different immune infiltration, different survival and sensitivity to drugs are discovered. Conclusion: We established a novel cuproptosis-related lncRNA risk model which can predict the outcome and immunotherapy response with satisfactory predictive effects. This risk model can provide a new insight into prognostic evaluation and may have potential to guide comprehensive treatment in bladder cancer.

Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study.

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Identification and application of species-specific peptide biomarkers from soft-shelled turtles (Pelodiscus sinensis) using post-translational modification detection-based peptidomics analysis.

The soft-shelled turtle is a commercially aquatic species in Asian countries, which serves as an important source of collagen with high nutritional and medicinal value, so it is of great significance to distinguish soft-shelled turtle derived collagen from others or adulterations. In this work, peptidomics analysis based on post-translational modification (PTM) assay was used to discover specific peptide biomarkers of soft-shelled turtle gelatin (STG). In total eight specific sequences and 74 peptides with different PTM types were screened out, and seven peptides with good signal responses and STG specificity were selected and validated as STG-specific peptide biomarkers. These peptide biomarkers could be used for distinguishing STG from other animal gelatins, and applied for ensuring the quality of collagens or gelatins from soft-shelled turtle with authenticity and traceability.

Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing.

BACKGROUND: Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. METHODS: We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). RESULTS: Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. CONCLUSIONS: Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer.

In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.

Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer.

PURPOSE: Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer. METHODS: Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study. RESULTS: Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study. CONCLUSIONS: The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer.

Biochemical recurrence related metabolic novel signature associates with immunity and ADT treatment responses in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is a unique cancer from a metabolic perspective. Androgen receptor assumes a vital part in normal and malignant prostate cells regarding almost all aspects of cell metabolism, such as glucose, fat, amino acids, nucleotides, and so on. METHODS: We used The Cancer Genome Atlas database as training set, Memorial Sloan-Kettering Cancer Center cohort as validation set, and Gene Expression Omnibus database (GSE70769) as test set to identify the optimal prognostic signature. We evaluated the signature in terms of biochemical progression-free survival (bPFS), ROC curve, clinicopathological features, independent prognostic indicators, tumor microenvironment, and infiltrating immune cells. Nomogram was built dependent on the results of cox regression analyses. GSEA algorithm was used to evaluate differences in metabolism. The signature's prediction of androgen deprivation therapy (ADT) response was validated based on two groups of basic cytological experiments treat with ADT (GSE143408 and GSE120343) and the transcriptional information of pre-ADT/post-ADT of six local PCa patients. RESULTS: We finally input four screened genes into the stepwise regression model to construct metabolism-related signature. The signature shows good prediction performance in training set, verification set, and test set. A nomogram based on the PSA, Gleason score, T staging, and the signature risk score could predict 1-, 3-, and 5-year bPFS with the high area under curve values. Based on gene-set enrichment analysis, the characteristics of four genes signature could influence some important metabolic biological processes of PCa and were serendipitously found to be significantly related to androgen response. Subsequently, two cytological experimental data sets and our local patient sequencing data set verified that the signature may be helpful to evaluate the therapeutic response of PCa to ADT. CONCLUSIONS: Our systematic study definite a metabolism-related gene signature to foresee prognosis of PCa patients which might add to individual prevention and treatment.

A Novel Prognostic Model for Acute Myeloid Leukemia Based on Gene Set Variation Analysis.

Acute myeloid leukemia (AML) is a malignant hematological malignancy with a poor prognosis. Risk stratification of patients with AML is mainly based on the characteristics of cytogenetics and molecular genetics; however, patients with favorable genetics may have a poor prognosis. Here, we focused on the activity changes of immunologic and hallmark gene sets in the AML population. Based on the enrichment score of gene sets by gene set variation analysis (GSVA), we identified three AML subtypes by the nonnegative matrix factorization (NMF) algorithm in the TCGA cohort. AML patients in subgroup 1 had worse overall survival (OS) than subgroups 2 and 3 (P < 0.001). The median overall survival (mOS) of subgroups 1-3 was 0.4, 2.2, and 1.7 years, respectively. Clinical characteristics, including age and FAB classification, were significantly different among each subgroup. Using the least absolute shrinkage and selection operator (LASSO) regression method, we discovered three prognostic gene sets and established the final prognostic model based on them. Patients in the high-risk group had significantly shorter OS than those in the low-risk group in the TCGA cohort (P < 0.001) with mOS of 2.2 and 0.7 years in the low- and high-risk groups, respectively. The results were further validated in the GSE146173 and GSE12417 cohorts. We further identified the key genes of prognostic gene sets using a protein-protein interaction network. In conclusion, the study established and validated a novel prognostic model for risk stratification in AML, which provides a new perspective for accurate prognosis assessment.

Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial.

BACKGROUND: This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC). METHODS: Patient eligibility mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. RESULTS: In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). CONCLUSIONS: Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. TRIAL REGISTRATION: ChiCTR1900024014, June 22, 2019.

Single-cell RNA-sequencing technology demonstrates the heterogeneity between aged prostate peripheral and transitional zone.

BACKGROUND: Identifying cellular and functional heterogeneity within aged prostate is critical for understanding the spatial distribution of prostate diseases. METHODS: Aged human prostate peripheral zone (PZ) and transitional zone (TZ) tissues were used for single-cell RNA-sequencing. Results were validated by immunofluorescence staining. RESULTS: We found that club/hillock epithelial cells, compared with other epithelial cells, had significantly higher NOTCH signaling activity and expressed higher levels of neuro-stems but lower androgen-related genes. These cells were primarily found in the TZ and provided a stem-like niche around the proximal prostate ducts. Significant heterogeneity was observed in the aged luminal population. A novel TFF3+ luminal subtype with elevated MYC and E2F pathway activities was observed, primarily in the PZ. Further analysis revealed that epithelial cells in the TZ had higher levels of stem- and inflammation-related pathway activities but lower androgen/lineage-related pathway activities than those in the PZ. Notably, the activation of MYC, E2F and DNA repair pathways significantly increased in PZ luminal cells. In the immune landscape, we found that the immune microenvironment in the TZ is more complex and disordered with more infiltration of NK and Treg cells. CD8 T cell and macrophage in the TZ exhibit both inflammation activation and suppression phenotypes. In the stroma, the TZ had a higher fibroblast density, and fibroblasts in the TZ exhibited stronger transcriptome activity in immunity and proliferation. Ligand-receptor interaction analysis revealed that fibroblasts could contribute to a NOTCH signaling niche for club/hillock cells in the TZ and balance the prostate immune microenvironment. The activation of stem properties, inflammatory infiltration and loss of androgen/lineage activity are prominent features distinguishing the TZ from PZ. CONCLUSIONS: Our study explains the heterogeneity between the TZ and PZ of aged prostate, which may help understand the spatial distribution of prostate diseases and establish a foundation for novel target discovery.

The Value of Lymph Node Dissection in Patients With Node-Positive Upper Urinary Tract Urothelial Cancer: A Retrospective Cohort Study.

Purpose: The value of lymphadenectomy during radical nephroureterectomy (RNU) remains unclear. This study aimed to determine the effects of the removed lymph node (RLN) counts, positive lymph node (pLN) counts, and pLN density (pLND) on survival outcomes in patients with node-positive upper urinary tract urothelial cancer (UTUC). Methods: A total of 306 patients with node-positive UTUC in the Surveillance, Epidemiology, and End Results database between 2004 and 2016 were identified. Multivariable Cox regression analyses were used to evaluate the effect of RLN counts, pLN counts, and pLND on survival outcomes. The maximally selected rank statistics were used to determine the most informative cutoff value for pLND on survival outcomes. Results: The RLN counts or pLN counts were not associated with survival outcomes, whereas higher pLND was associated with lower cancer-specific survival (CSS) and overall survival (OS) [hazard ratio (HR) 1.75, P = 0.014 and HR 1.62, P = 0.036, respectively]. The most informative cutoff value for pLND in relation to survival was 27%. Patients with pLND ≥27% had worse 5-year survival rates than those with pLND <27% (52.9% vs. 75.9% for CSS and 18.7% vs. 34.2% for OS, each P < 0.05). Furthermore, the multivariable Cox regression model with pLND could predict 5-year CSS (AUC 0.732 vs. 0.647) or OS (AUC 0.704 vs. 0.621) more accurately than the model without pLND. Conclusions: For patients with node-positive UTUC, more lymph nodes removed do not offer a better therapeutic effect. However, pLND provides additional prognostic value.

Identification of Pyroptosis-Related Gene Signatures and Construction of the Risk Model to Predict BCR in Prostate Cancer.

Prostate cancer is one of the most common malignant tumors in men. Pyroptosis is related to tumor immune infiltration and tumor microenvironment (TME) and has been confirmed to be related to the progression of a variety of tumors. However, the relationship between prostate cancer and pyroptosis, as well as TME and tumor immune infiltration, has not been discussed yet. We obtained and combined the RNA-seq data of prostate cancer from TCGA and GEO databases, analyzed the differential expression of pyroptosis-related genes (PRGs), and divided them into two groups according to the PRG expression level. The relationship between pyroptosis subtypes and the TME of prostate cancer was further verified, and the differential expression genes (DEGs) in the two subtypes were identified. The relationship between the DEGs and clinicopathology was explored and KEGG and GO enrichment analysis was conducted; it was found that most DEGs were enriched in immune-related pathways. Then, we randomly divided datasets into training and testing sets, performed the LASSO and multicox progression analysis, selected eight genes as prognostic signatures and used the eight genes, calculated the risk score, and then separated the entire cohort into high- and low-risk groups. The prognosis between two groups and the 1-, 3-, and 5-year ROC curves of biochemical relapse (BCR) were verified in training, testing, and the entire cohort, respectively. The TME, CSC index, mutation, and drug susceptibility were also discussed.

A Novel Gene Signature Associated With "E2F Target" Pathway for Predicting the Prognosis of Prostate Cancer.

Background: The effect of the adenoviral early region 2 binding factors (E2Fs) target pathway on prostate cancer is not clear. It is necessary to establish an E2F target-related gene signature to predict prognosis and facilitate clinical decision-making. Methods: An E2F target-related gene signature was established by univariate and LASSO Cox regression analyses, and its predictive ability was verified in multiple cohorts. Moreover, the enrichment pathway, immune microenvironment, and drug sensitivity of the activated E2F target pathway were also explored. Results: The E2F target-related gene signature consisted of MXD3, PLK1, EPHA10, and KIF4A. The patients with high-risk scores showed poor prognosis, therapeutic resistance, and immunosuppression, along with abnormal growth characteristics of cells. Tinib drugs showed high sensitivity to the expression of MXD3 and EPHA10 genes. Conclusion: Our research established an E2F target-related signature for predicting the prognosis of prostate cancer. This study provides insights into formulating individualized detection and treatment as well as provides a theoretical basis for future research.

Predictive role of ferroptosis-related long non-coding RNAs in bladder cancer and their association with immune microenvironment and immunotherapy response.

BACKGROUND: We have previously reported that ferroptosis has an important role in bladder cancer development. In this study, we aimed to further explore the possible predictive ability of ferroptosis-related long non-coding RNAs (lncRNAs) in bladder cancer and their relation with immune microenvironment and immunotherapy response. MATERIALS AND METHODS: The ferroptosis-related lncRNAs were identified by Pearson's correlation analysis. The predictive lncRNA signature was developed by univariate and multivariate regression analyses. Only the main effects of independent variables in multivariate analysis were included in this signature. The TCGA dataset was defined as the training cohort and GEO was the validation cohort in this study. All samples were grouped into a high- or low-risk group depending on risk signature. The prognostic role of lncRNA signature was explored through survival analysis and receiver operating characteristic curve (ROC) analysis in both TCGA and GEO cohorts. Additionally, the independent prognostic ability of the lncRNA signature was confirmed by multivariate independent analysis. Furthermore, the relationship between lncRNAs and immune microenvironment as well as immunotherapy response in bladder cancers was studied. RESULTS: The Kaplan-Meier curves identified significantly poorer overall survival outcomes for high-risk groups in both TCGA (p < 0.001) and GEO (p < 0.001) cohorts. The area under the curve (AUC) during ROC analysis of 1, 3, and 5 years was 0.781 ± 0.046, 0.784 ± 0.027, and 0.817 ± 0.025, respectively, in the TCGA cohort and 0.665 ± 0.177, 0.719 ± 0.068, and 0.791 ± 0.055, respectively, in the GEO cohort. The multivariate independent analysis in TCGA cohort identified age (p = 0.003), stage (p < 0.001), and signature risk score (p < 0.001) as independent risk factors for overall survival. Furthermore, this study demonstrated a significant difference in infiltration levels of various immune cells between high- and low-risk groups. The high risk group tended to have a lower expression of proteins including PD1 (p < 0.01), PD-L1 (p < 0.01), CTLA-4 (p < 0.05), etc. corresponding to various immune checkpoints. Additionally, the immunotherapy trial confirmed that the high-risk group tended to have a poorer treatment response than the low-risk group (p < 0.001). CONCLUSIONS: The ferroptosis-related lncRNAs exhibited a good predictive capacity for overall survival in bladder cancer. Additionally, they could be utilized to reveal tumour-immune microenvironment and immunotherapy responses.

Ferroptosis Mediation Patterns Reveal Novel Tool to Implicate Immunotherapy and Multi-Omics Characteristics in Bladder Cancer.

Background: The regulatory role of ferroptosis in malignant tumours has been recently demonstrated. However, the potential roles of ferroptosis mediation patterns in bladder cancer remain elusive. Materials and Methods: The ferroptosis mediation patterns of 889 bladder cancer samples were comprehensively evaluated based on ferroptosis-related genes. The underlying correlations between these mediation patterns and multi-omic characteristics of bladder cancer were systematically analysed. The ferroptosis mediation patterns of individual samples were quantified by ferropscore using the principal component analysis algorithm. The typical ferroptosis-related genes with prognostic roles were further randomly validated using immunohistochemical staining, real-time polymerase chain reaction and western blotting. Results: Three different ferroptosis mediation patterns were identified. The abundance of infiltration of 23 immune cells was different among the three mediation patterns. The quantification of ferroptosis mediation patterns in individual samples served as a promising tool for predicting patient survival outcomes; immune cell infiltration abundance; tumour mutation burden; oncogenic mutation status and tumour grade, stage and molecular subtypes. Low ferropscore combined with high tumour mutation burden was associated with the best survival prognosis. Expressions of PD-L1 (p < 0.001), PD-1 (p = 0.002) and CTLA-4 (p = 0.003) were all significantly upregulated in the high ferropscore group. Low ferropscores also predicted good immunotherapy response for anti-CTLA4 strategy. The mRNA and protein levels of FADS2, a typical ferroptosis-related gene used in the study, were higher in bladder cancer cell lines than in controlled SV-HUC-1 cells. In addition, immunohistochemical staining revealed significantly higher expression levels of FADS2 in human bladder cancer tumour tissues than in normal tissues. Conclusion: This study identified three distinct ferroptosis mediation patterns in bladder cancer. Quantification of ferroptosis mediation patterns in individual samples may help to improve the understanding of multiomic characteristics and guide future immunotherapy responses to bladder cancer.

Neoadjuvant Sintilimab and Chemotherapy for Resectable Stage IIIA Non-Small Cell Lung Cancer.

BACKGROUND: Evidence of neoadjuvant chemoimmunotherapy for locally advanced non-small cell lung cancer remains investigational and requires prospective validation. This phase II trial (https://www.chictr.org.cn/historyversionpub.aspx?regno=ChiCTR1900023758) aimed to investigate the safety and effectiveness of neoadjuvant PD-1 inhibitor sintilimab in addition to chemotherapy in the management of resectable stage IIIA non-small cell lung cancer. METHODS: Eligible patients received two to four 21-day cycles of neoadjuvant therapy: sintilimab (200 mg) and carboplatin (area under the curve 5) on day 1, gemcitabine (1000 mg/m2) on day 1 and day 8 for squamous cell carcinoma, or pemetrexed (500 mg/m2) on day 1 for adenocarcinoma and non-small cell lung cancer not otherwise specified. The primary endpoints were adverse events and major pathological response. The secondary endpoint was disease-free survival at 1 year. RESULTS: Fifty patients were enrolled, and 23 (46%) achieved partial response after neoadjuvant chemoimmunotherapy. Four (8%) patients experienced grade 3 to 5 adverse events. Thirty patients received surgery, none of whom experienced treatment-related surgery delays, and 13 (43.3%) of 30 patients achieved major pathological response (viable tumor ≤10%). With a median follow-up of 13.6 months, 85.3% of patients were disease-free at 1 year (N = 50). CONCLUSIONS: Neoadjuvant sintilimab with platinum-containing dual-agent chemotherapy was feasible and safe for patients with resectable stage IIIA non-small cell lung cancer.

Comparing the Survival Outcomes of Radical Prostatectomy Versus Radiotherapy for Patients With De Novo Metastasis Prostate Cancer: A Population-Based Study.

PURPOSE: The efficacy of local treatments (LTs) in selected patients with metastatic prostate cancer (mPCa) had been demonstrated. However, the comparative effectiveness between LTs is unclear. Here, we compared the impact of radical prostatectomy (RP) and brachytherapy (RT) on the survival outcomes of mPCa patients. MATERIALS AND METHODS: mPCa patients who received RT or RP between 2004 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable Cox proportional hazards analysis was used to evaluate the comparative risk of prostate cancer-specific mortality (CSM) and all-cause mortality (ACM) between LTs. A 1:1 propensity score matching (PSM) and adjusted standardized mortality ratio weighting (SMRW) were performed to balance the clinicopathological characteristics of the groups. RESULTS: Of 684 mPCa patients, 481 underwent RP and 203 received RT. After PSM, both groups included 148 cases, and RT resulted in comparable CSM versus RP [CSM: hazard ratio (HR) = 0.77, p = 0.325; ACM: HR = 0.73, p = 0.138], which was consistent with the SMRW model [CSM: HR = 0.83, p = 0.138; overall survival (OS): HR = 0.75, p = 0.132]. However, RP was associated with a lower CSM in the T1-2 subgroup (HR = 0.42, p = 0.048) and a lower ACM in the T1-2 (HR = 0.55, p = 0.031) and prostate-specific antigen (PSA) ≤20ng/ml (HR = 0.48, p = 0.022) subgroups. Besides, the results showed that the mortality risk was similar between the two groups in the T3-4, Gleason score (GS) >7, PSA >20 ng/ml, and all metastatic subgroups (all p > 0.100). CONCLUSIONS: RP could confer better survival outcomes than could RT in mPCa patients with favorable primary tumor features, but not in those with advanced primary tumor features. Moreover, the metastatic substage has limited impact on the comparative effectiveness between RP and RT. Further clinical trials are necessary to confirm the present results.

Identification of a Hypoxia-Related Gene Signature for Predicting Systemic Metastasis in Prostate Cancer.

Background: Systemic metastasis is the main cause of death in patients with prostate cancer. It is necessary to establish a more accurate model to distinguish and predict patients with a high risk of metastasis to optimize individualized treatment. Methods: In this study, it was determined that hypoxia could affect the metastasis-free survival of patients with prostate cancer, and a hypoxia-related gene signature composed of seven genes for predicting metastasis was established and verified in different cohorts. The study further evaluated the effects of ALDOB expression on the proliferation and invasion of the LNCaP and DU145 cell lines under hypoxia and finally constructed a nomogram containing specific clinical characteristics of prostate cancer combined with the hypoxia gene signature to quantify the metastasis risk of individual patients. Results: The hypoxia-related gene signature was identified as an independent risk factor for metastasis-free survival in patients with prostate cancer. The expression of ALDOB increased under hypoxia and promoted the proliferation and invasion of LNCaP and DU145 cells. In addition, patients with a high risk score showed therapeutic resistance and immunosuppression. Compared with other parameters, the nomogram had the strongest predictive power and net clinical benefit. Conclusion: The study established a hypoxia-related gene signature and a nomogram to distinguish and predict patients with a high risk of prostate cancer metastasis, which may help to optimize individualized treatment and explore possible therapeutic targets.