Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.

BACKGROUND: Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. METHODS: In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. RESULTS: A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. CONCLUSIONS: Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Ranking the attribution of high-risk genotypes among women with cervical precancers and cancers: a cross-sectional study in Ningbo, China.

BACKGROUND: The region-specific importance of carcinogenic HPV genotypes is required for optimizing HPV-based screening and promoting appropriate multivalent HPV prophylactic vaccines. This information is lacking for Ningbo, one of the first cities of China's Healthy City Innovation Pilot Program for Cervical Cancer Elimination. Here, we investigated high-risk HPV (HR-HPV) genotype-specific distribution and attribution to biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) before mass vaccination in Ningbo, China. METHODS: A total of 1393 eligible CIN2+ archived blocks (including 161 CIN2, 1107 CIN3, and 125 invasive cervical cancers [ICC]) were collected from 2017 to 2020 in Ningbo. HR-HPV DNA was genotyped using the SPF10-DEIA-LiPA25 version 1 detection system and the SureX HPV 25X Genotyping Kit. Genotype-specific attribution to CIN2+ was estimated using a fractional contribution approach. RESULTS: Ranking by the attributable proportions, HPV16 remained the most important genotype in both cervical precancers and cancers, accounting for 36.8% of CIN2, 53.2% of CIN3, and 73.3% of ICC cases. Among cervical precancers, HPV52 (17.3% in CIN2, 12.7% in CIN3) and HPV58 (13.9%, 14.9%) ranked second and third, while HPV33 (8.3%, 7.9%) and HPV31 (6.5%, 4.1%) ranked fourth and fifth, respectively. However, among ICCs, HPV18 (5.7%) accounted for the second highest proportion, followed by HPV33 (5.4%), HPV58 (4.0%), and HPV45 (3.2%). HPV18/45 together accounted for 46.8% of adenocarcinomas, which was slightly lower than that of HPV16 (47.7%). The remaining HR-HPV genotypes (HPV35/39/51/56/59/66/68) combined accounted for only 6.7% of CIN2, 2.9% of CIN3, and 4.2% of ICC. CONCLUSIONS: With Ningbo's strong medical resources, it will be important to continue HPV16/18 control efforts, and could broaden to HPV31/33/45/52/58 for maximum health benefits. However, different strategies should be proposed for other HR-HPV genotypes based on their lower carcinogenic risks.

Diagnosis, Treatment Patterns, and Outcomes in Real-World Patients with RET Fusion-Positive Non-small Cell Lung Cancer in China.

INTRODUCTION: Epidemiological studies on non-small cell lung cancer (NSCLC) have noted RET fusions as an oncogenic driver. However, real-world data on RET biomarker testing and treatment patterns in China remain limited. This study aimed to examine demographics, clinical and molecular features, and RET testing and treatment patterns and outcomes in patients with RET fusion-positive NSCLC. METHODS: Utilizing real-world data from the Chinese Multi-center Lung Cancer Precision Medicine Registry, this retrospective cohort study focused on Chinese patients diagnosed with RET fusion-positive NSCLC between January 1, 2016, and November 30, 2021. The cohort was divided into early-stage and advanced-stage subgroups. Demographics, clinical and molecular profiles, treatment received, and outcomes including real-world event free survival (rwEFS), real-world progression free survival (rwPFS), and overall survival (OS) were assessed. RESULTS: The study included 121 patients with RET fusion-positive NSCLC, comprising 80 early-stage and 58 advanced-stage patients. High biomarker testing rates were observed at diagnosis (75% for early-stage, 78% for advanced-stage). RET testing was often conducted via tissue samples (95.9%) and next-generation sequencing (89.3%). KIF5B (57.0%) and CCDC6 (20.7%) were the most common gene fusion partners. The most frequent oncogenic mutations were TP53 (15.7%) and EGFR (6.6%). Platinum-based chemotherapy was the most common first-line treatment among advanced-stage patients. Median rwPFS was 9.22 months for advanced-stage patients on first-line chemotherapy, and median OS was 30.7 months for all advanced-stage patients. The 2-year rwEFS rate for early-stage patients was 86.0%, with a median OS of 91.9 months. CONCLUSIONS: The study observed high biomarker testing rates at initial diagnosis for early- and advanced-stage RET fusion-positive NSCLC patients in China. The heterogeneous treatment pattern of advanced patients suggests the need for more precise, evidence-based treatment to guide clinical decisions. Given the existing therapeutic regimens fall short of adequately addressing treatment needs, targeted therapies are essential to improve outcomes.

Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages.

Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

High-Dose Furmonertinib in Patients With EGFR-Mutated NSCLC and Leptomeningeal Metastases: A Prospective Real-World Study.

INTRODUCTION: Leptomeningeal metastasis (LM) is one of the most severe complications of NSCLC. Furmonertinib is a pan-EGFR tyrosine kinase inhibitor (TKI) with a high rate of brain penetration and a wide therapeutic window. Here, we evaluated the efficacy and safety of high-dose furmonertinib in patients with EGFR-mutated NSCLC and LM. METHODS: This prospective real-world study included patients with EGFR-mutated NSCLC and LM treated with a high-dose furmonertinib (240 mg once daily) as a monotherapy or in combination with other treatments. The primary end point was overall survival, and the secondary end points included time to treatment discontinuation and clinical response rate. Additional efficacy evaluations included changes in brain magnetic resonance imaging by the response assessment in neuro-oncology-LM radiologic criteria. We also introduced next-generation sequencing-based assays to evaluate genomic and epigenomic features of cell-free DNA (cfDNA) in patients' cerebrospinal fluid (CSF) samples and to analyze their associations with patient outcomes. RESULTS: We enrolled 48 patients, of whom 35 (72.9%) had received third-generation EGFR TKIs. The median overall survival was 8.43 months (95% confidence interval: 5.48-11.39 mo), while the median time to treatment discontinuation was 8.27 months (95% confidence interval: 5.40-11.14 mo), and the clinical response rate was 75%. The LM objective response rate and disease control rate assessed with response assessment in neuro-oncology-LM radiologic criteria were 50.0% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. Briefly, 22 (45.8%) had adverse events possibly related to furmonertinib and 3 (6.3%) had a grade 3-elevated aminotransaminase or nausea or leucopenia, leading to a dose reduction to 160 mg daily. Furthermore, methylation analysis of cfDNA in CSF revealed that there was a considerable correlation between the changes of aberrant methylated fragments from lung cancer cells and the response of the patients. Meanwhile, the copy number burden scores derived from the low-pass whole genome sequencing assay may offer another objective and effective method for the diagnosis and evaluation of treatment efficacy in LM. CONCLUSIONS: In the real world, the high-dose furmonertinib-based treatment may potentially have clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients previously treated with other third-generation EGFR TKIs. Methylation and copy number burden analysis of cfDNA in CSF may be considered objective indicators for the diagnosis of LM and evaluation of treatment response.

Efficacy of PD-1 or PD-L1 inhibitors for the therapy of cervical cancer with varying PD-L1 expression levels: a single-arm meta-analysis.

Objective: To assess the effectiveness and tolerability of both PD-1 and PD-L1 inhibitors in advanced cervical cancer (CC), focusing on varying PD-L1 levels. Methods: A comprehensive exploration was carried out on EMBASE, PubMed, Cochrane Library databases as well as Web of Science up to May 25, 2024, for studies involving advanced CC patients receiving PD-1/PD-L1 inhibitors. Inclusion criteria were studies reporting objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), as well as median overall survival (OS). Data extraction and quality assessment were performed by two reviewers using the JBI Case Series Critical Appraisal Checklist, followed by a meta-analysis via STATA/MP 16.0. Results: Five eligible studies comprising 223 patients were chosen. ORR and DCR were 42% (95% CI: 17%-66%, P = 0.00) and 70% (95% CI: 22%-117%, P = 0.00), respectively, in the PD-L1 positive patients and were 36% (95% CI: 17%-54%, P = 0.00) and 47% (95% CI: 30%-63%, P = 0.00), respectively, in patients with PD-L1 negativity. For patients exhibiting PD-L1 positivity, median PFS and median OS were 3.98 months (95% CI: 0.80-7.16, P = 0.01) and 11.26 months (95% CI: 3.01-12.58, P = 0.00), respectively. Conclusion: With PD-1/PD-L1 inhibitors, PD-L1 positive CC patients demonstrate superior ORR, DCR, median PFS, and median OS, underscoring PD-L1 as one biomarker for immunotherapy response.

The assembly mechanism of Zein/EGCG/PEG nanoparticles in a water system and their adsorption behavior at the oil-water interface.

In this study, the self-assembly mechanism of Zein/(-)-epigallocatechin-3-gallate/polyethylene glycol (Zein/EGCG/PEG) composite nanoparticles and their interface adsorption behavior at the oil-water interface were investigated by coarse-grained molecular dynamics simulation. Fourier transform infrared spectroscopy and conformation analysis demonstrated that there were electrostatic and hydrogen bond interactions between Zein and EGCG, physical entanglement between PEG and Zein, and hydrogen bond interaction between EGCG and PEG. The nanoparticles accumulated at the oil-water interface, and there was an obvious interface layer between oil phase and water phase, as indicated by confocal laser scanning microscope and scanning electron microscope. The adsorbing of Zein/EGCG/PEG nanoparticles at the oil-water interface was confirmed by coarse-grained molecular dynamics simulation. Further findings confirmed that Zein/EGCG/PEG nanoparticles could serve as stabilizers for oleogels with self-supporting structure, viscoelastic solid behavior and temperature response characteristics. The current research offered a novel approach to enhance protein interface characteristics and create food-grade emulsifiers and oleogelators.

Breast cancer colonization by Malassezia globosa accelerates tumor growth.

Malassezia globosa is a lipophilic basidiomycetous yeast that occurs abundantly in breast tumors and that may contribute to a shortened overall survival of breast cancer (BRAC) patients, suggesting that the yeast may participate in the carcinogenesis of BRAC. However, the mechanisms involved in the M. globosa-based acceleration of BRAC are unknown. Here, we show that M. globosa can colonize mammary tissue in 7,12-dimethylbenz[a] anthracene-induced mice. The abundance of M. globosa shortened the overall survival and increased the tumor incidence. Transcriptome data illustrated that IL-17A plays a key role in tumor growth due to M. globosa colonization, and tumor-associated macrophage infiltration was elevated during M. globosa colonization which triggers M2 polarization of macrophages via toll-like receptors 4/nuclear factor kappa-B (Nf-κB) signaling. Our results show that the expression of sphingosine kinase 1 (Sphk1) is increased in breast tumors after inoculation with M. globosa. Moreover, we discovered that Sphk1-specific small interfering RNA blocked the formation of lipid droplets, which can effectively alleviate the expression of the signal transducer and activator of the transcription 3 (STAT3)/Nf-κB pathway. Taken together, our results demonstrate that M. globosa could be a possible factor for the progression of BRAC. The mechanisms by which M. globosa promotes BRAC development involve the IL-17A/macrophage axis. Meanwhile, Sphk1 overexpression was induced by M. globosa infection, which also promoted the proliferation of MCF-7 cells.IMPORTANCELiterature has suggested that Malassezia globosa is associated with breast tumors; however, this association has not been confirmed. Here, we found that M. globosa colonizes in breast fat pads leading to tumor growth. As a lipophilic yeast, the expression of sphingosine kinase 1 (Sphk1) was upregulated to promote tumor growth after M. globosa colonization. Moreover, the IL-17A/macrophages axis plays a key role in mechanisms involved in the M. globosa-induced breast cancer acceleration from the tumor immune microenvironment perspective.

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.

The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.

Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer.

There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.

Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Combined aqupla, paclitaxel liposome, and docetaxel treatment: survival and biomarker outcomes in recurrent ovarian cancer patients.

As one lethal malignancy in women's reproductive systems, ovarian cancer (OC) is frequently detected at an advanced phase during diagnosis. when the disease has spread widely. The absence of obvious symptoms and powerful screening tools in the early stages makes treatment difficult and the prognosis poor. Despite the clinical remission that can be achieved in some patients after initial treatment, the recurrence rate is conspicuous, posing a considerable challenge in treating recurrent OC (ROC). In the retrospective analysis, we compared the effects of two treatment regimens, aqupla combined with paclitaxel liposome (NP group) versus aqupla combined with docetaxel (ND group), on survival and biomarkers in patients with ROC. The study included 121 OC patients, and clinical data were collected through an electronic medical record system, outpatient review records, and a follow-up record system. The results revealed a notably higher overall remission rate in the ND group than the NP group, but revealed no notable inter-group discrepancy in toxicities, implying that the aqupla combined with docetaxel regimen may be more effective in platinum-sensitive ROC patients. Additionally, post-treatment CA125 levels were lower in patients in the ND group, suggesting that the regimen may be more effective in reducing tumour load. Survival analysis further revealed that treatment regimen, FIGO stage, number of recurrent lesions, and pretreatment CA125 level were independent prognostic factors affecting patients' 5-year OS and PFS. Overall for ROC patients, especially platinum-sensitive patients, the aqupla in combination with docetaxel regimen provided an improved survival benefit with a comparable safety profile, highlighting the importance of individualised treatment strategies.

Parthenolide enhances the metronomic chemotherapy effect of cyclophosphamide in lung cancer by inhibiting the NF-kB signaling pathway.

BACKGROUND: Parthenolide (PTL), a sesquiterpene lactone derived from the medicinal herb Chrysanthemum parthenium, exhibits various biological effects by targeting NF-kB, STAT3, and other pathways. It has emerged as a promising adjunct therapy for multiple malignancies. AIM: To evaluate the in vitro and in vivo effect of PTL on cyclophosphamide (CTX) metronomic chemotherapy. METHODS: The cytotoxicity of PTL and CTX on Lewis lung cancer cells (LLC cells) was assessed by measuring cell activity and apoptosis. The anti-tumor efficiency was evaluated using a tumor xenograft mice model, and the survival of mice and tumor volume were monitored. Additionally, the collected tumor tissues were analyzed for tumor microenvironment indicators and inflammatory factors. RESULTS: In vitro, PTL demonstrated a synergistic effect with CTX in inhibiting the growth of LLC cells and promoting apoptosis. In vivo, metronomic chemotherapy combined with PTL and CTX improved the survival rate of tumor-bearing mice and reduced tumor growth rate. Furthermore, metronomic chemotherapy combined with PTL and CTX reduced NF-κB activation and improved the tumor immune microenvironment by decreasing tumor angiogenesis, reducing Transforming growth factor ß, and α-SMA positive cells. CONCLUSION: PTL is an efficient compound that enhances the metronomic chemotherapy effects of CTX both in vitro and in vivo, suggesting its potential as a supplementary therapeutic strategy in metronomic chemotherapy to improve the chemotherapy effects.

Vebreltinib for Advanced Non-Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study.

PURPOSE: The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition (MET), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring c-Met alterations. METHODS: This multicenter, multicohort, open-label, single-arm, phase II trial enrolled patients with c-Met dysregulated, locally advanced or metastatic NSCLC from January 2020 to August 2022 across 17 centers. Cohort 1 included patients with MET exon 14 skipping (METex14)-mutant NSCLC who had not previously received MET inhibitors. Participants were administered vebreltinib at a dosage of 200 mg twice a day in 28-day cycles. The primary end point was the objective response rate (ORR), and the key secondary end point was the duration of response (DoR), both evaluated by a blinded independent review committee according to the RECIST version 1.1. RESULTS: As of August 9, 2022, 52 patients had been enrolled in cohort 1, of whom 35 (67.3%) were treatment-naïve. The ORR reached 75% (95% CI, 61.1 to 86). Among treatment-naïve patients, the ORR was 77.1% (95% CI, 59.9 to 89.6), and in previously treated patients, it was 70.6% (95% CI, 44.0 to 89.7). The disease control rate was 96.2%, with a median DoR of 15.9 months, a median progression-free survival of 14.1 months, and a median overall survival of 20.7 months. The most common treatment-related adverse events were peripheral edema (82.7%), QT prolongation (30.8%), and elevated serum creatinine (28.8%). CONCLUSION: Vebreltinib has shown promising efficacy and a favorable safety profile in patients with METex14-mutant NSCLC.

Exploring the antibiofilm efficacy of cinnamaldehyde against Malassezia globosa associated pityriasis versicolor.

BACKGROUND: Malassezia globosa is a commensal basidiomycetous yeast occurring on the skin that causes pityriasis versicolor (PV) and seborrheic dermatitis, but that has also been implicated in other dermatoses. Cinnamaldehyde (CM) has antibacterial, antioxidant, and anti-inflammatory activities, but the effect of CM on M. globosa-infected PV has not been clarified. PURPOSE: The study aimed to investigate the possible antifungal and antibiofilm activities of CM against M. globosa-infected PV in vivo and in vitro. METHODS: The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of CM against M. globosa. The crystal violet staining assay and XTT assay were used to investigate the inhibition of CM on biofilm formation and the eradication of mature biofilms. The visualizations of the biofilm and cell distribution in the biofilm matrix were performed with a scanning electron microscope and confocal laser scanning microscope. The kits of antioxidant kinase were used to determine the activities of oxidative stress markers in M. globosa-stimulated HaCaT cells. Western blot assays were used to evaluate the role of TLR2/NF-κB in vitro. Furthermore, the protective effect of CM was assessed in M. globosa-associated PV mice. The expressions of inflammatory cytokines and apoptosis were screened using ELISA assays. The expressions of interleukin-6 and tumor necrosis factor-α were measured by an immunohistochemistry method in vivo. RESULTS: Our results showed that the MIC of CM against planktonic cells of M. globosa was 4 µg/ml and treatment with 20 × MIC CM eradicated mature biofilms of M. globosa. In vitro, after CM treatment the levels of oxidative stress indicators (i.e., superoxide dismutase, catalase, glutathione) significantly increased, while the levels of malondialdehyde decreased. In addition, the expression of TLR2/NF-κB in HaCaT cells was significantly reduced after CM treatment. On the other hand, an in vivo therapeutic effect of CM was assessed against M. globosa-infected mice. The fungal load on the skin decreased after treatment with CM compared to the M. globosa-infected group. In addition, the uninfected animals showed a normal skin structure, whereas, the M. globosa-infected mice showed extensive infiltration of neutrophils in skin tissues that improved after treatment with CM. Meanwhile, the levels of inflammatory and apoptotic factors improved after CM treatment. CONCLUSION: Our results showed that CM inhibits the biofilm formation of M. globosa and eradicates mature biofilms of M. globosa. Treatment with CM significantly decreased oxidative stress, apoptosis, and inflammatory markers in the skin tissue and HaCaT cells. Hence, this study suggests that CM is a good candidate therapeutic agent against M. globosa-induced PV infections because of its antifungal, antibiofilm, and anti-inflammatory properties.

Integrated mendelian randomization analyses highlight AFF3 as a novel eQTL-mediated susceptibility gene in renal cancer and its potential mechanisms.

BACKGROUNDS: A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. METHODS: Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the "TwoSampleMR" R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. RESULTS: Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001-1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P < 0.05). Moreover, the TCGA-KIRC, the ICGC-RC, and the GSE159115 datasets verified that the AFF3 gene was more highly expressed in RC tumors than normal control via scRNA-sequencing and bulk RNA-sequencing (P < 0.05). Gene set enrichment analysis (GSEA) analysis identified six potential biological pathways of AFF3 involved in RC. As for the potential mechanism of AFF3 in RC, we concluded in this article that AFF3 eQTL could negatively modulate the levels of the X-11,315 metabolite (IVW method; OR = 0.9127; 95% CI = 0.8530-0.9765; P = 0.0081; heterogeneity = 0.4150; pleiotropy = 0.8852), exhibiting preventive effects against RC risks (IVW method; OR = 0.9987; 95% CI = 0.9975-0.9999; P = 0.0380; heterogeneity = 0.5362; pleiotropy = 0.9808). CONCLUSIONS: We concluded that AFF3 could serve as a novel eQTL-mediated susceptibility gene in RC and reveal its potential mechanism of elevating RC risks via negatively regulating the X-11,315 metabolite levels.

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor: a randomized double-blind trial.

OBJECTIVE: The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. METHODS: PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator's brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. RESULTS: Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR)10 mg = 0.390 (95% confidence interval {CI}, 0.201-0.756), P = 0.005; HR12 mg = 0.397 (0.208-0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR10 mg = 0.445 (0.210-0.939), P = 0.034; HR12 mg = 0.369 (0.174-0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR10 mg = 0.340 (0.156-0.742), P = 0.007; HR12 mg = 0.340 (0.159-0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. CONCLUSIONS: Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Elucidating the molecular mechanisms of pterostilbene against cervical cancer through an integrated bioinformatics and network pharmacology approach.

Pterostilbene (PTE), a natural phenolic compound, has exhibited promising anticancer properties in the preclinical treatment of cervical cancer (CC). This study aims to comprehensively investigate the potential targets and mechanisms underlying PTE's anticancer effects in CC, thereby providing a theoretical foundation for its future clinical application and development. To accomplish this, we employed a range of methodologies, including network pharmacology, bioinformatics, and computer simulation, with specific techniques such as WGCNA, PPI network construction, ROC curve analysis, KM survival analysis, GO functional enrichment, KEGG pathway enrichment, molecular docking, MDS, and single-gene GSEA. Utilizing eight drug target prediction databases, we have identified a total of 532 potential targets for PTE. By combining CC-related genes from the GeneCards disease database with significant genes derived from WGCNA analysis of the GSE63514 dataset, we obtained 7915 unique CC-related genes. By analyzing the intersection of the 7915 CC-related genes and the 2810 genes that impact overall survival time in CC, we identified 690 genes as crucial for CC. Through the use of a Venn diagram, we discovered 36 overlapping targets shared by PTE and CC. We have constructed a PPI network and identified 9 core candidate targets. ROC and KM curve analyses subsequently revealed IL1B, EGFR, IL1A, JUN, MYC, MMP1, MMP3, and ANXA5 as the key targets modulated by PTE in CC. GO and KEGG pathway enrichment analyses indicated significant enrichment of these key targets, primarily in the MAPK and IL-17 signaling pathways. Molecular docking analysis verified the effective binding of PTE to all nine key targets. MDS results showed that the protein-ligand complex between MMP1 and PTE was the most stable among the nine targets. Additionally, GSEA enrichment analysis suggested a potential link between elevated MMP1 expression and the activation of the IL-17 signaling pathway. In conclusion, our study has identified key targets and uncovered the molecular mechanism behind PTE's anticancer activity in CC, establishing a firm theoretical basis for further exploration of PTE's pharmacological effects in CC therapy.