Comparison of Efficacy and Safety of First-Line Treatment Options for Unresectable Stage III Non-Small Cell Lung Cancer: A Retrospective Analysis.

Background: Based on PACIFIC trial, durvalumab as consolidation therapy following concurrent chemoradiotherapy (cCRT) has been a new standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). In clinical applications, there are heterogeneous adjustments or novel strategies following specialized discussions in experienced multidisciplinary teams. This study retrospectively compared the efficacy and safety of different first-line treatments for unresectable stage III NSCLC. Methods: We retrospectively analyzed 397 patients who received first-line treatment for unresectable stage III NSCLC. Comparisons and statistical analyses of treatment were made in terms of efficacy and safety. Adverse events and responses were assessed using CTCAE v5.0 and RECIST v1.1. The progression-free survival (PFS) was estimated using the Kaplan-Meier method or the Cox survival regression model and compared using the log-rank test. Results: In wild-type driver genes group, the objective response rate (ORR), disease control rate (DCR), and median PFS (mPFS) were prolonged in the radiotherapy group compared to those in the nonradiotherapy group (ORR: 50.94% vs. 30.06%, p < 0.001; DCR: 98.11% vs. 80.37%, p < 0.001; and mPFS: 21.00 vs. 8.20 months, p < 0.001). The incidence of pneumonia at any grade in the radiotherapy group was higher than that in the nonradiotherapy group (9.43% vs. 2.45%, p = 0.008). In the radiotherapy group, the chemoradiotherapy (CRT) plus immunotherapy subgroup had longer mPFS than the CRT subgroup, with increased toxicity at any grade (24.60 vs. 17.90 months, p = 0.025, and 83.17% vs. 65.52%, p = 0.011). In the nonradiotherapy group, the DCR and mPFS were higher in the chemotherapy plus immunotherapy subgroup than in the chemotherapy subgroup, with increased toxicity at any grade (DCR: 93.67% vs. 67.86%, p < 0.001; mPFS: 13.53 vs. 5.07 months, p < 0.001; and 68.35% vs. 41.67%, p = 0.001). In the mutant driver genes group, the efficacy did not significantly differ among the radiotherapy subgroup, targeted therapy subgroup, and radiotherapy plus targeted therapy subgroup (ORR: p = 0.633; mPFS: p = 0.450). Conclusions: For unresectable stage III NSCLC patients with wild-type driver genes, the combination of radiotherapy and immunotherapy in the initial treatment was essential to significantly improve the efficacy. For patients with mutant driver genes, radiotherapy, targeted therapy, and the combination of radiotherapy and targeted therapy showed similar short-term efficacy.

Inhibition of ZEB1-AS1 confers cisplatin sensitivity in breast cancer by promoting microRNA-129-5p-dependent ZEB1 downregulation.

BACKGROUND: Breast cancer is the leading cause of cancer-related mortality in women worldwide. Long non-coding RNAs (lncRNAs) are of critical importance in tumor drug resistance. Herein, this study aims to determine the roles of lncRNA ZEB1-AS1 in drug resistance of breast cancer involving microRNA-129-5p (miR-129-5p) and ZEB1. METHODS: Microarray-based gene expression profiling of breast cancer was conducted to identify the differentially expressed lncRNAs. ZEB1 expression was measured in adjacent and cancerous tissues. Next, MCF-7 and MDA-MB-231 cells were treated with a series of inhibitor, mimic or siRNA to clarify the roles of lncRNA ZEB1-AS1 and miR-129-5p in drug resistance of breast cancer. Then the target relationship of miR-129-5p with lncRNA ZEB1-AS1 and ZEB1 was verified. The expression patterns of miR-129-5p, lncRNA ZEB1-AS1, Bcl-2, MDR-1, ZEB1 and corresponding proteins were evaluated. Moreover, the apoptosis and drug resistance of MCF-7 cell were detected by CCK-8 and flow cytometry respectively. RESULTS: LncRNA ZEB1-AS1 was observed to be an upregulated lncRNA in breast cancer, and ZEB1 overexpression was noted in breast cancerous tissues. MiR-129-5p was revealed to specifically bind to both ZEB1 and lncRNA ZEB1-AS1. Moreover, the expression levels of ZEB1-AS1, ZEB1, Bcl-2, MDR-1, and corresponding proteins were decreased, but the expression of miR-129-5p was increased with transfection of miR-129-5p mimic and lncRNA ZEB1-AS1 siRNA. Besides, drug resistance to cisplatin was inhibited, and cell apoptosis was promoted in breast cancer after transfection of miR-129-5p mimic, lncRNA ZEB1-AS1 siRNA, and ZEB1 siRNA. CONCLUSION: In conclusion, the study provides evidence that lncRNA ZEB1-AS1 silencing protects against drug resistance in breast cancer by promoting miR-129-5p-dependent ZEB1 downregulation. It may serve as a novel therapeutic target in breast cancer treatment.

MicroRNA-590-5p functions as a tumor suppressor in breast cancer conferring inhibitory effects on cell migration, invasion, and epithelial-mesenchymal transition by downregulating the Wnt-ß-catenin signaling pathway.

Breast cancer remains one of the foremost primary causes of female morbidity and mortality worldwide. During the current study, the effect of miR-590-5p and paired-like homeodomain transcription factor 2 (PITX2) on proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) of human breast cancer via the Wnt-ß-catenin signaling pathway was investigated. Breast cancer-related genes and related signaling pathways were obtained from KEGG database. The PITX2 regulatory microRNA was predicted. To define the contributory role by which miR-590-5p influences the progression of breast cancer, the interaction between miR-590-5p and PITX2 was explored; the proliferation, invasion, and migration abilities as well as the tumor growth and metastasis in nude mice were detected following the overexpression or silencing of miR-590-5p. PITX2 was determined to share a correlation with breast cancer and miR-590-5p was selected for further analysis. PITX2, Wnt-1, ß-catenin, N-cadherin, and vimentin all displayed higher levels, while miR-590-5p and E-cadherin expression were lower among breast cancer tissues than in the adjacent normal tissue. After overexpression of miR-590-5p or si-PITX2, the expression of E-cadherin was markedly increased, decreases in the expression of Wnt-1, ß-catenin, N-cadherin, and vimentin, as well as inhibited cell proliferation, invasion, migration, metastasis, and EMT were observed. This study provides evidence suggesting that the transfection of overexpressed miR-590-5p can act to alleviate the effects of breast cancer demonstrating an ability to inhibit the processes of cell proliferation, migration, and invasion as well as EMT by suppressing the expression of PITX2 and activation of the Wnt-ß-catenin pathway.

Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies.

Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.

Long non-coding RNA FBXL19-AS1 plays oncogenic role in colorectal cancer by sponging miR-203.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of the progression of human cancers, including colorectal cancer (CRC). The study of genome-wide lncRNA expression patterns in metastatic CRC could provide novel mechanism underlying CRC carcinogenesis. In here, we determined the lncRNA expression profiles correlating to CRC with or without lymph node metastasis (LNM) based on microarray analysis. We found that 2439 lncRNAs and 1654 mRNAs were differentially expressed in metastatic CRC relative to primary CRC. Among these dysregulated lncRNAs, FBXL19-AS1 was the most significantly upregulated lncRNA in metastatic tumors. Functionally, knockdown of FBXL19-AS1 played tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Overexpression of FBXL19-AS1 was markedly correlated with TNM stage and LNM in CRC. Bioinformatics analysis predicted that miR-203 was potentially targeted by FBXL19-AS1, which was confirmed by dual-luciferase reporter assay. Pearson's correlation analysis showed that miR-203 expression was negatively related to FBXL19-AS1 in tumor tissues. Finally, miR-203 inhibition abrogated the effect of FBXL19-AS1 knockdown on the proliferation and invasion of LoVo cells. Our results reveal the cancer-promoting effect of FBXL19-AS1, acting as a molecular sponge in negatively modulating miR-203, which might provide a new insight for understanding of CRC development.

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation.

To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR-8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up- or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non-small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non-small cell lung cancer cells. The results showed that the non-small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/GR-8-1 cells and involved in the acquired gefitinib resistance.

Reversal effects of local anesthetics on P-glycoprotein-mediated cancer multidrug resistance.

The existence of multidrug resistance (MDR) is the main reason for failure in cancer chemotherapy. The main mechanism of MDR is the overexpression of P-glycoprotein (P-gp). P-gp, a 170 kDa transmembrane phosphorylated glycoprotein encoded by ABCB1 belonging to a member of the ATP-binding cassette (ABC) super-family of the membrane transporters, is also known as the MDR protein. Local anesthetics (LAs) are a major contributor to medical practice. As a cornerstone of analgesia, LAs provides myriad benefits. Recent studies have shown that the LAs can interfere with receptors other than the traditional sodium channel. LA can suppress the proliferation of several cancer cells. The inhibition of P-gp could reverse MDR. Interestingly, the LAs, such as lidocaine, can repress ABCB1 (P-gp) expression and reverse MDR. Also, LAs can modulate the tumor necrosis factor/AKT pathway, the tumor necrosis factor/Src pathway, epidermal growth factor receptor, the Wnt pathway, and the RASSF1A/MDM2/p53 pathway to interfere with P-gp function. This means that LAs could be potentially useful in reversing cancer MDR. The aim of this review is to report the nonanesthetic functions of LAs, with a special focus on their anti-MDR effects and their potential beneficial implications in cancer chemotherapy.

MicroRNA-106b-5p regulates cisplatin chemosensitivity by targeting polycystic kidney disease-2 in non-small-cell lung cancer.

Systemic therapy with cytotoxic agents remains one of the main treatment methods for non-small-cell lung cancer (NSCLC). Cisplatin is a commonly used chemotherapeutic agent, that, when combined with other drugs, is an effective treatment for NSCLC. However, effective cancer therapy is hindered by a patient's resistance to cisplatin. Unfortunately, the potential mechanism underlying such resistance remains unclear. In this study, we explored the mechanism of microRNA-106b-5p (miR-106b-5p), which is involved in the resistance to cisplatin in the A549 cell line of NSCLC. Quantitative real-time PCR was used to test the expression of miR-106-5p in the A549 and the A549/DDP cell line of NSCLC. The cell counting kit-8 assay was used to detect cell viability. Flow cytometry was used to measure cell cycle and cell apoptosis. Luciferase reporter assays and western blot were performed to confirm whether polycystic kidney disease-2 (PKD2) is a direct target gene of miR-106b-5p. Immunohistochemistry was performed to examine the distribution of PKD2 expression in patients who are sensitive and resistant to cisplatin. The experiments indicated that the expression of miR-106b-5p was significantly decreased in A549/DDP compared with that in A549. MiR-106b-5p affected the tolerance of cells to cisplatin by negatively regulating PKD2. Upregulation of miR-106b-5p or downregulation of PKD2 expression can cause A549/DDP cells to become considerably more sensitive to cisplatin. The results showed that miR-106b-5p enhanced the sensitivity of A549/DDP cells to cisplatin by targeting the expression of PKD2. These findings suggest that the use of miR-106b-5p may be a promising clinical strategy in the treatment of NSCLC.

WITHDRAWN: The long non-coding RNA, LINC00635-001, sensitizes EGFR-TKI-resistant human lung cancer cells in vitro by inhibiting Akt activation.

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Liver X receptor as a drug target for the treatment of breast cancer.

Liver X receptor (LXR) has been exploited widely as a drug target in breast cancer treatment, and various mechanisms underlying the effects of LXR in this area are well studied. The activated LXR plays important roles in estrogen receptor α (ERα) breast cancer cells, such as reducing cell proliferation and arresting cell cycle progression. Different LXR ligands have diverse effects on the development of breast cancer, such as the inhibitory effect of oxysterol, which can return cells to normocholesterol conditions and target other metabolic genes. Moreover, 27-hydroxycholesterol, a locally produced cholesterol metabolite, reportedly promotes the proliferation of ERα breast cancer cells in vitro and facilitates tumor metastasis with other LXR ligands. Moreover, the expression of LXR also exerts potential effects on immune surveillance, tumor immunity, and tumor microenvironment. These advances in breast cancer research indicate that LXR may be a new therapeutic target to treat the refractory or drug-resistant subtypes of breast cancer.

LXR ligands sensitize EGFR-TKI-resistant human lung cancer cells in vitro by inhibiting Akt activation.

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. Here we investigate the effects of two novel liver x receptor (LXR) ligands (T0901317 or GW3965) on the development of acquired resistance to an EGFR TKI gefitinib. We observed known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation, MET gene amplification and loss of PTEN in the gefitinib-resistant HCC827-8-1 cells. However, we found expression of MET was lower in HCC827-8-1 cells than in HCC827 cells. T0901317 or GW3965 inhibited Akt activation and sensitized HCC827-8-1 cells to gefitinib-induced cytotoxicity. In contrast, LXR ligands alone had no significant effect on HCC827-8-1 cells. In conclusion, this combined treatment may be of interest for treatment of lung adenocarcinomas harboring EGFR mutations and acquired resistance to gefitinib.

Comparison of Efficacy and Safety of Second-Line Treatment Options for Advanced Small-Cell Lung Cancer: A Retrospective Analysis.

OBJECTIVE: As monotherapy such as topotecan has reached a plateau of effectiveness, new second-line treatments based on experience have been used in clinical application. This study compared the efficacy and safety of different second-line treatments for advanced small-cell lung cancer (SCLC). METHODS: A total of 380 patients with advanced SCLC were screened selectively in the retrospective study. Adverse events and patient responses were assessed using Common Terminology Criteria for Adverse Events v5.0 and Response Evaluation Criteria for Solid Tumors v1.1. The progression-free survival (PFS) was estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test. RESULTS: In the platinum-resistant group, disease control rate (DCR) and median PFS (mPFS) were prolonged in the combination group versus single-agent group (DCR: 49.24% vs 24.39%, P = .004; mPFS: 3.73 vs 1.90 months, P < .001). Grade 3/4 toxicity was similar between the 2 groups (P = .683). The mPFS did not differ among single-agent groups (P = .380). No significant difference was observed in mPFS of different combination therapy groups (P = .170). In terms of platinum-based chemotherapy, the DCR and mPFS were prolonged in irinotecan-platinum group versus taxol-platinum group (DCR: 56.14% vs 9.09%, P = .004; mPFS: 3.87 vs 1.93 months, P = .012). Grade 3/4 toxicity was similar between the 2 groups (P = .614). The mPFS was prolonged in the chemotherapy plus immunotherapy group versus single-agent chemotherapy group (P = .003). In the platinum-sensitive group, the mPFS did not differ between the combination group and single-agent group (P = .200). The mPFS did not differ among different single-agent groups (P = .260) or combination groups (P = .150). There was no difference in mPFS among different platinum-based chemotherapy groups (P = .830). CONCLUSIONS: For patients with platinum-resistant SCLC, combination therapy has shown better efficacy and acceptable toxicity profile than monotherapy. Among combination therapies, irinotecan-platinum has shown better efficacy than taxol-platinum. For patients with platinum-sensitive SCLC, the efficacy of different single-agent or combination therapies was similar.

A novel transcriptomic signature associated with lymphovascular invasion predicts clinical outcomes, tumor microenvironment, and therapeutic response in lung adenocarcinoma.

PURPOSE: Since TNM staging has limitations for predicting post-operative outcomes and relapse, more effective prediction tools need to be researched and developed. Lymphovascular invasion, LVI, as a histopathological feature, has been widely shown to have a correlation with poor prognosis and early recurrence of lung adenocarcinoma (LUAD). However, LVI assessment is limited by subjective bias, and therefore its efficacy in practical clinical application needs further clarification. The aim of this study was to formulate a new signature based on LVI-related genes to predict prognosis and recurrence in patients with lung adenocarcinoma. METHODS: Clinicopathological information, gene sequencing data and whole slide images (WSIs) of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA) databases. LVI statue were evaluated by professional pathologists, and then the differentially expressed genes (LVI DEGs) associated with LVI were screened. The least absolute shrinkage and selection operator (LASSO) and Step Cox regression models were used to construct LVI-associated risk scores (LVRS), including PAQR4, ARGHEF6, CKS1B, CFTR and SEC14L4. The validity of the LVRS score was evaluated on multiple external datasets and our JSSZL cohort dataset. Using LVRS scores and clinical information, nomogram were constructed for use by clinicians. In addition, we further explored the relationship between LVRS score and clinicopathological features, immune infiltration, tumor mutational load, and immunotherapy response, and confirmed the expression of key genes in LVRS score in lung adenocarcinoma tissues using qRT-PCR and immunohistochemistry (IHC) techniques. RESULTS: Based on the LVRS, patients could be classified into high-LVRS and low-LVRS groups. It was found that OS and PFS were significantly worse in the high-LVRS group than in the low-LVRS group (p < 0.001). By ROC curve analysis, it could be found that the nomogram combining LVRS and clinical information could accurately predict the prognosis of LUAD patients with the area under the curve of 1,3,5-year survival rate could reach 0.754, 0.741 and 0.735. The results of univariate and multivariate analysis showed that LVRS was an independent prognostic factor. At the same time, there were significant differences in the mutation profiles and immune microenvironment between the high-LVRS and low-LVRS groups, with the high-LVRS group having a significantly higher mutation rate than the low-LVRS group and exhibiting immunological "cold" features. By the experimental results, higher expression levels of PAQR4 and CKS1B were found in LUAD tissues, while lower expression levels of ARGHEF6, CFTR and SEC14L4 were observed. CONCLUSIONS: The LVRS established in this study serves as a valid tool to predict the prognosis and recurrence status of lung adenocarcinoma patients and has a predictive effect on the response to postoperative treatment. The establishment of LVRS may offer some theoretical support to clinical treatment strategies for patients with lung adenocarcinoma following surgical intervention.

CircATXN7 regulates the proliferation and invasion of esophageal cancer cells through miR-4319/NLRC5.

BACKGROUND: This study aimed to explore the molecular mechanism through which circular RNA of ataxin 7 (circATXN7) regulates the proliferation and invasion of esophageal cancer (EC) cells via microRNA (miR)-4319/NLR family CARD domain containing 5 (NLRC5). METHODS: The localization of circATXN7 in EC cells was determined by RNA fluorescent in situ hybridization (RNA-FISH). The mRNA levels of circATXN7, miR-4319, and NLRC5 were quantified by reverse transcription-polymerase chain reactions. The binding activity of circATXN7 to miR-4319 was assessed using RNA-binding protein immunoprecipitation. Whether circATXN7 regulates the proliferation of EC cells via miR-4319 was explored using dual-luciferase reporter gene colony formation assays. Protein levels were quantified by western blot. The effect of NLRC5 on the proliferation and invasion of EC cells was examined using colony formation and Transwell assays. A subcutaneous transplanted tumor nude mouse model was established to observe the effect of circATXN7 on the proliferation of EC cells in vivo. RESULTS: circATXN7 localized mainly to the cytoplasm. Overexpression or inhibition of miR-4319 significantly regulated the proliferation of EC cells, while circATXN7 competitively inhibited miR-4319 expression. Overexpression of miR-4319 significantly inhibited NLRC5 expression, indicating NLRC5 is a downstream regulatory target of miR-4319. circATXN7 influenced NLRC5 expression via miR-4319. In vivo tumor formation experiments in nude mice revealed that knocking down circATXN7 regulated NLRC5 expression via miR-4319 and significantly inhibited the proliferation of EC cells. CONCLUSIONS: In vitro cell and in vivo animal experiments showed that circATXN7 regulates the proliferation, invasion, and migration of EC cells through the miR-4319/NLRC5 signaling pathway.

Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study.

Background: Immune checkpoint inhibitors (ICIs) have dramatically changed the first-line treatment pattern of non-small cell lung cancer (NSCLC) without driver gene alterations. However, the optimal choice for second-line treatment after initial treatment with ICIs is unclear. This study aimed to clarify the efficacy and safety of ICI rechallenge therapy in locally advanced and advanced NSCLC. Methods: We retrospectively analyzed the histories of 224 patients with locally advanced or advanced NSCLC treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy and/or antiangiogenic therapy in first-line treatment. Progression-free survival 2 (PFS2) was the time from the first defined progress disease (PD) to the second disease progression or death. Efficacy evaluation was performed directly in accordance with RECIST v1.1 criteria. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Survival data were estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test in overall cohort and other subgroups. Results: There were no significant differences in objective response rate (ORR) and median PFS2 (mPFS2) between the ICI rechallenge group and non-rechallenge group (ORR: 10.3% vs. 15.3%, P=0.308; mPFS2: 5.33 vs. 4.40 months, P=0.715). And the ICI rechallenge group showed no new safety signals compared with non-rechallenge group. In ICI rechallenge group, patients resistant to first-line immunotherapy had a lower ORR and shorter PFS2 compared with those who responded to initial ICIs treatment (ORR: 7.0% vs. 17.6%, P=0.038; mPFS2: 3.68 vs. 5.91 months, P=0.014). No significant difference in mPFS2 was observed among different second-line treatment groups (P=0.362). Radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2. Conclusions: ICI rechallenge therapy beyond disease progression did not improve clinical outcomes in patients with NSCLC, but no new safety signals emerged. However, patients with favorable response to initial ICIs treatment still showed significant efficacy of subsequent ICI rechallenge therapy.

Systematic annotation of orphan RNAs reveals blood-accessible molecular barcodes of cancer identity and cancer-emergent oncogenic drivers.

From extrachromosomal DNA to neo-peptides, the broad reprogramming of the cancer genome leads to the emergence of molecules that are specific to the cancer state. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic and comprehensive search to identify, annotate, and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Together, our findings establish oncRNAs as an emergent class of cancer-specific non-coding RNAs with potential roles in tumor progression and clinical utility in liquid biopsies and disease monitoring.

Anlotinib combined with whole-brain radiotherapy in non-small cell lung cancer with multiple brain metastases that progressed or developed after at least one lines of prior treatment.

Background: Intracranial metastasis that failed standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with whole-brain radiotherapy (WBRT) for NSCLC with brain metastases (BMs) that progressed or developed after at least one line of prior treatment and compare the outcomes with that of the contemporary institutional control. Methods: NSCLC patients with multiple BMs that progressed or developed after at least one line of prior systematic treatment and treated with WBRT subsequently between 2019 and 2021 were selected retrospectively for analysis. Based on whether concurrent anlotinib had been used in combination with WBRT, the cases were divided into the anlotinib group and control group. The primary endpoints were intracranial progression-free survival (iPFS) and safety. Results: A total of 76 patients met the inclusion criteria of the study. Of the 76 patients, 34 received concurrent WBRT and anlotinib followed by anlotinib maintenance and 42 were treated with WBRT alone or in combination with other systemic agents at the physicians' discretion. The median follow-up for the entire cohort was 21 months. The median iPFS for the anlotinib and control group was 6.7 months (95% CI, 4.6-9.9) and 5.3 months (95% CI, 4.0-6.5), respectively (log-rank P = 0.04). There was no difference in overall survival between the two groups (log-rank P = 0.38). In the anlotinib group, treatment-related adverse events were reported in 15 patients (44.1%), with acute or late grade 3-5 adverse events identified in 14.7% of patients (n = 5). Conclusions: WBRT plus anlotinib, as a convenient chemo-free regimen, may represent an overall safe and effective procedure in advanced NSCLC with multiple BMs that progressed or developed after standard systematic treatment.

Efficacy and Safety of PD-1 Immune Checkpoint Inhibitors in Locally Advanced and Advanced Non-Small-Cell Lung Cancer Patients with Chronic Infection.

BACKGROUND: Immune checkpoint inhibitors have become new research hot spots in the treatment of non-small-cell lung cancer (NSCLC), but the efficacy and safety of immunotherapy for patients with chronic infection are still unclear because existing clinical trials often exclude those patients. MATERIALS AND METHODS: We identified 78 locally advanced or advanced NSCLC patients with chronic infection treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: Objective responses were observed in 19 out of 78 (24.36%) patients, and the disease control rate was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI: 3.71-9.27). PFS was 1.44 months (95% CI: 0.00-4.34) for monotherapy versus 7.34 months (95% CI: 4.50-10.18) for combination therapy (p = 0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, p = 0.001; PFS: 7.67 vs. 5.57 months, p = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs. 4.62, p = 0.027). The incidence of AEs of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 AEs. The incidence of leukopenia in any grade of AEs was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%), and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients and remained unchanged in 65.0% (39/60) patients. CONCLUSIONS: The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic infection, but still has the potential to increase the incidence of hepatitis.

Efficacy and safety of bevacizumab biosimilar compared with reference bevacizumab in locally advanced and advanced non-small cell lung cancer patients: A retrospective study.

Background: Bevacizumab has played an important role in the systemic treatment of patients with advanced non-small-cell lung cancer (NSCLC) without gene mutation. In recent years, bevacizumab biosimilar has received marketing approval based on the results of phase III clinical studies. However, more clinical data are needed to verify the efficacy and safety of bevacizumab biosimilar in clinical application. Materials and methods: We identified 946 patients with locally advanced or metastatic NSCLC who were treated with bevacizumab biosimilar or bevacizumab from January 1, 2019 to November 30, 2021. Comparisons and statistical analyses of bevacizumab biosimilar and bevacizumab were made in terms of efficacy and safety. Efficacy evaluation was performed directly in accordance with RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results: The objective response rates (ORRs) were 28.9% in the biosimilar group (n=551) and 30.9% in the reference group (n=395; unstratified ORR risk ratio: 0.934, 95% confidence interval [CI]: 0.677-1.138; unstratified ORR risk difference: -0.020, 95% CI: -0.118-0.035). The estimated median progression-free survival (mPFS) were 6.27 (95% CI: 5.53-7.01) and 4.93 (95% CI: 4.24-5.62) months in the biosimilar and reference groups, respectively (P=0.296). The number of treatment lines, combined treatment regimens and with or without radiotherapy were significant factors affecting the PFS of both groups (P<0.001, P=0.001, P=0.039). Different genetic mutations and dose intensity were not the main factors affecting PFS (P=0.627, P=0.946). The incidences of treatment-emergent adverse events (TEAEs) were 76.41% in the biosimilar group and 71.65% in the reference group (P=0.098). The incidences of grade 3 or higher TEAEs were 22.14% and 19.49% in the biosimilar and reference groups, respectively (P=0.324). Conclusions: Bevacizumab biosimilar is equivalent in efficacy to bevacizumab in patients with locally advanced and advanced NSCLC. It showed acceptable toxicity profile and no new adverse events. Patients who were excluded by clinical trials can also benefit from bevacizumab biosimilar.