Explore the vast range of titles available.

Cell-free DNA (cfDNA) in the circulating blood plasma of patients with cancer contains tumour-derived DNA sequences that can serve as biomarkers for guiding therapy, for the monitoring of drug resistance, and for the early detection of cancers. However, the analysis of cfDNA for clinical diagnostic applications remains challenging because of the low concentrations of cfDNA, and because cfDNA is fragmented into short lengths and is susceptible to chemical damage. Barcodes of unique molecular identifiers have been implemented to overcome the intrinsic errors of next-generation sequencing, which is the prevailing method for highly multiplexed cfDNA analysis. However, a number of methodological and pre-analytical factors limit the clinical sensitivity of the cfDNA-based detection of cancers from liquid biopsies. In this Review, we describe the state-of-the-art technologies for cfDNA analysis, with emphasis on multiplexing strategies, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve cancer diagnostics and patient care. This Review discusses the challenges and opportunities, biological and technical, of technologies for the analysis of cell-free DNA for the diagnosis of cancer.

PurposeTumor growth relies on the sufficient blood supply and continuously requires new blood vessels to maintain, which lead to vascular abnormalities (Folkman, N Engl J Med 285:1182–1186, 1971). Antiangiogenic therapy has emerged with the goal of normalizing vasculature and tumor microenvironment (TME). Some antiangiogenic therapies combined with chemotherapy, targeted therapy or immunotherapy have been approved for clinical application. In this review, we summarize the recent advances of antiangiogenic combination therapeutic strategies in advanced NSCLC.MethodsReferences of this review are searched through PubMed and EMBASE and the abstracts of cancer conferences. The ClinicalTrials.gov database was used for relative trials.ResultsBased on different mechanisms, antiangiogenic agents can be divided into monoclonal antibodies (mAbs), which mainly include bevacizumab and ramucirumab, and multi-target antiangiogenic tyrosine kinase inhibitors (TKIs) which include sunitinib, sorafenib, nintedanib, apatinib, anlotinib, fruquintinib, etc. In recent years, a number of large clinical studies have shown that antiangiogenic agents have conferred a significant overall survival (OS) benefit to patients with advanced non-small cell lung cancer (NSCLC). More and more evidences confirm that the combination of antiangiogenic agents with chemotherapy, targeted therapy and immunotherapy can improve the effect and prolong the survival of NSCLC patients. However, many problems about the application of antiangiogenic agents on advanced NSCLC patients still need to be explored. For example, the combination therapy of multi-target antiangiogenic agents is just beginning, and the biomarkers are not clear.ConclusionsAntiangiogenic agents can achieve therapeutic benefit in advanced NSCLC patients and the combination of chemotherapy, targeted therapy or immunotherapy can lead to synergistic effect. However, exploring the best combination therapy and efficacy-related biomarkers needs further study.

The relationship between circular RNA (circRNA) and cancer stem cells (CSCs) is uncertain. We have investigated the combined influence of CSCs, circRNA (hsa_circ_0003222), and immune checkpoint inhibitors in NSCLC progression and therapy resistance. We constructed lung CSCs (LCSCs; PC9 and A549). The effects of hsa_circ_0003222 in vitro were determined by cell counting, colony and sphere formation, and Transwell assays. A tumor xenograft model of metastasis and orthotopic model were built for in vivo analysis. We found that hsa_circ_0003222 was highly expressed in NSCLC tissues and LCSCs. Higher levels of hsa_circ_0003222 were associated with the stage, metastasis, and survival rate of patients with NSCLC. Reduced levels of hsa_circ_0003222 decreased tumor cell proliferation, migration, invasion, stemness-like properties, and chemoresistance. The silencing of hsa_circ_0003222 was found to downregulate PHF21B expression and its downstream, β-catenin by relieving the sponging effect of miR-527. Moreover, silencing hsa_circ_0003222 alleviated NSCLC resistance to anti-programmed cell death-ligand 1 (PD-L1)-based therapy in vivo. Our data demonstrate the significant role of hsa_circ_0003222 in NSCLC cell stemness-like properties. The manipulation of circRNAs in combination with anti-PD-L1 therapy may alleviate NSCLC stemness and progression.

The efficacy of ICIs combined with chemotherapy or chemotherapy alone was evaluated according to the Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) and RECIST version 1.1, and the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were determined. Median PFS and OS were assessed by the Kaplan–Meier (K–M) method, and the log-rank test was used to assess the differences in survival between the two groups. The median PFS of the EC group and the other group was both 6.5 months, and there was no significant difference in PFS between the two groups (P = 0.770) [Supplementary Figure 1A, http://links.lww.com/CM9/C93]. [...]our study suggests that immunotherapy should not be recommended for patients with PD-L1 ≤1%.

PurposeAnlotinib is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. The efficacy of anlotinib as a third-line or beyond therapy for SCLC was confirmed in the ALTER1202 trial. For lung cancer patients treated with antiangiogenesis agents, the phenomenon of cavitation is commonly seen in the lung target lesions. The impact of tumor cavitation on survival in lung cancer patients treated with vascular-targeted therapy remains controversial. Our retrospective study was to investigate the prognostic value of tumor cavitation in extensive-stage SCLC patients treated with anlotinib.MethodsA total of 73 extensive-stage SCLC patients confirmed by histopathology from January 2018 to January 2019 were retrospectively analyzed. All patients received anlotinib therapy at Shanghai Chest Hospital. We defined tumor cavitation of the lung target lesions as that part of solid component was changed to air-filled area according to chest CT. Progression-free survival (PFS) was calculated from the beginning of anlotinib therapy to the disease progression or the last follow-up visit.ResultsEleven (15.0%) patients had tumor cavitation during anlotinib therapy. The ORR of the 73 patients was 15.1%. Multivariate logistic regression analysis showed that tumor cavitation during anlotinib therapy was not associated with gender (P = 0.630), age (P = 0.190), smoking status (P = 0.165), anatomy type (P = 0.641), and the line of anlotinib therapy (P = 0.302). The median PFS of all patients was 2.6 months (95%CI 2.1–3.2). According to the univariate analysis, the median PFS in patients with and without tumor cavitation was 5.0 months and 2.2 months, respectively, and the difference was statistically significant (P = 0.041). According to the multivariate analysis, tumor cavitation was an independent factor for PFS after adjusting gender, age, smoking status, anatomy type, the line of anlotinib therapy, tumor cavitation, and response to anlotinib (adjusted HR 0.316, 95%CI 0.142–0.702; P = 0.005).ConclusionsIn 73 extensive-stage SCLC patients treated with anlotinib, no demographic/clinical characteristic was related to tumor cavitation, and tumor cavitation was an independent factor in predicting better PFS.

[...]45 patients with pathological slides were enrolled in the analysis set [Supplementary Figure 1, http://links.lww.com/CM9/C215]. The pathomic model demonstrated an area under the curve (AUC) of 0.811 (95% confidence interval [CI]: 0.756–0.867) for predicting the TIDE classifier in the training cohort, as depicted in Supplementary Figure 5A, http://links.lww.com/CM9/C215. [...]the researchers developed an integrated model combining PD-L1 expression and PS [Supplementary Figure 9D, http://links.lww.com/CM9/C215], which significantly enhanced the accuracy of response prediction (AUC: 0.702, 95% CI: 0.551–0.852). Pathway enrichment analysis was conducted utilizing the gene set enrichment analysis (GSEA) method to investigate the potential associations between the model and the outcomes.

Chemotherapy combined with PD-1 inhibitor treatment has revolutionized the standard of care for patients with NSCLC. However, the benefit is not universal, highlighting the need for precise prediction factors. Given their relationship with the immune system and non-invasive nature, serum cytokines are potential candidates for predicting the clinical effects of chemoimmunotherapy. Our study aims to evaluate the association of serum cytokines with the prognosis of patients with NSCLC treated with chemoimmunotherapy. Levels of 10 serum cytokines were detected in 60 NSCLC patients receiving chemotherapy plus PD-1 inhibitor-based treatment. Of these, dynamic samples from 19 patients were collected at baseline and after two treatment cycles. Their association with patients' clinicopathological characteristics, PFS and OS was described and investigated using survival analysis, cox regression and time-dependent ROC analysis. Preliminary evaluation of changes in cytokine levels associated with treatment response was conducted. Patients with lower baseline levels of serum IL-6, IL-5, IL-8, TNF-α and IL-10 had longer PFS, while patients with higher levels of IL-4 had longer PFS. Patients with lower levels of serum IL-6, IL-8, IL-22, TNF-α and IL-10 had longer OS, while patients with higher levels of IL-4 had longer OS. Multivariate analysis suggested that higher IL-6 and IL-5 levels were associated with poorer PFS, and higher IL-6 levels were associated with dismal OS. Additionally, changes in serum cytokine levels could be associated with treatment response. Our study suggests that serum cytokines, specifically IL-6, IL-5, IL-8, TNF-α, IL-10, and IL-4, are potential prognostic factors for patients with NSCLC receiving chemotherapy plus PD-1 inhibitor treatment.

Anlotinib is a new multitarget tyrosine kinase inhibitor for tumor angiogenesis, and its monotherapy exhibits a decent clinical efficacy. However, the process of combining Anlotinib and immune checkpoint therapy to achieve optimal antitumor effects while limiting side effects remains unclear. In this study, we found that effective low-dose Anlotinib was sufficient to inhibit tumor growth while reducing side effects compared with high doses. Effective low-dose Anlotinib treatments induced durable tumor vascular normalization and improved anti-PD-1 therapy in both short- and long-term treatment regimens. Mechanistically, the combination therapy increased the proportions of intratumoral CD4 + T, CD8 + T, and NK cells. Anlotinib-associated antitumor effects were independent of interferon γ; however, the combination therapy required CD8 + T cells to suppress tumor growth. Together, these results suggest that the combination of effective low-dose Anlotinib and PD-1 blockade induces durable antitumor effects with fewer side effects. Our findings indicate that antiangiogenic treatments combined with immune checkpoint therapy at an effective low-dose, rather than a tolerable high dose, would be more efficacious and safer.

Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection.

Immune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy. The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed. A total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) Cox proportional hazards models. On the other hand, decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Next, 91 patients comprised the decreased NLR group and 48 as the increased NLR group. Patients with decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Then, 64 patients comprised the decreased PLR group and 75 the increased PLR group. Decreased PLR was significantly associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions. Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in patients with stage IIIB-IV NSCLC treated with first-line PD-1 inhibitor combined with chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.