Patients with small-cell lung cancer (SCLC) patients demonstrate varied survival outcomes. Previous studies have reported that lipoproteins are associated with prognosis in various cancers; however, the role of low-density lipoprotein (LDL) and low-density lipoprotein- cholesterol (LDLR) in patients with SCLC has not been studied. In this study, the impact of LDL and LDLR on the prognosis of SCLC patients was evaluated. A total of 601 patients with SCLC were retrospectively evaluated, in which 198 patients had adequate tissues for immunohistochemistry, and serum LDL and LDLR expression levels at baseline were tested. X-tile tool, and univariate and multivariate Cox analysis were used to assess the association between LDL, LDLR and overall survival (OS). Univariate analysis demonstrated that a lower LDL level was significantly associated with superior OS (P = 0.037). Similarly, LDLR also significantly predicted OS (P = 0.003). Multivariate Cox analyses confirmed that lower LDL and LDLR expression was independent prognostic factors associated with longer OS (P = 0.019 and P = 0.027, respectively). This study showed that both LDL and LDLR are prognostic indexes for survival in patients with SCLC. Patients with high LDL or LDLR expression level may benefit from treatment that modulates lipoprotein combined with platinum-based chemotherapy.

Systemic inflammation plays a role in carcinogenesis and is related to overall survival in patients with different cancer types, including those treated with immune checkpoint blockade (ICB). The neutrophil-lymphocyte ratio (NLR) is calculated by circulating neutrophil to lymphocyte counts, which represents an indicator of the balance between the deleterious roles of neutrophilia and the beneficial roles of lymphocyte-mediated immunity. We hypothesized that the NLR may predict outcomes in metastatic colorectal cancer (mCRC) patients treated with immunotherapy. This retrospective study included 110 mCRC patients who were treated with immunotherapy at Sun Yat-sen University Cancer Center. Several inflammatory biomarkers were measured at baseline and after two cycles of treatment. The X-tile program was used to obtain the cutoff values. We examined the impact of both baseline and posttreatment inflammatory index levels on overall survival (OS). In univariate analysis, both a low baseline NLR (P = 0.014) and a decreased NLR after 2 cycles of immunotherapy (P < 0.001) were considerably correlated with better OS. In multivariate analysis, age, liver metastasis, baseline lymphocyte-monocyte ratio (LMR), baseline NLR and early changes in NLR independently predicted OS. Patients with both a low baseline NLR and an early NLR reduction had the longest OS (median, 29.63 months). The best outcomes were remarkably observed in patients who had both an early NLR reduction and a high tumor mutational burden (TMB) (≥10 mut/Mb) (P < 0.0001). Both a low baseline NLR and an early NLR reduction are significantly associated with a better prognosis in mCRC patients treated with immunotherapy. Further analysis indicated that the combination of NLR and TMB could obtain additional predictive power.

High-level tissue tumor mutational burden (tTMB) or blood TMB (bTMB) are associated with better response of immunotherapy in non-small cell lung cancer (NSCLC) patients. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified. We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and evaluated single-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. TMB of > 9 mutations/Mb was classified as high. Besides, we used tTMB fold-change to evaluate the influence of the enrolled region number on tTMB. We found both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r = 0.94, P = 2E-84; Pearson r = 0.47, P = 0.0067). It showed extremely high specificity (100%) but low sensitivity (43%) when using bTMB to define TMB-high patients, while most false-negative predictions were in early-stage patients. Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions’ number more than three. Moreover, ITH-high patients had significantly higher tTMB fold-change compared with ITH-low patients (2.32 vs. 1.02, P = 8.879e-05). The conversion rate of tTMB level (tTMB-low to tTMB-high) was numerically higher in ITH-high group than that in ITH-low group (16.67% vs. 3.84%). In summary, single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB. ITH has an impact on tTMB, especially in high-level ITH patients.

Small cell lung cancer (SCLC), which is characterized by rapid growth and early development of metastasis, is an extremely aggressive type of lung cancer.^1-3 Because most cases have metastasized to widespread sites at the time of diagnosis, 70% of patients present with extensive-stage SCLC (ES-SCLC).⁴ For several decades, the standard first-line chemotherapy for ES-SCLC has been etoposide combined with platinum (cisplatin or carboplatin).^5-7 Despite its high response rate, nearly all patients experienced quick disease relapse, with a median progression-free survival (PFS) of as long as 3 months, and poor survival outcomes, with a median overall survival (OS) of approximately 10 months.^8,9 Although some trials in Japan demonstrated that an irinotecan-based regimen as a first-line treatment for ES-SCLC had better PFS and OS, its OS benefit remained poor.¹⁰ Thus, improved first-line treatments are urgently needed.

KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1 months. The median progression-free and overall survival are 5.8 and 26.6 months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).

Background: There has been no study systematically assessing the causal effects of putative modifiable risk factors on lung cancer. In this study, we aimed to construct a modifiable risk factors atlas of lung cancer by using the two‐sample Mendelian randomization framework.Methods: We included 46 modifiable risk factors identified in previous studies. Traits with p‐value smaller than 0.05 were considered as suggestive risk factors. While the Bonferroni corrected p‐value for significant risk factors was set to be 8.33 × 10⁻⁴.Results: In this two‐sample Mendelian randomization analysis, we found that higher socioeconomic status was significantly correlated with lower risk of lung cancer, including years of schooling, college or university degree, and household income. While cigarettes smoked per day, time spent watching TV, polyunsaturated fatty acids, docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid in blood were significantly associated with higher risk of lung cancer. Suggestive risk factors for lung cancer were found to be serum vitamin A1, copper in blood, docosahexaenoic acid in blood, and body fat percentage.Conclusions: This study provided the first Mendelian randomization assessment of the causality between previously reported risk factors and lung cancer risk. Several modifiable targets, concerning socioeconomic status, lifestyle, dietary, and obesity, should be taken into consideration for the development of primary prevention strategies for lung cancer.