Phase 1b trial of anti-HER2 antibody inetetamab and pan-HER inhibitor pyrotinib in HER2-positive advanced lung cancer.

There remains an unmet need for targeted therapies against advanced non-small-cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti-HER2 agent, this prospective, single-arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti-HER2 antibody inetetamab and pan-HER TKI pyrotinib in HER2-posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose-escalation part, 240 mg, 320 mg; dose-expansion part, 320 mg). Primary endpoints were dose-limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose-escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment-related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4-8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2-mutant NSCLC.

A cross-sectional study of the relationship between premenstrual syndrome and missed nursing care among female nursing staff.

Purpose: Premenstrual syndrome (PMS) is a cyclical psychosomatic disorder prevalent among women of reproductive age. However, research on the potential impact of PMS on routine nursing schedules and activities is limited. This study aims to identify the prevalence of PMS among female nursing staff and to examine the relationship between PMS and missed nursing care (MNC). Method: Between November 1, 2022, and April 30, 2023, this study was conducted among female nursing staff working in nine inpatient departments at Sun Yat-sen University Cancer Center. This study used a cross-sectional design. The participants were recruited through convenience sampling. Data were collected using the standardized Menstrual Distress Questionnaire, the Oncology Missed Nursing Care self-rating scale, and a sociodemographic questionnaire. One-way analysis of variance, Fisher's least significant difference test for post-hoc comparisons, and Spearman's correlation coefficient were utilized for data analysis. A trend test was also performed to explore patterns in the severity of PMS and MNC over time. Results: We collected a total of 224 questionnaires, with 154 (68.7%) female nursing staff reporting PMS. The most common symptoms were low back pain (91.1%), abdominal discomfort (90.6%), cold hands and feet (87.1%), and lethargy (87.1%). Moreover, 91.5% of the 224 female nursing staff reported at least one MNC activity. The nursing activities most frequently missed or left incomplete were liquid intake and output monitoring as ordered (43.3%), medication administration within 30 min before or after the scheduled time (43.3%), and electrocardiogram monitoring as ordered (42.9%). "Abdominal discomfort" from the Menstrual Distress Questionnaire was significantly correlated with the majority of MNC activities (p < 0.001). Conclusions: This study provides evidence for a strong association between PMS and MNC among female nursing staff, suggesting that administrators should take the premenstrual conditions of female nursing staff into consideration. It is necessary to provide appropriate understanding and support to mitigate the impact on patient care and safety.

Remodeling the tumor-immune microenvironment by anti-CTLA4 blockade enhanced subsequent anti-PD-1 efficacy in advanced nasopharyngeal carcinoma.

Sequential immunotherapy has shown certain advantages in malignancy. Here, we aim to evaluate the efficacy of sequential anti-CTLA-4 and anti-PD-1 treatment for recurrent or metastatic nasopharyngeal carcinoma patients (R/M NPC). We retrospectively analysis 2 phase I trial of ipilimumab and camrelizumab in Chinese R/M NPC patients. These patients were initially treated with ipilimumab, a CTLA4 blockade, followed by anti-PD-1 treatment. We observed a durable tumor remission in these patients (mPFS: 12.3 months; mDoR: 20.9 months). Multimodal investigations of biopsy samples disclosed remodeling of tumor-immune microenvironment triggered by ipilimumab. In responders, we found increased tumoral PD-L1/PD-L2 expression and T-cell infiltration after ipilimumab treatment, accompanied by reduced stroma and malignant cell components. In contrast, non-responders exhibited increased B-cell infiltration and increased peripheral CD19 + B cells, suggesting a defective transition from memory B cells to plasma cells. This study proposes that sequential therapy can potentially enhance treatment efficacy in chemotherapy-resistant NPC patients and provides insights into how preexisting anti-CTLA4 blockade can influence subsequent anti-PD-1 efficacy by remodeling the TME. Additionally, our results highlight the need for therapeutic strategies targeting naïve/memory B cells.

Trends in pain undertreatment among lung cancer patients at the EOL: Analysis of urban city medical insurance data in China.

BACKGROUND: Cancer-related pain is one of the common priority symptoms in advanced lung cancer patients at the end-of-life (EOL). Alleviating pain is undoubtedly a critical component of palliative care in lung cancer. Our study was initiated to examined trends in opioid prescription-level outcomes as potential indicators of undertreated pain in China. METHODS: This study used data on 1330 patients diagnosed with lung cancer of urban city medical insurance in China who died between 2014 and 2017. Opioid prescription-level outcomes were determined by annual trends of the proportion of patients filling an opioid prescription, the total dose of opioids filled by decedents, and morphine milligram equivalents per day (MMED) at the EOL (defined as the 60 days before death). We further analyzed monthly changes in the number of opioid prescriptions filled, MMED, and mean daily dose of opioids per prescription (MDDP) of the last 60 days of life by year at death and age, respectively. RESULTS: A total of 959 patients with exact dates of death were included, with 432 cases (45.06%; 95% CI: 44.36%-45.77%) receiving at least one opioid prescription at the EOL. The declining trends were shown in the proportion of patients filling any opioid prescription, the total dose of opioids filled by decedents and MMED, with an annual decrease of 0.341% (p = 0.01), 104.23 mg (p = 0.011) and 2.84 mg (p = 0.014), respectively. Within the 31-60 days to the 0-30 days of life, the MMED declined 6.08 mg (95% CI: -7.14 to -5.03; p = 0.000351), while the number of opioid prescriptions rose 0.66 (95% CI: 0.160-1.16; p = 0.025). Like the MMED, the MDDP fell 4.11 mg (95% CI: -5.86 to -2.37; p = 0.005) within the last month before death compared to the previous month. CONCLUSION: Terminal lung cancer populations in urban China have experienced reduced access to opioids at the EOL. The clinicians did not prescribe a satisfactory dose of opioids per prescription, while the patients suffered increasing pain in the last 30 days of life. Sufficient opioid analgesic administration should be advocated for lung cancer patients during the EOL period.

LncRNA HEIH expression in cancer prognosis: A review and meta-analysis.

BACKGROUND: As a newly discovered lncRNA, lncRNA High expression in hepatocellular carcinoma (HEIH) has been reported to correlate with poor clinical outcomes in several different cancers, In addition, studies have shown that HEIH is overexpressed in a variety of cancers and plays an oncogenic role. The present meta-analysis aims to elucidate the relationship between HEIH expression and prognosis and clinicopathological features among cancer patients. METHODS: PubMed, Web of Science, Cochrane Library, and EMBASE database were comprehensively and systematically searched. pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were employed to assess the relationship between HEIH expression and clinical outcomes and clinicopathological features in cancer patients. CONCLUSION: The present study finally enrolled 11 studies which included 1227 cancer patients. The combined results indicated that HEIH overexpression was significantly associated with shorter overall survival (OS) (pooled HR = 2.03, 95% CI 1.74-2.38, P < .00001).Meanwhile, regarding clinicopathology of cancer patients, upregulated HEIH expression was closely related to larger tumor size (OR = 2.65, 95% CI: 1.52-4.65, P = .0006), advanced tumor T stage (OR = 2.41, 95 % CI: 1.54-3.77, P = .0001), advanced TNM stage (OR = 4.76, 95% CI: 2.73-8.29, P < .00001), distant metastasis (OR = 2.94, 95% CI: 1.75-4.96, P < .0001) and lymph node metastasis (OR = 2.07, 95% CI: 1.05-4.07, P = .04), respectively. CONCLUSIONS: High expression of HEIH in some cancers predicts shorter overall survival and higher clinical stage as well as larger tumor size. HEIH has great potential to become a prognostic marker for cancer patients.

Unilateral biportal endoscopy versus microscopic decompression in the treatment of lumbar spinal stenosis: A meta-analysis.

BACKGROUND: The aim of this study was to evaluate whether there is a superior clinical effect of unilateral biportal endoscopy compared with microscopic decompression in the treatment of lumbar spinal stenosis. METHODS: We searched CNKI, WANFANG, CQVIP, CBM, PubMed, and Web of Science up to January 2022, and selected studies that met our inclusion criteria. RESULTS: The results of this meta-analysis indicated that unilateral biportal endoscopy was demonstrated to be more beneficial for patients compared with microscopic decompression for the following outcomes: Operation time [standardized mean difference (SMD) = -0.943, 95% confidence interval (CI) (-1.856, -0.031), P = .043], hospital stays [SMD = -2.652, 95% CI (-4.390, -0.914), P = .003], EuroQol 5-Dimension questionnaire [SMD = 0.354, 95% CI (0.070, 0.638), P = .014], back pain visual analogue score [SMD = -0.506, 95% CI (-0.861, -0.151), P = .005], leg pain visual analogue score [SMD = -0.241, 95% CI (-0.371, -.0112), P = .000], the C-reactive protein level [SMD = -1.492,95% CI (-2.432, -0.552), P = .002]. Other outcomes demonstrated no significant differences between the 2 groups. CONCLUSION: For patients with lumbar spinal stenosis, unilateral biportal endoscopy was found to be more superior than microscopic decompression in terms of operation time, hospital stays, EuroQol 5-Dimension questionnaire, back visual analogue score, leg visual analogue score and the C-reactive protein level. There was no significant difference between the 2 groups in other outcome indicators.

The role and mechanism of JAK2/STAT3 signaling pathway regulated by m6A methyltransferase KIAA1429 in osteosarcoma.

Osteosarcoma (OS) is the most malignant bone tumor which mainly occurs in childhood or adolescence. The previous studies indicated that OS is difficult to treat. KIAA1429 is one of the components of m6A complex that regulating the process of m6A modification, which plays a crucial role in tumorigenesis. But the mechanism of KIAA1429 regulating OS cell identity was not entirely clear, which needs further investigate. RT-qPCR and western blotting were applied to determine KIAA1429 expression station in OS cells and tissues. To further detect the KIAA1429 function in OS cells, the ability of proliferation, migration and invasion were analyzed by Edu, wound-healing and transwell experiments respectively. Besides, RNA sequencing was also used to further find the downstream of KIAA1429 regulation and small molecule inhibitor was added to explore the specific role of signaling pathway. Our data found that KIAA1429 is up-regulated in human OS cell lines compared to the human osteoblast cells. Meanwhile, the deletion of KIAA1429 significantly decreased cell proliferation, migration, and invasion. Interestingly, the JAK2/STAT3 signal pathway was involved in KIAA1429 regulation on OS cell characters. The KIAA1429 eliminated OS cells exhibited a decreased activity of JAK2/STAT3 signal. And the addition of JAK2/STAT3 stimulator (colivelin) could distinctly rescue the decreased OS cells' proliferation, migration, and invasion upon KIAA1429 knockdown. In summary, these data demonstrated that KIAA1429/JAK2/STAT3 axis may a new target for OS therapy.

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC.

INTRODUCTION: According to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)-negative and tumor-infiltrating lymphocyte (TIL)-negative (type I); (2) PD-L1-positive and TIL-positive (type II); (3) PD-L1-negative and TIL-positive (type III); and (4) PD-L1-positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC. METHODS: On the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy. RESULTS: PD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06-0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13-0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes. CONCLUSIONS: Only patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.

Risk mapping of lung cancer: a comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies.

INTRODUCTION: A comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies was performed to map the different risk factors and assess the causality for lung cancer. METHODS: Systematic reviews and meta-analyses of observational and interventional studies were reviewed based on PubMed, Embase, Web of Science, and Cochrane Library. Mendelian randomization analyses were conducted to validate the causal associations of those various exposures with lung cancer using summary statistics from 10 genome-wide association studies (GWAS) consortia and other GWAS databases in MR-Base platform. RESULTS: In the review of meta-analyses, 105 risk factors associated with lung cancer were identified from 93 articles. It was found that 72 risk factors were nominally significant (P < 0.05) associated with lung cancer. Mendelian randomization analyses were performed to analyze 36 exposures based on 551 SNPs and 4,944,052 individuals, finding that 3 exposures had a consistent risk/protective effect on lung cancer with the results of the meta-analysis. In Mendelian randomization anaylses, smoking (OR 1.44, 95% CI 1.18-1.75; P = 0.001) and blood copper (OR 1.14, 95% CI 1.01-1.29; P = 0.039) significantly associated with increased risk of lung cancer, whereas aspirin use (OR 0.67, 95% CI 0.50-0.89; P = 0.006) showed protective effects. CONCLUSION: This study mapped putative associations of risk factors for lung cancer, revealing the causal hazard effect of smoking, blood copper, and the protective effect of aspirin use in the development of lung cancer. CLINICAL TRIAL REGISTRY: This study is registered with PROSPERO (CRD42020159082).

The maximum tumor growth rate predicts clinical outcomes of patients with small-cell lung cancer undergoing first-line chemotherapy plus immune-checkpoint inhibitor therapy.

BACKGROUND: Currently, no biomarkers can accurately predict survival outcomes in patients with SCLC undergoing treatment. Tumor growth rate (TGR; percent size change per month [%/m]) is suggested as an imaging predictor of response to anti-cancer treatment. We aimed to evaluate the predictive role of the maximum TGR (TGRmax) for outcomes of small-cell lung cancer (SCLC) patients undergoing first-line chemotherapy plus immune-checkpoint inhibitor (ICI) treatment. METHODS: Patients with SCLC receiving first-line chemotherapy plus immunotherapy were analyzed within this retrospective study. The X-tile program was used to identify the cut-off value of TGRmax based on maximum progression-free survival (PFS) stratification. The Kaplan-Meier methods and Cox regression models were used to evaluate the effect of the presence of TGRmax on PFS and overall survival (OS). RESULTS: In total, 104 patients were evaluated. Median (range) TGRmax was -33.9 (-65.2 to 21.6) %/m and the optimal cut-off value of TGRmax was -34.3%/m. Multivariate Cox regression analysis revealed that patients with TGRmax > -34.3%/m was associated with shorter PFS (hazard ratio [HR], 2.81; 95% CI, 1.71-4.63; p < 0.001) and OS (HR, 3.17; 95% CI, 1.41-7.08; p = 0.005). In patients who received partial response (PR), Kaplan-Meier survival analyses showed that superior PFS and OS (p = 0.005 and p = 0.009, respectively) benefit was observed when TGRmax ≤-34.3%/m. CONCLUSIONS: SCLC patients with TGRmax > -34.3%/m had worse PFS and OS in first-line ICI plus platin-based chemotherapy. TGRmax could independently serve as an early biomarker to predict the benefit from chemoimmunotherapy.

Complications of Unilateral Biportal Endoscopic Spinal Surgery for Lumbar Spinal Stenosis: A Meta-Analysis and Systematic Review.

BACKGROUND: In recent years, unilateral biportal endoscopic spinal surgery has been used for the treatment of lumbar spinal stenosis with good results. Some investigators counted the total incidence of complications in unilateral biportal endoscopic surgery for lumbar spinal stenosis, but none have analyzed the incidence of specific complications. The present study further counted the incidence of specific complications and gave the possible causes of the complications. METHODS: English databases including PubMed were searched to collect relevant literature on unilateral biportal endoscopic spinal surgery for lumbar spinal stenosis. The inquiry period is from January 1, 2015, to July 1, 2022. The literature was screened, information extracted, and risk of bias evaluated by the researchers, followed by Meta analysis using R4.2.1 and RStudio statistical software. RESULTS: In total, we included 14 studies involving 707 patients. The included studies were retrospective case series, The results of the single-arm rate meta-analysis showed that the total complication rate of unilateral biportal endoscopic surgery treatment of lumbar spinal stenosis was 8.1% (95% confidence interval [CI] [0.060; 0.103]); of which, the highest incidence of dural tear was 4.5% (95% CI [0.030; 0.064]), the incidence of symptomatic postoperative spinal epidural hematoma was approximately 1.1% (95% CI [0.001; 0.027]), the incidence of incomplete decompression was 2.0% (95% CI [0.007; 0.038]), the incidence of transient palsy was 2.6% (95% CI [0.005; 0.057]). CONCLUSIONS: The incidence of total complications of unilateral biportal endoscopic surgery for lumbar spinal stenosis was 8.1%, dural tear remained a major complication with an incidence of 4.5%, incomplete decompression was 2.0%, transient palsy was 2.6%, and, unexpectedly, symptomatic postoperative spinal epidural hematoma was only 1.1%.

Comparison of aprepitant versus desloratadine for EGFR-TKI-induced pruritus: A randomized phase 2 clinical trial.

BACKGROUND: Pruritus is one of the most common and challenging side effects of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and has impaired patients' quality of life and treatment compliance. Our study evaluated the efficacy and safety of aprepitant in managing EGFR-TKIs-related pruritus. METHODS: This randomized, double-blind, placebo-controlled study was conducted between December 2016 and August 2020 in China. Patients were eligible if they were 18 years or older and had histologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) with first onset of moderate to severe pruritus during EGFR-TKI treatment. RESULTS: A total of 130 eligible patients were randomly assigned to aprepitant (n = 65) or desloratadine (n = 65) groups. The median (interquartile range [Q1, Q3]) age was 63 (54, 70) years, and 79 (60.8%) were women. Mean visual analog scale scores at baseline were 6.35 (95% confidence interval [CI], 5.89-6.82) in the aprepitant group and 5.94 (95% CI, 5.56-6.32) in the desloratadine group. After 1 week of treatment, 33 (53.2%) patients responded to aprepitant, which was significantly higher than that of 14 (23.7%) patients responded to desloratadine (p = .001). Moreover, patients in the aprepitant group had a significantly shorter response time than patients in the desloratadine group (mean [days], 13.39 [95% CI, 11.08-15.70] vs. 16.67 [95% CI, 14.19-19.13], p = .04). The most frequent drug-related adverse events in aprepitant group and desloratadine were constipation and dry mouth, and all adverse events were grade 1-2. CONCLUSIONS: To the authors' knowledge, this is the first study to prospectively present that aprepitant elicited a better and faster response and mild toxicity for managing EGFR-TKI induced pruritus than desloratadine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02646020.

LncRNA LOXL1-AS1 expression in cancer prognosis: A meta-analysis.

BACKGROUND: Several studies showed that LncRNA LOXL1 antisense RNA 1 (LOXL1-AS1) is overexpressed in a variety of cancers and plays a role as an oncogene in cancer. The present meta-analysis aims to elucidate the relationship between LOXL1-AS1 expression and prognosis and clinicopathological features among cancer patients. METHODS: PubMed, Web of Science, Cochrane Library, and EMBASE database were comprehensively and systematically searched. Pooled odds ratios (ORs) and hazard ratios with a 95% confidence interval (CI) were employed to assess the relationship between LOXL1-AS1 expression and clinical outcomes and clinicopathological features in cancer patients. RESULTS: The present study finally enrolled 8 studies which included 657 cancer patients. The combined results indicated that the overexpression of LOXL1-AS1 was significantly associated with shorter overall survival (pooled hazard ratio = 1.99, 95% CI 1.49-2.65, P < .00001). Meanwhile, regarding clinicopathology of cancer patients, the upregulation of LOXL1-AS1 expression was closely related to lymph node metastasis (yes vs no OR = 4.01, 95% CI: 2.02-7.96, P < .0001) and distant metastasis (yes vs no OR = 3.04, 95% CI: 1.82-5.06, P < .0001), respectively. CONCLUSION: High expression of LOXL1-AS1 in some cancers predicts shorter overall survival, distant metastasis, and lymph node metastasis. LOXL1-AS1 shows great promise as a prognostic biomarker in cancer patients.

Genetic Liability to Insomnia and Lung Cancer Risk: A Mendelian Randomization Analysis.

Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer death worldwide, making its prevention an urgent issue. Meanwhile, the estimated prevalence of insomnia was as high as 30% globally. Research on the causal effect of insomnia on lung cancer incidence is still lacking. In this study, we aimed to assess the causality between the genetic liability to insomnia and lung cancer. We performed a two-sample Mendelian randomization analysis (inverse variance weighted) to determine the causality between the genetic liability to insomnia and lung cancer. Subgroup analysis was conducted, which included lung adenocarcinoma and lung squamous cell carcinoma. In the sensitivity analysis, we conducted heterogeneity test, MR Egger, single SNP analysis, leave-one-out analysis, and MR PRESSO. There were causalities between the genetic susceptibility to insomnia and increased incidence of lung cancer [odds ratio (95% confidence interval), 1.35 (1.14-1.59); P, < 0.001], lung adenocarcinoma [odds ratio (95% confidence interval), 1.35 (1.07-1.70); P, 0.01], and lung squamous cell carcinoma [odds ratio (95% confidence interval), 1.35 (1.06-1.72), P, 0.02]. No violation of Mendelian randomization assumptions was observed in the sensitivity analysis. There was a causal relationship between the genetic susceptibility to insomnia and the lung cancer, which was also observed in lung adenocarcinoma and lung squamous cell carcinoma. The underlying mechanism remains unknown. Effective intervention and management for insomnia were recommended to improve the sleep quality and to prevent lung cancer. Moreover, regular screening for lung cancer may be beneficial for patients with insomnia.

Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.

A modifiable risk factors atlas of lung cancer: A Mendelian randomization study.

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.

Investigating the Causal Relationship Between Physical Activity and Chronic Back Pain: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Recent observational studies have reported a negative association between physical activity and chronic back pain (CBP), but the causality of the association remains unknown. We introduce bidirectional Mendelian randomization (MR) to assess potential causal inference between physical activity and CBP. Materials and Methods: This two-sample MR used independent genetic variants associated with physical activity and CBP as genetic instruments from large genome-wide association studies (GWASs). The effects of both directions (physical activity to CBP and CBP to physical activity) were examined. Inverse variance-weighted meta-analysis and alternate methods (weighted median and MR-Egger) were used to combine the MR estimates of the genetic instruments. Multiple sensitivity analyses were conducted to examine the robustness of the results. Results: The MR set parallel GWAS cohorts, among which, those involved in the primary analysis were comprised of 337,234 participants for physical activity and 158,025 participants (29,531 cases) for CBP. No evidence of a causal relationship was found in the direction of physical activity to CBP [odds ratio (OR), 0.98; 95% CI, 0.85-1.13; p = 0.81]. In contrast, a negative causal relationship in the direction of CBP to physical activity was detected (ß = -0.07; 95% CI, -0.12 to -0.01; p = 0.02), implying a reduction in moderate-vigorous physical activity (approximately 146 MET-minutes/week) for participants with CBP relative to controls. Conclusion: The negative relationship between physical activity and CBP is probably derived from the reduced physical activity of patients experiencing CBP rather than the protective effect of physical activity on CBP.

Mendelian randomization study indicates lack of causal relationship between physical activity and lung cancer.

BACKGROUND: Previous researches have indicated physical activity (PA) may be associated with lower risk of lung cancer. However, causal relationship between PA and risk of lung cancer is not clear. We aimed to inspect the causal effect of PA on lung cancer. METHODS: We analyzed summary data of accelerator-measured PA and lung cancer from the genome-wide association study (GWAS) using two-sample Mendelian randomization (MR) method. We obtained summary data of accelerator-measured PA from UK Biobank, data of lung cancer patients from Consortium and International Lung Cancer Consortium (ILCCO) to investigate possible causal effect of PA on lung cancer. RESULTS: According to result of MR using inverse variance weighted method (IVW), we found that genetically predicted higher PA level did not causally decrease risk of lung cancer (OR 0.95, 95% CI 0.88-1.03, p = 0.238). Results of MR-Egger and weighted median method were consistent with IVW method. CONCLUSION: Our mendelian randomization study showed that genetically higher PA is not causally associated with risk of lung cancer. More researches are needed to investigate relationship between PA and lung cancer.