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Background: This study investigated the prognostic impact of epidermal growth factor receptor (EGFR) mutation in clinical stage I lung adenocarcinoma patients., Methods: Data for 952 patients who received surgical resection and underwent detection of oncogenic driver mutations were retrospectively collected. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using the log-rank test. The adjusted hazard ratio (aHR) with 95% CI of the prognosticator was calculated by Cox proportional hazards model, and cumulative incidence function was measured by competing risk regression model., Results: EGFR mutation was detected in 581 patients (61.0%) and was more frequent in women (63.9%), nonsmokers (85.5%), and those with ground-glass nodules (GGNs; 56.6%). EGFR mutation was not associated with recurrence and death in the entire cohort or GGN cohort. However, for patients with radiologic pure-solid appearance, EGFR mutation was an independent risk factor for RFS (aHR, 1.623; 95% CI, 1.192-2.210) and distant recurrence (aHR, 1.863; 95% CI, 1.311-2.650), but not OS. Subsequently, subgroup analysis based on EGFR mutation subtypes, including exon 19 deletions (19-Del), exon 21 L858R substitution (L858R), and rare mutations in patients with radiologic pure-solid appearance, revealed that all 3 subtypes have poorer RFS (19-Del: aHR, 1.424; 95% CI, 0.991-2.047; L858R: aHR, 1.708; 95% CI, 1.172-2.490; rare mutations: aHR, 2.500; 95% CI, 1.400-4.465) and higher prevalent distant recurrence (19-Del: aHR, 1.595; 95% CI, 1.061-2.400; L858R: aHR, 2.073; 95% CI, 1.371-3.140; rare mutations: aHR, 2.657; 95% CI, 1.397-5.050) compared with wild-type., Conclusions: In clinical stage I lung adenocarcinoma, EGFR mutation was associated with worse RFS and higher prevalent distant recurrence in patients with radiologic pure-solid appearance but not in patients with GGN., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

In recent years, predicting gene mutations on whole slide imaging (WSI) has gained prominence. The primary challenge is extracting global information and achieving unbiased semantic aggregation. To address this challenge, we propose a novel Transformer-based aggregation model, employing a self-learning weight aggregation mechanism to mitigate semantic bias caused by the abundance of features in WSI. Additionally, we adopt a random patch training method, which enhances model learning richness by randomly extracting feature vectors from WSI, thus addressing the issue of limited data. To demonstrate the model's effectiveness in predicting gene mutations, we leverage the lung adenocarcinoma dataset from Shandong Provincial Hospital for prior knowledge learning. Subsequently, we assess TP53, CSMD3, LRP1B, and TTN gene mutations using lung adenocarcinoma tissue pathology images and clinical data from The Cancer Genome Atlas (TCGA). The results indicate a notable increase in the AUC (Area Under the ROC Curve) value, averaging 4%, attesting to the model's performance improvement. Our research offers an efficient model to explore the correlation between pathological image features and molecular characteristics in lung adenocarcinoma patients. This model introduces a novel approach to clinical genetic testing, expected to enhance the efficiency of identifying molecular features and genetic testing in lung adenocarcinoma patients, ultimately providing more accurate and reliable results for related studies., (© 2024. International Federation for Medical and Biological Engineering.)

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03-0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02-0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8-94.5%) versus 0.0% (95% CI, 0.0-60.2%) in the validation set ( p = 0.019) and 80.0% (95% CI, 44.4-97.5%) versus 0.0% (95% CI, 0.0-36.9%) in the test set ( p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment ( p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.

Purpose: A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC., Methods and Materials: STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 10 11 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety., Results: 28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients., Conclusions: The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The National Central Cancer Registry estimates the number of new cancer cases and deaths in China in 2022, using incidence and mortality data collected by the National Cancer Center. Methods: According to the data of 700 cancer registries in 2018 and the data of 106 cancer registries from 2010 to 2018, the age-period-cohort model was used to estimate the incidence rate and mortality rate of all cancers and 23 types of cancer in 2022, stratified by gender and urban and rural areas. We estimated the number of new cancer cases and deaths in China in 2022 based on the estimated rate and population data in 2022. Results: The estimated results showed that in 2022, there were approximately 4 824 700 new cancer cases in China (2 533 900 in males and 2 290 800 in females), with an age-standardized incidence rate of Chinese population (ASIR) of 208.58 per 100 000 (212.67 per 100 000 for males and 208.08 per 100 000 for females). Approximately 2 903 900 new cancer cases occurred in urban areas, with an ASIR of 212.95 per 100 000. It was estimated about 1 920 800 new cancer cases in rural areas, and the ASIR was 199.65 per 100 000. The top five cancers (lung cancer 1 060 600, colorectal cancer 517 100, thyroid cancer 466 100, liver cancer 367 700 and female breast cancer 357 200) accounted for 57.4% of all new cases. The estimated number of deaths from cancer in China in 2022 was 2 574 200 (1 629 300 in males and 944 900 in females), with an age-standardized mortality rate of Chinese population (ASMR) of 97.08 per 100 000 (127.70 per 100 000 in males and 68.67 per 100 000 in females). The number of deaths from cancer in urban and rural areas was about 1 400 600 and 1 173 400, with the ASMR of 92.37 and 103.97 per 100 000 in urban and rural areas, respectively. The top five leading cause of cancers death (lung cancer 733 300, liver cancer 316 500, gastric cancer 260 400, colorectal cancer 240 000 and esophageal cancer 187 500) accounted for 67.5% of all cancer deaths. Lung cancer ranked first in the incidence and mortality in men and women. The incidence rate in urban areas was higher than that in rural areas, while the mortality rate was lower than that in rural areas. Conclusions: The burden of cancer in China is still relatively heavy, with significant differences in cancer patterns in gender, urban-rural, and regional. The burden of cancer presents a coexistence of developed and developing countries, and the situation of cancer prevention and control is still serious in China.

Background: To compare the diagnostic performance of Lung-RADS (lung imaging-reporting and data system) 2022 and PNI-GARS (pulmonary node imaging-grading and reporting system)., Methods: Pulmonary nodules (PNs) were selected at four centers, namely, CQ Center (January 1, 2018-December 31, 2021), HB Center (January 1, 2021-June 30, 2022), SC Center (September 1, 2021-December 31, 2021), and SX Center (January 1, 2021-December 31, 2021). PNs were divided into solid nodules (SNs), partial solid nodules (PSNs) and ground-glass nodules (GGNs), and they were then classified by the Lung-RADS and PNI-GARS. The sensitivity, specificity and agreement rate were compared between the two systems by the χ 2 test., Results: For SN and PSN, the sensitivity of PNI-GARS and Lung-RADS was close (SN 99.8% vs. 99.4%, P < 0.001; PSN 99.9% vs. 98.4%, P = 0.015), but the specificity (SN 51.2% > 35.1%, PSN 13.3% > 5.7%, all P < 0.001) and agreement rate (SN 81.1% > 74.5%, P < 0.001, PSN 94.6% > 92.7%, all P < 0.05) of PNI-GARS were superior to those of Lung-RADS. For GGN, the sensitivity (96.5%) and agreement rate (88.6%) of PNI-GARS were better than those of Lung-RADS (0, 18.5%, P < 0.001). For the whole sample, the sensitivity (98.5%) and agreement rate (87.0%) of PNI-GARS were better than Lung-RADS (57.5%, 56.5%, all P < 0.001), whereas the specificity was slightly lower (49.8% < 53.4%, P = 0.003)., Conclusion: PNI-GARS was superior to Lung-RADS in diagnostic performance, especially for GGN., (© 2024. The Author(s).)

Objectives: This study aimed to explore the role of inhibin subunit beta A (INHBA) in the progression of cervical cancer (CCa) and investigate its potential as a therapeutic target. Specifically, the objectives were to assess the expression levels of INHBA in CCa, examine its correlation with patient survival, and elucidate its impact on CCa cell proliferation, cell cycle regulation, migration, invasion, and in vivo tumor growth and metastasis. Methods: To achieve the objectives, we conducted a comprehensive set of experimental methods. INHBA expression in CCa was analyzed, and its association with patient survival was assessed using clinical data. In vitro experiments involved the investigation of INHBA's effects on CCa cell proliferation, cell cycle dynamics, migration, and invasion through the epithelial-mesenchymal transition (EMT) process. Additionally, in vivo experiments were performed to evaluate the influence of INHBA on CCa growth and lung metastasis. Results: The results of this study revealed upregulated expression of INHBA in CCa, with a significant association between high INHBA expression and poor patient survival. Functionally, INHBA was found to promote the proliferation of CCa cells, regulate the cell cycle, and enhance migration and invasion through the EMT process in vitro. Moreover, in vivo experiments demonstrated that INHBA facilitated the growth and lung metastasis of CCa. Conclusion: In conclusion, our findings suggest that INHBA plays a crucial role in the progression of cervical cancer. The upregulation of INHBA is associated with poor patient survival, and its involvement in promoting key aspects of cancer progression makes it a potential therapeutic target for CCa treatment. These results provide valuable insights into the molecular mechanisms underlying CCa and offer a foundation for further exploration of targeted therapeutic interventions., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Lung cancer is one of the more common malignant tumors posing a great threat to human life, and it is very urgent to find safe and effective therapeutic drugs. The antitumor effect of ginsenosides has been reported to be a treatment with a strong effect and a high safety profile., Objective: This paper aimed to investigate the inhibitory effect of ginsenoside Rb1 on 95D and NCI-H460 lung cancer cells and its pathway to promote apoptosis., Methods: We performed the CCK-8 assay, fluorescence staining assay, flow cytometry, scratch healing assay, and Transwell assay to detect the effects of different concentrations of ginsenoside Rb1 on the antitumor activity of 95D and NCI-H460 cells and Western Blot detected the mechanism of antitumor effect., Results: Ginsenoside Rb1 treatment significantly increased the inhibition and apoptosis rates of 95D and NCIH460 cells and inhibited the cell cycle transition from S phase to G2/M. Rb1 induces apoptosis by altering the levels of P53, Bax, Cyto-c, Caspase-8, Caspase-3, Cleaved Caspase-3, Bcl-2, MMP-2, and MMP-9 proteins and activating the external apoptotic pathway., Conclusion: Ginsenoside Rb1 inhibits proliferation and migration and induces apoptosis of 95D and NCI-H460 lung cancer cells by regulating the mitochondrial apoptotic pathway to achieve antitumor activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To evaluate the effect of intraoperative pain in microwave ablation of lung tumors (MWALT) on local efficacy and establish the pain risk prediction model., Methods: It was a retrospectively study. Consecutive patients with MWALT from September 2017 to December 2020 were divided into mild and severe pain groups. Local efficacy was evaluated by comparing technical success, technical effectiveness, and local progression-free survival (LPFS) in two groups. All cases were randomly allocated into training and validation cohorts at a ratio of 7:3. A nomogram model was established using predictors identified by logistics regression in training dataset. The calibration curves, C-statistic, and decision curve analysis (DCA) were used to evaluate the accuracy, ability, and clinical value of the nomogram., Results: A total of 263 patients (mild pain group: n = 126; severe pain group: n = 137) were included in the study. Technical success rate and technical effectiveness rate were 100% and 99.2% in the mild pain group and 98.5% and 97.8% in the severe pain group. LPFS rates at 12 and 24 months were 97.6% and 87.6% in the mild pain group and 91.9% and 79.3% in the severe pain group (p = 0.034; HR: 1.90). The nomogram was established based on three predictors: depth of nodule, puncture depth, and multi-antenna. The prediction ability and accuracy were verified by C-statistic and calibration curve. DCA curve suggested the proposed prediction model was clinically useful., Conclusions: Severe intraoperative pain in MWALT reduced the local efficacy. An established prediction model could accurately predict severe pain and assist physicians in choosing a suitable anesthesia type., Clinical Relevance Statement: This study firstly provides a prediction model for the risk of severe intraoperative pain in MWALT. Physicians can choose a suitable anesthesia type based on pain risk, in order to improve patients' tolerance as well as local efficacy of MWALT., Key Points: • The severe intraoperative pain in MWALT reduced the local efficacy. • Predictors of severe intraoperative pain in MWALT were the depth of nodule, puncture depth, and multi-antenna. • The prediction model established in this study can accurately predict the risk of severe pain in MWALT and assist physicians in choosing a suitable anesthesia type., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

The mechanisms underlying the involvement of long non-coding RNAs (lncRNAs) in the metastasis of small cell lung cancer (SCLC) remain largely unknown. Here, we identified that the lncRNA ITPR1-AS1 was upregulated in SCLC and lymph node metastasis tissues and positively correlated with SCLC malignant features. The overexpression of ITPR1-AS1 in SCLC was an independent risk factor for the overall survival of patients with SCLC. Our data confirmed that ITPR1-AS1 induces SCLC cell metastasis both in vitro and in vivo. Mechanistically, ITPR1-AS1 acts as a scaffold to enhance the interaction between SRC-associated in mitosis 68 kDa and heterogeneous nuclear ribonucleoprotein A1, which facilitates the alternative splicing of the H-Ras proto-oncogene (HRAS) pre-mRNA (P21 HRAS ). Moreover, we observed that ITPR1-AS1 could associate in a complex with and maintain the stability of DEAD-box polypeptide 3 (DDX3X), which inhibited the latter's ubiquitination and degradation. Our data provide evidence that ITPR1-AS1 activates the cRaf-MEK-ERK cascade by upregulating P21 HRAS production and stabilizing DDX3X, to promote SCLC metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Neoadjuvant immunochemotherapy is effective in resectable NSCLC. However, its role in unresectable stage IIIB NSCLC patients remains controversial. This study aimed to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy followed by surgical resection to treat initial unresectable stage IIIB NSCLC patients., Methods: This study retrospectively analyzed 59 initial unresectable stage IIIB NSCLC patients who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. Clinical characteristics, radiological and pathological responses, and survival outcomes were collected and evaluated., Results: Fifity-nine initial unresectable stage IIIB NSCLC patients were identified and divided into surgery (n = 23) and non-surgery (n = 36) groups with a median follow-up time of 15.0 months. The median PFS/DFS of the surgery group was significantly longer than the non-surgery group (not reached vs. 15.5 months, p = 0.0031). The median overall survival (OS) was not reached in both groups, and the OS rate was 100% (23/23) in the surgery group and 83.3% (30/36) in the non-surgery group. The pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in the MPR group compared to the non-MPR group (p = 0.034). All patients in the surgery group had an R0 resection, and no surgical-related mortality was recorded; only three patients (13.0%) experienced any postoperative complications., Conclusion: In this retrospective study, surgical resection after neoadjuvant immunochemotherapy was promising for initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the role of quantitative features of intranodular vessels based on deep learning in distinguishing pulmonary adenocarcinoma invasiveness., Materials and Methods: This retrospective study included 512 confirmed ground-glass nodules from 474 patients with 241 precursor glandular lesions (PGL), 126 minimally invasive adenocarcinomas (MIA), and 145 invasive adenocarcinomas (IAC). The pulmonary blood vessels were reconstructed on noncontrast computed tomography images using deep learning-based region-segmentation and region-growing techniques. The presence of intranodular vessels was evaluated based on the automatic calculation of vessel prevalence, vascular categories, and vessel volume percentage. Further comparisons were made between different invasive groups by the Mantel-Haenszel χ 2 test, χ 2 test, and analysis of variance., Results: The detection rate of intranodular vessels in PGL (33.2%) was significantly lower than that of MIA (46.8%, P = 0.011) and IAC (55.2%, P < 0.001), while the vascular categories were similar (all P > 0.05). Vascular changes were more common in IAC and MIA than in PGL, mainly in increased vessel volume percentage (12.4 ± 19.0% vs. 6.3 ± 13.1% vs. 3.9 ± 9.4%, P < 0.001). The average intranodular artery and vein volume percentage of IAC (7.5 ± 14.0% and 5.0 ± 10.1%) was higher than that of PGL (2.1 ± 6.9% and 1.7 ± 5.8%) and MIA (3.2 ± 9.1% and 3.1 ± 8.7%), with statistical significance (all P < 0.05)., Conclusions: The quantitative analysis of intranodular vessels on noncontrast computed tomography images demonstrated that the ground-glass nodules with increased internal vessel prevalence and volume percentages had higher possibility of tumor invasiveness., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of this study was to investigate the safety and efficacy of anti-programmed death ligand 1 (PD-L1) immunotherapy plus chemoradiotherapy for patients with limited-stage small cell lung cancer (LS-SCLC) in clinical practice. Patients with LS-SCLC treated with anti-PD-L1 (atezolizumab/durvalumab) plus chemoradiotherapy (CRT) as the initial treatment at three general hospitals between March 2020 and December 2021 were retrospectively analysed. 1:2 propensity score matching for controls that receive CRT only was performed. Clinical data (age, sex, history of cancer treatment, adverse events, etc.) were collected to evaluate toxicity, progression-free survival (PFS) and objective response rate (ORR). Researchers used univariate Chi-squared analyses to determine if anti-PD-L1 immunotherapy had a significant association with toxicity or ORR. Kaplan-Meier survival analysis, and the log-rank test were used to compare survival curves between the two groups. In the anti-PD-L1 plus CRT and CRT groups, 15 and 30 patients were analyzed; median follow-up was 16.39 months and 16.64 months, respectively. Incidence of toxicity between the two groups was similar and there were no new safety signals. Anti-PD-L1 immunotherapy significantly improved PFS ( P  = 0.02). The median PFS was not reached in the anti-PD-L1 plus CRT group versus 8.18 months [95% confidence interval (CI), 6.14-10.22 months] in the CRT group. The ORR were 93.33% and 76.67%, respectively ( P  = 0.34). This study supports adding anti-PD-L1 immunotherapy (atezolizumab/durvalumab) to CRT as an initial treatment option in patients with LS-SCLC for its favorable safety profile and efficacy.

Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT) is a compound extract from Salvia miltiorrhiza , which has favorable anti-inflammatory and anti-cancer activities. However, the role of DHT in NSCLC has not been fully studied. The anti-cancer drugs used for treating lung cancer often lead to apoptosis; however, the drug resistance of apoptosis restricts the effect of these drugs. Oncosis is a passive form of cell death that is different from apoptosis. It is characterized by cell swelling, and Porimin is a specific marker for oncosis. In this study, the role of DHT in mediating oncosis in A549 cells was investigated. In vitro, the MTS assay was used to detect cell activity after DHT treatment. Microscopy and electron microscopy were used to observe cell morphology changes. Western blotting was used to detect protein expression. Flow cytometry was used to detect intracellular reactive oxygen species (ROS) level, calcium ion (Ca 2+ ) level, and cell mortality. The intracellular Lactic dehydrogenase (LDH) level was detected by an LDH detection kit after DHT treatment. The ATP level was detected using an ATP detection kit. In vivo, Lewis lung cancer (LLC) xenograft mice were used to evaluate the anti-tumor effect of DHT. Hematoxylin and eosin (HE) staining was used to detect the pathology of lung cancer tumors. The detection of Porimin in the tumor tissues of the mice after DHT administration was assessed by immunohistochemistry (IHC). The results of this study showed that DHT treatment changed the cell morphology; destroyed the mitochondrial structure; increased the expression of Porimin; increased the levels of LDH, ROS, and Ca 2+ ; decreased the mitochondrial membrane potential and ATP level; and played an anti-tumor role in vitro by mediating oncosis in A549 cells. The in vivo studies showed that DHT could effectively inhibit tumor growth. The results of protein detection and IHC detection in the tumor tissues showed that the expression of Porimin was increased and that oncosis occurred in the tumor tissues of mice. DHT triggered Porimin-dependent oncosis by ROS-mediated mitochondrial dysfunction in NSCLC. The in vivo studies showed that DHT could inhibit tumor growth in LLC xenograft mice by triggering oncosis. This study indicates the potential for DHT to treat NSCLC.

Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non-small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rationale and Objectives: To investigate the clinical value of enlarged mediastinal and/or hilar lymph nodes on CT for patients with lung subsolid and solid nodules., Materials and Methods: The study was performed on patients who underwent surgical treatment for suspected lung cancer. One hundred seventeen subsolid nodules and 101 solid nodules with enlarged lymph nodes (LNs) were included in the study group. The same number of cases with normal LNs with a balanced distribution of the clinical T stage were randomly selected as the control group for each study group. The pathological statuses of the lymph nodes of these patients proven by histopathology after surgery were collected., Results: Lung solid lesions with enlarged LNs were more prone to lymph node metastasis (37.6% vs. 13.9%, p <0.001). However, there were only two and one metastatic lesions in the subsolid group with and without enlarged LNs, respectively. (2/117 vs. 1/117, p = 1.000). No pathological lymph node metastasis was observed in subsolid lesions under clinical stage T1b (cT1b), even though some of them (117/234) with enlarged LNs., Conclusion: The evaluative significance of enlarged LNs on CT is different for subsolid and solid lesions. CT is useful for lymph node evaluation and N staging of solid lesions but may has little value for subsolid lesions. There is a very low possibility of lymph node metastasis occurring in patients with subsolid lesions under cT1b. Enlarged LNs on CT may not be critical in subsequent management and treatment for subsolid nodules., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma is still cancer with the highest mortality. Hypoxia and immunity play an essential role in the occurrence and development of tumors. Therefore, this study is mainly to find new early diagnosis and prognosis markers and explore the relationship among the markers and immunity and hypoxia, to improve the prognosis of patients. Firstly, based on the clinical database in TCGA, we determined the most critical clinicopathological parameters affecting the prognosis of patients through a variety of analysis methods. According to pathological parameters, logistic most minor absolute contraction selection operator (lasso), univariate and multivariate regression analysis, the risk genes related to early prognosis were screened, and the risk model was established. Then, in different risk groups, GSEA and CIBERSORT algorithms were used to analyze the distribution and enrichment of the immune cells and hypoxia, to study the effects of early prognostic indicators on hypoxia and immunity. At the same time, we analyzed the different levels of risk genes in normal cells (BSEA-2B) and tumor cells (H1299, A549, PC9, and H1975). Finally, A549 and PC9 cells were induced by CoCl2 to establish a hypoxic environment, and the correlation between risk genes and HIF1A was analyzed. The risk model based on risk genes (CYP4B1, KRT6A, and FAM83A) was accurate and stable for the prognosis of patients. It is closely related to immunity and hypoxia. In BSEA-2B cells, the mRNA and protein expression of CYP4B1 was higher, while the expression of KRT6A and FAM83A was lower. Finally, we found that FAM83A and HIF1A showed a significant positive correlation when A549 and PC9 cells were exposed to hypoxia. The discovery of early diagnostic markers related to immunity, hypoxia, and prognosis, provides a new idea for early screening and prognostic treatment of lung adenocarcinoma., (© 2023. The Author(s).)

Background: Previous studies have suggested the applicability of three classifications of subsolid nodules (SSNs). However, few studies have unraveled the natural history of the three types of SSNs., Methods: A retrospective study from two medical centers between November 2007 and November 2017 was conducted to explore the long-term follow-up results of three different types of SSNs, which were divided into pure ground-glass nodules (pGGNs), heterogeneous ground-glass nodules (hGGNs), and real part-solid nodules (rPSNs)., Results: A total of 306 consecutive patients, including 361 SSNs with long-term follow-up, were reviewed. The median growth times of pGGNs, hGGNs, and rPSNs were 7.7, 6.0, and 2.0 years, respectively. For pGGNs, the median period of development into rPSNs was 4.6 years, while that of hGGNs was 1.8 years, and the time from pGGNs to hGGNs was 3.1 years (p < 0.05). In SSNs with an initial lung window consolidation tumor ratio (LW-CTR) >0.5 and mediastinum window (MW)-CTR >0.2, all cases with growth were identified within 5 years. Meanwhile, in SSNs whose LW-CTR and MW-CTR were 0, it took over 5 years to detect nodular growth. Pathologically, 90.6% of initial SSNs with LW-CTR >0 were invasive carcinomas (invasive adenocarcinoma and micro-invasive adenocarcinoma). Among patients with rPSNs in the initial state, 100.0% of the final pathological results were invasive carcinoma. Cox regression showed that age (p = 0.038), initial maximal diameter (p < 0.001), and LW-CTR (p = 0.002) were independent risk factors for SSN growth., Conclusions: pGGNs, hGGNs, and rPSNs have significantly different natural histories. Age, initial nodule diameter, and LW-CTR are important risk factors for SSN growth., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The most commonly diagnosed and most lethal subtype of lung cancer is lung adenocarcinoma (LUAD). Therefore, more detailed understanding of the potential mechanism and identification of potential targets of lung adenocarcinoma is needed. A growing number of reports reveals that long non-coding RNAs (lncRNAs) play crucial roles in cancer progression. In present study, we found that lncRNA LINC00115 was upregulated in LUAD tissues and cells. Functional studies revealed that LINC00115 knockdown inhibits the proliferation, growth, invasion, and migration of LUAD cells. Mechanically, we indicated that miR-154-3p is target microRNA of LINC00115, and the effect of downregulated LINC00115 on LUAD cells was partially reversed by the miR-154-3p antisense oligonucleotide (ASO-miR-154-3p). Further investigation revealed that Specificity protein 3 (Sp3) directly interacted with miR-154-3p, and the Sp3 level was positively correlated with the LINC00115 expression. Rescue experiments further showed that Sp3 overexpression partially restored the effect of downregulated LINC00115 on LUAD cells. Similarly, in vivo experiments confirmed that downregulated LINC00115 inhibited xenograft growth and Sp3 expression. Our results demonstrated that LINC00115 knockdown inhibited LUAD progression via sponging miR-154-3p to modulate Sp3 expression. These data indicate that the LINC00115/miR-154-3p/Sp3 axis can be a potential therapeutic target of LUAD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Transbronchial mediastinal cryobiopsy is a novel sampling technique for mediastinal disease. Despite the possibility of lung cancer misdiagnosis, the improved diagnostic yield of this approach for non-lung-cancer lesions compared with standard endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) highlights its diagnostic potential as a complementary technique to conventional biopsy. We aimed to evaluate the safety profile and added value of the combined use of transbronchial mediastinal cryobiopsy and standard EBUS-TBNA for the diagnosis of mediastinal diseases., Methods: We conducted an open-label, randomised trial at three hospital sites in Europe and Asia. Eligible patients were aged 15 years or older, with at least one mediastinal lesion of 1 cm or longer in the short axis that required diagnostic bronchoscopy. Participants were randomly assigned (1:1) using a block randomisation scheme generated by a computer (block size of four participants based on a random table from an independent statistician) to the combined use of EBUS-TBNA and transbronchial mediastinal cryobiopsy (combined group) or EBUS-TBNA alone (control group). Because of the nature of the intervention, neither participants nor investigators were masked to group assignment. The coprimary outcomes were differences in procedure-related complications and diagnostic yield (defined as the proportion of participants for whom mediastinal biopsy led to a definitive diagnosis), assessed in the full analysis set, including all the patients who met the eligibility criteria and had a biopsy. A fully paired, intraindividual diagnostic analysis in participants who had both needle aspiration and mediastinal cryobiopsy was conducted, in addition to interindividual comparisons. This trial is now complete and is registered with ClinicalTrials.gov, NCT04572984., Findings: Between Oct 12, 2020, and Sept 9, 2021, 297 consecutive patients were assessed for eligibility and 271 were enrolled and randomly assigned to the combined group (n=136) or the control group (n=135). The addition of cryobiopsy to standard sampling significantly increased the overall diagnostic yield for mediastinal lesions, as shown by both interindividual (126 [93%] of 136 participants in the combined group vs 109 [81%] of 135 in the control group; risk ratio [RR] 1·15 [95% CI 1·04-1·26]; p=0·0039) and intraindividual (126 [94%] of 134 vs 110 [82%] of 134; RR 1·15 [95% CI 1·05-1·25]; p=0·0026) analyses. In subgroup analyses in the intraindividual population, diagnostic yields were similar for mediastinal metastasis (68 [99%] of 69 participants in the combined group vs 68 [99%] of 69 in the control group; RR 1·00 [95% CI 0·96-1·04]; p=1·00), whereas the combined approach was more sensitive than standard needle aspiration in benign disorders (45 [94%] of 48 vs 32 [67%] of 48; RR 1·41 [95% CI 1·14-1·74]; p=0·0009). The combined approach also resulted in an improved suitability of tissue samples for molecular and immunological analyses of non-small-cell lung cancer. The incidence of adverse events related to the biopsy procedure did not differ between trial groups, as grade 3-4 airway bleeding occurred in three (2%) patients in the combined group and two (1%) in the control group (RR 0·67 [95% CI 0·11-3·96]; p=1·00). There were no severe complications causing death or disability., Interpretation: The addition of mediastinal cryobiopsy to standard EBUS-TBNA resulted in a significant improvement in diagnostic yield for mediastinal lesions, with a good safety profile. These data suggest that this combined approach is a valid first-line diagnostic tool for mediastinal diseases., Funding: National Natural Science Foundation of China., Competing Interests: Declaration of interests FJFH reports honoraria for advisory board activities and lecture fees from Pulmonx, Erbe, Olympus, and Uptake. WMK received honoraria for advisory board activities, consultancies, and lectures from Roche Diagnostics International and Bayer Aktiengesellschaft. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: The fact that studies on anti-programmed cell death 1 (PD-1) or its relevant ligand 1 (PD-L1) have yielded such few responses greatly decreases the confidence in immunotherapy with checkpoint inhibitors for advanced osteosarcoma. We intended to characterize the expression of various checkpoint molecules with immunohistochemistry in osteosarcoma specimens and analyzed the relationship of the expression of these checkpoint molecules with patients' clinical courses., Methods: This study was a retrospective non-intervention study from August 1st 2017 to March 1st 2020. Immunohistochemistry for B7-H3 (CD276, Cluster of Differentiation 276), CD47 (Cluster of Differentiation 47), PD-L1 (programmed cell death ligand 1), TIM3 (mucin-domain containing-3), TGF-β (TransformingGrowth Factor β), CXCR 4 (Chemokine Receptor 4), CD27 (Cluster of Differentiation 27), IDO1 (Indoleamine 2,3-dioxygenase 1), KIRs (Killer cell Immunoglobulin-like Receptors), and SDF-1 (Stromal cell-Derived Factor-1) was performed on 35 resected osteosarcoma specimens. Patients progressed upon first-line chemotherapy with evaluable lesions were qualified for this study, and their specimens previously stored in the pathological department repository would be retrieved for analysis. Associations between the immunohischemistry markers and clinicopathological variables and survival were evaluated by the χ 2 displayed by cross-table, Cox proportional hazards regression model, and Kaplan-Meier plots., Results: The positive rates of B7-H3, CD47, PD-L1, TIM3, and TGF-β expression in this sample of 35 heavily treated osteosarcomas were 29% (10/35), 15% (5/35), 9% (3/35), 6% (2/35), and 6% (2/35), respectively, and diverse staining intensities were observed. Among these advanced patients, 15/35 (43%) had positive checkpoint expression, of which 33% (5/15) showed evidence of the co-expression of more than one checkpoint molecule. We did not find any obvious correlation with clinicopathological characteristics and the positive expression of these molecules., Conclusions: The present study highlights that only a small subset of progressive osteosarcomas, which had been heavily-treated, expressed tumor immune-associated checkpoint molecules, of which B7-H3 was the most positively expressed checkpoint and might be a promising target for further osteosarcoma investigation., (© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Lung cancer is the most common type of cancer and the leading cause of cancer‑associated death worldwide. Despite the availability of various treatments such as surgery, chemoradiotherapy, targeted drugs and immunotherapy, treatment is expensive and the prognosis remains poor. At present, lung cancer drugs and treatment programs remain in a state of continuous exploration and research to improve the prognosis, and to reduce the pain and economic burden for the patients. Type 2 diabetes is a common chronic disease in middle‑aged and elderly patients, leading to significantly increased complications of cardiovascular and cerebrovascular diseases. Epidemiology shows that type 2 diabetes also increases the incidence of malignant tumors, including lung, liver, colorectal and pancreatic cancer. Metformin is a biguanide, widely used as a first‑line oral drug in treating type 2 diabetes. Metformin has a hypoglycemic effect and a biological antitumor impact, reducing the incidence of various tumors, including lung cancer, and improving the prognosis of patients with tumors. The anti‑lung cancer effect of metformin involves a variety of mechanisms that can improve the therapeutic effect and prognosis of lung cancer, as a single drug or in combination with other therapies. The present study aims to review the associated literature and the therapeutic effects of metformin on lung cancer.

Lung cancer is the leading cause of malignant tumor-related deaths worldwide. The presence of tumor-initiating cells in lung cancer leads to tumor recurrence, metastasis, and resistance to conventional treatment. Cleavage and polyadenylation specificity factor 4 (CPSF4) activation in tumor cells contributes to the poor prognosis of lung cancer. However, the precise biological functions and molecular mechanisms of CPSF4 in the regulation of tumor-initiating cells remain unclear. We demonstrated that CPSF4 promotes tumor-initiating phenotype and confers chemoresistance to paclitaxel both in vitro and in vivo. Mechanistically, we showed that CPSF4 binds to the promoters of vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) and activated their transcription. In addition, we showed that CPSF4/VEGF/NRP2-mediated tumor-initiating phenotype and chemoresistance through TAZ induction. Furthermore, analysis of clinical data revealed that lung cancer patients with high CPSF4 expression exhibit high expression levels of VEGF, NRP2, and TAZ and that expression of these proteins are positively correlated with poor prognosis. Importantly, selective inhibition of VEGF, NRP2, or TAZ markedly suppressed CPSF4-mediated tumor-initiating phenotype and chemoresistance. Our findings reveal the mechanism of CPSF4 modulating tumor-initiating phenotype and chemoresistance in lung cancer and indicate that the CPSF4-VEGF-NRP2-TAZ signaling pathway may be a prognosis marker and therapeutic target in lung cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A novel hyaluronic acid (HA)-modified hybrid nanocomplex HA-SeSe-COOH/siR-93C@PAMAM, which could efficiently deliver siRNA into tumor cells via a redox-mediated intracellular disassembly, was constructed for enhanced antitumor efficacy. Thereinto, siR-93C (siRNA) and positive PAMAM were firstly mixed into the electrostatic nano-intermediate, and then diselenide bond (-SeSe-)-modified HA was coved to shield excessive positive charges. This hybrid nanocomplex displayed uniform dynamic sizes, high stability, controlled zeta potential and narrow PDI distribution. Moreover, the -SeSe- linkage displayed GSH/ROS dual responsive properties, improving intracellular trafficking of siRNA. In vitro assays in A549 cell line presented that HA-SeSe-COOH/siR-93C@PAMAM has low cytotoxicity, rapid lysosomal escape and significant transfection efficiency; besides, an efficient proliferation inhibition ability and enhanced apoptosis. Furthermore, in animal studies, this negative-surfaced hybrid nanocomplex showed a prolonged circulation in blood and improved inhibition of tumor growth. All these results verified our hypothesis in this study that diselenide bonds-modified HA could promote not only stability and safety of nanoparticles in vivo but also intracellular behavior of siRNA via redox-dual sensitive properties; furthermore, this hybrid nanocomplex provided a visible potential approach for siRNA delivery in the antitumor field.

Propofol is widely used in clinical anesthesia due to its advantages of rapid onset and less adverse reactions. This study focused on the role of propofol in the balance of Th17/Treg in elderly patients with lung cancer during perioperative period. Patients undergoing lung cancer surgery were anesthetized by propofol or sevoflurane. Veinal blood was collected at different time points to evaluate the changes of Th17/Treg cell. Propofol better maintained the balance of Th17/Treg in vivo. The peripheral blood of patients with lung cancer was collected in vitro before surgery. Cluster of differentiation (CD)4 + T cells were obtained and then treated with propofol at different concentrations and γ-aminobutyric acid A (GABAA) receptor antagonists. Propofol affected Th17/Treg cell balance by increasing Th17 cells, decreasing Treg cells, thus elevating Th17/Treg ratio, and inhibited invasion and migration of lung cancer cells through GABAA receptor, which was counteracted by GABAA receptor inhibitors. Subsequently, tumor in situ model of lung cancer in aged mice was established. Propofol anesthetized mice had lower change of Th17/Treg ratio, higher survival rate and less metastasis. In brief, propofol regulated balance of Th17/Treg in elderly patients undergoing lung cancer surgery through GABAA receptor. Additionally, propofol could inhibit metastasis of lung cancer., (© 2022. The Author(s).)

Background: Real-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs., Materials and Methods: Adults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre- and ≥1-month post-index observations., Results: A total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of &gt;80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively., Conclusions: Brigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities., (© The Author(s) 2022. Published by Oxford University Press.)

In order to solve the problem of the effect of CT images on the diagnosis of lungs, the authors proposed a method for the diagnosis of invasive mucinous adenocarcinoma of the lungs based on CT radiomic features, and the modified method is found by reviewing past cases: among the 34 cases of primary pulmonary lymphoma, 12 cases were nodular mass type, 19 cases were nonnodular mass type, and 3 cases were mixed type; 13 cases involved bilateral lung lobes, 7 cases involved right lung, and 4 cases involved left lung example. There were 17 cases of tumor consolidation density shadow, 17 cases of mixed density shadow, the average CT value was about 32HU, 15 cases of cavitation sign, 6 cases of cavity, 9 cases of angiography sign, 30 cases of air bronchus sign, 22 cases of bronchiectasis, bronchial stenosis or amputation in 8 cases, pleural effusion in 12 cases, lymph node enlargement in 15 cases, and pleural metastasis in 2 cases. The final pathological results included 24 cases of membrane-associated lymphoid tissue (MALT) lymphoma, 9 cases of diffuse large B-cell lymphoma (DLBCL), and 1 case of T-cell lymphoma. The CT manifestations of primary pulmonary lymphoma (PPL) are diverse and do not have obvious specificity, the imaging manifestations are correlated with pathological types, and air bronchial signs, bronchiectasis, angiography signs, and other signs are used for the diagnosis of PPL. This is of great significance for the diagnosis of PPL., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Aizhu Sheng et al.)

Background: The purpose of this retrospective study was to demonstrate the safety and feasibility of three-port single-intercostal video-assisted thoracoscopic surgery (SIC-VATS) segmentectomy compared to uniportal video-assisted thoracoscopic surgery (UVATS) segmentectomy., Methods: We included 544 patients diagnosed with cT1N0M0 non-small-cell lung cancer (NSCLC) who underwent thoracoscopic segmentectomy between January 2020 and August 2021, including 147 and 397 patients who underwent three-port SIC-VATS and UVATS, respectively. After incorporating preoperative clinical variables, we compared surgical outcomes and perioperative indicators between the two groups by propensity score matching analysis., Results: After 1:1 propensity score matching, each group comprised 143 patients with no significant differences in baseline demographics and characteristics. There was no significant difference in operative time (p = 0.469), blood loss (p = 0.501), number of dissected lymph nodes (p = 0.228), dwell time of the main chest drain (p = 0.065), hospital stay (p = 0.243), or major complication rate (p = 0.295) between the three-port SIC-VATS and UVATS groups., Conclusions: The three-port SIC-VATS was as safe and feasible as UVATS for patients who are diagnosed with early-stage NSCLC., (© 2022. The Author(s).)

Background: Patients with non-small cell lung cancer (NSCLC) and preexisting interstitial lung disease (ILD) are often excluded from clinical trials of immune checkpoint inhibitors (ICIs), leaving a gap in knowledge., Research Question: What are the clinical outcomes of ICIs in patients with NSCLC and preexisting ILD?, Study Design and Methods: Systematic searches were conducted of PubMed, EMBASE, and Cochrane Library through April 2021 with no language or study design restrictions. Studies reporting the safety and efficacy data among patients with cancer and ILD receiving ICI therapy were collected. The primary end points were clinical efficacy to immunotherapy and the incidence of immune-related adverse events, especially for checkpoint inhibitor pneumonitis (CIP)., Results: A total of 179 patients in 10 studies were included. The pooled overall response rate (ORR) and pooled disease control rate (DCR) were 34% (95% CI, 20-47) and 66% (95% CI, 56-75), respectively. The ORR in patients with preexisting ILD was significantly higher than that in patients without ILD (OR, 1.99; 95% CI, 1.31-3.00). The DCR and progression-free survival in patients with preexisting ILD were not inferior to those without ILD (pooled OR, 1.46; 95% CI, 0.94-2.25 for DCR). The pooled incidences of any grade and grade 3 or higher CIP were 27% (95% CI, 17-37) and 15% (95% CI, 9-22) in patients with preexisting ILD, and 10% (95% CI, 6-13) and 4% (95% CI, 2-6) in patients without ILD. Meta-analysis found a significantly higher incidence rate of any grade and grade 3 or higher CIP in patients with NSCLC and preexisting ILD than in those patients without ILD (OR, 3.23 [95% CI, 2.06-5.06]; OR, 2.91 [95% CI, 1.47-5.74])., Interpretation: Programmed cell death protein 1/programmed cell death ligand 1 inhibitors had favorable efficacy in NSCLC with preexisting ILD. CIP is frequent in patients with preexisting ILD who receive ICI therapy but is often mild and easily manageable. Clinicians should be cautious when using ICIs in patients with preexisting ILD., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: Functional lung avoidance (FLA) radiation therapy (RT) aims to minimize post-RT pulmonary toxicity by preferentially avoiding dose to high-functioning lung (HFL) regions. A common limitation is that FLA approaches do not consider the conducting architecture for gas exchange. We previously proposed the functionally weighted airway sparing (FWAS) method to spare airways connected to HFL regions, showing that it is possible to substantially reduce risk of radiation-induced airway injury. Here, we compare the performance of FLA and FWAS and propose a novel method combining both approaches., Methods: We used breath-hold computed tomography (BHCT) and simulation 4-dimensional computed tomography (4DCT) from 12 lung stereotactic ablative radiation therapy patients. Four planning strategies were examined: (1) Conventional: no sparing other than clinical dose-volume constraints; (2) FLA: using a 4DCT-based ventilation map to delineate the HFL, plans were optimized to reduce mean dose and V 13.50 in HFL; (3) FWAS: we autosegemented 11 to 13 generations of individual airways from each patient's BHCT and assigned priorities based on the relative contribution of each airway to total ventilation. We used these priorities in the optimization along with airway dose constraints, estimated as a function of airway diameter and 5% probability of collapse; and (4) FLA + FWAS: we combined information from the 2 strategies. We prioritized clinical dose constraints for organs at risk and planning target volume in all plans. We performed the evaluation in terms of ventilation preservation accounting for radiation-induced damage to both lung parenchyma and airways., Results: We observed average ventilation preservation for FLA, FWAS, and FLA + FWAS as 3%, 8.5%, and 14.5% higher, respectively, than for Conventional plans for patients with ventilation preservation in Conventional plans <90%. Generalized estimated equations showed that all improvements were statistically significant (P ≤ .036). We observed no clinically relevant improvements in outcomes of the sparing techniques in patients with ventilation preservation in Conventional plans ≥90%., Conclusions: These initial results suggest that it is crucial to consider the parallel and the serial nature of the lung to improve post-radiation therapy lung function and, consequently, quality of life for patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: For NSCLC patients with complete resection, the prognostic role of EGFR mutation for recurrence, especially for CNS metastasis, is still controversial. In this study, we aimed to identify the characteristics of the recurrence pattern of lung adenocarcinoma based on EGFR mutation status., Methods: Overall, 888 patients with completely surgically resected LUAD who underwent EGFR mutation status analysis from two Chinese institutions were included. Sites and data of initial recurrence were recorded. The recurrence patterns according to EGFR mutation status were estimated by Kaplan-Meier analysis, and hazard rate curves were generated., Results: 245 (27.6%) of 888 patients suffered from recurrence. Before and after PSM, there were no statistically significant differences between the EGFR mutation and EGFR WT groups for all types of recurrence, including CNS metastasis. Multivariable Cox analysis revealed that EGFR status was not a risk factor for all types of recurrence, including CNS metastasis (HR 0.88, 95% CI 0.54-1.46, p = 0.632). The CNS metastasis hazard curve in the EGFR mutation group showed that the first peak occurred at approximately 24-26 months after surgery, which was 10 months later than that in the EGFR WT group. In addition, the second peak time in the EGFR mutation group was approximately 2 years later than that in the EGFR WT group., Conclusions: EGFR mutation was not an independent prognostic factor for postoperative recurrence. EGFR-mutated LUADs did not have a clinical course with a higher incidence of CNS metastasis. However, the peak hazards for recurrence of CNS metastasis occur at a later time point in the EGFR mutant group compared with the EGFR wild type group., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: To investigate whether genetic status is associated with the prognosis of patients with clinical stage (c-stage) I non-small cell lung cancer (NSCLC) with radiological pure-solid manifestations., Materials and Methods: We included 340 patients with pure-solid c-stage I NSCLC and evaluated their clinicopathological and genetic information. Disease recurrence and death were also observed at the end of the 5-year follow-up period. A Cox proportional hazards model was performed to identify the effect of clinicopathological variables, including genetic status, on oncological outcomes. Recurrence-free survival (RFS) and overall survival (OS) were calculated by Kaplan-Meier curves and were compared using log-rank tests., Results: The gene-mutation rate of c-stage I NSCLC with a radiological pure-solid appearance was 55.9% (190/340), and the frequencies of EGFR, KRAS, ALK, ROS1 and fused genes were 69.5% (132/190), 16.8% (32/190), 8.9% (17/190), 1.6% (3/190) and 3.2% (6/190), respectively. The 5-year RFS and OS rates of eligible patients were 57.1% and 76.5%, respectively. A multivariable analysis revealed that genetic status was an independent significant prognostic factor associated with RFS (hazard ratio [HR] = 1.416, 95% confidence interval [CI]: 1.020-1.964, p = 0.038) but not with OS. RFS was lower in the genetic mutation group compared with the wild-type group (p = 0.027), with 5-year RFS rate (65.7 vs. 51.6%), but the difference in OS (mutated group vs. wild-type group: 78.0% vs. 75.3%) was not statistically significant (p = 0.602). Additionally, we found that pathological nodal involvement (HR = 2.455, 95% CI: 1.745-3.454, p < 0.001 for RFS; HR = 2.204, 95% CI: 1.409-3.447, p = 0.001 for OS) was also a valuable prognostic factor in patients with pure-solid c-stage I NSCLC., Conclusion: Our study provides a comprehensive description of the mutational landscape of c-stage I NSCLC, and indicates that genetic status has an impact on disease recurrence in patients with c-stage I NSCLC with pure-solid appearance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to discuss whether a diameter of 3 cm is a threshold for diagnosing lung adenocarcinomas presenting with radiological pure ground-glass mass (PGGM, pure ground-glass opacity > 3 cm) as adenocarcinomas in situ or minimally invasive adenocarcinomas (AIS-MIAs). Another aim was to identify CT features and patient prognosis that differentiate AIS-MIAs from invasive adenocarcinomas (IACs) in patients with PGGMs., Methods: From June 2007 to October 2015, 69 resected PGGMs with HRCT and followed up for ≥ 5 years were included in this study and divided into AIS-MIA (n = 13) and IAC (n = 56) groups. Firth's logistic regression model was performed to determine CT characteristics that helped distinguish IACs from AIS-MIAs. The discriminatory power of the significant predictors was tested with the area under the receiver operating characteristics curve (AUC). Disease recurrence was also evaluated., Results: Univariable and multivariable analyses identified that the mean CT attenuation (odds ratio: 1.054, p = 0.0087) was the sole significant predictor for preoperatively discriminating IACs from AIS-MIAs in patients with PGGMs. The CT attenuation had an excellent differentiating accuracy (AUC: 0.981), with the optimal cut-off value at -600 HU (sensitivity: 87.5%; specificity: 100%). Additionally, no recurrence was observed in patients manifesting with PGGMs > 3 cm, and the 5-year recurrence-free survival and overall survival rates were both 100%, even in cases of IAC., Conclusions: This study demonstrated that PGGMs > 3 cm could still be AIS-MIAs. When PGGMs are encountered in clinical practice, the CT value may be the only valuable parameter to preoperatively distinguish IACs from AIS-MIAs., Key Points: • Patients with pure ground-glass opacity > 3 cm in diameter are rare but can be diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. • The mean CT attenuation is the sole significant CT parameter that differentiates invasive adenocarcinoma from adenocarcinoma in situ or minimally invasive adenocarcinoma in patients with pure ground-glass opacity > 3 cm. • Lung adenocarcinoma with pure ground-glass opacity > 3 cm has an excellent prognosis, even in cases of invasive adenocarcinoma., (© 2021. European Society of Radiology.)

Machine learning (ML) has demonstrated promise in predicting mortality; however, understanding spatial variation in risk factor contributions to mortality rate requires explainability. We applied explainable artificial intelligence (XAI) on a stack-ensemble machine learning model framework to explore and visualize the spatial distribution of the contributions of known risk factors to lung and bronchus cancer (LBC) mortality rates in the conterminous United States. We used five base-learners-generalized linear model (GLM), random forest (RF), Gradient boosting machine (GBM), extreme Gradient boosting machine (XGBoost), and Deep Neural Network (DNN) for developing stack-ensemble models. Then we applied several model-agnostic approaches to interpret and visualize the stack ensemble model's output in global and local scales (at the county level). The stack ensemble generally performs better than all the base learners and three spatial regression models. A permutation-based feature importance technique ranked smoking prevalence as the most important predictor, followed by poverty and elevation. However, the impact of these risk factors on LBC mortality rates varies spatially. This is the first study to use ensemble machine learning with explainable algorithms to explore and visualize the spatial heterogeneity of the relationships between LBC mortality and risk factors in the contiguous USA., (© 2021. The Author(s).)

Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P < 0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer., (© 2021. Higher Education Press.)

Machine-assisted pathological recognition has been focused on supervised learning (SL) that suffers from a significant annotation bottleneck. We propose a semi-supervised learning (SSL) method based on the mean teacher architecture using 13,111 whole slide images of colorectal cancer from 8803 subjects from 13 independent centers. SSL (~3150 labeled, ~40,950 unlabeled; ~6300 labeled, ~37,800 unlabeled patches) performs significantly better than the SL. No significant difference is found between SSL (~6300 labeled, ~37,800 unlabeled) and SL (~44,100 labeled) at patch-level diagnoses (area under the curve (AUC): 0.980 ± 0.014 vs. 0.987 ± 0.008, P value = 0.134) and patient-level diagnoses (AUC: 0.974 ± 0.013 vs. 0.980 ± 0.010, P value = 0.117), which is close to human pathologists (average AUC: 0.969). The evaluation on 15,000 lung and 294,912 lymph node images also confirm SSL can achieve similar performance as that of SL with massive annotations. SSL dramatically reduces the annotations, which has great potential to effectively build expert-level pathological artificial intelligence platforms in practice., (© 2021. The Author(s).)

Purpose: To investigate the clinical value and pathologic basis of cystic airspace within lung adenocarcinomas manifesting as subsolid nodules., Patients and Methods: A retrospective study was conducted on a total of 541 surgically confirmed lung adenocarcinomas manifesting as subsolid nodules in computed tomography images, including 87 cases with cystic airspace and 454 cases without cystic airspace. The pathologic characteristics of the cases with and without cystic airspace were compared. The investigation of the pathologic structure of cystic airspace was attempted on the postoperative paraffin sections., Results: There was a significant difference in the containing of cystic airspace between preinvasive and invasive adenocarcinomas (10.5 vs 26.6%; P < .001). Multivariate analysis indicated that cystic airspace is an independent predictor of invasive adenocarcinomas (odds ratio, 3.220; 95% confidence interval, 1.822-5.687). Nodules containing multiple cystic airspaces are more likely to be invasive adenocarcinomas than nodules with a single cystic airspace (47.1 vs 72.2%; P < .05). On paraffin sections, the walls of the cystic airspace seemed to be mainly composed of atypical hyperplasia and/or tumor cells on the surface and the remaining smooth muscle cells and stroma below, which is similar to the structure of bronchi., Conclusions: Cystic airspace may be a reliable predictor of invasive adenocarcinomas, the classification method based on the number of cystic airspaces might be suitable for the computed tomography-based typing of cystic airspace within subsolid nodules. Cystic airspace may derive from the destroyed and enlarged bronchi owing to the growth or infiltration of atypical hyperplasia and/or tumor cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To elucidate the clinicopathological characteristics and oncological outcomes of clinical T1aN0M0 (c-T1N0M0) lung cancer based on the newest 8th TNM classification., Methods: A total of 257 patients with c-T1aN0M0 lung cancer were retrospectively included in this study. According to the solid component size manifesting on the high-resolution computed tomography (HRCT), all lesions were classified as the pure ground-glass nodule (pure-GGN) with a diameter > 3 cm (n = 19), part-solid (n = 174), and pure-solid (n = 64) groups. We evaluated the prognostic impact of clinicopathologic variables including radiological presentations by establishing Cox proportional hazards model., Results: When we evaluated the prognostic impact based on the radiological subtypes, the 5-year recurrence-free survival (RFS) and overall survival (OS) were significantly different among pure-GGN, part-solid, and pure-solid groups (RFS: 100% versus 95.4% versus 76.6%, p < 0.0001; OS: 100% versus 98.9% versus 87.5%, p < 0.0001). Cox regression analysis revealed the preoperative carcinoembryonic antigen (CEA) level and consolidation tumor ratio (CTR) were independently significant prognosticators related to RFS and OS. Furthermore, a receiver operating characteristic (ROC) verified the CTR (area under ROC [AUC] 0.784, 95%CI 0.697-0.869) was equipped with good performance to predict the postoperative recurrence with a cutoff point at 0.5. Lung cancer with higher CTR tended to be associated with lower survival in the c-T1aN0M0 stage., Conclusions: For the c-T1aN0M0 lung cancer, pulmonary nodules manifested as the pure-GGN and part-solid subtypes had an excellent prognosis and may be considered as the "early-stage" cancer, whereas those with pure-solid appearance were associated with the high risk of recurrence despite the sub-centimeter size., Key Points: • Radiological subtypes could further stratify the risk of lung cancer in cT1a. • Sub-solid nodule has a favorable survival in c-T1a lung cancer, whereas pure-solid nodule is not always "early-stage" lung cancer and is relatively prone to postoperative recurrence despite the sub-centimeter size. • The preoperative CEA level and CTR are valuable prognosticators to predict the recurrence in c-T1a lung cancer., (© 2021. European Society of Radiology.)

Objectives: To accurately describe the pattern, timing and predictors of disease recurrence after curative resection for different types of early-stage lung adenocarcinoma (LUAD)., Methods: A total of 1962 patients with early-stage LUAD were included. The presence of micropapillary, solid components or poorly differentiated cancer as a clinical variable was named "high-grade" adenocarcinoma (HGADC), while others were classified as "low-grade" adenocarcinoma (LGADC). Predictive factors for specific recurrence patterns were assessed by univariate and multivariate analyses using Cox-proportional hazard regression models. Event dynamics, based on the hazard rate, were evaluated., Results: At a median follow-up of 36.0 months, 137 (6.98%) of 1962 patients suffered from recurrence. Multivariable Cox analysis revealed that HGADC was an independent predictor for overall recurrence (hazard ratio [HR] 3.08, 95% confidence interval [CI] 2.09-4.52, p < 0.001), local recurrence (HR 2.77, 95% CI 1.38-5.55, p < 0.001), distant metastasis (HR 3.22, 95% CI 2.03-5.11, p < 0.001), chest recurrence (HR 2.80, 95% CI 1.65-4.75, p < 0.001) and brain recurrence (HR 4.11, 95% CI 1.83-9.22, p < 0.001). However, HGADC (HR 1.56, 95% CI 0.63-3.86, p = 0.335 in univariate analysis) was not a risk factor for bone recurrence. The hazard curve of the whole group presented a double-peaked pattern. Different types of LUAD had different hazard curves. HGADC patients exhibited higher hazard rates than LGADC patients during the whole follow-up. In addition, the recurrence hazard curve in HGADC patients showed a typical "double-peaked" pattern, while the curve in LGADC patients displayed a smooth curve after surgery., Conclusions: Different postoperative recurrence patterns were seen in HGADC and LGADC. Site-specific recurrence patterns were also different in HGADC and LGADC types., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Anaplastic lymphoma kinase (ALK) rearrangements are drivers of a subset of non-small cell lung cancer (NSCLC). The rapid progression of ALK inhibitors has significantly prolonged the progression-free survival of patients with ALK gene-sensitive mutations. However, the response of patients with rare ALK rearrangements to tyrosine kinase inhibitors remains unknown. Here, we report a rare case of striatin (STRN)-ALK-positive NSCLC showing primary resistance to first-line therapy alectinib and limited clinical activity of crizotinib in the alectinib-resistant setting., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Although many studies have demonstrated the impact of vitamin D and calcium on lung cancer, it remains the discrepancy for the effect of vitamin D and calcium on lung cancer. In this study, we aimed to verify the roles of vitamin D and calcium in the incidence and prognosis of lung cancer. A systematic literature search was performed by February 29, 2020. The relative risks (RRs) and hazard ratio (HRs) were pooled to evaluate the risk for the incidence and mortality of lung cancer. A total of 58,625 lung cancer cases from 40 studies were included. The risk (RR: 0.915, 95% Cl: 0.849-0.986) and mortality (RR: 0.718, 95% Cl: 0.530-0.973) of lung cancer were significantly decreased due to high circulating 25(OH)D level. Although the separate intake of vitamin D (RR: 0.909, 95% Cl: 0.801-1.031) and calcium (RR: 0.890, 95% Cl: 0.741-1.070) did not exhibit a protective effect on lung cancer, the combination supplement of vitamin D and calcium significantly decreased the incidence of lung cancer (RR: 0.811, 95% Cl: 0.659-0.999). High level of serum 25(OH)D could play the preventive role in lung cancer. Furthermore, vitamin D could be supplemented together with calcium against lung cancer.

Background: Despite the efficacy of crizotinib in non-small cell lung cancer (NSCLC) with genomic rearrangement between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), clinical outcomes are heterogeneous among these patients. In our study, we investigated concurrent molecular factors that could contribute to the heterogeneity of their clinical outcomes to crizotinib therapy., Methods: We retrospectively analyzed the clinical and targeted sequencing data from 32 crizotinib-treated patients with EML4-ALK-rearranged advanced NSCLC., Results: Analysis of the mutation profile revealed the detection of concurrent deleterious mutations in 17 patients (53 %, 17/32). Of which, 5 patients had deleterious copy number variations and 12 patients had deleterious single nucleotide variations. Seven patients did not harbor any concurrent mutations from the genes included in the panel. The remaining 8 patients harbored concurrent mutations which were either non-deleterious or variants of uncertain significance. TP53, detected from 34 % (11/32) of the patients and the most commonly co-occurring mutation in our cohort, was not significantly associated with survival outcomes. Interestingly, significantly shorter progression-free survival (P = 0.032) was observed in patients harboring concurrent deleterious mutations, particularly copy number amplifications (PFS, P = 0.0021; OS, P = 0.034), than those without concurrent deleterious mutations. Harboring more copy number variations, reflected by chromosomal fluctuation coefficient varscore, was associated with shorter progression-free survival (P = 0.02)., Conclusion: Our study revealed that concurrent deleterious mutations, particularly copy number amplifications in oncogenic genes have prognostic implications in patients with EML4-ALK-rearranged NSCLC receiving crizotinib therapy. These observations advance the understanding of the heterogeneity of treatment responses among patients with EML4-ALK-rearranged tumors., Competing Interests: Declaration of Competing Interest Analyn Lizaso, Bing Yu, Jing Lin, and Songan Chen are employees of Burning Rock Biotech., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Whether the combination of gefitinib and chemotherapy is beneficial for advanced non-small cell lung cancer (NSCLC) remains controversial. This study aimed to summarize the currently available evidence and compare the efficacy and safety of gefitinib combined with chemotherapy versus chemotherapy alone for treating advanced NSCLC., Methods: Literature on comparing the effects of gefitinib combined with chemotherapy and chemotherapy alone in treating NSCLC was retrieved from the PubMed, EMBASE and Cochrane Database. The primary outcome measures included progression-free survival (PFS) and overall survival (OS). Revman 5.3 was used for data processing., Results: Seven randomized controlled trials were included, involving a total of 1418 patients. There appeared a significant improvement in PFS (hazard ratio (HR) = 0.60 [95% CI 0.43, 0.82], P = .001) after treatment with gefitinib combined with chemotherapy when compared with chemotherapy alone. The subgroup analysis showed a significant advantage of sequential administration (HR = 0.67 [95% CI 0.57, 0.79], P < .00001). There was no significant improvement in OS (HR = 0.92 [95% CI 0.71, 1.20], P = .54), and no significant improvement in overall response rate (ORR) (HR = 0.98 [95% CI 0.67, 1.44], P = .93). The risks of rash and diarrhea (odds ratios) were higher in gefitinib combined with chemotherapy group when compared with chemotherapy alone, and there were significant differences on grade 3/4 rash and thrombocytopenia between 2 groups., Conclusion: Gefitinib combined with chemotherapy is superior to chemotherapy alone in PFS, sequential administration prolongs the patients' PFS, however, a survival advantage is not shown in OS or ORR. Gefitinib combined with chemotherapy aggravates rash, diarrhea and thrombocytopenia.

Background: Although lung-protective strategies are widely used in thoracic surgery, postoperative atelectasis can still occur. Both lung ultrasound (LUS) and diaphragmatic excursion assessments are accurate and noninvasive for bedside imaging and examination. This study aimed to test the feasibility of using LUS during the perioperative period of video-assisted thoracic surgery (VATS) and to continuously evaluate aeration changes through LUS examination and diaphragmatic excursion assessment., Methods: Between January 2019 and May 2019, data were prospectively collected from patients that were scheduled to undergo a VATS with one-lung ventilation (OLV). LUS was performed at four specific timepoints: before the induction of general anesthesia (timepoint A), 5 minutes after intubation (timepoint B), at the end of surgery (timepoint C), and 15 minutes after extubation (timepoint D). Diaphragmatic excursion assessment was performed only at the first (timepoint A) and last timepoints (timepoint D) for the use of paralytics during surgery., Results: This study included 80 consecutive patients (37 men, 43 women). Among them were patients undergoing lobectomy (14 patients; 17.5%), segmentectomy (35 patients, 43.8%), wedge resection (19 patients; 23.8%), or mediastinal tumor resection (12 patients, 15.0%). LUS was possible for all patients. As a result, LUS helped detect postoperative atelectasis in 12 patients (15.0%). Among them were 4 (33.3%) lung resection patients and 8 (66.7%) mediastinal tumor resection patients. Pneumothorax and small effusions were also diagnosed through LUS examination. There was significant aeration loss throughout the surgery from the start of induction (P<0.001). We discovered that changes in LUS scores were found to be associated with an increase of diaphragmatic excursions after assessment (Spearman's r=-0.54, P<0.001)., Conclusions: LUS is feasible during all phases of the perioperative period in VATS and can facilitate the early investigation of perioperative atelectasis. Perioperative LUS and diaphragmatic excursion assessment are also feasible for the continuous assessment of aeration loss in patients undergoing VATS.

Background: Lung adenocarcinomas (LUADs) that display radiologically as subsolid nodules (SSNs) exhibit more indolent biological behaviour than solid LUADs. SSNs, commonly encompassing pre-invasive and invasive yet early-stage adenocarcinomas, can be categorised as pure ground-glass nodules and part-solid nodules. The genomic characteristics of SSNs remain poorly understood., Methods: We subjected 154 SSN samples from 120 treatment-naïve Chinese patients to whole-exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced-stage LUADs were defined. In addition, we investigated the intratumour heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher's exact and Wilcoxon rank sum tests were used in the statistical analysis., Results: The median somatic mutation rate across the SSN cohort was 1.12 mutations per Mb. Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10 , TP53 , STK11 and KR A S . The differences between SSNs and advanced-stage LUADs at a genomic level were unravelled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multicentric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR , TP53 , RBM10 and ARID1B , suggesting that these genes play roles in the progression of LUADs., Conclusions: Our study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs., Competing Interests: Conflict of interest: Y. Li has nothing to disclose. Conflict of interest: X. Li has nothing to disclose. Conflict of interest: H. Li has nothing to disclose. Conflict of interest: Y. Zhao has nothing to disclose. Conflict of interest: Z. Liu has nothing to disclose. Conflict of interest: K. Sun has nothing to disclose. Conflict of interest: X. Zhu has nothing to disclose. Conflict of interest: Q. Qi has nothing to disclose. Conflict of interest: B. An has nothing to disclose. Conflict of interest: D. Shen has nothing to disclose. Conflict of interest: R. Li has nothing to disclose. Conflict of interest: T. Liu has nothing to disclose. Conflict of interest: J. Mi has nothing to disclose. Conflict of interest: L. Wang has nothing to disclose. Conflict of interest: F. Yang has nothing to disclose. Conflict of interest: F. Bai has nothing to disclose. Conflict of interest: J. Wang has nothing to disclose., (Copyright ©ERS 2020.)

Objective: To evaluate the effect of dexmedetomidine on lung injury and CCAAT/enhancer-binding protein homologous protein (CHOP) expression in elderly patients with lung cancer undergoing thoracoscopic lobectomy. Methods: A total of 120 elderly patients with lung cancer who underwent elective thoracoscopic lobectomy were selected from the Second Affiliated Hospital of Zhengzhou University from October 2018 to March 2019. The random phenotype was divided into dexmedetomidine group (group D, n= 60) and control group (group C, n= 60). The elapsed time before postoperative awake and spontaneous breathing recovery and agitation occurrence were recorded. The mean arterial pressure (MAP), heart rate (HR), oxygen saturation (SPO(2)), oxygen partial pressure (PaO(2)), alveolar-arterial oxygen partial pressure difference[P(A-a)O(2)], end-tidal carbon dioxide partial pressure (P(ET)CO(2)), and airway pressure peak (P(peak)) were recorded before the anesthetic induction (T(0)), immediately after tracheal intubation (T(1)), immediately after unilateral pulmonary ventilation(T(2)), 1 hour after unilateral pulmonary ventilation (T(3)), immediately after bilateral pulmonary ventilation (T(4)), and at the end of surgery(T(5)). The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, IL-10, super oxide dismutase (SOD) and malondialdehyde (MDA)were compared at the time of T(0), T(1), T(2), T(3), T(4) and T(5) in two groups. The ratios of alveolar damage (IQA), apoptotic index (AI), and the expression of CHOP mRNA and their protein in lung tissue were detected. Results: The recovery time of conscious and spontaneous breathing in group D were significantly shorter than that in group C ( P< 0.05). The MAP and HR of the two groups at T(1)-T(5) were significantly lower than those at T(0)( P< 0.05).The levels of P(peak) in group C at T(3)-T(5) was significantly higher than those in group D ( P< 0.05). The SpO(2) values in the group D at T(1)-T(5) were significantly higher than those in group C ( P< 0.05). The P(A-a)O(2) values in the group D at T(1)-T(5) was significantly lower than those in group C ( P< 0.05).The levels of IL-6, IL-8 and MDA in group D at T(1)-T(5) were significantly lower than those in group C( P< 0.05). The levels of IL-10 and SOD in group D at T(1)-T(5) were significantly higher than those in group C ( P< 0.05). The values of IQA, AI, and the expression of CHOP mRNA and their protein in the two groups at T(4) were significantly higher than those at T(2) ( P< 0.05). The values of IQA, AI, and the expression of CHOP mRNA and their protein in group D at T(4) were significantly lower than those in group C ( P< 0.05). Conclusions: Dexmedetomidine could attenuate the extent of lung injury in elderly patients with lung cancer undergoing thoracoscopic lobectomy. The pulmonary protective mechanism could be related to the inhibition of inflammatory factors in dexmedetomidine, improving oxidative stress and reducing Chop-mediated apoptosis of lung tissue by the protein.

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer-related deaths worldwide. Despite early diagnosis and treatment improvement, the majority of patients will still suffer from metastatic disease (mCRC), which has a poor prognosis. Molecular diversity of CRC requires personalized targeted approach for improving patient outcomes. Antiangiogenic agents proved to be beneficial in the continuum of mCRC treatment. For efficient epidermal growth factor receptor (EGFR) directed therapy, subtle molecular selection and better strategies to overcome resistance are needed. BRAF mutant and HER-2 positive mCRC will soon be provided with approved targeted treatments and check-point inhibitors demonstrated effectiveness in microsatellite instability (MSI) - high mCRC. Moreover, numeorous promising agents are entering clinical trial arena. This review summarizes actual and possible targets and current and promising agents for mCRC treatment. With broader accessibility of liquid biopsy we could track molecular evolution of CRC and target genetic alterations as they emerge.

Afatinib, a selective and irreversible inhibitor of tyrosine kinase, was approved for the treatment of advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) overexpression in 2013. Cetuximab (CTX), an anti-EGFR monoclonal antibody, is co-administered with afatinib to improve efficacy. Unfortunately, dose-related adverse reactions caused by combination therapy have affected patient compliance, and have resulted in treatment discontinuation in severe cases. In the present study, afatinib was encapsulated in "liposomes" (LPs) to achieve longer circulation in the blood and an enhanced permeability-and-retention effect in tumors. Concomitantly, CTX was designed to bind to drug-loaded LPs to form "immuno-LPs" for tumor-cell selectivity and therapeutic activity. In vitro, the cellular internalization rate of immuno-LPs was significantly higher than that of LPs (p < 0.05). In vivo, a markedly increased area under the curve and prolonged terminal half-life were detected in rats injected with the two LP formulations, indicating that LP encapsulation protected afatinib from binding to hemoglobin to control the risk of idiosyncratic drug reactions. Compared with free afatinib and LPs, immuno-LPs exhibited strongly enhanced drug delivery and antitumor efficacy in an NSCLC xenograft model, with stronger tumor selectivity and potentially fewer side-effects. Hence, EGFR-targeting immuno-LPs appear to be promising for NSCLC treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study aimed to explore the effects of lncRNA BCAR4 on the viability and aggressiveness of non-small cell lung cancer (NSCLC) cells. qRT-PCR was used to determine the expression of BCAR4 and GLI2 downstream genes in NSCLC tissues and cell lines. Chromatin isolation by RNA purification (CHIRP) and Western blot were employed to measure the expression of the GLI2 downstream proteins. Ki-67 expression in nude mice tumors was tested by immunohistochemistry. MTT assay, wound healing assay, and Transwell assay were used to assess NSCLC cell viability and aggressiveness, respectively. Tumor xenograft was conducted to determine the effects of BCAR4 and GLI2 on NSCLC tumorigenesis in vivo. The expression of BCAR4 in NSCLC tissues and cells was significantly higher than the normal level. The overexpression of BCAR4 promoted NSCLC cell viability, migration, and invasion. The suppression of BCAR4 and GLI2 showed the opposite effects. The overexpression of BCAR4 led to an increase in the expression of GLI2 downstream proteins, while the suppression of BCAR4 and GLI2 reduced their expression. In a tumor xenograft assay, the tumors in mice of the BCAR4 group showed the biggest volume, while those in mice of the si-GLI2 group showed the smallest volume. Ki-67 showed much higher levels in the BCAR4 overexpression group but much lower levels in the si-GLI2 group. In summary, the cooperative mechanism of lncRNA BCAR4 and GLI2 might provide a new opportunity for treating NSCLC.