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Artificial intelligence neural network analysis and application of CT imaging features to predict lymph node metastasis in non-small cell lung cancer.

Computed tomography (CT) is important in the diagnosing of lung cancer. The combination of CT features and artificial intelligence algorithm have been used in the diagnosis of various lung diseases. However, limited studies focused on the relationship between the combination of CT features and artificial intelligence algorithm and lymph node metastasis in non-small cell lung cancer (NSCLC). This study developed an algorithm for lung cancer CT image segmentation based on an artificial neural network model and investigated the role of a nomogram model based on CT images for predicting lymph node metastasis in lung cancer. Wiener filtering and fuzzy enhancement were first used to suppress image noise and improve image contrast. Next, texture features and fractal features were extracted. In the third step, the artificial neural network model was trained and tested according to the best parameters of the network. The area under the curve (AUC) of the constructed nomogram model on the training set and the test set were 0.859 (sensitivity, 0.810 specificity, 0.773) and 0.864 (sensitivity, 0.820 specificity, 0.753), respectively. The decision curve indicated that the model had good clinical application value. The lung cancer CT images contained 13 significant regional features of cancer. The best classification function obtained from training and testing data was Levenberg-Marquardt backpropagation. The sensitivity, specificity, and accuracy in the training stage could reach 98.4%, 100%, and 98.6%, respectively, and the corresponding indexes in the test stage reached 90.9%, 100%, and 95.1%, respectively. The image segmentation algorithm based on the artificial neural network model could extract CT lung cancer lesions efficiently and quasi-determinately, which could be used as an effective tool for radiologists to diagnose lung cancer. The nomogram model based on CT image features and related clinical indicators was an effective method for noninvasive prediction of lymph node metastasis in lung cancer.

Identifying biomarkers of ventilator induced lung injury during one-lung ventilation surgery a scoping review.

Ventilator-induced lung injury (VILI) can occur as a result of mechanical ventilation to two lungs. Thoracic surgery often requires one-lung ventilation (OLV). The potential for VILI is likely higher in OLV. The impact of OLV on development of post-operative pulmonary complications is not well understood. We aimed to perform a scoping review to determine reliable biomarkers of VILI after OLV. A scoping review was performed using Cochrane Collaboration methodology. We searched Medline, EMBASE and SCOPUS. Gray literature was searched. Studies of adult human or animal models without pre-existing lung damage exposed to OLV, with biomarker responses analyzed were included. After screening 5,613 eligible papers, 89 papers were chosen for full text review, with 29 meeting inclusion. Approximately half (52%, n15) of studies were conducted in humans in an intra-operative setting. Bronchoalveolar lavage (BAL) serum analyses with enzyme-linked immunosorbent assay (ELISA)-based assays were most commonly used. The majority of analytes were investigated by a single study. Of the analytes that were investigated by two or more studies (n31), only 16 were concordant in their findings. Across all sample types and studies 84% (n66) of the 79 inflammatory markers and 75% (n6) of the 8 anti-inflammatory markers tested were found to increase. Half (48%) of all studies showed an increase in TNF-α or IL-6. A scoping review of the state of the evidence demonstrated that candidate biomarkers with the most evidence and greatest reliability are general markers of inflammation, such as IL-6 and TNF-α assessed using ELISA assays. Studies were limited in the number of biomarkers measured concurrently, sample size, and studies using human participants. In conclusion these identified markers can potentially serve as outcome measures for studies on OLV.

Safety and effectiveness of neoadjuvant immunotherapy combined with chemotherapy followed by surgical resection in patients with stage I-IIIA small-cell lung cancer a retrospective single-arm clinical trial.

Immunotherapy, chemotherapy and surgery all have significant roles in the management of small-cell lung cancer (SCLC). Neoadjuvant immunotherapy combined with chemotherapy followed by surgery has shown encouraging efficacy for resectable SCLC with a good tolerability and considerable survival benefit. However, there are still few data on whether surgery for stage I-IIIA SCLC can be performed after immunotherapy with chemotherapy. Therefore, we investigated the safety and effectiveness of neoadjuvant immunotherapy combined with chemotherapy followed by surgery in patients with stage I-IIIA SCLC in the hope of adding new ideas to the treatment of SCLC. The study group comprised 19 patients with stage I-IIIA SCLC who received neoadjuvant immunotherapy and chemotherapy between 2019 and 2021. Patients received 2-4 cycles of immunotherapy combined with platinum-containing dual-drug chemotherapy (platinum paclitaxel) before surgery. Imaging evaluation was performed every two cycles until surgery. Tumor response to neoadjuvant therapy, neoadjuvant treatment related adverse events, perioperative and postoperative complications, surgical resection rate, and degree of tumor regression were evaluated. We obtained follow-up data from the patients regular examination or treatment in hospital. If we cant complete it, contacting patients by telephone or WeChat would be adopted by us. The follow-up was not terminated until 3 months after surgery. The objective response rate (ORR) was 84.2% (1619), and no patients had progressive disease (PD). Of the 10 patients who underwent surgery, and approximately 9 (90.0%) had R0 resection. There were no perioperative deaths, and 1 case of pyothorax. The rate of pathological complete remission (pCR) and major pathological response (MPR) was 30.0% (310), and 40.0% (410) respectively. Grade 3-4 adverse reactions comprised 1 case of anemia and 1 case of constipation. Neoadjuvant immunotherapy combined with chemotherapy followed by surgical resection for patients with stage I-IIIA SCLC is effective and safe with a high ORR and MPR rate, as well as a high R0 resection rate and a tolerable toxicity profile. Whether this regimen gives a survival benefit should be confirmed by further follow-up and larger, randomized controlled trials are required to confirm our findings.

Noscapine-Amino Acid Conjugates Suppress the Progression of Cancer Cells.

Lung cancer is the leading cause of cancer deaths globally 1 in 16 people are diagnosed with lung cancer in their lifetime. Microtubules, a critical cytoskeletal assembly, have an essential role in cell division. Interference with the microtubule assembly leads to genetic instability during mitosis and cancer cell death. Currently, available antimitotic drugs such as vincas and taxanes are limited due to side effects such as alopecia, myelosuppression, and drug resistance. Noscapine, an opium alkaloid, is a tubulin-binding agent and can alter the microtubule assembly, causing cancer cell death. Amino acids are fundamental building blocks for protein synthesis, making them essential for the biosynthesis of cancer cells. However, the ability of amino acids in drug transportation has yet to be exploited in developing noscapine analogues as a potential drug candidate for cancer. Hence, in the present study, we have explored the ninth position of noscapine by introducing a hydroxymethylene group using the Blanc reaction and further coupled it with a series of amino acids to construct five target conjugates in good yields. The synthesized amino acid conjugate molecules were biologically evaluated against the A549 lung cancer cell line, among which the noscapine-tryptophan conjugate showed IC

Perioperative outcomes of robotic lobectomy for early-stage non-small cell lung cancer in elderly patients.

Minimally invasive surgery has become the standard for the early-stage non-small cell lung cancer (NSCLC). The appropriateness of the kind of lung resection for the elderly patients is still debated. We retrospectively reviewed patients with older than 75 years who underwent robotic lobectomy between May 2016 to June 2022. We selected 103 patients who met the inclusion criteria of the study. The preoperative cardiorespiratory functional evaluations were collected, and the risk of postoperative complications was calculated according to the Charlson Comorbidity Index, the American College of Surgery surgical risk calculator (ACS-NSQIP), EVAD score, and American Society of Anesthesiology (ASA) score. The patients were divided in two groups according to the presence of postoperative complications. Forty-three patients were female, and 72.8% of the total population were former or active smokers. Thirty-five patients reported postoperative complications. The analysis of the two groups showed that the predicted postoperative forced expiratory volumes in the first second (FEV1) and forced vital capacity (FVC) were significantly lower in patients presenting postoperative complications (p0.04). Moreover, the upstaging rate and the unexpected nodal metastases were higher in the postoperative complication groups. Robotic-assisted lobectomy for early-stage lung cancer is a safe and feasible approach in selected elderly patients. The factors that could predict the complication rate was the predicted postoperative FEV1 and the nodal disease.

Immune checkpoint inhibitors alone or in combination with chemotherapy for treatment of advanced non-small cell lung cancer after first-line platinum-based chemotherapy A propensity score matching analysis.

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of several cancer types. However, data are lacking with regard to the clinical responsiveness of ICIs in patients with advanced non-small cell lung cancer (NSCLC) after standard first-line chemotherapy. Therefore, we aimed to evaluate the clinical efficacy of ICI alone or in combination with chemotherapy for patients with advanced NSCLC after first-line platinum-based chemotherapy. We retrospectively collected patients with confirmed advanced NSCLC who underwent ICI monotherapy or ICI plus chemotherapy after first-line platinum-based chemotherapy between January 2018 and December 2020. A propensity score matching analysis was used to balance baseline characteristics between the two treatment groups. Kaplan-Meier methods and multivariable Cox regressions were used for survival analyses. Among 832 eligible patients, 222 received ICI monotherapy and 610 received ICI plus chemotherapy. The median overall survival (OS) of patients who received ICI plus chemotherapy was 16.0 months compared with 13.1 months in patients who received ICI monotherapy (HR 0.64, 95% CI 0.49-0.85, P 0.002). After 11 propensity score matching, all baseline characteristics were well-balanced between the two treatment groups. Patients who received ICI plus chemotherapy had significantly longer OS than those who received ICI monotherapy (NR vs. 13.1 months, HR 0.50, 95% CI 0.34-0.71, P < 0.001). Meanwhile, the median time to treatment discontinuation was 4.4 months in the ICI-chemo group and 3.5 months in the ICI-mono group (HR 0.72, 95% CI 0.58-0.89, P 0.002). The multivariate analysis indicated that treatment regimen was an independent prognostic factor for OS (HR 0.488, 95% CI 0.337-0.707, P < 0.001). Moreover, a nomogram that integrated both treatment regimens and clinicopathological factors was created for survival prediction. Our study indicated that patients with advanced NSCLC who received ICI plus chemotherapy after first-line platinum-based chemotherapy tended to have longer OS than those who received ICI monotherapy. The multivariate analysis showed that treatment regimen was an independent prognostic factor for OS. Future prospective studies are needed to confirm these findings.

Comparison of the efficacy and safety in the treatment strategies between chemotherapy combined with antiangiogenic and with immune checkpoint inhibitors in advanced non-small cell lung cancer patients with negative PD-L1 expression A network meta-analysis.

In the first-line treatment of advanced non-small cell lung cancer (NSCLC), for those patients with negative PD-L1 expression, which treatment strategy has the better efficacy and safety between chemotherapy combined with antiangiogenic and with immune checkpoint inhibitors (ICIs) is still unclear due to the absence of head-to-head clinical trials. This study aims to answer the question by performing a systematic review and network meta-analysis (NMA). Electronic databases (PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov) were systematically searched accordingly to extract eligible studies from inception to October 2022, as well as the abstracts from the most recent main oncology congresses (American Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO), World Conference on Lung Cancer (WCLC), and European Society for Medical Oncology (ESMO)). Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) of grades 3 to 5 were independently extracted and collected by two reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. We used Cochranes risk of bias tool for randomized controlled trials through RevMan 5.3 to ascertain the quality of the included studies. NMA with a Bayesian random-effects model was performed by R (version 4.0.4). According to the ranking list from OS-NMA, pembrolizumab combined with chemotherapy has the most effective ranking first (surface under the cumulative ranking (SUCRA) 0.809844) (pooled HR 0.65 0.51-0.83). On PFS, the triple combination of nivolumabbevacizumabchemotherapy ranks first (NMA estimate HR 0.35 0.28-0.43). On safety, in combination with chemotherapy, sintilimab has minimal toxicity, followed by pembrolizumabchemo. In advanced NSCLC patients with negative PD-L1 expression, pembrolizumabchemo ranks first in the efficacy of OS and does not apparently increase the incidence of any grade ≥ 3 AE as compared with chemo alone. On PFS, pembrolizumab also has advantages, but for patients with squamous cell carcinoma, camrelizumabchemo seems to be a better choice. httpswww.crd.york.ac.ukprospero, identifier CRD42021231441.

Mutations matter An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer.

About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs. Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA. Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p0.005) and male sex (1-sided p0.039), KRAS G12C mutation with peritoneal metastases (1-sided p0.035), KRAS G12V mutation with female sex (1-sided p0.025) and no surgery for primary tumor (1-sided p0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months HR 0.45 0.21-0.99, p0.04). No difference in survival was observed for mutations at codon 121361 (p0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p0.036) and mOS (p0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p0.031). Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.

Single-cell analyses reveal the therapeutic effects of ATHENA and its mechanism in a rhabdomyosarcoma patient.

Whole-cell tumor vaccines tend to suffer from low immunogenicity. Our previous study showed that irradiated lung cancer cell vaccines in mouse models enhance antitumor efficacy by eliciting an intensive T cells response and improving immunogenicity. Based on these findings, we developed an improved whole-cell tumor vaccine, Autologous Tumor Holo antigEn immuNe Activation (ATHENA). In this study, we report the successful treatment of a 6-year-old male diagnosed with meningeal rhabdomyosarcoma with pulmonary and liver metastases using ATHENA. After 6 cycles of therapy, PETCT showed the therapeutic efficacy of ATHENA. We profiled the immune response by single-cell RNA sequencing (scRNA-seq). Flow cytometry analysis was implemented to validate the status transitions of CD8 In CD8 Such studies not only show that ATHENA therapy may be a promising alternative treatment for tumor patients but provide a novel idea to analyses the mechanisms of rare cases or personalized cancer treatment.

Pyroptosis A new insight of non-small-cell lung cancer treatment.

Non-small cell lung cancer (NSCLC) has become one of the most common malignant tumors. Emerging evidence has shown that tumor resistance to apoptosis by damaging or bypassing apoptotic cell death is a major contributor to poor responses to therapy in patients with NSCLC. Pyroptosis is a new type of cytolytic and inflammatory programmed death distinct from apoptosis. Currently, pyroptosis has been reported to cause a strong inflammatory response and significant tumor suppression. It is considered a promising therapeutic strategy and prognosis for NSCLC. In this review, we summarized the characteristics of pyroptosis from its underlying basis and role in NSCLC, thereby providing the potential of pyroptosis as a therapeutic strategy and highlighting the challenges of activating pyroptosis in NSCLC treatment.

Hyperprogressive disease in non-small cell lung cancer treated with immune checkpoint inhibitor therapy, fact or myth

The therapeutic landscape for patients with non-small cell lung cancer (NSCLC) has dramatically evolved with the development and adoption of immune checkpoint inhibitors (ICI) as front-line therapy. These novel antibodies target the interactions in immunoregulatory pathways, between programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) and B7, resulting in the activation of T cells and cytotoxic response to induce an immunologic response. ICIs have demonstrated significant survival benefits and sustained responses in the treatment of NSCLC leading to the long-term survival of up to 5 year. One unusual response to ICI is a phenomenon termed Hyperprogressive Disease (HYD), which occurs in a subset of patients for whom ICI therapy can induce rapid disease growth, which ultimately leads to poorer outcomes with an incidence rate ranging from 5 to 37% in NSCLC patients. Prior reviews demonstrated that HYD can be defined by rapid tumor progression, deterioration of patients symptoms or new onset of disease. The mechanism of HYD could be related to genomic and tumor microenvironment changes and altered immune response. It will be important to establish a common definition of HYD for future research and clinical care.

Improvements in survival for patients with stage IV adenocarcinoma in the lung, diagnosed between 2010 - 2020 - A population-based registry study from Norway.

We investigated how the prognosis for Norwegian patients with stage IV, adenocarcinoma (NSCLC) has developed during the last decade, to observe if increased survival coincides with the introduction of immunotherapy at a population level. Incidence data from the Cancer Registry of Norway are virtually complete and includes information about histological subtypes and biomarkers. The data was used to analyze median and relative survival for females and males diagnosed with stage IV NSCLC, divided by histological subgroups and age-groups. During 2010 - 2020, 14472 patients were diagnosed with lung cancer in stage IV, in Norway. Among them 6351 patients (43%) were classified with adenocarcinoma. The median survival has increased for both sexes, but the largest increase is seen in females. From 2010 to 2020, median survival for females in the 0-69 group increased from 6.7 months to 12 months and from 3.7 months to 10 months for the 70 age group. For the equivalent male age groups, we see an increase from 6.1 months to 7.7 months for the 0-69 group, and an increase from 3.8 months to 4.5 months for the 70 group. When excluding patients with EGFRALK mutations from the survival analysis, the groups continue to display an increased survival from 2010 to 2020, although modest in the male 70 group. The 1-year relative survival (RS) has increased for both sexes, from 32.4% to 51.2 in females and 25.4% to 44.5% in males. When EGFRALK positive patients were excluded from the analysis 1-year RS in females rose from 32.4% to 47.4% and for males from 25.4% to 41.8%. A real-world patient population of stage IV, NSCLC adenocarcinoma have had a clinically meaningful increase in both median and relative survival from 2010 - 2020. The steepest survival increase has taken place after 2016, the time point where immunotherapy was implemented as a treatment option for the stage IV, adenocarcinoma population not harboring targetable mutations (EGFRALK).

Pathological complete remission in ALK-positive lung cancer patient after multiple lines of conversion therapy.

Traditional therapeutic approaches for the treatment of advanced non-small-cell lung cancer (NSCLC) are based on chemotherapy. However, the discovery and understanding of oncogenic driver alterations has led to the development of targeted therapies that have substantially improved patient outcomes. Still, to date, there have been no reports of patients with advanced anaplastic lymphoma kinase (ALK)-positive lung cancer achieving clinical complete response (cCR) in the systemic lesion and pathological complete remission (pCR) in primary lung lesion after multiple lines of conversion therapy. In this case, a 55-year-old man was diagnosed with ALK-positive, stage IV lung adenocarcinoma using immunohistochemistry and next generation sequencing (NGS) tests. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, were used respectively as first-line, second-line, and third-line therapy. The patient received treatment with crizotinib and achieved partial response (PR), but 5 months later the efficacy was evaluated as progressive disease (PD). Ceritinib was used as the second-line treatment, but the disease progressed 6 months later. Alectinib was used as the third-line treatment, but the efficacy was evaluated as PD. From April 2019 to November 2019, the patient received 4 cycles of induction chemotherapy with pemetrexedcarboplatinbevacizumab and then switched to pemetrexedbevacizumab as the fourth-line treatment, and received the fifth line treatment, cetuximabpaclitaxel liposomenedaplatin, for 1 cycle, but the disease still progressed. Then the patient received the sixth line of treatment, camrelizumablorlatinib, for 9 antitumor cycles, resulting in PR. The patient underwent surgery followed by maintenance treatment with lorlatinib and achieved cCR. To our knowledge, this is the first documented case of cCR in a patient with ALK-positive advanced lung adenocarcinoma treated with multiple lines of therapy followed by surgical treatment. This case reveals the possible survival benefit of immunotherapy after multiple line treatment in ALK-positive advanced lung adenocarcinoma, indicating that it is possible find new therapeutic targets based on NGS molecular detection and provide precise therapeutic strategies for clinical practice when drug resistance or progression occurs in cancer therapy.

Surface guided 3DCRT in deep-inspiration breath-hold for left sided breast cancer radiotherapy implementation and first clinical experience in Iran.

The aim of the study is to evaluate the overall accuracy of the surface-guided radiotherapy (SGRT) workflow through a comprehensive commissioning and quality assurance procedures and assess the potential benefits of deep-inspiration breath-hold (DIBH) radiotherapy as a cardiac and lung dose reduction approach for left-sided breast cancer irradiation. Accuracy and reproducibility of the optical surface scanner used for DIBH treatment were evaluated using different phantoms. Patient positioning accuracy and reproducibility of DIBH treatment were evaluated. Twenty patients were studied for treatment plan quality in target dose coverage and healthy organ sparing for the two different treatment techniques. Reproducibility tests for the surface scanner showed good stability within 1 mm in all directions. The maximum position variation between applied shifts on the couch and the scanner measured offsets is 1 mm in all directions. The clinical study of 200 fractions showed good agreement between the surface scanner and portal imaging with the isocenter position deviation of less than 3 mm in each lateral, longitudinal, and vertical direction. The standard deviation of the DIBH level showed a value of < 2 mm during all evaluated DIBHs. Compared to the free breathing (FB) technique, DIBH showed significant reduction of 48% for heart mean dose, 43% for heart V25, and 20% for ipsilateral lung V20. Surface-guided radiotherapy can be regarded as an accurate tool for patient positioning and monitoring in breast radiotherapy. DIBH treatment are considered to be effective techniques in heart and ipsilateral lung dose reductions for left breast radiotherapy.

Setup accuracy and dose attenuation of a wooden immobilization system for lung stereotactic body radiotherapy.

We evaluated the setup error and dose absorption of an immobilization system with a shell and wooden baseplate (SW) for lung stereotactic body radiotherapy (SBRT). Setup errors in 109 patients immobilized with an SW or BodyFix system (BF) were compared. Dose attenuation rates of materials for baseplates were measured with an ion-chamber. Ionization measurements were performed from 90° to 180° gantry angle in 10° increments, with the ball water equivalent phantom placed at the center of the wood and carbon baseplates whose effects on dose distribution were compared using an electron portal imaging device. The ratio for the anterior-posterior, cranial-caudal, and right-left of the cases within 3-mm registered shifts in interfractional setup error were 90.9%, 89.2%, and 97.4% for the SW, and 93.2%, 91.6%, and 98.0% for the BF, respectively. For intrafractional setup error, 98.3%, 97.4%, and 99.1% for the SW and 96.6%, 95.8%, and 98.7% for the BF were within 3-mm registered shifts, respectively. In the center position, the average (minimummaximum) dose attenuation rates from 90° to 180° for the wooden and carbon baseplates were 0.5 (0.12.8)% and 1.0 (-0.110.1)% with 6 MV, respectively. The gamma passing rates of 2%2 mm for the wooden and carbon baseplates were 99.7% and 98.3% (p < 0.01). The immobilization system with an SW is effective for lung SBRT since it is comparable to the BF in setup accuracy. Moreover, the wooden baseplate had lower radiation attenuation rates and affected the dose distribution less than the carbon baseplate.

Dynamic conformal arc radiotherapy for locally advanced lung cancer a comparison with static-beam conformal radiotherapy.

This study investigated whether the dose distribution of lung cancer can be improved by dynamic arc conformal radiotherapy (dynamic CRT) compared with static multiple-beam radiotherapy (static CRT). A dummy study of static CRT and dynamic CRT was performed, designed to meet the predetermined dose constraints. A dose of 60 Gy in 30 fractions was administered using two dose prescription methods dose prescribed to the isocenter (IC prescription), and dose prescribed to > 50% of the planning target volume (D50 prescription). Dose-volume parameters were compared between the plans. Among 20 patients with locally advanced lung cancer, dose conformity was significantly better with dynamic CRT than static CRT (median conformity index 1.3 The dynamic CRT technique showed better target coverage and lower doses to the spinal cord in exchange for increased low-dose lung area, compared with static CRT. Dynamic CRT with D50 prescription instead of prescription to the isocenter has excellent dose distribution profiles without compromising doses to organs at risk for lung cancer at favorable locations.

Differentiating Immune-Related Adrenal Insufficiency From Low Cardiac Output Syndrome A Case Report.

We report a case of a 58-year-old woman with secondary adrenocortical insufficiency due to adrenocorticotropic hormone (ACTH) deficiency after pembrolizumab treatment that required differentiation from low cardiac output syndrome. The patient had chronic heart failure due to radiation cardiomyopathy and underwent implantation of cardiac resynchronization therapy defibrillator (CRT-D). One year ago, she was diagnosed with squamous cell lung cancer and started combination therapy with carboplatin, paclitaxel, and pembrolizumab. She was hospitalized for anorexia, nausea, and hypotension. A diagnosis of secondary hypoadrenocorticism due to isolated ACTH deficiency was made, and from the course of the disease, it was diagnosed as a side effect of immune checkpoint inhibitors (ICIs). As the indications for ICIs continue to expand, it is necessary to understand the screening and management of their side effects.

Pembrolizumab-Induced Lichen Planus in a Patient With Non-Small-Cell Lung Carcinoma (NSCLC) That Correlates to Therapeutic Response.

Immune checkpoint inhibitors are increasingly being used in the treatment of various solid organ and hematologic malignancies. Dermatologic toxicities associated with programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) therapy have been widely reported in the literature. Lichen planus is an inflammatory disease frequently seen in areas of the skin and oral mucous membrane lining. This autoimmune disorder is T-cell mediated with multiple contributing factors like emotional stress, genetic predisposition, isotopic response, or drugs. With increasing use of immunotherapy, early recognition and prompt treatment of associated adverse events are critical to ensure patient safety. Cutaneous toxicities are among the most commonly observed adverse events with this class of drugs. Here, we report a case of lichen planus in a 66-year-old male patient receiving pembrolizumab for stage IV non-small cell lung cancer (NSCLC). He was diagnosed 56 months ago with advanced lung cancer with brain metastasis. He has received 62 cycles of pembrolizumab and continues to be in complete clinical and radiographic remission. Pembrolizumab is a drug that helps immune cells in killing cancer cells by binding to the PD-1 protein. This case highlights the potential cutaneous side effects that may result in a patient with pembrolizumab and the fact that it can serve as a clinical biomarker and show therapeutic effectiveness of the treatment.

Identification of glycolysis genes signature for predicting prognosis in malignant pleural mesothelioma by bioinformatics and machine learning.

Glycolysis-related genes as prognostic markers in malignant pleural mesothelioma (MPM) is still unclear. We hope to explore the relationship between glycolytic pathway genes and MPM prognosis by constructing prognostic risk models through bioinformatics and machine learning. The authors screened the dataset GSE51024 from the GEO database for Gene set enrichment analysis (GSEA), and performed differentially expressed genes (DEGs) of glycolytic pathway gene sets. Then, Cox regression analysis was used to identify prognosis-associated glycolytic genes and establish a risk model. Further, the validity of the risk model was evaluated using the dataset GSE67487 in GEO database, and finally, a specimen classification model was constructed by support vector machine (SVM) and random forest (RF) to further screen prognostic genes. By DEGs, five glycolysis-related pathway gene sets (17 glycolytic genes) were identified to be highly expressed in MPM tumor tissues. Also 11 genes associated with MPM prognosis were identified in TCGA-MPM patients, and 6 (COL5A1, ALDH2, KIF20A, ADH1B, SDC1, VCAN) of them were included by Multi-factor COX analysis to construct a prognostic risk model for MPM patients, with Area under the ROC curve (AUC) was 0.830. Further, dataset GSE67487 also confirmed the validity of the risk model, with a significant difference in overall survival (OS) between the low-risk and high-risk groups (P < 0.05). The final machine learning screened the five prognostic genes with the highest risk of MPM, in order of importance, were ALDH2, KIF20A, COL5A1, ADH1B and SDC1. A risk model based on six glycolytic genes (ALDH2, KIF20A, COL5A1, ADH1B, SDC1, VCAN) can effectively predict the prognosis of MPM patients.

Molecular bases of morphologically diffused tumors across multiple cancer types.

Gastric cancer has two distinct subtypes the diffuse (DGC) and the intestinal (IGC) subtypes. Morphologically, the former each consists of numerous scattered tiny tumors while the latter each has one or a few solid biomasses. The former tends to be more aggressive and takes place in younger patients than the latter. While these have long been documented, little is known about the underlying causes. Our hypothesis is that the level of sialic acid (SA) accumulation on the cancer cell surfaces is a key reason for the observed differences. Our transcriptomic data-based analyses provide evidence that (i) DGCs tend to deploy more SAs on cancer cell surfaces than IGCs (ii) this gives rise to considerably stronger cell-cell electrostatic repulsion in DGCs due to the negative charge that each SA carries and (iii) such repulsion drives stronger cell protrusion and metastasis. Similar observations as well as our transcriptomic data-based predictions hold for multiple other cancer types, namely breast, lung, prostate plus liver and thyroid cancers, each known to have diffuse-like vs. non-diffused subtypes as well as more aggressive behaviors like DGCs vs. IGCs. Hence, we speculate that the discovery presented here applies not only to gastric cancer but multiple and even potentially all cancer types having diffuse-like and non-diffused subtypes.

Feiyanning formula modulates the molecular mechanism of osimertinib resistance in lung cancer by regulating the Wntβ-catenin pathway.

Feiyanning Formula (FYN), a Chinese herbal formula derived from summarized clinical experience, is proven to have anti-tumor effects in lung cancer patients. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), can improve progression-free survival and overall survival of patients but drug resistance is inevitable. The current study evaluated the effects of FYN in osimertinib-resistant HCC827OR and PC9OR cells. FYN preferentially inhibited the proliferation and migration of HCC827OR and PC9OR cells. Moreover, FYN and osimertinib exhibited synergistic inhibitory effects on proliferation and migration. Real-time qPCR (RT-qPCR) and western blotting results indicated that FYN downregulated gene and protein levels of GSK3β and SRFS1, which are enriched in the Wntβ-catenin pathway. Besides, FYN inhibited tumor growth and exhibited synergistic effects with osimertinib

Carbon Nanotubes as Carriers in Drug Delivery for Non-Small Cell Lung Cancer, Mechanistic Analysis of Their Carcinogenic Potential, Safety Profiling and Identification of Biomarkers.

Non-small cell lung cancer (NSCLC) is a global burden leading to millions of deaths worldwide every year. Nanomedicine refers to the use of materials at the nanoscale for drug delivery and subsequent therapeutic approaches in cancer. Carbon nanotubes (CNTs) are widely used as nanocarriers for therapeutic molecules such as plasmids, siRNAs, antisense agents, aptamers and molecules related to the immunotherapy for several cancers. They are usually functionalized and loaded with standard drug molecules to improve their therapeutic efficiency. Functionalization and drug loading possibly decrease the genotoxic and carcinogenic potential of CNTs. In addition, the targeted cytotoxic properties of the drug improve and undesired toxicity decreases after drug loading andor conjugation with proteins, including antibodies. For intended drug delivery, a lysosomal pH of 5.5 is more suitable and effective for the slow and extended release of cytotoxic drugs than a physiological of pH 7.4. Remarkably, CNTs possess intrinsic antitumor properties and are usually internalized by endocytosis. After being internalized, several mechanisms are involved in the therapeutic and carcinogenic effects of CNTs. They are generally safe for therapy, and their toxicity profile remains dependent on their physicochemical properties. Moreover, the dose, route, duration of exposure, surface properties and degradative potential determine the toxicity outcomes of CNTs locally or systemically. In summary, the use of CNTs in drug delivery and NSCLC therapy, as well as their genotoxic and carcinogenic potential and the possible mechanisms, has been discussed in this review. The therapeutic index is generally high for NSCLC cells treated with drug-loaded CNTs therefore, they are effective carriers in implementing targeted therapy for NSCLC.

Network Pharmacology and Molecular Docking Analysis on Molecular Targets and Mechanisms of Aidi Injection Treating of Nonsmall Cell Lung Cancer.

Aidi injection (ADI) is a compound preparation injection of Chinese herbs used to treat patients of nonsmall cell lung cancer (NSCLC) in China. This study aimed to reveal the mechanism of ADI in the treatment of NSCLC by using network pharmacology and molecular docking. The related targets of ADI and NSCLC were obtained from multiple databases. The network diagram of disease-drug-components-targets (DDCT) and protein-protein interaction (PPI) was constructed to screen key targets. Then, the key targets and main signaling pathways were screened by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Next, in order to validate the results of network pharmacology, expression analysis and survival analysis of key genes were performed. Finally, we carried out the technology of molecular docking to further validate the accuracy of the above results. A total of 207 targets of ADI and 5282 targets of NSCLC were obtained finally. Through the construction of DDCT and PPI network diagrams, 28 key targets were finally obtained. The results of the KEGG enrichment analysis indicated that multiple signaling pathways were associated with NSCLC, which included the MAPK signaling pathway, the IL-17 signaling pathway, and the PI3KAKT signaling pathway. The key genes in the signaling pathway mainly include TP53, CASP3, MMP9, AKT1, PTGS2, and MAPK1. The results of differently expressed analysis of key genes showed that TP53, CASP3, MMP9, AKT1, PTGS2, and MAPK1 had statistical differences in lung squamous cell carcinoma (LUSC) compared with normal tissue ( This study revealed the potential mechanism of ADI in the treatment of NSCLC with multipathways and multitargets and provided a scientific basis for the in-depth study of ADI in the treatment of NSCLC.

Inhibitory role of puerarin on the A549 lung cancer cell line.

Although more and more drugs had been proved to be effective in controlling tumor cells, lung cancer was still the leading cause of cancer-related deaths all over the world. This study aimed to investigate the effect and mechanism of puerarin on the invasion and metastasis of A549 lung cancer cell line. A medium containing puerarin was prepared according to the gradient concentration, and 10, 20, and 40 µmolL were selected as the experimental group (low, medium, and high concentration groups, respectively) according to the cytotoxicity experiment. Meanwhile, 0 µmolL was used as the control group. Following administration, metastasis-related indexes were detected by the cell scratch test, cell migration test, gene difference detection, and western blotting. 24 hours after administration, the cell scratch and Transwell showed that the migration ability of A549 cells decreased with the increasing puerarin concentration. The polymerase chain reaction (PCR) and western blotting results demonstrated that the expression of the cell invasion and metastasis-related factor, matrix metallopeptidase 9 (MMP9), was negatively correlated with drug concentration. Further investigation demonstrated that the phosphorylation of extracellular signal-regulated kinase (ERK) was also inhibited. Puerarin can inhibit the expression of invasion and metastasis-related factors by inhibiting the phosphorylation of ERK.

Immunotherapy for combined pulmonary fibrosis and emphysema with advanced lung cancer two case reports and a concise review.

It is unclear whether immunotherapy for combined pulmonary fibrosis and emphysema (CPFE) with advanced lung cancer (CPFE-LC) is safe. We reported on two cases of primary CPFE-LC, where the initial focus was on the lung cancer and not on the CPFE. The two patients underwent surgical resections of the lung cancer, and were placed on a combination of immunotherapy and chemotherapy after progressive lung cancer was observed. One patient showed a worsening of respiratory symptoms with increased consolidation and ground-glass shadows, and an increased extent of honeycombing and other fibrosis on high-resolution computed tomography (HRCT) (>10%). He suffered acute exacerbations of interstitial lung disease (AE-ILD) after successful treatment with radiotherapy and follow-up immunotherapy and developed a progressive-fibrosing phenotype. The other patient had a tumor that had shrunk with no progression of the CPFE fibrosis. The two patients died of AE-ILD and tumor invasion, respectively. Immunotherapy combined with comprehensive therapy may provide benefits for patients with CPFE-LC to a certain extent. However, immune-related adverse effects may limit the use of immunotherapy in CPFE-LC, and the choice of immunotherapy should be cautious in CPFE-LC with a history of radiation pneumonitis or AE-ILD.

Prognostic factors of survival in patients with non-small cell lung cancer a competing risk model using the SEER database.

To explore the prognostic factors of survival in non-small cell lung cancer (NSCLC) patients using the competing risk analysis. This was a retrospective cohort study. NSCLC patients with complete data were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Outcomes were censored, cancer-specific mortality in NSCLC, and other-cause mortality. Grays test was used in univariable analysis, and a multivariable Fine-Gray competing risk model with backward elimination was used to explore the prognostic factors of survival. The screened variables were incorporated into a random survival forest (RSF) model for the prediction of 1-, 3-, and 5-year survival in patients with NSCLC. Receiver operator characteristic (ROC) curves, calibration curves, the value of area under the curve (AUC), and decision curve analysis (DCA) were used to evaluate the performance. Totally 1,251 eligible patients were included, 678 (54.20%) patients were cancer-specific mortality, and 128 (10.23%) patients were other-cause mortality. The median follow-up time was 26 months. Age, primary site, N stage, M stage, surgery type, tumor size, and lymph nodes (LNs) count were included in the multivariable Fine-Gray model for further analysis (P<0.05). The six most important features (surgery type, tumor size, M stage, LNs count, N stage, and primary site) were included in the competing risk analysis using the RSF model. The value of AUC for predicting 1-, 3-, and 5-year survival in the testing set were 0.796, 0.804, and 0.792, respectively. Calibration curves were well-fitted. DCA curves showed that the RSF model had similar or greater clinical net benefits in survival compared with the 8th edition the American Joint Committee on Cancer (AJCC) staging. The good performance of the RSF model under different surgery types, T, N, and M stages. We conducted a competing risk analysis using the RSF model for predicting the 1-, 3-, and 5-year survival of NSCLC. We generated a web calculator (httpsgithub.comYingChen19Prognostic-factors-of-long-term-survival-of-non-small-cell-lung-cancer), which could provide a convenient assessment and could help improve the prognosis and survival of NSCLC.

Comparison of bronchial methylene blue staining and modified inflation-deflation method in identifying the intersegmental plane during lung segmentectomy.

Identification of the intersegmental plane (ISP) is the critical step in lung segmentectomy because of the complicated anatomic variations. Bronchial methylene blue staining was developed by our team in 2015 and is now commonly used at our center, it could rapidly and accurately identify the ISP. In this study, we aimed to compare bronchial methylene blue staining with the modified inflation-deflation method in terms of their perioperative characteristics and to present our experience of the methylene blue method. From June 2020 to September 2021, the data of 112 patients with pulmonary ground-glass nodules who underwent segmentectomy by video-assisted thoracoscopic surgery were retrospectively reviewed. Sixty-two patients underwent bronchial methylene blue staining, and 50 patients underwent the modified inflation-deflation method. Both methods could accurately identify the ISP. The time taken to clearly display the ISP (82.94±28.08 Compared with the modified inflation-deflation method, the bronchial methylene blue staining method can quickly display the ISP and shorten the surgical duration. This method is safe and feasible, can be widely applied during thoracoscopic anatomic segmentectomy.

Prediction of

BRAF inhibitors have been approved for the treatment of melanoma, non-small cell lung cancer, and colon cancer. Real-time polymerase chain reaction or next-generation sequencing were clinically used for We adopted a penalized logistic regression for the The area under the curve of the receiver operating characteristic curve on the test set was 0.98 in thyroid carcinoma, 0.90 in colon adenocarcinoma, and 0.85 in cutaneous melanoma. The area under the precision-recall of the test set was 0.98 in thyroid carcinoma, 0.71 in colon adenocarcinoma, and 0.65 in cutaneous melanoma. Our penalized logistic regression model can predict

Curcumin suppresses lung cancer progression via circRUNX1 mediated miR-760RAB3D axis.

Curcumin is a natural chemical component that has an anticancer effect. The aim of this study was to explore the potential molecular mechanism of curcumin regulating lung cancer (LC) progression. The expression of circRUNX1, miR-760 and Ras-like GTPase 3D (RAB3D) was detected by qRT-PCR. Cell proliferation were determined by CCK8 assay and colony formation assay. Cell apoptosis, migration and invasion were detected by flow cytometry, wound healing and transwell assays. Protein levels were examined by western blot (WB) analysis. RNA interaction was confirmed by dual-luciferase reporter assay. LC xenograft tumors were constructed using BALBc nude mice. CircRUNX1 was upregulated in LC and its expression could be inhibited by curcumin. Curcumin reduced LC cell proliferation, metastasis, and accelerate apoptosis, while circRUNX1 overexpression reversed these effects. MiR-760 was confirmed to be a target of circRUNX1, which could reverse the effects of circRUNX1 on curcumin-treated LC cell functions. RAB3D was a target of miR-760, and its knockdown reversed the promotion effect of miR-760 inhibitor on the progression of curcumin-treated LC cells. Curcumin suppressed LC progression via circRUNX1miR-760RAB3D axis.

Clinical characteristics of adrenal insufficiency induced by pembrolizumab in non-small-cell lung cancer.

Immune checkpoint inhibitors have significantly improved the clinical outcomes of many cancer types, but they induce a range of immune-related adverse events (irAEs). Although adrenal insufficiency (AI) is a rare irAE, it can lead to serious consequences. This study aimed to determine the clinical features of patients with advanced non-small-cell lung cancer (NSCLC) who developed AI following pembrolizumab treatment. We retrospectively reviewed and analyzed the clinical data of all patients with NSCLC treated with pembrolizumab at Juntendo University Hospital from February 2017 to December 2020. The diagnosis of AI was established based on the Endocrine Emergency Guidance for the acute management of endocrine complications of checkpoint inhibitor therapy in the UK and the clinical practice guidelines of the Japan Endocrine Society. AI was clinically suspected in 59 out of 186 patients treated with pembrolizumab, and 10 (5.4%) cases were confirmed. The symptoms included hyponatremia (n 9), fatigue (n 8), and loss of appetite (n 6). All patients had low adrenocorticotropic hormone (ACTH) levels, and five patients were diagnosed with isolated ACTH deficiency. All patients completely recovered with corticosteroid replacement. The median time to onset of AI was 8.0 (range 3.8-15.2) months. The median progression-free survival in these patients was 22.4 (95% confidence interval 11.2-not reached) months. The incidence of AI among patients treated with pembrolizumab is more frequent than previously reported. In addition, secondary AI, especially isolated ACTH deficiency, is a major form of AI induced by pembrolizumab.

Co-development of an evidence-based personalised smoking cessation intervention for use in a lung cancer screening context.

Optimising smoking cessation services within a low radiation-dose computed tomography (LDCT) lung cancer screening programme has the potential to improve cost-effectiveness and overall efficacy of the programme. However, evidence on the optimal design and integration of cessation services is limited. We co-developed a personalised cessation and relapse prevention intervention incorporating medical imaging collected during lung cancer screening. The intervention is designed to initiate and support quit attempts among smokers attending screening as part of the Yorkshire Enhanced Stop Smoking study (YESS ISRCTN63825779). Patients and public were involved in the development of an intervention designed to meet the needs of the target population. An iterative co-development approach was used. Eight members of the public with a history of smoking completed an online survey to inform the visual presentation of risk information in subsequent focus groups for acceptability testing. Three focus groups (n 13) were conducted in deprived areas of Yorkshire and South Wales with members of the public who were current smokers or recent quitters (within the last year). Exemplar images of the heart and lungs acquired by LDCT, absolute and relative lung cancer risk, and lung age were shown. Data were analysed thematically, and discussed in stakeholder workshops. Draft versions of the intervention were developed, underpinned by the Extended Parallel Processing Model to increase self-efficacy and response-efficacy. The intervention was further refined in a second stakeholder workshop with a patient panel. Individual LDCT scan images of the lungs and heart, in conjunction with artistic impressions to facilitate interpretation, were considered by public participants to be most impactful in prompting cessation. Public participants thought it important to have a trained practitioner guiding them through the intervention and emphasising the short-term benefits of quitting. Presentation of absolute and relative risk of lung cancer and lung age were considered highly demotivating due to reinforcement of fatalistic beliefs. An acceptable personalised intervention booklet utilising LDCT scan images has been developed for delivery by a trained smoking cessation practitioner. Our findings highlight the benefit of co-development during intervention development and the need for further evaluation of effectiveness. Supporting patients to stop smoking when they attend lung cancer screening will improve the overall benefit and value for money of the service. This study developed a booklet containing pictures of a person’s own lungs and heart taken during a lung cancer screening scan. The booklet shows areas of damage to the heart and lungs caused by smoking, delivered alongside positive messages to build confidence to stop smoking and let patients know about the benefits of stopping smoking. To develop the booklet, we worked with members of public who currently or used to smoke. Eight members of public completed a survey asking about the best ways to present information about risk. Thirteen members of the public took part in focus groups to co-develop the booklet. One workshop with academic and healthcare professionals and one workshop with a public involvement panel were held to develop and finalise the booklet. Members of the public said they wanted information about the short-term benefits of quitting smoking, and that coloured drawings next to the scan picture would help them to understand what the scan picture meant. Having someone specially trained to guide them through the booklet was considered important. Being told about their risk for lung cancer in the future was off-putting and might discourage a quit attempt. We have co-developed a booklet to support people to quit smoking when they go for lung cancer screening. The booklet is currently being tested to see whether it can support people to quit smoking.

Identification of serum MiRNAs as candidate biomarkers for non-small cell lung cancer diagnosis.

Lung cancer is one of the most common solid tumors worldwide and the leading cause of cancer-associated death. Non-small cell lung cancer (NSCLC) is accounts for approximately 85% of all the lung cancers and lung squamous carcinoma (SCC) and adenocarcinoma (ADC) are the main subtypes of NSCLC. Early diagnose using serum biomarkers could improve the overall survival of patients. In this study, we aimed to identify miRNAs from serum with clinical utility in the diagnosis of NSCLC. Ten patients with SCC, ten patients with ADC and five noncancerous individuals were enrolled in the screening cohort. miRNA expression levels in serum were measured by microarray analysis. Candidate miRNAs were validated by real-time quantitative polymerase chain reaction analysis in a validation cohort of 78 NSCLC patients and 44 noncancerous individuals. Receiver operating characteristic curves were used to assess the diagnostic performance of serum miRNAs for NSCLC. Logistic regression was used to evaluate the diagnostic value of the combination of markers. Six candidate miRNAs were differentially expressed between NSCLC patients and noncancerous individuals in the screening set (fold change > 2, p < 0.05). Among them, expression levels of miR-3149 and miR-4769.3p were confirmed to be significantly increased in tumor serum in the validation set. The area under the curve values of miR-3149 and miR-4769.3p in distinguishing NSCLC patients from noncancerous controls were 0.830 and 0.735, respectively. When combined with tumor markers CEA and Cyfra21-1, the joint diagnostic model increased the area under the curve to 0.898. Serum miRNAs miR-3149 and miR-4769.3p were up-regulated in NSCLC and may be potential biomarkers for early diagnosis of lung cancer.

Acetyltransferase NAT10 regulates the Wntβ-catenin signaling pathway to promote colorectal cancer progression via ac

N The clinical significance of NAT10 was explored based on the TCGA and GEO data sets and the 80 CRC patients cohort of our hospital. qRT-PCR, dot blot, WB, and IHC were performed to detect the level of NAT10 and ac NAT10 promotes the CRC progression through the NAT10KIF23GSK-3ββ-catenin axis and its expression is mediated by GSK-3β which forms a feedback loop. Our findings provide a potential prognosis or therapeutic target for CRC and remodelin deserves more attention.

Oncogenic KRAS alters splicing factor phosphorylation and alternative splicing in lung cancer.

Alternative RNA splicing is widely dysregulated in cancers including lung adenocarcinoma, where aberrant splicing events are frequently caused by somatic splice site mutations or somatic mutations of splicing factor genes. However, the majority of mis-splicing in cancers is unexplained by these known mechanisms. We hypothesize that the aberrant Ras signaling characteristic of lung cancers plays a role in promoting the alternative splicing observed in tumors. We recently performed transcriptome and proteome profiling of human lung epithelial cells ectopically expressing oncogenic KRAS and another cancer-associated Ras GTPase, RIT1. Unbiased analysis of phosphoproteome data identified altered splicing factor phosphorylation in KRAS-mutant cells, so we performed differential alternative splicing analysis using rMATS to identify significantly altered isoforms in lung epithelial cells. To determine whether these isoforms were uniquely regulated by KRAS, we performed a large-scale splicing screen in which we generated over 300 unique RNA sequencing profiles of isogenic A549 lung adenocarcinoma cells ectopically expressing 75 different wild-type or variant alleles across 28 genes implicated in lung cancer. Mass spectrometry data showed widespread downregulation of splicing factor phosphorylation in lung epithelial cells expressing mutant KRAS compared to cells expressing wild-type KRAS. We observed alternative splicing in the same cells, with 2196 and 2416 skipped exon events in KRAS Proteomic and transcriptomic profiling of lung epithelial cells uncovered splicing factor phosphorylation and mRNA splicing events regulated by oncogenic KRAS. These data suggest that in addition to widespread transcriptional changes, the Ras signaling pathway can promote post-transcriptional splicing changes that may contribute to oncogenic processes.

Rationale and protocol design of a phase II study of first-line osimertinib treatment for patients with poor performance status and EGFR mutation-positive non-small cell lung cancer (OPENTORG2040).

Cancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status however, no evidence exists of the drugs effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status. The OPENTORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed. Our study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated. Japan Registry of Clinical Trials jRCTs041200100 (registration date February 12, 2021).

A hierarchical GAN method with ensemble CNN for accurate nodule detection.

Lung cancer can evolve into one of the deadliest diseases whose early detection is one of the major survival factors. However, early detection is a challenging task due to the unclear structure, shape, and the size of the nodule. Hence, radiologists need automated tools to make accurate decisions. This paper develops a new approach based on generative adversarial network (GAN) architecture for nodule detection to propose a two-step GAN model containing lung segmentation and nodule localization. The first generator comprises a U-net network, while the second utilizes a mask R-CNN. The task of lung segmentation involves a two-class classification of the pixels in each image, categorizing lung pixels in one class and the rest in the other. The classifier becomes imbalanced due to numerous non-lung pixels, decreasing the model performance. This problem is resolved by using the focal loss function for training the generator. Moreover, a new loss function is developed as the nodule localization generator to enhance the diagnosis quality. Discriminator nets are implemented in GANs as an ensemble of convolutional neural networks (ECNNs), using multiple CNNs and connecting their outputs to make a final decision. Several experiments are designed to assess the model on the well-known LUNA dataset. The experiments indicate that the proposed model can reduce the error of the state-of-the-art models on the IoU criterion by about 35 and 16% for lung segmentation and nodule localization, respectively. Unlike recent studies, the proposed method considers two loss functions for generators, further promoting the goal achievements. Moreover, the network of discriminators is regarded as ECNNs, generating rich features for decisions.

Pulmonary nodule detection based on IR-UNet .

Lung cancer is one of the cancers with the highest incidence rate and death rate worldwide. An initial lesion of the lung appears as nodules in the lungs on CT images, and early and timely diagnosis can greatly improve the survival rate. Automatic detection of lung nodules can greatly improve work efficiency and accuracy rate. However, owing to the three-dimensional complex structure of lung CT data and the variation in shapes and appearances of lung nodules, high-precision detection of pulmonary nodules remains challenging. To address the problem, a new 3D framework IR-UNet is proposed for automatic pulmonary nodule detection in this paper. First, the Inception Net and ResNet are combined as the building blocks. Second, the squeeze-and-excitation structure is introduced into building blocks for better feature extraction. Finally, two short skip pathways are redesigned based on the U-shaped network. To verify the effectiveness of our algorithm, systematic experiments are conducted on the LUNA16 dataset. Experimental results show that the proposed network performs better than several existing lung nodule detection methods with the sensitivity of 1 FPscan, 4 FPsscan, and 8 FPsscan being 90.13%, 94.77%, and 95.78%, respectively. Therefore, it comes to the conclusion that our proposed model has achieved superior performance for lung nodule detection.

Amentoflavone and methyl hesperidin, novel lead molecules targeting epitranscriptomic modulator in acute myeloid leukemia in silico drug screening and molecular dynamics simulation approach.

M Targeting METTL3 has opened a new window in the development of novel inhibitorsdrugs. In this study, commercially available natural compounds were randomly screened to avoid the bias of screening small molecules on the basis of structural similarity. From 810 compounds that were screened, 80 commercially available compounds were showing better score when compared with the existing substratesubstrate-analogue and the inhibitor bound crystal structures in terms of docking score and binding energy calculation. Among this pool of compounds, the best seven small molecules have been selected and further validated by different computational tools like binding energy calculation, molecular dynamics simulation, ADME analysis, and toxicity prediction. The novel hits found in this study can function as lead compounds which can be developed into inhibitors as well as drugs, specific against METTL3.

Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer.

Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibiting lncRNA (TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

Longitudinal multi-omics analyses of the gut-liver axis reveals metabolic dysregulation in hepatitis C infection and cirrhosis.

The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut-liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome however, how these changes impact metabolism across the gut-liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut-liver axis of patients with HCV across a fibrosis severity gradient before (n 29) and 6 months after (n 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus-mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus-mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii, which correlated with liver disease severity markers. These results develop our understanding of the gut-liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies.

Human genetic diversity alters off-target outcomes of therapeutic gene editing.

CRISPR gene editing holds great promise to modify DNA sequences in somatic cells to treat disease. However, standard computational and biochemical methods to predict off-target potential focus on reference genomes. We developed an efficient tool called CRISPRme that considers single-nucleotide polymorphism (SNP) and indel genetic variants to nominate and prioritize off-target sites. We tested the software with a BCL11A enhancer targeting guide RNA (gRNA) showing promise in clinical trials for sickle cell disease and β-thalassemia and found that the top candidate off-target is produced by an allele common in African-ancestry populations (MAF 4.5%) that introduces a protospacer adjacent motif (PAM) sequence. We validated that SpCas9 generates strictly allele-specific indels and pericentric inversions in CD34

Indole-3-carbinol in vitro antiviral activity against SARS-Cov-2 virus and in vivo toxicity.

The effects of indole-3-carbinol (I3C) compound have been described deeply as antitumor drug in multiple cancers. Herein, I3C compound was tested for toxicity and antiviral activity against SARS-CoV-2 infection. Antiviral activity was assessed in vitro in both in VeroE6 cell line and human Lung Organoids (hLORGs) where I3C exhibited a direct anti-SARS-CoV-2 replication activity with an antiviral effect and a modulation of the expression of genes implicated in innate immunity and inflammatory response was observed at 16.67 μM. Importantly, we further show the I3C is also effective against the SARS-CoV-2 Omicron variant. In mouse model, instead, we assessed possible toxicity effects of I3C through two different routes of administration intragastrically (i.g.) and intraperitoneally (i.p.). The LD50 (lethal dose 50%) values in mice were estimated to be 1410 and 1759 mgkg i.g. while estimated values for i.p. administration were 444.5 mgkg and 375 mgkg in male and female mice, respectively. Below these values, I3C (in particular at 550 mgkg for i.g. and 250 mgkg for i.p.) induces neither death, nor abnormal toxic symptoms as well as no histopathological lesions of the tissues analysed. These tolerated doses are much higher than those already proven effective in pre-clinical cancer models and in vitro experiments. In conclusion, I3C exhibits a significant antiviral activity, and no toxicity effects were recorded for this compound at the indicated doses, characterizing it as a safe and potential antiviral compound. The results presented in this study could provide experimental pre-clinical data necessary for the start of human clinical trials with I3C for the treatment of SARS-CoV-2 and beyond.

TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma.

Interleukin-8 (IL-8CXCL8) is a pro-angiogenic and pro-inflammatory chemokine that plays a role in cancer development. Non-small cell lung carcinoma (NSCLC) produces high amounts of IL-8, which is associated with poor prognosis and resistance to chemo-radio and immunotherapy. However, the signaling pathways that lead to IL-8 production in NSCLC are unresolved. Here, we show that expression and release of IL-8 are regulated autonomously by TRAIL death receptors in several squamous and adenocarcinoma NSCLC cell lines. NSCLC constitutively secrete IL-8, which could be further enhanced by glucose withdrawal or by treatment with TRAIL or TNFα. In A549 cells, constitutive and inducible IL-8 production was dependent on NF-κB and MEKERK MAP Kinases. DR4 and DR5, known regulators of these signaling pathways, participated in constitutive and glucose deprivation-induced IL-8 secretion. These receptors were mainly located intracellularly. While DR4 signaled through the NF-κB pathway, DR4 and DR5 both regulated the ERK-MAPK and Akt pathways. FADD, caspase-8, RIPK1, and TRADD also regulated IL-8. Analysis of mRNA expression data from patients indicated that IL-8 transcripts correlated with TRAIL, DR4, and DR5 expression levels. Furthermore, TRAIL receptor expression levels also correlated with markers of angiogenesis and neutrophil infiltration in lung squamous carcinoma and adenocarcinoma. Collectively, these data suggest that TRAIL receptor signaling contributes to a pro-tumorigenic inflammatory signature associated with NSCLC.

Effects of Cinobufagin on the Proliferation, Migration, and Invasion of H1299 Lung Cancer Cells.

Cinobufagin (CB), with its steroidal nucleus structure, is one of the major, biologically active components of Chan Su. Recent studies have shown that CB exerts inhibitory effects against numerous cancer cells. However, the effects of CB regarding the metastasis of non-small cell lung cancer (NSCLC) and the involved mechanisms need to be further studied. The purpose of the present study aimed to report the inhibitory function of CB against proliferation and metastasis of H1299 cells. CB inhibited proliferation of H1299 lung cancer cells with an IC

YAP-VGLL4 antagonism defines the major physiological function of the Hippo signaling effector YAP.

The Hippo-YAP signaling pathway plays a critical role in development, homeostasis, regeneration, and tumorigenesis by converging on YAP, a coactivator for the TEAD family DNA-binding transcription factors, to regulate downstream transcription programs. Given its pivotal role as the nuclear effector of the Hippo pathway, YAP is indispensable in multiple developmental and tissue contexts. Here we report that the essentiality of YAP in liver and lung development can be genetically bypassed by simultaneous inactivation of the TEAD corepressor VGLL4. This striking antagonistic epistasis suggests that the major physiological function of YAP is to antagonize VGLL4. We further show that the YAP-VGLL4 antagonism plays a widespread role in regulating Hippo pathway output beyond normal development, as inactivation of

Environmental microcystin exposure triggers the poor prognosis of prostate cancer Evidence from case-control, animal, and in vitro studies.

Microcystin-leucine-arginine (MC-LR) is positively linked with multiple cancers in humans. However, the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological studies. No reported studies have linked MC-LR exposure to the poor prognosis of prostate cancer by conducting experimental studies. The content of MC-LR was detected in most of the aquatic food in wet markets and supermarkets in Nanjing and posed a health risk for consumers. MC-LR levels in both prostate cancer tissues and serum were significantly higher than controls. The adjusted odds ratio (OR) for prostate cancer risk by serum MC-LR was 1.75 (95%CI 1.21-2.52) in the whole subjects, and a positive correlation between MC-LR and advanced tumor stage was observed. Survival curve analysis indicated patients with higher MC-LR levels in tissues exhibited poorer overall survival. Human, animal, and cell studies confirmed that MC-LR exposure increases the expression of estrogen receptor-α (ERα) and promotes epithelial-mesenchymal transition (EMT) in prostate cancer. Moreover, MC-LR-induced decreased E-cadherin levels, increased vimentin levels, and increased migratory and invasive capacities of prostate cancer cells were markedly suppressed upon ERα knockdown. MC-LR-induced xenograft tumor growth and lung metastasis in BALBc nude mice can be effectively alleviated with ERα knockdown. Our data demonstrated that MC-LR upregulated vimentin and downregulated E-cadherin through activating ERα, promoting migration and invasion of prostate cancer cells. Our findings highlight the role of MC-LR in prostate cancer, providing new perspectives to understand MC-LR-induced prostatic toxicity.

Fine particulate matter and cardiorespiratory health in China A systematic review and meta-analysis of epidemiological studies.

This review aimed to systematically summarize the epidemiological literature on the cardiorespiratory effects of PM

Factors Associated with Hospital Length of Stay and Adverse Events following Percutaneous Ablation of Lung Tumors.

To explore the association between risk factors established in the surgical literature and hospital length of stay (HLOS), adverse events, and hospital readmission within 30 days after percutaneous image-guided thermal ablation of lung tumors. This bi-institutional retrospective cohort study included 131 consecutive adult patients (67 men 51% median age, 65 years) with 180 primary or metastatic lung tumors treated in 131 sessions (74 cryoablation and 57 microwave ablation) from 2006 to 2019. Age-adjusted Charlson Comorbidity Index, sex, performance status, smoking status, chronic obstructive pulmonary disease (COPD), primary lung cancer versus pulmonary metastases, number of tumors treated per session, maximum axial tumor diameter, ablation modality, number of pleural punctures, anesthesia type, pulmonary artery-to-aorta ratio, lung densitometry, sarcopenia, and adipopenia were evaluated. Associations between risk factors and outcomes were assessed using univariable and multivariable generalized linear models. In univariable analysis, HLOS was associated with current smoking (incidence rate ratio IRR, 4.54 1.23-16.8 P .02), COPD (IRR, 3.56 1.40-9.04 P .01), cryoablations with ≥3 pleural punctures (IRR, 3.13 1.07-9.14 P .04), general anesthesia (IRR, 10.8 4.18-27.8 P < .001), and sarcopenia (IRR, 2.66 1.10-6.44 P .03). After multivariable adjustment, COPD (IRR, 3.56 1.57-8.11 P .003) and general anesthesia (IRR, 12.1 4.39-33.5 P < .001) were the only risk factors associated with longer HLOS. No associations were observed between risk factors and adverse events in multivariable analysis. Tumors treated per session were associated with risk of hospital readmission (P .03). Identified preprocedural risk factors from the surgical literature may aid in risk stratification for HLOS after percutaneous ablation of lung tumors, but were not associated with adverse events.

Fungal antitumor protein D1 is internalized via endocytosis and inhibits non-small cell lung cancer proliferation through MAPK signaling pathway.

Lung cancer has the highest mortality among cancer-related deaths worldwide. Among lung cancers, non-small cell lung cancer (NSCLC) is the most common histological type. In the previous research, we isolated a protein (D1) from Boletus bicolor that inhibits the proliferation of NSCLC cell lines. In this study, we elucidated the internalization mechanism and antitumor mechanism of protein D1 in A549 cells. Protein D1 has a strong inhibitory effect on A549 cells. It binds to secretory carrier membrane protein 3 on the A549 cell membrane and enters A549 cells by clathrin-mediated endocytosis. In vitro, protein D1 activates mitogen-activated protein kinase (MAPK) signaling pathway. JNK and p38MAPK are the biological targets for protein D1. In vivo, protein D1 inhibits the tumor growth of NSCLC xenografts by inducing apoptosis and inhibiting cell proliferation. Protein D1 alters the expression of genes related to apoptosis, cell cycle, and MAPK signaling pathway in tumor cells.

Sirt3 activates autophagy to prevent DOX-induced senescence by inactivating PI3KAKTmTOR pathway in A549 cells.

Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates mitochondrial redox homeostasis and autophagy and is involved in physiological and pathological processes such as aging, cellular metabolism, and tumorigenesis. We here investigate how Sirt3 regulates doxorubicin (DOX)-induced senescence in lung cancer A549 cells. Sirt3 greatly reduced DOX-induced upregulation of senescence marker proteins p53, p16, p21 and SA-β-Gal activity as well as ROS levels. Notably, Sirt3 reversed DOX-induced autophagic flux blockage, as shown by increased p62 degradation and LC3IILC3I ratio. Importantly, the autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) partially abolished the antioxidant stress and antiaging effects of Sirt3, while the autophagy activator rapamycin (Rap) potentiated these effects of Sirt3, demonstrating that autophagy mediates the anti-aging effects of Sirt3. Additionally, Sirt3 inhibited the DOX-induced activation of the phosphatidylinositol-3-kinase (PI3K)AKTmammalian target of rapamycin (mTOR) signaling pathway, which in turn activated autophagy. The PI3K inhibitor LY294002 promoted the antioxidant stress and antiaging effects of Sirt3, while the AKT activator SC-79 reversed these effects of Sirt3. Taken together, Sirt3 counteracts DOX-induced senescence by improving autophagic flux.

Neoadjuvant Immunotherapy in Oncogene-Positive Non-Small Cell Lung Cancer A Multicenter Study.

Preoperative immunotherapy has shed light on the management of resectable non-small cell lung cancer (NSCLC). However, whether neoadjuvant immunotherapy benefits patients with oncogene-positive NSCLC remains unknown. Data were retrieved from 4 institutions in the period from August 2018 to May 2021. Eligible patients were aged ≥18 years with histologically confirmed stage IIA to stage IIIB (T1-2 N1-2 or T3-4 N0-2) NSCLC that was deemed to be surgically resectable. The neoadjuvant regimen included immune checkpoint inhibitors alone or in combination with platinum-based doublets. Surgical resection was performed 4 to 6 weeks after the first day of the last cycle of treatment. The primary end point was major pathologic response (MPR ≤10% viable tumor cells). Analyses were categorized according to the patients oncogene (EGFR, ALK, KRAS, MET, BRAF, ROS1, RET) status. Overall, 137 patients were identified 46 (33%) patients had nonsquamous cell cancer, and 114 (83%) had stage IIIAB disease. Oncogene alterations were identified in 22 (16%) patients, of whom only 2 patients (222 9%) had an MPR compared with 65 (65115 56.5%) in the oncogene-negative population (P < .001). Similar results were retained after propensity score matching for age, sex, smoking status, histologic type, stage, and cycles of neoadjuvant treatment. Squamous cell carcinoma (odds ratio, 2.54 95% CI, 1.08-5.99) and positive oncogene status (odds ratio, 0.13 95% CI, 0.03-0.64) were found to be indicators for MPR by logistic regression. The 1-year event-free survival rate was 75.4% in the oncogene-positive group, which was not significantly different from 85.5% in the oncogene-negative population (P .23). Patients with stage II-III oncogene-positive NSCLCs respond less than patients with oncogene-negative NSCLCs after neoadjuvant immunotherapy.

Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors.

Resistance to MET inhibition occurs inevitably in MET-dependent non-small cell lung cancer and the underlying mechanisms are insufficiently understood. We describe resistance mechanisms in patients with MET exon 14 skipping mutation (METΔ Pre- and post-treatment biopsies were analysed by NGS (next generation sequencing), digital droplet PCR (polymerase chain reaction), and FISH (fluorescense in situ hybridization). A patient-derived xenograft model was generated in one case. Of 26 patients with MET tyrosine kinase inhibitor treatment, eight had paired pre- and post-treatment biopsies (Three with MET amplification, three with METΔ Resistance to MET inhibition is heterogeneous with on- and off-target mechanisms occurring regardless of the initial MET aberration. Switching therapy between different types of kinase inhibitors can lead to repeated responses in cases with second-site mutations. Controlled clinical trials in this setting with larger patient numbers are needed, as evidence to date is limited to preclinical data and case series.

Lathyrol promotes ER stress-induced apoptosis and proliferation inhibition in lung cancer cells by targeting SERCA2.

Lathyrol is a natural product isolated from the traditional Chinese medicine Semen Euphorbiae with unknown anti-tumor effects. We found that lathyrol had significant inhibitory effect on lung cancer cells by inducing apoptosis and inhibiting proliferation. Subsequently, we demonstrated for the first time that endoplasmic reticulum (ER) stress is a key anti-tumor mechanism of lathyrol. Furthermore, we found that lathyrol can induce ER stress in lung cancer cells by upregulating the protein expression levels of GRP78, PERK, p-eIF2α, CHOP, and ATF4, and the inhibitory effect of lathyrol on lung cancer cells was significantly reversed when cells were pretreated with ER stress inhibitor. In addition, we found that inhibition of SERCA2 resulted in depletion of the ER Ca

AIF-1, a potential biomarker of aggressive tumor behavior in patients with non-small cell lung cancer.

Allogeneic inflammatory factor-1 (AIF-1) overexpression has been reported to be associated with tumorigenesis and tumor metastasis. This study aimed to investigate the role of AIF-1 in the development and progression of non-small cell lung cancer (NSCLC). AIF-1, IL-6, and VEGF expressions in human NSCLC tissue were examined by immunofluorescence staining. Bioinformatics analyses were performed to identify AIF-1-related molecules and pathways in NSCLC. Human lung cancer A549 cell proliferation was assessed by CCK-8 assay, and cell migration was evaluated with wound-healing assay. IL-6 and VEGF secretions in A549 cell culture supernatants were quantified using the Elecsys IL-6 immunoassay kit and Vascular Endothelial Growth Factor Assay Kit. RT-PCR and western blot were performed to quantify the expressions of AIF-1, IL-6, and VEGF mRNAs and proteins involved in p38-MAPK and JAKSTAT3 signaling such as p-p38 and p-STAT3. The effects of AIF-1 on A549 cell proliferation and the expressions of IL-6 and VEGF were assessed using SB203580 and ruxolitinib. The results showed that AIF-1 expression was higher in human NSCLC tissue than that in paracancer tissue. High AIF-1 expression was associated with metastasis, higher TNM stage, and poorer survival. Bioinformatics connected AIF-1 to JAKSTAT signaling in NSCLC. AIF-1 increased A549 cell proliferation, migration, IL-6 secretion and, VEGF secretion, and these effects were attenuated by inhibition of p38-MAPK or JAKSTAT3 signaling. In conclusion, AIF-1 may promote aggressive NSCLC behavior via activation of p38-MAPK and JAKSTAT signaling.

Patterns of care and outcomes in immigrants with non-small cell lung cancer. A population-based study (Sweden).

While studies have found lower cancer risks and better cancer survival in immigrant populations, it is debated whether cancer care is offered on equal terms to all residents regardless of background. Our aim was to study patterns of care and outcomes in immigrants in a country with a tax-financed universal health care system. We used a population-based database to compare clinical presentation, management and mortality between Swedish-born and immigrant patients with non-small cell lung cancer (NSCLC). Analyses were adjusted for potential confounders. We identified 40,075 patients diagnosed with NSCLC of which 84% were born in Sweden, 7% in Nordic and 9% in Non-Nordic countries. Non-Nordic immigrants were to a higher extent male, smokers, younger at diagnosis, had a better performance status and a higher educational level. No differences were seen regarding comorbidity burden or stage at diagnosis. Non-Nordic immigrants more often underwent positron emission tomography (PET) (aHR 1.32 95% CI 1.19-1.45) and were more often discussed in a multidisciplinary team setting (aHR 1.30 95% CI 1.17-1.44). There were no differences in treatment modalities following adjustment for age, with the exception of concurrent chemoradiotherapy in stage IIIA disease which was more common in Non-Nordic immigrants (aOR 1.34 95% CI 1.03-1.74). Both overall and cause specific survival in non-metastatic disease were higher among Non-Nordic immigrants. Overall mortality in stage I-II HR 0.81 95% CI 0.73-0.90 and stage IIIA HR 0.75 95% CI 0.65-0.86. Following full adjustments, cause-specific mortality in stage I-II was aHR 0.86, 95% CI 0.75-0.98. Taken together, only minor differences in management and outcomes were observed between Swedish-born and immigrant patients. We conclude that lung cancer care is offered on equal terms. If anything, outcomes were better in Non-Nordic immigrants with early stage NSCLC.

Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non-Small Cell Lung Cancer With High Tumor Mutation Burden A Nonrandomized Controlled Trial.

Antiangiogenic drug combinations with anti-programmed cell death 1 protein and anti-programmed cell death 1 ligand 1 (PD-L1) agents are a novel treatment option for lung cancer. However, survival remains limited, and the activity of these combinations for tumors with high tumor mutation burden (TMB) is unknown. To assess the clinical benefits and safety of atezolizumab plus bevacizumab for patients with high-TMB advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, single-arm, open-label, phase 2 nonrandomized controlled trial (Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients TELMA) included treatment-naive patients aged 18 years or older with confirmed stage IIIB-IV nonsquamous NSCLC with TMB of 10 or more mutationsmegabase and no EGFR, ALK, STK11, MDM2, or ROS1 alterations. From May 2019 through January 2021, patients were assessed at 13 sites in Spain, with follow-up until February 28, 2022. Participants were given atezolizumab, 1200 mg, plus bevacizumab, 15 mgkg, on day 1 of each 21-day cycle. Treatment was continued until documented disease progression, unacceptable toxic effects, patient withdrawal, investigator decision, or death. The primary end point was 12-month progression-free survival (PFS) rate (according to Response Evaluation Criteria in Solid Tumours, version 1.1 criteria) PFS was defined as the time from enrollment to disease progression or death. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. A total of 307 patients were assessed for trial eligibility, of whom 266 were ineligible for enrollment. Of the 41 patients enrolled, 3 did not fulfill all inclusion criteria and were excluded. The remaining 38 patients (28 73.7% male mean SD age, 63.7 8.3 years) constituted the per-protocol population. The 12-month PFS rate was 51.3% (95% CI, 34.2%-66.0%), which met the primary end point. The 12-month overall survival (OS) rate was 72.0% (95% CI, 54.1%-83.9%). The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. The median time to response was 2.8 months (IQR, 2.8-3.58 months), with a median duration of response of 11.7 months (range, 3.57-22.4 months the response was ongoing at cutoff). Of 16 responses, 8 (50.0%) were ongoing. Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 15.8%) and pruritus (6 15.8%). For bevacizumab, they were hypertension (10 26.3%) and proteinuria (4 10.5%). Drug discontinuation occurred in 2 patients receiving atezolizumab (5.3%) and 3 patients receiving bevacizumab (7.9%). PD-L1 levels were not associated with response, PFS, or OS. These findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC. ClinicalTrials.gov Identifier NCT03836066.

Emerging Strategies for the Treatment of Small Cell Lung Cancer A Review.

Small cell lung cancer (SCLC) is an aggressive disease that is characterized by rapid growth and the early development of metastases. Patients typically respond to initial chemotherapy but quickly experience relapse, resulting in a poor long-term outcome. Therapeutic innovations that substantially improve survival have historically been limited, and reliable, predictive biomarkers are lacking. This review examines the biologic characteristics of SCLC, the current treatment landscape, and ongoing efforts to identify novel therapeutic targets. Ongoing research has advanced the understanding of molecular categories and the immunologic microenvironment of SCLC, which in turn has helped improve disease classification and staging. Recently, immunotherapy-based regimens have become available for the management of SCLC, with 2 programmed cell death 1 ligand 1 inhibitors approved in combination with chemotherapy for first-line treatment of extensive-stage disease. For second-line treatment, a novel alkylating agent, lurbinectedin, which inhibits oncogenic transcription, has been approved for use in patients with metastatic SCLC. Furthermore, a wide variety of therapies and innovative combination regimens are being continuously evaluated. Potential therapeutic strategies, including aurora kinase A inhibitors, polyadenosine diphosphate-ribose polymerase inhibitors, ataxia telangiectasia and Rad3-related inhibitors, cyclin-dependent kinase 7 inhibitors, delta-like protein 3 agents, antiganglioside agents, CD47 inhibitors, and lysine-specific histone demethylase 1a inhibitors, are also being examined. Therapeutic optimization of SCLC remains a challenge, but recent trial results and drug approvals are encouraging. Advances in research have revealed critical information regarding biologic characteristics of the disease, which may lead to the identification of vulnerabilities and the development of new therapies. Further research focused on identifying biomarkers and evaluating innovative therapies will be paramount to improving treatment outcomes for patients with SCLC.

Brain metastases from small cell lung cancer and non-small cell lung cancer comparison of spatial distribution and identification of metastatic risk regions.

This study aims to investigate the spatial distribution difference of brain metastases (BM) between small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and to identify the metastatic risk in brain regions. T1-enhanced MR images of 2997 BM from 728 eligible patients with SCLC and NSCLC were retrospectively reviewed by three independent medical institutions in China. All images were spatially normalised according to the Montreal Neurological Institute space, following BM delineation confirmed by three senior radiologists. The brain regions in the normalised images were identified based on the merged Anatomical Automatic Labeling atlas, and all BM locations were mapped onto these brain regions. Two-tailed proportional hypothesis testing was used to compare the BM observed rate with the expected rate based on the regions volume, and metastatic risk regions were finally identified. In SCLC and NSCLC, BM was mainly present in the deep white matter (22.51% and 17.96%, respectively), cerebellar hemisphere (9.84% and 7.46%, respectively) and middle frontal gyrus (6.72% and 7.97%, respectively). The cerebellar hemisphere was a high-risk brain region in the SCLC. The precentral gyrus, middle frontal gyrus, paracentral lobule and cerebellar hemisphere were high-risk BM in the NSCLC. The inferior frontal gyrus and the temporal pole were a low-risk brain region in the SCLC and NSCLC, respectively. The spatial BM distribution between SCLC and NSCLC is similar. Several critical brain regions had relatively low BM frequency in both SCLC and NSCLC, where a low-dose radiation distribution can be delivered due to adequate preoperative evaluations.

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis.

Morphogenesis and organogenesis in the low organisms have been found to be modulated by a number of proteins, and one of such factor, deformed epidermal auto-regulatory factor-1 (DEAF-1) has been initially identified in Drosophila. The mammalian homologue of DEAF-1 and structurally related proteins have been identified, and they formed a family with over 20 members. The factors regulate gene expression through association with co-repressors, recognition of genomic marker, to exert histone modification by catalyze addition of some chemical groups to certain amino acid residues on histone and non-histone proteins, and degradation host proteins, so as to regulate cell cycle progression and execution of cell death. The formation of fused genes during chromosomal translocation, exemplified with myeloid transforming gene on chromosome 8 (MTG8)eight-to-twenty one translocation (ETO) ZMYND2, MTG receptor 1 (MTGR1)ZMYND3, MTG on chromosome 16MTGR2ZMYND4 and BS69ZMYND11 contributes to malignant transformation. Other anomaly like copy number variation (CNV) of BS69ZMYND11 and promoter hyper methylation of BLUZMYND10 has been noted in malignancies. It has been reported that when fusing with Runt-related transcription factor 1 (RUNX1), the binding of MTG8ZMYND2 with co-repressors is disturbed, and silencing of BLUZMYND10 abrogates its ability to inhibition of cell cycle and promotion of apoptotic death. Further characterization of the implication of ZMYND proteins in carcinogenesis would enhance understanding of the mechanisms of occurrence and early diagnosis of tumors, and effective antitumor efficacy.

Survival Outcomes of Sublobectomy and Lobectomy in Elderly Patients with Peripheral Solid-Dominant Non-small Cell Lung Cancer.

According to the JCOG0802 study, there were many non-cancer-related deaths in the lobectomy group. Meanwhile, the median age of the enrolled patients in the JCOG0802 study was 67 years old. Whether this difference in perioperative outcomes and survival outcomes is related to age remains unknown. We aim to investigate whether the sublobectomy was comparable to lobectomy in elderly (≥ 75 years old) patients with peripheral solid-dominant 50% ≤ consolidation tumor ratio (CTR) ≤ 1 and diameter ≤ 2 cm non-small cell lung cancer (NSCLC). We retrospectively included 10,830 patients who underwent surgery treatment at two large-volume medical centers, Taizhou Hospital of Zhejiang Province and Shanghai Chest Hospital, from January 2016 to January 2018. Of these, 164 patients aged ≥ 75 years, tumor ≤ 2 cm, and 50% ≤ CTR ≤ 1 who received lobectomy or sublobectomy were included in our study. The perioperative outcomes, survival analyses, analysis of death patterns, tumor recurrence patterns, and Cox regression analyses were performed. On perioperative outcomes, sublobectomy was associated with a shorter operation time (p < 0.001), and in terms of survival outcomes, the 5-year overall survival (OS, p 0.85) and 5-year disease-free surivial (DFS, p 0.58) did not differ significantly between the two groups. The Cox regression analyses showed that CTR value, visceral pleural infiltration, and smoking were independent risk factors for worse OS. Furthermore, tumor recurrence pattern and death patterns between the two groups did not differ significantly. Sublobectomy could achieve superior perioperative outcomes and equivalent oncological efficacy in comparison with lobectomy in elderly patients (≥ 75 years old) with peripheral solid-dominant and diameter ≤ 2 cm NSCLC.

Risk Factors and Impact on Outcomes of Lung Cancer Patients Concurrent with Deep Vein Thrombosis.

Many investigations on prognostic factors in lung cancer have been conducted however, little is known regarding the outcomes of lung cancer cases complicated by deep vein thrombosis (DVT). This study aimed to determine the risk factors and impact on outcomes of lung cancer patients concurrent with DVT. Lung cancer patients who underwent lower-extremity venous ultrasound were enrolled in this study. The patients were divided into a DVT group and a non-DVT group. Demographic information, clinical characteristics, and survival were analyzed by t-test, Wilcoxon test, chi-squared test, and logistic regression analysis. Of the 160 enrolled lung cancer patients, DVT was detected in 30 patients. Among the DVT group, adenocarcinoma was the most common histological type (2730, 90.00%). Lung cancer complicated with DVT was associated with advanced stage, more severe myocardial injury, and a hypercoagulable state (P < .05). Differences in driver genes between the two groups were not significant. Radiologically, lung cancer patients with DVT were more likely to present with pericardial effusion and pleural effusion than patients without DVT (P < .05). Following multivariable logistic regression analysis, advanced stage (OR 5.368, 95%CI 1.871-18.165, P .021), NT-proBNP >300 pgml (OR 5.575, 95%CI 1.733-3.722, P .018), D-dimer >5 mgL (OR 8.449, 95%CI 4.323-18.536, P .004), CRP >12 mgL (OR 6.687, 95%CI 1.967-13.617, P .010), and serum CEA >25 ngml (OR 4.755, 95%CI 1.358-3.123, P .029) were independent risk factors for adenocarcinoma complicated with DVT. Finally, survival analysis revealed that the occurrence of DVT resulted in a poorer prognosis despite anticoagulant therapy (P < .05). DVT is a potential complication in patients with lung adenocarcinoma and could represent a prognostic marker for unfavorable outcome. It is essential to screen for DVT in high-risk adenocarcinoma patients.

Joint 2022 European Society of Thoracic Surgeons and The American Association for Thoracic Surgery guidelines for the prevention of cancer-associated venous thromboembolism in thoracic surgery.

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a potentially fatal but preventable postoperative complication. Thoracic oncology patients undergoing surgical resection, often after multimodality induction therapy, represent among the highest risk groups for postoperative VTE. Currently there are no VTE prophylaxis guidelines specific to these thoracic surgery patients. Evidenced-based recommendations will help clinicians manage and mitigate risk of VTE in the postoperative period and inform best practice. These joint evidence-based guidelines from The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons aim to inform clinicians and patients in decisions about prophylaxis to prevent VTE in patients undergoing surgical resection for lung or esophageal cancer. The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons formed a multidisciplinary guideline panel that included broad membership to minimize potential bias when formulating recommendations. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. The panel agreed on 24 recommendations focused on pharmacological and mechanical methods for prophylaxis in patients undergoing lobectomy and segmentectomy, pneumonectomy, and esophagectomy, as well as extended resections for lung cancer. The certainty of the supporting evidence for the majority of recommendations was judged as low or very low, largely due to a lack of direct evidence for thoracic surgery. The panel made conditional recommendations for use of parenteral anticoagulation for VTE prevention, in combination with mechanical methods, over no prophylaxis for cancer patients undergoing anatomic lung resection or esophagectomy. Other key recommendations include conditional recommendations for using parenteral anticoagulants over direct oral anticoagulants, with use of direct oral anticoagulants suggested only in the context of clinical trials conditional recommendation for using extended prophylaxis for 28 to 35 days over in-hospital prophylaxis only for patients at moderate or high risk of thrombosis and conditional recommendations for VTE screening in patients undergoing pneumonectomy and esophagectomy. Future research priorities include the role of preoperative thromboprophylaxis and the role of risk stratification to guide use of extended prophylaxis. (J Thorac Cardiovasc Surg 2022▪1-31).

A risk model for decline in health status after acute myocardial infarction among older adults.

Health status is increasingly recognized as an important patient-centered outcome after acute myocardial infarction (AMI). Yet drivers of decline in health status after AMI remain largely unknown in older adults. We sought to develop and validate a predictive risk model for health status decline among older adult survivors of AMI. Using data from a prospective cohort study conducted from 2013 to 2017 of 3041 patients age ≥75 years hospitalized with acute myocardial infarction at 94 U.S. hospitals, we examined a broad array of demographic, clinical, functional, and psychosocial variables for their association with health status decline, defined as a decrease of ≥5 points in the Short Form-12 (SF-12) physical component score from hospitalization to 6 months post-discharge. Model selection was performed in logistic regression models of 20 imputed datasets to yield a parsimonious risk prediction model. Model discrimination and calibration were evaluated using c-statistics and calibration plots, respectively. Of the 2571 participants included in the main analyses, 30% of patients experienced health status decline from hospitalization to 6 months post-discharge. The risk model contained 14 factors, 10 associated with higher risk of health status decline (age, pre-existing AMI, pre-existing cancer, pre-existing COPD, pre-existing diabetes, history of falls, presenting Killip class, acute kidney injury, baseline health status, and mobility impairment) and four associated with lower risk of health status decline (male sex, higher hemoglobin, receipt of revascularization, and arrhythmia during hospitalization). The model displayed good discrimination (c-statistic 0.74 in validation cohort) and calibration (p > 0.05) in both development and validation cohorts. We used split sampling to develop and validate a risk model for health status decline in older adults after hospitalization for AMI and identified several risk factors that may be modifiable to mitigate the threat of this important patient-centered outcome. External validation of this risk model is warranted.

Non-small cell lung cancer with EGFR (L858R and E709X) and CNNB1 mutations responded to afatinib.

Lung cancer with complex epidermal growth factor receptor (EGFR) and CTNNB1 comutations is rare, and the efficacy of tyrosine kinase inhibitors (TKIs) is generally poor. Here, we encountered a lung cancer patient with complex EGFR (L858R and E709X) and CTNNB1 comutations who successfully responded to afatinib. A 78-year-old woman visited our hospital with a cough and bloody sputum that had worsened over the past year. She had multiple mass shadows in both lungs and nodular shadows in the bronchi. The patient was diagnosed with lung adenocarcinoma cT4N3M1c stage IVB. A genetic analysis of the primary tumor using the Oncomine Dx target test multi-CDx system revealed positivity for EGFR (L858R and E709X) and CTNNB1 mutations. The expression of programmed death ligand 1 (22C3 clones) in tumor cells was negative by immunostaining. The patient was treated with afatinib as first-line therapy and achieved clinical improvement and a partial response and is continuing treatment 1 year later. Case reports of lung cancer patients with EGFRCTNNB1 comutations are rare, and TKIs are not considered to be effective. We herein present the first case report of lung cancer with the co-occurrence of uncommon and complex EGFR (L858R and E709X) and CTNNB1 mutations that was successfully treated with afatinib.

Markers of activation of coagulation in cancer patients.

Prothrombotic tendency is characteristic of tumors. The aim of the study is to investigate the changes in the laboratory parameters for coagulation and fibrinolysis, namely in fibrinogen, thrombin-antithrombin complex (ТАТ), tissue factor (ТF), prothrombin fragment (F12), antithrombin III (AT III), D-dimer and screening coagulation tests in cancer patients before initiation of chemotherapy. Levels of F12, fibrinogen, ТАТ, AT III, TF, D-dimer, PT, aPTT and TT were measured baseline in 80 patients with breast and lung cancer before systemic treatment. The same parameters were investigated in 65 healthy volunteers. TF, ТАТ, F12 were measured by ELISA AT III, D-dimer, fibrinogen and screening coagulation tests were measured by automated coagulation system Sysmex CS 2000i. RESULTS Levels of F12, fibrinogen, ТАТ, TF, and D-dimer in cancer patients were significantly higher than those in the control group, while the levels of ATIII activity were significantly lower (p < 0.001). The highest area under the ROC curve was for D-dimer, which made it a good marker for the risk of thrombosis. Higher levels of TF, ТАТ, F12, fibrinogen and D-dimer and lower activity of АТ III in cancer patients support our hypothesis of an association between malignant disease and coagulation disorders. Cancer patients are at an increased risk of thrombosis wherefore antithrombotic prophylaxis may be considered (Tab. 6, Fig. 2, Ref. 34). Text in PDF www.elis.sk Keywords coagulation, fibrinolysis, cancer.

Cutaneous adverse events associated with PD-1 inhibitor-based therapy in patients with non-small-cell lung cancer.

Designing a multitarget In(III) compound to overcome the resistance of lung cancer cells to cisplatin.

Designing novel anticancer non-platinum metal agents is fully challenging. Herein, a series of little-known indium (In) 2-acetylpyridine thiosemicarbazone compounds as potential anticancer agents were designed, synthesized, and characterized. The hydrogen atoms at the N-4 position with the alkyl of the In compounds significantly increased cellular uptake and cytotoxicity. In(III) compounds showed significantly higher cytotoxicity toward cisplatin-resistant cell lines than cisplatin. More importantly, C4 greatly inhibited A549DDP tumor growth in a vaccinated mouse model. C4 exerted cytotoxic effects

Scrape cytology and radiological solid size correlation can be used in the intraoperative management of subsolid lung nodules.

The term radiologic subsolid lung nodule (SLN) represents a heterogeneous group of non-neoplastic and neoplastic lesions. Intraoperative evaluation (IO) is often required to differentiate and diagnose. The current study aims to investigate the feasibility and reliability of scrape cytology (SC) and radiologic solid size correlation for the IO diagnosis of SLNs. Sixty-eight patients with SLN signs were eligible to take part in the study due to intraoperatively prepared SC slides. We managed to complete the blind radiologic solid size measurement and cytologic evaluation retrospectively. Cases were grouped into three categories based on their cytological features Group-0 (Benign), Group-1 (mild atypical features), and Group-2 (severe atypical featuresunequivocally carcinoma). IO diagnoses were given by combining the radiologic solid size and cytological findings. Cytological features of Group-1 were observed in 100%, 93%, 32.5%, and 17% of the AIS, MIA, IA, and benign lesions, respectively. Cytological features of Group-2 were observed in 67.5%, and 7% of the IA and MIA, respectively. By combining cytology with radiologic solid size, 100%, 85%, 71%, and 83% of the AIS, IA, MIA, and benign lesions respectively were diagnosed correctly. Fifteen (15%) percent of the IA cases were underdiagnosed as MIA since their radiological solid sizes were less than 0.5 cm with cytological features of Group-1. Conversely, 29% of the MIA cases were overdiagnosed as IA since their radiological solid sizes were greater than 0.5 cm. SLNs should be handled with caution in terms of IO management. SC and radiologic solid size correlation both provide a practical and tissue-protecting approach for the IO evaluation of SLNs, ensuring a high consistency between IO and definitive diagnosis.

An alternative

Particularly since the wide-ranging health effects of asbestos exposure became known, great emphasis has been placed on detailed toxicity testing of known but also newly developed fiber materials. Exposure to respirable pollutants like fibers can lead to tissue injury causing lung diseases such as pulmonary fibrosis or cancer. In order to detect the toxic potential of such aerosols at an early stage, the development of suitable test systems is essential. In this study, we illustrate the development of an advanced

Recommendation for imaging follow-up strategy based on time-specific disease failure for nasopharyngeal carcinoma.

To develop a common follow-up strategy for appropriate imaging examination at an appropriate time for nasopharyngeal carcinoma (NPC). Independent prognostic factors were identified by Cox regression analysis, and a nomogram model was developed. Random survival forest (RSF) model was constructed to depict probability of disease failure during a 5-year follow-up and establish a reasonable risk-based follow-up strategy. The nomogram model finally categorized the patients into three risk groups. RSF model demonstrated distribution trends for local and regional recurrences, bone metastasis, liver metastasis, and lung metastasis of NPC. Adequate imaging at follow-up should be considered between 10 and 21 months for patients at moderate-risk of recurrence or metastasis and 7-36 months for those at high-risk. The temporal distribution of incidence rates of recurrence or metastasis varied among different risk groups. We recommend implementing a focused and targeted imaging surveillance intervention at appropriate times to improve its efficiency and reduce costs.

Treatment response and safety of immunotherapy for advanced non-small cell lung cancer with comorbid chronic obstructive pulmonary disease a retrospective cohort study.

Immunotherapy has provided a novel therapeutic option for lung cancer but studies involving patients with advanced non-small cell lung cancer (NSCLC) coupled with various degrees of comorbid chronic obstructive pulmonary disease (COPD) are limited. Thus, we performed a retrospective cohort study to optimize the use of immunotherapy in this special population. We enrolled a total of 99 patients with advanced (stage IIIBC-IV) NSCLC with comorbid COPD who had received immune checkpoint inhibitors (ICIs) according to the inclusion and exclusion criteria. They were divided into four groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline criteria as follows no COPD group (n There were statistically significant differences in the incidence of irAEs among the four groups (P0.003). The incidence of irAEs in patients with no COPD (n Immunotherapy should be selected with caution for advanced NSCLC patients with comorbid severe COPD, considering the limited efficacy and the increased risk of immune-related adverse events related to the immune-checkpoint inhibitors administration in this special population.

Immune thrombocytopenia in a small cell lung cancer patient treated with atezolizumab a case report.

Immune checkpoint inhibitors (ICIs), an enormous oncological breakthrough in the last 10 years, have become the standard treatments for several types of solid cancers. Although ICIs are generally well tolerated and result in favorable outcomes, they also cause unique immune-related adverse events (irAEs) across bodily systems and organs. Compared to most common irAEs, which occur in the endocrine, skin, pulmonary system, and gastrointestinal tract, haematological irAEs (haem-irAEs) are relatively rare but potentially life-threatening events that are occasionally irreversible and refractory. Currently, haem-irAEs are not sufficiently understood, management, and lack consensus, while other common irAEs have well been characterized and managed. The reports of ICI-related thrombocytopenia in small cell lung cancer (SCLC) are rarely seen. Hence, we reported a rare case of severe steriod-resistant ICI-related thrombocytopenia after received chemotherapy plus anti-PD-L1 inhibitor in SCLC patient. Our case exemplifies the diagnosis, diagnosis of exclusion, treatment, and prognosis of thrombocytopenia in the pattern of combination therapy, meanwhile, the subject of diagnosis, therapies, therapeutic strategies for refractory type and incidence, potential biomarkers, mechanisms and prognosis in ICI-related thrombocytopenia have been fully discussed. Herein, we present a 64-year-old man diagnosed advanced SCLC developed refractory immune-related severe thrombocytopenia, who achieved favorable outcomes of cancer following chemotherapy combined with atezolizumab administrated. Routine blood re-examination on the third day of 6th therapy showed a thrombocyte count of 11×10 Although ICI-related severe thrombocytopenia is rare, it may persist or even be fatal. Clinicians should pay more attention to its diagnosis and prompt treatment. Once developed thrombocytopenia, large doses of methylprednisolone, ntermittent platelet transfusion, thrombopoietin should be timely administrated, also plasma exchange or rilzabrutinib, other immunosuppressive drugs, or IL-6 inhibitor warrant apply if steriod-resistant.

Onco-biome in pharmacotherapy for lung cancer a narrative review.

The gut microbiota (GM) was recently recognized to play an important role in modulating systemic immune responses and is known to influence the effects or adverse events of immune checkpoint blockade (ICB) or carcinogenesis by crosstalk with regulators of cancer-related immunity, and this relationship is complex and multifactorial. Diversity in the gut microbiome and the abundance of specific bacterial species have been identified to be associated with better response and prognosis. Therefore, the purpose of the current interest in the gut microbiome is to enable modulation of the immune system in donor cancer patients by the administration of specific bacterial species and enabling their dominance. To understand this terra incognita is to uncover the role of the mechanisms underlying unknown organ functions, and this knowledge will lead to enhanced immunotherapy for lung cancer patients. In this article, we summarized the literature on the relationship between the microbiome and lung cancer and the potential of the microbiome as a therapeutic target. This article is organized into the following sections introduction, methods, microbiota and cancer development, microbiota and lung cancer treatment, future directions, and conclusion. The gut microbiome is currently becoming the hallmark of cancer research and has an established and critical role in regulating antitumor immunity and the response to ICB in patients with lung cancers.

Multi-omics consensus portfolio to refine the classification of lung adenocarcinoma with prognostic stratification, tumor microenvironment, and unique sensitivity to first-line therapies.

Molecular classification of lung adenocarcinoma (LUAD) based on transcriptomic features has been widely studied. The complementarity of data obtained from multilayer molecular biology could help the LUAD classification via combining multi-omics information. We successfully divided samples from the The Cancer Genome Atlas (TCGA) (n437) into four subtypes (CS1, CS2, CS3 and CS4) by 10 comprehensive multi-omics clustering methods in the movics R package. Meanwhile, external validation sets from different sequencing technologies proved the robustness of the grouping model. The relationship between subtypes, prognosis, molecular features, tumor microenvironment and response to first-line therapy was further analyzed. Next we used univariate Cox regression analysis and Lasso regression analysis to explore the application of biomarkers in clinical prognosis and constructed a prognostic model. CS1 showed the worst overall survival (OS) among all four clusters, possibly related to its poor immune infiltration, higher tumor mutation and worse chromosomal stability. Patients in different subtypes differed significantly in cancer stem cell characteristics, activation of cancer-related pathways, sensitivity to chemotherapy and immunotherapy. The prognostic model showed good predictive performance. The 1-, 2- and 3-year areas under the curve of risk score were 0.779, 0.742 and 0.678, respectively. Seven genes ( Four LUAD subtypes with different molecular characteristics and clinical implications were identified successfully through bioinformatic analysis. Our results may contribute to precision medicine and inform the development of rational clinical strategies for targeted and immune therapies.

Multimodal therapy of epithelioid pleural mesothelioma improved survival by changing the surgical treatment approach.

The exact role and type of surgery for malignant pleural mesothelioma (MPM) remains controversial. This study aimed at analyzing a 20-year single center perioperative experience in MPM surgery at our high-volume thoracic surgery center and comparing the overall survival after trimodal extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication combined with hyperthermic intrathoracic chemoperfusion (EPDHITOC) and adjuvant chemotherapy with that after chemotherapy (CTx) alone. Patients with epithelioid MPM treated with neoadjuvant chemotherapy, EPP and adjuvant radiotherapy within a trimodal concept or EPDHITOC in combination with adjuvant chemotherapy between 2001 and 2018 were included in this retrospective analysis. Surgical cohorts were compared to patients treated with standard chemotherapy. Overall, 182 patients (69 EPP, 57 EPDHITOC, 56 CTx) were analyzed. Due to occupational exposure to asbestos for most of the patients, 154 patients (84.6%) were male. The patients in the surgical cohorts were significantly younger than those in the CTx cohort. There was no significant difference between the proportion of patient age and side. The median overall survival of the EPDHITOC cohort with 38.1 months was significantly longer than that of the EPP and CTx cohorts (24.0 and 15.8 months). Better survival was significantly associated with an ECOG 0 performance status, age below 70 years, and negative lymph node status. In the multivariate analysis, EPDHITOC was significantly associated with improved overall survival. Perioperative morbidity was lower in the EPDHITOC group than in the EPP cohort. EPDHITOC is feasible and safe for localized epithelioid pleural mesothelioma. Changing the surgical approach to a less radical lung-sparing technique may improve overall survival compared to trimodal EPP.

Immune profile analysis of peripheral blood and tumors of lung cancer patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have become central to lung cancer drug therapy, and establishing biomarkers that can predict effects and adverse events (AEs) is awaited. We prospectively analyzed the association between the immune-related molecular expression in peripheral blood mononuclear cells (PBMCs) and lung cancer tissues, and the effects of ICI monotherapy. Twenty-one patients with advanced non-small cell lung cancer (NSCLC) who received ICI monotherapy were included. Changes in the expression of immune-related molecules in PBMCs before and after the administration of ICI were analyzed by flow cytometry. The major histocompatibility complex (MHC) class I and programmed cell death-ligand 1 (PD-L1) expression of cancer cells, and the PD-L1, CD8 and CD103 expression of tumor infiltrating immune cells in lung cancer tissue before the administration of ICI were confirmed by immunohistochemistry (IHC). Twenty-one patients were investigated, including 11 adenocarcinoma and 10 squamous cell carcinoma cases. Anti-programmed cell death protein-1 (PD-1) antibody (n18) and anti-PD-L1 antibody (n3) were administered. The clinical responses were graded as follows complete response (CR) (n1), partial response (PR) (n7), stable disease (SD) (n10) and progressive disease (PD) (n3). Among immune-related molecules expressed in PBMCs, the CD103 The CD103

Development and verification of new monoclonal orthopedia homeobox (OTP) specific antibodies for pulmonary carcinoid diagnostics.

Orthopedia homeobox (OTP) has shown to be a useful prognostic marker to predict outcome in pulmonary carcinoids, which is also supported by the World Health Organization. However, the discontinuation of the initially used polyclonal antibody and absence of a reliable routinely applicable monoclonal OTP antibody hampers implementation in routine diagnostics. Here, new monoclonal antibodies directed against OTP were developed and verified on formalin-fixed paraffin-embedded tissue of pulmonary neuroendocrine tumors (NETs) for clinical diagnostics. OTP specific monoclonal antibodies were produced from mice immunised with a recombinant human OTP protein fragment. Enzyme-linked immunosorbent assay (ELISA) positive hybridomas were evaluated using immunohistochemistry (IHC). Following epitope-mapping and isotyping, purified monoclonal antibodies were validated for IHC in formalin-fixed paraffin-embedded tissues, the optimal dilution was determined, and results were cross validated with the OTP polyclonal antibody (HPA039365, Atlas Antibodies). Staining protocols were optimized on two automated staining platforms and performance was harmonized using a tissue microarray (TMA). Two clones (CL11222 and CL11225) were selected for purified monoclonal antibody (mAb) production. Intratumor heterogeneity assessment revealed similar performance for both clones. While clone CL11225 displayed a unique epitope compared to those present in the polyclonal antibody, this clone performed most similar to the polyclonal antibody. Cross-platform assessment revealed an excellent agreement for clone CL11225 while clone CL11222 showed somewhat discordant results on Dako. New monoclonal OTP specific antibodies have been developed and verified on different automated immunohistochemical staining platforms. The OTP specific monoclonal antibodies showed excellent agreement with the often-used polyclonal antibody allowing application in routine diagnostics.

Establishment and validation of a nomogram model for predicting postoperative recurrence-free survival in stage IA3 lung adenocarcinoma a retrospective cohort study.

The increased use of computed tomography has brought a corresponding increase in the numbers of early-stage lung cancer patients receiving treatment. However, even for stage IA3 lung adenocarcinoma, many patients experience postoperative recurrence and metastasis. The existing TNM staging system for lung cancer does not take many clinical and pathological factors into consideration, resulting in the failure to detect and intervene as soon as possible in those with high recurrence risk. The purpose of this study was to explore the risk factors for postoperative recurrence-free survival (RFS) in patients with stage IA3 lung adenocarcinoma, and to construct and verify a nomogram model for predicting RFS in patients with the disease. This study analyzed patients with stage IA3 lung adenocarcinoma who underwent surgical treatment. Univariate and multivariate analysis were used to analyze the independent risk factors for postoperative RFS and establish a nomogram model. Concordance index (C-index), receiver operating characteristic curve, clinical decision analysis, and calibration curve were used to evaluate the discrimination and calibration of the nomogram model. Data from two other institutions were used for external validation, and the nomogram scores were combined with X-tile software to screen high-risk groups of recurrence. The internal cohort included 235 eligible patients with stage IA3 lung adenocarcinoma from 7,235 lung cancer. Multivariate analysis showed smoking, solid nodules, mucinous lung adenocarcinoma, and micropapillary component ≥5% were independent risk factors for RFS. A nomogram model was constructed based on the above results and the bootstrap method was used for internal validation. The internal and external validation C-indexes of the nomogram were 0.822 (95% CI 0.751-0.891) and 0.812, respectively, indicating the obvious prediction performance was good. The X-tile software combined with nomogram scores showed the low-risk group (5-RFS rate, 0.65-0.99) had better RFS than the high-risk group (5-RFS rate, 0.20-0.65) (P<0.0001). We constructed a nomogram model for predicting postoperative RFS in patients with stage IA3 lung adenocarcinoma which can individually evaluate the risk of postoperative recurrence, screen high-risk groups, and develop individualized follow-up and intervention strategies to improve the survival rate of the patients.

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died median follow-up 14.6 months (range, 0.53-29.5 months). PFS was longer for TTF-1-positive patients than for TTF-1-negative patients median, 12.2 TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

Safety and efficacy of immunotherapy rechallenge following checkpoint inhibitor-related pneumonitis in advanced lung cancer patients a retrospective multi-center cohort study.

Checkpoint inhibitor-related pneumonitis (CIP) induced by immune checkpoint inhibitors (ICIs) is one of the most fatal immune-related adverse events (irAE). However, only limited data are available on rechallenge with ICIs after CIP. We evaluated the efficacy and safety of rechallenge after CIP in patients with advanced lung cancer to identify the potential populations that would benefit. We conducted a multicenter retrospective study of advanced lung cancer patients who received further ICI treatment (rechallenge) or did not undergo re-administration after grade ≥1 CIP between May 2017 and May 2021. Progression-free survival (PFS) and overall survival (OS) were estimated from first or second ICI initiation to disease progression (PFS1 and PFS2, respectively), death, or last follow-up (OS1 and OS2, respectively). The recurrence of CIP and new irAEs in these patients after ICI rechallenge were calculated. Among 107 patients afflicted with CIP, 45 (42.1%) received ICI rechallenge. Multivariate analysis showed that severe grade (grades ≥3) and ground-glass opacity of pneumonitis lesions were negatively associated with rechallenge. Following rechallenge, 9 (20.0%) patients developed recurrent pneumonitis, and 11 (24.4%) developed a new irAE. Severe grade of CIP and poor performance status at initial CIP as well as levels of interleukin (IL)-6 and C-reactive protein (CRP), and absolute white blood cell and neutrophil counts at the time of ICI rechallenge were associated with a higher recurrence rate. The median (95% confidence interval) PFS1 and PFS2 were 17.9 (9.9-24.2) and 15.5 (5.5-25.6) months, respectively. The median (95% confidence interval) OS1 and OS2 were 23.5 (16.5-30.5) and 18.4 (10.1-26.7) months, respectively. Lower OS2 was observed in patients with severe grade of CIP and poor performance status at the initial CIP, recurrence of CIP, and in patients with high levels of CRP and IL-6 at rechallenge. Only IL-6 was found to affect OS2 on multivariate analysis. ICI rechallenge following CIP may be a promising treatment for patients with advanced lung cancer, particularly in those with low-grade of CIP and good performance status at initial CIP, and low levels of IL-6 and CRP at the time of initial challenge. Prospective studies are needed for further verification.

Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022).

The use of the white-light thoracoscopy is hampered by the low contrast between oncologic margins and surrounding normal parenchyma. As a result, many patients with in situ or micro-infiltrating adenocarcinoma have to undergo lobectomy due to a lack of tactile and visual feedback in the resection of solitary pulmonary nodules. Near-infrared (NIR) guided indocyanine green (ICG) fluorescence imaging technique has been widely investigated due to its unique capability in addressing the current challenges however, there is no special consensus on the evidence and recommendations for its preoperative and intraoperative applications. This manuscript will describe the development process of a consensus on ICG fluorescence-guided thoracoscopic resection of pulmonary lesions and make recommendations that can be applied in a greater number of centers. Specifically, an expert panel of thoracic surgeons and radiographers was formed. Based on the quality of evidence and strength of recommendations, the consensus was developed in conjunction with the

ADK-VR2, a cell line derived from a treatment-naïve patient with

ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

Development and validation of the artificial intelligence (AI)-based diagnostic model for bronchial lumen identification.

Bronchoscopy is a key step in the diagnosis and treatment of respiratory diseases. However, the level of expertise varies among different bronchoscopists. Artificial intelligence (AI) may help them identify bronchial lumens. Thus, a bronchoscopy quality-control system based on AI was built to improve the performance of bronchoscopists. This single-center observational study consecutively collected bronchoscopy videos from Shanghai Chest Hospital and segmented each video into 31 different anatomical locations to develop an AI-assisted system based on a convolutional neural network (CNN) model. We then designed a single-center trial to compare the accuracy of lumen recognition by bronchoscopists with and without the assistance of the AI system. A total of 28,441 qualified images of bronchial lumen were used to train the CNNs. In the cross-validation set, the optimal accuracy of the six models was between 91.83% and 96.62%. In the test set, the visual geometry group 16 (VGG-16) achieved optimal performance with an accuracy of 91.88%, and an area under the curve of 0.995. In the clinical evaluation, the accuracy rate of the AI system alone was 54.30% (202372). For the identification of bronchi except for segmental bronchi, the accuracy was 82.69% (129156). In group 1, the recognition accuracy rates of doctors A, B, a and b alone were 42.47%, 34.68%, 28.76%, and 29.57%, respectively, but increased to 57.53%, 54.57%, 54.57%, and 46.24% respectively when combined with the AI system. Similarly, in group 2, the recognition accuracy rates of doctors C, D, c, and d were 37.90%, 41.40%, 30.91%, and 33.60% respectively, but increased to 51.61%, 47.85%, 53.49%, and 54.30% respectively, when combined with the AI system. Except for doctor D, the accuracy of doctors in recognizing lumen was significantly higher with AI assistance than without AI assistance, regardless of their experience (P<0.001). Our AI system could better recognize bronchial lumen and reduce differences in the operation levels of different bronchoscopists. It could be used to improve the quality of everyday bronchoscopies.

Erratum to

This corrects the article DOI 10.21037tlcr-21-536..

Pan-cancer analyses reveal multi-omics and clinical characteristics of RIO kinase 2 in cancer.

RIO kinase 2 has emerged as a critical kinase for ribosome maturation, and recently it has also been found to play a fundamental role in cancer, being involved in the occurrence and progression of glioblastoma, liver cancer, prostate cancer, non-small cell lung cancer, and acute myeloid leukemia. However, our knowledge in this regard is fragmented and limited and it is difficult to determine the exact role of RIO kinase 2 in tumors. Here, we conducted an integrated pan-cancer analysis comprising 33 cancer-types to determine the function of RIO kinase 2 in malignancies. The results show that RIO kinase 2 is highly expressed in all types of cancer and is significantly associated with tumor survival, metastasis, and immune cell infiltration. Moreover, RIO kinase 2 alteration

Validation of Traditional Prognosis Scoring Systems and Skeletal Oncology Research Group Nomogram for Predicting Survival of Spinal Metastasis Patients Undergoing Surgery.

Many scoring systems that predict overall patient survival are based on clinical parameters and primary tumor type. To date, no consensus exists regarding which scoring system has the greatest predictive survival accuracy, especially when applied to specific primary tumors. Additionally, such scores usually fail to include modern treatment modalities, which influence patient survival. This study aimed to evaluate both the overall predictive accuracy of such scoring systems and the predictive accuracy based on the primary tumor. A retrospective review on spinal metastasis patients who were aged more than 18 years and underwent surgical treatment was conducted between October 2008 and August 2018. Patients were scored based on data before the time of surgery. A survival probability was calculated for each patient using the given scoring systems. The predictive ability of each scoring system was assessed using receiver operating characteristic analysis at postoperative time points area under the curve was then calculated to quantify predictive accuracy. A total of 186 patients were included in this analysis 101 (54.3%) were men and the mean age was 57.1 years. Primary tumors were lung in 37 (20%), breast in 26 (14%), prostate in 20 (10.8%), hematologic malignancy in 18 (9.7%), thyroid in 10 (5.4%), gastrointestinal tumor in 25 (13.4%), and others in 40 (21.5%). The primary tumor was unidentified in 10 patients (5.3%). The overall survival was 201 days. For survival prediction, the Skeletal Oncology Research Group (SORG) nomogram showed the highest performance when compared to other prognosis scores in all tumor metastasis but a lower performance to predict survival with lung cancer. The revised Katagiri score demonstrated acceptable performance to predict death for breast cancer metastasis. The Tomita and revised Tokuhashi scores revealed acceptable performance in lung cancer metastasis. The New England Spinal Metastasis Score showed acceptable performance for predicting death in prostate cancer metastasis. SORG nomogram demonstrated acceptable performance for predicting death in hematologic malignancy metastasis at all time points. The results of this study demonstrated inconsistent predictive performance among the prediction models for the specific primary tumor types. The SORG nomogram revealed the highest predictive performance when compared to previous survival prediction models.

Pituitary metastasis as the first manifestation of lung carcinoma.

Pituitary metastases are rare. Clinical presentation could range from asymptomatic to panhypopituitarism or local symptoms. We present a case report of a 43-year-old male patient with a new onset headache, visual disturbances, and panhypopituitarism. The investigation led to the diagnosis of pituitary metastasis as the first manifestation of underlying lung cancer.

Autoencoder Networks Decipher the Association between Lung Cancer and Alzheimers Disease.

Lung cancer is the most common malignancy and is responsible for the largest cancer-related mortality worldwide. Alzheimers disease is a degenerative neurological disease that burdens healthcare worldwide. While the two diseases are distinct, several transcriptomic studies have demonstrated they are linked. However, no concordant conclusion on how they are associated has been drawn. Since these studies utilized conventional bioinformatics methods, such as the differentially expressed gene (DEG) analysis, it is naturally expected that the proportion of DEGs having either the same or inverse directions in lung cancer and Alzheimers disease is substantial. This raises the inconsistency. Therefore, a novel bioinformatics method capable of determining the direction of association is desirable. In this study, the moderated

Assessing the efficacy of immunotherapy in lung squamous carcinoma using artificial intelligence neural network.

At present, immunotherapy is a very promising treatment method for lung cancer patients, while the factors affecting response are still controversial. It is crucial to predict the efficacy of lung squamous carcinoma patients who received immunotherapy. In our retrospective study, we enrolled lung squamous carcinoma patients who received immunotherapy at Beijing Chest Hospital from January 2017 to November 2021. All patients were grouped into two cohorts randomly, the training cohort (80% of the total) and the test cohort (20% of the total). The training cohort was used to build neural network models to assess the efficacy and outcome of immunotherapy in lung squamous carcinoma based on clinical information. The main outcome was the disease control rate (DCR), and then the secondary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 289 patients were included in this study. The DCR model had area under the receiver operating characteristic curve (AUC) value of 0.9526 (95%CI, 0.9088-0.9879) in internal validation and 0.9491 (95%CI, 0.8704-1.0000) in external validation. The ORR model had AUC of 0.8030 (95%CI, 0.7437-0.8545) in internal validation and 0.7040 (95%CI, 0.5457-0.8379) in external validation. The PFS model had AUC of 0.8531 (95%CI, 0.8024-0.8975) in internal validation and 0.7602 (95%CI, 0.6236-0.8733) in external validation. The OS model had AUC of 0.8006 (95%CI, 0.7995-0.8017) in internal validation and 0.7382 (95%CI, 0.7366-0.7398) in external validation. The neural network models show benefits in the efficacy evaluation of immunotherapy to lung squamous carcinoma patients, especially the DCR and ORR models. In our retrospective study, we found that neoadjuvant and adjuvant immunotherapy may bring greater efficacy benefits to patients.

Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448).

Lazertinib (YH25448) is a novel third-generation tyrosine kinase inhibitor (TKI) developed as a treatment for EGFR mutant non-small cell lung cancer. To better understand the nature of lazertinib inhibition, we determined crystal structures of lazertinib in complex with both WT and mutant EGFR and compared its binding mode to that of structurally related EGFR TKIs. We observe that lazertinib binds EGFR with a distinctive pyrazole moiety enabling hydrogen bonds and van der Waals interactions facilitated through hydrophilic amine and hydrophobic phenyl groups, respectively. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858RT790M) and to a lesser extent HER2. The molecular basis for lazertinib inhibition of EGFR reported here highlights previously unexplored binding interactions leading to improved medicinal chemistry properties compared to clinically approved osimertinib (AZD9291) and offers novel strategies for structure-guided design of tyrosine kinase inhibitors.

The safety and efficacy of oxaliplatin-loaded drug-eluting beads transarterial chemoembolization for the treatment of unresectable or advanced lung cancer.

Immunotherapy and targeted therapy for lung cancer Current status and future perspectives.

Lung cancer has the highest incidence of morbidity and mortality throughout the globe. A large number of patients are diagnosed with lung cancer at the later stages of the disease. This eliminates surgery as an option and places complete dependence on radiotherapy or chemotherapy, andor a combination of both, to halt disease progression by targeting the tumor cells. Unfortunately, these therapies have rarely proved to be effective, and this necessitates the search for alternative preventive approaches to reduce the mortality rate of lung cancer. One of the effective therapies against lung cancer comprises targeting the tumor microenvironment. Like any other cancer cells, lung cancer cells tend to use multiple pathways to maintain their survival and suppress different immune responses from the hosts body. This review comprehensively covers the role and the mechanisms that involve the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lung adenocarcinoma and methods of treating it by altering the tumor microenvironment. It focuses on the insight and understanding of the lung cancer tumor microenvironment and chemokines, cytokines, and activating molecules that take part in angiogenesis and metastasis. The review paper accounts for the novel and current immunotherapy and targeted therapy available for lung cancer in clinical trials and in the research phases in depth. Special attention is being paid to mark out single or multiple genes that are required for malignancy and survival while developing targeted therapies for lung cancer treatment.

Facilitative glucose transporters (GLUTs), which are encoded by solute carrier 2A (

Drug-induced liver injury in COVID-19 treatment Incidence, mechanisms and clinical management.

The COVID-19 outbreak triggered a serious and potentially lethal pandemic, resulting in massive health and economic losses worldwide. The most common clinical manifestations of COVID-19 patients are pneumonia and acute respiratory distress syndrome, with a variety of complications. Multiple organ failure and damage, ultimately leading to patient death, are possible as a result of medication combinations, and this is exemplified by DILI. We hope to summarize DILI caused by the antiviral drugs favipiravir, remdesivir, lopinavirritonavir, and hydroxychloroquine in COVID-19 patients in this review. The incidence of liver injury in the treatment of COVID-19 patients was searched on PubMed to investigate DILI cases. The cumulative prevalence of acute liver injury was 23.7% (16.1%-33.1%). We discuss the frequency of these events, potential mechanisms, and new insights into surveillance strategies. Furthermore, we also describe medication recommendations aimed at preserving DILI caused by treatment in COVID-19 patients.

Epidemiology and prediction model of patients with carcinosarcoma in the United States.

Carcinosarcoma is a rare biphasic tumor composed of both carcinoma and sarcoma elements, which occurs at various sites. Most studies are case reports or small population-based studies for a single disease site, so comprehensive evaluations of epidemiology and prognostic factors for carcinosarcoma are needed. Surveillance, Epidemiology, and End Results (SEER)-8 (1975-2019) provided data for the epidemiological analysis. SEER-17 (2000-2019) provided data on the primary tumor sites, initial treatment, construction, and validation of the nomogram. The age-adjusted incidence per 100,000 persons of carcinosarcoma increased significantly from 0.46 to 0.91 1975-2019 average annual percent change (AAPC) 1.3%, In this study, the incidence, prevalence, and mortality of carcinosarcoma have increased over the past decades. There was a rapid rise in the incidence of localized stage in recent years, which reflected improved early detection. The prognosis of carcinosarcoma remains poor, signifying the urgency of exploring targeted cancer control treatments. Explicating distribution and gender disparities of carcinosarcoma may facilitate disease screening and medical surveillance. The nomogram demonstrated good predictive capacity and facilitated clinical decision-making.

High tumor burden in non-small-cell lung cancer A review of the literature.

Lung cancer is the leading cause of cancer death worldwide and the majority of the patients have advancedmetastatic disease on presentation. In clinical practice, several biomarkers and clinical factors are taken into account when choosing the best treatment option in advanced non-small-cell lung cancer (NSCLC). One potential marker may be tumor burden (TB). However, this concept is not specifically defined in NSCLC, and usually, it is used as a synonymous for aggressive disease. A non-systematic literature review was conducted. We searched for eligible randomized controlled trials from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials with a cutoff at February 2021. The keywords included non-small-cell lung cancer, tumor burden, aggressive disease, prognosis biomarker, predictive biomarker, and immunotherapy. This review addresses the definition of TB in advanced NSCLC, the pathophysiology of high TB lesions, and the role of TB as a prognosis biomarker. The concept of aggressive disease, as high tumor burden definition, remains poorly defined and rarely considered in clinical research or clinical practice in oncology. The identification of this subgroup of patients could be interesting for defining and optimizing a more aggressive treatment strategy.

Effects of cigarette smoke extract derived from heated tobacco products on the proliferation of lung cancer stem cells.

Epidemiological studies have suggested that cigarette smoking can increase a persons risk of developing several types of cancer, including lung cancer. Lung cancer originates from cancer stem cells (CSCs), which constitute a minor cell population in tumors, and contribute to drug resistance and recurrence. Heated tobacco products (HTPs) produce aerosols that contain nicotine and toxic chemicals. Current evidence, however, is insufficient to accurately determine if HTPs are less harmful than burned cigarettes. This study has investigated the effects of cigarette smoke extract (CSE) from HTPs on lung CSCs in lung cancer cell lines. We found that CSEs induced the proliferation of lung CSCs and increased the expression levels of stem cell markers. In addition, CSE induced epithelial-mesenchymal transition (EMT) expression and cytokine production. These results suggest that HTPs can induce lung CSCs in vitro.

Recovering the angiogenicangiostatic balance in NNK-induced lung carcinoma via 12 weeks of submaximal swimming and

Carcinogen nitrosamine 4-(methyl-trosamino)-1-(3-pyridyl)-1-butanone (NNK) remarkably affects the actions of growth factors EGFR, VEGFR-2, as well as the natural tumor suppressors TGFβ-1 and TIMP-1. We propose that utilizing non-chemical interventions such as swimming and Male rats were randomly placed into seven groups Control (C), Solvent (S), (NNK), NNK In comparison with control group, there was a significant increase in the levels of VEGFR-2 in NNK, NNKE, NNKNS, NSE, and NNKNSE groups We recommend 12 weeks of submaximal swimming and 125 μgkg

Managing MMP-2, MMP-9, VEGFR-2, TGFβ-1, and TIMP-1 in NNK-induced lung carcinoma by nonchemical interventions in female rats.

Smart and flexible methods are attracting remarkable interest in cancer-related biological and chemical therapies. To achieve a safer, affordable, and more effective cancer treatment, we evaluated the application of submaximal swimming and A 12-weeks protocol of submaximal swimming was performed in pathologic and non-pathologic groups. NNK and NS groups, respectively received weekly doses of 125 mgkg and 125 μgkg of body weight. By the end of the protocol, the ratios of MMP-2, MMP-9, and TIMP-1 determined by using immunohistochemistry essay, and RT-PCR analysis for VEGFR-2 and TGFβ-1. As a result, treatment with exercise and NNK resulted in VEGFR-2 overexpression ( IHC and gene assays indicate a favorable and acceptable effect of the designed training protocol besides the treatment with

Type XXVIII Collagen Regulates Renal Interstitial Fibrosis and Epithelial-Mesenchymal Transition by SREBP1-Mediated HKDC1 Expression.

A novel collagen called type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. Preliminary data showed that renal tubular epithelial cells could proliferate, migrate, and undergo an epithelial-mesenchymal transition (EMT) when COL28 was overexpressed however, it is still unknown how this occurs and what the underlying mechanism is. We analyzed the differential expression of genes (DEGs) in the stable COL28 overexpression HK-2 cell lines by RNA-sequencing analysis, before which Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) analyses were performed. Genes related to COL28 promoting HK-2 cell proliferation and EMT were screened and verified. By using western blot and immunofluorescence, the effects of COL28 on the expression of We screened and verified that HKDC1 was related to COL28 and promoted HK-2 cell proliferation and EMT. WB showed that in HK-2 cells, COL28 overexpression increased Overexpression of COL28 can aggravate renal interstitial fibrosis by encouraging renal tubular epithelial cells to undergo EMT, and interference with HKDC1 expression can alleviate fibrosis by reversing EMT induced by COL28 overexpression.