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An explainable AI-driven biomarker discovery framework for Non-Small Cell Lung Cancer classification.

Non-Small Cell Lung Cancer (NSCLC) exhibits intrinsic heterogeneity at the molecular level that aids in distinguishing between its two prominent subtypes - Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC). This paper proposes a novel explainable AI (XAI)-based deep learning framework to discover a small set of NSCLC biomarkers. The proposed framework comprises three modules - an autoencoder to shrink the input feature space, a feed-forward neural network to classify NSCLC instances into LUAD and LUSC, and a biomarker discovery module that leverages the combined network comprising the autoencoder and the feed-forward neural network. In the biomarker discovery module, XAI methods uncovered a set of 52 relevant biomarkers for NSCLC subtype classification. To evaluate the classification performance of the discovered biomarkers, multiple machine-learning models are constructed using these biomarkers. Using 10-Fold cross-validation, Multilayer Perceptron achieved an accuracy of 95.74% (±1.27) at 95% confidence interval. Further, using Drug-Gene Interaction Database, we observe that 14 of the discovered biomarkers are druggable. In addition, 28 biomarkers aid the prediction of the survivability of the patients. Out of 52 discovered biomarkers, we find that 45 biomarkers have been reported in previous studies on distinguishing between the two NSCLC subtypes. To the best of our knowledge, the remaining seven biomarkers have not yet been reported for NSCLC subtyping and could be further explored for their contribution to targeted therapy of lung cancer.

Honeycomb resin-based spin-column solid-phase extraction for efficient determination of alectinib and its metabolite in human urine.

Alectinib and its metabolite, M4, have demonstrated a satisfactory clinical therapeutic effect in the treatment of anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer. Due to individual differences among patients, therapeutic drug monitoring (TDM) is critical for guaranteeing appropriate clinical drug use. To realize TDM for alectinib and its metabolite, M4, a honeycomb phenol-formaldehyde resin (PFR) with excellent hydrophilic properties, abundant adsorption force, and a stable porous structure was synthesized by modifying the porogens F127 and P123. The prepared PFR was employed as an adsorbent in a simple and efficient spin-column solid-phase extraction (SPE) process. A rapid method for detecting alectinib and its metabolite M4 in urine was thereby established. The established method showed a linear range of 0.0200 μg mL

A Novel Tri-Functional Liposome Re-Educates Cold Tumor and Abrogates Tumor Growth by Synergizing Autophagy Inhibition and PD-L1 Blockade.

Immunotherapy has been regarded as a breakthrough in cancer treatment and achieved great success. However, the poor response rate is still a formidable challenge of current immunotherapies, especially in solid tumors without sufficient infiltration of immune cells, also known as cold tumor. SAR405 is a highly specific VPS34 inhibitor and has been suggested as a potential approach converting cold tumor into hot tumor by inhibiting autophagy. In this study, a tri-functional doxorubicin (DOX) plus SAR405 liposome system is established and further modified with a novel anti-PD-L1 peptide JY4 for targeted delivery (DOX-SAR-JY4

Image-Based Deep Neural Network for Individualizing Radiotherapy Dose Is Transportable Across Health Systems.

We developed a deep neural network that queries the lung computed tomography-derived feature space to identify radiation sensitivity parameters that can predict treatment failures and hence guide the individualization of radiotherapy dose. In this article, we examine the transportability of this model across health systems. This multicenter cohort-based registry included 1,120 patients with cancer in the lung treated with stereotactic body radiotherapy. Pretherapy lung computed tomography images from the internal study cohort (n 849) were input into a multitask deep neural network to generate an image fingerprint score that predicts time to local failure. Deep learning (DL) scores were input into a regression model to derive There were substantive differences in the baseline patient characteristics of the two study populations, permitting an assessment of model transportability. In the external cohort, radiation treatments in patients with high DL scores failed at a significantly higher rate with 3-year cumulative incidences of local failure of 28.5% (95% CI, 19.8 to 37.8) versus 10.2% (95% CI, 5.9 to 16.2 hazard ratio, 3.3 95% CI, 1.74 to 6.49 Our results support the development and implementation of new DL-guided treatment guidance tools in the image-replete and highly standardized discipline of radiation oncology.

CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified however, the molecular basis for this resistance remains unknown in 30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant LUAD. Loss of CBX5 confers resistance to multiple EGFRi in both cell culture and mice. We found that CBX5 loss in EGFR-mutant LUAD cells leads to increased expression of the transcription factor E2F1, which in turn stimulates expression of the antiapoptotic gene

Association Between Surgical Quality Metric Adherence and Overall Survival Among US Veterans With Early-Stage Non-Small Cell Lung Cancer.

Surgical resection remains the preferred treatment for functionally fit patients diagnosed with early-stage non-small cell lung cancer (NSCLC). Process-based intraoperative quality metrics (QMs) are important for optimizing long-term outcomes following curative-intent resection. To develop a practical surgical quality score for patients diagnosed with clinical stage I NSCLC who received definitive surgical treatment. This retrospective cohort study used a uniquely compiled data set of US veterans diagnosed with clinical stage I NSCLC who received definitive surgical treatment from October 2006 through September 2016. The data were analyzed from April 1 to September 1, 2022. Based on contemporary treatment guidelines, 5 surgical QMs were defined timely surgery, minimally invasive approach, anatomic resection, adequate lymph node sampling, and negative surgical margin. The study developed a surgical quality score reflecting the association between these QMs and overall survival (OS), which was further validated in a cohort of patients using data from the National Cancer Database (NCDB). The study also examined the association between the surgical quality score and recurrence-free survival (RFS). Surgical treatment of early-stage NSCLC. Overall survival and RFS. The study included 9628 veterans who underwent surgical treatment between 2006 and 2016. The cohort consisted of 1446 patients who had a mean (SD) age of 67.6 (7.9) years and included 9278 males (96.4%) and 350 females (3.6%). Among the cohort, 5627 individuals (58.4%) identified as being smokers at the time of surgical treatment. The QMs were met as follows timely surgery (6633 68.9%), minimally invasive approach (3986 41.4%), lobectomy (6843 71.1%) or segmentectomy (532 5.5%), adequate lymph node sampling (3278 34.0%), and negative surgical margin (9312 96.7%). The median (IQR) follow-up time was 6.2 (2.5-11.4) years. An integer-based score (termed the Veterans Affairs Lung Cancer Operative quality VALCAN-O score) from 0 (no QMs met) to 13 (all QMs met) was constructed, with higher scores reflecting progressively better risk-adjusted OS. The median (IQR) OS differed substantially between the score categories (score of 0-5 points, 2.6 1.0-5.7 years of OS 6-8 points, 4.3 1.7-8.6 years 9-11 points, 6.3 2.6-11.4 years and 12-13 points, 7.0 3.0-12.5 years P < .001). In addition, risk-adjusted RFS improved in a stepwise manner between the score categories (6-8 vs 0-5 points, multivariable-adjusted hazard ratio aHR, 0.62 95% CI, 0.48-0.79 P < .001 12-13 vs 0-5 points, aHR, 0.39 95% CI, 0.31-0.49 P < .001). In the validation cohort, which included 107 674 nonveteran patients, the score remained associated with OS. The findings of this study suggest that adherence to intraoperative QMs may be associated with improved OS and RFS. Efforts to improve adherence to surgical QMs may improve patient outcomes following curative-intent resection of early-stage lung cancer.

An Adjusted Treatment Comparison Comparing Amivantamab Versus Real-World Clinical Practice in Europe and the United States for Patients with Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Exon 20 Insertion Mutations.

Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776 Cohort D). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence. RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW average treatment effect among the treated ATT). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR investigator- INV and independent review committee-assessed IRC), overall survival (OS), progression-free survival (PFS INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively. Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU US cohort (response rate ratio RR 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52 months (hazard ratio HR 0.47 p < 0.0001), 6.93 versus 4.17 months (HR 0.55 p < 0.0001) and 12.42 versus 5.36 months (HR 0.44 p < 0.0001) for amivantamab versus the adjusted EU US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment. Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy. CHRYSALIS NCT02609776.

Osimertinib for EGFR-Mutant Non-Small-Cell Lung Cancer Central Nervous System Metastases Current Evidence and Future Perspectives on Therapeutic Strategies.

Central nervous system (CNS) metastases are common in non-small-cell lung cancer (NSCLC) and associated with poor prognosis and high disease burden. Effective options are needed to treat CNS metastases, and delay or prevent their formation. For epidermal growth factor receptor mutation-positive (EGFRm) advanced NSCLC and brain metastases, upfront EGFR-tyrosine kinase inhibitors (TKIs) are recommended by the joint European Association of Neuro-Oncology-European Society for Medical Oncology and experts. While early-generation EGFR-TKIs have limited CNS efficacy, the third-generation, irreversible, EGFR-TKI osimertinib has potent efficacy in NSCLC CNS metastases. This review discusses the CNS data of osimertinib in the context of therapeutic strategies and future prospects based on expert review of published literature and relevant clinical, real-world, and ongoing studies in this setting. Osimertinib penetrates the blood-brain barrier and achieves greater exposure in the brain compared with other EGFR-TKIs. Osimertinib has demonstrated CNS efficacy, including in leptomeningeal metastases, in EGFRm advanced disease. In EGFRm stage IB-IIIA NSCLC, adjuvant osimertinib reduced CNS disease recurrence versus placebo. The burden and poor prognosis of CNS metastases necessitate more therapeutic options for their management and reduced risk of recurrence in patients with EGFRm NSCLC. Clinical studies are ongoing in advanced disease to investigate osimertinib combinations with chemotherapyradiation therapy and optimal treatment post-CNS progression with osimertinib. Further prospective research evaluating treatments using CNS-specific endpoints and evaluating CNS resistance is needed to improve outcomes for patients with CNS metastases.

Oligometastatic Colorectal Cancer A Review of Definitions and Patient Selection for Local Therapies.

Nearly one-third of patients diagnosed with colorectal cancer (CRC) will ultimately develop metastatic disease. While a small percentage of patients can be considered for curative resection, more patients have limited disease that can be considered for local therapy. Challenges remain in defining oligometastatic CRC as well as developing treatment strategies guided by high level evidence. In this review, we present the challenges in defining oligometastatic CRC and summarize the current literature on treatment and outcomes of local therapy in patients with metastatic CRC. For patients with liver- andor lung-confined CRC metastases, surgical resection is the standard of care given the potential for long-term progression-free and overall survival. For patients with liver- or lung-confined disease not amenable to surgical resection, non-surgical local therapies, such as thermal ablation, hepatic arterial infusion pump (HAIP), or stereotactic body radiation therapy (SBRT), should be considered. For patients with more advanced disease, such as lymph node or bony metastases, the role of metastasis-directed therapy is controversial. Emerging data suggests that SBRT to ablate all metastases can improve progression-free and overall survival. Multidisciplinary management is critical for patients with metastatic CRC due to the complexity of their cases and the nuanced patient, tumor, biological, and anatomical factors that must be weighed when considering local therapy. High-quality prospective randomized data in CRC are needed to further clarify the role of local ablative therapy in patients with unresectable oligometastatic CRC with ongoing studies including the RESOLUTE trial (ACTRN12621001198819) and the upcoming NCTN ERASur trial (NCT05673148).

Targeting Redundant ROBO1 and SDF-1 Pathways Prevents Adult Hemangioblast Derived-EPC and CEC Activity Effectively Blocking Tumor Neovascularization.

Neovascularization is a key therapeutic target for cancer treatment. However, anti-angiogenic therapies have shown modest success, as tumors develop rapid resistance to treatment owing to activation of redundant pathways that aid vascularization. We hypothesized that simultaneously targeting different pathways of neovascularization will circumvent the current issue of drug resistance and offer enhanced therapeutic benefits. To test this hypothesis, we made use of two distinct models of tumor-neovascularization, which exhibit equally dense microvasculature but show disparate sensitivity to anti-SDF-1 treatment. Lewis lung carcinoma (LLC) is primarily a vasculogenic-tumor that is associated with HSC functioning as a hemangioblast to generate circulating Endothelial Progenitor Cells contributing to formation of new blood vessels, and responds to anti-SDF-1 treatment. B16F0 melanoma is an angiogenic-tumor that derives new blood vessels from existing vasculature and is resistant to anti-SDF-1 therapy. In this study, we observed increased expression of the angiogenic-factor, Robo1 predominantly expressed on the blood vessels of B16F0 tumor. Blockade of Robo1 by the decoy receptor, RoboN, resulted in reduced microvascular-density and tumor-growth. However, this was associated with mobilization of BM-cells into the B16F0 tumor, thus switching the mode of neovascularization from angiogenic to vasculogenic. The use of a combinatorial treatment of RoboN and the monoclonal anti-SDF-1 antibody effectively attenuated tumor-growth and inhibited both angiogenic and BM-derived microvessels.

Overview of genetic and epigenetic regulation of human papillomavirus and apoptosis in cervical cancer.

Cervical cancer is the fourth most common cancer affecting women worldwide after breast, colorectal and lung cancers. Owing to a lack of awareness and resources, low- and middle-income countries bear most of the burden of cervical cancer. In developed countries, the incidence rate has been halved over the past three decades due to robust screening and implementation of vaccine programs. HPV is not the sole cause of cervical cancer but acts as a principal factor in the pathogenesis of cervical cancer. By integrating into the host genome, its oncogenic proteins (E6 and E7) alter and interfere with the standard signal transduction machinery of the host. Apoptosis is a key pathway affected by aberrant genetic mutations, polymorphisms and epigenetic mechanisms during cervical carcinogenesis. Along with DNA methylation and histone modifications, non-coding RNAs have also been implicated as epigenetic modulators in various malignancies and are being explored for reversing disease severity. This review emphasizes various genetic and epigenetic approaches regulating apoptotic pathways and HPV E6 and E7 genes that can be targeted to overcome the challenges in cervical cancer treatment. In addition, it also discusses the apoptosis targeting novel drug molecules in cervical cancer which are currently undergoing clinical and pre-clinical trials.

Targeted Delivery of Metformin Against Lung Cancer Cells Via Hyaluronan-Modified Mesoporous Silica Nanoparticles.

Metformin (Metf), a biguanide widely used to manage type 2 diabetes mellitus, has recently entered the spotlight as a hopeful anti-tumor agent. In this work, because of the hyaluronic acid (HA) capability to specifically target CD44 receptors over-expressed on the surface of non-small lung cancer cells, a tumor-targeted drug delivery nanocarrier-based HA-coated mesoporous silica nanoparticles (MSNs) have been used for active targeting and efficient delivery of Metf. For this purpose, the synthesized MSNs-HA were characterized using BET, FE-EM, DLS, and FTIR. Confocal microscopy was applied to show the enhanced cellular uptake of the FITC-labelled MSNs-HA compared to MSNs without HA coating. MTT and qPCR results also revealed superior cytotoxicity and pro-apoptotic effects of Metf-loaded MSNs-HA (MetfMSNs-HA) against the A549 lung cancer cells compared to the free Metf and MSNsMetf due to the efficient CD44-targeting capability and delivery of MetfMSNs-HA. Besides, it was demonstrated that MetfMSNs-HA could effectively trigger the AMP-activated protein kinase α (AMPKα) pathway and inhibit the mammalian target rapamycin (mTOR), increasing the growth suppression. In conclusion, this preliminary work disclosed the great potential of MetfMSNs-HA in targeted therapy of lung cancer cells.

Is the generalizability of a developed artificial intelligence algorithm for COVID-19 on chest CT sufficient for clinical use Results from the International Consortium for COVID-19 Imaging AI (ICOVAI).

Only few published artificial intelligence (AI) studies for COVID-19 imaging have been externally validated. Assessing the generalizability of developed models is essential, especially when considering clinical implementation. We report the development of the International Consortium for COVID-19 Imaging AI (ICOVAI) model and perform independent external validation. The ICOVAI model was developed using multicenter data (n 1286 CT scans) to quantify disease extent and assess COVID-19 likelihood using the COVID-19 Reporting and Data System (CO-RADS). A ResUNet model was modified to automatically delineate lung contours and infectious lung opacities on CT scans, after which a random forest predicted the CO-RADS score. After internal testing, the model was externally validated on a multicenter dataset (n 400) by independent researchers. CO-RADS classification performance was calculated using linearly weighted Cohens kappa and segmentation performance using Dice Similarity Coefficient (DSC). Regarding internal versus external testing, segmentation performance of lung contours was equally excellent (DSC 0.97 vs. DSC 0.97, p 0.97). Lung opacities segmentation performance was adequate internally (DSC 0.76), but significantly worse on external validation (DSC 0.59, p < 0.0001). For CO-RADS classification, agreement with radiologists on the internal set was substantial (kappa 0.78), but significantly lower on the external set (kappa 0.62, p < 0.0001). In this multicenter study, a model developed for CO-RADS score prediction and quantification of COVID-19 disease extent was found to have a significant reduction in performance on independent external validation versus internal testing. The limited reproducibility of the model restricted its potential for clinical use. The study demonstrates the importance of independent external validation of AI models. • The ICOVAI model for prediction of CO-RADS and quantification of disease extent on chest CT of COVID-19 patients was developed using a large sample of multicenter data. • There was substantial performance on internal testing however, performance was significantly reduced on external validation, performed by independent researchers. The limited generalizability of the model restricts its potential for clinical use. • Results of AI models for COVID-19 imaging on internal tests may not generalize well to external data, demonstrating the importance of independent external validation.

Bayesian hierarchical model-based network meta-analysis to overcome survival extrapolation challenges caused by data immaturity.

Bayesian hierarchical model-based network meta-analysis for survival outcomes are shown to overcome data immaturity issues in the evidence network, they impacts incremental mean life years and cost–effectiveness ratios, affecting reimbursement decisions.

Design and development of novel 1,2,3-triazole chalcone derivatives as potential anti-osteosarcoma agents

Osteosarcoma (OS) is an uncommon tumour that mainly affects bone in children and adolescents. The current treatment options of OS are of limited significance due to their immense side effects. In the present manuscript, we have developed a novel series of 1,2,3-triazole chalcone derivatives as potential agents against OS. The compounds were synthesized and evaluated for their PI3K and mTOR inhibitory activity using luminescent kinase assay, and Lance ultra assay, resp. The entire set of compounds showed significant to moderate inhibition of both kinases in the nanomolar range. The three most active compounds

Wide-field Stokes polarimetric microscopy for second harmonic generation imaging.

We employ wide-field second harmonic generation (SHG) microscopy together with nonlinear Stokes polarimetry for quick ultrastructural investigation of large sample areas (700 μm × 700 μm) in thin histology sections. The Stokes vector components for SHG are obtained from the polarimetric measurements with incident and outgoing linear and circular polarization states. The Stokes components are used to construct the images of polarimetric parameters and deduce the maps of ultrastructural parameters of achiral and chiral nonlinear susceptibility tensor components ratios and cylindrical axis orientation in fibrillar materials. The large area imaging was employed for lung tumor margin investigations. The imaging shows reduced SHG intensity, increased achiral susceptibility ratio values, and preferential orientation of collagen strands along the boarder of tumor margin. The wide-field Stokes polarimetric SHG microscopy opens a possibility of quick large area imaging of ultrastructural parameters of tissue collagen, which can be used for nonlinear histopathology investigations.

Cancer-Responsive Multifunctional Nanoplatform Based on Peptide Self-Assembly for Highly Efficient Combined Cancer Therapy by Alleviating Hypoxia and Improving the Immunosuppressive Microenvironment.

Hypoxia, as a main feature of the tumor microenvironment, has greatly limited the efficacy of photodynamic therapy (PDT), as well as its clinical application. Here, a multifunctional composite nanoplatform, the peptideCe6MnO

Ultrasound-guided stellate ganglion block improves sleep quality in elderly patients early after thoracoscopic surgery for lung cancer a randomized controlled study.

To investigate the effects of ultrasound-guided stellate ganglion block (SGB) on sleep quality in elderly patients with lung cancer early after thoracoscopic surgery. A total of 86 patients with lung cancer (ASA class I-III, aged 60-80 years) undergoing elective thoracoscopic surgery were randomized into stellate ganglion block (SGB) group ( Thirty-six patients in SGB group and 35 in the control group were analyzed. In both groups, most of the patients had insomnia after surgery, but compared with those in the control group, the patients in SGB group had significantly longer sleep duration ( Ultrasound-guided SGB improves objective and subjective sleep quality in elderly patients early after thoracoscopic surgery for lung cancer to alleviate stress responses and sleep disorders, reduce postoperative hospital stay, and accelerate postoperative recovery of the patients. 探讨超声引导下星状神经节阻滞(SGB)对老年肺癌患者胸腔镜手术后早期睡眠的影响。 纳入我院择期行胸腔镜手术的肺癌患者86例，年龄6080岁，BMI 2027 kgm 最后SGB组有36例患者，对照组有35例患者纳入分析。两组患者术后大多出现失眠，但与对照组相比，SGB组患者术后第1晚及术后第2晚的睡眠持续时间更长（ 超声引导下SGB可以改善老年肺癌患者胸腔镜手术后早期客观及主观睡眠，使应激反应与睡眠障碍间的恶性循环关系有所缓解，减少术后住院天数，促进患者快速康复。

Effective personalized neoantigen vaccine plus anti-PD-1 in a PD-1 blockade-resistant lung cancer patient.

Immunotherapy based on immune checkpoint inhibitors (ICIs) is very effective in lung cancer treatment. However, many patients with initial response will later develop resistance. There are not many treatment options for patients with drug resistance. Herein, we report a patient with lung cancer who became resistant to ICI, treated with personalized vaccine plus ICI. Based on the patients own somatic mutational profile, personalized neoantigen vaccines were designed and manufactured unique to the patient. Our report indicated that personalized vaccine plus ICI was safe and might overcome ICI resistance. A new ICI resistance mutation on

Lifestyle, genetic risk and incidence of cancer a prospective cohort study of 13 cancer types.

Genetic and lifestyle factors are associated with cancer risk. We investigated the benefits of adhering to lifestyle advice by the World Cancer Research Fund (WCRF) with the risk of 13 types of cancer and whether these associations differ according to genetic risk using data from the UK Biobank. In 2006-2010, participants aged 37-73 years had their lifestyle assessed and were followed up for incident cancers until 2015-2019. Analyses were restricted to those of White European ancestry with no prior history of malignant cancer (n 195 822). Polygenic risk scores (PRSs) were computed for 13 cancer types and these cancers combined (overall cancer), and a lifestyle index was calculated from WCRF recommendations. Associations with cancer incidence were estimated using Cox regression, adjusting for relevant confounders. Additive and multiplicative interactions between lifestyle index and PRSs were assessed. There were 15 240 incident cancers during the 1 926 987 person-years of follow-up (median follow-up 10.2 years). After adjusting for confounders, the lifestyle index was associated with a lower risk of overall cancer hazard ratio per standard deviation increase (95% CI) 0.89 (0.87, 0.90) and of eight specific cancer types. There was no evidence of interactions on the multiplicative scale. There was evidence of additive interactions in risks for colorectal, breast, pancreatic, lung and bladder cancers, such that the recommended lifestyle was associated with greater change in absolute risk for persons at higher genetic risk (P < 0.0003 for all). The recommended lifestyle has beneficial associations with most cancers. In terms of absolute risk, the protective association is greater for higher genetic risk groups for some cancers. These findings have important implications for persons most genetically predisposed to those cancers and for targeted strategies for cancer prevention.

Lnc-TMEM132D-AS1 as a potential therapeutic target for acquired resistance to osimertinib in non-small-cell lung cancer.

Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in non-small-cell lung cancer (NSCLC). Current knowledge about the role of long non-coding RNAs (lncRNAs) in this phenomenon is insufficient. In this study, we screened the differentially expressed lncRNAs between osimertinib-sensitive and -resistant NSCLC cell lines, and determined that lnc-TMEM132D-AS1 was significantly upregulated in osimertinib-resistant NSCLC cells, as well as in the plasma of osimertinib-resistant NSCLC patients. Lnc-TMEM132D-AS1 markedly decreased the osimertinib sensitivity of NSCLC cells. After osimertinib exposure, it increased the cell proliferation and colony formation, decreased the cell apoptosis, and induced M2G-phase cell cycle arrest. After identifying its cytoplasmic localization, a functional lnc-TMEM132D-AS1-miRNA-mRNA interaction network and a protein-protein interaction (PPI) network were constructed to analyze its putative target genes and biological functions. Lnc-TMEM132D-AS1 could directly bind to miR-766-5p and lead to the upregulation of ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), resulting in an increase in cell proliferation. Moreover, upregulated ENTPD1 was also associated with enhanced tumor infiltration of immunosuppressive cells and poor prognosis in NSCLC patients. In summary, lnc-TMEM132D-AS1 plays a crucial role in osimertinib resistance. It may serve as a prognostic biomarker and a potential therapeutic target for acquired resistance to osimertinib in NSCLC.

Respiratory motion tracking of spine stereotactic radiotherapy in prone position.

The CyberKnife system is a specialized device for non-coplanar irradiation however, it possesses the geometric restriction that the beam cannot be irradiated from under the treatment couch. Prone positioning is expected to reduce the dose to normal lung tissue in spinal stereotactic body radiotherapy (SBRT) owing to the efficiency of beam arrangement however, respiratory motion occurs. Therefore, the Xsight spine prone tracking (XSPT) system is used to reduce the effects of respiratory motion. The purpose of this study was to evaluate the motion-tracking error of the spine in the prone position. Data from all 25 patients who underwent spinal SBRT at our institution between April 2020 and February 2022 using CyberKnife (VSI, version 11.1.0) with the XSPT tracking system were retrospectively analyzed using log files. The tumor motion, correlation, and prediction errors for each patient were examined. Furthermore, to assess the potential relationships between the parameters, the relationships between the tumor-motion amplitudes and correlation or prediction errors were investigated using linear regression. The tumor-motion amplitudes in each direction were as follows superior-inferior (SI), 0.51 ± 0.39 mm left-right (LR), 0.37 ± 0.29 mm and anterior-posterior (AP), 3.43 ± 1.63 mm. The overall mean correlation and prediction errors were 0.66 ± 0.48 mm and 0.06 ± 0.07 mm, respectively. The prediction errors were strongly correlated with the tumor-motion amplitudes, whereas the correlation errors were not. This study demonstrated that the correlation error of spinal SBRT in the prone position is sufficiently small to be independent of the tumor-motion amplitude. Furthermore, the prediction error is small, contributing only slightly to the tracking error. These findings will improve the understanding of how to compensate for respiratory-motion uncertainty in the prone position.

Heat treatment-induced autophagy promotes breast cancer cell invasion and metastasis via TGF-

Insufficient thermal ablation can accelerate malignant behaviors and metastases in some solid tumors, and epithelial-mesenchymal transition (EMT) and autophagy are involved in tumor metastasis. It has been found that TGF- BC cells were treated with sublethal heat treatment to simulate insufficient MWA, and the effects of heat treatment on the BC cell phenotypes were explored. CCK-8, colony formation, flow cytometry, Transwell, and wound healing assays were performed to evaluate the influence of sublethal heat treatment on the proliferation, apoptosis, invasion, and migration of BC cells. Western blotting, real-time quantitative PCR, immunofluorescence, and transmission electron microscopy were carried out to determine the changes in markers associated with autophagy and EMT following sublethal heat treatment. Results showed that heat treatment promoted the proliferation of surviving BC cells, which was accompanied by autophagy induction. Heat treatment-induced autophagy up-regulated TGF- Heat treatment-induced autophagy promoted invasion and metastasis via TGF-

The prognostic value of comprehensive geriatric assessment on the management of older patients with small cell lung cancer.

The prognostic value of a comprehensive geriatric assessment (CGA) for the management of older small cell lung cancer (SCLC) patients remains to be established. A retrospective cohort enrolled 21 SCLC patients over 65 years from March 2018 to 2019 at the Yonsei Cancer Center. The CGA included the following instruments frailty, body mass index, sarcopenia (circumference of arm and calf, Timed Up and Go test, grip strength), comorbidity, polypharmacy, activities of daily living (ADL), Instrumental ADL, nutrition, depression, and cognitive function. The correlations of oncological and geriatric variables with overall survival (OS) were determined. The log-rank test with Cox model and Kaplan-Meier method were used for the analysis. The median age was 75 years (range, 67 to 85). All patients had the Eastern Cooperative Oncology Group performance status 0-2. The median survival was 9.93 months (range, 1.53 to 36.30). Among CGA parameters, ADL and nutritional status had significant differences in OS in univariate analysis. In multivariate analysis, only nutritional status was independently associated with survival (hazard ratio, 0.17 95% confidence interval, 0.05 to 0.57). Median OS for low nutritional status was 5.63 months and the normal nutrition group was 15.5 months (p 0.004). Pre-treatment nutritional status measured by CGA appears to be a predictor of OS in older SCLC patients. However, for further generalization of the implication of CGA in SCLC, a larger scale study with prospective design is strongly needed.

The Association between Exposure to Second-Hand Smoke and Disease in the Chinese Population A Systematic Review and Meta-Analysis.

To analyze the association between exposure to second-hand smoke (SHS) and 23 diseases, categorized into four classifications, among the Chinese population. We searched the literature up to June 30, 2021, and eligible studies were identified according to the PECOS format Participants and Competitors (Chinese population), Exposure (SHS), Outcomes (Disease or Death), and Study design (Case-control or Cohort). In total, 53 studies were selected. The odds ratio ( The effect of SHS exposure in China was similar to that in Western countries, but its definition and characterization require further clarification. Studies on the association between SHS exposure and certain diseases with high incidence rates are insufficient.

Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer current status and perspectives.

Over the past decade, targeted therapy for oncogene-driven NSCLC and immune checkpoint inhibitors for non-oncogene-driven NSCLC, respectively, have greatly improved the survival and quality of life for patients with unresectable NSCLC. Increasingly, these biomarker-guided systemic therapies given before or after surgery have been used in patients with early-stage NSCLC. In March 2022, the US FDA granted the approval of neoadjuvant nivolumab and chemotherapy for patients with stage IB-IIIA NSCLC. Several phase IIIII trials are evaluating the clinical efficacy of various neoadjuvant immune checkpoint inhibitor combinations for non-oncogene-driven NSCLC and neoadjuvant molecular targeted therapies for oncogene-driven NSCLC, respectively. However, clinical application of precision neoadjuvant treatment requires a paradigm shift in the biomarker testing and multidisciplinary collaboration at the diagnosis of early-stage NSCLC. In this comprehensive review, we summarize the current diagnosis and treatment landscape, recent advances, new challenges in biomarker testing and endpoint selections, practical considerations for a timely multidisciplinary collaboration at diagnosis, and perspectives in emerging neoadjuvant precision systemic therapy for patients with resectable, early-stage NSCLC. These biomarker-guided neoadjuvant therapies hold the promise to improve surgical and pathological outcomes, reduce systemic recurrences, guide postoperative therapy, and improve cure rates in patients with resectable NSCLC.

Optimizing molecular testing of lung cancer needle biopsy specimens potential solutions from an interdisciplinary qualitative study.

Molecular testing can detect actionable genomic alterations and tumor cell surface proteins in patients with non-small cell lung cancer (NSCLC). However, utilization remains suboptimal, representing missed treatment opportunities. This study aimed to identify challenges and potential solutions to obtaining percutaneous lung needle biopsy specimens for successful molecular testing in patients with advanced NSCLC. This interdisciplinary qualitative study included ten radiologists and four pathologists from academic and community settings across the United States who routinely perform and analyze percutaneous lung needle biopsies. Participants underwent semi-structured one-on-one interviews (Phase 1). Interview questionnaires were constructed based on a literature review of key lines of inquiry and conducted by professional market researchers using the theoretical domains framework. Primary barriers to molecular testing were identified using thematic analysis. Subsequently, multidisciplinary focus groups were convened to identify potential solutions (Phase 2). Four themes emerged as barriers to molecular testing and were matched to the clinical workflow (1) biopsy request, (2) biopsy procedure, (3) specimen analysis, and (4) communication. The nineteen potential solutions included adding a checkbox to indicate molecular testing in the biopsy request, leveraging pre-procedural imaging to guide biopsies, conserving tissue through appropriate allocation strategies and next generation sequencing panels instead of sequential single-gene assays, instituting reflex-molecular testing upon NSCLC diagnosis, tracking and communicating biopsy outcomes at multidisciplinary tumor boards, and improving integration of radiologists and pathologists into oncology care teams. Potential solutions exist to increase successful molecular testing of lung needle biopsy specimens in patients with advanced NSCLC.

An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells.

Antisense oligonucleotide (ASO) medicine for clinical applications has been becoming a reality. We previously developed a gapmer ASO targeting SerArg repetitive matrix 4 (SRRM4) that is abnormally expressed in small cell lung cancer (SCLC). However the detailed mechanism of ASO through repressing SRRM4 has not been completely elucidated. Further, effectiveness of SRRM4 ASO to prostate cancer (PCa) cells expressing SRRM4 similar to SCLC remains to be elucidated. RE1-silencing transcription factor (REST) is a tumor suppressor, and its splicing isoform (sREST) is abnormally expressed by SRRM4 and causes carcinogenesis with neuroendocrine phenotype in SCLC. The present study aimed to understand the contribution of REST splicing by SRRM4 ASO administration. SRRM4 expression and REST splicing were analyzed by RT-qPCR and conventional RT-PCR after treating SRRM4 ASO, and cell viability was analyzed in vitro. Exogenous reconstitution of Flag-tagged REST plasmid in SCLC cells and the splice-switching oligonucleotide (SSO) specific for REST was analyzed for cell viability. Furthermore, we expanded the application of SRRM4 ASO in PCa cells abnormally expressing SRRM4 mRNA in vitro. SRRM4 ASO successfully downregulated SRRM4 expression, followed by repressed cell viability of SCLC and PCa cells in a dose-dependent manner. Administration of SRRM4 ASO then modified the alternative splicing of REST, resulting reduced cell viability. REST SSO specifically modified REST splicing increased REST expression, resulting in reduced cell viability. Our data demonstrate that a gapmer ASO targeting SRRM4 (SRRM4 ASO) reduces cell viability through splicing changes of REST, followed by affecting REST-controlled genes in recalcitrant tumors SCLC and PCa cells.

Genomic and immunogenomic analysis of three prognostic signature genes in LUAD.

Searching for immunotherapy-related markers is an important research content to screen for target populations suitable for immunotherapy. Prognosis-related genes in early stage lung cancer may also affect the tumor immune microenvironment, which in turn affects immunotherapy. We analyzed the differential genes affecting lung cancer patients receiving immunotherapy through the Cancer Treatment Response gene signature DataBase (CTR-DB), and set a threshold to obtain a total of 176 differential genes between response and non-response to immunotherapy. Functional enrichment analysis found that these differential genes were mainly involved in immune regulation-related pathways. The early-stage lung adenocarcinoma (LUAD) prognostic model was constructed through the cancer genome atlas (TCGA) database, and three target genes (MMP12, NFE2, HOXC8) were screened to calculate the risk score of early-stage LUAD. The receiver operating characteristic (ROC) curve indicated that the model had good prognostic value, and the validation set (GSE50081, GSE11969 and GSE42127) from the gene expression omnibus (GEO) analysis indicated that the model had good stability, and the risk score was correlated with immune infiltrations to varying degrees. Multi-type survival analysis and immune infiltration analysis revealed that the transcriptome, methylation and the copy number variation (CNV) levels of the three genes were correlated with patient prognosis and some tumor microenvironment (TME) components. Drug sensitivity analysis found that the three genes may affect some anti-tumor drugs. The mRNA expression of immune checkpoint-related genes showed significant differences between the high and low group of the three genes, and there may be a mutual regulatory network between immune checkpoint-related genes and target genes. Tumor immune dysfunction and exclusion (TIDE) analysis found that three genes were associated with immunotherapy response and maybe the potential predictors to immunotherapy, consistent with the CTR-DB database analysis. From the perspective of data mining, this study suggests that MMP12, NFE2, and HOXC8 may be involved in tumor immune regulation and affect immunotherapy. They are expected to become markers of immunotherapy and are worthy of further experimental research.

Using Community Health Advisors to Increase Lung Cancer Screening Awareness in the Black Belt a Pilot Study.

Disease stage at the time of diagnosis is the most important determinant of prognosis for lung cancer. Despite demonstrated effectiveness of lung cancer screening (LCS) in reducing lung cancer mortality, early detection continues to elude populations with the highest risk for lung cancer death. Consistent with the national rate, current screening rate in Alabama is dismal at 4.2%. While public awareness of LCS may be a likely cause, there are no studies that have thoroughly evaluated current knowledge of LCS within the Deep South. Therefore, we measured LCS knowledge before and after receiving education delivered by community health advisors (CHAs) among high-risk individuals living in medically underserved communities of Alabama and to determine impact of psychological, demographic, health status, and cognitive factors on rate of lung cancer screening participation. Participants were recruited from one urban county and six rural Black Belt counties (characterized by poverty, rurality, unemployment, low educational attainment, and disproportionate lack of access to health services). One hundred individuals (i) aged between 55 and 80 years (ii) currently smoke or have quit within the past 15 years and (iii) have at least a total of 30-pack-year smoking history were recruited. Knowledge scores to assess lung cancer knowledge were calculated. Paired t-test was used to assess pre- and post-knowledge score improvement. Screening for lung cancer was modeled as a function of predisposed factors (age, gender, insurance, education, fatalism, smoking status, and history of family lung cancer). Average age was 62.94 (SD 6.28), mostly female (54%) mostly current smokers (53%). Most participants (80.85%) reported no family history of cancer. Fatalism was low, with a majority of the participants disagreeing that a cancer diagnosis is pre-destined (67.7%) and that there are no treatments for lung cancer (88.66%). Overall, lung cancer knowledge increased significantly from baseline of 4.64 (SD 2.37) to 7.61 (SD 2.26). Of the 100 participants, 23 underwent screening due to lack of access to primary care providers and reluctance of PCPs to provide referral to LCS. Sixty-five percent of those who were screened reported no family history of lung cancer. Regression analysis revealed no significant association between risk factors and the decision to get screened by participants. Our study demonstrates that while CHA delivered education initiatives increases lung cancer screening knowledge, there are significant structural barriers that prohibit effective utilization of LCS which needs to be addressed.

Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.

Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR

AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage.

The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC

ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms.

Type II topoisomerases (TOP2) poisons represent one class of the most successful and widely prescribed chemotherapeutics, which is frontline therapy for a myriad of systemic cancers and solid tumors, including lymphomas, leukemias, and lung cancer. Despite this, treatment with this class of drugs induces unwanted side effects (including cardiovascular morbidity and secondary malignancies). Additionally, the emergence of drug resistance also greatly compromises the clinical use of these drugs. To enhance therapeutic efficiency while lowering unwanted side effects, new insights into effective combination therapy are required. In this study we found that KU60019, a novel, and highly specific ATM kinase inhibitor interferes with the association of ATM with TOP2β and stabilizes TOP2β-DNA cleavage complex, thereby impairing the repair of TOP2 poison-induced DSBs and contributes to genome stability, leading to accelerated cell death. In H1299 as well as in A549 lung cancer cell lines, biologically, KU60019 combined with VP-16 (one of the TOP2 poisons) synergistically suppressed the growth of cells and survival and triggered a much higher apoptosis rate. In summary, we provide a proof-of-concept strategy that ATM inhibitors combined with TOP2 poison would synergistically suppresses lung cancer cell survival as well as reduce DNA damage responses, thus may lowering the possibility of cardiotoxicity and secondary malignancy linked to therapy.

Tumor-specific intracellular delivery peptide-guided transport of a catalytic toxin.

There continues to be a need for cancer-specific ligands that can deliver a wide variety of therapeutic cargos. Ligands demonstrating both tumor-specificity and the ability to mediate efficient cellular uptake of a therapeutic are critical to expand targeted therapies. We previously reported the selection of a peptide from a peptide library using a non-small cell lung cancer (NSCLC) cell line as the target. Here we optimize our lead peptide by a series of chemical modifications including truncations, N-terminal capping, and changes in valency. The resultant 10 amino acid peptide has an affinity of <40 nM on four different NSCLC cell lines as a monomer and is stable in human serum for >48 h. The peptide rapidly internalizes upon cell binding and traffics to the lysosome. The peptide homes to a tumor in an animal model and is retained up to 72 h. Importantly, we demonstrate that the peptide can deliver the cytotoxic protein saporin specifically to cancer cells in vitro and in vivo, resulting in an effective anticancer agent.

Deciphering the exact breakpoints of structural variations using long sequencing reads with DeBreak.

Long-read sequencing has demonstrated great potential for characterizing all types of structural variations (SVs). However, existing algorithms have insufficient sensitivity and precision. To address these limitations, we present DeBreak, a computational method for comprehensive and accurate SV discovery. Based on alignment results, DeBreak employs a density-based approach for clustering SV candidates together with a local de novo assembly approach for reconstructing long insertions. A partial order alignment algorithm ensures precise SV breakpoints with single base-pair resolution, and a k-means clustering method can report multi-allele SV events. DeBreak outperforms existing tools on both simulated and real long-read sequencing data from both PacBio and Nanopore platforms. An important application of DeBreak is analyzing cancer genomes for potentially tumor-driving SVs. DeBreak can also be used for supplementing whole-genome assembly-based SV discovery.

In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma.

Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBAactivin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.

LncRNA BC promotes lung adenocarcinoma progression by modulating IMPAD1 alternative splicing.

The therapeutic value of targeted therapies in patients with lung cancer is reduced when tumours acquire secondary resistance after an initial period of successful treatment. However, the molecular events behind the resistance to targeted therapies in lung cancer remain largely unknown. To discover the important role and mechanism of lncRNA BC in promoting tumor metastasis and influencing clinical prognosis of LUAD. Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in lung cancer cells. The functional role and mechanism of lncRNA were further investigated by gain- and loss-of-function assays. RNA pull-down, protein assays, and mass spectrometry were used to identify proteins that interacted with lncRNA. TaqMan PCR was used to measure lncRNA in lung adenocarcinoma and adjacent nontumor tissues from 428 patients. The clinical significance of lncRNA identified was statistically confirmed in this cohort of patients. In this study, we show that the long non-coding RNA BC009639 (BC) is involved in acquired resistance to EGFR-targeted therapies. Among the 235 long non-coding RNAs that were differentially expressed in lung cancer cell lines, with different metastatic potentials, BC promoted growth, invasion, metastasis, and resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), both in vitro and in vivo. BC was highly expressed in 428 patients with lung adenocarcinoma (LUAD) and high BC expression correlated with reduced efficacy of EGFR-TKI therapy. To uncover the molecular mechanism of BC-mediated EGFR-TKI resistance in lung cancer, we screened and identified nucleolin and hnRNPK that interact with BC. BC formed the splicing complex with nucleolin and hnRNPK to facilitate the production of a non-protein-coding inositol monophosphatase domain containing 1 (IMPAD1) splice variant, instead of the protein-coding variant. The BC-mediated alternative splicing (AS) of IMPAD1 resulted in the induction of the epithelial-mesenchymal transition and resistance to EGFR-TKI in lung cancer. High BC expression correlated with clinical progress and poor survival among 402 patients with LUAD. Through alternative splicing, BC boosted the non-coding IMPAD1-203 transcript variant while suppressing the IMPAD1-201 variant. In order to control the processing of pre-mRNA, BC not only attracted RNA binding proteins (NCL, IGF2BP1) or splicing factors (hnRNPK), but also controlled the formation of the splicing-regulator complex by creating RNA-RNA-duplexes. Our results reveal an important role for BC in mediating resistance to EGFR-targeted therapy in LUAD through IMPAD1 AS and in implication for the targeted therapy resistance.

Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor a real-world outcomes analysis.

For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set. The study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicines tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS). Of 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutationsmegabase (mutsMb)). Comparing low TMB (<10 mutsMb), high TMB (10-19 mutsMb), and very high TMB (≥20 mutsMb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 mutsMb showed a more favorable rwPFS (HR 0.56 (95% CI 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 mutsMb cohort, the CI is wide and does not reach statistical significance (HR 1.68 (95% CI 0.52 to 5.48)). This study provides evidence that higher TMB cut-offs, such as 20 mutsMb, can identify patients with prolonged benefit from ICPI. TMB ≥20 mutsMb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC.

Safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant chemotherapy combined with immunotherapy.

Short and long-term association of exposure to ambient black carbon with all-cause and cause-specific mortality A systematic review and meta-analysis.

Black carbon (BC) is a product of incomplete or inefficient combustion and may be associated with a variety of adverse effects on human health. The objective of this study was to analyze the association between various mortalities and long-short-term exposure to BC as an independent pollutant. In this systematic review, we searched 4 databases for original research in English up to 6

Discovery of a Chemical Probe to Study Implications of BPTF Bromodomain Inhibition in Cellular and in vivo Experiments.

The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.

Metabolism and pharmacokinetic study of deuterated osimertinib.

Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (C

Non-Tuberculous Mycobacteria with Enlarged Mediastinal Lymph Node by Next Generation Sequencing Case Report.

A young patient characterized by rapid enlargement of mediastinal lymph nodes was diagnosed as non-tuberculous mycobacterial pulmonary disease (NTM-PD) by bronchoalveolar lavage fluid Next Generation Sequencing (NGS). Laboratory examination, Chest CT scan, electronic bronchoscopy, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were performed to diagnose non-tuberculous mycobacterium pulmonary disease. Detection of bird-intracellular mycobacterium complex in bronchoalveolar lavage fluid by NGS. Chest CT scan showed multiple enlarged lymph nodes in mediastinum. 4R region TBNA chronic granulomatous inflammation, positive bacilli were found by acid-fast staining. After the anti-NTM treatment, the symptoms of the patients were relieved. When the patient shows mediastinal lymph node enlargement of unknown cause, NTM-PD can be considered and NGS can be used to assist in the diagnosis.

Esterase D interacts with metallothionein 2A and inhibits the migration of A549 lung cancer cells in vitro.

Esterase D (ESD) is a nonspecific esterase widely distributed in various organisms. ESD plays an important role in regulating cholesterol efflux, inhibiting viral replication and lung cancer growth. MT2A (metallothionein 2A) is the most important isoform of metallothionein (MTs) in human and high expression of MT2A in tumors represents poor prognosis and metastatic behavior. However, there are no reports about the molecular mechanism of ESD in the regulation of tumor metastasis. In this study, we found for the first time that activation ESD promoted its interaction with MT2A and decreased the protein level of MT2A, which resulting in the concentration of free zinc ions up-regulated, and inhibited the migration of A549 lung cancer cells in vitro.

Cardiac progenitors instruct second heart field fate through Wnts.

The heart develops in a synchronized sequence of proliferation and differentiation of cardiac progenitor cells (CPCs) from two anatomically distinct pools of cells, the first heart field (FHF) and second heart field (SHF). Congenital heart defects arise upon dysregulation of these processes, many of which are restricted to derivatives of the FHF or SHF. Of the conserved set of signaling pathways that regulate development, the Wnt signaling pathway has long been known for its importance in SHF development. The source of such Wnts has remained elusive, though it has been postulated that these Wnts are secreted from ectodermal or endodermal sources. The central question remains unanswered Where do these Wnts come from Here, we show that CPCs autoregulate SHF development via Wnt through genetic manipulation of a key Wnt export protein (Wls), scRNA-seq analysis of CPCs, and use of our precardiac organoid system. Through this, we identify dysregulated developmental trajectories of anterior SHF cell fate, leading to a striking single ventricle phenotype in knockout embryos. We then applied our findings to our precardiac organoid model and found that Wnt2 is sufficient to restore SHF cell fate in our model of disrupted endogenous Wnt signaling. In this study, we provide a basis for SHF cell fate decision-proliferation vs. differentiation-autoregulated by CPCs through Wnt.

Different Liquid Biopsies for the Management of Non-Small Cell Lung Cancer in the Mutational Oncology Era.

In the last ten years, liquid biopsy has been slowly joining the traditional invasive techniques for the diagnosis and monitoring of tumors. Liquid biopsies allow easy repeated sampling of blood, reflect the tumor scenario, and make personalized therapy real for the patient. Liquid biopsies isolate and utilize different substrates present in patients body fluids such as circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc. One of the most-used solid cancers in the development of the non-invasive liquid biopsy approach that has benefited from scientific advances is non-small cell lung cancer (NSCLC). Using liquid biopsy, it is possible to have more details on NSCLC staging, progression, heterogeneity, gene mutations and clonal evolution, etc., basing the treatment on precision medicine as well as on the screening of markers for therapeutic resistance. With this review, the authors propose a complete and current overview of all different liquid biopsies available to date, to understand how much has been carried out and how much remains to be completed for a better characterization of NSCLC.

FLVCR1-AS1 and FBXL19-AS1 Two Putative lncRNA Candidates in Multiple Human Cancers.

(1) Background Mounting evidence supports the idea that one of the most critical agents in controlling gene expression could be long non-coding RNAs (lncRNAs). Upregulation of lncRNA is observed in the different processes related to pathologies, such as tumor occurrence and development. Among the crescent number of lncRNAs discovered, FLVCR1-AS1 and FBXL19-AS1 have been identified as oncogenes in many cancer progression and prognosis types, including cholangiocarcinoma, gastric cancer, glioma and glioblastoma, hepatocellular carcinoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, and osteosarcoma. Therefore, abnormal FBXL19-AS1 and FLVCR1-AS1 expression affect a variety of cellular activities, including metastasis, aggressiveness, and proliferation (2) Methods This study was searched via PubMed and Google Scholar databases until May 2022 (3) Results FLVCR1-AS1 and FBXL19-AS1 participate in tumorigenesis and have an active role in impacting several signaling pathways that regulate cell proliferation, migration, invasion, metastasis, and EMT (4) Conclusions Our review focuses on the possible molecular mechanisms in a variety of cancers regulated by FLVCR1-AS1 and FBXL19-AS1. It is not surprising that there has been significant interest in the possibility that these lncRNAs might be used as biomarkers for diagnosis or as a target to improve a broader range of cancers in the future.

Association of Body Weight With Response to Vitamin D Supplementation and Metabolism.

In the Vitamin D and Omega-3 Trial (VITAL), the effects of randomized vitamin D supplementation (cholecalciferol), 2000 IUd, reduced the risk of several health outcomes among participants with normal, but not elevated, body weights. It was unclear whether weight had any association with the outcomes of the supplementation. To investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation. VITAL is a completed randomized, double-blind, placebo-controlled trial for the primary prevention of cancer and cardiovascular disease. In the present cohort study, an analysis was conducted in a subset of VITAL participants who provided a blood sample at baseline and a subset with a repeated sample at 2 years follow-up. VITAL was conducted from July 1, 2010, to November 10, 2018 data analysis for the present study was conducted from August 1, 2021, to November 9, 2021. Treatment outcomes of vitamin D, 2000 IUd, supplementation vs placebo associated with clinical and novel vitamin D-related biomarkers by BMI category adjusted for other factors associated with vitamin D status. Multivariable-adjusted means (SE) or 95% CIs of vitamin D-related serum biomarkers at baseline and follow-up total 25-hydroxyvitamin D (25-OHD), 25-OHD3, free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D-binding protein (VDBP), albumin, parathyroid hormone (PTH), and calcium, and log-transformed as needed. A total of 16 515 participants (mean SD age, 67.7 7.0 years 8371 women 50.7% 12420 non-Hispanic White 76.9%) were analyzed at baseline, including 2742 with a follow-up blood sample. Before randomization, serum total 25-OHD levels were incrementally lower at higher BMI categories (adjusted mean SE underweight, 32.3 0.7 ngmL normal weight, 32.3 0.1 ngmL overweight, 30.5 0.1 ngmL obesity class I, 29.0 0.2 ngmL and obesity class II, 28.0 0.2 ngmL P < .001 for linear trend). Similarly, baseline 25-OHD3, FVD, BioD, VDBP, albumin, and calcium levels were lower with higher BMI, while PTH level was higher (all P < .001 for linear trend). Compared with placebo, randomization to vitamin D supplementation was associated with an increase in total 25-OHD, 25-OHD3, FVD, and BioD levels compared with placebo at 2 years follow-up, but increases were significantly lower at higher BMI categories (all treatment effect interactions P < .001). Supplementation did not substantially change VDBP, albumin, PTH, or calcium levels. In this randomized cohort study, vitamin D supplementation increased serum vitamin D-related biomarkers, with a blunted response observed for participants with overweight or obesity at baseline. These longitudinal findings suggest that BMI may be associated with modified response to vitamin D supplementation and may in part explain the observed diminished outcomes of supplementation for various health outcomes among individuals with higher BMI.

Diagnostic Accuracy of Slow-Capillary Endobronchial Ultrasound Needle Aspiration in Determining PD-L1 Expression in Non-Small Cell Lung Cancer.

The role of EBUS-TBNA in the diagnosis and staging of lung cancer is well established. EBUS-TBNA can be performed using different aspiration techniques. The most common aspiration technique is known as suction. One alternative to the suction technique is the slow-pull capillary aspiration. To the best of our knowledge, no studies have assessed the diagnostic yield of slow-pull capillary EBUS-TBNA in PD-L1 amplification assessment in NSCLC. Herein, we conducted a single-centre retrospective study to establish the diagnostic yield of slow-pull capillary EBUS-TBNA in terms of PD-L1 in patients with NSCLC and hilarmediastinal lymphadenopathies subsequent to NSCLC. Patients with hilar andor mediastinal lymph node (LN) NSCLC metastasis, diagnosed by EBUS-TBNA between January 2021 and April 2022 at Pulmonology Unit of Ospedali Riuniti di Ancona (Ancona, Italy) were enrolled. We evaluated patient characteristics, including demographic information, CT scan FDG-PET features and final histological diagnoses, including PD-L1 assessment. A total of 174 patients underwent EBUS-TBNA for diagnosis of hilarmediastinal lymphadenopathies between January 2021 and April 2022 in the Interventional Pulmonology Unit of the Ospedali Riuniti di Ancona. Slow-pull capillary aspiration was adopted in 60 patients (34.5%), and in 3060 patients (50.0%) NSCLC was diagnosed. EBUS-TBNA with slow-pull capillary aspiration provided adequate sampling for molecular biology and PD-L1 testing in 96.7% of patients (2930) in 1529 (51.7%) samples with more than 1000 viable cellsHPF were identified, whereas in 1429 (48.3%) samples contained 101-1000 viable cellsHPF. These retrospective study shows that slow-pull capillary aspiration carries an excellent diagnostic accuracy, almost equal to that one reported in literature, supporting its use in EBUS-TBNA for PD-L1 testing in NSCLC.

Sex-Specific miRNA Differences in Liquid Biopsies from Subjects with Solid Tumors and Healthy Controls.

Dysregulation of epigenetic mechanisms has been recognized to play a crucial role in cancer development, but these mechanisms vary between sexes. Therefore, we focused on sex-specific differences in the context of cancer-based data from a recent study. A total of 12 cell-free DNA methylation targets in CpG-rich promoter regions and 48 miRNAs were analyzed by qPCR in plasma samples from 8 female and 7 male healthy controls as well as 48 female and 80 male subjects with solid tumors of the bladder, brain, colorectal region (CRC), lung, stomach, pancreas, and liver. Due to the small sample size in some groups andor the non-balanced distribution of men and women, sex-specific differences were evaluated statistically only in healthy subjects, CRC, stomach or pancreas cancer patients, and all cancer subjects combined (

PU.1 negatively regulates tumorigenesis in non-small-cell lung cancer.

PU.1 is a key transcription factor that modulates hematopoietic cell differentiation and is involved in various physiological and pathological processes. PU.1 has been described to have multiple roles in a diverse range of cancers, but its contribution in non-small-cell lung cancer (NSCLC) has not been clearly elucidated. Fifty pairs of lung adenocarcinoma (LUAD) tissues and paraneoplastic tissues were collected. RT-qPCR assay was used to test PU.1 expression. Expression of PU.1 in LUAD cell lines and control cell lines was detected by RT-qPCR, and the role of PU.1 in LUAD was investigated by in vitro experiment. Levels of the major proteins in the apoptotic pathway were also detected by Western blot. The expression of PU.1 was remarkably downregulated in LUAD. Overexpression of PU.1 impaired the viability of LUAD cells as well as their metastatic function. In addition, PU.1 promoted apoptosis of LUAD cells by decreasing Bcl2 and increasing BaxBak1 expression. PU.1 plays an inhibitory role in LUAD, mainly promoting the apoptosis of LUAD cells.

Adherence to the 2021 dietary guidelines of the European Society of Cardiology on cardiovascular disease prevention in residents of the Pomeranian Voivodeship with increased cardiovascular risk.

Good eating habits can reduce cardiovascular risk. The aim of the study was to check the compliance with the new ESC dietary guidelines in people with increased risk of cardiovascular disease (CVD). The study included 1244 current or former smokers (636 men and 608 women) with mean (SD) age 61.6 (6.4) years who volunteered for the MOLTEST BIS lung cancer prevention program. During the workout, 49% of them were diagnosed with one of the following arterial hypertension (HA), diabetes (DM), coronary artery disease (CAD). Patients with lung cancer were excluded from the study. Participants completed Food Frequency Questionnaire (FFQ-6) and food intake was assessed with 24-h dietary recall method. Only 2% of the studied declared consuming more than 2 servings of both fruit and vegetables every day, and only 3% of the respondents confirmed the daily nut consumption. Most of them had weight excess, consumed too little fiber and too much energy from total and saturated fats. The mean animal to plant protein ratio was higher than recommended, as was the ratio of omega 6 to 3 fatty acids. Only 40% of participants with with HA, DM or CAD had a daily cholesterol intake less than 200 mg, and only 12% of them realized intake of saturated fats lower than 7% of total energy. Our smokers with increased cardiovascular risk did not comply with the ESC 2021 dietary recommendations. The most common mistake was inadequate consumption of vegetables, fruits and nuts.

An Integrated Radiologic-Pathologic Understanding of COVID-19 Pneumonia.

This article reviews the radiologic and pathologic findings of the epithelial and endothelial injuries in COVID-19 pneumonia to help radiologists understand the fundamental nature of the disease. The radiologic and pathologic manifestations of COVID-19 pneumonia result from epithelial and endothelial injuries based on viral toxicity and immunopathologic effects. The pathologic features of mild and reversible COVID-19 pneumonia involve nonspecific pneumonia or an organizing pneumonia pattern, while the pathologic features of potentially fatal and irreversible COVID-19 pneumonia are characterized by diffuse alveolar damage followed by fibrosis or acute fibrinous organizing pneumonia. These pathologic responses of epithelial injuries observed in COVID-19 pneumonia are not specific to SARS-CoV-2 but rather constitute universal responses to viral pneumonia. Endothelial injury in COVID-19 pneumonia is a prominent feature compared with other types of viral pneumonia and encompasses various vascular abnormalities at different levels, including pulmonary thromboembolism, vascular engorgement, peripheral vascular reduction, a vascular tree-in-bud pattern, and lung perfusion abnormality. Chest CT with different imaging techniques (eg, CT quantification, dual-energy CT perfusion) can fully capture the various manifestations of epithelial and endothelial injuries. CT can thus aid in establishing prognosis and identifying patients at risk for deterioration.

The nucleoporin (NUP) ELYS, encoded by

Erratum Hydrogen gas promotes apoptosis of lung adenocarcinoma A549 cells through X-linked inhibitor of apoptosis and baculoviral inhibitor of apoptosis protein repeat-containing 3.

This corrects the article DOI 10.4103jcrt.jcrt113721.

Computed tomography findings, associated factors, and management of pulmonary nodules in 54,326 healthy individuals.

To investigate the pulmonary nodules detected by low-dose computed tomography (LDCT), identified factors affecting the size and number of pulmonary nodules (single or multiple), and the pulmonary nodules diagnosed and management as lung cancer in healthy individuals. A retrospective analysis was conducted on 54,326 healthy individuals who received chest LDCT screening. According to the results of screening, the detection rates of pulmonary nodules, grouped according to the size and number of pulmonary nodules (single or multiple), and the patients gender, age, history of smoking, hypertension, and diabetes were statistically analyzed to determine the correlation between each factor and the characteristics of the nodules. The pulmonary nodules in healthy individuals diagnosed with lung cancer were managed with differently protocols. The detection rate of pulmonary nodules was 38.8% (21,05554,326). The baseline demographic characteristics of patients with pulmonary nodules were 58% male and 42% female patients, 25.7% smoking and 74.3% nonsmoking individuals, 40-60 years old accounted for 49%, 54.8% multiple nodules, and 45.2% single nodules, and ≤5-mm size accounted for 80.4%, 6-10 mm for 18.2%, and 11-30 mm for 1.4%. Multiple pulmonary nodules were more common in hypertensive patients. Diabetes is not an independent risk factor for several pulmonary nodules. Of all patients with lung nodules, 26 were diagnosed with lung cancer, accounting for 0.1% of all patients with pulmonary nodules, 0.6% with nodules ≥5 mm, and 2.2% with nodules ≥8 mm, respectively. Twenty-six patients with lung cancer were treated with surgical resection (57.7%), microwave ablation (MWA, 38.5%), and follow-up (3.8%). LDCT was suitable for large-scale pulmonary nodules screening in healthy individuals, which was helpful for the early detection of suspicious lesions in the lung. In addition to surgical resection, MWA is an option for early lung cancer treatment.

Phrenic nerve injury after the percutaneous microwave ablation of lung tumors A single-center analysis.

This study aimed to analyze the cases of phrenic nerve injury caused by the percutaneous microwave ablation of lung tumors conducted at our center and to explore the risk factors. The data of 455 patients who underwent the percutaneous microwave ablation of lung tumors at the Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University from July 2017 to October 2021, were retrospectively analyzed. The cases of phrenic nerve injury after the percutaneous ablation were reported to analyze the risk factors involved, such as the shortest distance between tumor margin and phrenic nerve, tumor size, and ablation energy. The groups were divided based on the shortest distance between the tumor edge and the phrenic nerve into group 1, d ≤ l cm group 2, 1 < d ≤2 cm and group 3, d >2 cm. Lesions with a distance ≤2 cm were compared in terms of tumor size and ablation energy. Among the 455 patients included in this study, 348 had primary lung cancer, and 107 had oligometastatic cancer. A total of 579 lesions were detected, with maximum diameter of 1.27 ± 0.55 cm, and the ablation energy was 9,000 (4,800-72,000) J. Six patients developed phrenic nerve injury, with an incidence of 1.32%. For these six patients, the shortest distance from the lesion edge to the phrenic nerve was 0.75 ± 0.48 cm, and the ablation energy was 10,500 (8,400-34,650) J. There were statistically significant differences in phrenic nerve injury among groups 1, 2, and 3 (P < 0.05). In patients with a distance (d) ≤ 2 cm, there were no significant differences in tumor diameter and energy between the phrenic nerve injury group and the non-injury group (P 0.80 P 0.41). In five out of six patients, the diaphragm level completely recovered to the pre-procedure state, and the recovery time of the phrenic nerve was 9.60 ± 5.60 months. Another one was re-examined 11 months after the procedure, and the level of the diaphragm on the affected side had partially recovered. Phrenic nerve injury is a rare but not negligible complication of thermal ablation and is more likely to occur in lesions with a distance ≤2 cm from the phrenic nerve.

Pancreatic intra-arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma A pilot study.

To preliminarily evaluate the efficacy and safety of pancreatic intra-arterial infusion chemotherapy (PAIC) with nab-paclitaxel in patients with advanced pancreatic carcinoma. Fifteen patients with advanced pancreatic carcinoma received monthly, inpatient, 3-h, continuous PAIC of nab-paclitaxel at 180 mgm Fifteen patients with advanced pancreatic carcinoma were enrolled in this study, including 10 male and 5 female patients. The mean age at the time of treatment was 66.3 years (53-84 years). A total of 49 cycles of PAIC (mean 3.27 cyclespatient) were performed. The most common treatment-related toxicities were alopecia, diarrhea, and nauseavomiting. No procedure-related complications were observed. The longest overall survival observed was 22 months and the maximum number of treatments for the same patient was six cycles. PAIC contributed a high rate (1315 86.67%) and fast (1015 66.67%) easement of pain, with apparent symptom relief within 24 h, especially local pain symptom. The pain anesis rate was 13 (86.67%). CBR was achieved in 13 (86.67%) patients (95%CI 59.54,98.34). ORR was achieved in four (26.67%) patients (95%CI 7.79,55.10). Disease Control Rate was achieved in 14 (93.33%) patients. The mPFS was 5.22 months (interquartile range IQR, 4.27-7.85 months). The mOS was 8.97 months (IQR, 5.65-13.70 months). In this study, the dose of the chemotherapeutics and the schedule of the transcatheter pancreatic arterial chemotherapy perfusion were shown to be safe, well-tolerated, and effective for the relief of clinical symptoms and CBR. These advantages can quickly establish the treatment belief and improve patient quality of life. This regimen requires further investigation in patients with advanced pancreatic carcinoma.

Reminiscence therapy involved care programs as an option to improve psychological disorders and patient satisfaction in elderly lung cancer patients A randomized, controlled study.

Reminiscence therapy (RT) is frequently used with elderly patients to improve their psychological status, but a few studies have examined its application in lung cancer patients. This study explored whether a reminiscence therapy-involved care program (RTICP) could improve cognitive functions, anxiety, depression, patient satisfaction, and survival in elderly lung cancer patients. This randomized, controlled study enrolled 138 elderly post-operative lung cancer patients into two groups, an RTICP group (n 69) and a usual care program (UCP) group (n 69), for a 12-month intervention period and a follow-up period. During the 12-month intervention, the Mini-Mental State Examination (MMSE) score, the Hospital Anxiety and Depression Scale for anxiety (HADS-A) and depression (HADS-D), patient satisfaction, disease-free survival (DFS), and overall survival (OS) were evaluated. MMSE and patient satisfaction were elevated in the RTICP group compared to the UCP group at month (M) 12. Additionally, RTICP reduced HADS-A at M6, M9, and M12 and the anxiety rate at M9, HADS-D at M9, and M12 compared to UCP, whereas the depression rate was no different between the two groups at any time (all P > 0.050). Moreover, DFS and OS were no different between the two groups (all P > 0.050). RTICP, considered as an optional psychological intervention, enhances cognitive functions, alleviates anxiety and depression feelings, and elevates satisfaction among elderly lung cancer patients.

Investigating the effect of

The quantitative magnetic resonance imaging (MRI) parameters were initially used in the study of central nervous system diseases and has since been widely used in the diagnosis of breast, liver, rectum, and prostate diseases. In our study, we aimed to evaluate the effect of ARHGEF10L gene on tumor growth in gastric cancer in nude mice using quantitative MRI parameters. A nude mice model of gastric cancer was established, and the mice were divided into a control group and an shARHGEF10L group (N 10). T2-fs and intravoxel incoherent motions (IVIM) imaging were performed in the mice coil with a 3.0 T MR system. The differences in quantitative parameters (apparent diffusion coefficient ADC, D, D , f values) were compared between both groups, and the effect of ARHGEF10L expression on tumor growth in tumor-bearing mice was investigated. The data were analyzed using Statistical Package for the Social Sciences (SPSS) 17.0 software package. The ADC and D values of tumor imaging in the shARHGEF10L group were higher than those in the control group, and the differences were statistically significant. There was no significant difference in the D or F values between both groups. The ADC and D values of the quantitative IVIM imaging parameters can be used to effectively assess the growth of gastric cancer in nude mice, suggesting that ARHGEF10L may promote the growth of tumor cells.

The efficacy of postoperative radiotherapy for patients with non-small cell lung cancer An updated systematic review and meta-analysis.

The controversy over the efficacy of postoperative radiotherapy (PORT) has existed for a long time. The present study reassessed the overall survival (OS) and disease-free survival (DFS) data to investigate whether PORT can improve survival in resectable non-small cell lung cancer (NSCLC) patients. The following databases were used to perform literature search PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Embase (from January 1, 1986 to July 5, 2021). The results of overall survival (OS) and disease-free survival (DFS) were calculated as hazard ratio (HR). Confidence intervals are chosen with 95% confidence intervals. A total of 12 RCTs and 19 retrospective cohort studies were found to meet the inclusion criteria. A significant DFS improvement was detected in the PORT group (4111 patients from 15 studies), although statistical difference was not detected for OS between the non-PORT and PORT groups (31 studies, 49,342 total patients). PORT prolonged OS in patients undergoing PORT plus postoperative chemotherapy (POCT) and in pN2 patients. Patients with a median radiation dose of 50.4 Gy and a median radiation dose of 54 Gy had a better OS after PORT. However, if the total radiotherapy dose went up to 60 Gy, PORT increased the risk of death in NSCLC patients. Significant difference in OS was not found in the results of studies with regard to treatment methods, pathologic stages, study type, radiation beam quality, and radiation dose. Patients undergoing postoperative chemoradiotherapy and pN2 patients can benefit from PORT. Patients exposed to median radiation doses of 50.4 and 54 Gy demonstrated relatively good efficacy. For patients with non-small-cell lung cancer, PORT has not been proven to extend OS, but its effect on DFS remains strong.

Microwave ablation of the lung Comparison of 19G with 14G and 16G microwave antennas in

Percutaneous image-guided thermal ablation has an increasing role in the treatment of primary and metastatic lung tumors. Although microwave ablation (MWA) has emerged advantageous as a new ablation technology, more research is needed to improve it. This study aims to investigate the ablation zone of three microwave antennas in ex vivo porcine lung. In the ex vivo standard model and porcine lung model, MWA was performed in three power output settings (50 W, 60 W, and 70 W) for 3, 6, 9, and 12 min using three microwave antennas, with outer diameter of 1.03 mm (19G), 1.6 mm (16G), and 2.0 mm (14G). A total of 108 and 216 sessions were performed (3 or 6 sessions per time setting with the 14G, 16G, and 19G microwave antennas). After the MWA was complete, we evaluated the shape and extent of the coagulation zone and measured the maximum long-axis (along the needle axis length L) and maximum short-axis (perpendicular to the needle diameter D) of the ablation zones using a ruler subsequently, the sphericity index (LD) was calculated. The sphericity index can be simplified as long-axisshort-axis. In the ex vivo standard model study, the long- and short-axis diameters and sphericity indices were not statistically different between the 14G, 16G, and 19G groups. In the ex vivo porcine lung study, the long- and short-axis diameters did not differ statistically between the 14G, 16G, and 19G groups (P < 0.05 each). The sphericity index for the 19G microwave antenna was higher than the sphericity indices for the 14G and 16G microwave antennas (P < 0.05) however, the index for the 14G microwave antenna was not statistically different than that for the 16G microwave antenna (P > 0.05). The ablation zone of the 19G antenna was the same as those of the 14G and 16G antennas in vitro. Thus, the 19G antenna may reduce the incidence of complications in lung tumor ablation.

The relationship between

Gut microbiota dysbiosis is involved in intestinal diseases. The resident microorganisms in the digestive tract contribute to maintenance of gut homeostasis. Some bacterial species have been identified and are suspected to play a role in colorectal cancer (CRC). Many studies have found that Clostridium butyricum has a close relationship with CRC, and the mechanism is becoming increasingly clear. This review discusses the possible relationship between C. butyricum and CRC.

Chinese expert consensus on intestinal microecology and management of digestive tract complications related to tumor treatment (version 2022).

The human gut microbiota represents a complex ecosystem that is composed of bacteria, fungi, viruses, and archaea. It affects many physiological functions including metabolism, inflammation, and the immune response. The gut microbiota also plays a role in preventing infection. Chemotherapy disrupts an organisms microbiome, increasing the risk of microbial invasive infection therefore, restoring the gut microbiota composition is one potential strategy to reduce this risk. The gut microbiome can develop colonization resistance, in which pathogenic bacteria and other competing microorganisms are destroyed through attacks on bacterial cell walls by bacteriocins, antimicrobial peptides, and other proteins produced by symbiotic bacteria. There is also a direct way. For example, Escherichia coli colonized in the human body competes with pathogenic Escherichia coli 0157 for proline, which shows that symbiotic bacteria compete with pathogens for resources and niches, thus improving the hosts ability to resist pathogenic bacteria. Increased attention has been given to the impact of microecological changes in the digestive tract on tumor treatment. After 2019, the global pandemic of novel coronavirus disease 2019 (COVID-19), the development of novel tumor-targeting drugs, immune checkpoint inhibitors, and the increased prevalence of antimicrobial resistance have posed serious challenges and threats to public health. Currently, it is becoming increasingly important to manage the adverse effects and complications after chemotherapy. Gastrointestinal reactions are a common clinical presentation in patients with solid and hematologic tumors after chemotherapy, which increases the treatment risks of patients and affects treatment efficacy and prognosis. Gastrointestinal symptoms after chemotherapy range from nausea, vomiting, and anorexia to severe oral and intestinal mucositis, abdominal pain, diarrhea, and constipation, which are often closely associated with the dose and toxicity of chemotherapeutic drugs. It is particularly important to profile the gastrointestinal microecological flora and monitor the impact of antibiotics in older patients, low immune function, neutropenia, and bone marrow suppression, especially in complex clinical situations involving special pathogenic microbial infections (such as clostridioides difficile, multidrug-resistant Escherichia coli, carbapenem-resistant bacteria, and norovirus).

CT-guided percutaneous transthoracic needle biopsy (PTNB) A thoracic surgeons learning curve and experience summary.

Few studies have investigated the learning process of percutaneous transthoracic needle biopsy (PTNB). Here, we aimed to evaluate the number of cases required to achieve proficiency by plotting the learning curve of PTNB. Data were collected from 94 consecutive patients who underwent computed tomography-guided PTNB by a thoracic surgeon at the Affiliated Hospital of Xuzhou Medical University between May 2021 and February 2022. The data collected included patient information, relevant examination results, intraoperative parameters, postoperative complications, and diagnostic results. The inflection points of the cumulative sum curve were around cases 13 and 24, according to which three phases were identified, including phase I, phase II, and phase III. A significant downtrend was observed regarding operative time (phase I, 26.53 ± 9.13 min vs. phase III, 18.42 ± 4.29 min, p < 0.05), rate of false-negative (phase I, 15.4% vs. phase III, 5.7% p < 0.05), rate of pneumothorax (phase I, 30.8% vs. phase III, 12.9% p < 0.05), and rate of hemoptysis (phase I, 15.4% vs. phase III, 2.9% p < 0.05). Thirteen cases were accumulated to lay the technical foundation, and 24 cases were required to achieve proficiency. In this study we summarize our own experience and provide specific guidance for young doctors with no experience in biopsy.

Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine HE-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factorMET-mediated PI3KAKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

Effect of Ropivacaine Combined with Dexmedetomidine for Serratus Anterior Plane Block Plus Patient-Controlled Intravenous Analgesia on Postoperative Recovery Quality of Patients Undergoing Thoracoscopic Radical Resection of Lung Cancer.

To study the postoperative analgesic effect of ropivacaine combined with dexmedetomidine for serratus anterior plane block (SAPB) under ultrasound visualization plus patient-controlled intravenous analgesia (PCIA) in patients undergoing thoracoscopic radical resection of lung cancer. A total of 129 patients undergoing elective thoracoscopic surgery were enrolled. The patients were randomly assigned to three groups ( Compared with those of the control group, the VAS scores of the Group R and Group RD were significantly lower at 10 min, 6 h, and 12 h after extubation ( 0.5% ropivacaine and 1 μgkg dexmedetomidine SAPB combined with PCIA can significantly reduce postoperative pain and improve postoperative recovery quality in patients undergoing thoracoscopic radical resection of lung cancer.

Zi Huangjing

To primarily explore the efficacy of Zi Huangjing This study was designed as a prospective, single-arm, multicenter clinical trial. According to the plan of the study, patients with malignant tumors who had received at least one cycle of chemotherapy and had moderate-to-severe CRF (Piper Fatigue Scale score≥4) were enrolled. All the enrolled patients took Zi Huangjing Eventually, 47 patients completed the entire study. After treatment, the mean score of the Piper Fatigue Scale assessed before the third cycle of chemotherapy (day 42) was 3.21±1.67, which was significantly lower than that at baseline (5.89±1.36) ( According to our preliminary investigation, Zi Huangjing

Early detection of lung cancer biomarkers in exhaled breath by modified armchair stanene nanoribbons.

In this study, we analyze armchair stanene nanoribbons as excellent sensing substances for the early diagnosis of lung cancer using density functional theory and the non-equilibrium Green function. Four modified configurations of surface- and edge-defected armchair stanene nanoribbons were studied to improve the sensing performance. Our probes indicated that the adsorption energy of armchair stanene nanoribbons is at least five times greater than that of other previously reported substances, such as single-wall carbon nanotubes, phosphorene, and silicene. A noticeable reduction in the current was observed, implying the high sensitivity of our sensing configurations. The adsorption energy and current results suggest that configurations with a single vacancy and edge defects improve the sensitivity and selectivity of the system because of their free dangling bonds. The calculated results demonstrate that the both-side edge defected armchair stanene nanoribbons reduce the adsorption energy to -8.35 eV and increase the sensitivity up to 45% for toluene detection. This reduction in adsorption energy and the surge of sensitivity shows ultra-high sensing performance, yielding a more efficient structure for the future design of early-diagnosis lung cancer sensing applications, thus improving lung cancer patients survival and life expectancy.

Development and validation of a combined metabolism and immune prognostic model in lung adenocarcinoma.

Tumor metabolism and immune response can affect the biological behavior of tumor cells. There is an obvious relationship between glycolysis and immune response. However, the association between metabolism and immune response and prognosis in lung adenocarcinoma (LUAD) has not yet been examined in a comprehensive and detailed manner. The establishment of reliable models for predicting the prognosis of LUAD based on glycolysis ability and immune status is still highly anticipated. The expression of genes were obtained from online databases, and the differentially expressed genes in LUAD tissues and adjacent tissues were identified. We used LUAD samples in The Cancer Genome Atlas (TCGA) database as training set and the Gene Expression Omnibus (GEO) databases as validation sets. The best predictive model was constructed using least absolute selection and shrinkage operator (LASSO) regression and Cox regression. The receiver operator characteristic (ROC) curve is used to verify the accuracy of the model. The expression status of the Glycolysis-related genes (GRGs) and the status of the immune cells in LUCD patients were further analyzed. The protein levels of the 3 identified genes were then tested in LUAD patients. We identified 3 GRGs and immune-related genes (i.e., fibroblast growth factor 2, hyaluronan-mediated motor receptor, and nuclear receptor 0B2) and constructed a stable comprehensive index of glycolysis and immunity (CIGI) prediction model. The validation results for this CIGI model were quite stable across different datasets and patient subgroups and the CIGI score can be included as an independent prognostic factor for LUAD patients. The area under the curve (AUC) values of 1-, 3- and 5-year of the finally established nomogram model are 0.767, 0.735 and 0.769. Further analysis showed that LUAD patients in the low-risk group had lower levels of glycolytic gene expression than those in the high-risk group and exhibited an immunosuppressed state. Finally, hyaluronan-mediated motor receptor may play a role in inhibiting cancer, while fibroblast growth factor 2 and nuclear receptor 0B2 may play roles in promoting cancer. In this study, we established a new prognostic prediction model for LUAD patients that combines glycolysis ability and immune status.

In lung adenocarcinoma, low expression of the cell surface extracellular nucleotidase CD39 is related to immune infiltration and a poor prognosis.

Extracellular nucleotidase on the cell surface CD39 plays a crucial role in the tumor microenvironment in the immunosuppressive adenosine pathway. However, the association between CD39 and lung adenocarcinoma has rarely been recorded. This study aimed to explore the involvement of CD39 in the biological processes of lung cancer. First, a prediction model was established by analyzing the expression of CD39 in lung adenocarcinoma and its relationships with clinical evidence of lung adenocarcinoma using The Cancer Genome Atlas (TCGA) and Tumor IMmune Estimation Resource (TIMER) databases. In the TCGA and TIMER databases, the relationship between CD39 and immune cells and the relationship with immune-related expressed genes were studied. Subsequently, using gene set enrichment analysis (GSEA), the potential mechanism of action was investigated. Lung adenocarcinoma patients with elevated CD39 expression had improved overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). CD39 expression was reduced in lung adenocarcinoma tumor tissue in the TCGA and TIMER databases. The nomograms C-index was 0.688 (0.665-0.712), indicating some consistency in the prediction model. According to the TIMER and TCGA databases, CD39 expression was strongly connected with several immune cells invading and with immune checkpoint-related markers such as PDCD1, CD274, CTLA-4, and several functional T cells. GSEA revealed that CD39 influences the extracellular matrix, immunological microenvironment, programmed death 1 (PD-1) expression, glucose metabolism, PTEN stability, inflammatory response, and angiogenesis in lung cancer. The current studys findings demonstrated that CD39 can be employed as a possible predictive biomarker for lung adenocarcinoma and may enhance the patients poor prognosis by preventing the immunological escape of tumor cells from the lung adenocarcinoma tumor microenvironment.

Survival benefit of resection surgery for lung adenocarcinoma with bone metastases and a post-operative prognosis nomogram establishment and validation.

Surgical resection is not usually recommended for lung adenocarcinoma (LUAD) patients with bone metastases. However, the criteria for surgery are constantly being adjusted and there is a need to focus on the prognostic role of cancer-directed surgery (CDS) for bone metastatic LUAD patients investigate the factors influencing survival of CDS. We determined the survival benefit of CDS for LUAD patients with bone metastases and to develop a prognostic nomogram to predict overall survival (OS) for patients after surgery. LUAD patients with bone metastases from the Surveillance, Epidemiology, and End Results (SEER) database between 2010-2015 were included and divided into CDS and non-CDS groups. The propensity score matching (PSM) was used to balance baseline characteristics. We used Kaplan-Meier curves and log-rank tests to compare cancer-specific survival (CSS) and OS between the two groups. Patients underwent CDS were randomly divided into training and validation cohorts to develop and validate a nomogram model to predict postoperative prognosis outcome-OS. Patients who underwent CDS had a better OS and CSS than those who did not underwent CDS (e.g., 1-year OS rate 56.9% These results indicated that patients with bone metastasis of LUAD received survival benefit from CDS. The prognostic nomograms could assist clinicians in specifying individualized assessments, but further research is needed.

Oligoprogression in non-small cell lung cancer a narrative review.

Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers and is the most common non-cutaneous cancer world-wide. In NSCLC, oligometastatic and oligoprogressive disease (OPD) have been recognized as separate entities within the realm of metastatic disease and are emerging concepts in the context of targeted systemic therapies. Our objectives are to discuss the current literature regarding the evolving definitions of OPD in the context of oligometastatic disease (OMD) for NSCLC. Further, to discuss current and future clinical trials that have shaped our local approach with stereotactic body radiation therapy (SBRT)stereotactic ablative radiotherapy (SABR). Literature on OPD in NSCLC and local ablative therapy (LAT) including SBRTSABR and stereotactic radiosurgery (SRS) was reviewed. Oligoprogression is defined as limited (usually 3-5) metastatic areas progressing while onoff systemic therapy in the background of oligometastatic or polymetastatic disease. Prognosis in OPD with treatment (such as LAT and systemic therapy) may be more favorable. Outcomes for patients progressing on tyrosine kinase inhibitors (TKIs) with molecular mutations such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) who receive LAT are promising. Patients presenting with NSCLC metastasis with progression at a limited number of sites onoff a given line of systemic therapy may have favorable outcomes with aggressive LAT, which includes SBRTSABRSRS. Further studies need to be completed to further optimize treatment recommendations.

Molecular typing and prognostic model of lung adenocarcinoma based on cuprotosis-related lncRNAs.

Previous research has shown the heterogeneity of lung adenocarcinoma (LUAD) accounts for the different effects and prognoses of the same treatment. Cuprotosis is a newly discovered form of programmed cell death involved in the development of tumors. Therefore, it is important to study the long non-coding RNAs (lncRNAs) that regulate cuprotosis to identify molecular subtypes and predict survival of LUAD. The expression profile, clinical, and mutation data of LUAD were downloaded from The Cancer Genome Atlas (TCGA), and the ConsensusClusterPlus package was used to cluster LUADs based on cuprotosis-related lncRNAs (CR-lncRNAs). The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were used to construct a prognostic model. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were used for assessing immune cells infiltration and immune function. The tumor microenvironment (TME) score was calculated by ESTIMATE, and the tumor mutational burden (TMB) and Tumor Immune Dysfunction and Exclusion (TIDE) were used to evaluate the efficacy of immunotherapy. Firstly, 501 CR-lncRNAs were identified based on the co-expression relationship of 19 cuprotosis genes. And univariate Cox further obtained 34 prognosis-related CR-lncRNAs. The unsupervised consensus clustering divided LUAD samples into cluster A and cluster B, and showed cluster A had better prognosis, more immune cells infiltration, stronger immune function, and a higher TME score. Subsequently, we used Lasso Cox regression to construct a prognostic model, and univariate and multivariate Cox analyses showed the risk score could be an independent prognostic indicator. Immune cells infiltration, immune function, and TME score were increased markedly in the low-risk group, while TMB and TIDE suggested the efficacy of immunotherapy might be increased in high-risk group. Our research identified two new molecular subtypes and constructed a novel prognostic model of LUAD which could provide new direction for its diagnosis, treatment, and prognosis.

Characterization of driver mutations in Chinese non-small cell lung cancer patients using a novel targeted sequencing panel.

The identification of driver mutations has greatly promoted the precise diagnosis and treatment of non-small cell lung cancer (NSCLC), but there is lack of targeted sequencing panels specifically designed and applied to Chinese NSCLC patients. This study aimed to design and validate of a novel sequencing panel for comprehensive characterization of driver mutations in Chinese NSCLC patients, facilitating further exploration of downstream pathway alterations and therapeutic utility. A novel target sequencing panel including 21 driver genes was designed and examined in a cohort of 260 Chinese NSCLC patients who underwent surgery in Peking Union Medical College Hospital (PUMCH). Genetic alterations were identified and further analyzed for driver mutations, downstream pathways and therapeutic utilities. The most frequently identified driver mutations in PUMCH NSCLC cohort were on genes Our study provides a novel target sequencing panel suitable for Chinese NSCLC patients, which can effectively identify driver mutations, analyze downstream pathway alterations and predict therapeutic utility. Overall it is promising to further optimize and apply this panel in clinic with convenience and effectiveness.

Prognostic impact of pathologically confirmed rib invasion in patients with lung cancer requiring chest wall resection.

Primary lung cancer that invades the chest wall is classified as T3 regardless of the depth of invasion. This study assessed the prognostic impact of pathologically confirmed rib invasion in patients with pT3N0-1 lung cancer requiring chest wall resection. We retrospectively analyzed the records of patients with non-small cell lung cancer (NSCLC) who underwent combined lung and chest wall resection with rib involvement from 2006 to 2019. The median follow-up period was 64.0 months. In total, 42 patients (41 men, 1 woman) were enrolled. The median patient age was 64 years (range, 42-79 years). The median tumor size before treatment was 56.5 mm (range, 21-80 mm), and an osteolytic sign was identified on computed tomography (CT) in 42.9% (1842). Among 27 patients who received induction chemoradiotherapy, 5 (18.5%) achieved a complete pathological response. The operations comprised 36 lobectomies, 5 segmentectomies, and 1 wedge resection with resection of 2.5 ribs on average. Pathological examination revealed rib invasion in 18 (42.9%) patients. The 5-year disease-free and overall survival rates with pathological rib invasion were 44.4% and 77.4% (P0.0114), respectively and those without pathological rib invasion were 44.7% and 81.3% (P0.0222), respectively. Pathologically confirmed rib invasion was the only factor identified to have a prognostic impact in the univariate and multivariate analyses hazard ratio (HR), 5.98 95% confidence interval (CI) 1.37-26.1. Locoregional recurrence and distant metastases were more common in patients with than without pathologically confirmed rib invasion 4 (22.2%) and 6 (33.3%), respectively, among 18 patients with pathological rib invasion 2 (8.3%) and 3 (12.5%), respectively, among 24 patients without pathological rib invasion (P0.0073). Pathologically confirmed rib invasion was found to have a significant unfavorable prognostic impact in patients with pT3N0-1 lung cancer requiring chest wall resection. Multimodal therapy may be preferable in these patients to prevent local and distant relapse.

High SERPINH1 expression predicts poor prognosis in lung adenocarcinoma.

Serpine Protease Inhibitorclade H1 (SERPINH1) is abnormally expressed in a variety of tumor tissues and is linked to the biological processes of tumorigenesis, migration, invasion, and metastasis. SERPINH1 expression and prognosis in malignant tumors, such as gastric, colorectal, and breast cancers, have previously been studied, but the gene has not yet been investigated in lung adenocarcinoma (LUAD) in terms of prognosis and the potential mechanisms of action. SERPINH1 was identified as an independent prognostic factor for LUAD in The Cancer Genome Atlas (TCGA) cohort and Affiliated Hospital of Nantong University (NTU) cohort (the LUAD data set) by univariate and multivariate Cox regression analyses. Additionally, we performed immunohistochemical staining to analyze the expression of SERPINH1 in LUAD and normal lung tissue. Based on the TCGA database, we analyzed the correlation of this gene with the tumor mutation burden (TMB), tumor microenvironment, immune infiltration, immune checkpoints, and anti-tumor drugs using the R language-related R package. SERPINH1 was highly expressed in LUAD tissue. Kaplan-Meier survival curves in both the TCGA cohort and the NTU cohort showed that the SERPINH1 low-expression group had a higher survival rate than the high-expression group. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of the SERPINH1 co-expressed genes revealed that the gene was associated with the extracellular matrix and cell proliferation and migration. The analysis of SERPINH1 and the TMB revealed a superior survival advantage for patients with high TMB and high SERPINH1 expression, and worse survival for those with low TMB and high SERPINH1 expression. The analysis of the tumor microenvironment (TME) and immune infiltration revealed that the high and low expression of SERPINH1 was associated with different immune infiltration characteristics. The analysis of the immune checkpoints and anti-tumor drugs showed that immunotherapy and anti-neoplastic treatment were more efficacious in the high SERPINH1 expression group than the low SERPINH1 expression group. Using LUAD tissues and clinical samples, we showed that SERPINH1 can be used as a prognostic biomarker for LUAD. Our findings provide a new approach and strategy for the clinical treatment of LUAD patients.

Robotic lung resection a narrative review of the current role on primary lung cancer treatment.

Robotic-assisted thoracic surgery (RATS) has increasingly been applied to primary lung cancer treatment. Given the many facilities provided by the robotic platform in the manipulation of tissues and precision of movements, there is continuous enquiring about its contribution to the improvement of surgical outcomes. Also, the possibility to perform complex resections in a minimally invasive way using a robotic approach starts to become possible as the centers learning curve expands. We propose to perform a review of the current status of robotic surgery for lung cancer focusing on key frontier points sublobar resections, quality of lymphadenectomy, complex resections, postoperative outcomes, and innovative technologies to arrive. We performed a narrative review of the literature aggregating the most current references available in English. According to the current data, the flourishing of the robotic platform seems to be in line with the spread of sublobar resections. The technological benefits inherent to the platform, also seem to promote an increase in the quality of lymphadenectomy and a shorter learning curve when compared to video-assisted thoracic surgery (VATS) with equivalent oncological results. Its application in complex resections such as bronchial sleeve already presents consistent results and new technology acquisitions such as three-dimensional reconstructions, augmented reality and artificial intelligence tend to be implemented collaborating with the digitization of surgery. Robotic surgery for lung cancer resection is at least equivalent to the VATS approach considering the currently available literature. However, more practice time and prospective clinical trials are needed to identify more exact benefits.

Preventive and therapeutic effects of green tea on lung cancer a narrative review of evidence from clinical and basic research.

Green tea is a popular beverage worldwide and has numerous health-promoting properties. Accumulating evidence indicates that green tea has preventive and therapeutic effects on lung cancer. This study aimed to investigate the association between green tea consumption and lung cancer. We performed a narrative review to summarized the association between green tea consumption and lung cancer. Green tea consumption is known to decrease lung cancer risk in the general population, as indicated by meta-analyses of observational studies. Two active components of green tea, theabrownin and (-)-epigallocatechin gallate (EGCG), mediate the antitumor activity of green tea. Theabrownin promotes apoptosis, induces cell cycle arrest, and inhibits the migration, clone formation, and proliferation of lung cancer cell lines Observational studies have indicated that green tea has preventive effects on lung cancer.

Ensartinib in advanced ALK-positive non-small cell lung cancer a multicenter, open-label, two-staged, phase 1 trial.

Ensartinib, a potent second-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET and ROS1, was evaluated in a phase I clinical trial in patients with advanced, ALK-rearranged non-small cell lung cancer (NSCLC). Patients with advanced, ALK or ROS1-positive NSCLC were recruited from 2 centers in China. This study consisted of dose escalation and expansion stages. Patients were treated with oral ensartinib dosage of escalation stage was from 150, 200, 225 to 250 mg per day, expansion stage was recommended phase II dose (RP2D) in continuous 28-day cycles. The primary objectives were safety, dose limited toxicity (DLT), maximum tolerated dose (MTD), and RP2D based on tolerability. Key secondary objectives included pharmacokinetic (PK) and anti-tumor activity. Forty-eight patients were enrolled, 37 (77.1%) were ALK TKI-naïve, 11 (22.9%) patients had previously received crizotinib, ceritinib or alectinib. Ensartinib was well tolerated and common treatment-related adverse events (TRAEs) included rash (87.5%), transaminase elevation (60.4%), pruritus (45.8%) and creatinine elevation (35.4%). The top 3 grade 3-5 TRAEs were rash (14.6%), elevated alanine aminotransferase (ALT) (12.5%) and aspartate transaminase (AST) (4.2%). Two DLTs were observed in 250 mg, so MTD and RP2D was 225 mg per day. Ensartinib was moderately absorbed (median Tmax 3.00-4.00 h) and slowly eliminated (mean T12 21.0-30.2 h). The area under the curve (AUC) of ensartinib reached saturation at 200 to 225 mg and no major accumulation after daily administration. For all patients, the objective response rate (ORR) and disease control rates (DCR) were 64.6 % and 81.3%, median progression-free survival (mPFS) was 16.79 months. In subgroup analysis, the ORR and mPFS was 81.3% and 45.5%, 25.73 and 4.14 months in TKI-naïve and -treated ALK patients, respectively. The intra-cranial ORR and mPFS for patients with measurable brain metastases were 66.7% and 22.90 months. ALK abundance may predict the efficacy of ensartinib. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed specific signaling pathways enrichment in long and short progression-free survival (PFS) groups. Ensartinib was well tolerated under 225 mg (MTD) and demonstrated promising anti-tumor activity in ALK NSCLC patients, including those with CNS metastases and those previously TKI-treated. ClinicalTrials.gov NCT02959619.

Correlation between oncogene integrator complex subunit 7 and a poor prognosis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common types of cancer worldwide with high incidence and mortality rates. The integrator complex subunit 7 (INTS7) encodes a subunit of the integrator complex that mediates small-nuclear ribonucleic acid (RNA) processing and has been shown to be associated with RNA polymerase II. However, the clinical significance of INTS7 in LUAD is still not clear and needs to be investigated. The single-cell sequencing of a publicly available data set was conducted to compare the expression levels and percentages of INTS7 in lung malignant cells at different classifications and stages. Further, 33 cancer types from The Cancer Genome Atlas (TCGA) database were analyzed, protein-protein interaction (PPI) networks were constructed, and functional annotations were undertaken for the INTS7 gene. INTS7 small-interfering RNAs were transfected into LUAD cell lines, and cell biological behaviors, such as migration, invasion, apoptosis and proliferation capacity, were then examined. We found that the expression of INTS7 was significantly more upregulated in the LUAD tissues than the adjacent normal tissues. Increased INTS7 messenger RNA expression was correlated with TNM (tumor node metastasis classification) stage and gender in LUAD patients. Further, the Kaplan-Meier survival analysis indicated that LUAD patients with high INTS7 expression levels had a worse prognosis than those with low INTS7 expression levels. Finally, we found that silencing INTS7 inhibited LUAD cell viability and invasion These results suggest that INTS7 can be used as a potential therapy target and prognostic marker for LUAD. Further, INTS7 may aggravate migration and invasion, induce the proliferation, and attenuate the apoptosis capacity of cells in LUAD.

A dense fissure is not a contra-indication for uniportal thoracoscopic lobectomy.

A dense fissure is a main cause of a postoperative prolonged air leak (PAL). Such a fissure, if exposed, sometimes incidentally injures the pulmonary artery. We investigated whether uniportal thoracoscopic lobectomy which is considered technically more difficult than the conventional multiportal approach was appropriate for patients with dense fissures. From February 2019 to January 2022, 140 patients with primary lung cancer underwent uniportal thoracoscopic lobectomy with ≥ ND2a-1 lymphadenectomy. Patients were divided into those with dense (n22) and separated (n118) fissures. All dense fissures were treated using a fissureless technique without exposure of the pulmonary artery. We compared the characteristics and perioperative results of the two groups. We used multivariate analysis to identify factors predictive of PAL. Although dense fissures were significantly associated with right upper lobectomies, the other patient characteristics and perioperative results were similar between the two groups. No significant pulmonary artery injuries occurred in the fissureless group. In subgroup analyses of right upper lobectomy patients, we found no other significant between-group differences in patient characteristics or perioperative results. In multivariate analyses, right upper lobectomy odds ratio (OR) 0.047, 95% confidence interval (CI) 0.0044-0.49, P0.011 or smoking index (OR 1.03, 95% CI 1-1.07, P0.048) was the factor predictive of PAL. A dense fissure is not a contraindication for uniportal thoracoscopic lobectomy using the fissureless technique, which is thus safe.

Clinical significance of mean corpuscular volume as a prognostic indicator of radiotherapy for locally advanced lung cancer a retrospective cohort study.

Although the prognosis of solid tumors is related to the mean corpuscular volume (MCV), which can roughly predict the prognosis of patients, its correlation with locally advanced lung cancer is still unclear. We evaluated the relationship between serum MCV levels and prognosis in patients before radiotherapy. We retrospectively collected the age, sex, smoking history, TNM stage, ECOG score, hematocrit (HCT), MCV, mean corpuscular hemoglobin (MCH), and red blood cell distribution width-standard deviation (RDW-SD) of patients with locally advanced lung cancer who received chest radiotherapy from 2013 to 2017, and analyzed the relationship between this information and the overall survival (OS). Among all patients, 89 were male (79.5%), 23 were female (20.5%), 46 (41.1%) were older than 65 years, and 66 (58.9%) were younger than 65 years. Seventy-four patients had MCV <93.65 fL, 38 patients had MCV ≥93.65 fL, and the median follow-up period was 24 months. The patients with high T stage, high N stage, and high MCV had lower OS (P<0.05). In the Cox regression analysis, MCV odds ratio (OR) 0.534, 95% confidence interval (CI) 0.349-0.818, P0.01, T stage (OR 0.654, 95% CI 0.440-0.972, P0.04) and N stage (OR 0.545, 95% CI 0.371-0.801, P0.01) were predictors of prognosis. In the clinical treatment of patients with locally advanced lung cancer, MCV can be used to roughly predict their survival time.

Efficacy and safety comparison of PD-1 inhibitors

Evidence from clinical research and meta-analyses have suggested that programmed cell death 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors plus chemotherapy could achieve a significant survival benefit for extensive-stage small-cell lung cancer (ES-SCLC) patients. However clinical researches concerned about the comparation between the PD-1 and PD-L1 inhibitors were relatively lacking. We collected the data of ES-SCLC patients treated with PD-1 inhibitors or PD-L1 inhibitors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoint included adverse events (AEs). The data of 221 ES-SCLC patients treated with PD-1 (n146) or PD-L1 inhibitors (n75) between February 2017 and June 2020 were retrospectively collected. The median OS (mOS) and median PFS (mPFS) were 19.07 and 8.27 months, respectively, in patients treated with PD-1 inhibitors. In the PD-L1 group, mOS has not been reached, and mPFS was 7.95 months. No significant differences were observed between the 2 groups in OS hazard ratio (HR), 1.472 95% confidence interval (CI), 0.847-2.220 P0.198 and PFS (HR, 0.816 95% CI, 0.577-1.155 P0.251). The rates of patients showed AEs of any grade treated with PD-1 or PD-L1 were 67.12% and 64.00%, with no significant difference (P0.642, χ PD-1 and PD-L1 inhibitors might achieved comparable survival benefit and safety in ES-SCLC patients. A longer PFS was observed in patients treated with PD-1 inhibitors in the first-line treatment, and the PD-1 inhibitor camrelizumab might have achieved a better PFS compared with other ICIs.

Comparison of oncological outcomes between trisegmentectomy and lobectomy for non-small cell lung cancer in the left upper division.

The left upper lobe is one of the largest lobes in the lungs and is divided into two anatomical units the upper division (segments 12 and segment 3) and lingula (segments 4 and 5). This anatomical classification is similar to that used for the right upper and middle lobes. Although bilobectomy is not recommended for right upper or middle lobe tumors close to the interlobar plane, lobectomy is often performed for tumors located close to the intersegmental plane in the left upper division. To aid in establishing trisegmentectomy as a standard treatment for clinical N0 non-small cell lung cancer (NSCLC) in the left upper lobe, we aimed to re-assess its feasibility based on oncological outcomes according to tumor location. We retrospectively analyzed the data of patients with clinical N0 NSCLC in the left upper division who underwent left upper lobectomy or trisegmentectomy between April 2006 and December 2020. After propensity score matching, oncological outcomes were compared between the trisegmentectomy and lobectomy groups. To verify whether trisegmentectomy was indicated regardless of tumor distance from the intersegmental plane, we compared the recurrence-free survival (RFS) rates following trisegmentectomy between patients with tumors ≤20 and >20 mm from the intersegmental plane. After propensity score matching, 46 patients were included in each group. There was no significant difference in the 5-year RFS rate between the lobectomy and trisegmentectomy groups (75.5% Our analysis suggests that oncological outcomes (i.e., RFS rates) following trisegmentectomy for clinical N0 NSCLC in the left upper division are not significantly inferior to those following lobectomy, even if the tumor is located close to the intersegmental plane.

Improving lung cancer screening rates among patients with head and neck cancer in a radiation oncology clinic.

The United States Preventive Services Task Force (USPSTF) recommends lung cancer screening via annual low dose computed tomography (LDCT) for high risk patients. Despite the strong evidence of a mortality benefit from several randomized clinical trials, rates of lung cancer screening remain low. We plan to assess how screening guidelines are implemented in a radiation oncology clinic for patients with head and neck cancer. A single institution, retrospective chart review was used to identify patients with head and neck cancer seen in a radiation oncology clinic who were potentially eligible for lung cancer screening under the current USPSTF guidelines. Patients who were potentially screening-eligible were enrolled in a phone survey to assess their knowledge about lung cancer screening and willingness to be screened. Of the 184 patients with head and neck cancer seen in the clinic, 8 (4%) patients were eligible for lung cancer screening under the previous USPSTF recommendations, including 1 (0.5%) patient already being screened. One patient (0.5%) became eligible under the expanded guidelines. All 184 patients had smoking history documented. Of the 87 current or former smokers, there were 24 (28%) who did not have pack-years documented of the 82 former smokers, there were 8 (10%) who did not have quit date documented. Among the 16 phone survey participants (response rate 70%) only 6 (38%) were aware there is a way to screen for lung cancer and 12 (75%) patients would be interested in screening if they are found to be eligible. These findings highlight a potential opportunity to increase rates of lung cancer screening among patients with head and neck cancer by both enhancing provider awareness as well as patient education at the community level.

Basal cell adhesion molecule promotes metastasis-associated processes in ovarian cancer.

Basal cell adhesion molecule (BCAM) is a laminin α5 (LAMA5) binding membrane-bound protein with a putative role in cancer. Besides full-length BCAM1, an isoform lacking most of the cytoplasmic domain (BCAM2), and a soluble form (sBCAM) of unknown function are known. In ovarian carcinoma (OC), all BCAM forms are abundant and associated with poor survival, yet BCAMs contribution to peritoneal metastatic spread remains enigmatic. Biochemical, omics-based and real-time cell assays were employed to identify the source of sBCAM and metastasis-related functions of different BCAM forms. OC cells, explanted omentum and a mouse model of peritoneal colonisation were used in loss- and gain-of-function experiments. We identified ADAM10 as a major BCAM sheddase produced by OC cells and identified proteolytic cleavage sites proximal to the transmembrane domain. Recombinant soluble BCAM inhibited single-cell adhesion and migration identically to membrane-bound isoforms, confirming its biological activity in OC. Intriguingly, this seemingly anti-tumorigenic potential of BCAM contrasts with a novel pro-metastatic function discovered in the present study. Thus, all queried BCAM forms decreased the compactness of tumour cell spheroids by inhibiting LAMA5 - integrin β1 interactions, promoted spheroid dispersion in a three-dimensional collagen matrix, induced clearance of mesothelial cells at spheroid attachment sites in vitro and enhanced invasion of spheroids into omental tissue both ex vivo and in vivo. Membrane-bound BCAM as well as sBCAM shed by ADAM10 act as decoys rather than signalling receptors to modulate metastasis-related functions. While BCAM appears to have tumour-suppressive effects on single cells, it promotes the dispersion of OC cell spheroids by regulating LAMA5-integrin-β1-dependent compaction and thereby facilitating invasion of metastatic target sites. As peritoneal dissemination is majorly mediated by spheroids, these findings offer an explanation for the association of BCAM with a poor clinical outcome of OC, suggesting novel therapeutic options.

Increasing cure rates of solid tumors by immune checkpoint inhibitors.

Immunotherapy has become the central pillar of cancer therapy. Immune checkpoint inhibitors (ICIs), a major category of tumor immunotherapy, reactivate preexisting anticancer immunity. Initially, ICIs were approved only for advanced and metastatic cancers in the salvage setting after or concurrent with chemotherapy at a response rate of around 20-30% with a few exceptions. With significant progress over the decade, advances in immunotherapy have led to numerous clinical trials investigating ICIs as neoadjuvant andor adjuvant therapies for resectable solid tumors. The promising results of these trials have led to the United States Food and Drug Administration (FDA) approvals of ICIs as neoadjuvant or adjuvant therapies for non-small cell lung cancer, melanoma, triple-negative breast cancer, and bladder cancer, and the list continues to grow. This therapy represents a paradigm shift in cancer treatment, as many early-stage cancer patients could be cured with the introduction of immunotherapy in the early stages of cancer. Therefore, this topic became one of the main themes at the 2021 China Cancer Immunotherapy Workshop co-organized by the Chinese American Hematologist and Oncologist Network, the China National Medical Products Administration and the Tsinghua University School of Medicine. This review article summarizes the current landscape of ICI-based immunotherapy, emphasizing the new clinical developments of ICIs as curative neoadjuvant and adjuvant therapies for early-stage disease.

Chylothorax and chylopericardial tamponade following lobectomy and lymphadenectomy a rare presentation.

Although postoperative chylothorax following lung cancer surgery is rare, it is a recognized complication in 0.25-3% of patients. However, cases of cardiac tamponade caused by chylopericardium after lung cancer surgery are extremely rare. We describe hitherto unreported sequelae of chyle leak following lobectomy and systematic mediastinal lymph node dissection (SLND) causing pericardial tamponade and cardiovascular compromise. The patient was successfully treated with minimally invasive surgical repair and ligation. We also discuss the development of chylopericardium as a potential complication of lobectomy and SLND. The anatomical characteristics of the thoracic duct warrant special attention in postoperative chyle leak management in patients who undergo definitive mediastinal lymph node dissection. Surgeons should be aware that chylopericardium is a rare but potential complication of lobectomy and SLND as it may help with early diagnosis, management, and prevention of cardiac tamponade.

Transcriptome analysis reveals the differential inflammatory effects between propofol and sevoflurane during lung cancer resection a randomized pilot study.

Propofol and sevoflurane are two commonly used perioperative anesthetics. Some studies have found that these anesthetic drugs affect tumorigenesis. Previous studies have mostly focused on in vitro experiments, and the specimens collected were mainly peripheral body fluids, lacking direct evidence of the impact of anesthetic drugs on human tissues. This study aimed to elucidate the effects of propofol and sevoflurane on lung cancer using next-generation sequencing through an in vivo experiment. Patients were randomly assigned to a group receiving either propofol or sevoflurane during surgery. Then, the patients tumor and paired normal samples were collected and sequenced by next-generation sequencing. Differentially expressed genes (DEG) were analyzed by two statistical models, followed by cluster analysis, PCA, Gene Ontology, and KEGG pathway analysis. Candidate genes were confirmed by qRT-PCR. The demographic data of the two study groups were not statistically significant. Through single-factor model analysis, 810 DEG in the propofol group and 508 DEG in the sevoflurane group were obtained. To better reflect the differential effects between propofol and sevoflurane while reducing the false-positive DEG, we used multifactor model analysis, which resulted in 124 DEG. In PCA and cluster analysis, four groups (propofol cancer group, propofol normal group, sevoflurane cancer group, sevoflurane normal group) were separated adequately, indicating the accuracy of the analysis. We chose seven significant pathways (cellular response to interleukin-1, chemokine-mediated signaling pathway, chemokine signaling pathway, cytokine-cytokine receptor interaction, inflammatory response, immune response, and TNF signaling pathway) for downstream analysis. Based on the pathway analysis, three candidate genes (CXCR1, CXCL8, and TNFAIP3) were chosen, and their qRT-PCR results were consistent with the sequencing results. Through RNA-seq analysis, the effects of propofol and sevoflurane during lung cancer resection were different, mainly in inflammatory-related pathways, which might be possibly by targeting CXCL8. Trial registry number was ChiCTR1900026213 .

Systematic review of economic evaluations on stereotactic ablative radiotherapy (SABR) compared to other radiotherapy techniques or surgical procedures for early-stage non-small cell lung cancer.

Stereotactic ablative radiotherapy (SABR) is recommended as first-choice treatment to inoperable early-stage non-small cell lung cancer (NSCLC). However, it is not widely adopted in developing countries, and its cost-effectiveness is unclear. We aimed to perform a systematic review of full economic evaluations (EE) that compared SABR with other radiotherapy or surgical procedures to assess the results and methodological approach. The protocol was registered on PROSPERO (CRD42021241640). We included full EE studies with early-stage NSCLC in which one group was submitted to SABR. Studies that were partial EE, included advanced NSCLC or other neoplasm were excluded. We performed the last search on June 2021 in Medline, EMBASE and other databases. The reporting quality were assessed by CHEERS checklist. The main characteristics of each study were tabulated, and the results were presented by a narrative synthesis. We included nine studies. Three compared radiotherapy techniques, in which SABR was found to be dominant or cost-effective. Six compared SABR with surgery, and in this group, there was not a unanimous decision. All included only direct healthcare costs but varied about categories included. The parameters used in the model-based studies were highly heterogeneous using mixed data from various sources. The items properly reported varied from 29 to 67%. The studies were all from developed countries and lacked in reporting quality. We recommend that developing countries produce their own studies. More strict alignment to reporting guidelines and use of robust evidence as model parameters are also advised.

Expression of PD-L1 through evolution phase from pre-invasive to invasive lung adenocarcinoma.

This study evaluated programmed cell death-ligand 1 (PD-L1) expression from pre-invasive adenocarcinoma to invasive lung adenocarcinoma, aimed to investigate the potential association of PD-L1 pathway with lung adenocarcinoma early evolution. We evaluated PD-L1 expression in 1123 resected lung specimens of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) of stage IA1-IA3. PD-L1 expression was defined based on the proportion of stained tumor cells using the tumor proportion score < 1% (negative), ≥ 1% (positive) and ≥ 50% (strongly positive). Correlations between PD-L1 expression and T stage, pathological subtype, adenocarcinoma grade, spread through air space (STAS), vascular invasion, lymphatic invasion and driven genes were analyzed. There was almost no PD-L1 expression in AIS or MIA. However, PD-L1 expression was correlated with invasiveness of lung adenocarcinoma. The percentages of PD-L1 positive in IA1-IA3 were 7.22%, 11.29%, and 14.20%, respectively. The strongly positive rates of PD-L1 were 0.38%, 1.64%, and 3.70% in IA1-IA3, respectively. PD-L1 expression and positive rate were also associated with poor pathological subtype and poor biological behavior, such as adenocarcinoma Grade 3, micropapillary or solid dominant subtype, STAS and vascular invasion. Finally, PD-L1 positive rate seems also corrected with driven gene ALK, ROS-1 and KRAS. PD-L1 expression was positively correlated with the emergence of invasiveness and poor pathological subtype or biological behavior of early-stage lung adenocarcinoma. PD-L1 pathway may be involved in the early evolution of lung adenocarcinoma from AIS to IAC.

Spherical pneumonia caused by Ralstonia mannitolilytica a case report and literature review.

Spherical pneumonia is an extremely rare condition that is difficult to diagnose. It is a specific type of lung infection that often manifests as a round or round-like mass on chest imaging. Spherical pneumonia is easily misdiagnosed as a pulmonary tumor therefore, awareness of this disease must be strengthened. The patient was a 29-year-old female who had persistent cough and sputum for approximately 1 month and fever for 5 days. Chest computed tomography (CT) at our hospital revealed a mass in the lower lobe of the right lung near the hilar region, with obstructive pulmonary atelectasis and obstructive pneumonia. Although lung cancer was suspected, Ralstonia mannitolilytica was detected by metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid, and no cancer cells or Mycobacterium tuberculosis were detected. Finally, the patient was diagnosed with spherical pneumonia caused by R. mannitolilytica. Anti-infective treatment, symptomatic treatment, and administration of a traditional Chinese medicine decoction were performed based on the syndrome differentiation. After 10 days of treatment, chest CT revealed few lesions in the lower lobe of the right lung, which were significantly reduced compared with those in the past. Spherical pneumonia caused by R. mannitolilytica has not yet been reported and differential diagnosis is key in clinical diagnosis. When spherical pneumonia is difficult to diagnose, mNGS may be a better alternative.

Cost-effectiveness of atezolizumab versus pembrolizumab as first-line treatment in PD-L1-positive advanced non-small-cell lung cancer in Spain.

Atezolizumab has recently been approved for first-line treatment of high PD-L1 expression metastatic Non-Small-Cell Lung Cancer (NSCLC) patients with no EGFR or ALK mutations, on the basis of the IMpower110 trial. This study aims to estimate the cost-effectiveness of atezolizumab compared with pembrolizumab among these patients in Spanish settings, based on the results of the two cut-offs of the IMpower110 study. A three-state partitioned-survival model was adapted to Spanish settings to calculate health outcomes and costs over a lifetime horizon. Clinical data for atezolizumab were collected from the interim and the exploratory results (data cut-off Sept18 and Feb20, respectively) of the IMpower110 trial while a network meta-analysis was used to model pembrolizumab treatment. Utility data were collected from the trial. Direct medical costs were considered based on resources identified by experts. Costs and outcomes were discounted at 3% per year. Health outcomes were expressed as cost per Life Year (LY) and cost per Quality-Adjusted Life Year (QALY). Both deterministic and probabilistic sensitivity analyses were performed to assess the robustness of results. Over a lifetime horizon, the incremental results showed that atezolizumab generated similar health outcomes (LYs and QALYs) to pembrolizumab, with minimal differences depending on the cut-off used ( 0.70 and 0.42 LYs and QALYs with Sept18 cut-off and - 0.80 and - 0.72 LYs and QALYs with Feb20 cut-off). However, for both cut-offs, atezolizumab produced meaningfully less costs than pembrolizumab (€ - 54,261 with Sept18 cut-off and € - 81,907 with Feb20 cut-off). The sensitivity analyses carried out confirmed the robustness of the base-case results. The cost-effectiveness analysis, comparing the two cut-off of IMpower110, shows that atezolizumab provides similar health gains to pembrolizumab but at a lower cost for the first-line treatment of metastasic NSCLC patients in Spain.

Phosphorylation of TGIF2 represents a therapeutic target that drives EMT and metastasis of lung adenocarcinoma.

TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that is phosphorylated by EGFRERK signaling. However, the functions of phosphorylated (p)-TGIF2 in cancer are largely unknown. Here, we investigated the roles of p-TGIF2 in promoting epithelial-mesenchymal transition (EMT) and metastasis in lung adenocarcinoma (LUAD). In vitro and in vivo experiments were conducted to investigate the role of TGIF2 in LUAD EMT and metastasis. Dual-luciferase reporter and ChIP assays were employed to observe the direct transcriptional regulation of E-cadherin by TGIF2 and HDAC1. Co-immunoprecipitation was performed to identify the interaction between TGIF2 and HDAC1. Downregulating the expression of TGIF2 inhibited LUAD cell migration, EMT and metastasis in vitro and in vivo. Phosphorylation of TGIF2 by EGFRERK signaling was required for TGIF2-promoted LUAD EMT and metastasis since phosphorylation-deficient TGIF2 mutant lost these functions. Phosphorylation of TGIF2 was necessary to recruit HDAC1 to the E-cadherin promoter sequence and subsequently suppress E-cadherin transcription. Meanwhile, inhibition of HDAC1 repressed the TGIF2 phosphorylation-induced migration and EMT of LUAD cells. In xenograft mouse models, both inhibition of ERK and HDAC1 could significantly inhibited TGIF2-enhanced metastasis. Furthermore, TGIF2-positive staining was significantly correlated with E-cadherin-negative staining in human lung cancer specimens. Our study reveals the novel function of p-TGIF2 in promoting EMT and metastasis in LUAD p-TGIF2 could be a potential therapeutic target to inhibit LUAD metastasis.

Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1.

Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. RNA-seq was performed to determine the downstream pathways of ACK. Using Lasso Cox regression analysis, we built a risk signature with ACK1-related autophagy genes in the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) project. The performance of the signature in predicting the tumor immune environment and response to immunotherapy and chemotherapy were assessed in LUAD. CCK8, mRFP-GFP-LC3 assay, western blot, colony formation, wound healing, and transwell migration assays were conducted to evaluate the effects of the ACK1 inhibitor on lung cancer cells. A subcutaneous NSCLC xenograft model was used for in vivo study. RNA-seq revealed the regulatory role of ACK1 in autophagy. Furthermore, the risk signature separated LUAD patients into low- and high-risk groups with significantly different prognoses. The two groups displayed different tumor immune environments regarding 28 immune cell subsets. The low-risk groups showed high immune scores, high CTLA4 expression levels, high immunophenoscore, and low DNA mismatch repair capacity, suggesting a better response to immunotherapy. This signature also predicted sensitivity to commonly used chemotherapy and targeted drugs. In vitro, the ACK1 inhibitors (AIM-100 and Dasatinib) appeared to trigger adaptive autophagy-like response to protect lung cancer cells from apoptosis and activated the AMPKmTOR signaling pathway, partially explaining its moderate antitumor efficacy. However, blocking lysosomal degradation with chloroquineBafilamycine A1 or inhibiting AMPK signaling with compound CshPRKAA1 enhanced the ACK1 inhibitors cytotoxic effects on lung cancer cells. The efficacy of the combined therapy was also verified using a mouse xenograft model. The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion.

PDQ Cancer Information Summaries

This PDQ cancer information summary has current information about the treatment of a type of childhood lung cancer called tracheobronchial tumors. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (Date Last Modified) is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.

GeneReviews

Dyskeratosis congenita and related telomere biology disorders (DCTBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest andor neck, and oral leukoplakia, although this may not be present in all individuals. People with DCTBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the headneck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DCTBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DCTBD vary at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. A majority of individuals with DCTBD have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on lymphocyte subsets. To date, The mode of inheritance of DCTBD varies by gene X-linked

Norepinephrine inhibits CD8

Mental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies. In this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrines (NE) effect on immunotherapy. The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8 NE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8

A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung.

The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.