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Large-scale clinico-genomic profile of non-small cell lung cancer with KRAS G12C Results from LC-SCRUM-Asia study.

KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear. Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated. From March 2015 to March 2021, 10,023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14 %), including G12C in 376 (4.0 %), G12D in 289 (3.1 %) and G12V in 251 (2.7 %). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males 73 % vs 63 %, p < 0.001 smokers 89 % vs 76 %, p < 0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mutMb, p < 0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50 % (52 %, p 0.08). The overall survival in patients with KRAS G12C (median, 24.6 months) was not different between patients with other mutation subtypes (G12V 18.2 months, p 0.23 G12D 20.6 months, p 0.65 other KRAS mutations 18.3 months, p 0.20). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p 0.90), but significantly longer than that in G12D- (2.0 months, p 0.02) and other KRAS mutation-positive patients (2.5 months, p 0.02). The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.

Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types.

Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences. Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers. We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66 95% CI, 0.49-0.83 P 9.77 × 10 This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention. This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).

Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD) An observational and exploratory case series of non-asian patients.

Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.

Lung cancer presenting with central nervous system metastasis Clinicopathological and molecular analysis of 171 cases.

A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48-96 mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13171 (7.6 %) and 32163 (19.6 %) cases, respectively mainly TTF1- (40.0 %) and HepPar1 (38.1 %) adenocarcinomas were affected by SMARCA24 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinomaLCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (23) was found in 45166 (27.1 %) of cases with amplification verified by CISH in 1838 (47.4 % of immunopositive cases and 10.5 % of the whole cohort) all but one were adenocarcinomas. Other genetic abnormalities detected included EML4ALK rearrangements in 3 (1.8 % 2 TTF1 adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.

Modeling Costs and Life-Years Gained by Population-Wide Next-Generation Sequencing or Single-Gene Testing in Nonsquamous Non-Small-Cell Lung Cancer in the United States.

Many patients with actionable driver oncogenes (ADOs) are never identified and thus never receive targeted treatment. This study evaluated the economic impact and the potential life-years gained (LYG) that can be attributed to the extent of next-generation sequencing (NGS) testing in the United States compared with single-gene testing (SGT) in patients with metastatic nonsquamous non-small-cell lung cancer in the United States. A model was developed to evaluate incremental rates of SGT or NSG testing on the basis of LYG and cost per LYG. ADOs included for NGS included Each incremental 10% increase in NGS testing produces an average of 2,627.4 additional LYG, with an average cost savings per LYG of $75 US dollars (USD). Replacing SGT at the current rate of 80% with NGS testing would result in an average additional 21,09.6 LYG and reduce cost per LYG by an average of $599 USD. If 100% of eligible patients were tested with NGS and each identified patient had matched treatment, the total average cost per LYG would be $16,641.57 USD. On the basis of current evidence, population-level simulations demonstrate that clinically relevant gains in survival with non-negligible reduction in costs are obtainable from widespread adoption of NGS testing and appropriate treatment matching for patients with advanced nonsquamous non-small-cell lung cancer.

Sybil A Validated Deep Learning Model to Predict Future Lung Cancer Risk From a Single Low-Dose Chest Computed Tomography.

Low-dose computed tomography (LDCT) for lung cancer screening is effective, although most eligible people are not being screened. Tools that provide personalized future cancer risk assessment could focus approaches toward those most likely to benefit. We hypothesized that a deep learning model assessing the entire volumetric LDCT data could be built to predict individual risk without requiring additional demographic or clinical data. We developed a model called Sybil using LDCTs from the National Lung Screening Trial (NLST). Sybil requires only one LDCT and does not require clinical data or radiologist annotations it can run in real time in the background on a radiology reading station. Sybil was validated on three independent data sets a heldout set of 6,282 LDCTs from NLST participants, 8,821 LDCTs from Massachusetts General Hospital (MGH), and 12,280 LDCTs from Chang Gung Memorial Hospital (CGMH, which included people with a range of smoking history including nonsmokers). Sybil achieved area under the receiver-operator curves for lung cancer prediction at 1 year of 0.92 (95% CI, 0.88 to 0.95) on NLST, 0.86 (95% CI, 0.82 to 0.90) on MGH, and 0.94 (95% CI, 0.91 to 1.00) on CGMH external validation sets. Concordance indices over 6 years were 0.75 (95% CI, 0.72 to 0.78), 0.81 (95% CI, 0.77 to 0.85), and 0.80 (95% CI, 0.75 to 0.86) for NLST, MGH, and CGMH, respectively. Sybil can accurately predict an individuals future lung cancer risk from a single LDCT scan to further enable personalized screening. Future study is required to understand Sybils clinical applications. Our model and annotations are publicly available.

Unravelling the genetic links between Parkinsons disease and lung cancer.

Increase evidence from epidemiological studies have shown an inverse association between Parkinsons disease (PD) and lung cancer. PD and lung cancer are both geriatric diseases, where these two diseases are sharing some common genetic determinants. Several PD-associated genes including alpha synuclein (SNCA), PTEN-induced kinase 1 (PINK1), parkin, parkinsonism associated deglycase (DJ-1), leucine-rich repeat kinase 2 (LRRK2), F-box protein 7 (FBXO7) and ubiquitin C-terminal hydrolase L1 (UCHL1) were reported to have altered expressions in lung cancer patients. This indicates that certain PD-associated genes might be important in conferring anticancer effects. This review aims to depict the physiological functions of these genes, and discuss the putative roles of these PD-associated genes in lung cancer. The understanding of the roles of these genes in the lung cancer progression might be important in the identification of new treatment targets for lung cancer. Gene therapy that aims to alter the expressions of these genes could be developed for future anticancer therapy. As a result, studying the roles of these genes in lung cancer may also help to understand their involvements as well as their roles in the pathogenesis of PD.

Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature Multilayered cross-talks in the setting of coinfections and comorbidities.

The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.

Prognostic significance of tumor-associated macrophages polarization markers in lung cancer a pooled analysis of 5105 patients.

The prognostic significance of tumor-associated macrophages (TAMs) in patients with lung cancer (LCa) remains controversial. We therefore conducted the present study to systematically evaluate the role of different TAMs markers and histologic locations on the prognosis of LCa. Searches of Web of Science, PubMed, and EMBASE databases were performed up to 28 February 2022. The pooled analysis was conducted in random-effect or fixed-effects model with hazard risk (HR) and 95% confidence interval (CI) for survival data including overall survival (OS), and disease-free survival (DFS) from raw or adjusted measures, according to different TAMs markers and histologic locations. Including a total of 5105 patients from 30 eligible studies, the results indicated that the total count of CD68 TAMs was negatively associated with OS and DFS, which was also observed in the relationship of CD68 or CD204 TAMs in tumor stroma (TS) with OS and DFS (all P<0.05). Conversely, higher CD68 TAMs density in tumor nest (TN) or TNTS ratio of CD68 TAMs predicted better OS (all P<0.05). Similarly, higher HLA-DR TAMs density was correlated with better OS in TN and TS (all P<0.05). Besides, neither nest CD163 TAM density nor stromal CD163 TAM density was a prognostic factor in LCa patients (all P>0.05). Our study indicated that different TAMs markers and histologic locations could bring about different prognostic effects in LCa patients. Great understanding of the infiltration modes of TAMs may contribute to improve outcomes of LCa patients.

Engineering Transferrin-Decorated Pullulan-Based Prodrug Nanoparticles for Redox Responsive Paclitaxel Delivery to Metastatic Lung Cancer Cells.

Paclitaxel (PTX) remains a cornerstone in the treatment of locally advanced and metastatic lung cancer. To improve its therapeutic indices against lung cancer, novel redox-sensitive pullulanPTX-based prodrug NPs (PULL-SS-PTX NPs) were accomplished, which were further surface-decorated with transferrin (TF), a cancer cell-targeting ligand, to afford TF-PULL-SS-PTX NPs. These prodrug NPs (drug content, >37% and average size, 134-163 nm) rapidly dismantled their self-assembled architecture upon exposure to simulated reducing conditions, causing a triggered drug release as compared to the control scaffold (PULL-CC-PTX NPs). These scaffolds also evidenced outstanding colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between the cancer and healthy cells. Intravenously delivered redox-sensitive NPs exhibited improved tumor-suppressing properties as compared to the control nanovesicles (PULL-CC-PTX NPs) in a B16-F10 melanoma lung metastasis mice model. The targeting efficiency and associated augmented anticancer potentials of TF-PULL-SS-PTX NPs relative to TF-free redox-responsive NPs and Taxol intravenous injection were also established on the transferrin receptor (TFR) overexpressed Lewis lung carcinoma (LLC-luc) cell-bearing mice model. Moreover, the TF-functionalized scaffold displayed a reduced systemic toxicity compared to that of Taxol intravenous injection. Overall, the proposed TF-decorated prodrug NPs could be a promising nanomedicine for intracellular PTX delivery against metastatic lung cancer.

Incidence, Timing, and Factors Associated With Suicide Among Patients Undergoing Surgery for Cancer in the US.

The risk and timing of suicide among patients who undergo surgery for cancer remain largely unknown, and, to our knowledge, there are currently no organized programs in place to implement regular suicide screening among this patient population. To evaluate the incidence, timing, and factors associated with suicide among patients undergoing cancer operations. This retrospective population-based cohort study used data from the Surveillance, Epidemiology, and End Results Program database to examine the incidence of suicide, compared with the general US population, and timing of suicide among patients undergoing surgery for the 15 deadliest cancers in the US from 2000 to 2016. A Fine-Gray competing risks regression model was used to identify factors associated with an increased risk of suicide among patients in the cohort. Data were analyzed from September 2021 to January 2022. Surgery for cancer. Incidence, compared with the general US population, timing, and factors associated with suicide after surgery for cancer. From 2000 to 2016, 1 811 397 patients (74.4% female median IQR age, 62.0 52.0-72.0 years) met study inclusion criteria. Of these patients, 1494 (0.08%) committed suicide after undergoing surgery for cancer. The incidence of suicide, compared with the general US population, was statistically significantly higher among patients undergoing surgery for cancers of the larynx (standardized mortality ratio SMR, 4.02 95% CI, 2.67-5.81), oral cavity and pharynx (SMR, 2.43 95% CI, 1.93-3.03), esophagus (SMR, 2.25 95% CI, 1.43-3.38), bladder (SMR, 2.09 95% CI, 1.53-2.78), pancreas (SMR, 2.08 95% CI, 1.29-3.19), lung (SMR, 1.73 95% CI, 1.47-2.02), stomach (SMR, 1.70 95% CI, 1.22-2.31), ovary (SMR, 1.64 95% CI, 1.13-2.31), brain (SMR, 1.61 95% CI, 1.12-2.26), and colon and rectum (SMR, 1.28 95% CI, 1.16-1.40). Approximately 3%, 21%, and 50% of suicides were committed within the first month, first year, and first 3 years after surgery, respectively. Patients who were male, White, and divorced or single were at greatest risk of suicide. In this cohort study, the incidence of suicide among patients undergoing cancer operations was statistically significantly elevated compared with the general population, highlighting the need for programs to actively implement regular suicide screening among such patients, especially those whose demographic and tumor characteristics are associated with the highest suicide risk.

Circ0060937 Contributes to the Development of Lung Cancer via Positively Regulating LAD1 Expression by Binding to miR-1304-5p.

In view of the significance of circular RNA (circRNA) in multiple carcinogeneses, our study focused on circ0060937 and investigated its function and molecular mechanism in lung cancer. Quantitative real-time PCR (qPCR) and western blot assays were applied for expression analysis of circ0060937, miR-1304-5p, LAD1, and several marker proteins. Functional experiments, including colony formation assay, EdU assay, transwell analysis, sphere formation assay, and flow cytometry experiment, were conducted for cell behavior analysis. The putative binding relationship between circ0060937 and miR-1304-5p was validated by dual-luciferase reporter experiment and pull-down analysis. Animal models were established to ascertain the role of circ0060937. Upregulation of circ0060937 was shown in lung cancer tissues and cell lines. Circ0060937 downregulation repressed A549 and H1299 cell proliferative, migratory, invasive, and sphere formation abilities, and circ0060937 absence also decelerated tumorigenesis in animal models. Circ0060937 bound to miR-1304-5p to positively regulate LAD1 expression. The inhibitory effects of circ0060937 absence on A549 and H1299 cell malignant behaviors were largely reversed by miR-1304-5p inhibition or LAD1 overexpression, hinting that circ0060937 affected lung cancer progression via modulating the miR-1304-5pLAD1 axis. Circ0060937 downregulation decreased the expression of LAD1 by releasing miR-1304-5p to effectively repress lung cancer cell growth and in vivo tumorigenesis.

Complete remissions following immunotherapy or immuno-oncology combinations in cancer patients the MOUSEION-03 meta-analysis.

Immunotherapy has determined unprecedented long-term responses in several hematological and solid tumors. In the MOUSEION-03 study, we conducted a meta-analysis to determine the possibility of achieving complete remissions (CR) with immunotherapy or immuno-oncology combinations in cancer patients. The primary endpoint was to assess the incidence of CR in cancer patients receiving immune checkpoint inhibitors (ICIs) alone or in combination with other agents versus control treatments. The pooled odds ratio (OR) and 95% confidence interval (CI) for CR rate were extracted. A total of 12,130 potentially relevant trials were identified 5 phase II and 80 phase III randomized studies (37 monotherapies and 48 combinations) and 49,425 cancer patients were included. The most frequent types of malignancies were non-small cell lung cancer (n 14,249 29%), urothelial cancer (n 6536 13%), renal cell carcinoma (n 5743 12%), and melanoma (n 2904 6%). In patients treated with immunotherapy (as monotherapy or in combination with other anticancer agents), the pooled OR was 1.67 (1.52-1.84). The highest OR was registered by immune-based combinations with two ICIs (3.56, 95% CI 1.28-9.90). To the best of the authors knowledge, no comprehensive meta-analysis on the use of ICIs and ICI-based combinations in solid tumors to systematically investigate the probability to achieve CR has been published so far. Although CR is not a common event in several cancer patients receiving immunotherapy, the MOUSEION-03 suggests that the use of ICIs may significantly increase the chance of achieving CR in comparison with control treatments.

Cancer statistics, 2023.

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stableincreasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

Exosomal proteomics identifies RAB13 as a potential regulator of metastasis for HCC.

Exosomal proteins from cancer cells are becoming new biomarkers for cancer monitoring and efficacy evaluation. However, their biological function and molecular mechanism underlying tumor metastasis are largely unknown. Bioinformatic methods such as bulk gene expression analysis, single-cell RNA sequencing data analysis, and gene set enrichment analysis were employed to identify metastasis-associated proteins. The in vitro and in vivo experiments were used to investigate the function of RAB13 in HCC metastasis. We identified RAB13 as one of the critical regulators of metastasis in HCC-derived exosomes for the first time. In vitro, the invasiveness of HCC cell lines could be attenuated by RAB13 silence. In vivo, tumor size and proportion of high-grade lung metastatic nodule could be reduced in the mice with orthotopic transplantation of tumors and intravenously injected with exosomes derived from MHCC97H cell with RAB13 silence (si-RAB13-Exo), as compared with those without RAB13 silence (si-NC-Exo). Moreover, in si-RAB13-Exo group, circulating tumor cell counts were decreased at the third, fourth, and fifth weeks after orthotopic transplantation of tumors, and MMP2 (matrix metalloproteinase 2)TIMP2 (tissue inhibitor of metalloproteinases 2) ratio was also significantly decreased. In addition, RAB13 expression was also associated with VEGF levels, microvessel density, and tube formation of vascular endothelial cells by both in vitro and in vivo models, indicating that RAB13 was associated with angiogenesis in HCC. We have demonstrated exosomal RAB13 as a potential regulator of metastasis for HCC by in silico, in vitro, and in vivo methods, which greatly improve our understanding of the functional impact of exosomal proteins on HCC metastasis.

Markers of malnutrition, inflammation and tissue remodeling are associated with one-year outcomes in patients with advanced heart failure.

A number of predictive models and biomarkers have been developed to assess outcomes in patients with advanced heart failure (HF). We sought to evaluate whether markers of malnutrition, inflammation and tissue remodeling are associated with mortality in patients with advanced HF during a one-year follow-up. We analyzed 200 consecutive patients with advanced HF. We assessed markers of inflammation and malnutrition the neutrophil percentage-to-albumin ratio (NPAR), the advanced lung cancer inflammation index (ALI) and high sensitivity C-reactive protein (hsCRP). The level of tenascin-C (TNC), marker of remodeling, was measured by sandwich enzyme-linked immunosorbent assay (ELISA) with a commercially available kit (Human TNC ELISA Kit, SunRedBio Technology Co, Ltd, Shanghai, China). The median age of the patients was 58 (51-64) years. The independent predictors of death were ALI OR 0.966 0.941-0.992, p0.01 and NPAR OR 1.373 1.126-1.674, p0.002 values, TNC OR 1.040 1.020-1.050, p<0.001, hsCRP 1.187 1.037-1.360, p0.01, NT-proBNP OR 1.110 1.100-1.200, p0.02, bilirubin OR 1.079 1.014-1.149, p0.02 and creatinine OR 1.034 1.013-1.055, p0.001 serum levels. The ROC curve analysis indicated a good discriminatory power of the TNC AUC 0.807, NTproBNP AUC0.760 and hsCRP (AUC0.706 serum levels, the ALI AUC 0.749 and NPAR AUC0.785 values in predicting mortality during one-year follow-up. Our study demonstrated that a lower advanced lung cancer inflammation index and a higher neutrophil percentage-to-albumin ratio and higher tenascin, NT-proBNP, hsCRP, bilirubin and creatinine serum concentrations are associated with one-year mortality in patients with advanced heart failure.

Primary gastric choriocarcinoma a rare and aggressive gastrointestinal malignancy.

A 40-year-old male with no previous medical history presented to emergency department with a 2-week history of progressive dyspnea. He also described night sweats and weight loss (15 kg) during the last 3 months. Thoraco-abdominal computed tomography showed multiple bilateral lung nodules associated with supra-clavicular, hilar and peri-esophageal lymphadenopathies and gastric parietal thickening. These imaging features were suggestive of primary gastric cancer with lung and lymph node metastases. Therefore, he undergone upper digestive endoscopy that showed a large ulcerated protruding lesion at the greater curvature of the body suggestive of malignancy. Gastric biopsies of the lesion confirmed a solid neoplasia constituted by solid nests and sheets of highly pleomorphic, bizarre cells with cytotrophoblastic and syncytiotrophoblastic differentiation that, on immunohistochemistry, stained positive for β-HCG, SALL-4 and glypican-3. CT-guided biopsy of lung nodules revealed malignant cells with similar histopathological and immunohistochemical features. Elevated serum alpha-fetoprotein and β-HCG were also detected. Clinical and ultrasound examination were negative for testicular masses. These findings were consistent with a primary gastric choriocarcinoma presenting with lung and lymph node metastases (stage IV). Although chemotherapy was started, the patient evolved unfavorably and died after 9 months. Primary gastric choriocarcinoma is a rare and aggressive gastrointestinal malignancy. This case demonstrates its rapid growth rate and high metastatic potential that may lead to symptoms from secondary involvement of distant organs.

Prognostic value of NOX2 as a potential biomarker for lung adenocarcinoma using TCGA and clinical validation.

Lung adenocarcinoma (LUAD) is associated with high morbidity and mortality therefore, effective biomarkers are essential. In recent years, a rapid increase in the efficiency of high‑throughput sequencing technologies and the continuous improvement of comprehensive online databases have facilitated the study of the genomic changes that affect tumor progression, including the identification of tumor biomarkers. Therefore, the identification of genes that may affect the progression and prognosis of LUAD is necessary. In the present study, the CIBERSORT and ESTIMATE bioinformatics packages were used to evaluate data from The Cancer Genome Atlas, including assessment of the proportion of tumor‑infiltrating immune cells in the tumor microenvironment, Cox regression analysis of differentially expressed genes and cross analysis of protein‑protein interaction networks. Myeloid cell NADPH oxidase isoform 2 (NOX2), an indispensable gene in the immune system, was demonstrated to serve a vital role in LUAD pathogenesis. Western blotting and immunohistochemistry confirmed that, at the protein level, NOX2 expression was increased in normal cells compared with cancer cells. Furthermore, reverse transcription‑quantitative PCR results at the mRNA level were consistent with these results, which confirmed that the abundance of NOX2 was significantly reduced in LUAD patients. NOX2 may be used as a novel marker and an independent prognostic indicator of LUAD. Its potential function was enriched in tumor immune and metabolic signaling pathways, which could provide clues for the study of the signaling pathways and molecular networks related to the disease progression of LUAD, which would be helpful for the assessment of prognosis in the clinical setting.

Is individual perfusion dose-response different than ventilation dose-response for lung cancer patients treated with radiotherapy

Current ventilation and perfusion dose-response studies focus on single-modalities (ventilation or perfusion) and perform pulmonary-toxicity assessment related to radiotherapy on a population-based basis. This study aims at quantitative and clinical evaluation of intrapatient differences between ventilation and perfusion dose-responses among lung cancer patients treated with radiotherapy. 20 patients enrolled on a prospective functional avoidance protocol underwent single photon emission computed tomography-CT ventilation and perfusion scans pre- and post-radiotherapy. Relative changes in pre- to post-treatment ventilation and perfusion in lung regions receiving ≥20 Gy were calculated. In addition, the slopes of the linear fit to the relative ventilation and perfusion changes in regions receiving 0-60 Gy were calculated. A radiologist read and assigned a functional defect score to pre- and post-treatment ventilationperfusion scans. 25% of patients had a difference >35% between ventilation and perfusion pre- to post-treatment changes and 20-30% of patients had opposite directions for ventilation and perfusion pre- to post-treatment changes. Using a semi-quantitative scale, radiologist assessment showed that 20% of patients had different pre- to post-treatment ventilation changes when compared to pre- to post-treatment perfusion changes. Our data showed that ventilation dose-response can differ from perfusion dose-response for 20-30% of patients. Therefore, when performing thoracic dose-response in cancer patients, it is insufficient to look at ventilation or perfusion alone but rather both modes of functional imaging may be needed when predicting for clinical outcomes. The significance of this study can be highlighted by the differences between the intrapatient dose-response assessments of this analysis compared to existing population-based dose-response analyses. Elucidating intrapatient ventilation and perfusion dose-response differences may be valuable in predicting pulmonary toxicity in lung cancer patients post-radiotherapy.

Ethnic disparities in the immune microenvironment of triple negative breast cancer and its role in therapeutic outcomes.

In 2020, newly diagnosed breast cancer (BC) cases surpassed that of lung cancer among women, making it the most common female cancer globally. In spite of recent increases in incidence rates, mortality due to BC has declined since 1989. These declines have been attributed to advancements in treatment modalities as well as increased mammography surveillance. Despite these advances, African American (AA) women are 40% more likely to die from BC than Caucasian women. Multifactorial etiology has been implicated in the disparity of BC mortality rates among AA women. As an example, AA women have a disproportionate incidence of triple negative breast cancer (TNBC), which has a poor prognosis and marginal treatment options. Increasingly, the tumor microenvironment (TME) has gained relevance as it relates to primary tumor progression, metastasis and treatment possibilities. The treatment outcomes or pathological complete response (pCR) in TNBC among AA women are affected by differences in TME. The TME of AA women exhibit several variances in acellular and cellular components associated with pro-tumorigenic effects. For example, increased levels of the adipocyte-related hormone, resistin, the pro-inflammatory cytokine, IL-6, and the CC chemokine, CCL2, within the TME of AA women gives rise to an increased density of M2 macrophages, also known as tumor-associated macrophages. Elevated levels of vascular endothelial growth factor in the TME of AA women increase the vascular density or vascularity, which facilitate aggressive tumor growth and metastasis. Furthermore, a pro-tumorigenic TME is supported by increased levels of the CXC chemokine, CXCL12 that results in the recruitment of regulatory T lymphocytes (T

Association of Phase Angle with Overall Survival in Patients with Cancer A Prospective Multicenter Cohort Study.

Low phase angle (PhA) is related with poor clinical status of cancer patients. The objective of this study was to establish sex- and age-specific cutoff points and examine the association between PhA and overall survival (OS) in Chinese cancer patients. This cohort study included data on 1,814 patients with cancer from December 2013 to October 2020. The association between low PhA and overall survival was analyzed using the Kaplan-Meier method and Cox regression model. Among 1,814 participants, there were 993 (54.70%) male and 821 (45.30%) female patients. The optimal cutoff points of low PhA were 4.8°, 4.2°, 4.4°, and 3.8° for the young male, elderly male, young female, and elderly female, respectively. Low PhA was independently associated with poorer OS in young female, elderly female and male (

RET aberrant cancers and RET inhibitor therapies Current state-of-the-art and future perspectives.

Precision oncology informed by genomic information has evolved in leaps and bounds over the last decade. Although non-small cell lung cancer (NSCLC) has moved to center-stage as the poster child of precision oncology, multiple targetable genomic alterations have been identified in various cancer types. RET alterations occur in roughly 2% of all human cancers. The role of RET as oncogenic driver was initially identified in 1985 after the discovery that transfection with human lymphoma DNA transforms NIH-3T3 fibroblasts. Germline RET mutations are causative of multiple endocrine neoplasia type 2 syndrome, and RET fusions are found in 10-20% of papillary thyroid cases and are detected in most patients with advanced sporadic medullary thyroid cancer. RET fusions are oncogenic drivers in 2% of Non-small cell lung cancer. Rapid translation and regulatory approval of selective RET inhibitors, selpercatinib and pralsetinib, have opened up the field of RET precision oncology. This review provides an update on RET precision oncology from bench to bedside and back. We explore the impact of selective RET inhibitor in patients with advanced NSCLC, thyroid cancer, and other cancers in a tissue-agnostic fashion, resistance mechanisms, and future directions.

Elimination of Cancer Cells in Co-Culture Role of Different Nanocarriers in Regulation of CD47 and Calreticulin-Induced Phagocytosis.

Under healthy conditions, pro- and anti-phagocytic signals are balanced. Cluster of Differentiation 47 (CD47) is believed to act as an anti-phagocytic marker that is highly expressed on multiple types of human cancer cells including acute myeloid leukemia (AML) and lung and liver carcinomas, allowing them to escape phagocytosis by macrophages. Downregulating CD47 on cancer cells discloses calreticulin (CRT) to macrophages and recovers their phagocytic activity. Herein, we postulate that using a modified graphene oxide (GO) carrier to deliver small interfering RNA (siRNA) CD47 (CD47siRNA) in AML, A549 lung, and HepG2 liver cancer cells in co-culture

A Retrospective Study of Patients Undergoing Palliative Radiotherapy for Airway Obstruction due to Lung Cancer.

In advanced stage lung cancer, bulky tumors can cause serious symptoms such as malignant airway obstruction (MAO). Prompt response to airway obstruction might be essential to improve quality of life and prolong life expectancy. Palliative external beam radiotherapy (EBRT) is a less invasive and highly safe treatment method that can alleviate symptoms and at the same time treat lung cancer. However, there are few reports on the results of palliative radiotherapy performed for improving airway obstruction and obstructive pneumonia. Therefore, this study retrospectively examined the effectiveness of palliative radiotherapy. We reviewed 38 lung cancer patients with MAO who underwent EBRT. Patients were treated with a median dose of 37.5 Gy (range30-40 Gy) in 10-20 fractions. Whether a patient was a responder or non-responder was assessed by whether the bronchus that was obstructed before EBRT reopened or improvement of obstructive pneumonia was observed on follow-up chest X-ray or computed tomography after EBRT. The median survival time was 135 days (range31-469 days) for the responders to EBRT and 45 days (range23-355 days) for non-responders this difference was statistically significant (p0.03). One-year overall survival rate was 18.5% and 0% for the responders to EBRT and non-responders, respectively. Palliative EBRT might be an important option for non-curative lung cancer patients with MAO.

Relationship Between TTF-1 Expression and PFS of Pemetrexed-containing Chemotherapy in Non-squamous-NSCLC Patients With and Without Driver Genes.

We performed a retrospective study too clarify whether the presence or absence of driver genes affects the relationship between thyroid transcription factor-1 (TTF-1) expression and response to pemetrexed (PEM) in non-squamous non-small cell lung cancer (non-sq-NSCLC) patients. We reviewed the medical charts of patients treated with PEM-containing chemotherapy during the period from February 2016 to February 2022 at Mito Medical Center-University of Tsukuba, Ryugasaki Saiseikai General Hospital, and University of Tsukuba Hospital. During the period of the study, 185 driver gene-negative patients negative, and 65 driver gene-positive patients were evaluated. Among the 165 driver gene-negative patients, progression free survival (PFS) of TTF-1-expressing patients treated with PEM-containing chemotherapy was significantly longer compared to that of TTF-1-negative patients. In the analysis of 65 driver gene-positive patients, the PFS of TTF-1-positive patients treated with PEM-containing chemotherapy did not differ significantly from that of TTF-1-negative patients. There was no significant difference in PFS between driver gene-negative and driver gene-positive patients treated with PEM-containing chemotherapy. Comparison between four groups defined according to the presence of driver gene and TTF-1 expression indicated shorter PFS only in driver gene-negative and TTF-1-negative patients. In driver gene-positive non-sq NSCLC patients, expression of TTF does not affect the survival outcome of PEM-containing-chemotherapy. In other words, in these patients, second-line or later-line PEM-containing chemotherapy after development of resistance for specific-tyrosine kinase inhibitor could be expected to have the same level of efficacy as first-line PEM containing chemotherapy in driver gene-negative, TTF-1-positive non-sq NSCLC patients.

Neutrophil-to-Lymphocyte Ratio Is a Major Prognostic Factor in Non-small Cell Lung Carcinoma Patients Undergoing First Line Immunotherapy With Pembrolizumab.

Lung cancer is one of the most common malignant neoplastic diseases and by far the leading cause of cancer death worldwide. Recently, immune checkpoint inhibitors (ICIs) have received increasing attention for playing a crucial role in non-small cell lung cancer (NSCLC). Biomarkers, such as programmed cell death-ligand 1 (PD-L1) and tumor mutational burden (TMB), seemed to be helpful in selecting patients who are more likely to benefit from ICI treatment however, their role has not yet been fully clarified. In this retrospective study, we evaluated the relationship between pre-treatment peripheral blood neutrophil-to-lymphocyte ratio (NLR) and survival in 252 patients suffering from advanced NSCLC who had received pembrolizumab as their first-line immunotherapy. Compared to their NLR low counterparts who had a median overall survival (OS) of 34.8 months, patients with NLRs above 4.8 had a median OS of 7.6 months (HR3.26, 95%Cl2.3-4.6, p-value<0.0000001). In multivariate Cox regression analysis, alongside other variables, such as metastatic sites, age, and sex, NLR and PD-L1 predicted progression-free survival and OS furthermore, a very high NLR - over 10 - seemed to forecast a very dismal prognosis in patients undergoing immunotherapy, with sudden deaths in the days immediately following therapy (median OS3.8 months). NLR acts as a valuable and reliable prognostic factor in non-small cell lung carcinoma patients undergoing first line immunotherapy with pembrolizumab. Additional investigation is necessary to fully elucidate the underlying biological rationale, which can be found in myeloid derived suppressor cells, a heterogeneous population of cells with neutrophil-like immunophenotypic features.

A Case of Intraocular Metastasis of Lung Cancer Diagnosed Using Cell Block Preparation of the Vitreous Humor.

Masquerade syndrome is characterized by uveitis-like manifestations caused by tumor cell infiltration into the ocular tissues. The aim of the study was to report a lung cancer patient with persistent unilateral vitreous opacity, who was eventually diagnosed with masquerade syndrome using cell block preparation. An 82-year-old female complained of blurred vision in her left eye (OS). Because of pulmonary adenocarcinoma, she had previously received anticancer drug treatment at another Hospital and achieved partial remission. Ophthalmic examinations revealed anterior chamber inflammation and vitreous opacity OS. Corticosteroid eye drops were administered, but the inflammation did not improve, and was referred to the Hokkaido University Hospital. The left best-corrected visual acuity was 0.1 with normal intraocular pressure. Anterior chamber inflammation was 2 cells, and vitreous haze was 4 OS. B-mode ultrasonography showed diffuse heterogeneous high echoic changes in the vitreous cavity. She underwent vitrectomy, and cell block preparation of the vitreous infusion fluids was performed. Cytopathology revealed adenocarcinoma cells with a high nuclearcytoplasmic ratio and glandular formation. The immunocytochemical study showed that tumor cells were positive for thyroid transcription factor-1 (TTF-1), napsin A, and CK7, therefore diagnosis of masquerade syndrome due to intraocular metastasis of pulmonary adenocarcinoma was reached. Chemoradiotherapy was administered, and the eye got phthisis bulbi after irradiation 2 years after diagnosis. Cell block preparation using vitreous humor may be useful in the diagnosis and management of intraocular metastasis of pulmonary adenocarcinoma in patients with prolonged vitreous opacity.

Apelin promotes osteosarcoma metastasis by upregulating PLOD2 expression via the Hippo signaling pathway and hsacirc0000004miR-1303 axis.

Osteosarcoma is a highly mortal bone tumor, with a high metastatic potential, promoted in part by the enzyme procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2). Increasing level of PLOD2 in osteosarcoma tissue correlates with lymphatic and distant metastasis. The adipokine apelin (APLN) is also found in different cancers and APLN upregulation promotes angiogenesis and metastasis, but its effects on osteosarcoma metastasis are uncertain. We explored APLN functioning in metastatic osteosarcoma. An analysis of records from the Gene Expression Omnibus (GEO) database showed higher levels of APLN expression in osteosarcoma tissue than in normal tissue. Similarly, levels of

Positive Expression of Retinol-Binding Protein 4 Is Related to the Malignant Clinical Features Leading to Poor Prognosis of Glioblastoma.

Retinol-binding protein 4 (RBP4) is a monomeric-binding protein belonging to the lipocalin protein family, which has been reported to be dysregulated in several malignancies such as breast cancer and lung cancer. However, the expression and function of RBP4 in glioblastoma (GBM) are completely unknown. TCGA datasets were used for analyzing the mRNA level of RBP4 in GBM and its clinical relevance. A retrospective GBM cohort ( Both the higher mRNA level and protein level of RBP4 in GBM tissues were significantly correlated with poorer patients overall survival. Multivariate analysis identified RBP4 as a novel independent prognostic predictor in GBM patients. Overexpression of RBP4 resulted in enhanced GBM proliferation capacity, which was consistent with clinical findings on the positive correlation between RBP4 level and tumor size. Meanwhile, overexpressing RBP4 promoted GBM cell migration and invasion, while silencing RBP4 led to the opposite results. RBP4 overexpression in tumor tissues is correlated with poorer prognosis of GBM patients, which functions by promoting GBM proliferation and invasion, thus, may serve as an invaluable predictive biomarker and therapeutic target.

Predictive Nomogram for Hyperprogressive Disease During Anti-PD-1PD-L1 Treatment in Patients with Advanced Non-Small Cell Lung Cancer.

Various studies have reported that anti-PD-1PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed. This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated. Anti-PD-1PD-L1 therapy resulted in a 9.66% (17176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS 7.00 vs 12.00 months, P<0.01 PFS 2.00 vs 5.00 months, P<0.001, respectively). The HPD prediction nomogram included APTT (P<0.01), CD4 CD25 CD127-low cells (Treg cells) (P<0.01), the presence of liver metastasis (P<0.05), and more than two metastatic sites (P<0.05). Then, patients were divided into two groups by the HPD score calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%). The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.

Contralateral esophageal sparing technique in definitive radiotherapy for non-small cell lung cancer dosimetric parameters and normal tissue complication probability modeling.

The purpose of this study was to assess the benefit of the contralateral esophageal sparing technique (CEST) in definitive radiotherapy of non-small cell lung cancer (NSCLC). We retrospectively reviewed radiation plans for 13 patients who underwent definitive chemoradiation for locally advanced NSCLC. Alternative plans were prepared with the use of CEST, with an additional margin of 5 mm from planning treatment volume (PTV). Normal tissue complication probability (NTCP) analyses for the esophagus and tumor control probability (TCP) for the PTV were performed for original and CEST plans using the equivalent uniform dose (EUD)-based mathematical model. In all cases, the CEST plan allowed for the reduction of esophageal dose, with a mean of 3.8 Gy (range, 0.7 to 8.7 Gy). The mean reductions of V40 and V60 to the esophagus were 6.4 Gy (range, 2.1 to 17.2 Gy) and 1.9 Gy (range, 3.4 to 10.0 Gy), respectively. There was no substantial decrease in the maximal dose to the esophagus. Reduction of NTCP was achieved for all patients (range, 5-73%), and TCP was not affected (-1.8 to 6.7%). The application of CEST in definitive radiotherapy of locally advanced NSCLC allows for reducing selected dosimetric parameters to the esophagus without compromising TCP.

Hypofractionated radiotherapy in postmastectomy locally advanced breast cancer an interim report on acute toxicities and dosimetry.

There is a growing interest in the use of hypofractionation in the setting of post-mastectomy radiation therapy (PMRT). Here, we present an interim report on the acute toxicities and the dosimetry of a 15-day hypofractionated regimen. Patients aged 18-75 years who underwent mastectomy and had pathological stage IIB-IIIC or any clinical stage who had received neoadjuvant chemotherapy were treated with PMRT at a dose of 43.5 Gy in 15 fractions. Acute toxicities were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Between September 2020 and September 2021, 92 patients were enrolled in the study. Majority experienced grade 1 dermatitis during the course of treatment. Skin toxicities peaked two weeks after PMRT in which 57 patients (62%) had grade 2 dermatitis and 6 patients (7%) had grade 3 dermatitis. Most resolved one month after treatment, with all resolving at three months. Grade 2 fatigue occurred in 4 patients (4%). There were no grade 3 fatigue or pneumonitis of any grade. The average V95% for the chest wall, axilla, and supraclavicular fossa were 91.5%, 99.3%, and 97.5%, respectively. Average ipsilateral lung V17 was 43.6%, while the mean heart dose averaged at 3.46 Gy. This interim report showed that hypofractionated PMRT is associated with a low incidence of clinically significant acute toxicities. With the use of the 3-dimensional conformal radiotherapy technique and volume-based planning, adequate target volume coverage and acceptable heart doses were achieved, although with a slightly higher ipsilateral lung dose.

Helical tomotherapy experience in breast cancer adjuvant radiotherapy and acute toxicity results.

This study aimed to evaluate acute toxicity and oncological outcomes of breast cancer patients who underwent adjuvant radiotherapy (RT) with tomotherapy. The results of 114 patients who underwent adjuvant RT with Tomotherapy device between 17.08.10-12.06.2021 in Ankara Atatürk Training and Research Hospital and Ankara City Hospital were evaluated retrospectively. The primary endpoint of the study was acute adverse events, and the secondary endpoints were overall survival (OS) and disease-free survival (DFS). The results of 103 patients who met the inclusion criteria were analyzed. The median follow-up was 21 (range 1-125.8) months. Grade 3 esophagitis was not observed in any patient no esophagitis was observed in 60 (58.3%) patients. Grade 3 dermatitis was observed in 3 (2.9%) patients. In addition, dermatitis was not observed in 47 (45.6%) patients. The relationship between chest wall volume and esophagitis development was statistically significant (p 0.006 Z score -2769). The median OS was 24.1 (range 1-128.5) and median disease-free survival was 21.1 (range 1-125.8) months. Five patients (4.9%) died and 9 patients (8.7%) relapsed. Local recurrence was observed in only 1 (1%) patient. There was a statistically significant correlation between OS and contralateral lung V20 dose p < 0.001 Spearman Correlation Coefficient (SCC) -406) and heart mean dose (p < 0.001 SCC -370). There was a statically significant correlation between DFS and cN (p < 0.001) pN (p < 0.001) heart mean dose (p < 0.001 SCC -351) contralateral lung V5 dose (p 0.041 SCC -213) contralateral lung V20 dose (p < 0.001 SCC -434). Acute toxicity results show improvement in breast cancer adjuvant radiotherapy with helical tomotherapy.

LiverTox Clinical and Research Information on Drug-Induced Liver Injury

Tremelimumab is a monoclonal antibody check point inhibitor that is used in combination with durvalumab, a second check point inhibitor, in the therapy of unresectable hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). The combination of tremelimumab and durvalumab is associated with a relatively high rate of serum aminotransferase elevations during therapy and an appreciable rate of clinically apparent immune mediated liver injury which can be severe and even fatal.

FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites.

EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules.

Nasopharyngeal carcinoma (NPC) is a diverse cancer with no well-defined tumor antigen, associated with oncogenic Epstein-Barr Virus (EBV), and with usually late-stage diagnosis and survival <40%. Current radiotherapy and chemotherapy have low effectiveness and cause adverse effects, which calls for the need of new therapy. In this regard, adoptive immunotherapy using γδ T cells has potential, but needs to be coupled with butyrophilin 2A1 and 3A1 protein expression to achieve tumoricidal effect.

Battles against aberrant KEAP1-NRF2 signaling in lung cancer intertwined metabolic and immune networks.

The Kelch-like ECH-associated protein 1nuclear factor erythroid-derived 2-like 2 (KEAP1NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that celltissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-chemo-immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partnerseffectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Radiation Therapy Modulates Tumor Physical Characteristics to Reduce Intratumoral Pressure and Enhance Intratumoral Drug Delivery and Retention.

High intratumoral pressure, caused by tumor cell-to-cell interactions, interstitial fluid pressure, and surrounding stromal composition, plays a substantial role in resistance to intratumoral drug delivery and distribution. Radiation therapy (XRT) is commonly administered in conjunction with different intratumoral drugs, but assessing how radiation can reduce pressure locally and help intratumoral drug administration and retention is important. 344SQ-parental or 344SQ-anti-programmed cell death protein 1-resistant lung adenocarcinoma cells were established in 129SvEv mice, and irradiated with either 1 Gy × 2, 5 Gy × 3, 8 Gy × 3, 12 Gy × 3, or 20 Gy × 1. Intratumoral pressure was measured every 3 to 4 days after XRT. Contrast dye was injected into the tumors 3- and 6-days after XRT, and imaged to measure drug retention. In the 344SQ-parental model, low-dose radiation (1 Gy × 2) created an early window of reduced intratumoral pressure 1 to 3 days after XRT compared with untreated control. High-dose stereotactic radiation (12 Gy × 3) reduced intratumoral pressure 3 to 12 days after XRT, and 20 Gy × 1 showed a delayed pressure reduction on day 12. Intermediate doses of radiation did not significantly affect intratumoral pressure. In the more aggressive 344SQ-anti-programmed cell death protein 1-resistant model, low-dose radiation reduced pressure 1 to 5 days after XRT, and 12 Gy × 3 reduced pressure 1 to 3 days after XRT. Moreover, both 1 Gy × 2 and 12 Gy × 3 significantly improved drug retention 3 days after XRT however, there was no significance detected 6 days after XRT. Lastly, a histopathologic evaluation showed that 1 Gy × 2 reduced collagen deposition within the tumor, and 12 Gy × 3 led to more necrotic core and higher extracellular matrix formation in the tumor periphery. Optimized low-dose XRT, as well as higher stereotactic XRT regimen led to a reduction in intratumoral pressure and increased drug retention. The findings from this work can be readily translated into the clinic to enhance intratumoral injections of various anticancer agents.

Exploration of immunotherapy in advanced pulmonary lymphoepithelioma-like carcinoma.

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and histologically distinctive subtype of nonsmall cell lung cancer (NSCLC). High expression of programmed death ligand 1 (PD-L1) and scarcity of druggable driver mutations raise the potential of immunotherapy for advanced PELEC. However, evidence on the clinical impact of immune-checkpoint inhibitors (ICIs) remained limited and unconvincing. The present study retrospectively enrolled advanced PLELC patients who received ICIs either as up-front or salvage therapy in SYSUCC between March 15, 2017 and March 15, 2022. The comparative efficacy of chemoimmunotherapy vs chemotherapy in the first-line setting and chemoimmunotherapy vs ICIs monotherapy in the ≥2 line setting was investigated. A total of 96 patients were finally enrolled 49 PLELC patients received immunotherapy plus platinum-based chemotherapy, while 45 patients received platinum-based chemotherapy as first-line treatment. Patients with chemoimmunotherapy significantly obtain more survival benefits than those receiving chemotherapy (median progression-free survival PFS 15.6 vs 8.6 months, P .0015). Additionally, patients with chemoimmunotherapy obtained more PFS benefits than those with ICIs monotherapy in the ≥2 line of therapy (median PFS 21.7 months vs 7.8 months, P .094). A significant correlation was observed between prognostic nutritional index (PNI) and favorable treatment outcomes in patients receiving first-line chemoimmunotherapy (median PFS 17.8 months vs 7.6 months, P < .0001). Likewise, patients in the monocyte-to-lymphocyte ratio (MLR)-high group had significantly shorter PFS than the MLR-low group (median PFS 11.2 months vs not reached, P .0009). Our study elucidated the superior efficacy of ICIs therapy, especially chemoimmunotherapy in advanced PLELC, which may provide new insight into the role of immunotherapy in advanced PLELC.

Pulmonary vein thrombosis associated with metastatic uterine leiomyosarcoma a case report.

Pulmonary vein thrombosis (PVT) is rarely associated with malignancies. Leiomyosarcoma, a malignant tumor originating from smooth muscles, has never been reported as the etiology of PVT. In this case report, we described a 43-year-old Kurdish woman with a known case of leiomyosarcoma who presented with hemoptysis, dyspnea, and pleuritic chest pain. Chest computed tomography (CT) angiography revealed a thrombus in the left infero-posterior pulmonary vein. She was successfully treated with unfractionated heparin administered intravenously followed by orally administered warfarin. At the end of the article, we describe and compare other reports of malignancy-related PVT. While malignancies are not a common cause of PVT, both primary lung tumors and metastatic cancers could be associated with PVT. Delay in diagnosis may lead to serious complications and even death. Therefore, clinicians should be aware of the possibility of the development of PVT in different malignancies for appropriate diagnosis and treatment.

Improving survival after pulmonary metastasectomy for sarcoma analysis of prognostic factors.

Metastatic sarcoma confers a grave prognosis to patients and poses a management dilemma for clinicians. Pulmonary metastasectomy is frequently performed for the recurrence of sarcomatous tumours in the lung, but the evidence-base is poor. No guidelines exist to inform clinicians on appropriate patient selection and surgical technique. This review aims to establish and analyse the most important prognostic factors for survival post pulmonary metastasectomy for recurrent sarcoma. We summarise the key tumour, peri-operative and patient characteristics that should guide surgical management. A comprehensive search of the literature utilising OVID Medline and PubMed databases was conducted to identify all relevant research within the past 15 years. We evaluated all articles that specifically studied sarcoma patients (both bone and soft tissue). Disease-free interval and tumour burden remain important prognostic factors, while tumour grade is likely not significant. VATS is a safe and viable alternative to thoracotomy without sacrificing survival outcomes. No single peri-operative characteristic provides useful prognostic information in isolation.

Antibody-drug conjugates in lung cancer dawn of a new era

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work we summarize the ADCs recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.

Vascular Invasion Predicts Recurrence in Stage IA2-IB Lung Adenocarcinoma but not Squamous Cell Carcinoma.

Lymphovascular invasion (LVI) is an adverse prognostic feature in resected stage I non-small cell lung cancer (NSCLC) however, it is unclear if the prognostic significance applies to both lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). A retrospective review of HE-stained slides from surgically resected AJCC 8 The cohorts of LUAD and LUSC showed no significant differences in 5-year RFS (81% each), stage, age, race, or surgical procedure. The presence of LVI, VI, and LI was predictive of 5-year RFS for LUAD (LVI 71% vs. LVI - 92%, P < 0.001 VI 64% vs. VI - 90%, P < 0.001 LI 75% vs. LI - 84%, P 0.030) but not LUSC (LVI 84% vs. LVI - 79%, P 0.740 VI 83% vs. VI- 80%, P 0.852 LI 84% vs. LI - 81%, P 0.757). Among LUAD with LVI, VI was a stronger predictor of 5-year RFS than the remaining subset of VI-LI tumors (64% vs. 87%, P 004). Subset analysis of LI among LUAD stratified by VI showed no significant prognostic advantage to adding LI for risk stratification (VI-LI 87% vs. VI-LI - 92%, P 0.347 VILI 62% vs. VI LI- 66%, P 0.422). VI was present in 36% of LUAD. Vascular invasion is a strong predictor of recurrence in stage IA2-IB LUAD but not in LUSC. Adjuvant therapy trials should be directed at this subgroup.

B cell receptor (BCR) endocytosis.

The B cell receptor (BCR) interacts with foreign antigens to mediate B cell activation and secretion of antibodies. B cell activation begins with initiation of signaling pathways, such as NFAT, NF-κB, and MAPK, and endocytosis of the BCR-antigen complex. Many studies have investigated the signaling pathways associated with BCR activation, and this work has led to significant advances in drug therapies to treat cancer and autoimmune diseases that are linked to aberrant BCR signaling. Less is known, however, about the mechanisms of BCR endocytosis and the role endocytosis plays in B cell pathogenesis. This chapter will review key characteristics of the BCR, including a review of signaling pathways, and endocytic mechanisms associated with the activated BCR. We will also review recent studies investigating the role of BCR endocytosis disease pathogenesis.

Bioinformatic analysis of prognostic metabolism-related genes in lung adenocarcinoma.

Objective To construct and validate a prognostic model for lung adenocarcinoma based on bioinformatics of metabolic genes. Methods Lung adenocarcinoma-related data from The Cancer Genome Atlas (TCGA) database and gene expression omnibus (GEO) were acquired, and LASSO regression was used to construct multi-gene prognostic models and calculate risk-score (RS). Univariate and multivariate Cox independent prognostic analysis was performed. The area under receiver operating characteristic (ROC) curve (AUC) of the model was evaluated by ROC curve and survival analysis was performed. Nomogram were constructed to evaluate the feasibility of the model, and metabolic gene functional enrichment analysis was performed by GSEA. Tumor immune estimation resource (TIMER) database was used to analyze the correlation of patients RS with immune cell infiltration and with the expression of immune checkpoint molecules. Results The TCGA database was used to construct a prognostic model for lung adenocarcinoma based on 18 metabolism-related genes, and RS was used as an independent prognostic factor. The area under the ROC curve was 0.713. Survival analysis showed that overall survival was higher in the low-risk group compared to the high-risk group, and the prognostic model was associated with infiltration of immune cells and with the expression of immune checkpoint molecules. Conclusion RS is an independent prognostic factor in the prognostic model of lung adenocarcinoma with metabolic genes, suggesting a high prognostic value of this model.

PDS5B inhibits the proliferation of A549 human lung cancer cells via downregulation of Wnt5a.

Objective To investigate the effect of PDS5B on the biological function of A549 human lung cancer cells and possible molecular mechanism. Methods The proliferation of lung cancer cells was detected by MTT assay and colony formation assay after silencing or overexpressing PDS5B of A549 cells. The cell migration was detected by scratch assay and Transwell

Determinants of Lung Cancer Screening in a Minnesota Urban Indigenous Community - A Community Based, Participatory, Action-Oriented Study.

Although lung cancer screening with annual low-dose chest computed tomography has been shown to reduce lung cancer deaths, it remains underutilized. Northern Plains American Indian and Alaska Native communities experience extreme lung cancer disparities, and little is known about the acceptance and adoption of lung cancer screening in these groups. We conducted interviews with healthcare professionals and focus groups with patients in an urban Minnesota community clinic serving AIAN. Data collection took place during Winter 2019-2020. Indigenous researchers collected and analyzed the data for emergent themes using simultaneous collaborative consensus with a lung cancer screening researcher. Participants reported some similar barriers to lung cancer screening as previous studies reported but also shared some new insights into traditional ways of knowing and recommendations for effectively implementing this evidence-based preventive care service. Lung screening is largely acceptable to patients and healthcare personnel in an AIAN-serving community clinic. We identified barriers as previously reported in other populations but also identified some unique barriers and motivators. For example, the concept of the seven generations may provide motivation to maintain ones health for future generations while providing additional support during screening for persons traumatized by the Western medicine health system may facilitate increased screening uptake.

Circulating tumor cells PD-L1 expression detection and correlation of therapeutic efficacy of immune checkpoint inhibition in advanced non-small-cell lung cancer.

This study investigated whether programmed death-ligand 1 (PD-L1) expression of circulating tumor cells (CTCs) in peripheral blood can serve as a predictive biomarker for immunotherapy efficacy in patients with advanced non-small-cell lung cancer (NSCLC). We employed a negative enrichment method to isolate CTCs. We identified PD-L1 CTCs as PD-L14,6-diamidino-2-phenylindole (DAPI)CD45-circulating tumor cells through an immunofluorescence method. Tumor tissue PD-L1 expression was determined by immunohistochemical staining. The correlation between CTC PD-L1 expression and patients prognostic features was estimated through the Kaplan-Meier method. CTCs released a higher detection rate of PD-L1 expression than tumor tissues (53.0% vs. 42.1%). No correlation was observed between them. Forty-nine NSCLC patients received anti-PD-1PD-L1 immunotherapy (three with combined anti-PD-1PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), two with four cycles of combined immune checkpoint inhibitors ICIs plus chemotherapy and ICI monotherapy for maintenance). Patients with PD-L1 expression on tissue or CTCs had a median progression-free survival (mPFS) of 5.6 months (n 36, 95% confidence interval CI 3.6-7.5 months), significantly longer than those without PD-L1 detection (n 9, mPFS of 1.4 months, 95% CI 1.3-1.5 months, log-rank p 0.032). The multivariable Cox proportional-hazard model suggested that the tissue or CTC PD-L1 expression was associated with a lower risk of progression (hazard ratio 0.45, 95% CI 0.21-0.98, p 0.043). CTCs and tumor tissues reveal heterogeneous expression of PD-L1 in NSCLC patients. Patients with baseline PD-L1 expression on CTCs or tissue showed prolonged mPFS and may help to identify the subsets of patients who potentially benefit from immunotherapy.

T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis.

Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.

Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22.

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.

High-dose continuous-infusion ifosfamide in advanced thymic epithelial Tumors A TYME network study.

We reported the efficacy and safety results of high-dose, continuous-infusion Ifosfamide,in patients with advanced thymoma (TM) and thymic carcinoma (TC). This was a multicentric, prospective study in patients with advanced TM or TC, who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis or anti-PD(L)1 was allowed. Patients received Ifosfamide (1 gm2day) and sodium-2-mercaptoethanesulfonate (1 gm2day), as continuous infusion, via a portable pumps for 14 consecutive days. Treatment was administered every 4 weeks until progression or unacceptable toxicity, up to a maximum of 6 cycles. The primary endpoint was the overall response rate (ORR) assessed by RECIST1.1. Secondary endpoints included disease control rate (DCR), Progression-free survival (PFS), overall survival (OS), and safety. Eighteen patients were enrolled from October 2020 to January 2022. Twelve patients had a TC, 5 a TM and 1 a mixed TMTC. Sixty-one percent of patients (1118) had stage IVB disease according to Masaoka-Koga, and 39% (718) had an ECOG-PS 2. The median number of previous lines of therapy was 2 (range1-5), and 72% (1318) and 61% (1118) of patients were pretreated with an anti-angiogenesis drug and an anti-PD(L)1 drug respectively. The ORR and the disease control rate (DCR) were 28 % (95 %CI 10 %-53 %) and 67 % (95 %CI 41 %-86 %), respectively. The median follow-up for PFS was 17.3 months (95 %CI 4.3-NA), and median PFS was 5.4 months (95 %CI 2.9-6.4). The median duration of response and SD was respectively 19.6 months (95 %CI 3.5-NA) and 6.0 months (95 % CI 3.8-6.4). In patients with TC, the ORR and DCR were 15 % (95 % CI 2 %-45 %) and 54 % (95 % CI 25 %-81 %), respectively. In the subgroup of 5 patients with TM, 2 PR and 3 SD were observed. Most patients had only mild (grade 1-2) AEs, the most common being nausea and vomiting (39% 718) and transaminases elevation (33% 618). Twenty-two percent of patients (418) experienced an AEs of grade 3 and required ifosfamide dose reduction. No patients had severe AEs. High-dose continuous-infusion Ifosfamide can be considered as a valuable treatment option in patients with advanced thymic epithelial tumors.

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2021 update. Full-length version.

Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably. Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the Clinical Practice Guidelines process of the French National Authority for Health (HAS), including an online vote using a Likert scale. After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.

Investment in Prevention Health Care Delivery Research by the National Institutes of Health.

Research assessing the delivery of preventive health care has considerable potential for improving health outcomes and reducing health care costs for the United States population. To characterize the prevention health care delivery research grant portfolio supported by the National Institutes of Health (NIH). A random sample of 14,523 NIH research projects funded during 2012-2019 was selected and coded for various study topics using a structured taxonomy. We analyzed the subset of prevention research projects, for which health care delivery was identified as an independent or dependent variable, including study characteristics and funding trends. Overall, 11.2% of NIH-funded prevention research projects were relevant to health care delivery. Of these projects, 68.6% assessed access to care, 53.4% examined quality, and 27.1% assessed costs. Over the study period, the percentage of funded prevention research projects involving health care delivery increased from 10.9%-15.1%. Over half of the projects assessed research related to the prevention of a new health condition, identification of risk factors, or health promotion (55.5%), whereas < half addressed prevention of disease progressionrecurrence (40.4%), screening for early disease (20.2%), or screening for risk factors (1.4%). human immunodeficiency virusacquired immune deficiency syndrome, cancer, and substance use were the most prevalent health topics studied, whereas other topics-such as lung diseases and Alzheimer disease-were less frequently studied. Health care delivery research comprises a modest portion of the NIH prevention research portfolio and is mostly focused on access and quality of care cost-related analyses are less prevalent.human immunodeficiency virusacquired immune deficiency syndrome, cancer, and substance use are frequently studied health topics in this portfolio.

Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models.

Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src-signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer.

Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.

Asbestos-associated pulmonary disease.

Exposure to asbestos can cause both benign and malignant, pulmonary and pleural diseases. In the current era of low asbestos exposure, it is critical to be aware of complications from asbestos exposure as they often arise after decades of exposure, asbestos-related pulmonary complications include asbestosis, pleural plaques, diffuse pleural thickening, benign asbestos-related pleural effusions and malignant pleural mesothelioma. Multiple recent studies are featured in this review, including a study evaluating imaging characteristics of asbestos with other fibrotic lung diseases, a study that quantified pleural plaques on computed tomography imaging and its impact on pulmonary function, a study that examined the risk of lung cancer with pleural plaques among two large cohorts and a review of nonasbestos causes of malignant mesothelioma. Asbestos-related pulmonary and pleural diseases continue to cause significant morbidity and mortality. This review summarizes the current advances in this field and highlights areas that need additional research.

Chemical Proteomics with Novel Fully Functionalized Fragments and Stringent Target Prioritization Identifies the Glutathione-Dependent Isomerase GSTZ1 as a Lung Cancer Target.

Photoreactive fragment-like probes have been applied to discover target proteins that constitute novel cellular vulnerabilities and to identify viable chemical hits for drug discovery. Through forming covalent bonds, functionalized probes can achieve stronger target engagement and require less effort for on-target mechanism validation. However, the design of probe libraries, which directly affects the biological target space that is interrogated, and effective target prioritization remain critical challenges of such a chemical proteomic platform. In this study, we designed and synthesized a diverse panel of 20 fragment-based probes containing natural product-based privileged structural motifs for small-molecule lead discovery. These probes were fully functionalized with orthogonal diazirine and alkyne moieties and used for protein crosslinking in live lung cancer cells, target enrichment

Disparities in thoracic surgical oncology.

Disparities in access and outcomes of thoracic surgical oncology are long standing. This article examines the patient, population, and systems-level factors that contribute to these disparities and inequities. The need for research and policy to identify and solve these problems is apparent. As leaders in the field of thoracic oncology, surgeons will be instrumental in narrowing these gaps and moving the discipline forward.

The oncologic efficacy of extended thoracic resections.

Locally invasive lung cancers pose unique challenges for management. Surgical resection of these tumors can pose high morbidity due to the invasion into surrounding structures, including the spine, chest wall, and great vessels. With advances in immunotherapy and chemoradiation, the role for radical resection of these malignancies and associated oncologic outcomes is evolving. This article reviews the current literature of extended thoracic resections with a focus on technical approach, functional outcomes, and oncologic efficacy.

Updates in pathology and molecular diagnostics to inform the evolving landscape of thoracic surgery and oncology.

The pathologic assessment of lung cancers provides essential guidance to the surgeon and oncologist who are considering the best treatment strategies for patients with both early and advanced-stage disease. The management of patients with lung cancer is predicated first and foremost on access to an accurate diagnosis, even when the sample size is limited, as is often the case with use of modern, minimally invasive sampling techniques. Once the diagnosis and disease stage are established, predictive biomarker testing may be essential, particularly for those patients with nonsmall cell lung carcinoma (NSCLC) being considered for immunotherapy or genomic biomarker-driven targeted therapy. This review will discuss the best practices for the diagnosis of NSCLC using morphology and immunohistochemistry, thus providing the surgeon with needed information to understand and critically evaluate pathology reports. Controversial and evolving topics including tumor spread through airspaces, evaluation of multiple tumors, and staging based on invasive tumor size will be addressed. Clinical genomic profiling in NSCLC is driven by published guidelines and reflects evidence based on clinical trials and regulatory approvals. In this fast-moving space, surgeons should be aware of the critical immunohistochemical and genomic biomarkers that drive systemic therapy decisions and anticipate when such testing will be required, both to ensure adequate sampling and to advise the pathologist when tumor material will be required for biomarker analysis. The basic approaches to and sample requirements for molecular biomarker testing will be addressed. As biomarker testing moves exclusively from advanced-stage patients into earlier stage disease, the surgeon should be aware of the relevant markers and work with the pathologist and oncologist to ensure that this information is available to facilitate timely access to therapies not just in the advanced setting, but in consideration of neoadjuvant and adjuvant care.

The oncologic efficacy of extended resections for lung cancer.

Extended lung resections for T3-T4 non-small-cell lung cancer remain challenging. Multimodal management is mandatory in multidisciplinary tumor boards, and here the determination of resectability is key. Long-term oncologic efficacy depends mostly on complete resection (R0) and the extent of N2 disease. The development of novel innovative treatments (targeted therapy and immune checkpoint inhibitors) sets interesting perspectives to reinforce current therapeutic options in the induction and adjuvant setting.

Contemporary issues in the surgical management of pleural mesothelioma.

The surgical management of pleural mesothelioma (PM) can be divided into diagnostic, staging, palliation, and cytoreductive surgery. In the cytoreductive surgical setting, the combination of different treatment modalities has led to better outcomes than surgery alone. The scarcity of high-quality studies has led to heterogeneity in management of PM across the mesothelioma treatment centers. Here, we review the literature regarding the most important open questions and ongoing clinical trials.

Sublobar resections for lung cancer Finally, some answers and some more questions

The Lung Cancer Study Group Trial, published in 1995, set the tone for lobectomy as the standard of care for early-stage nonsmall cell lung cancer. Twenty-seven years and two randomized trials later, does the thoracic oncology community have clarity regarding the choice type of resection, or more questions

The evolving landscape of thoracic surgical oncology.

The history of Thoracic Surgical Oncology warrants attribution to the strong foundational contributions of the past. Current surgical approaches and techniques along with newer systemic therapies are the product of iterative modifications to prior successes. Progress also fosters traditional thinking to be challenged and other classic topics to be revisited with a contemporary perspective. Cumulatively, past and present clinical and scientific efforts point toward a promising future in the evolving landscape of Thoracic Surgical Oncology.

Salvage surgery in lung cancer following definitive therapies.

Salvage surgery refers to operative resection of persistent or recurrent disease in patients initially treated with intention-to-cure nonoperative management. In non-small-cell lung cancer, salvage surgery may be effective in treating selected patients with locally progressive tumors, recurrent local or locoregional disease, or local complications after nonoperative therapy. Importantly, those patients who may be candidates for salvage surgery are evolving, in terms of disease stage as well as the types of attempted definitive therapy received.

The role of immunotherapy and targeted therapy in the multimodal therapy for resectable lung cancer.

As the immunotherapeutic milieu in resectable nonsmall cell lung cancer continues to evolve, the field of thoracic oncology actively moves towards better patient selection based on biomarkers and oncogenic drivers. In this article, we review the current standard of oncologic care in this population and discuss the ongoing phase III clinical trials investigating the use of immunotherapy or targeted therapy in the perioperative period. We also discuss genotyping initiatives, biomarkers, and trial endpoints.

Lymph node sampling-what are the numbers

Lung cancer is a deadly disease. Lymph node staging is the most important prognostic factor, and lymphatic drainage of the lung is complex. Major advances have been made in this field over the last several decades, but there is much left to understand and improve upon. Herein, we review the history of the lymphatic system and the creation of lymph node maps, the evolution of tumor, node, and metastasis lung cancer classification, the importance of lung cancer staging, techniques for lymph node dissection, and our recommendations regarding a minimum number of nodes to sample during pulmonary resection.

Robotics in the diagnosis and staging of lung cancer.

The diagnosis of peripheral small lung lesions by electromagnetic navigational bronchoscopy is still inferior to computed tomography (CT) guided percutaneous transthoracic needle lung biopsy. Robotic bronchoscopy is a new technology that may be a potential breakthrough in the diagnosis of small lung lesions. Real-time tools such as electromagnetic navigation, radial-endobronchial ultrasound, and cone beam CT may further improve the diagnostic yield rate may further improve the diagnostic yield rate. In this article, we reviewed early experience of robotic bronchoscopy for diagnosis and staging of lung cancer.

CDKL3 Promotes Non-small Cell Lung Cancer by Suppressing Autophagy Via Activation of PI3KAktmTOR Pathway.

This study aimed to assess the role of cyclin-dependent kinase-like 3 (CDKL3) in the progression of non-small cell lung cancer (NSCLC) as well as the underlying mechanisms. Western blot and qRT-PCR were utilized to analyze CDKL3 expression in 30 pairs of NSCLC and paraneoplastic tissues. A549 cells with CDKL3 knockdown and PC9 cells with CDKL3 overexpression were constructed by infecting cells with lentiviruses expressing shRNA of CDKL3 and expressing a full-length CDKL3 mRNA, respectively. The CCK-8 assay, flow cytometry, wound healing assay, and Transwell assay were carried out to detect cell viability, apoptosis, migration, and invasion, respectively. Autophagosome morphology was observed by electron microscopy experiments, the expression of key components of the PI3KAktmTOR pathway was examined via Western blot and their mRNA expression levels were determined. Besides, the stably infected NSCLC cells with reduced expression or overexpression of CDKL3 were inoculated into the right-back flank of mice to generate tumors. The results showed that CDKL3 expression was dramatically increased in NSCLC tissues. Moreover, CDKL3 promoted the viability and migration of NSCLC cells by suppressing autophagy in vitro and in vivo. In addition, CDKL3 might modulate PI3KAktmTOR signaling in NSCLC. Overall, CDKL3 might promote NSCLC cell viability and metastasis by inhibiting autophagy and activating the PI3KAktmTOR signaling pathway.

SPOCK2 and SPRED1 function downstream of EZH2 to impede the malignant progression of lung adenocarcinoma in vitro and in vivo.

Enhancer of zeste homolog 2 (EZH2) is an important epigenetic regulator, and is associated with the malignant progression of lung cancer. However, the mechanisms of EZH2 on lung adenocarcinoma (LUAD) remain unclear. The relationship between EZH2 and SPOCK2 or SPRED1 was confirmed by dual-luciferase reporter assay. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to examine the expression of SPOCK2 and SPRED1 and their prognostic values of LUAD. The effects of SPOCK2 and SPRED1 on the biological characters of LUAD cells were identified on functional assays in vitro and in vivo. Our results showed that EZH2 suppressed the expression and transcriptional activity of SPOCK2 and SPRED1, and these effects were reversed by the EZH2 inhibitor, Tazemetostat. SPOCK2 and SPRED1 were expressed at low levels in LUAD patients, and a high expression level of SPOCK2 or SPRED1 predicted better survival. Moreover, overexpression of SPOCK2 or SPRED1 could inhibit tumoral proliferation, migration ratio, and invasion activity in vitro as well as retard tumor growth in vivo. However, EZH2 elevation could rescue these impacts and accelerate LUAD progression. Our findings reveal that SPOCK2 and SPRED1 are epigenetically suppressed by EZH2 and may act as novel regulators to inhibit the proliferation, migration, and invasion of LUAD cells.

Diagnostic performance of cryobiopsy guided by radial-probe EBUS with a guide sheath for peripheral pulmonary lesions.

Transbronchial lung cryobiopsy (TBCB) has developed rapidly and has become one of the research hotspots of lung biopsy technology. The present study sought to evaluate the efficacy of TBCB guided by radial-probe EBUS (RP-EBUS) and a guide sheath (GS) without fluoroscopy for peripheral pulmonary lesions. In this retrospective study, McNemars test was used in order to compare TBCB and transbronchial forceps biopsy (TBFB) in terms of diagnostic performance. A multivariate logistic regression model was designed to explore the association between predictive variables and the diagnostic yield of TBCB. A total of 168 patients underwent GS-guided RP-EBUS. Of those, 157 had lesions that were visible and 11 had lesions that were not. Of those 157 patients, 24 were excluded because of missing data or an unclear final diagnosis. Therefore, 133 patients underwent RP-EBUS-GS-guided TBFB and TBCB. The pooled diagnostic yield of RP-EBUS-GS-guided TBCB without fluoroscopy was 71.5% (103144). In 133 patients, the diagnostic yield of TBCB was significantly higher than that of TBFB (77.4% vs. 59.4% p < 0.05). Multivariate analysis indicated that lesion size and site were independently associated with the diagnostic yield of TBCB (OR 2.8, p 0.03 and OR 4.1, p 0.01, respectively), although cryoprobe size was not. There was no significant difference between the 1.1-mm cryoprobe and the 1.9-mm cryoprobe in terms of diagnostic performance (78.4% vs. 76.8% p > 0.05). GS-guided RP-EBUS is regarded as a practical option for guiding cryobiopsy, although it may not be able to replace fluoroscopy. Peripheral pulmonary lesions not located in the upper lobes or larger than 30 mm are significantly associated with a higher diagnostic yield of cryobiopsy.

Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor.

The common epidermal growth factor receptor (EGFR) mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-tyrosine kinase inhibitors (EGFR-TKI). However, the clinical outcome and response to treatment for many other rarer mutations are still unclear. In this study, we report the results of Brazilian patients in stage IB-IIIA non-small cell lung cancer (NSCLC) following complete resection with minimal residual disease and EGFR mutations treated with adjuvant chemotherapy andor EGFR-TKIs. The frequency of EGFR mutations was investigated in 70 cases of early stage NSCLC. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, as well as in exons 3, 7, 14, 16, 22, 27, and 28, andor the presence of different mutations in a single tumor (complex mutations) are considered rare. EGFR mutations were detected in 23 tumors (32.9%). Fourteen cases carried rare mutations and were treated with platinum-based chemotherapy and two cases were treated with erlotinib. The clinical outcome is described case by case with references to the literature. Notably, we found two rare EGFR mutations and one of them with an unknown response to chemotherapy andor EGFR-TKIs. We have provided complementary information concerning the clinical outcome and treatment of patients with early stage NSCLC for several rare EGFR mutations not previously or only rarely reported. Description of cases harboring rare mutations can support the decision-making process in this subset of patients.

Validation of the North America expert consensus statement on reporting CT findings for COVID-19 in individuals with lung cancer.

The aim of our study was to validate the use of the standardized Radiological Society of North America (RSNA) reporting system in individuals with known lung cancer who presented to the emergency department with suspected COVID-19. We included patients aged 18 years or older from the Cancer Institute of the State of São Paulo (ICESP) with a confirmed diagnosis of lung cancer, admitted to the emergency department and undergoing chest computed tomography (CT) for suspicion of COVID-19. Comparison between SARS-CoV2 RT-PCR across RSNA categories was performed in all patients and further stratified by diagnosis of lung cancer progression. Among 58 individuals included in the analysis (65±9 years, 43% men), 20 had positive RT-PCR. Less than a half (43%) had no new lung findings in the CT. Positive RT-PCR was present in 75% of those with typical findings according to RSNA and in only 9% when these findings were classified as atypical or negative (P<0.001). Diagnostic accuracy was even higher when stratified by the presence or absence of progressive disease (PD). Extent of pulmonary inflammatory changes was strongly associated with higher mortality, reaching a lethality of 83% in patients with >25% of lung involvement and 100% when there was >50% of lung involvement. The lung involvement score was also highly predictive of prognosis in this population as was reported for non-lung cancer individuals. Collectively, our results demonstrated that diagnostic and prognostic values of chest CT findings in COVID-19 are robust to the presence of lung abnormalities related to lung cancer.

miR-6742-5p regulates the invasion and migration of lung adenocarcinoma cells via mediating FGF8ERK12MMP9MMP2 signaling pathway.

microRNAs (miRNAs) are involved in the progression of Lung adenocarcinoma (LUAD), however, the functions of miR-6742-5p in LUAD remains unknown, thereby this study was carried on. The mRNA and miRNA expression data from the LUAD and normal control were obtained from Gene Expression Omnibus (GEO) database, TargetScan and mirDIP were applied to predict the relationship between miR-6742-5p and FGF8.Q-PCR, western blot, dual-luciferase, wound Healing and transwell assays were performed to test the functions of miR-6742-5p in LUAD. Bioinformatics analysis and dual-luciferase identified FGF8 is the target-gene of miR-6742-5p, which is declined in LUAD of human tissues and cell lines, and miR-6742-5P OE suppressed the progression of LUAD in nude mice. MiR-6742-5p OE and KD suppressed or increased the abilities of LUAD metastasis tested by wound healing and transwell assays H522 and PC-9 cells, these effects about miR-6742-5p OE were reversed by FGF8 miR-6742-5p OE, KD inhibited and increased the expression of FGF8 as its downstream p-ERK12, MMP-2-9, these results were corrected by ERK12 inhibitor Ro 67-7476 the miR-6742-5p KD increased the migrated and invaded cells and suppressed by MMPs inhibitor S3304. These results identified the negative correlation of miR-6742-5p with FGF8-ERK12 signal pathway in LUAD progression. We conclude that miR-6742-5p might be a regulator of LUAD progression by targeting FGF8ERK12MMPs signaling pathway, which provides a novel therapeutic target for LUAD.

Glyphosate Exposure and Urinary Oxidative Stress Biomarkers in the Agricultural Health Study.

Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study. This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male non-farmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2-deoxyguanosine 8-OHdG, 8-iso-prostaglandin-F2α 8-isoprostane, and malondialdehyde MDA) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker. Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs. lowest glyphosate quartile geometric mean ratio GMR1.15, 95% confidence interval CI1.03-1.28, Ptrend.02) and MDA (GMR 1.20, 95% CI 1.03-1.40, Ptrend.06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with significantly increased 8-OHdG and MDA levels. Compared with non-farmers, we observed elevated 8-isoprostane levels among farmers with recent, high past 12-month, or high lifetime glyphosate use. Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide.

Ringlike Peripheral Increased Iodine Concentration for the Differentiation of Primary Lung Cancer and Pulmonary Metastases on Contrast-Enhanced Dual-Energy CT.

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

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

Single-cell gene regulatory network prediction by explainable AI.

The molecular heterogeneity of cancer cells contributes to the often partial response to targeted therapies and relapse of disease due to the escape of resistant cell populations. While single-cell sequencing has started to improve our understanding of this heterogeneity, it offers a mostly descriptive view on cellular types and states. To obtain more functional insights, we propose scGeneRAI, an explainable deep learning approach that uses layer-wise relevance propagation (LRP) to infer gene regulatory networks from static single-cell RNA sequencing data for individual cells. We benchmark our method with synthetic data and apply it to single-cell RNA sequencing data of a cohort of human lung cancers. From the predicted single-cell networks our approach reveals characteristic network patterns for tumor cells and normal epithelial cells and identifies subnetworks that are observed only in (subgroups of) tumor cells of certain patients. While current state-of-the-art methods are limited by their ability to only predict average networks for cell populations, our approach facilitates the reconstruction of networks down to the level of single cells which can be utilized to characterize the heterogeneity of gene regulation within and across tumors.

Clinical profile of small-cell lung cancer in North India A 12-year analysis from a tertiary care center.

The small cell variant is a relatively uncommon but aggressive form of lung cancer. The present study aims to analyse the clinical characteristics, treatment outcomes and prognostic factors of an ambispectively enrolled large cohort of small cell lung cancer (SCLC) in the Indian population over a decade-long period. All patients diagnosed with SCLC between 2008 and 2020 at a tertiary care lung cancer clinic were included. The clinical details, demographics, details of investigations, treatment and survival outcomes were recorded and analysed. A total of 361 patients were included. The majority were males (86.4%) with a mean (SD) age of 57.3 (12.3) years. Further, 34.9% were current smokers, with the median smoking index being 520 (interquartile range IQR 260-1000). The majority had good performance status, that is, the Eastern Cooperative Oncology Group scale (ECOG) 0 or 1 (65%), and Karnofsky Performance Scale (KPS) ≥70 (85.9%). Also, 73.3% had extensive stage disease. The median time from symptom onset to definitive diagnosis was 91 days. Treatment details were available for 179 patients chemotherapy only (n 128), combined chemo-radiotherapy (n 41) and radiotherapy only (n 10). The median (IQR) progression-free survival (PFS) was 182 (94 to 306) days and the median (IQR) overall survival (OS) was 205 (94 to 429) days. On univariate analysis, factors that significantly affected survival included smoking index and performance status. However, on multivariate analysis, only the performance status significantly affected PFS, whereas none of these factors were significant for OS. SCLC predominantly affects males with a heavy smoking index. The diagnosis is usually made late survival remains poor and is predominantly affected by the performance status.

Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 37 activation capabilities.

New quinoline-pyridine hybrids were designed and synthesised as PIM-12 kinase inhibitors. Compounds

The landscape of differential splicing and transcript alternations in severe COVID-19 infection.

Viral infections can modulate the widespread alternations of cellular splicing, favouring viral replication within the host cells by overcoming host immune responses. However, how SARS-CoV-2 induces host cell differential splicing and affects the landscape of transcript alternation in severe COVID-19 infection remains elusive. Understanding the differential splicing and transcript alternations in severe COVID-19 infection may improve our molecular insights into the SARS-CoV-2 pathogenesis. In this study, we analysed the publicly available blood and lung transcriptome data of severe COVID-19 patients, blood transcriptome data of recovered COVID-19 patients at 12-, 16- and 24-week postinfection and healthy controls. We identified a significant transcript isoform switching in the individual blood and lung RNA-seq data of severe COVID-19-infected patients and 25 common genes that alter their transcript isoform in both blood and lung samples. Altered transcripts show significant loss of the open reading frame, functional domains and switch from coding to noncoding transcript, impacting normal cellular functions. Furthermore, we identified the expression of several novel recurrent chimeric transcripts in the blood samples from severe COVID-19 patients. Moreover, the analysis of the isoform switching into blood samples from recovered COVID-19 patients highlights that there is no significant isoform switching in 16- and 24-week postinfection, and the levels of expressed chimeric transcripts are reduced. This finding emphasizes that SARS-CoV-2 severe infection induces widespread splicing in the host cells, which could help the virus alter the host immune responses and facilitate the viral replication within the host and the efficient translation of viral proteins.

Quality of life after treatment with immune checkpoint inhibitors for lung cancer the impact of age.

Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment. However, it remains unclear as to whether changes in Health-Related Quality-of-Life (HRQoL) are associated with the age of lung cancer patients treated using ICIs. This study aimed to evaluate this possible association and to compare ICI-treated patients HRQoL scores with normative data of an age-matched non-cancer general population. Lung cancer patients from the OncoLifeS data-biobank were included if they were treated with ICIs, irrespective of other treatments, at the University Medical Center Groningen between 2015 and 2021 and had completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30), both at the start of ICI treatment and after six months. Association of age as a continuous variable (per 10 years) and changes in HRQoL scores between baseline and 6 months was assessed using multivariable regression analyses. Clinical relevance of differences in HRQoL scores between OncoLifeS and the general population was classified into trivial, small, medium, and large, for three age groups (<60, 60-69 and ≥ 70 years). 151 patients were included with a mean age of 65.8 years. An increase in age per 10 years was associated with a larger decrease in the summary HRQoL score(β -3.28,CI95%-6.42-0.14), physical(β -4.8, CI95% -8.71-0.88), cognitive(β -4.51,CI95%-8.24-0.78), role functioning(β -5.41,CI95%-10.78-0.05), symptom burden(β -3.66,CI95%-6.6-0.73), and smaller negative changes in financial difficulties(β 6.5 95 % CI 3.16 9.85). OncoLifeS HRQoL scores were lower than those of the general population and differences were most often classified as large and medium. Older lung cancer patients experience larger deteriorations in most HRQoL domains after 6 months of ICI treatment. Also, these patients showed significantly lower HRQoL scores compared to the general population.

Immune infiltration patterns and identification of new diagnostic biomarkers GDF10, NCKAP5, and RTKN2 in non-small cell lung cancer.

This study aimed to identify potential biomarkers for non-small cell lung cancer (NSCLC) and analyze the role of immune cell infiltration in NSCLC. R software was used to screen differentially expressed genes (DEGs) from NSCLC datasets obtained from the Gene Expression Omnibus (GEO) database, and functional correlation analysis was performed. The machine learning algorithms were used to screen the potential biomarkers of NSCLC. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. The protein and mRNA expression levels of potential biomarkers were verified based on the Human Protein Atlas (HPA) database and qRT-PCR. CIBERSORT was used to evaluate the infiltration of immune cells in NSCLC tissues, and the correlation between potential biomarkers and infiltrated immune cell was analyzed. Finally, specific siRNAs were utilized to reduce the GDF10, NCKAP5, and RTKN2 expression in A549 and H1975 cells. The proliferation ability of A549 and H1975 cells was detected by MTT assay. A total of 848 upregulated DEGs and 1308 downregulated DEGs were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the DEGs were mainly related to cell division. Disease ontology (DO) enrichment analysis showed that the diseases with these DEGs were mainly lung diseases, including NSCLC. In addition,three potential biomarkers were identified GDF10, NCKAP5, and RTKN2. Immune cell infiltration analysis showed that resting NK cells, activated dendritic cells, and Tregs may be involved in the pathogenesis of NSCLC. Meanwhile, GDF10, NCKAP5, and RTKN2 were negatively correlated with Tregs and naïve B cells but were positively correlated with activated dendritic cells and resting NK cells. Immunohistochemical staining showed that the expression of GDF10, NCKAP5, and RTKN2 in the lung tissue of patients with NSCLC was lower than that of normal lung tissue. qRT-PCR also confirmed that the mRNA expression of three biomarkers in NSCLC cell lines A549 and H1975 were significantly lower than those in human normal lung epithelial cells BEAS-2B. An MTT assay showed that GDF10, NCKAP5, and RTKN2 knockdown significantly promoted the proliferation of A549 and H1975 cells. The in vitro experiments showed that GDF10, NCKAP5, and RTKN2 played the inhibitory effects on NSCLC cell lines proliferation. Hence, GDF10, NCKAP5, and RTKN2 can be used as diagnostic biomarkers for NSCLC.

Toxicities and Deaths From Intercurrent Disease Following Contemporary Postoperative Radiotherapy in Resected Non-Small-Cell Lung Cancer.

The role of postoperative radiotherapy (PORT) in patients with resected locally advanced non-small-cell lung cancer (NSCLC) remains controversial due to the radiation techniques used in randomized trials. We conducted a retrospective cohort study evaluating contemporary PORT techniques to evaluate the safety of PORT and risk of death from intercurrent disease . We analyzed consecutive patients with NSCLC treated in a single center that underwent PORT for pN2 disease andor positive margin, with 3-dimensional conformal radiotherapy (3DRT), intensity modulated radiotherapy , or proton RT (PRT), between 2008 and 2019. Clinical details were collected including intercurrent deaths, defined as death without cancer recurrence. Kaplan-Meier and Cox-Proportional Hazards Models were used. Of 119 patients, 21 (17.6%) received 3DRT, 47 (39.5%) intensity modulated radiotherapy, and 51 (42.9%) PRT. Median follow-up was 40 months (range 8-136) and median RT dose was 5040cGy. Most patients (65.5%) received sequential adjuvant chemoRT 18.5% received concurrent chemoRT. The rate of grade 3 toxicities was 9.2%. There were 13 (10.9%) deaths from intercurrent diseases, including 6 from second primary cancers and 2 from cardiopulmonary diseases. There were 2 additional deaths from cardiopulmonary disease in patients with cancer progression at time of death. Mean, V5Gy, V30Gy heart doses and mean lung doses were significantly lower with PRT. Three-year OS and disease-free-survival were 70.1% and 49.9%. PORT using contemporary techniques was well tolerated with acceptable toxicity and low rates of intercurrent deaths. Proton therapy significantly reduced heart and lung doses, but radiotherapy modality was not associated with differences in intercurrent disease.

A mitochondrial-targeted near-infrared fluorescent probe for visualizing the fluctuation of hypochlorite acid in idiopathic pulmonary fibrosis mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disease destroying lungs irreversibly with high mortality rates. There are challenges in diagnosing IPF and treating it at an early stage. Mounting evidence suggests that hypochlorous acid (HClO) can help in diagnosing inflammation and relevant conditions. Pulmonary fibrosis is linked to the mitochondrial oxidative stress where excessive HClO production is a key molecular mechanism. Measuring mitochondrial HClO levels assists in the investigations of how the mitochondrial oxidative stress affects IPF. Herein, NIR-PTZ-HClO was developed and optimized as a probe for detecting fluctuations in HClO concentrations of cells and mice models through near-infrared (NIR) fluorescence. The probe featured large Stokes shift of 150 nm, NIR turn-on signal at 650 nm, high sensitivity (45-fold) and quick HClO detection (2 s). The probe is selective for HClO in the presence of range of other analytes. NIR-PTZ-HClO visualized both endogenous and exogenous HClO in living cells (RAW264.7, H460 and A549). The probe monitored HClO in mice models with IPF and moreover the HClO profile could be tracked during the IPF process. The probe also detected precipitous decrease in HClO levels in IPF mice treated with OFEV. NIR-PTZ-HClO probe has thus the potential for earlier diagnosis of lung fibrosis, thereby improving the treatment efficacy.

A 46-Year-Old Woman With Chronic Dyspnea and Diarrhea.

A 46-year-old previously healthy woman presented with dyspnea, fatigue, and diarrhea. She had been experiencing these symptoms for > 1 year, but they had worsened in the few weeks prior to presentation. She had become progressively dyspneic on exertion and at rest and had increased the number of pillows she was sleeping on at night. She reported having episodes of nonbloody, watery diarrhea five to six times a day. The episodes were not associated with abdominal pain or recent travel and occurred even with fasting. Review of systems was positive for intermittent hot flashes, heart palpitations, and myalgias. She was premenopausal. She denied fever, weight loss, cough, hemoptysis, chest pain, or new edema. She had a pertinent medical history of gastritis, a nonspecific murmur since childhood, current tobacco use with a five pack-year history, and a family history of non-first-degree relatives having lung, breast, and colon cancer. She had not received medical care since moving from Brazil to the United States 4 years earlier.

Circular RNA, circular RARS, promotes aerobic glycolysis of non-small-cell lung cancer by binding with LDHA.

Accumulating evidence has highlighted the critical roles of circular RNAs (circRNAs) in non-small-cell lung cancer (NSCLC). This study aims to unveil the roles of circRARS (circular RARS) (hsacirc0001551) in NSCLC. Quantitative real-time PCR was used to determine the expression of circRARS in NSCLC tissues and cells. Kaplan-Meier analysis was used to determine the prognostic value of circRARS expression. CCK8, transwell, and wound healing assays were used to assess the proliferation, invasion, and migration abilities of NSCLC cells. RNA pull-down, cell fraction, glucose consumption, lactate production, and lactate dehydrogenase activity assays were conducted to explore the potential mechanisms of circRARS in NSCLC. circRARS is upregulated in NSCLC tissues and positively correlated with smoking status, lymph node metastasis, and higher tumor stages. NSCLC patients with high expression of circRARS have poor overall survival. Functional assays demonstrated that circRARS accelerated the proliferation, invasion, and migration of NSCLC cells in vitro. The cell fraction suggested that circRARS mainly accumulated in cytoplasm and the RNA pull-down assay showed lactate dehydrogenase (LDHA) could bind with circRARS. Furthermore, circRARS positively regulates LDHA activity and LDHA expression at the transcription level. Moreover, downregulated circRARS decreases glucose consumption and lactate production and compromises aerobic glycolysis in NSCLC cells. Finally, rescue assays showed circRARS could promote NSCLC cell proliferation by regulating LDHA activity. This study shows that circRARS can promote glycolysis and tumor progression in NSCLC by regulating LDHA.

A case of late and lethal Trousseaus syndrome induced by pembrolizumab in lung adenocarcinoma.

Trousseaus syndrome is a relatively rare reported event in immunotherapy-related clinical trials, mostly occurring in the early period of immune checkpoint inhibitor (ICI) therapy. Here, we report an unusual case of late and lethal Trousseaus syndrome during pembrolizumab maintenance therapy in a lung adenocarcinoma harboring tumor protein p53 (TP53) mutation. The patient has experienced severe coagulation abnormalities manifesting as cerebral infarction, partial infarction of both kidneys and spleen after 23 cycles of pembrolizumab use and was resistant to anticoagulants. The late occurrence of coagulation abnormalities in this case reveals a possible correlation between TP53 mutations and Trousseaus syndrome when patients are treated with ICIs. In clinical practice, symptoms associated with abnormal coagulation or fibrinolytic function in malignant tumors are known as Trousseaus syndrome. Its main clinical features include cerebral infarction, myocardial infarction, peripheral arterial embolism, etc. Trousseaus syndrome is a relatively rare reported event in immune checkpoint inhibitors (ICIs)-related clinical studies, mostly occurring in the early period of ICI therapy. Here, we report an unusual case of late and lethal Trousseaus syndrome during pembrolizumab, one of the ICI agents, maintenance therapy in a lung adenocarcinoma harboring tumor protein p53 (TP53) mutation. This patient has experienced severe coagulation abnormalities manifesting as cerebral infarction, partial infarction of both kidneys and spleen after 23 cycles of pembrolizumab use and was resistant to anticoagulants. The late occurrence of coagulation abnormalities in this case reveals a possible correlation between TP53 mutations and Trousseaus syndrome when patients are treated with ICIs.

CCL2, CCL8, CXCL12 chemokines in resectable non-small cell lung cancer (NSCLC).

Complex networks of chemokines are part of the immune reaction targeted against tumor cells. Chemokines influence cancer growth. It is unclear whether the concentrations of chemokines at the time of NSCLC (non-small cell lung cancer) diagnosis differ from healthy controls and reflect the extent of NSCLC. To compare chemokine concentrations (CCL2, CCL8, CXCL12) in the plasma of patients with resectable NSCLC to those without cancer. To determine whether the chemokine concentrations differ relative to the stage of disease. Sixty-nine patients undergoing surgery for provensuspected NSCLC were enrolled. They underwent standard diagnostic and staging procedures to determine resectability, surgery was performed. Forty-two patients were diagnosed with NSCLC, while 27patients had benign lung lesions and functioned as the control group. Chemokine concentrations in peripheral blood were assessed using ELISA. Parametric statistics were used for the analysis of results. There were no differences in plasma chemokine concentrations in NSCLC patients compared to controls. CXCL12 concentrations correlated positively with tumor extent expressed as clinical stage, (mean values stage I 5.08 ngmL, SEM 0.59 stage II and IIIA 7.82 ngmL SEM 1.06 P0.022). Patients with NSCLC stages IIIIIA had significantly higher CXCL12 concentrations than controls (mean values stage IIIIIA 7.82 ngmL SEM 1.06 controls 5.3 ngmL SEM 0.46 P0.017). CXCL12 was related to tumor growth and could potentially be used as a biomarker of advanced disease.

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Advances in the Diagnosis and Treatment of a Driving Target RET Rearrangements in non-Small-Cell Lung Cancer (NSCLC) Especially in China.

In the era of precision medicine, with the deepening of the research on malignant tumor driving genes, clinical oncology has fully entered the era of targeted therapy. For non-small-cell lung cancer (NSCLC), the development of targeted drugs targeting driver genes, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has successfully opened up a new model of targeted therapy. At present, proto-oncogene rearranged during transfection (RET) fusion gene is an important novel oncogenic driving target, and specific receptor tyrosine kinase inhibitors (TKIs) targeting RET fusion have been approved. This article will review the latest research about the molecular characteristics, pathogenesis, detection, and clinical treatment strategies of RET rearrangements especially in China.

Vaccination against SARS-CoV-2 in adults with a diagnosis of cancer a short review.

Compared to individuals without cancer, patients with a diagnosis of malignancy bear a higher risk of becoming infected with SARS-CoV‑2, suffer more frequently from disease-related complications, and are more likely to die due to coronavirus disease 2019 (COVID-19). Depending on the type of cancer and the treatment received, the immune response to vaccination may also be affected in patients with certain types of malignancy. Therefore, there is a need for more specific COVID-19 vaccination recommendations in individuals with a diagnosis of cancer. Furthermore, pre-exposition prophylaxis should be considered for some patients. This short review summarizes some challenges in prevention of (severe) COVID-19 in individuals with a diagnosis of cancer and compares guidelines given by the US

Dual Cytotoxic Responses Induced by Treatment of A549 Human Lung Cancer Cells with Sweet Bee Venom in a Dose-Dependent Manner.

Sweet bee venom (sBV) is purified from We used microscopic analysis to observe the morphological changes in A549 cells after sBV treatment. The MTT assay was used to examine the cytotoxic effect after dose-dependent sBV treatment. Molecular changes in sBV were evaluated by the expression of apoptosis marker proteins using western blot analysis. Microscopic analysis suggested that the growth inhibitory effect occurred in a dose-dependent manner however, cell lysis occurred at a concentration over 20 μgmL of sBV. The MTT assay indicated that sBV treatment exhibited a growth inhibitory effect at a concentration over 5 μgmL. On fluorescence activated cell sorting analysis, G0 dead cells were observed after G1 arrest at treatment concentrations up to 10 μgmL. However, rapid cell rupture was observed at a concentration of 20 μgmL. Western blot analysis demonstrated that sBV treatment modulated the expression of multiple cell death-related proteins, including cleaved-PARP, cleaved-caspase 9, p53, Bcl2, and Bax. sBV induced cell death in A549 human lung cancer cells at a pharmacological concentration, albeit causing hemolytic cell death at a high concentration.

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The current clinical practice for patients affected by Non-Small Cell Lung Cancer (NSCLC) with uncommon mutation is based on afatinib and osimertinib, second and third generation of Tyrosine Kinase Inhibitor (TKI) respectively. For uncommon EGFR mutations, it is still unclear which EGFR TKI is most effective, since there are few dedicated prospective studies and Next Generation Sequencing (NGS) techniques trace an increasingly large and sometimes little-known population of EGFR mutations. To determine the economic impact associated to afatinib and osimertinib, a Budget Impact model considering a 3-year time horizon with two scenarios was developed a first scenario, called AS IS, based on treatment with afatinib and osimertinib according to a distribution of market shares as emerged from clinical practice a second suitable scenario, called TO BE, based on reviewed literature data, assuming for each year a 10%, 15% and 20% increase in afatinib use, respectively. Budget Impact analysis was conducted using a dynamic cohort model, in which the annual number of patients with NSCLC and uncommon mutations was equally distributed over 12 months. Progression-free survival (PFS) data for afatinib and osimertinib were extrapolated up to 36 months from published Kaplan Meier curves, and then the number of patients was estimated for each treatment. The increase of 10% in afatinib use allowed a saving of drug acquisition costs for the Italian NHS, over the 3-year time horizon, of –€ 622,432. The univariate sensitivity analysis shows the market share of osimertinib to be the parameter significantly affecting the results achieved in the base case. The potential increase in the use of afatinib in patients with NSCLC and uncommon mutations leads to lower drug acquisition costs, lower Budget Impact and a saving of money for the Italian NHS.

Cost-benefit analysis of ALK diagnosis vs. non-diagnosis in patients with advanced non-small cell lung cancer in Spain.

In recent years, target therapies to specific molecular alterations in advanced non-small cell lung cancer (NSCLC) have been identified and have shown superior efficacy compared to non-targeted treatments. Anaplastic lymphoma kinase (ALK) is one of the therapeutic targets nevertheless, ALK diagnosis is not performed in all NSCLC patients in Spain. The objective of this study is to estimate in monetary terms the benefit for the Spanish society of ALK diagnosis in advanced NSCLC patients. A cost-benefit analysis of ALK diagnosis vs. non-diagnosis in advanced NSCLC patients was carried out from the Spanish social perspective, with a time horizon of 5 years. Costs, benefits and the cost-benefit ratio were measured. The analysis has considered the overall survival in advanced NSCLC patients treated with the ALK-tyrosine kinase inhibitor (TKI) alectinib. The natural history of NSCLC was simulated using a Markov model. A 3% discount rate was applied to both costs and benefits. The result was tested using a deterministic sensitivity analysis. The cost of ALK diagnosis vs. non-diagnosis in the base case would be €10.19 million, generating benefits of €11.71 million. The cost-benefit ratio would be €1.15. In the sensitivity analysis, the cost-benefit ratio could range from €0.89 to €2.10. The results justify the universal application of ALK diagnosis in advanced NSCLC, which generates a benefit for Spanish society that outweighs its costs and allows optimal treatment with targeted therapies for these patients.

FGF9 promotes cell proliferation and tumorigenesis in TM3 mouse Leydig progenitor cells.

Fibroblast growth factor 9 (FGF9) modulates cell proliferation, differentiation and motility for development and tissue repair in normal cells. Growing evidence shows that abnormal activation of FGF9 signaling is associated with tumor malignancy. We have previously reported that FGF9 increases MA-10 mouse Leydig tumor cell proliferation,

Artificial intelligence based on serum biomarkers predicts the efficacy of lenvatinib for unresectable hepatocellular carcinoma.

Lenvatinib has been effective not only as a first-line but also as a later-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) in real-world clinical practice. How to predict the efficacy of lenvatinib and guide appropriate therapy selection in patients with uHCC have become important issues. This study aimed to investigate the impact of serum biomarkers on the treatment outcomes of patients with uHCC treated with lenvatinib in a real-world setting using an artificial intelligence algorithm. We measured serum biomarkers, including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, and circulating angiogenic factors (CAFs i.e., vascular endothelial growth factor, angiopoietin-2, fibroblast growth factor-19 FGF19, and FGF21) and analyzed treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with uHCC treated with lenvatinib. The results of this study demonstrated that an AFP reduction ≥ 40% from baseline within 8 weeks after lenvatinib induction was associated with a higher ORR. With baseline biomarkers using a decision tree-based model, we identified patients with high, intermediate, and low ORRs (84.6%, 21.7% and 0%, respectively odds ratio, 53.04, P < 0.001, high versus intermediatelow groups). Based on the decision tree-based survival predictive model, baseline AFP was the most important factor for OS, followed by ALBI grade and FGF21.

German Index of Socioeconomic Deprivation (GISD) Revision, update and applications.

Regional deprivation indices enable researchers to analyse associations between socioeconomic disadvantages and health outcomes even if the health data of interest does not include information on the individuals socioeconomic position. This article introduces the recent revision of the German Index of Socioeconomic Deprivation (GISD) and presents associations with life expectancy as well as age-standardised cardiovascular mortality rates and cancer incidences as applications. The GISD measures the level of socioeconomic deprivation using administrative data of education, employment, and income situations at the district and municipality level from the INKAR database. The indicators are weighted via principal component analyses. The regional distribution is depicted cartographically, regional level associations with health outcomes are presented. The principal component analysis indicates medium to high correlations of the indicators with the index subdimensions. Correlation analyses show that in districts with the lowest deprivation, the average life expectancy of men is approximately six years longer (up to three years longer for women) than for those from districts with the highest deprivation. A similar social gradient is observed for cardiovascular mortality and lung cancer incidence. The GISD provides a valuable tool to analyse socioeconomic inequalities in health conditions, diseases, and their determinants at the regional level.

Analysis of M6A associated lncRNAs in prognosis and immune response of NSCLC patients.

Distinguishing between N6-methyladenosine (m6A)-associated long noncoding RNAs (lncRNAs) is crucial in non-small-cell lung cancer (NSCLC) patients. In this research, the prognosis and immunotherapeutic response of lncRNAs and m6A in NSCLC were examined. lncRNAs related to m6A were identified using co-expression analyses, and their prognostic impact on patients with NSCLC was assessed using univariate Cox regression analysis. Sixty-three m6A-associated lncRNAs were determined as prognostic lncRNAs, and on this basis, 25 m6A-associated lncRNAs were screened by least absolute shrinkage and selection operator (lasso) Cox regression. Multivariable Cox analysis obtained 14 m6A-associated lncRNAs for the construction of risk model. The NSCLC patients were grouped into different risk subgroups in accordance with the median of the risk fraction in each data, and we evaluated the differences of potential immunotherapeutic characteristics and drug sensitivity prediction between the two subgroups. By using this model to recombine patients, they can be effectively distinguished in terms of the immunotherapy response. Furthermore, candidate compounds for the differentiation of NSCLC subtypes were identified. The model based on 14 m6A-associated lncRNAs is a promising prognostic biomarker, which may help to predict the efficacy of immunotherapy in NSCLC patients and provide a theoretical basis for improving the outcome of patients.

Primary pulmonary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type a case report and literature review.

Primary pulmonary mucosa-associated lymphoid tissue (MALT)-derived lymphoma is a low-grade B-cell non-Hodgkins lymphoma. It is rare with unclear clinical and imaging findings, requiring biopsy or surgery for diagnosis. Here, we provide a new case to learn the symptoms, diagnosis and treatment of primary pulmonary MALT lymphoma. The patient was a 51-year-old male. During the annual physical examination in 2019, a shadow in the lower lobe of the right lung was accidentally found in his chest computed tomography image. In 2020, the size and density of the shadows increased, which was suspected to be lung adenocarcinoma. The patient underwent video-assisted thoracoscopic surgery and segmental resection. Pathological examination showed residual germinal centers around the tumor cells, and many inflammatory cells had diffusely infiltrated, mainly monocyte-like B cells. Immunohistochemical analysis showed that CD3, CD20, Bcl-2, CD43, CK-pan and CD23 were positive, while BCL-6, CD5, CD10, c-myc and cyclin D1 were negative. The patient was diagnosed with MALT extranodal marginal zone B-cell lymphoma. The patient did not receive chemotherapy or radiotherapy after the operation but was still under close observation. Primary pulmonary MALT develops slowly and tends to be inert and spontaneous. Due to the lack of specific clinical symptoms and imaging findings, it can easily be misdiagnosed as tuberculosis, lung cancer, or infection. Thoracoscopic resection may be a good choice for the diagnosis and treatment.