Datasets:

Gaborandi

/

Lung_Cancer_pubmed_abstracts

like 1

The Bidirectional Relationship between Pulmonary Tuberculosis and Lung Cancer.

Lung cancer and pulmonary tuberculosis are two significant public health problems that continue to take millions of lives each year. They may have similar symptoms and, in some cases, are diagnosed simultaneously or may have a causal relationship. In tuberculosis disease, the chronic inflammation, different produced molecules, genomic changes, and fibrosis are believed to be important factors that may promote carcinogenesis. As a reverse reaction, the development of carcinogenesis and the treatment may induce the reactivation of latent tuberculosis infection. Moreover, the recently used checkpoint inhibitors are a debatable subject since they help treat lung cancer but may lead to the reactivation of pulmonary tuberculosis and checkpoint-induced pneumonitis. Pulmonary rehabilitation is an effective intervention in post-tuberculosis patients and lung cancer patients and should be recommended to improve outcomes in these pathologies.

Comparison of Pre-Diagnosis Physical Activity and Its Correlates between Lung and Other Cancer Patients Accelerometer Data from the UK Biobank Prospective Cohort.

Physical activity (PA) plays an important role in health outcomes for people with cancer, and pre-diagnosis PA influences PA behaviors after cancer treatment. Less is known about the PA of lung cancer patients, and the strong history of smoking could influence pre-diagnosis levels of PA and place them at risk for health problems. This study aimed to compare pre-diagnosis PA and its correlates in patients with lung cancer and other types of cancer (female breast, colorectal, and prostate cancer) and examine the relationship between pre-diagnosis PA and all-cause mortality. This study used data from the UK Biobank, which is a national cohort study with accelerometry data. We included 2662 participants and used adjusted linear regressions and survival analyses. Male and female lung cancer groups spent a mean of 78 and 91 minday in pre-diagnosis moderate to vigorous PA (MVPA), respectively this is lower than the 3 other types of cancer ( The present study suggests that lung cancer patients are the most inactive population before diagnosis. The identified difference in correlates of PA suggest that cancer-specific approaches are needed in PA research and practices. This study also highlights the importance of high PA for individuals with high cancer risk.

The Italian Experience in the Development of Mesothelioma Registries A Pathway for Other Countries to Address the Negative Legacy of Asbestos.

Asbestos (all forms, including chrysotile, crocidolite, amosite, tremolite, actinolite, and anthophyllite) is carcinogenic to humans and causally associated with mesothelioma and cancer of the lung, larynx, and ovary. It is one of the carcinogens most diffuse in the world, in workplaces, but also in the environment and is responsible for a very high global cancer burden. A large number of countries, mostly with high-income economies, has banned the use of asbestos which, however, is still widespread in low- and middle-income countries. It remains, thus, one of the most common occupational and environmental carcinogens worldwide. Italy issued an asbestos ban in 1992, following the dramatic observation of a large increase in mortality from mesothelioma and other asbestos-related diseases in exposed workers and also in subjects with non-occupational exposure. A mesothelioma registry was also organized and still monitors the occurrence of mesothelioma cases, conducting a case-by-case evaluation of asbestos exposure. In this report, we describe two Italian communities, Casale Monferrato and Broni, that faced an epidemic of mesothelioma resulting from the production of asbestos cement and the diffuse environmental exposure we present the activity and results of the Italian mesothelioma registry (ReNaM), describe the risk-communication activities at the local and national level with a focus on international cooperation and also describe the interaction between mesothelioma registration and medical services specialized in mesothelioma diagnosis and treatment in an area at high risk of mesothelioma. Finally, we assess the potential application of the solutions and methods already developed in Italy in a city in Colombia with high mesothelioma incidence associated with the production of asbestos-cement materials and the presence of diffuse environmental asbestos pollution.

Derived Neutrophil-Lymphocyte Ratio and C-Reactive Protein as Prognostic Factors for Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy.

Natural Language Processing Applications for Computer-Aided Diagnosis in Oncology.

In the era of big data, text-based medical data, such as electronic health records (EHR) and electronic medical records (EMR), are growing rapidly. EHR and EMR are collected from patients to record their basic information, lab tests, vital signs, clinical notes, and reports. EHR and EMR contain the helpful information to assist oncologists in computer-aided diagnosis and decision making. However, it is time consuming for doctors to extract the valuable information they need and analyze the information from the EHR and EMR data. Recently, more and more research works have applied natural language processing (NLP) techniques, i.e., rule-based, machine learning-based, and deep learning-based techniques, on the EHR and EMR data for computer-aided diagnosis in oncology. The objective of this review is to narratively review the recent progress in the area of NLP applications for computer-aided diagnosis in oncology. Moreover, we intend to reduce the research gap between artificial intelligence (AI) experts and clinical specialists to design better NLP applications. We originally identified 295 articles from the three electronic databases PubMed, Google Scholar, and ACL Anthology then, we removed the duplicated papers and manually screened the irrelevant papers based on the content of the abstract finally, we included a total of 23 articles after the screening process of the literature review. Furthermore, we provided an in-depth analysis and categorized these studies into seven cancer types breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, colorectal cancer, and brain tumors. Additionally, we identified the current limitations of NLP applications on supporting the clinical practices and we suggest some promising future research directions in this paper.

Assessment of Calcium Score Cutoff Point for Clinically Significant Aortic Stenosis on Lung Cancer Screening Program Low-Dose Computed Tomography-A Cross-Sectional Analysis.

Low-dose computed tomography (LDCT) is predominantly applied in lung cancer screening programs. Tobacco smoking is the main risk factor for developing lung cancer but is also common for cardiovascular diseases, including aortic stenosis (AS). Consequently, an increased prevalence of cardiovascular diseases is expected in lung cancer screenees. Therefore, initial aortic valve calcification evaluation should be additionally performed on LDCT. The aim of this study was to estimate a calcium score (CS) cutoff point for clinically significant AS diagnosis based on LDCT, confirmed by echocardiographic examination. The study included 6631 heavy smokers who participated in a lung cancer screening program (MOLTEST BIS). LDCTs were performed on all individuals and were additionally assessed for aortic valve calcification with the use of CS according to the Agatston method. Patients with CS ≥ 900 were referred for echocardiography to confirm the diagnosis of AS and to evaluate its severity. Of 6631 individuals, 54 met the inclusion criteria and underwent echocardiography for confirmation and assessment of AS. Based on that data, receiver operating characteristic (ROC) curves of CS were plotted, and cutoff points for clinically significant AS diagnosis were established A CS of 1758 for at least moderate AS had 85.71% (CI 65.36-95.02%) sensitivity and 75.76% (CI 58.98-87.17%) specificity a CS of 2665 for severe AS had 87.5% (CI 73.89-94.54%) sensitivity and 76.92% (CI 49.74-91.82%) specificity. This is the first study to assess possible CS cutoff points for diagnosing clinically significant AS detected by LDCT in lung cancer screening participants. LDCT with CS assessment could enable early detection of patients with clinically significant AS and therefore identify patients who require appropriate treatment.

Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. In total, 320 patients were included of which 26.3% ( Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.

Wntβ-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors From Non-Small-Cell Lung Cancer to Other Cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1PD-L1 antibody and chemotherapy, or an anti-PD-1PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wntβ-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wntβ-catenin signaling. First, we will review the molecular biology of Wntβ-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.

A Mitochondrion-Targeting Protein (B2) Primes ROSNrf2-Mediated Stress Signals, Triggering Apoptosis and Necroptosis in Lung Cancer.

The betanodavirus B2 protein targets mitochondria and triggers mitochondrion-mediated cell death signaling in lung cancer cells however, its molecular mechanism remains unknown. In this study, we observed that B2 triggers hydrogen peroxideNrf2-involved stress signals in the dynamic regulation of non-small lung cancer cell (NSCLC)-programmed cell death. Here, the B2 protein works as a necrotic inducer that triggers lung cancer death via p53 upregulation and RIP3 expression, suggesting a new perspective on lung cancer therapy. We employed the B2 protein to target A549 lung cancer cells and solid tumors in NODSCID mice. Tumors were collected and processed for the hematoxylin and eosin staining of tissue and cell sections, and their sera were used for blood biochemistry analysis. We observed that B2 killed an A549 cell-induced solid tumor in NODSCID mice however, the mutant ΔB2 did not. In NODSCID mice, B2 (but not ΔB2) induced both p53Bax-mediated apoptosis and RIPK3-mediated necroptosis. Finally, immunochemistry analysis showed hydrogen peroxide p38Nrf2 stress strongly inhibited the production of tumor markers CD133, Thy1, and napsin, which correlate with migration and invasion in cancer cells. This B2-triggered, ROSNrf2-mediated stress signal triggered multiple signals via pathways that killed A549 lung cancer tumor cells in vivo. Our results provide novel insight into lung cancer management and drug therapy.

Liquid Biopsy Detecting Circulating Tumor Cells in Patients with Non-Small Cell Lung Cancer Preliminary Results of a Pilot Study.

Lung cancer is still the leading cause of cancer-related death worldwide. Interest is growing towards early detection and advances in liquid biopsy to isolate circulating tumor cells (CTCs). This pilot study aimed to detect epithelial CTCs in the peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients. We used Smart BioSurface

Artificial Intelligence Assisted Computational Tomographic Detection of Lung Nodules for Prognostic Cancer Examination A Large-Scale Clinical Trial.

Low-dose computed tomography (LDCT) has emerged as a standard method for detecting early-stage lung cancer. However, the tedious computer tomography (CT) slide reading, patient-by-patient check, and lack of standard criteria to determine the vague but possible nodule leads to variable outcomes of CT slide interpretation. To determine the artificial intelligence (AI)-assisted CT examination, AI algorithm-assisted CT screening was embedded in the hospital picture archiving and communication system, and a 200 person-scaled clinical trial was conducted at two medical centers. With AI algorithm-assisted CT screening, the sensitivity of detecting nodules sized 4-5 mm, 610 mm, 1120 mm, and gt20 mm increased by 41%, 11.2%, 10.3%, and 18.7%, respectively. Remarkably, the overall sensitivity of detecting varied nodules increased by 20.7% from 67.7% to 88.4%. Furthermore, the sensitivity increased by 18.5% from 72.5% to 91% for detecting ground glass nodules (GGN), which is challenging for radiologists and physicians. The free-response operating characteristic (FROC) AI score was ≥0.4, and the AI algorithm standalone CT screening sensitivity reached gt95% with an area under the localization receiver operating characteristic curve (LROC-AUC) of gt0.88. Our study demonstrates that AI algorithm-embedded CT screening significantly ameliorates tedious LDCT practices for doctors.

Systemic and Airway Epigenetic Disruptions Are Associated with Health Status in COPD.

Epigenetic modifications are common in chronic obstructive pulmonary disease (COPD) however, their clinical relevance is largely unknown. We hypothesized that epigenetic disruptions are associated with symptoms and health status in COPD. We profiled the blood (

Biomonitoring Exposure and Early Diagnosis in Silicosis A Comprehensive Review of the Current Literature.

Silicosis is a particular form of lung fibrosis attributable to occupational exposure to crystalline silica. The occupational exposure to crystalline silica also increases the risk of chronic obstructive pulmonary disease (COPD), cancer and lung infections, especially pulmonary tuberculosis. Silicosis is currently diagnosed in previously exposed workers by standard chest X-ray, when lesions are visible and irreversible. Therefore, it would be necessary to find specific and non-invasive markers that could detect silicosis in earlier stages, before the occurrence of X-ray opacities. In this narrative review, we present several diagnostic, monitoring and predictive biomarkers with high potential in the management of silicosis, such as pro- and anti-inflammatory cytokines (TNF (Tumour necrosis factor-α), IL-1 (Interleukin-1), IL-6, IL-10), CC16 (Clara cell 16, an indirect marker of epithelial cell destruction), KL-6 (Krebs von den Lungen 6, an indirect marker of alveolar epithelial damage), neopterin (indicator of cellular immunity) and

Impact of Liver Metastases and Number of Metastatic Sites on Immune-Checkpoint Inhibitors Efficacy in Patients with Different Solid Tumors A Retrospective Study.

ICIs have dramatically improved patient outcomes in different malignancies. However, the impact of liver metastases (LM) and number of metastatic sites (MS) remains unclear in patients treated with single-agent anti-PD(L)1. We aimed to assess the prognostic impact of LM and MS number on progression-free survival (PFS) and overall survival (OS) in a large single-arm retrospective multicentric cohort (IMMUCARE) of patients treated with anti-PD(L)-1 for different solid tumors. A total of 759 patients were enrolled from January 2012 to October 2018. The primary tumor types were non-small cell lung cancer (71%), melanoma (19%), or urologic cancer (10%). At the time of ICI initiation, 167 patients (22%) had LM and 370 patients (49%) had more than MS. LM was associated with a shorter median PFS of 1.9 months (95% CI 1.8-2.5) vs. 4.0 months (95% CI 3.6-5.4) in patients without LM ( The presence of LM or multiple MS were associated with poorer survival outcomes in patients treated with anti-PD(L)-1.

Low-Dose Metformin Treatment Reduces In Vitro Growth of the LL2 Non-small Cell Lung Cancer Cell Line.

Lung cancer maintains a relatively small survival rate (19%) over a 5-year period and up to 80-85% of all lung cancer diagnoses are Non-Small Cell Lung Cancer (NSCLC). To determine whether metformin reduces non-small cell lung cancer (NSCLC) LL2 cell growth, cells were grown in vitro and treated with metformin for 48 h. qPCR was used to assess genes related to cell cycle regulation and pro-apoptotic markers, namely Cyclin D, CDK4, p27, p21, and HES1. Treatment with 10 mM metformin significantly reduced HES1 expression (

CIGB-300 Anticancer Peptide Differentially Interacts with CK2 Subunits and Regulates Specific Signaling Mediators in a Highly Sensitive Large Cell Lung Carcinoma Cell Model.

Large cell lung carcinoma (LCLC) is one form of NSCLC that spreads more aggressively than some other forms, and it represents an unmet medical need. Here, we investigated for the first time the effect of the anti-CK2 CIGB-300 peptide in NCI-H460 cells as an LCLC model. NCI-H460 cells were highly sensitive toward CIGB-300 cytotoxicity, reaching a peak of apoptosis at 6 h. Moreover, CIGB-300 slightly impaired the cell cycle of NCI-H460 cells. The CIGB-300 interactomics profile revealed in more than 300 proteins that many of them participated in biological processes relevant in cancer. Interrogation of the CK2 subunits targeting by CIGB-300 indicated the higher binding of the peptide to the CK2α catalytic subunit by in vivo pull-down assays plus immunoblotting analysis and confocal microscopy. The down-regulation of both phosphorylation and protein levels of the ribonuclear protein S6 (RPS6) was observed 48 h post treatment. Altogether, we have found that NCI-H460 cells are the most CIGB-300-sensitive solid tumor cell line described so far, and also, the findings we provide here uncover novel features linked to CK2 targeting by the CIGB-300 anticancer peptide.

TGFβ1-Induced EMT in the MCF10A Mammary Epithelial Cell Line Model Is Executed Independently of SNAIL1 and ZEB1 but Relies on JUNB-Coordinated Transcriptional Regulation.

Epithelial-mesenchymal transition (EMT) fosters cancer cell invasion and metastasis, the main cause of cancer-related mortality. Growing evidence that SNAIL and ZEB transcription factors, typically portrayed as master regulators of EMT, may be dispensable for this process, led us to re-investigate its mechanistic underpinnings. For this, we used an unbiased computational approach that integrated time-resolved analyses of chromatin structure and differential gene expression, to predict transcriptional regulators of TGFβ1-inducible EMT in the MCF10A mammary epithelial cell line model. Bioinformatic analyses indicated comparatively minor contributions of SNAIL proteins and ZEB1 to TGFβ1-induced EMT, whereas the AP-1 subunit JUNB was anticipated to have a much larger impact. CRISPRCas9-mediated loss-of-function studies confirmed that TGFβ1-induced EMT proceeded independently of SNAIL proteins and ZEB1. In contrast, JUNB was necessary and sufficient for EMT in MCF10A cells, but not in A549 lung cancer cells, indicating cell-type-specificity of JUNB EMT-regulatory capacity. Nonetheless, the JUNB-dependence of EMT-associated transcriptional reprogramming in MCF10A cells allowed to define a gene expression signature which was regulated by TGFβ1 in diverse cellular backgrounds, showed positively correlated expression with TGFβ signaling in multiple cancer transcriptomes, and was predictive of patient survival in several cancer types. Altogether, our findings provide novel mechanistic insights into the context-dependent control of TGFβ1-driven EMT and thereby may lead to improved diagnostic and therapeutic options.

Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer.

Immune checkpoints are unique components of the bodys defense mechanism that safeguard the body from immune responses that are potent enough to harm healthy body cells. When proteins present on the surface of T cells recognize and bind to the proteins present on other tumor cells, immune checkpoints are triggered. These proteins are called immunological checkpoints. The T cells receive an onoff signal when the checkpoints interact with companion proteins. This might avert the hosts immune system from eliminating cancer cells. The standard care plan for the treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the use of drugs targeting immune checkpoints, in particular programmed cell death protein 1. These drugs are now extended for their potential to manage SCLC. However, it is acknowledged that these drugs have specific immune related adverse effects. Herein, we discuss the use of immune checkpoint inhibitors in patients with NSCLC and SCLC, their outcomes, and future perspectives.

Real World Data for Pancreatic Adenocarcinoma from a Population-Based Study in France.

Pancreatic cancer is associated with high mortality rates, and most cases are diagnosed at advanced stages. This study aimed to evaluate the prognostic factors for survival in pancreatic adenocarcinoma. Data from the Finistere registry of digestive database were used in this analysis. This retrospective population-based study included 2117 patients with pancreatic adenocarcinoma diagnosed between 2005 and 2019. Cox regression was used to assess the impact of different prognostic factors. The overall median age was 74 (IQR 65.0-81.0). The majority of pancreatic adenocarcinoma 1120 (52.90%) occurred in the head of the pancreas. The type of surgical resection correlated with age (pancreaticoduodenectomy performed in 13.39% of patients aged under 65 years and only 1.49% of patients aged ≥ 80 years). For the entire cohort, 1-year mortality rate after diagnosis was 77.81%. Chemotherapy was associated with better survival for both operated (HR 0.17 95% CI 0.22 0.64

Heavy Ion-Responsive lncRNA EBLN3P Functions in the Radiosensitization of Non-Small Cell Lung Cancer Cells Mediated by TNPO1.

In recent decades, the rapid development of radiotherapy has dramatically increased the cure rate of malignant tumors. Heavy-ion radiotherapy, which is characterized by the Bragg Peak because of its excellent physical properties, induces extensive unrepairable DNA damage in tumor tissues, while normal tissues in the path of ion beams suffer less damage. However, there are few prognostic molecular biomarkers that can be used to assess the efficacy of heavy ion radiotherapy. In this study, we focus on non-small cell lung cancer (NSCLC) radiotherapy and use RNA sequencing and bioinformatic analysis to investigate the gene expression profiles of A549 cells exposed to X-ray or carbon ion irradiation to screen the key genes involved in the stronger tumor-killing effect induced by carbon ions. The potential ceRNA network was predicted and verified by polymerase chain amplification, western blotting analysis, colony formation assay, and apoptosis assay. The results of the experiments indicated that lncRNA EBLN3P plays a critical role in inhibiting carbon ion-induced cell proliferation and inducing apoptosis of NSCLC cells. These functions were achieved by the EBLN3PmiR-144-3pTNPO1 (transportin-1) ceRNA network. In summary, the lncRNA EBLN3P functions as a ceRNA to mediate lung cancer inhibition induced by carbon ion irradiation by sponging miR-144-3p to regulate TNPO1 expression, indicating that EBLN3P may be a promising target for increasing the treatment efficacy of conventional radiotherapy for NSCLC.

Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic LeukemiaSmall Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study.

Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLLSLL, without del(17p), were randomly assigned 11 to once-daily ibrutinib 420 mg until disease progressionunacceptable toxicity (

Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer.

Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence of drug tolerant or resistant cells, ultimately resulting in tumor relapse. Recently, cellular barcoding strategies have arisen as a powerful tool to investigate the clonal evolution of these subpopulations in response to anti-cancer drugs. In this review, we provide an overview of the currently available treatment options for NSCLC, focusing on EGFR targeted therapy, and discuss the common mechanisms of resistance to EGFR-TKIs. We also review the characteristics of drug-tolerant persister (DTP) cells and the mechanistic basis of drug tolerance in EGFR-mutant NSCLC. Lastly, we address how cellular barcoding can be applied to investigate the response and the behavior of DTP cells upon EGFR-TKI treatment.

Developing and Validating a Lung Cancer Risk Prediction Model A Nationwide Population-Based Study.

Lung cancer can be challenging to diagnose in the early stages, where treatment options are optimal. We aimed to develop 1-year prediction models for the individual risk of incident lung cancer for all individuals aged 40 or above living in Denmark on 1 January 2017. The study was conducted using population-based registers on health and sociodemographics from 2007-2016. We applied backward selection on all variables by logistic regression to develop a risk model for lung cancer and applied the models to the validation cohort, calculated receiver-operating characteristic curves, and estimated the corresponding areas under the curve (AUC). In the populations without and with previously confirmed cancer, 42742,826,249 (0.15%) and 482172,513 (0.3%) individuals received a lung cancer diagnosis in 2017, respectively. For both populations, older age was a relevant predictor, and the most complex models, containing variables related to diagnoses, medication, general practitioner, and specialist contacts, as well as baseline sociodemographic characteristics, had the highest AUC. These models achieved a positive predictive value (PPV) of 0.0127 (0.006) and a negative predictive value (NPV) of 0.989 (0.997) with a 1% cut-off in the population without (with) previous cancer. This corresponds to 1.2% of the screened population experiencing a positive prediction, of which 1.3% would be incident with lung cancer. We have developed and tested a prediction model with a reasonable potential to support clinicians and healthcare planners in identifying patients at risk of lung cancer.

Changing Patterns in Cancer Mortality from 1987 to 2020 in China.

China has the highest number of new cancer cases and deaths worldwide, posing huge health and economic burdens to society and affected families. This study comprehensively analyzed secular trends of national cancer mortality statistics to inform future prevention and intervention programs in China. The annual estimate of overall cancer mortality and its major subtypes were derived from the National Health Commission (NHC). Joinpoint analysis was used to detect changes in trends, and we used age-period-cohort modeling to estimate cohort and period effects in Cancers between 1987 and 2020. Net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks were calculated. The age-standardized cancer mortality in urban China has shown a steady downward trend but has not decreased significantly in rural areas. Almost all cancer deaths in urban areas have shown a downward trend, except for colorectal cancer in men. Decreasing mortality from cancers in rural of the stomach, esophagus, liver, leukemia, and nasopharynx was observed, while lung, colorectal cancer female breast, and cervical cancer mortality increased. Birth cohort risks peaked in the cohorts born around 1920-1930 and tended to decline in successive cohorts for most cancers except for leukemia, lung cancer in rural, and breast and cervical cancer in females, whose relative risks were rising in the very recent cohorts. In addition, mortality rates for almost all types of cancer in older Chinese show an upward trend. Although the age-standardized overall cancer mortality rate has declined, and the urban-rural gap narrowed, the absolute cancer cases kept increasing due to the growing elderly population in China. The rising mortality related to lung, colorectal, female breast, and cervical cancer should receive higher priority in managing cancer burden and calls for targeted public health actions to reverse the trend.

Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators.

Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM tumors in comparison to 4T1-LM tumors, and reduced lung metastases after surgical resection of primary 4T1 tumors. These results indicated, for the first time, that highly metastatic TNBC cells have limited iron metabolism, and they can be more effectively targeted by iron chelators.

Thoracic Radiotherapy in Extensive Disease Small Cell Lung Cancer Multicenter Prospective Observational TRENDS Study.

(1) Introduction Small cell lung cancer (SCLC) is an aggressive tumor type, accounting for about 15% of all lung cancers. Radiotherapy (RT) plays a fundamental role in both early and advanced stages. Currently, in advanced disease, the use of consolidative chest RT should be recommended for patients with good response to platinum-based first-line chemotherapy, but its use has not yet been standardized. The present prospective study aims to evaluate the pattern of care of consolidative chest RT in patients with advanced stage SCLC, and its effectiveness in terms of disease control and tolerability. (2) Materials and methods This study was a multicenter prospective observational trial, proposed and conducted within the AIRO lung study group to evaluate the pattern of care of consolidative chest RT after first-line chemotherapy in patients with advanced SCLC. The patient and tumor characteristics, doses, fractionation and volumes of thoracic RT and prophylactic cranial irradiation (PCI), as well as the thoracic and extrathoracic response to the treatment, toxicity and clinical outcomes, were collected and analyzed. (3) Results From January 2017 to December 2019, sixty-four patients were enrolled. Median follow-up was 33 months. The median age was 68 years (range 42-81) 38 patients (59%) were male and 26 (41%) female. Carboplatin etoposide for 6 cycles was the most commonly used first-line therapeutic scheme (42%). With regard to consolidative chest RT, 56% of patients (35) received 30 Gy in 10 factions and 16 patients (26%) received 45 Gy in 15 sessions. The modulated intensity technique was used in 84.5% of cases, and post-chemotherapy macroscopic residual disease was the target volume in 87.5% of patients. Forty-four patients (69%) also underwent PCI. At the last follow-up, over 60% of patients did not experience chest disease progression, while 67% showed extrathoracic progression. At the first radiological evaluation after RT, complete response and stable disease were recorded in 6% and 46% of the cases, respectively. Two patients had a long-term complete response to the combined treatment. The brain was the first site of extrathoracic progression in 28%. 1y and 2y OS and PFS were 67%, 19%, 28% and 6%, respectively. Consolidative chest RT was well-tolerated in the majority of patients it was interrupted in three cases (due to G2 pulmonary toxicity, disease progression and clinical decay, respectively). Only 1 patient developed G3 asthenia. (4) Conclusions Consolidative chest RT has been shown to be useful in reducing the risk of thoracic disease progression and is absolutely well-tolerated in patients with advanced stage SCLC with good response after first-line chemotherapy. Among the Italian centers that participated in this study, there is still variability in the choice of fractionation and target volumes, although the guidelines contain clear recommendations. The aim of future research should be to clarify the role and modalities of chest RT in the era of immunotherapy in advanced-stage SCLC.

VATS versus Open Lobectomy following Induction Therapy for Stage III NSCLC A Propensity Score-Matched Analysis.

This study aims to evaluate the perioperative and oncologic outcomes of thoracoscopic lobectomy for advanced stage III NSCLC. We retrospectively reviewed 205 consecutive patients who underwent VATS or open lobectomy for clinical stage III lung cancer between January 2013 and December 2020. The perioperative and oncologic outcomes of the two approaches were compared. Long-term survival was assessed using the Kaplan-Meier estimator. Propensity score-matched (PSM) comparisons were used to obtain a well-balanced cohort of patients undergoing VATS and open lobectomy. VATS lobectomy was performed in 77 (37.6%) patients and open lobectomy in 128 (62.4%) patients. Twelve patients (15.6%) converted from VATS to the open approach. PSM resulted in 64 cases in each group, which were well matched according to twelve potential prognostic factors, including tumor size, histology, and pTNM stage. Between the VATS and the open group, there were no significant differences in unmatched and matched analyses, respectively, of the overall postoperative complications ( For the advanced stage III NSCLC, VATS lobectomy achieved equivalent postoperative and oncologic outcomes when compared with open lobectomy without increasing the risk of procedure-related locoregional recurrence.

The Impact of Surgical Experience in VATS Lobectomy on Conversion and Patient Quality of Life Results from a Comprehensive National Video-Assisted Thoracic Surgical Database.

Although unexpected conversion during Video-Assisted Thoracic Surgery (VATS) lobectomy is up to 23%, the effects on postoperative outcomes remain debatable. This retrospective study aimed (i) to identify potential preoperative risk factors of VATS conversion to standard thoracotomy (ii) to assess the impact of surgical experience in VATS lobectomy on conversion rate and patient health-related quality of life. We extracted detailed information on VATS lobectomy procedures performed consecutively (2014-2019). Predictors of conversion were assessed with univariable and multivariable logistic regressions. To assess the impact of VATS lobectomy experience, observations were divided according to surgeons experiences with VATS lobectomy. The impact of VATS lobectomy experience on conversion and occurrence of postoperative complications was evaluated using logistic regressions. The impact of VATS lobectomy experience on EuroQoL-5D (EQ-5D) scores at discharge was assessed using Tobit regressions. A total of 11,772 patients underwent planned VATS for non-small-cell lung cancer (NSCLC), with 1074 (9.1%) requiring conversion to thoracotomy. The independent predictors at multivariable analysis were FEV1% (OR 0.99 95% CI 0.98-0.99, Clinical nodal involvement was confirmed as the most critical predictor of conversion. Greater experience in VATS lobectomy did not decrease conversion rate and postoperative complications but was positively associated with postoperative patient quality of life.

Effects of Whole and Partial Heart Irradiation on Collagen, Mast Cells, and Toll-like Receptor 4 in the Mouse Heart.

In radiation therapy of tumors in the chest, such as in lung or esophageal cancer, part of the heart may be situated in the radiation field. This can lead to the development of radiation-induced heart disease. The mechanisms by which radiation causes long-term injury to the heart are not fully understood, but investigations in pre-clinical research models can contribute to mechanistic insights. Recent developments in X-ray technology have enabled partial heart irradiation in mouse models. In this study, adult male and female C57BL6J mice were exposed to whole heart (a single dose of 8 or 16 Gy) and partial heart irradiation (16 Gy to 40% of the heart). Plasma samples were collected at 5 days and 2 weeks after the irradiation for metabolomics analysis, and the cardiac collagen deposition, mast cell numbers, and left ventricular expression of Toll-like receptor 4 (TLR4) were examined in the irradiated and unirradiated parts of the heart at 6 months after the irradiation. Small differences were found in the plasma metabolite profiles between the groups. However, the collagen deposition did not differ between the irradiated and unirradiated parts of the heart, and radiation did not upregulate the mast cell numbers in either part of the heart. Lastly, an increase in the expression of TLR4 was seen only after a single dose of 8 Gy to the whole heart. These results suggest that adverse tissue remodeling was not different between the irradiated and unirradiated portions of the mouse heart. While there were no clear differences between male and female animals, additional work in larger cohorts may be required to confirm this result, and to test the inhibition of TLR4 as an intervention strategy in radiation-induced heart disease.

Morphologic Severity of Atypia Is Predictive of Lung Cancer Diagnosis.

In cytologic analysis of lung nodules, specimens classified as atypia cannot be definitively diagnosed as benign or malignant. Atypia patients are typically subject to additional procedures to obtain repeat samples, thus delaying diagnosis. We evaluate morphologic categories predictive of lung cancer in atypia patients. This retrospective study stratified patients evaluated for primary lung nodules based on cytologic diagnoses. Atypia patients were further stratified based on the most severe verbiage used to describe the atypical cytology. Logistic regressions and receiver operator characteristic curves were performed. Of 129 patients with cytologic atypia, 62.8% later had cytologically or histologically confirmed lung cancer and 37.2% had benign respiratory processes. Atypia severity significantly predicted final diagnosis even while controlling for pack years and modified Herder score (

Combining STAT3-Targeting Agents with Immune Checkpoint Inhibitors in NSCLC.

Despite recent therapeutic advances, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) with multiple tumor-promoting effects in NSCLC, including proliferation, anti-apoptosis, angiogenesis, invasion, metastasis, immunosuppression, and drug resistance. Recent studies suggest that STAT3 activation contributes to resistance to immune checkpoint inhibitors. Thus, STAT3 represents an attractive target whose pharmacological modulation in NSCLC may assist in enhancing the efficacy of or overcoming resistance to immune checkpoint inhibitors. In this review, we discuss the biological mechanisms through which STAT3 inhibition synergizes with or overcomes resistance to immune checkpoint inhibitors and highlight the therapeutic strategy of using drugs that target STAT3 as potential combination partners for immune checkpoint inhibitors in the management of NSCLC patients.

Continuous Relationship of Operative Duration with Risk of Adverse Perioperative Outcomes and Early Discharge Undergoing Thoracoscopic Lung Cancer Surgery.

For thoracoscopic lung cancer surgery, the continuous relationship and the trigger point of operative duration with a risk of adverse perioperative outcomes (APOs) and early discharge remain unknown. This study enrolled 12,392 patients who underwent this surgical treatment. Five groups were stratified by operative duration lt60 min, 60-120 min, 120-180 min, 180-240 min, and ≥240 min. APOs included intraoperative hypoxemia, delayed extubation, postoperative pulmonary complications (PPCs), prolonged air leakage (PAL), postoperative atrial fibrillation (POAF), and transfusion. A restricted cubic spline (RCS) plot was used to characterize the continuous relationship of operative duration with the risk of APOs and early discharge. The risks of the aforementioned APOs increased with each additional hour after the first hour. A J-shaped association with APOs was observed, with a higher risk in those with prolonged operative duration compared with those with shorter values. However, the probability of early discharge decreased from 0.465 to 0.350, 0.217, and 0.227 for each additional hour of operative duration compared with counterparts (lt60 min), showing an inverse J-shaped association. The 90 min procedure appears to be a tipping point for a sharp increase in APOs and a significant reduction in early discharge. Our findings have important and meaningful implications for risk predictions and clinical interventions, and early rehabilitation, for APOs.

Evaluation of Microsatellite Instability Molecular Analysis versus Immuno-Histochemical Interpretation in Malignant Neoplasms with Different Localizations.

MMR gene germline mutations are considered a major genetic disorder in patients with hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome A total of 15% of sporadic colon carcinomas are MSI-High. MSI has also been observed in other cancers, such as endometrial, gastric, and ovarian cancer. The aim of the current study was to correlate and outline the optimal method between the molecular testing of the instability of microsatellite DNA regions (MSI status) and the loss of protein expression by immunehistochemistry (MMR). A total of 242 paraffin-embedded tissues from gastrointestinal, gynecological, genitourinary, lung, breast, and unknown primary cancer patients were analyzed for the expression of

Immune Pathways with Aging Characteristics Improve Immunotherapy Benefits and Drug Prediction in Human Cancer.

(1) Background Perturbation of immune-related pathways can make substantial contributions to cancer. However, whether and how the aging process affects immune-related pathways during tumorigenesis remains largely unexplored. (2) Methods Here, we comprehensively investigated the immune-related genes and pathways among 25 cancer types using genomic and transcriptomic data. (3) Results We identified several pathways that showed aging-related characteristics in various cancers, further validated by conventional aging-related gene sets. Genomic analysis revealed high mutation burdens in cytokines and cytokines receptors pathways, which were strongly correlated with aging in diverse cancers. Moreover, immune-related pathways were found to be favorable prognostic factors in melanoma. Furthermore, the expression level of these pathways had close associations with patient response to immune checkpoint blockade therapy in melanoma and non-small cell lung cancer. Applying a net-work-based method, we predicted immune- and aging-related genes in pan-cancer and utilized these genes for potential immunotherapy drug discovery. Mapping drug target data to our top-ranked genes identified potential drug targets, FYN, JUN, and SRC. (4) Conclusions Taken together, our systematic study helped interpret the associations among immune-related pathways, aging, and cancer and could serve as a resource for promoting clinical treatment.

Therapeutic Targeting of Cancer-Associated Fibroblasts in the Non-Small Cell Lung Cancer Tumor Microenvironment.

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. The most common lung cancer is non-small cell lung cancer (NSCLC), with an overall 5-year survival rate of around 20% because NSCLC is a metastatic disease. A better understanding of the mechanism underlying lung cancer metastasis is therefore urgently needed. The tumor microenvironment involves different types of stromal cells and functions as key components in the progression of NSCLC. Through epithelial-mesenchymal transition (EMT), in which epithelial cells lose their polarity and acquire mesenchymal potential, cancer cells acquire metastatic abilities, as well as cancer stem-cell-like potential. We previously reported that cancer-associated fibroblasts (CAFs) interact with lung cancer cells to allow for the acquisition of malignancy and treatment resistance by paracrine loops via EMT signals in the tumor microenvironment. Furthermore, CAFs regulate the cytotoxic activity of immune cells via various cytokines and chemokines, creating a microenvironment of immune tolerance. Regulation of CAFs can therefore affect immune responses. Recent research has shown several roles of CAFs in NSCLC tumorigenesis, owing to their heterogeneity, so molecular markers of CAFs should be elucidated to better classify tumor-promoting subtypes and facilitate the establishment of CAF-specific targeted therapies. CAF-targeted cancer treatments may suppress EMT and regulate the niche of cancer stem cells and the immunosuppressive network and thus may prove useful for NSCLC treatment through multiple mechanisms.

A Subset of PD-1-Expressing CD56

(1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme BCD4 Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56CD3-CD16GranzymeB median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56CD3-CD16CD57 (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56

Early Identification of Pneumonitis in Patients Irradiated for Lung Cancer-Final Results of the PARALUC Trial.

Radiotherapy of lung cancer may cause pneumonitis that generally occurs weeks or months following therapy and can be missed. This prospective trial aimed to pave the way for a mobile application (app) allowing early diagnosis of pneumonitis. The primary goal was the identification of the optimal cut-off of a score to detect pneumonitis of grade ≥2 after radiotherapy for lung cancer. Based on the severity of symptoms (cough, dyspnea, fever), scoring points were 0-9. Receiver operating characteristic (ROC)-curves were used to describe the sensitivity and specificity. The area under the ROC-curve (AUC) was calculated to judge the accuracy of the score, Youden-index was employed to define the optimal cut-off. Until trial termination, 57 of 98 patients were included. Eight of 42 patients evaluable for the primary endpoint (presence or absence of radiation pneumonitis) experienced pneumonitis. AUC was 0.987 (0.961-1.000). The highest sensitivity was achieved with 0-4 points (100%), followed by 5 points (87.5%), highest specificity with 5-6 points (100%). The highest Youden-index was found for 5 points (87.5%). The rate of patient satisfaction with the symptom-based scoring system was 93.5%. A cut-off of 5 points was identified as optimal to differentiate between pneumonitis and no pneumonitis. Moreover, pneumonitis was significantly associated with an increase of ≥3 points from baseline (

Chloroquine Enhances Death in Lung Adenocarcinoma A549 Cells Exposed to Cold Atmospheric Plasma Jet.

Cold atmospheric plasma (CAP) is an intensively-studied approach for the treatment of malignant neoplasms. Various active oxygen and nitrogen compounds are believed to be the main cytotoxic effectors on biotargets however, the comprehensive mechanism of CAP interaction with living cells and tissues remains elusive. In this study, we experimentally determined the optimal discharge regime (or semi-selective regime) for the direct CAP jet treatment of cancer cells, under which lung adenocarcinoma A549, A427 and NCI-H23 cells demonstrated substantial suppression of viability, coupled with a weak viability decrease of healthy lung fibroblasts Wi-38 and MRC-5. The death of CAP-exposed cancer and healthy cells under semi-selective conditions was caspase-dependent. We showed that there was an accumulation of lysosomes in the treated cells. The increased activity of lysosomal protease Cathepsin D, the transcriptional upregulation of autophagy-related MAPLC3B gene in cancer cells and the changes in autophagy-related proteins may have indicated the activation of autophagy. The addition of the autophagy inhibitor chloroquine (CQ) after the CAP jet treatment increased the death of A549 cancer cells in a synergistic manner and showed a low effect on the viability of CAP-treated Wi-38 cells. Downregulation of Drp1 mitochondrial protein and upregulation of PINK1 protein in CAP CQ treated cells indicated that CQ increased the CAP-dependent destabilization of mitochondria. We concluded that CAP weakly activated pro-survival autophagy in irradiated cells, and CQ promoted CAP-dependent cell death due to the destabilization of autophagosomes formation and mitochondria homeostasis. To summarize, the combination of CAP treatment with CQ could be useful for the development of cold plasma-based antitumor approaches for clinical application.

Papillary thyroid cancer (PTC) is the most prevalent histological type of thyroid cancer (TC) worldwide. Although tumor metastasis occurs in regional lymph nodes, distant metastasis (DM) may also occur. Radioactive iodine (RAI) therapy is an effective treatment for TC however, resistance to RAI occurs in patients with DM. Therefore, in this study, we investigated the efficacy of DM-related biomarkers as therapeutic targets for PTC therapy. ABCA1 expression was higher in aggressive BCPAP cells than in other PTC cells in terms of migration and invasion capacity. The knockdown of

Silencing of circCRIM1 Drives IGF2BP1-Mediated NSCLC Immune Evasion.

Circular RNAs (circRNAs) have been found to have significant impacts on non-small cell lung cancer (NSCLC) progression through various mechanisms. However, the mechanism of circRNAs modulating tumor immune evasion in NSCLC has yet to be well-revealed. Through analyzing the expression profiles of circRNAs in NSCLC tissues, RNA FISH, pull-down assay, mass spectrometry analysis, and RIP, circCRIM1 was identified, and its interaction with IGF2BP1 was confirmed. The effects of circCRIM1 on modulating tumor immune evasion were explored via co-culture in vitro and in tumor xenograft models. Subsequently, we evaluated the regulatory effects of circCRIM1 on IGF2BP1 and screened its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circCRIM1 could regulate the stability of target mRNA. circCRIM1 was downregulated in NSCLC, and its expression was positively correlated with favorable prognoses. Furthermore, circCRIM1 was more stable than its linear transcript and was mainly localized in the cytoplasm. Mechanistically, circCRIM1 destabilized HLA-F mRNA via competitive binding to IGF2BP1. Importantly, the overexpression of circCRIM1 suppressed the immune evasion of NSCLC and promoted the expressions of Granzyme B, IFN-γ, and TNF-α of CD8 T and NK cell in vitro co-culture assays and tumor xenograft models. This study identifies circCRIM1 as a new tumor suppressor that inhibits tumor immune evasion through a competitive combination with IGF2BP1 to destabilize HLA-F mRNA.

Electrochemical Biosensors Based on Carbon Nanomaterials for Diagnosis of Human Respiratory Diseases.

In recent years, respiratory diseases have increasingly become a global concern, largely due to the outbreak of Coronavirus Disease 2019 (COVID-19). This inevitably causes great attention to be given to the development of highly efficient and minimal or non-invasive methods for the diagnosis of respiratory diseases. And electrochemical biosensors based on carbon nanomaterials show great potential in fulfilling the requirement, not only because of the superior performance of electrochemical analysis, but also given the excellent properties of the carbon nanomaterials. In this paper, we review the most recent advances in research, development and applications of electrochemical biosensors based on the use of carbon nanomaterials for diagnosis of human respiratory diseases in the last 10 years. We first briefly introduce the characteristics of several common human respiratory diseases, including influenza, COVID-19, pulmonary fibrosis, tuberculosis and lung cancer. Then, we describe the working principles and fabrication of various electrochemical biosensors based on carbon nanomaterials used for diagnosis of these respiratory diseases. Finally, we summarize the advantages, challenges, and future perspectives for the currently available electrochemical biosensors based on carbon nanomaterials for detecting human respiratory diseases.

Significance of Pulmonary Endothelial Injury and the Role of Cyclooxygenase-2 and Prostanoid Signaling.

The endothelium plays a key role in the dynamic balance of hemodynamic, humoral and inflammatory processes in the human body. Its central importance and the resulting therapeutic concepts are the subject of ongoing research efforts and form the basis for the treatment of numerous diseases. The pulmonary endothelium is an essential component for the gas exchange in humans. Pulmonary endothelial dysfunction has serious consequences for the oxygenation and the gas exchange in humans with the potential of consecutive multiple organ failure. Therefore, in this review, the dysfunction of the pulmonary endothel due to viral, bacterial, and fungal infections, ventilator-related injury, and aspiration is presented in a medical context. Selected aspects of the interaction of endothelial cells with primarily alveolar macrophages are reviewed in more detail. Elucidation of underlying causes and mechanisms of damage and repair may lead to new therapeutic approaches. Specific emphasis is placed on the processes leading to the induction of cyclooxygenase-2 and downstream prostanoid-based signaling pathways associated with this enzyme.

Single-Cell Profiling Comparisons of Tumor Microenvironment between Primary Advanced Lung Adenocarcinomas and Brain Metastases and Machine Learning Algorithms in Predicting Immunotherapeutic Responses.

Brain metastasis (BM) occurs commonly in patients with lung adenocarcinomas. Limited evidence indicates safety and efficacy of immunotherapy for this metastatic tumor, though immune checkpoint blockade has become the front-line treatment for primary advanced non-small cell lung cancer. We aim to comprehensively compare tumor microenvironments (TME) between primary tumors (PT) and BM at single-cell resolution. Single-cell RNA transcriptomics from tumor samples of PT (N 23) and BM (N 16) and bulk sequencing data were analyzed to explore potential differences in immunotherapeutic efficacy between PT and BM of lung adenocarcinomas. Multiple machine learning algorithms were used to develop and validate models that predict responses to immunotherapy using the external cohorts. We found obviously less infiltration of immune cells in BM than PT, characterized specifically by deletion of anti-cancer CD8 Trm cells and more dysfunctional CD8 Tem cells in BM tumors. Meanwhile, macrophages and dendritic cells within BM demonstrated more pro-tumoral and anti-inflammatory effects, represented by distinct distribution and function of SPP1 and C1Qs tumor-associated microphages, and inhibited antigen presentation capacity and HLA-I gene expression, respectively. Besides, we also found the lack of inflammatory-like CAFs and enrichment of pericytes within BM tumors, which may be critical factors in shaping inhibitory TME. Cell communication analysis further revealed mechanisms of the immunosuppressive effects associated with the activation of some unfavorable pathways, such as TGFβ signaling, highlighting the important roles of stromal cells in the anti-inflammatory microenvironment, especially specific pericytes. Furthermore, pericyte-related genes were identified to optimally predict immunotherapeutic responses by machine learning models with great predictive performance. Overall, various factors contribute to the immunosuppressive TME within BM tumors, represented by the lack of critical anti-cancer immune cells. Meanwhile, pericytes may help shape the TME and targeting the associated mechanisms may enhance immunotherapy efficacy for BM tumors in patients with lung adenocarcinomas.

Modeling Human Lung Cells Exposure to Wildfire Uncovers Aberrant lncRNAs Signature.

Emissions generated by wildfires are a growing threat to human health and are characterized by a unique chemical composition that is tightly dependent on geographic factors such as fuel type. Long noncoding RNAs (lncRNAs) are a class of RNA molecules proven to be critical to many biological processes, and their condition-specific expression patterns are emerging as prominent prognostic and diagnostic biomarkers for human disease. We utilized a new air-liquid interface (ALI) direct exposure system that we designed and validated in house to expose immortalized human tracheobronchial epithelial cells (AALE) to two unique wildfire smokes representative of geographic regions (Sierra Forest and Great Basin). We conducted an RNAseq analysis on the exposed cell cultures and proved through both principal component and differential expression analysis that each smoke has a unique effect on the LncRNA expression profiles of the exposed cells when compared to the control samples. Our study proves that there is a link between the geographic origin of wildfire smoke and the resulting LncRNA expression profile in exposed lung cells and also serves as a proof of concept for the in-house designed ALI exposure system. Our study serves as an introduction to the scientific community of how unique expression patterns of LncRNAs in patients with wildfire smoke-related disease can be utilized as prognostic and diagnostic tools, as the current roles of LncRNA expression profiles in wildfire smoke-related disease, other than this study, are completely uncharted.

The Role of JAKSTAT Pathway in Fibrotic Diseases Molecular and Cellular Mechanisms.

There are four members of the JAK family and seven of the STAT family in mammals. The JAKSTAT molecular pathway could be activated by broad hormones, cytokines, growth factors, and more. The JAKSTAT signaling pathway extensively mediates various biological processes such as cell proliferation, differentiation, migration, apoptosis, and immune regulation. JAKSTAT activation is closely related to growth and development, homeostasis, various solid tumors, inflammatory illness, and autoimmune diseases. Recently, with the deepening understanding of the JAKSTAT pathway, the relationship between JAKSTAT and the pathophysiology of fibrotic diseases was noticed, including the liver, renal, heart, bone marrow, and lung. JAK inhibitor has been approved for myelofibrosis, and subsequently, JAKSTAT may serve as a promising target for fibrosis in other organs. Therefore, this article reviews the roles and mechanisms of the JAKSTAT signaling pathway in fibrotic diseases.

Pathogenetic Mechanisms of Liver-Associated Injuries, Management, and Current Challenges in COVID-19 Patients.

The global outbreak of COVID-19 possesses serious challenges and adverse impacts for patients with progression of chronic liver disease and has become a major threat to public health. COVID-19 patients have a high risk of lung injury and multiorgan dysfunction that remains a major challenge to hepatology. COVID-19 patients and those with liver injury exhibit clinical manifestations, including elevation in ALT, AST, GGT, bilirubin, TNF-α, and IL-6 and reduction in the levels of CD4 and CD8. Liver injury in COVID-19 patients is induced through multiple factors, including a direct attack of SARS-CoV-2 on liver hepatocytes, hypoxia reperfusion dysfunction, cytokine release syndrome, drug-induced hepatotoxicity caused by lopinavir and ritonavir, immune-mediated inflammation, renin-angiotensin system, and coagulopathy. Cellular and molecular mechanisms underlying liver dysfunction are not fully understood in severe COVID-19 attacks. High mortality and the development of chronic liver diseases such as cirrhosis, alcoholic liver disease, autoimmune hepatitis, nonalcoholic fatty liver disease, and hepatocellular carcinoma are also associated with patients with liver damage. COVID-19 patients with preexisting or developing liver disease should be managed. They often need hospitalization and medication, especially in conjunction with liver transplants. In the present review, we highlight the attack of SARS-CoV-2 on liver hepatocytes by exploring the cellular and molecular events underlying the pathophysiological mechanisms in COVID-19 patients with liver injury. We also discuss the development of chronic liver diseases during the progression of SARS-CoV-2 replication. Lastly, we explore management principles in COVID-19 patients with liver injury and liver transplantation.

Biological Effects of Human Exposure to Environmental Cadmium.

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd

First Evidence of the Protective Effects of 2-Pentadecyl-2-Oxazoline (PEA-OXA) in In Vitro Models of Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) is a serious inflammatory lung disorder and a complication of SARS-CoV-2 infection. In patients with severe SARS-CoV-2 infection, the transition to ARDS is principally due to the occurrence of a cytokine storm and an exacerbated inflammatory response. The effectiveness of ultra-micronized palmitoylethanolamide (PEA-um) during the earliest stage of COVID-19 has already been suggested. In this study, we evaluated its protective effects as well as the effectiveness of its congener, 2-pentadecyl-2-oxazoline (PEA-OXA), using in vitro models of acute lung injury. In detail, human lung epithelial cells (A549) activated by polyinosinic-polycytidylic acid (poly-(IC)) or Transforming Growth Factor-beta (TGF-β) were treated with PEA-OXA or PEA. The release of IL-6 and the appearance of Epithelial-Mesenchymal Transition (EMT) were measured by ELISA and immunofluorescence assays, respectively. A possible mechanism of action for PEA-OXA and PEA was also investigated. Our results showed that both PEA-OXA and PEA were able to counteract poly-(IC)-induced IL-6 release, as well as to revert TGF-β-induced EMT. In addition, PEA was able to produce an entourage effect on the levels of the two endocannabinoids AEA and 2-AG, while PEA-OXA only increased PEA endogenous levels, in poly-(IC)-stimulated A549 cells. These results evidence for the first time the superiority of PEA-OXA over PEA in exerting protective effects and point to PEA-OXA as a new promising candidate in the management of acute lung injury.

Silver Nanoparticles Phytofabricated through

Silver nanoparticles (AgNPs) have unlocked numerous novel disciplines in nanobiotechnological protocols due to their larger surface area-to-volume ratios, which are attributed to the marked reactivity of nanosilver, and due to their extremely small size, which enables AgNPs to enter cells, interact with organelles, and yield distinct biological effects. AgNPs are capable of bypassing immune cells, staying in the system for longer periods and with a higher distribution, reaching target tissues at higher concentrations, avoiding diffusion to adjacent tissues, releasing therapeutic agents or drugs for specific stimuli to achieve a longer duration at a specific rate, and yielding desired effects. The phytofabrication of AgNPs is a cost-effective, one-step, environmentally friendly, and easy method that harnesses sustainable resources and naturally available components of plant extracts (PEs). In addition, it processes various catalytic activities for the degradation of various organic pollutants. For the phytofabrication of AgNPs, plant products can be used in a multifunctional manner as a reducing agent, a stabilizing agent, and a functionalizing agent. In addition, they can be used to curtail the requirements for any additional stabilizing agents and to help the reaction stages subside.

Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds.

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimers disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound

The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner.

The NRF2KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (

GK-1 Induces Oxidative Stress, Mitochondrial Dysfunction, Decreased Membrane Potential, and Impaired Autophagy Flux in a Mouse Model of Breast Cancer.

Breast cancer (BC) is the second most common cancer worldwide in women. During the last decades, the mortality due to breast cancer has progressively decreased due to early diagnosis and the emergence of more effective new treatments. However, human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) remain with poor prognoses. In our research group, we are proposing the GK-1 immunomodulatory peptide as a new alternative for immunotherapy of these aggressive tumors. GK-1 reduced the growth rate of established tumors and effectively reduced lung metastasis in the 4T1 experimental murine model of breast cancer. Herein, the effect of GK-1 on the redox state, mitochondrial metabolism, and autophagy of triple-negative tumors that can be linked to cancer evolution was studied. GK-1 decreased catalase activity, reduced glutathione (GSH) content and GSHoxidized glutathione (GSSG) ratio while increased hydrogen peroxide (H

Skin Barrier Function and Infant Tidal Flow-Volume Loops-A Population-Based Observational Study.

The relationship between the skin barrier- and lung function in infancy is largely unexplored. We aimed to explore if reduced skin barrier function by high transepidermal water loss (TEWL), or manifestations of eczema or Filaggrin ( From the population-based PreventADALL cohort, 899 infants with lung function measurements and information on either TEWL, eczema at three months of age andor Neither a high TEWL, nor eczema or Overall, a high TEWL, eczema or

Health economic analysis of patients treated with isavuconazole in a German comprehensive cancer centre.

Invasive fungal diseases (IFD) are life-threatening and demand timely and appropriate treatment. Research showed that isavuconazole treatment positively affects clinical outcome and length of hospital stay (LOS). The aim of this study was to assess the hospital costs of patients diagnosed with IFD and treated with isavuconazole using real-world data from a German cancer centre. Data and LOS collected from Jan-2016 to Jun-2021 at Department I of Internal Medicine, University Hospital Cologne were retrieved. Case-related resources consumed during the hospital stay across isavuconazole routes of administration (oral, parenteral, and mixed administration) were identified, quantified, valued and compared via a cost analysis that adopted the healthcare payer perspective. In total, 101 cases with isavuconazole treatment were identified (oral n 22, 21.8% parenteral n 59, 58.4% mixed n 20, 19.8%). Median total LOS was greater in the mixed group (46.5 days p .009). Median ICU LOS and ventilation duration were both longest in the parenteral-only group (16 days, p .008 224 h, p .003). Invasive aspergillosis was the most frequent isavuconazole indication (n 86, 85.2%). Average hospital costs were highest in the mixed group (€ 101,226). The median overall costs of cases treated with isavuconazole was € 52,050. Treating IFD is resource intensive, often requires intensive care and implies high rates of in-hospital mortality. Our study emphasises the high hospital treatment costs and thus the need for reimbursement systems to enable live-saving costly treatments.

A radiomics-based deep learning approach to predict progression free-survival after tyrosine kinase inhibitor therapy in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for non-small cell lung cancer (NSCLC) with EGFR mutations. Approximately half of the patients with EGFR-mutated NSCLC are treated with EGFR-TKIs and develop disease progression within 1 year. Therefore, the early prediction of tumor progression in patients who receive EGFR-TKIs can facilitate patient management and development of treatment strategies. We proposed a deep learning approach based on both quantitative computed tomography (CT) characteristics and clinical data to predict progression-free survival (PFS) in patients with advanced NSCLC after EGFR-TKI treatment. A total of 593 radiomic features were extracted from pretreatment chest CT images. The DeepSurv models for the progression risk stratification of EGFR-TKI treatment were proposed based on CT radiomic and clinical features from 270 stage IIIB-IV EGFR-mutant NSCLC patients. Time-dependent PFS predictions at 3, 12, 18, and 24 months and estimated personalized PFS curves were calculated using the DeepSurv models. The model combining clinical and radiomic features demonstrated better prediction performance than the clinical model. The model achieving areas under the curve of 0.76, 0.77, 0.76, and 0.86 can predict PFS at 3, 12, 18, and 24 months, respectively. The personalized PFS curves showed significant differences (p < 0.003) between groups with good (PFS > median) and poor (PFS < median) tumor control. The DeepSurv models provided reliable multi-time-point PFS predictions for EGFR-TKI treatment. The personalized PFS curves can help make accurate and individualized predictions of tumor progression. The proposed deep learning approach holds promise for improving the pre-TKI personalized management of patients with EGFR-mutated NSCLC.

Long-term exposure to house dust mites accelerates lung cancer development in mice.

Individuals with certain chronic inflammatory lung diseases have a higher risk of developing lung cancer (LC). However, the underlying mechanisms remain largely unknown. Here, we hypothesized that chronic exposure to house dust mites (HDM), a common indoor aeroallergen associated with the development of asthma, accelerates LC development through the induction of chronic lung inflammation (CLI). METHODS The effects of HDM and heat-inactivated HDM (HI-HDM) extracts were evaluated in two preclinical mouse models of LC (a chemically-induced model using the carcinogen urethane and a genetically-driven model with oncogenic Kras Collectively, these data indicate that long-term exposure to HDM can accelerate lung tumorigenesis in susceptible hosts (e.g., mice and potentially humans exposed to lung carcinogens or genetically predisposed to develop LC).

Role of antiangiogenic agents in first-line treatment for advanced NSCLC in the era of immunotherapy.

Anti-angiogenetic drugs plus chemotherapy (anti-angio-chemo) and immune checkpoint inhibitors plus chemotherapy (ICI-chemo) are superior to traditional chemotherapy in the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, in the absence of a direct comparison of ICI-chemo with anti-angio-chemo, the superior one between them has not been decided, and the benefit of adding anti-angiogenetic agents to ICI-chemo remains controversial. This study aimed to investigate the role of antiangiogenic agents for advanced NSCLC in the era of immunotherapy. Eligible randomized controlled trials (RCTs) comparing chemotherapy versus therapeutic regimens involving ICIs or anti-angiogenetic drugs were included. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and rate of grade 3-4 toxicity assessment. R-4.3.1 was utilized to perform the analysis. A total of 54 studies with a sample size of 25,046 were finally enrolled. Atezolizumab Bevacizumab Chemotherapy significantly improved the ORR compared with Atezolizumab Chemotherapy (Odds ratio (OR) 2.73, 95% confidence interval (CI) 1.27-5.87). The trend also favored Atezolizumab Bevacizumab Chemotherapy in PFS and OS (hazard ratio (HR) 0.71, 95% CI 0.39-1.31 HR 0.94, 95% CI 0.77-1.16, respectively). In addition, Pembrolizumab Chemotherapy and Camrelizumab Chemotherapy significantly prolonged the PFS compared to Bevacizumab Chemotherapy (HR 0.65, 95% CI 0.46-0.92 HR 0.63, 95% CI 0.41-0.97 respectively). Meanwhile, Pembrolizumab Chemotherapy and Sintilimab Chemotherapy yielded more OS benefits than Bevacizumab Chemotherapy (HR 0.69, 95% CI 0.56-0.83 HR 0.64, 95%CI 0.46-0.91 respectively). Scheme between Atezolizumab Bevacizumab Chemotherapy and Atezolizumab Chemotherapy made no significant difference (OR 1.18, 95%CI 0.56-2.42) concerning the rate of grade 3-4 toxicity. It seemed that ICI-chemo yielded more improvement in quality-adjusted life-year (QALY) than Bevacizumab Chemotherapy in cost-effectiveness analysis. Our results suggest that ICI-chemo is associated with potentially longer survival, better cost-effectiveness outcomes, and comparable safety profiles than anti-angio-chemo. Also, adding bevacizumab to ICI-chemo seemed to provide additional therapeutic benefits without adding treatment burden. Our findings would supplement the current standard of care and help the design of future clinical trials for the first-line treatment of patients with advanced NSCLC.

Population-Based Screening Using Low-Dose Chest Computed Tomography A Systematic Review of Health Economic Evaluations.

Chest low-dose computed tomography (LDCT) is a promising technology for population-based screening because it is non-invasive, relatively inexpensive, associated with low radiation and highly sensitive to lung cancer. To improve the cost-effectiveness of lung cancer screening, simultaneous screening for other diseases could be considered. This systematic review was conducted to analyse studies that published evidence on the cost-effectiveness of chest LDCT screening programs for different diseases. Scopus and PubMed were searched for English publications (1 January 2011-22 July 2022) using search terms related to screening, computed tomography and cost-effectiveness. An additional search specifically searched for the cost-effectiveness of screening for lung cancer, chronic obstructive pulmonary disease or cardiovascular disease. Included publications should present a full health economic evaluation of population screening with chest LDCT. The extracted data included the disease screened for, model type, country context of screening, inclusion of comorbidities or incidental findings, incremental costs, incremental effects and the resulting cost-effectiveness ratio amongst others. Reporting quality was assessed using the 2022 Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. The search yielded 1799 unique papers, of which 43 were included. Most papers focused on lung cancer screening (n 40), and three were on coronary calcium scoring. Microsimulation was the most commonly applied modelling type (n 16), followed by life table analysis (n 10) and Markov cohort models (n 10). Studies reflected the healthcare context of the US (n 15), Canada (n 4), the UK (n 3) and 13 other countries. The reported incremental cost-effectiveness ratio ranged from US$10,000 to US$90,000quality-adjusted life year (QALY) for lung cancer screening compared to no screening and was US$15,900QALY-US$45,300QALY for coronary calcium scoring compared to no screening. Almost all health economic evaluations of LDCT screening focused on lung cancer. Literature regarding the health economic benefits of simultaneous LDCT screening for multiple diseases is absent. Most studies suggest LDCT screening is cost-effective for current and former smokers aged 55-74 with a minimum of 30 pack-years of smoking history. Consequently, more evidence on LDCT is needed to support further cost-effectiveness analyses. Preferably evidence on simultaneous screening for multiple diseases is needed, but alternatively, on single-disease screening. Prospective Register of Ongoing Systematic Reviews registration CRD42021290228 can be accessed httpswww.crd.york.ac.ukprosperodisplayrecord.phpRecordID290228 .

Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors.

Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 lossinhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.

How I treat HER2-low advanced breast cancer.

Targeting low levels of human receptor epidermal growth factor 2 (HER2) expression has reshaped the treatment paradigm for half of the patients with advanced breast cancer. HER2-low is currently defined as a HER2 immunohistochemical expression of 1 or 2 without amplification by in-situ hybridization. Until recently, HER2-targeted agents were ineffective in treating patients with HER2-low disease. In this narrative review, we summarize the current management of HER2-low breast cancer. We highlight the findings of the DESTINY-Breast 04 phase 3 trial, which confirmed the efficacy of trastuzumab-deruxtecan (T-DXd) for the treatment of patients with advanced, pretreated HER2-low breast cancer. We also discuss how to implement this new treatment option in treatment algorithms of hormone receptor (HR)-positive and triple-negative tumors, as well as how to optimally manage selected toxicities of T-DXd. T-DXd is currently the standard of care for patients with advanced, pretreated, HER2-low breast cancer. Based on the design of the DESTINY-Breast04 trial, the current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer. Up to 10-15% of the patients receiving T-DXd are expected to develop interstitial lung disease, which in 1-2% of the cases can be fatal. Adequate monitoring and prompt management are required to minimize the impact of ILD and to safely implement T-DXd in clinical practice.

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. No DLTs occurred in parts A (n18) or B (n85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copiesmL on day 8, cycle 1 in part A (n6) and below the detection limit for most patients (86% (1922)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n43), and 20% in the urothelial cancer dose-expansion cohort (n35). Intravenous V937pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. NCT02043665.

Vaginal metastases of Wilms Tumor in a pediatric patient a rare case.

Wilms tumor is the second most common pediatric abdominal cancer, however, it rarely involves the female reproductive tract. There are few cases reported in the literature describing uterine, ovarian, cervical and vaginal involvement. We report the case of a 7-year-old girl presenting with a large renal mass with retroperitoneal nodal and lung metastases she was diagnosed with stage 4 favorable histology Wilms tumor. She was treated with surgery, chemotherapy and radiation. She presented with vaginal bleeding 10 months after completing treatment biopsy of a vaginal mass confirmed recurrence, and this was sent for molecular profiling, which did not identify an inherited cancer predisposition or targetable mutation. She was again treated with chemotherapy examination redemonstrated a small vaginal mass, but re-biopsy of the lesion was negative for malignancy. Due to high risk of local relapse, ongoing chemotherapy and pelvic radiation ensued. End of treatment imaging and vaginoscopy showed no residual disease. Vaginal metastases of Wilms tumor are very rare this is the second reported case in the literature. Pediatric clinicians should have a strong suspicion for vaginal metastases in cancer patients presenting with vaginal bleeding especially when their pubertal development does not suggest that bleeding would be secondary to menarche. Long-term gynecologic care for these patients is paramount to reduce morbidity from chemotherapy and pelvic radiation. Fertility preservation counselling should be made early, through referral to a specialist.

A Wntβ-catenin signaling inhibitor, IMU1003, suppresses the emergence of osimertinib-resistant colonies from gefitinib-resistant non-small cell lung cancer cells.

Drug resistance has become a challenge in effective longterm molecular targeted therapy. Longterm non-small cell lung cancer (NSCLC) treatments with the first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) shorten the effective duration of the third-generation EGFR-TKI, osimertinib, via genetic or epigenetic mechanisms in addition to the gatekeeper mutation T790M. This study reproduced this persistence in vitro using gefitinib-resistant NSCLC PC-9 cells (GR cells) and revealed that pharmacological nuclear localization inhibition of β-catenin suppressed the osimertinib resistance. Osimertinib effectively reduced GR cell survival but left significantly more resistant colonies than parental PC-9 cells. The nuclear fraction of β-catenin was enriched in GR cells during acquisition of osimertinib resistance. A chemical nuclear localization inhibitor of β-catenin, IMU1003, dramatically decreased the emergence of osimertinib-resistant colonies. Forced nuclear localization of β-catenin reduced IMU1003 efficacy. Thus, suppression of the nuclear β-catenin function may overcome the transgenerational EGFR-TKI-resistance.

Role of iodine density value on dual-energy CT for detection of high tumor cell proportion region in lung cancer during CT-guided transthoracic biopsy.

This study aimed to identify regions with at least 20% tumor cell content in lung cancer tumors by using spectral parameters from dual-layer spectral detector computed tomography (SDCT) to design the puncture path for transthoracic lung biopsy (TTLB). This prospective study recruited patients with suspected lung cancer. Forty-one patients were enrolled to identify the high tumor cell proportion region (HTPR) and then another 15 patients to validate the accuracy of the HTPR. In each of the 41 patients, the suspected regions with high or low tumor cell proportions were punctured according to local iodine density (IoD) values for separate biopsies. The tumor cell proportions of 82 specimens were assessed and classified into high and low tumor cell proportions based on the threshold value of 20 %. The performance of spectral parameters was analyzed to distinguish the HTPR (tumor cell proportion ≥ 20 %) from the low tumor cell proportion region (LTPR). The cutoff value of optimal spectral parameter was used to prospectively guide the biopsy of the HTPR in 15 cases for further validation, and then the accuracy was calculated. The AUC values of spectral parameters were all higher than those of CT Spectral CT parameters can be used to identify regions with at least 20% tumor cell content in lung cancer for biopsies.

Long-term comparative efficacy and safety of nivolumab plus ipilimumab relative to other first-line therapies for advanced non-small-cell lung cancer A systematic literature review and network meta-analysis.

To quantify the long-term comparative efficacy and safety of nivolumab in combination with ipilimumab (NIVO IPI) relative to other immunotherapy (IO)-based regimens and chemotherapy in patients with first-line advanced non-small cell lung cancer (aNSCLC). Phase 3 randomized controlled-trials (RCTs) with minimum 3-year follow-up evaluating IO-based regimens approved for first-line aNSCLC were identified via systematic literature review. Analytic populations were defined by levels of PD-L1 expression and histology. Due to presence of proportional hazards violations, time-varying hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were estimated via Bayesian fractional polynomial network meta-analysis. For safety endpoints, odds ratios (ORs) were estimated using indirect treatment comparisons (ITCs). CheckMate 227, KEYNOTE-189, KEYNOTE-407, KEYNOTE-024, KEYNOTE-042, and IMpower150 were included in the base case analysis. For OS and PFS, HRs of NIVO IPI relative to other IO-based regimens trended downward over time across analytic populations. The 36-month OS HRs of NIVO IPI versus comparators were 0.69 (95 % credible interval 0.47, 1.00) versus pembrolizumab chemotherapy and 0.65 (0.45, 0.93) versus atezolizumab bevacizumab chemotherapy in the non-squamous and PD-L1 all-comers population 0.73 (0.53, 1.02) versus pembrolizumab chemotherapy in the squamous and PD-L1 all-comers population and 1.05 (0.83, 1.32) versus pembrolizumab in the mixed histology and PD-L1 ≥ 50 % population. For PFS, 36-month HR point estimates ranged from 0.46 to 0.85 (only statistically significant versus pembrolizumab chemotherapy in the squamous population 0.46 0.31, 0.69). Adverse events (AEs) leading to discontinuation were not statistically significantly different between NIVO IPI and pembrolizumab chemotherapy, nor between NIVO IPI and pembrolizumab monotherapy, although treatment-related grade ≥ 3 AEs were higher with NIVO IPI than pembrolizumab monotherapy (OR 2.21 1.30, 3.75). This study indicates trends towards long-term benefit with NIVO IPI compared with other IO-based combinations, with manageable toxicities.

Data From a One-Stop-Shop Comprehensive Cancer Screening Center.

Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit. Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate. Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.

Sub-second photon dose prediction via transformer neural networks.

Fast dose calculation is critical for online and real-time adaptive therapy workflows. While modern physics-based dose algorithms must compromise accuracy to achieve low computation times, deep learning models can potentially perform dose prediction tasks with both high fidelity and speed. We present a deep learning algorithm that, exploiting synergies between transformer and convolutional layers, accurately predicts broad photon beam dose distributions in few milliseconds. The proposed improved Dose Transformer Algorithm (iDoTA) maps arbitrary patient geometries and beam information (in the form of a 3D projected shape resulting from a simple ray tracing calculation) to their corresponding 3D dose distribution. Treating the 3D CT input and dose output volumes as a sequence of 2D slices along the direction of the photon beam, iDoTA solves the dose prediction task as sequence modeling. The proposed model combines a Transformer backbone routing long-range information between all elements in the sequence, with a series of 3D convolutions extracting local features of the data. We train iDoTA on a dataset of 1700 beam dose distributions, using 11 clinical volumetric modulated arc therapy (VMAT) plans (from prostate, lung, and head and neck cancer patients with 194-354 beams per plan) to assess its accuracy and speed. iDoTA predicts individual photon beams in ≈50 ms with a high gamma pass rate of Offering the millisecond speed prediction per beam angle needed in online and real-time adaptive treatments, iDoTA represents a new state of the art in data-driven photon dose calculation. The proposed model can massively speed-up current photon workflows, reducing calculation times from few minutes to just a few seconds.

Primary Cutaneous Ewing Sarcoma of the Scalp With Metastasis to the Lung An Unusual Manifestation During Pregnancy.

A 32-year-old G2P1L1 (5 months pregnant) woman presented with a 3-month history of a slow-growing cystic lesion on her scalp vertex. Similar lesions in the exact location were excised twice in the past with a diagnosis of trichilemmal carcinoma (TC). A biopsy of the scalp lesion showed morphology and immunoprofile consistent with previously diagnosed TC. Staging PETCT demonstrated a 4.7 cm right upper lobe lung, and a subsequent lung biopsy showed a small, round blue-cell tumor with necrosis, morphologically identical to the prior biopsies from the scalp. Considering the unusual clinical course of TC, a lung biopsy was sent for next-generation sequencing that showed EWSR1-FLI1 (type1) fusion. Additionally, CD99 immunostaining revealed uniform cytoplasmic and membranous staining in the tumor cells. The previous scalp excision specimen was also sent for mutation analysis, which showed EWSR1-FLI1 fusion. In conjunction with clinical history and histological and molecular findings, a definitive diagnosis of primary cutaneous Ewing sarcoma (PCES) with local recurrence and metastasis to the lung was made. We present a case of PCES, which was previously misdiagnosed and treated as TC. This case emphasizes the importance of CD99 in the initial screening of cutaneous small round blue-cell tumors to avoid misdiagnosis from other morphological overlaps. Also, despite its rarity, PCES should be included in the differential diagnosis of small, round, blue cell tumors at cutaneous sites. Our case also exemplifies common biases in medical decision-making, including premature closure and anchoring bias which can result in misdiagnosis or diagnostic delay and associated delay in appropriate management.

Periosteal Ewing Sarcoma Imaging Features and Clinical Outcomes in 7 Patients.

The aim of this study was to describe imaging features, treatment, and prognosis of patients with periosteal Ewing sarcoma (PES). Seven patients with PES treated between 2001 and 2020 were studied retrospectively for presenting symptoms, imaging features, treatment, and prognosis. Among the 7 patients (mean age, 27.3 years) with local pain andor mass of less than 6 months duration, 4 were males and 3 females (1.31). These surface tumors involved 3 long bones and 4 pelvic bones. Radiographs showed cortical erosions with 2 and CT with 4 long bone tumors. All 7 surface tumors showed normal marrow on MRI, and 4 tumors demonstrated normal marrow activity on 18FFDG fluorodeoxyglucose PET-CT. The only exception was a PES involving iliac bone with thin cortex and marrow extension, which demonstrated hypermetabolic marrow activity. All patients were treated initially with chemotherapy and optional radiation treatment with complete tumor resolution of a tibial PES in 1 patient. The remaining 2 patients with long bone PES had tumor resection and limb-salvage surgery and the 4 patients with pelvic bone PES had hemipelvectomy after chemotherapyradiation treatment. Five patients were disease-free with long-term survival. A patient with a long bone PES and solitary lung metastasis at onset had tumor resection and metastasectomy with complete recovery without tumor recurrence. The 2 patients with pubic bone PES had complete recovery without tumor recurrence however, the remaining 2 patients with iliac bone PES developed distant metastases and died within 2 years of diagnosis. Periosteal Ewing sarcoma arises in periosteum of bone and spares medullary cavity. As compared with its intramedullary counterpart, the tumor has better prognosis with long-term survival. Rarely, the surface tumor arising at a bone with thin cortex, such as iliac bone or scapula, may have medullary involvement. We have described our experience in diagnosis and clinical management in 7 patients of this rare surface variant of the more common intramedullary Ewing sarcoma.

Cytoprotective, Antiproliferative, and Anti-Oxidant Potential of the Hydroethanolic Extract of

Dendrimer-Mediated Intracellular Delivery of Fibronectin Guides Macrophage Polarization to Alleviate Acute Lung Injury.

Fibronectin (FN) is an essential glycoprotein in the extracellular matrix with favorable biological functions for potential applications in various biomedical fields including wound healing, regenerative medicine, tissue engineering, as well as diagnosis and treatment of cancer and inflammatory diseases. Herein, we aim to explore the influence of intracellular FN delivery on macrophage functions and its possible therapeutic applications. We prepared phenylboronic acid (PBA)-functionalized generation 5 (G5) poly(amidoamine) dendrimers (G5.NH

Novel HER2-Targeted Peptide for NIR-II Imaging of Tumor.

Molecular targets serve a crucial role in drug development. Herein, we discovered a novel peptide that can specifically target the human epidermal growth factor receptor 2 (HER2) and thus named it Herceptide. In our study, Herceptide was conjugated to the near-infrared fluorescent dye indocyanine green (ICG) to obtain a probe, ICG-Herceptide. Importantly, specific binding to HER2 was revealed by molecular docking, surface plasmon resonance analysis, and competition assays. The probe showed high binding affinity (

Utilization and Survival Impact of Hypofractionated Radiotherapy in Stage I Non-small Cell Lung Cancer.

The optimal fractionation schedule in unresected stage I non-small cell lung cancer (NSCLC) unsuitable for stereotactic body radiation therapy is unclear. Given the lack of comparative data regarding nonstereotactic body radiation therapy schemas, we compared overall survival (OS) with hypofractionated radiotherapy (HFRT) versus conventionally fractionated radiotherapy (CFRT) and examined the OS impact of different HFRT doses. This retrospective analysis included 2159 patients from the National Cancer Database diagnosed with stage I (cT1-2aN0M0) NSCLC between 2008 and 2016. Patients underwent CFRT (70≤BED10 biologically effective dose <100 Gy10 in ≥30 fractions), low-dose HFRT (LD-HFRT 70≤BED10 assuming αβ10 <100 Gy10 in 11 to 24 fractions), or high-dose HFRT (HD-HFRT 100≤BED10 ≤120 Gy10 in 6 to 10 fractions). Patients who received surgery, chemotherapy, or immunotherapy were excluded. We compared CFRT versus all HFRT, and separately CFRT versus LD-HFRT and CFRT versus HD-HFRT. OS was evaluated with the Kaplan-Meier estimator, log-rank test, and Cox regression. A total of 63.2% of patients underwent CFRT, 23.5% LD-HFRT, and 13.3% HD-HFRT. OS was significantly longer with HFRT versus CFRT on univariable (28.2 mo 95% CI, 25.6-31.7 vs 26.4 mo 25.0-27.9 log-rank0.0025) but not multivariable analysis (MVA hazard ratio HR 0.90 P0.062). MVA yielded no significant difference in OS between CFRT and LD-HFRT (HR 0.96, P0.53). OS was significantly longer with HD-HFRT versus CFRT on MVA (HR, 0.75 P0.003). However, on sensitivity analysis using different multivariable modeling techniques, this did not retain statistical significance (HR, 0.83 P0.12). For stage I NSCLC, HFRT does not show a robust OS benefit compared with CFRT but may be preferred given the convenience and lower costs.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A51 expressers (CYP3A511 and CYP3A513) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A51 (CYP3A533). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A51 should be 33.33-50.00% higher than that in CYP3A51 expressers. A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A51 required higher doses.

Suicide Risk Among Individuals Diagnosed With Cancer in the US, 2000-2016.

Individuals diagnosed with cancer have elevated suicide risks compared with the general population. National estimates of suicide risks among individuals with cancer are lacking in the US, and knowledge about risk factors is limited. To provide contemporary estimates of suicide risks associated with cancer and to identify sociodemographic and clinical factors associated with suicide risks among individuals diagnosed with cancer. A population-based cohort of individuals diagnosed with cancer from January 1, 2000, to December 31, 2016, from 43 states in the US were followed up through December 31, 2016. Standardized mortality ratios (SMRs) were calculated adjusting for attained age at death, sex, and race and ethnicity groups to compare suicide risks in the cancer cohort vs the general US population. Cox proportional hazards regression models were fitted to identify cancer-specific risk factors of suicide among the cancer cohort. Analyses were conducted from October 27, 2020, to May 13, 2022. The main outcomes were risk of suicide death compared with the general population, measured by the standardized mortality ratio and risk of suicide death associated with sociodemographic and clinical factors among individuals with cancer. Diagnosis of cancer. Among a total of 16 771 397 individuals with cancer, 8 536 814 (50.9%) were 65 years or older at cancer diagnosis, 8 645 631 (51.5%) were male, 13 149 273 (78.4%) were non-Hispanic White, and 20 792 (0.1%) died from suicide. The overall SMR for suicide was 1.26 (95% CI, 1.24-1.28), with a decreasing trend (from an SMR of 1.67 95% CI, 1.47-1.88 in 2000 to 1.16 95% CI, 1.11-1.21 in 2016). Compared with the general population, elevated suicide risks were observed in the cancer cohort across all sociodemographic groups, with particularly high SMRs among Hispanic individuals (SMR, 1.48 95% CI, 1.38-1.58), Medicaid-insured individuals (SMR, 1.72 95% CI, 1.61-1.84), Medicare-insured individuals 64 years or younger (SMR, 1.94 95% CI, 1.80-2.07), or uninsured individuals (SMR, 1.66 95% CI, 1.53-1.80). Moreover, the highest SMR was observed in the first 6 months after the cancer diagnosis (SMR, 7.19 95% CI, 6.97-7.41). Among individuals diagnosed with cancer, relatively higher suicide risks (ie, hazard ratios) were observed for cancer types with a poor prognosis and high symptom burden in the first 2 years after diagnosis, including cancers of oral cavity and pharynx, esophagus, stomach, brain and other nervous system, pancreas, and lung. After 2 years, individuals with cancers subject to long-term quality-of-life impairments, such as oral cavity and pharynx, leukemia, female breast, uterine, and bladder, had higher suicide risks. In this cohort study of individuals with cancer, elevated suicide risks remained despite a decreasing trend during the past 2 decades. Suicide risks varied by sociodemographic and clinical factors. Timely symptom management and targeted psychosocial interventions are warranted for suicide prevention in individuals diagnosed with cancer.

Real-world adjuvant chemotherapy patterns and outcomes among elderly patients with resected early non-small-cell lung cancer in the USA.

Lung cancer is one of the deadliest cancers in the USA. Most lung cancers are a type called non-small-cell lung cancer (NSCLC). Patients with NSCLC that has not spread to other parts of the body generally have surgery and may receive treatment before surgery, after surgery or both to help fight the cancer. It is not clear how often people receive treatment before or after surgery. It is important to know how patients are being treated because it helps clinicians decide how to use the new treatments that are becoming available. This study used a large database of more than 7000 people aged 65 years and older with lung cancer in the USA to understand how they are treated. More than a third of patients had stage IA NSCLC (39%), followed by stage IB (24%), stage II (20%), stage IIIA (15%) and stage IIIB (2%). Most people had surgery (64%) and some received another treatment after surgery (27%). That treatment was most often about 2 months of chemotherapy, on average. The study also tried to understand how the timing of treatment may have been important for their survival. People who received treatment after surgery lived the longest if they received that treatment about 6–8 weeks after the surgery. Overall, the study showed that a substantial proportion of people do not receive treatment for their NSCLC after surgery, even though treatment after surgery is recommended by medical guidelines. There is a need for more effective treatments for these patients, and when those treatments are given may be important for their survival.

Prognostic significance of tumor infiltrating lymphocytes on first-line pembrolizumab efficacy in advanced non-small cell lung cancer.

Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting. Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N 93) or surgical resections (N 14) before first-line pembrolizumab. A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%. Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS.

Biosynthesis, Characterization, and Augmented Anticancer Activity of ZrO

Fabrication of ZnO nanoparticles (NPs) via green process has received enormous attention for its application in biomedicine. Here, a simple and cost-effective green route is reported for the synthesis of ZrO

Factors Associated with Leg Ulcers in Adults with Sickle Cell Disease in Brazil.

To define the prevalence of leg ulcers and identify the clinical and laboratory factors associated with leg ulcers in adult participants. The authors conducted a cross-sectional study of 1,109 patients who were 18 years or older with SS or Sβ0-thalassemia genotypes from a Brazilian cohort. Investigators assessed the prevalence of factors associated with leg ulcers from 2013 to 2017. The prevalence of leg ulcers was 21%. Increasing age (odds ratio OR, 1.07 range, 1.06-1.09), male sex (OR, 2.03 range, 1.44-2.87), treatment with chronic transfusion therapy (OR, 1.88 range, 1.15-3.03), higher indirect bilirubin levels (OR, 1.48 range, 1.02-2.16), and low hemoglobin levels (OR, 2.17 range, 1.52-3.11) were associated with leg ulcers. Participants who self-reported as Black (OR, 6.75 range, 2.63-21.32), mixed (OR, 3.91 range, 1.55-12.20), and otherunknown (OR, 3.84 range, 1.04-15.24) were more likely to have leg ulcers compared with those who self-reported as White. The prevalence of leg ulcers in this Brazilian cohort was higher than the prevalence reported in developed countries. Known factors such as age and male sex were corroborated. The increased bilirubin level and decreased hemoglobin levels among participants with leg ulcers support the hypothesis that hemolysis is correlated with leg ulcer pathogenesis. Self-reported black skin color was an independent predictor of leg ulcers and warrants further study to understand the etiology and implications of this finding.

Impact of COVID-19 Pandemic on Non-Small Cell Lung Cancer Care.

We assessed the impact of COVID-19 on healthcare visits, timing of stage IV NSCLC diagnosis and immunotherapy initiation, and rates of switching to extended dosing schedules of immunotherapies among patients with stage IV NSCLC. This retrospective study examined electronic health record data of adult patients receiving treatment for stage IV NSCLC within The US Oncology Network and Onmark. Endpoints were compared for February-July 2019 (before COVID) vs. February-July 2020 (during COVID). The study found rapid decreases in numbers of patients with clinicvital visits, immunotherapy initiations, and new diagnoses of stage IV NSCLC during April-May 2020 vs. April-May 2019. The rate of delays of immunotherapy administrations and proportions of patients with such delays increased from February to March of 2020. These patterns may have resulted from the increase in COVID-19 cases during this period and the corresponding quarantine and lockdowns. However, when comparing pre COVID-19 and during COVID-19 for May and after, the differences in delay of immuno-oncology administrations became less marked, likely due to lifting of lockdowns. The rate of switching from shorter to longer dosing schedules increased from May-July 2020. This was mainly attributed to pembrolizumab, likely due to FDA approval of the pembrolizumab 6W dosing schedule in April 2020.

Adherence to Oral Chemotherapy in Acute Lymphoblastic Leukemia during Maintenance Therapy in Children, Adolescents, and Young Adults A Systematic Review.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. Treatment is long and involves 2-3 years of a prolonged maintenance phase composed of oral chemotherapies. Adherence to these medications is critical to achieving good outcomes. However, adherence is difficult to determine, as there is currently no consensus on measures of adherence or criteria to determine nonadherence. Furthermore, there have been few studies in pediatric B-ALL describing factors associated with nonadherence. Thus, we performed a systematic review of literature on oral chemotherapy adherence during maintenance therapy in ALL following PRISMA guidelines. Published studies demonstrated various objective and subjective methods of assessing adherence without generalizable definitions of nonadherence. However, the results of these studies suggested that nonadherence to oral maintenance chemotherapy was associated with increased risk of relapse. Future studies of B-ALL therapy should utilize a uniform assessment of adherence and definitions of nonadherence to better determine the impact of nonadherence on B-ALL outcomes and identify predictors of nonadherence that could yield targets for adherence improving interventions.

Drug Repurposing in Non-Small Cell Lung Carcinoma Old Solutions for New Problems.

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in 2022. The majority (80%) of lung cancer cases belong to the non-small cell lung carcinoma (NSCLC) subtype. Despite the increased screening efforts, the median five-year survival of metastatic NSCLC remains low at approximately 3%. Common treatment approaches for NSCLC include surgery, multimodal chemotherapy, and concurrent radio and chemotherapy. NSCLC exhibits high rates of resistance to treatment, driven by its heterogeneity and the plasticity of cancer stem cells (CSCs). Drug repurposing offers a faster and cheaper way to develop new antineoplastic purposes for existing drugs, to help overcome therapy resistance. The decrease in time and funds needed stems from the availability of the pharmacokinetic and pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved drugs to be repurposed. This review provides a synopsis of the drug-repurposing approaches and mechanisms of action of potential candidate drugs used in treating NSCLC, including but not limited to antihypertensives, anti-hyperlipidemics, anti-inflammatory drugs, anti-diabetics, and anti-microbials.

Retrospective Assessment of Complementary Liquid Biopsy on Tissue Single-Gene Testing for Tumor Genotyping in Advanced NSCLC.

Biomarker testing is key for non-small cell lung cancer (NSCLC) management and plasma based next-generation sequencing (NGS) is increasingly characterized as a non-invasive alternative. This study aimed to evaluate the value of complementary circulating tumor DNA (ctDNA) NGS on tissue single-gene testing (SGT). Ninety-one advanced stage NSCLC patients with tumor genotyping by tissue SGT (3 genes) followed by ctDNA (38 genes amplicon panel) were included. ctDNA was positive in 47% (

Successful Treatment with Brigatinib after Alectinib-Induced Hemolytic Anemia in Patients with Metastatic Lung Adenocarcinoma-A Case Series.

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor used in the treatment of advanced ALK-rearrangement positive non-small-cell lung cancer (NSCLC). Many tolerable adverse events were reported with the use of Alectinib nevertheless, hemolytic anemia was not mentioned in the safety analysis. In this case, series, we report four cases of Alectinib-induced oxidative hemolytic anemia and discuss different etiologic hypotheses on the underlying mechanism of such overlooked adverse event of the drug. Furthermore, we draw attention to the successful treatment with Brigatinib, an alternative second-generation ALK-inhibitor without recurrence of hemolytic anemia in three of our four cases, suggesting a probable class effect.

Efficacy of Immunotherapy in Second-Line Treatment of

Background The implementation of next-generation sequencing (NGS) into daily practice allows for the identification of a greater number of molecular abnormalities. We aimed to confirm the benefits of immunotherapy in the group of patients with

LKB1 Loss Assessed by Immunohistochemistry as a Prognostic Marker to First-Line Therapy in Advanced Non-Small-Cell Lung Cancer.

(1) Background Liver kinase B1 (LKB1) is a tumor suppressor gene involved in cell growth and metabolism. However, its alterations are not routinely assessed for guiding therapy in clinical practice. We assessed LKB1 expression by immunohistochemistry as a potential biomarker. (2) Methods This bicentric retrospective cohort study analyzed data from patients with advanced NSCLC who initiated platinum-based chemotherapy or epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) between January 2016 and December 2020. Kaplan-Meier and Cox regression models were used for survival curves and multivariate analysis. (3) Results 110 patients were evaluated, and the clinical stage IV predominated the lung adenocarcinoma histology. LKB1 loss was observed in 66.3% of cases. LKB1 loss was associated with non-smokers, the absence of wood smoke exposure and an EGFR wild-type status. The median progression-free survival (PFS) and overall survival (OS) in the population were 11.1 and 26.8 months, respectively, in the loss group, compared with cases exhibiting a positive expression. After an adjustment by age, smoking status, Eastern Cooperative Oncology Group Performance Score (ECOG-PS), EGFR status and type of administered therapy, LKB1 loss was significantly associated with worse PFS and OS. (4) Conclusion Patients with an LKB1 loss had worse clinical outcomes. This study warrants prospective assessments to confirm the prognostic role of the LKB1 expression in advanced NSCLC.

Development and Validation of a Prediction Model for Positive Findings of Preoperative Flexible Bronchoscopy in Patients with Peripheral Lung Cancer.

(1) Background It has yet to be determined whether preoperative flexible bronchoscopy (FB) should be routinely performed in patients with peripheral lung cancer. The aim of this study was to construct a model to predict the probability of positive FB findings, which would help assess the necessity of preoperative FB. (2) Methods A total of 380 consecutive patients with peripheral lung cancer who underwent preoperative FB were recruited for this study. A prediction model was developed through univariate and multivariate logistic regression, with predictors including gender, age, body mass index (BMI), smoking, history of chronic lung diseases, respiratory symptoms, lesion size, lesion type, lesion location in the bronchi, and lesion location in the lobe. The predictive performance of the model was evaluated by validation using 1000 iterations of bootstrap resampling. Model discrimination was assessed using the area under the receiver operating characteristics curve (AUC), and calibration was assessed using the Brier score and calibration plots. (3) Results The model suggested that male patients with respiratory symptoms, decreased BMI, solid lesions, and lesions located in lower-order bronchi were more likely to have positive FB findings. The AUC and Brier score of the model for internal validation were 0.784 and 0.162, respectively. The calibration curve for the probability of positive FB findings showed convincing concordance between the predicted and actual results. (4) Conclusions Our prediction model estimated the pretest probability of positive FB findings in patients with peripheral lung cancers. Males and patients with lower BMI, the presence of respiratory symptoms, larger lesions, solid lesions, and lesions located in lower-order bronchi were associated with increased positive FB findings. The use of our model can be of assistance when making clinical decisions about preoperative FB.

Disparate Time-to-Treatment and Varied Incidence of Actionable Non-Small Cell Lung Cancer Molecular Alterations in British Columbia A Historical Cohort Study.

non-small cell lung cancer (NSCLC) outcomes remain suboptimal for early-stage disease despite emerging advances in systemic therapy for the peri-operative period. Next-generation sequencing (NGS) identifies driver mutations for which targeted therapies have been developed that improve survival. The BC lung cancer screening program, which was initiated in May 2022, is expected to identify people with early and late stages of NSCLC. It is crucial to first understand the molecular epidemiology and patterns of time to initiate treatment across its five health authorities (HA) to optimize the delivery of care for NSCLC in BC. In this way, we may harness the benefits of targeted therapy for more people with NSCLC as novel advances in therapy continue to emerge. to compare (a) the frequency of actionable NSCLC molecular alterations among HAs and (b) the time to treatment initiation. a retrospective observational study was conducted with prospectively collected data from the BC CGL Database. Adults with late stage NSCLC who underwent targeted NGS were included for the time period from May 2020 to June 2021. Demographics, actionable molecular alterations, PDL-1 expression, and time to treatment across HAs were examined. Using appropriate statistical tests for comparison among HAs, pgt0.05 was deemed significant. 582 patients underwent NGSIHC and analysis during the study period. The mean age was 71 (10.1), and 326 (56%) patients were female. A significantly higher proportion of all EGFRm were identified within Vancouver Coastal Health (VCHA) and Fraser Health Authority (FHA) compared to the other health authorities ( actionable NSCLC driver mutations are present in all regional HAs, with disparity noted in time to initiate treatment between HAs. This provides evidence for the importance of molecular testing for patients in all BC HAs to guide personalized and timely NSCLC treatment.

Stereotactic Body Radiotherapy (SBRT) in Very Limited-Stage Small Cell Lung Cancer (VLS-SCLC).

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour with metastatic propensity. Stereotactic body radiation therapy (SBRT) is an emerging therapeutic option for SCLC, despite limited supporting evidence. By evaluating the use of SBRT in very limited stage (VLS) SCLC at our institution, we aimed to contribute to the existing knowledge in this area while establishing a basis for further research. We performed a retrospective review of all cases of VLS-SCLC treated with SBRT between 2013 and 2020. Baseline demographics, diagnostic, and treatment information were collected. The primary outcome was overall survival (OS). We identified 46 patients with pathologically confirmed VLS-SCLC 25 were treated with SBRT, and the remainder received either surgery, conventional radiation therapy, chemotherapy, or palliative-intent therapy. After a median follow-up of 23.7 months, 44% of the patients had died the median OS was of 24.4 months for the SBRT cohort and 67.0 months for the curative intent non-SBRT cohort. The difference in disease recurrence and survival between cohorts was underpowered and not statistically significant. Higher baseline ECOG and comorbidity was noted in the SBRT cohort.

Lung Cancer Gene Regulatory Network of Transcription Factors Related to the Hallmarks of Cancer.

The transcriptomic analysis of microarray and RNA-Seq datasets followed our own bioinformatic pipeline to identify a transcriptional regulatory network of lung cancer. Twenty-six transcription factors are dysregulated and co-expressed in most of the lung cancer and pulmonary arterial hypertension datasets, which makes them the most frequently dysregulated transcription factors. Co-expression, gene regulatory, coregulatory, and transcriptional regulatory networks, along with fibration symmetries, were constructed to identify common connection patterns, alignments, main regulators, and target genes in order to analyze transcription factor complex formation, as well as its synchronized co-expression patterns in every type of lung cancer. The regulatory function of the most frequently dysregulated transcription factors over lung cancer deregulated genes was validated with ChEA3 enrichment analysis. A Kaplan-Meier plotter analysis linked the dysregulation of the top transcription factors with lung cancer patients survival. Our results indicate that lung cancer has unique and common deregulated genes and transcription factors with pulmonary arterial hypertension, co-expressed and regulated in a coordinated and cooperative manner by the transcriptional regulatory network that might be associated with critical biological processes and signaling pathways related to the acquisition of the hallmarks of cancer, making them potentially relevant tumor biomarkers for lung cancer early diagnosis and targets for the development of personalized therapies against lung cancer.

Here, we describe the anticancer activity of our novel bis-triazoles

Deuterium Content of the Organic Compounds in Food Has an Impact on Tumor Growth in Mice.

Research with deuterium-depleted water (DDW) in the last two decades proved that the deuteriumhydrogen ratio has a key role in cell cycle regulation and cellular metabolism. The present study aimed to investigate the possible effect of deuterium-depleted yolk (DDyolk) alone and in combination with DDW on cancer growth in two in vivo mouse models. To produce DDyolk, the drinking water of laying hens was replaced with DDW (25 ppm) for 6 weeks, resulting in a 60 ppm D level in dried egg yolk that was used as a deuterium-depleted food additive. In one model, 4T1, a cell line with a high metastatic capacity to the lung was inoculated in the mices mammary pad. After three weeks of treatment with DDW andor DDyolk, the tumor volume in the lungs was smaller in all treated groups vs. controls with natural D levels. Tumor growth and survival in mice transplanted with an MCF-7 breast cancer cell line showed that the anticancer effect of DDW was enhanced by food containing the deuterium-depleted yolk. The study confirmed the importance of the DH ratio in consumed water and in metabolic water produced by the mitochondria while oxidizing nutrient molecules. This is in line with the concept that the initiation of cell growth requires the cells to generate a higher DH ratio, but DDW, DDyolk, or the naturally low-D lipids in a ketogenic diet, have a significant effect on tumor growth by preventing the cells from raising the DH ratio to the threshold.

Diagnostic, Management, and Research Considerations for Pediatric Acute Respiratory Distress Syndrome in Resource-Limited Settings From the Second Pediatric Acute Lung Injury Consensus Conference.

Diagnosis of pediatric acute respiratory distress syndrome (PARDS) in resource-limited settings (RLS) is challenging and remains poorly described. We conducted a review of the literature to optimize recognition of PARDS in RLS and to provide recommendationsstatements for clinical practice and future research in these settings as part of the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2). MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). We included studies related to precipitating factors for PARDS, mechanical ventilation (MV), pulmonary and nonpulmonary ancillary treatments, and long-term outcomes in children who survive PARDS in RLS. Titleabstract review, full-text review, and data extraction using a standardized data collection form. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Seventy-seven studies were identified for full-text extraction. We were unable to identify any literature on which to base recommendations. We gained consensus on six clinical statements (good practice, definition, and policy) and five research statements. Clinicians should be aware of diseases and comorbidities, uncommon in most high-income settings, that predispose to the development of PARDS in RLS. Because of difficulties in recognizing PARDS and to avoid underdiagnosis, the PALICC-2 possible PARDS definition allows exclusion of imaging criteria when all other criteria are met, including noninvasive metrics of hypoxemia. The availability of MV support, regular MV training and education, as well as accessibility and costs of pulmonary and nonpulmonary ancillary therapies are other concerns related to management of PARDS in RLS. Data on long-term outcomes and feasibility of follow-up in PARDS survivors from RLS are also lacking. To date, PARDS remains poorly described in RLS. Clinicians working in these settings should be aware of common precipitating factors for PARDS in their patients. Future studies utilizing the PALICC-2 definitions are urgently needed to describe the epidemiology, management, and outcomes of PARDS in RLS.

Leveraging Clinical Informatics and Data Science to Improve Care and Facilitate Research in Pediatric Acute Respiratory Distress Syndrome From the Second Pediatric Acute Lung Injury Consensus Conference.

The use of electronic algorithms, clinical decision support systems, and other clinical informatics interventions is increasing in critical care. Pediatric acute respiratory distress syndrome (PARDS) is a complex, dynamic condition associated with large amounts of clinical data and frequent decisions at the bedside. Novel data-driven technologies that can help screen, prompt, and support clinician decision-making could have a significant impact on patient outcomes. We sought to identify and summarize relevant evidence related to clinical informatics interventions in both PARDS and adult respiratory distress syndrome (ARDS), for the second Pediatric Acute Lung Injury Consensus Conference. MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). We included studies of pediatric or adult critically ill patients with or at risk of ARDS that examined automated screening tools, electronic algorithms, or clinical decision support systems. Titleabstract review, full text review, and data extraction using a standardized data extraction form. The Grading of Recommendations Assessment, Development and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-six studies were identified for full text extraction to address the PatientInterventionComparatorOutcome questions, and 14 were used for the recommendationsstatements. Two clinical recommendations were generated, related to the use of electronic screening tools and automated monitoring of compliance with best practice guidelines. Two research statements were generated, related to the development of multicenter data collaborations and the design of generalizable algorithms and electronic tools. One policy statement was generated, related to the provision of material and human resources by healthcare organizations to empower clinicians to develop clinical informatics interventions to improve the care of patients with PARDS. We present two clinical recommendations and three statements (two research one policy) for the use of electronic algorithms and clinical informatics tools for patients with PARDS based on a systematic review of the literature and expert consensus.

An Autoantibody Subset Can Be Used for SCLC Early Detection.

Posttranslational modifications induce autoantibodies in small cell lung cancer and predict risk.

Assessing the Impact of Open-Label Designs in Patient-Reported Outcomes Investigation in Oncology Clinical Trials.

Knowledge of treatment assignment may affect patient-reported outcomes (PROs), which is of concern in oncology, where open-label trials are common. This study measured the magnitude of open-label bias by comparing PROs for similar patient groups in oncology trials with different degrees of concealment. Individual patient data from ipilimumab arms of two melanoma and docetaxel arms of two non-small cell lung cancer (NSCLC) trials were adjusted for differences using propensity score weighting. Patients were aware of treatment assignment in CA184-022 and CheckMate 057 (open-label), but not in MDX010-20 and VITAL (blinded). Overall survival (OS) and mean changes from baseline to week 12 in EORTC QLQ-C30 (melanoma) and LCSS (NSCLC) scores were compared between open-label and blinded groups. After adjustment, baseline characteristics were balanced between blinded (melanoma, n 125 NSCLC, n 424) and open-label groups (melanoma, n 69 NSCLC, n 205). Study discontinuation and PRO completion rates at week 12 and OS were similar. There was no clear direction in differences in change scores between groups. In the melanoma trials, role functioning (mean 95% confidence interval CI-5.2-15.4, 5.0), global health status (-1.3-8.7, 6.1), pain (6.2-1.8, 14.2) favored the blinded while emotional functioning (2.2-5.8, 10.2) and diarrhea (-8.3-17.3, 0.7) favored the open-label group. In the NSCLC trials, changes in dyspnea (5.4-0.7, 11.5) favored the blinded and changes in appetite (-1.2-8.1, 5.7) favored the open-label group. None were clinicallystatistically significant. This study adds to the growing evidence demonstrating that concerns regarding open-label bias should not prohibit the interpretation of large and meaningful treatment effects on PROs.

Efficacy and Toxicity of Combined Inhibition of EGFR and VEGF in Patients With Advanced Non-small Cell Lung Cancer Harboring Activating EGFR Mutations A Systematic Review and Meta-analysis.

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways have demonstrated promising results for treatment of advanced non-small cell lung cancer. We conducted a systematic review and meta-analysis to assess the efficacy and toxicity of the combined treatment with EGFR tyrosine kinase inhibitors (TKIs) and VEGF blockade for patients with advanced non-small cell lung cancer harboring activating EGFR mutations, in comparison to EGFR TKIs alone. The electronic databases were searched for relevant randomized trials between 2000 and 2022. The primary endpoints were overall survival (OS) and progression-free survival. Secondary endpoints included objective response rate (ORR), disease control rate, and grade ≥3 adverse events (AEs). The pooled hazard ratios (HR) and odds ratios were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. A total of 1528 patients from 8 trials were evaluated for analyses. The combination treatment decreased the risk of disease progression by 37% (HR0.63 95% CI, 0.56 to 0.72) but had no added benefit on OS compared with EGFR inhibition alone (HR0.90 95% CI, 0.76 to 1.05). There was no significant difference in objective response rate or disease control rate between treatments. There was a significantly increased number of AEs reported in the dual treatment arm (odds ratio3.02 95% CI, 1.71 to 5.31), with proteinuria and hypertension being the most significantly increased AEs. This meta-analysis suggests combined inhibition of EGFR and VEGF pathways significantly improves progression-free survival, with no OS benefit, and increases AEs. Mature OS data are needed along with results from more trials exploring this strategy with third-generation EGFR TKIs to strengthen these results.

Oncology whats new in 2022.

The past year has brought several innovations in medical oncology, opening up promising new options for many solid tumors, both localized and metastatic. Immunotherapy, a real spearhead of emerging therapies in metastatic diseases, is seeing its use extend to adjuvant and neoadjuvant modalities, particularly in colon and lung cancers. 2022 also sees a great deal of focus on targeted therapies, as well as on antibody-drug conjugates, which creates new standards in both breast and lung cancers. Here we present the major advances in solid tumors. L’année écoulée a apporté son lot d’innovations en oncologie médicale, ouvrant de nouvelles options prometteuses pour bon nombre de tumeurs solides, qu’elles soient localisées ou métastatiques. L’immunothérapie, véritable fer de lance des thérapies émergentes dans les maladies métastatiques, voit son usage s’étendre à des modalités adjuvantes et néoadjuvantes, notamment dans les cancers du côlon et du poumon. 2022 donne également la part belle aux thérapies ciblées mais aussi aux conjuguées anticorps-médicaments qui apportent de nouveaux standards tant pour les cancers du sein que du poumon. Nous vous présentons ici les avancées majeures concernant les tumeurs solides.

Angiotensin-(1-7) alleviates acute lung injury by activating the Mas receptor in neutrophil.

Acute lung injury (ALI) is a major cause of mortality and morbidity in the clinic. None of the current pharmacological interventions has achieved a detectable benefit. The renin-angiotensin system (RAS) is a complex humoral system essentially involved in the regulation of ALI. In the RAS family, angiotensin (Ang)-(1-7) was found to provide protection by counteracting the effects of Ang II in various cardiopulmonary disease models. The downstream receptor of Ang-(1-7) is the G protein-coupled receptor (GPCR) Mas. We hypothesize that the Ang-(1-7)-Mas pathway would protect patients from ALI. To establish a 2-hit ALI model, the mice underwent intratracheal instillation of hydrochloric acid followed by ventilator-induced lung injury (VILI). ALI was evaluated based on lung edema, histology, myeloperoxidase activity, and proinflammatory cytokine production. The effects of the infusion or inhalation of Ang-(1-7) and Mas receptor blocker A779 were examined. The human neutrophils were isolated, and Mas receptor expression was examined. The neutrophil responses to platelet-activating factor (PAF) stimulation were tested by measuring the formation of reactive oxygen species (ROS), neutrophil adhesion, and chemotaxis. Next, in the mouse model, the neutrophils were depleted using an anti-ly6G antibody. The infusion or inhalation of Ang-(1-7) protected mice from ALI as evidenced by decreases in lung edema, the histological lung injury score, myeloperoxidase activity, and proinflammatory cytokine production. Such effects were largely blocked by the Mas receptor blocker A779. Mas receptor expression in the neutrophils was identified at both the messenger ribonucleic acid and protein levels. Ang-(1-7) prevented neutrophil responses to PAF stimulation, including the formation of ROS, neutrophil adhesion, and chemotaxis, while A779 alleviated these effects. The importance of neutrophils in ALI was further confirmed by neutrophil depletion using the anti-ly6G antibody however, A779 partially reversed the protective role of neutrophil depletion in ALI, indicating the critical role of Ang-(1-7)-Mas signaling in other pulmonary cells. Ang-(1-7)Mas receptor attenuates the key features of ALI by regulating neutrophil activation. Our study provides new evidence of their role in the pathogenesis of ALI and may lead to the development of a promising therapeutic strategy.

Anlotinib suppresses lung adenocarcinoma growth via inhibiting FASN-mediated lipid metabolism.

Anlotinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, has been widely used in advanced lung cancer patients, but the intrinsic mechanism of cancer cell elimination is not fully disclosed. In this study, we reported that anlotinib suppressed lung adenocarcinoma (LUAD) growth through inhibiting fatty acid synthase (FASN)-mediated lipid metabolism. To investigate the underlying mechanisms of anlotinib, an A549 cell line-derived xenograft model was constructed and a proteomics technique was employed to screen potential markers. Gas chromatography-mass spectrometry (GC-MS) profiling of medium-long chain fatty acid and neutral lipid droplet fluorescence staining were employed to detect lipid metabolism in cancer cells. Subsequently, the effects of anlotinib on FASN expression were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Short hairpin RNA (shRNA) knockdown of FASN was used to assess the role of FASN in the antitumor effect of anlotinib. A patient-derived xenograft (PDX) model was established to validate the efficacy of anlotinib in the patient and IHC staining of FASN was examined. Our data revealed that anlotinib significantly decreased the expression of proteins related to lipid metabolism. GC-MS profiling of medium-long chain fatty acid and neutral lipid droplet fluorescence staining validated that anlotinib could disturb the fatty acid metabolism in cancer cells, especially de novo lipogenesis. Mechanically, the messenger RNA (mRNA) and protein of FASN were down-regulated by anlotinib in A549 cells and FASN knockdown could diminish the antitumor effect of anlotinib Anlotinib could inhibit the growth of LUAD through FASN-mediated lipid metabolism. Our findings provide new insights into the antitumor mechanism of anlotinib in lung adenocarcinoma.