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Neutrophil phenotypes implicated in the pathophysiology of post-traumatic sepsis.

The disruption of immune homeostasis after trauma is a major cause of post-traumatic organ dysfunction andor sepsis. Recently, a variety of neutrophil phenotypes with distinct functions have been identified and suggested as involved in various clinical conditions. The association between neutrophil phenotypes and post-traumatic immunodeficiency has also been reported, yet the specific neutrophil phenotypes and their functional significance in post-traumatic sepsis have not been fully clarified. Therefore, we sought to investigate neutrophil phenotypic changes in a murine model, as these may hold prognostic value in post-traumatic sepsis. Third-degree burns affecting 25% of the body surface area were used to establish trauma model, and sepsis was induced 24 h later through cecal ligation and puncture (CLP). The BurnCLP post-traumatic sepsis model and the ShamCLP control model were established to assess the immunological status after trauma. Histopathological evaluation was performed on the spleen, liver, kidneys, and lung tissues. Immunological evaluation included the assessment of neutrophil markers using mass cytometry as well as cytokine measurements in serum and ascitic fluid through multiplex analysis using LUMINEX The BurnCLP group had a lower survival rate than the ShamCLP group. Histopathological examination revealed an impaired immune response and more advanced organ damage in the BurnCLP group. Furthermore, the BurnCLP group exhibited higher levels of transforming growth factor-beta 1 in the blood and generally lower levels of cytokines than the ShamCLP group. CD11b, which is involved in neutrophil adhesion and migration, was highly expressed on neutrophils in the BurnCLP group. The expression of CD172a, which is related to the inhibition of phagocytosis, was also upregulated on neutrophils in the BurnCLP group. The expression of sialic acid-binding lg-like lectin F and CD68 also differed between the two groups. Different neutrophil phenotypes were observed between BurnCLP and ShamCLP groups, suggesting that neutrophils are implicated in the immune imbalance following trauma. However, further studies are needed to prove the causal relationships between neutrophil phenotypes and outcomes, including survival rate and organ dysfunction.

Dietary factors and the risk of lung cancer by epidermal growth factor receptor mutation status and histological subtypes.

Previous studies have reported differential associations of certain dietary factors such as soy consumption by epidermal growth factor receptor mutant ( A total of 3,170 cases and 4,238 controls from three different studies (Genes and Environment in Lung Cancer Study, Lung Cancer Consortium Singapore Study, and Multi-ethnic Cohort Study) were included. Information on demographics, lifestyle, and dietary consumption was obtained using questionnaires. Diet was assessed by using the number of standard servings of each item consumed per week. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between meat, vegetables, and fruits consumption with lung cancer risk after adjusting for potential confounders. We identified a significant inverse association between higher consumption of fruits and the risk of lung cancer (2nd tertile OR 0.54, 95%CI 0.46-0.65 3rd tertile OR 0.77, 95%CI 0.65-0.91), compared with the lower (1st tertile) consumption of fruits. Higher vegetable consumption was significantly associated with a lower risk of Differential associations between vegetable consumption with

Neuromyelitis optica spectrum disorders associated with AQP4-positive-cancer-A case series.

Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune, astrocytopathic diseases affecting the central nervous system(CNS), especially the central optic nerve and spinal cord. Aquaporin 4-immunoglobulin G (AQP4-IgG) is the dominant pathogenic antibody and can be detected in about 80% of patients with NMOSD. Although only a few cases were reported on NMOSD associated with cancer, they demonstrated the potential paraneoplastic link between cancer and NMOSD. In the present study, we report three NMOSD cases associated with cancer, which are teratoma and lung adenocarcinoma, teratoma, and transverse colon adenocarcinoma, respectively. Pathological staining of tumor sections revealed a high AQP4 expression. After tumor removal, all cases were stable and suffered no further relapses, which revealed the potential paraneoplastic mechanism between cancer and NMOSD. One of our patients serum AQP4-IgG was transiently slightly elevated even though AQP4 was highly expressed in tumor cells, which indicates that AQP4 is not the main pathogenic antibody but might be induced by other underlying pathogenic antibody-antigen reactions.

Circular RNA hsacirc0004689 (circSWT1) promotes NSCLC progression via the miR-370-3pSNAIL axis by inducing cell epithelial-mesenchymal transition (EMT).

Previous studies have reported the role of circular RNAs (circRNAs) in the progression of non-small-cell lung cancer (NSCLC). SWT1-derived circRNAs were confirmed to affect the apoptosis of cardiomyocytes however, the biological functions of SWT1-derived circRNAs in cancers are still unknown. Here, we investigated the potential role of SWT1-derived circRNAs in NSCLC. We used quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression of circSWT1 in NSCLC tissues and paired normal tissues. The potential functions of circSWT1 in tumor progression were assessed by CCK-8, colony formation, wound healing, and matrigel transwell assays in vitro and by xenograft tumor models in vivo. Next, epithelial-mesenchymal transition (EMT) was evaluated by western blotting, immunofluorescence, and immunohistochemistry (IHC). Moreover, circRIP, RNA pulldown assays, luciferase reporter gene assays, and FISH were conducted to illuminate the molecular mechanisms of circSWT1 via the miR-370-3pSNAIL signal pathway. Then, we knocked out SNAIL in A549 and H1299 cells to identify the roles of circSWT1 in the progression and EMT of NSCLC through SNAIL. Finally, circSWT1 functions were confirmed in vivo using xenograft tumor models. CircSWT1 expression was significantly upregulated in NSCLC tissues, and high expression of circSWT1 predicted poor prognosis in NSCLC via survival analysis. In addition, overexpression of circSWT1 promoted the invasion and migration of NSCLC cells. Subsequently, we found that overexpression of circSWT1 induced EMT and that knockdown of circSWT1 inhibited EMT in NSCLC cells. Mechanistically, circSWT1 relieved the inhibition of downstream SNAIL by sponging miR-370-3p. Moreover, we found that these effects could be reversed by knocking out SNAIL. Finally, we verified that circSWT1 promoted NSCLC progression and EMT in xenograft tumor models. CircSWT1 promoted the invasion, migration, and EMT of NSCLC. CircSWT1 could serve as a potential biomarker and a potential therapeutic target for NSCLC.

Clinical correlations with EGFR circulating tumor DNA testing in all-stage lung adenocarcinoma.

Information on genetic alterations, notably EGFR mutations, is important for guiding non-small-cell lung cancer (NSCLC) treatment. Circulating tumor DNA (ctDNA) analysis represents a less invasive alternative to tissue biopsy for analyzing mutation status, but its clinical value may vary across disease stages. To explore clinical correlates of ctDNA and tissueplasma-based EGFR mutation (EGFRm) status across all NSCLC stages. Ninety patients were analyzed, representing three cohorts newly-diagnosed early-stage, advanced-stage, and recurrent NSCLC. Relationships among clinicalsurgical parameters, ctDNA, EGFRm status, and survival outcomes were analyzed. Plasmatissue EGFRm concordance was lower in early-stage (58.6%) than in advanced-stage patients (87.5%). In early-stage patients, ctDNA levels were variable and not significantly associated with clinicalsurgical parameters. In advanced-stage patients, time to EGFR-TKI treatment failure (TTF), but not overall survival (OS), was significantly longer in EGFRm-positive vs. EGFRm-negative patients. In patients with recurrent disease, 40% of plasma samples were EGFRT790M-positive at recurrence. In T790M-positive patients, we noted slight trends toward longer OS with vs. without osimertinib treatment and longer OS and TTF with second-line vs. later-line osimertinib. Our results affirm the use of ctDNA testing in advanced-stage and recurrent NSCLC. Further studies on osimertinib as early-line therapy, clinical correlates and the utility of plasma-based testing in early-stage NSCLC are warranted.

Extensive genomic analysis in patients with

This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across In this descriptive and single-center study, we included 188 patients with solid tumors harboring The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were Performing extensive genomic analysis in patients with known

An Innovative Method Predicting the Visibility of Radial Endobronchial Ultrasound for Peripheral Pulmonary Nodules by Virtual Bronchoscopic Navigation.

LncRNA FAM138B inhibits the progression of non-small cell lung cancer through miR-105-5p.

As a type of lung cancer, non-small cell lung cancer (NSCLC) has the characteristics of high mortality and high recurrence rate, which poses a great threat to human life and health. Due to the high risk of surgical treatment and the slow recovery of wounds, non-coding RNAs, especially lncRNAs are used as new potential clinical prognostic markers to prevent and treat cancer in advance. This study aims to explore the role of FAM138B in NSCLC and its possibility as a prognostic biomarker. Real-timequantitative polymerase chain reaction (RT-qPCR) was used to detect the expression and overexpression level of lncRNA FAM138B (FAM138B) in cells and tissues. The CCK-8, Transwell migration and invasion methods were performed to observe the cell transfection.The interaction between FAM138B and miR-105-5p was predicted by the bioinformatics tool starBase v2.0, and verified by the luciferase reporter gene experiment. Kaplan-Meier and Cox regression analyses were used to determine the prognostic significance of FAM138B in NSCLC. The expression of FAM138B is down-regulated in NSCLC cells and tissues. Overexpression of FAM138B can inhibit the expression level of miR-105-5p in NSCLC cells, and the ability of NSCLC cells to proliferate, migrate and invade is downregulated. FAM138B targets miR-105-5p, and there is a negative correlation between FAM138B and miR-105-5p. It is confirmed that FAM138B inhibits the progression of NSCLC by targeting miR-105-5p and can be a potential prognostic biomarker for NSCLC.

Impact of Sotorasib on the Pharmacokinetics and Pharmacodynamics of Metformin, a MATE12K Substrate, in Healthy Subjects.

The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S. Food and Drug Administration in 2021 for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults who have received at least one prior systemic therapy METHODS This was a phase I, single-center, open-label, three-period, fixed-sequence study. Subjects received single oral doses of metformin 850 mg, sotorasib 960 mg, and metformin 850 mg with sotorasib 960 mg. Urine and plasma were collected and assayed for metformin and sotorasib pharmacokinetics. Blood glucose was also measured for metformin pharmacodynamics. In addition, an in vitro study was conducted to determine whether sotorasib was an inhibitor of MATE12K or OCT2 transport. Geometric least-squares mean ratio of sotorasib area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.910 and 0.812, respectively, when sotorasib was coadministered with metformin compared with administration of sotorasib alone. Geometric least-squares mean ratio of metformin area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.99 and 1.00, respectively, when comparing metformin coadministered with sotorasib to metformin alone. Geometric mean estimates of serum glucose area under the concentration-time curve from time 0 to 2 h following metformin alone, sotorasib alone, and metformin with sotorasib were 179, 222, and 194, respectively. These results demonstrated that coadministration of metformin with sotorasib does not impact sotorasib exposure to a clinically significant extent. Coadministration of sotorasib with metformin does not affect metformin exposure or its antihyperglycemic effect, in contrast to the inhibitory effect observed in vitro. Doses of sotorasib 960 mg and metformin 850 mg were safe and well tolerated when coadministered to healthy subjects.

Targeting regulation of VEGF by BPTF in non-small cell lung cancer and its potential clinical significance.

VEGF facilitates tumor angiogenesis, and bevacizumab targeting VEGF is used in anti-tumor therapy. It is meaningful to clarify the upstream regulatory mechanism of VEGF. BPTF is important in chromosomal remodeling, and promotes the progression of tumors. However, its role in promoting tumor angiogenesis by targeting VEGF has not been fully reported. This study aims to elucidate the expression regulation of VEGF by BPTF and its clinical significance in NSCLC. 1. BPTF siRNA and shRNA plasmids were used to reduce the expression of BPTF by transfection in vivo and in vitro. BPTF, VEGF and CD144 expressions were examined by immunofluorescence and Western Blot. 2. The expressions of BPTF, VEGF, CD144 and CD31 were detected in lung adenocarcinoma samples by immunofluorescence, Western blot and immunohistochemical staining. 3. 26 lung adenocarcinoma patients treated by bevacizumab were divided into 2 groups according to the treatment efficacy. BPTF and VEGF expressions were analyzed. 1. BPTF knockdown inhibited the expression of VEGF and CD144 in vivo and in vitro. 2. Compared with para-cancer tissues, BPTF, VEGF, CD144 and CD31 were highly expressed in lung adenocarcinoma. 3. In 75 lung adenocarcinoma specimens, BPTF and VEGF overexpression was correlated with lymph node metastasis and clinical stage. The 5-year survival rate of patients with BPTF and VEGF low expression was higher, and BPTF expression was positively correlated with VEGF expression. 4. Among 26 patients treated with bevacizumab, the patients with BPTF overexpression are more sensitive to the treatment. BPTF positively regulates VEGF expression and its high expression predicts a better efficacy of bevacizumab treatment in NSCLC.

A rare case of bladder cancer that metastasized to brain, heart, and lung lymph nodes benefited from immunotherapy.

Bladder cancer is a common malignant tumor of the genitourinary system, with the primary cause of death being metastasis. The most common metastatic sites are the lymph nodes, liver, lung, bone, peritoneum, pleura, kidney, adrenal gland, and the intestine. Brain and heart metastases are rare. In this report, we describe a patient who had pulmonary lymph node metastases more than a year after being diagnosed with bladder cancer, followed by brain and cardiac metastases more than two years later. Following the failure of standard first-line chemotherapy, the patient accepted 6 cycles of tislelizumab immunotherapy. The re-examination revealed that the bilateral frontal brain metastases had vanished, the right temporal lobe metastases had been greatly decreased, the neurological symptoms had been alleviated, and the cardiac metastases had disappeared. This is a rare clinical case with encouraging effects of tislelizumab and can serve as a model for the treatment of similar patients.

Targeting the Lysosomal Degradation of Rab22a-NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis.

Rab22a-NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a-NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52-mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63-linked ubiquitin chains on lysine112 of Rab22a-NeoF1, which is responsible for the binding of Rab22a-NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a-NeoF1. PINK1 is able to phosphorylate Rab22a-NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a-NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a-NeoF1. These findings reveal that the lysosomal degradation of Rab22a-NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A-NeoF1 fusion gene.

Idiopathic pulmonary fibrosis and intestinal disorders An observational study.

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by a progressive decline in lung function and a specific histopathologic pattern defined as usual interstitial pneumonia. Early diagnosis and new therapeutic protocols have contributed to a reduction in disease progression. Thus, some patients may develop extrapulmonary diseases including malignancies and chronic pathologies. The aim of this study was to investigate the frequency of intestinal disorders such as polyps, colorectal carcinoma (CRC), and chronic inflammatory bowel disease (IBD) in patients with IPF. From the database of 189 patients with IPF (148 males, 78.3 % 41 females, 21.7 %) residing in the district of Modena, we identified 44 patients (36 males, 81.8 % 8 females, 18.2 %) with a histologically confirmed intestinal disease. Intestinal polyps were detected in 41 cases (93.2 %), of which 4 were associated with CRC and 1 with IBD 1 patient had only CRC (2.3 %), and 2 patients had only IBD (4.5 %). Both males and females developed bowel disease, but males seemed to have a higher number of polyps and high-grade adenomas with a predisposition to malignant transformation. As patients with IPF may present with intestinal diseases that can evolve into malignancies in some cases, they should undergo appropriate follow-up and targeted colorectal screening. Thus, colorectal pathologies should not take a back seat. These preliminary results encourage further research to select suitable patients for specific diagnostic and therapeutic procedures in order to prolong survival and improve the quality of life.

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Ex-vivo 1.5T MR Imaging versus CT in Estimating the Size of the Pathologically Invasive Component of Lung Adenocarcinoma Spectrum Lesions.

The purpose of this study was to investigate whether ex-vivo MRI enables accurate estimation of the invasive component of lung adenocarcinoma. We retrospectively reviewed 32 patients with lung adenocarcinoma who underwent lung lobectomy. The specimens underwent MRI at 1.5T. The boundary between the lesion and the normal lung was evaluated on a 5-point scale in each three MRI sequences, and a one-way analysis of variance and post-hoc tests were performed. The invasive component size was measured histopathologically. The maximum diameter of each solid component measured on CT and MR T1-weighted (T1W) images and the maximum size obtained from histopathologic images were compared using the Wilcoxon signed-rank test. Inter-reader agreement was evaluated using intraclass correlation coefficients (ICC). T1W images were determined to be optimal for the delineation of the lesions (P < 0.001). The histopathologic invasive area corresponded to the area where the T1W ex-vivo MR image showed a high signal intensity that was almost equal to the intravascular blood signal. The maximum diameter of the solid component on CT was overestimated compared with the maximum invasive size on histopathology (mean, 153% P < 0.05), while that on MRI was evaluated mostly accurately without overestimation (mean, 108% P 0.48). The interobserver reliability of the measurements using CT and MRI was good (ICC 0.71 on CT, 0.74 on MRI). Ex-vivo MRI was more accurate than conventional CT in delineating the invasive component of lung adenocarcinoma.

Metabolomics study of ribavirin in the treatment of orthotopic lung cancer based on UPLC-Q-TOFMS.

Ribavirin is a common antiviral drug, especially for patients with hepatitis C. Our recent studies demonstrated that ribavirin showed anti-tumor activity in colorectal cancer and hepatocellular carcinoma, but its effects on lung cancer remains unclear. This study aimed to evaluate the anti-tumor activity of ribavirin against lung cancer and elucidate the underlying mechanism. We established orthotopic mouse model of lung cancer (LLC and GLC-82) and employed an ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOFMS)-based metabolomics approach. We found that ribavirin significantly inhibited the proliferation and colony formation of lung cancer cells. Tumor sizes of orthotopic lung cancer in ribavirin-treated groups were also significantly lower than those in control groups. Metabolomics analysis revealed that ribavirin mainly affected 5 metabolic pathways in orthotopic lung tumor models, taurine and hypotaurine metabolism, nicotinate and nicotinamide metabolism, linoleic acid metabolism, arginine biosynthesis and arachidonic acid metabolism. Furthermore, we identified 5 upregulated metabolites including β-nicotinamide adenine dinucleotide (NAD

Pulmonary Nodules, Lung Cancer Screening, and Lung Cancer in the Medicare Population.

Early detection of lung cancer through management of pulmonary nodules (PNs) may reduce lung cancer mortality. We assessed the relationship between PNs and lung cancer. How common are PNs in the Medicare population What is the rate of lung cancer after detection of PNs What is the relative proportion of early-stage lung cancer diagnosed after reporting of PNs vs through low-dose CT (LDCT) scan screening Using the Surveillance Epidemiology and End Results Program-Medicare database, we defined two cohorts those in the 5% sample with ≥ 12 months of Medicare Parts A and B coverage from 2014 through 2019 (5% sample cohort) and those with a diagnosis of lung cancer from 2015 through 2017 with coverage for the prior 18-month period (lung cancer cohort). We defined PNs as chest CT scans with accompanying codes of 793.11 (International Classification of Diseases ICD, Ninth Revision) or R91.1 (ICD, Tenth Revision) denoting a solitary PN. Patients in the lung cancer cohort were classified by whether they had undergone LDCT scan screening and whether they had a diagnosis of PN or neither (reference) within 18 months before diagnosis. We compared cancer stage and survival across groups. Of 627,547 patients in the 5% sample cohort, 5.0% demonstrated PNs over median of 5.0 years of follow-up. Cumulative 1- and 2-year lung cancer rates after initial PN diagnosis were 3.2% and 4.7%, respectively. Of 44,194 patients in the lung cancer cohort, 15.7%, 2.9%, and 81.4% were in the PN, LDCT scan, and reference groups, respectively. Of patients in the PN, LDCT scan, and reference groups, 58.1%, 50.3%, and 24.4% respectively, had disease of a localized stage. Among all patients with localized disease, 30.0% and 4.9% were in the PN and LDCT scan and groups, respectively. Three-year lung cancer-specific survival rates were 75.0%, 75.6%, and 49.4% for the PN, LDCT scan, and reference groups. Patients with lung cancer who received a diagnosis after identification of PNs tended to have localized disease. Of all patients with localized disease, almost one-third had PNs that were diagnosed previously, compared with 5% of patients who had undergone LDCT scan screening. PNs represent a relatively common presentation of potentially curable lung cancer.

Mapping the landscape of lung cancer breath analysis A scoping review (ELCABA).

Lung cancer is the leading cause of cancer death worldwide due to its late-stage detection. Lung cancer screening, including low-dose computed tomography (low-dose CT), provides an initial clinical solution. Nevertheless, further innovations and refinements would help to alleviate remaining limitations. The non-invasive, gentle, and fast nature of breath analysis (BA) makes this technology highly attractive to supplement low-dose CT for an improved screening algorithm. However, BA has not taken hold in everyday clinical practice. One reason might be the heterogeneity and variety of BA methods. This scoping review is a comprehensive summary of study designs, breath analytical methods, and suggested biomarkers in lung cancer. Furthermore, this synthesis provides a framework with core outcomes for future studies in lung cancer BA. This work supports future research for evidence synthesis, meta-analysis, and translation into clinical routine workflows.

Patient specific evaluation of breathing motion induced interplay effects.

In lung SABR, interplay between target motion and dynamically changing beam parameters can affect the target coverage. To identify the potential need for motion-management techniques, a comprehensive methodology for pre-treatment estimation of interplay effects has been implemented. In conjunction with an alpha-version of VeriSoft and OCTAVIUS 4D (PTW-Freiburg, Germany), a method is presented to calculate a virtual, motion-simulated 3D dose distribution based on measurement data acquired in a stationary phantom and a subsequent correction with time-dependent target-motion patterns. In-house software has been developed to create user-defined motion patterns based on either simplistic or real patient-breathing patterns including the definition of the exact beam starting phase. The approach was validated by programmed couch and phantom motion during beam delivery. Five different breathing traces with extremely altered beam-on phases (0 % and 50 % respiratory phase) and a superior-inferior motion altitude of 25 mm were used to probe the influence of interplay effects for 14 lung SABR plans. Gamma analysis (2 %2mm) was used for quantification. Validation measurements resulted in >98 % pass rates. Regarding the interplay effect evaluation, gamma pass rates of <92 % were observed for sinusoidal breathing patterns with <25 number of breaths per delivery time (NBs) and realistic patterns with <18 NBs. The potential influence of interplay effects on the target coverage is highly dependent on the patients breathing behaviour. The presented moving-platform-free approach can be used for verification of ITV-based treatment plans to identify whether the clinical goals are achievable without explicit use of a respiratory management technique.

Patient impressions of the impact of comorbidities on lung cancer screening benefits and harms A qualitative analysis.

To learn about the beliefs and preferences of lung cancer screening (LCS) among patients undergoing LCS decision making. Specifically, we investigated how their comorbidity influences their interest in screening. The goal was to inform shared-decision making discussions around the role of comorbidities and LCS. We recruited English-speaking LCS-eligible individuals with comorbidities from general medicine outpatient clinics at an academic medical center in New York City. The interviewers followed a semi-structured interview guide and all interviews were professionally transcribed. Study investigators independently conducted thematic analysis of de-identified transcripts after coding, investigators discussed and agreed upon identified themes (Jacobs et al., 1999 3). This study was IRB-approved. We achieved thematic saturation after 15 interviews. We identified the following themes 1) Comorbidities were perceived as unrelated to LCS decision-making, 2) Lung cancer knowledge is valuable and worth any risks, 3) No matter what the guidelines or my providers say, the LCS decision is up to me. Implications of these findings are that conversations where providers recommend against LCS may likely require time, patient education, and appreciation of the patient perspective.

NMNAT2 An important metabolic enzyme affecting the disease progression.

Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an evolutionarily conserved nicotinamide adenine dinucleotide (NAD

Parathyroid carcinoma Report of 10 patients and literature review.

Parathyroid carcinoma (PC) is a rare disease with high rates of misdiagnosis and recurrence. This report summarized the clinical and pathological characteristics of 10 patients with PC at our hospital, to improve the early recognition and prognosis of PC. The clinical manifestations, imaging findings, pathological features, treatments, and prognostic data of 10 patients diagnosed with PC at the First Medical Center, Chinese PLA General Hospital from 2003 to 2021 were analyzed. There were 7 male and 3 female patients with PC whose average age was 41.4 ± 9.4 years. All patients had bone involvement (bone pain andor osteoporosis), meanwhile 6 patients had kidney stones and 7 patients had palpable neck masses. Five patients presented with tumor metastasis, invading lymph nodes, lung, liver, or bone. Laboratory examinations revealed elevated serum total calcium (4.15 ± 0.81 mmolL), parathyroid hormone (PTH, 1236.1 ± 519.9 pgmL) and alkaline phosphatase (405.8 ± 219.0 IUL) levels. Especially, hypercalcemic crisis occurred in 9 patients. The diagnosis of PC depended on histopathological features of the parathyroid tumor, including capsular andor vascular invasion. All patients underwent at least en bloc resection. In the follow-up, six patients with relatively high preoperative PTH levels (1519.5 ± 436.8 pgmL) relapsed postoperatively. Two patients with the Ki-67 index ≥ 10% in parathyroid tumor tissue and distant metastasis died within 2 years after the operation. Severe bone pain, kidney stones, hypercalcemic crisis, and markedly elevated PTH usually indicate PC. A markedly elevated PTH level, tumor metastasis, and the Ki-67 index ≥ 10% may be indicators of poor prognosis.

Serum microRNAs as new criteria for referral to early palliative care services in treatment-naïve advanced cancer patients.

A major obstacle to the implementation of early palliative care (EPC) is the lack of objective criteria for referral to EPC. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers. The present study investigated objective definitions for referral to EPC using microRNA. A total of 178 serum samples were obtained from patients with lung, gastrointestinal, colorectal, bile duct, pancreas and bladder cancers who were treatment-naïve and received chemotherapy between January 2011 and December 2013 at National Cancer Center Hospital East. We investigated expression levels of miRNAs using microarrays. The primary outcome was prediction of admission to a palliative care unit ≤6 months after first visit. Diagnostic models using clinical characteristics, miRNAs and combinations of both were constructed. The miRNA models were constructed using 6 miRNA levels. The best areas under the receiver operating characteristic curve (AUCs) of the clinical model was 0.741, while the average AUCs of miRNA-based models and combination models were 0.769 and 0.806, respectively. Combination models showed higher AUCs than the clinical model (

Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer.

RNA-binding proteins (RBPs) have emerged as important players in multiple biological processes including transcription regulation, splicing, R-loop homeostasis, DNA rearrangement, miRNA function, biogenesis, and ribosome biogenesis. A large number of RBPs had already been identified by different approaches in various organisms and exhibited regulatory functions on RNAs fate. RBPs can either directly or indirectly interact with their target RNAs or mRNAs to assume a key biological function whose outcome may trigger disease or normal biological events. They also exert distinct functions related to their canonical and non-canonical forms. This review summarizes the current understanding of a wide range of RBPs functions and highlights their emerging roles in the regulation of diverse pathways, different physiological processes, and their molecular links with diseases. Various types of diseases, encompassing colorectal carcinoma, non-small cell lung carcinoma, amyotrophic lateral sclerosis, and Severe acute respiratory syndrome coronavirus 2, aberrantly express RBPs. We also highlight some recent advances in the field that could prompt the development of RBPs-based therapeutic interventions.

Staplers versus energy devices for the intersegmental plane separation in thoracoscopic segmentectomy a comparative study.

In segmentectomy, in addition to the anatomy of the segmental hilum, the identification and separation of the intersegmental plane is also an important step of the operation. Because of its simplicity and high efficiency, most thoracic surgeons choose the staplers. But the energy devices also have its unique advantages in the separation of the intersegmental plane. This study compared the clinical efficacy of staplers and energy devices in the separation of the intersegmental planes during the uniport thoracoscopic segmentectomy through the clinical data. Clinical data of 89 patients undergoing uniport VATS lung segmentectomy from January 2019 to October 2020 at the First Affiliated Hospital of Soochow University were analyzed retrospectively. According to the different treatment methods of intersegmental plane, the patients were divided into two groups, 55 in the stapler group and 34 in the energy device group. The clinical data of the two groups were compared and analyzed statistically. And the univariate and multivariate logistic regression were also used to explore the influencing factors of postoperative complications. Lung segmentectomy was successfully operated in both groups. There were statistically significant differences in operative duration, number of staplers used, surgical expenses and postoperative complications (P < 0.05). In terms of general data, including tumor location, operative hemorrhage, drainage volume on the first postoperative day, total postoperative drainage volume, postoperative chest tube retention duration, postoperative hospital stay, postoperative blood routine indexes, and postoperative pulmonary function indexes after 3 months, no significant differences were observed (P > 0.05). Smoking history (OR 5.08, 95% CI 1.05-24.56, P 0.043) and intersegmental plane treatment (OR 3.18, 95% CI 1.11-9.14, P 0.031) were risk factors for postoperative complications. Patients of the energy device group had a higher incidence of postoperative complications. In uniport thoracoscopic segmentectomy, the use of energy devices to treat the intersegmental plane will result in longer operative duration and higher postoperative complication rate, but it does not affect postoperative recovery and can help reduce surgical expenses. Both methods are safe and reliable. Clinically, the two methods can be reasonably selected according to the specific situation.

Incidence of and risk factors for non-hematologic toxicity with combined radiotherapy and CDK46 inhibitors in metastatic breast cancer using dose-volume parameters analysis a multicenter cohort study.

There is a lack of data on combined radiotherapy (RT) and cyclin-dependent kinase 4 and 6 inhibitor (CDK46i) risk factors and toxicity. This study aimed to assess the incidence of and risk factors for non-hematologic toxicities in patients treated with combined RT and CDK46i using dose-volume parameter analysis. We conducted a retrospective multicenter cohort study of patients with metastatic breast cancer receiving RT within 14 days of CDK46i use. The endpoint was non-hematologic toxicities. Patient characteristics and RT treatment planning data were compared between the moderate or higher toxicities (≥ grade 2) group and the non-moderate toxicities group. Sixty patients were included in the study. CDK46i was provided at a median daily dose of 125 mg and 200 mg for palbociclib and abemaciclib, respectively. In patients who received concurrent RT and CDK46i (N 29), the median concurrent prescribed duration of CDK46i was 14 days. The median delivered RT dose was 30 Gy and 10 fractions. The rate of grade 2 and 3 non-hematologic toxicities was 30% and 2%, respectively. There was no difference in toxicity between concurrent and sequential use of CDK46i. The moderate pneumonitis group had a larger lung V20 equivalent dose of 2 Gy per fraction and planning target volume than the non-moderate pneumonitis group. Moderate toxicities are frequent with combined RT and CDK46i. Caution is necessary concerning the combined RT and CDK46i. Particularly, reducing the dose to normal organs is necessary for combined RT and CDK46i.

Risk of secondary tumours in patients with non-metastatic and metastatic human retinoblastoma.

Retinoblastoma is an intraocular cancer in children and infants. Despite all the available treatment options and high survival rates in children with retinoblastoma, exposure to secondary tumours in adulthood is one of the concerns that physicians face. In many cases, dysfunction of the RB1 gene is the main cause of secondary tumours due to retinoblastoma. Therefore, the aim of this study was to evaluate the incidence of other secondary tumours in children with retinoblastoma. In this regard, we performed continuous and integrated bioinformatics analyses to find genes, protein products, and signal pathways involved in other cancers. 1170 high-expression genes and 960 low-expression genes between non-invasive and invasive retinoblastoma were isolated. After examining the signal pathways, we observed bladder cancer and small cell lung cancer in the overexpressed genes. We also observed 5 cancers of endometriosis, prostate, non-small cell lung cancer, glioblastoma and renal cell carcinoma in low-expression genes. Based on the P-value index, non-small cell lung cancer, prostate and bladder cancers had the highest risk, and endometriosis cancer showed a lower probability of developing a secondary tumour in patients with retinoblastoma. In addition, the network between proteins also showed us that TP53, CDK2, SRC, MAPK1 proteins with high expression and JUN, HSP90AA1, and UBC proteins with low-expression play a significant role in candidate cancers. Lastly, we used continuous bioinformatics analysis to show that seven cancers are strongly linked to retinoblastoma cancer. Of course, more research is needed to find the best way to care for children who have been treated for retinoblastoma.

Diabetes mellitus degenerates cisplatin-induced nephrotoxicity in short hydration method a propensity score-matching analysis.

Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mgm

USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity.

Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. Kras

Effect of EGFR amplification on the prognosis of EGFR-mutated advanced non-small-cell lung cancer patients a prospective observational study.

Epidermal growth factor receptor (EGFR) amplification refers to the copy number increase of EGFR gene, and is often identified as a bypass way of Epidermal growth factor receptor Tyrosine kinase inhibitors (EGFR-TKI) resistance. We aimed to explore the effect of EGFR amplification on EGFR mutation treatment-naive advanced non-squamous non-small cell lung cancer (NSCLC) patients. We conducted a prospective observational study in single center, enrolling advanced non-squamous NSCLC patients receiving Tyrosine kinase inhibitors (TKIs) between March 3, 2019, and February 1, 2022. Next-generation sequencing (NGS) was used to detect genetic alterations in tumor tissue samples. Progression-free survival (PFS) curves were performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate factors affecting the efficacy of TKIs. A total of 117 treatment-naive advanced NSCLC patients were identified in this study. EGFR amplification was found in 22 of 117 (18.8%) patients with EGFR mutations. Of 22 patients with EGFR amplification, 10 patients harbored EGFR 19 del, 11 patients with 21-L858R. The median follow-up time was 22.47 months. The median PFS of the patients with or without EGFR amplification was 8.25 months and 10.67 months, respectively (log-rank test, P 0.63). In multivariate analysis, EGFR amplification was not an independent prognosis factor for the patients receiving first-line TKIs HR 1.38, 95%CI (0.73-2.58), P 0.321. Subgroup analysis revealed that EGFR amplification is a risk factor for progression in the brain metastasis population. HR 2.28, 95%CI (1.01, 5.14), P 0.047. EGFR amplification is not an independent prognosis factor for PFS in advanced non-squamous NSCLC patients receiving first-line TKIs. However, it is an independent risk factor for PFS in the brain metastasis population.

Establishing a whole blood CD4

Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62L The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments. The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.

A Phase I, Open-Label, Dose Confirmation, Escalation, and Expansion Trial of BI 1810631 as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations.

BI 1810631 is a human HER2-selective tyrosine kinase inhibitor that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertion mutations, whilst sparing EGFR signaling. This phase IaIb, open-label, non-randomized study will determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 1810631 in patients with HER2 aberration-positive solid tumors (NCT04886804). In phase Ia, patients with histologicallycytologically confirmed HER2 aberration-positive advancedmetastatic solid tumors will receive BI 1810631 orally twice daily (BID) or once daily (QD) at escalating doses. Starting dose level is 15 mg BID QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee. Dose escalation will continue until MTDrecommended phase II dose and preferred phase Ib schedule for each schedule is determined. In phase Ib, patients with HER2 tyrosine kinase domain (TKD) mutation-positive non-small cell lung cancer (NSCLC) who have previously received ≥1 line of systemic therapy will be enrolled initially, with possible inclusion of additional NSCLC cohorts in the future, including untreated patients. The primary endpoints will be MTD based on number of dose-limiting toxicities (DLTs)number of patients with DLTs (phase Ia) and objective response (phase Ib). Secondary endpoints include PK parameters (phase IaIb) duration of response, disease control, duration of disease control, and progression-free survival (phase Ib). BI 1810631 could be an effective and tolerable EGFR-sparing oral treatment for patients with HER2 mutation-positive NSCLC, including exon 20 insertion mutations. NCT04886804.

The role of endoscopy in exploration of the mediastinum, indications and results.

Since 2005, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a standard pulmonological tool. The procedure is safe and well tolerated by patients, with minimal morbidity and almost no mortality. A previous review on the technique was published in 2012. However, over the last ten years, a number of new studies have been published on benign (sarcoidosis, tuberculosis…) as well as malignant diseases (lung cancer, metastases of extra-thoracic cancers, search for mutations and specific oncogenic markers…). These developments have led to expanded indications for EBUS-TBNA, with which it is indispensable to be familiar, in terms of staging as well as diagnosis. In view of optimizing lymph node sampling, several publications have described and discussed EBUS exploration by means of newly available tools (biopsy forceps, larger needles…), and proposed interpretation of the images thereby produced. Given the ongoing evolution of linear EBUS, it seemed indispensable that information on this marvelous tool be updated. This review is aimed at summarizing the novel elements we have found the most important.

Retrospective study of outcomes after extended resection for tracheobronchial adenoid cystic carcinoma.

Tracheobronchial adenoid cystic carcinoma is a rare, slow-growing malignancy with a considerable propensity for local extension that may require complex airway resection to achieve tumor-free margins. The objective of this study was to assess whether our experience supports complex airway resection for tracheobronchial adenoid cystic carcinoma. Consecutive patients who underwent curative resection for tracheobronchial adenoid cystic carcinoma at our institution between 1970 and 2019 were included retrospectively and classified as having had complex or standard resection. Complex surgery included total tracheal replacement, associated esophageal resection, pneumonectomy, total laryngectomy with tracheal resection, and carinal resection. Standard surgery included tracheal resection, bronchoplastic resection, lobectomy, and bilobectomy. We obtained data from medical records, referring physicians, patients, relatives, and public death records. Of 59 included patients, 38 had complex and 21 had standard surgery. All 4 (6.8%) patients who died postoperatively had undergone complex surgery. Postoperative morbidity was 32.2% overall and was significantly higher after complex surgery (P .043). Overall 5- and 10-year survival rates were 81.5% and 60.2%, with no significant differences between groups (P .31). By univariate analysis, T4 tumor and microscopically detectable tumor in the operative specimen margins and gross tumor in the operative specimen margins were associated with poorer survival (P < .05). In the subgroup with microscopically detectable tumor resection, survival was significantly better with adjuvant radiotherapy (P < .05). Complex resection for extended tracheobronchial adenoid cystic carcinoma may achieve local control and satisfying long-term survival. However, this demanding procedure is associated with high postoperative morbidity and mortality rates. Because adjuvant radiotherapy improved outcomes after resection resulting in microscopically detectable tumor in the operative specimen margins, expected outcomes after resection with no detectable tumor in the margins must be compared to those after resection resulting in microscopically detectable tumor in the margins plus radiotherapy, according to the operative risk.

Clinicopathologic outcomes of preoperative targeted therapy in patients with clinical stage I to III non-small cell lung cancer.

Targeted therapy improves outcomes in patients with advanced-stage non-small cell lung cancer (NSCLC) and in the adjuvant setting, but data on its use before surgery are limited. We sought to investigate the safety and feasibility of preoperative targeted therapy in patients with operable NSCLC. We retrospectively reviewed 51 patients with clinical stage I to III NSCLC who received targeted therapy, alone or in combination with chemotherapy, before surgical resection with curative intent, treated from 2004 to 2021. The primary outcome was the safety and feasibility of preoperative targeted therapy secondary outcomes included objective response rate, major pathologic response (defined as ≤10% viable tumor) rate, recurrence-free survival (RFS), and overall survival. Of the 51 patients included, 46 had an activating epidermal growth factor receptor gene alteration and 5 had an anaplastic lymphoma kinase fusion. Overall, 37 of 46 evaluable patients experienced at least 1 adverse event before surgery however, only 3 patients experienced a grade 3 or 4 event. The objective response rate was 38% (1745) for all evaluable patients and 44% (1432) for patients with clinical stage II or III disease. The major pathologic response rate was 20% (944) 2 patients had a complete pathologic response. Median RFS was 3.8 years (95% CI, 2.8 to not reached). Targeted therapy alone was associated with better RFS than combination therapy (P .009) in patients with clinical stage II or III disease. Preoperative targeted therapy was well tolerated and associated with good outcomes, with or without induction chemotherapy. In addition, radiographic response and pathologic response were strongly correlated.

The role of FOXP3 in non-small cell lung cancer and its therapeutic potentials.

Although in the last few decades we have witnessed the rapid development of treatments for non-small cell lung cancer (NSCLC), it still remains the leading cause of cancer-related death. Increasing efforts have been devoted to exploring potential biomarkers and molecular targets for NSCLC. Foxp3, a transcription factor that was discovered as a master regulator of regulatory T cells (Tregs), has been found to express abnormally in tumoral cells including lung cancer cells. In recent years, increasing evidence have surfaced, revealing the carcinogenic effect of FOXP3 in lung cancer. In this review, we analyzed and summarized the function of FOXP3, its regulation and therapeutic potentials in NSCLC, with a hope to facilitate the development of novel treatments for NSCLC.

Autoantibody signatures discovered by HuProt protein microarray to enhance the diagnosis of lung cancer.

This study aims to discover novel autoantibodies against tumor-associated antigens (TAAs) and establish diagnostic models for assisting in the diagnosis of lung cancer and discrimination of pulmonary nodules (PNs). Ten autoantibodies to TAAbs (TAAbs) were discovered by means of protein microarray and their serum level was also higher in 212 LC patients than that in 212 NC of validation cohort 1 (P < 0.05). The model 1 comprising 4 TAAbs and CEA reached an AUC of 0.813 (95%CI 0.762-0.864) for diagnosing LC from normal individuals. Five TAAbs existed a significant difference between 105 malignant pulmonary nodules (MPNs) and 105 benign pulmonary nodules (BPNs) patients in validation cohort 2 (P < 0.05). Model 2 could distinguish MPNs from BPNs with an AUC of 0.845. High-throughput protein microarray is an efficient approach in discovering novel TAAbs which could be used as biomarkers in lung cancer diagnosis.

Tobacco Smoking-Related Mutational Signatures in Classifying Smoking-Associated and Nonsmoking-Associated NSCLC.

Patient-reported smoking history is frequently used as a stratification factor in NSCLC-directed clinical research. Nevertheless, this classification does not fully reflect the mutational processes in a tumor. Next-generation sequencing can identify mutational signatures associated with tobacco smoking, such as single-base signature 4 and indel-based signature 3. This provides an opportunity to redefine the classification of smoking- and nonsmoking-associated NSCLC on the basis of individual genomic tumor characteristics and could contribute to reducing the lung cancer stigma. Whole genome sequencing data and clinical records were obtained from three prospective cohorts of metastatic NSCLC (N 316). Relative contributions and absolute counts of single-base signature 4 and indel-based signature 3 were combined with relative contributions of age-related signatures to divide the cohort into smoking-associated (smoking high) and nonsmoking-associated (smoking low) clusters. The smoking high (n 169) and smoking low (n 147) clusters differed considerably in tumor mutational burden, signature contribution, and mutational landscape. This signature-based classification overlapped considerably with smoking history. Yet, 26% of patients with an active smoking history were included in the smoking low cluster, of which 52% harbored an EGFRALKRETROS1 alteration, and 4% of patients without smoking history were included in the smoking high cluster. These discordant samples had similar genomic contexts to the rest of their respective cluster. A substantial subset of metastatic NSCLC is differently classified into smoking- and nonsmoking-associated tumors on the basis of smoking-related mutational signatures than on the basis of smoking history. This signature-based classification more accurately classifies patients on the basis of genome-wide context and should therefore be considered as a stratification factor in clinical research.

Biochemical characterization and anti-cancer activity of tangential flow filtration system assisted purification of fucoglucan from Laminaria japonica.

Polysaccharide from Laminaria japonica (LJPS) exhibits multiple biological functions. However, we found that crude LJPS doesnt show good anti-lung cancer activity in this study. We therefore used tangential flow filtration (TFF) system to optimize the anticancer activity of LJPS. We divided the crude LJPS into two fractions by TFF system with a 10 kDa filter and denoted as retentate (10K-R) and filtration (10K-F). The chemical assay revealed that the main molecular mass of 10K-R and 10K-F is about 985 and 3 kDa, respectively. The main components of 10K-R include fucose (19.3 %), and glucose (59.5 %) while glucose (88.6 %) is a major component of 10K-F. Biological functions showed that 10K-R but not 10K-F inhibited the viability and mobility of cancer cells. 10K-R downregulated expressions of transforming growth factor β receptor and Slug, and inhibited intracellular signaling molecules, including FAK, AKT, ERK12, and Smad2. This study is the first concept to purify the polysaccharide by TFF system and showed the potential mechanism of 10K-R inhibited cancer cells.

Repositioning itraconazole for amelioration of bleomycin-induced pulmonary fibrosis Targeting HMGB1TLR4 Axis, NLRP3 inflammasomeNF-κB signaling, and autophagy.

Bleomycin (BLM) is one of the antitumor medications that had proven efficacy in the treatment of a wide range of malignant conditions. Pulmonary fibrosis which is frequently encountered during the course of bleomycin therapy may significantly reduce the potential efficacy of bleomycin in cancer therapy. This study tested the hypothesis that itraconazole may have mitigating effects on BLM-induced pulmonary fibrosis and tried to delineate the potential mechanisms of these effects. In a rat model of pulmonary fibrosis elicited by BLM, the effect of different doses of itraconazole was explored at the biochemical, histopathological, and electron microscopic levels. Itraconazole, in a dose-dependent manner, exhibited significant effects on the pro-oxidantantioxidant balance, the inflammatory consequences, high-mobility group box 1toll-like receptor-4 Axis, autophagy and nuclear factor kappa BNod-like receptor protein 3 inflammasome signaling and alleviated the histopathological, immunohistochemical, and electron microscopic perturbations induced by BLM in the pulmonary tissues. In view of the afore-mentioned data, itraconazole may be a promising drug that efficiently mitigates the deleterious effects of BLM on the pulmonary tissues.

Proteomic analysis of brain metastatic lung adenocarcinoma reveals intertumoral heterogeneity and specific alterations associated with the timing of brain metastases.

Brain metastases are associated with considerable negative effects on patients outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases. Proteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259. Out of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. Pathways associated with the immune system, cell-cellmatrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases. This is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.

Osimertinib-tolerant lung cancer cells are susceptible to ferroptosis.

Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs), such as osimertinib, show great success in non-small-cell lung cancer patients with EGFR mutated tumors. However, almost all patients develop resistance to EGFR-TKIs owing to secondary EGFR mutations. Although genetic and irreversible resistance mechanisms have been proposed, little is known about non-genetic and reversible resistance mechanisms. From this perspective, a recent study revealed that acute drug exposure generates drug-tolerant persister cells (DTPs) as a form of non-genetic resistance. However, the biological characteristics of DTPs remain unclear. As lipid peroxidation is related to cancer progression and drug resistance, we focused on ferroptosis, namely programmed cell death induced by the accumulation of lipid peroxides, in DTPs. We examined the biological characteristics of ferroptosis in osimertinib-mediated DTPs derived from PC9 lung adenocarcinoma cells. Unlike PC9 cells, established PC9 DTPs were highly sensitive to the ferroptosis inducer RSL3. Accordingly, PC9 DTPs had increased levels of lipid reactive oxygen species and ferrous ion accumulation. Moreover, RSL3-mediated cell death in PC9 DTPs was completely rescued by treatment with the iron chelator deferoxamine. These results suggest that PC9 DTPs showed increased intracellular ferrous ion accumulation and were susceptible to ferroptosis.

Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies.

The most severe alterations in Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection are seen in the lung. However, other organs also are affected. Here, we report histopathologic findings in the liver and detection of viral proteins and RNA in COVID-19 autopsies performed at the Semmelweis University (Budapest, Hungary). Between March 2020 through March 2022, 150 autopsies on patients who died of COVID-19 were analyzed. Cause-of-death categories were formed based on the association with SARS-CoV-2 as strong, contributive, or weak. Samples for histopathologic study were obtained from all organs, fixed in formalin, and embedded in paraffin (FFPE). Immunohistochemical study (IHC) to detect SARS-CoV-2 spike protein and nucleocapsid protein (NP), CD31, claudin-5, factor VIII, macrosialin (CD68), and cytokeratin 7, with reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization (ISH, RNAscope®) for SARS-CoV-2 RNA were conducted using FFPE samples of livers taken from 20 autopsies performed ≤ 2 days postmortem. All glass slides were scanned the digital images were evaluated by semiquantitative scoring and scores were analyzed statistically. Steatosis, single-cell and focalzonal hepatocyte necrosis, portal fibrosis, and chronic inflammation were found in varying percentages. Sinusoidal ectasia, endothelial cell disruption, and fibrin-filled sinusoids were seen in all cases these were assessed semiquantitatively for severity (SEF scored). SEF scores did not correlate with cause-of-death categories (p 0.92) or with severity of lung alterations (p 0.96). SARS-CoV-2 RNA was detected in 1320 cases by PCR and in 920 by ISH, with IHC demonstration of spike protein in 420 cases and NP in 1520. Viral RNA and proteins were located in endothelial and Kupffer cells, and in portal macrophages, but not in hepatocytes and cholangiocytes. In conclusion, endothelial damage (SEF scores) was the most common alteration in the liver and was a characteristic, but not specific alteration in COVID-19, suggesting an important role in the pathogenesis of COVID-19-associated liver disease. Detection of SARS-CoV-2 RNA and viral proteins in liver non-parenchymal cells suggests that while the most extended primary viral cytotoxic effect occurs in the lung, viral components are present in other organs too, as in the liver. The necrosisapoptosis and endothelial damage associated with viral infection in COVID-19 suggest that those patients who survive more severe COVID-19 may face prolonged liver repair and accordingly should be followed regularly in the post-COVID period.

Feature selection methods and predictive models in CT lung cancer radiomics.

Radiomics is a technique that extracts quantitative features from medical images using data-characterization algorithms. Radiomic features can be used to identify tissue characteristics and radiologic phenotyping that is not observable by clinicians. A typical workflow for a radiomics study includes cohort selection, radiomic feature extraction, feature and predictive model selection, and model training and validation. While there has been increasing attention given to radiomic feature extraction, standardization, and reproducibility, currently, there is a lack of rigorous evaluation of feature selection methods and predictive models. Herein, we review the published radiomics investigations in CT lung cancer and provide an overview of the commonly used radiomic feature selection methods and predictive models. We also compare limitations of various methods in clinical applications and present sources of uncertainty associated with those methods. This review is expected to help raise awareness of the impact of radiomic feature and model selection methods on the integrity of radiomics studies.

Expression of paired box 9 defines an aggressive subset of lung adenocarcinoma preferentially occurring in smokers.

A distinct subset of lung adenocarcinomas (LADs), arising from a series of peripheral lung cells defined as the terminal respiratory unit (TRU), is characterised by thyroid transcription factor 1 (TTF-1) expression. The clinical relevance of transcription factors (TFs) other than TTF-1 remains unknown in LAD and was explored in the present study. Seventy-one LAD samples were subjected to high-throughput transcriptome screening of LAD using cap analysis gene expression (CAGE) sequencing data CAGE provides genome-wide expression levels of the transcription start sites (TSSs). In total, 1083 invasive LAD samples were subjected to immunohistochemical examination for paired box 9 (PAX9) and TTF-1 expression levels. PAX9 is an endoderm development-associated TF that most strongly and inversely correlates with the expression of TTF-1 TSS subsets. Immunohistochemically, PAX9 expression was restricted to the nuclei of ciliated epithelial and basal cells in the bronchi and bronchioles and the nuclei of epithelial cells of the bronchial glands moreover, PAX9 expression was observed in 304 LADs (28%). PAX9-positive LADs were significantly associated with heavy smoking, non-lepidic subtype, EGFR wild-type tumours and PD-L1 expression (all P < 0.0001). All these characteristics were opposite to those of TRU-type LADs with TTF-1 expression. PAX9 expression was an independent prognostic factor for decreased overall survival (P 0.022). Our results revealed that PAX9 expression defines an aggressive subset of LADs preferentially occurring in smokers that may arise from bronchial or bronchiolar cells.

CT-guided placement of microcoil end in the pleural cavity for video-assisted thoracic surgical resection of ground-glass opacity a retrospective study.

The aim of the study was to investigate and summarize the effectiveness and safety of CT-guided microcoil localization before video-assisted thoracic surgery (VATS) for the removal of ground-glass opacity (GGO). A total of 147 patients with GGO who were treated at our hospital between January 2019 and February 2021 were retrospectively analyzed. They were divided into two groups according to the final position at the end of the microcoil intracavity (n 78) and extracavity (n 69), which were compared based on puncture complications and influence of the coil end position on VATS. The proportions of supine and prone positions in the intracavity group were significantly higher than those in the extracavity group (82.1% vs. 66.7%, P < 0.05). The incidence of intrapulmonary hemorrhage, chest pain, and coil displacement in the intracavity group was significantly lower than that in the extracavity group (28.2% vs. 46.4%, 19.2% vs. 39.1%, 1.3% vs. 11.6%, P < 0.05, respectively) however, the incidence of pneumothorax was not significantly different (P > 0.05). The time of VATS and the rate of conversion to thoracotomy in the intracavity group were significantly lower than those in the extracavity group (103.4 ± 21.0 min vs. 112.2 ± 17.3 min, 0% vs. 5.8%, P < 0.05, respectively). CT-guided placement of the microcoil is a practical, simple, and convenient localization method before VATS, with a high success rate and few complications. Furthermore, it is a better alternative method to place the end of the coil in the pleural cavity because of the lower complication rate, shorter VATS time, and lower rate of thoracotomy conversion.

Association of CYP19A1 rs28757157 polymorphism with lung cancer risk in the Chinese Han population.

Lung cancer is the leading cause of cancer death globally. Recent studies have revealed that CYP19A1 gene plays a crucial role in cancer initiation and development. The aim of this study was to assess the association of CYP19A1 genetic polymorphisms with the risk of lung cancer in the Chinese Han population. This study randomly recruited 489 lung cancer patients and 467 healthy controls. The genotypes of four single nucleotide polymorphisms (SNPs) of the CYP19A1 gene were identified by the Agena MassARRY technique. Genetic model analysis was used to assess the association between genetic variations and lung cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the effect of four selected SNPs on lung cancer risk. CYP19A1 rs28757157 might contribute to an increased risk of lung cancer (p 0.025, OR 1.30, 95% CI 1.03-1.64). In stratified analysis, rs28757157 was associated with an increased cancer risk in the population aged under 60 years, females, smokers, and drinkers. Besides, rs3751592 and rs59429575 were also identified as risk biomarkers in the population under 60 years and drinkers. Meanwhile, a relationship between an enhanced risk of squamous cell carcinoma and rs28757157 was found, while the rs3751592 CC genotype was identified as a risk factor for lung adenocarcinoma development. This study has identified revealed that the three SNPs (rs28757157, rs3751592, and rs59429575) of CYP19A1 are associated with lung cancer in the Chinese Han population. These findings will provide theoretical support for further functional studies of CYP19A1 in lung cancer.

Three-dimensional printed customized uncemented unipolar prosthesis combined with ligament reconstruction for tumorous defect of the distal femur in children.

Hemiarthroplasty following tumor resection of the distal femur in children provides a chance to preserve the proximal tibial physis for limb elongation. Based on three-dimensional (3D) printing technology, the uncemented unipolar prosthesis with joint stability reinforced structures (JSRSs) was custom-designed for our cases. This study aimed to describe the design and assess the short-term outcomes of this refined prosthetic hemiarthroplasty. Seven patients (four females and three males) received 3D-printed customized uncemented unipolar prosthesis for hemiarthroplasty after removal of the distal femur, from September 2019 to October 2020 at our Orthopedics department. The limb function, growth of the preserved proximal tibial physis, joint stability, and limb length discrepancy (LLD) were assessed. Complications were recorded. Six patients survived with no evidence of metastasis or local recurrence at the last follow-up, and one patient died of lung metastasis at 19 months postoperatively. Follow-up ranged from 19 to 32 months, with an average of 26 months. Elongation of the tibia was observed in all cases. At the last follow-up, four patients exhibited equal growth length compared with the healthy contralateral tibia. LLD ranged from 0.8 to 1.6 cm with a mean of 1.3 cm. The average knee range of motion was 95.3° of flexion and 4.5° of extension. All patients achieved satisfactory postoperative limb function with a mean MSTS score of 25.8. The results of the drawer, Lachman, and pivot shift tests were negative in all patients. During follow-up, painless joint space narrowing was observed in two patients. The screw for ligament fixation loosened in one of the seven patients at 17 months postoperatively. No subluxation of the joint, angular deformity, or breakage of the implant was detected in the remaining patients. 3D-printed customized uncemented unipolar prosthesis with JSRS would be a good choice for reconstructing tumorous defect in the distal femur in children.

Sex differences involved in persistent atrial fibrillation recurrence after radiofrequency ablation.

In recent years, the difference in outcomes of radiofrequency catheter ablation (RFCA) in persistent atrial fibrillation patients has risen. In particular, biological sex seems involved in a different response to the AF ablation procedure. In our study, we analyzed the AF recurrences after RFCA assessing the other association between malefemale patients with the outcomes. We enrolled 106 patients (74.5% men) with persistent atrial fibrillation with scheduled follow-up. The baseline clinical characteristics and AF recurrence after RFCA were compared between men and women. Cox regression analyses were performed to determine the risk predictors of AF recurrence. The proportion of RFCA in women was lower than that in men. Men with persistent AF were younger than women (58.6 ± 10.4 years vs. 65.1 ± 8.7 years, respectively p 0.003). The left atrium (LA) diameter was higher in males (43.7 ± 4.6 mm vs. 41.3 ± 5.5 mm p 0.028), and the level of left heart ejection fraction (LVEF) was higher in females (59.4 ± 6.9% vs. 64.1 ± 5.5% p 0.001). Sex differences in AF recurrence after RFCA were significant during the median 24.4-month (interquartile range 15.2-30.6 months) follow-up period, and the recurrence rate of AF in women was significantly higher than that in men (p 0.005). Univariable Cox regression analysis showed that female sex was a risk factor for persistent AF recurrence after RFCA HR 2.099 (1.087-4.053). Univariate Cox regression analysis revealed that non-PV ablation not associated with AF recurrence HR 1.003 (0.516-1.947). In a monocentric cohort of persistent AF patients, the female biological sex was associated with a higher risk of AF recurrence after RFCA.

Timing of hypoxia PETCT imaging after 18F-fluoromisonidazole injection in non-small cell lung cancer patients.

Positron emission tomography (PET)computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is of interest to help develop novel hypoxia modifiers and guide radiation treatment planning. Yet, the optimal post-injection (p.i.) timing of hypoxic imaging remains questionable. Therefore, we investigated the correlation between hypoxia-related quantitative values in FMISO-PET acquired at 2 and 4 h p.i. in patients with non-small cell lung cancer (NSCLC). Patients with resectable NSCLC participated in the ATOM clinical trial (NCT02628080) which investigated the hypoxia modifying effects of atovaquone. Two-hour and four-hour FMISO PETCT images acquired at baseline and pre-surgery visits (n 58) were compared. Cohort 1 (n 14) received atovaquone treatment, while cohort 2 (n 15) did not. Spearmans rank correlation coefficients (ρ) assessed the relationship between hypoxia-related metrics, including standardised uptake value (SUV), tumour-to-blood ratio (TBR), and tumour hypoxic volume (HV) defined by voxels with TBR ≥ 1.4. As the primary imaging-related trial endpoint used to evaluate the action of atovaquone on tumour hypoxia in patients with NSCLC was change in tumour HV from baseline, this was also assessed in patients (n 20) with sufficient baseline 2- and 4-h scan HV to reliably measure change (predefined as ≥ 1.5 mL). Tumours were divided into four subregions or distance categories edge, outer, inner, and centre, using MATLAB. In tumours overall, strong correlation (P < 0.001) was observed for SUV

Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors.

Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.

Human papillomavirus prevalence, persistence and cervical dysplasia in females with cystic fibrosis.

A higher risk of human papillomavirus (HPV)-related cervical intra-epithelial neoplasia (CIN) is suspected among females with cystic fibrosis (CF). We conducted a single center prospective cohort study among females attending the Lyon adult CF center. We performed a cervical cytology (Hologic Thinprep®) and HPV testing with genotyping (Clinical Arrays Papillomavirus Genomica, enabling 35 genotype detection, 20 of which are high-risk (HR-HPV)) at inclusion. We followed all females with positive HPV tests at 6, 12 and 24 months to evaluate HPV persistence, and performed a colposcopy in cases of abnormal cytology. We included eighty-five participants, 18 (21%) of whom were lung-transplanted. The mean age at inclusion was 31.9 (range 18-59) years. The prevalence of HPV (all types) was 31.8%. HR-HPV was found in 25.9% of the whole cohort, 44.4% of transplanted patients, and 20.1% of nontransplanted patients. Genotype-specific HR-HPV persistence at 12 months was 43.5% among transplanted and 34.6% among nontransplanted patients. Overall, 17.6% (1585) of females had an abnormal cytology 44.4% (818) among transplanted and 10.4% (767) among nontransplanted patients. CIN was identified in 12 (14.1%) patients (6 low-grade, 6 high-grade). High-grade CIN developed in 4 nontransplanted patients. Transplanted females had high HR-HPV, abnormal cervical cytology and CIN prevalence rates compared to large published cohorts in the general non-CF population. Although HR-HPV prevalence and persistence were globally not significantly different in nontransplanted females compared to the general population, we reported high frequencies of abnormal cytology and CIN. Cervical cancer screening and prevention should be promoted among females with CF.

The synthetic molecule stauprimide impairs cell growth and migration in triple-negative breast cancer.

Stauprimide, a semi-synthetic derivative of staurosporine, is known mainly for its potent differentiation-enhancing properties in embryonic stem cells. Here, we studied the effects of stauprimide in cell growth and migration of triple-negative breast cancer cells in vitro, evaluating its potential antitumoral activity in an orthotopic mouse model of breast cancer in vivo. Our results from survival curves, EdU incorporation, cell cycle analysis and annexin-V detection in MDA-MB-231 cells indicated that stauprimide inhibited cell proliferation, arresting cell cycle in G

Medicare Hospice Policy Changes and Beneficiaries Rate of Live Discharge and Length-of-Stay.

The 2014 Improving Medicare Post-Acute Care Transformation (IMPACT) Act systemized audits of long hospice stays, and the 2016 two-tier payment system decreased daily reimbursement rates after 60 days of enrollment. Both aimed to reduce long stays. Examine how live discharge rates and length of stay changed in relation to the policies. We computed monthly hospice-level percent live discharges and length of stay using 2008-2019 Medicare hospice claims. We compared prepolicies trends and postpolicies trends overall, within Alzheimers disease and related dementias (ADRD) patients, within lung cancer patients, and stratified by hospice ownership (for-profit vs. nonprofitgovernment-owned). We included 10,539,912 and 10,453,025 episodes of care in the analytical samples for live discharge and length of stay analyses, respectively. Overall percent live discharges declined during the prepolicies period (-0.13 percentage-points per month, 95% CI -0.14, -0.12), but exhibited no significant change during the postpolicies period. Trends were driven primarily by for-profits, with similar patterns within ADRD and lung cancer patients. Overall, mean length of stay increased over time, with greater rate of increase during the postpolicies period (0.41 days per month, 95% CI 0.39, 0.42) compared to the prepolicies period (0.12 days per month, 95% CI 0.10, 0.14). Length-of-stay increased faster among ADRD patients, but changed minimally for lung cancer patients. Live discharge rates declined significantly during the prepolicies period, but plateaued after implementation of the policies, driven by changes in for-profits. However, the policies did not reduce length of stay, which increased at faster rates, suggesting that postpolicies excess live discharges were not restricted to long-stay patients.

Knowledge-Based Quality Assurance and Model Maintenance in Lung Cancer Radiation Therapy in a Statewide Quality Consortium of Academic and Community Practice Centers.

Locally advanced lung cancer (LALC) treatment planning is often complex due to challenging tradeoffs related to large targets near organs at risk, making the judgment of plan quality difficult. The purpose of this work was to update and maintain a multi-institutional knowledge-based planning (KBP) model developed by a statewide consortium of academic and community practices for use as a plan quality assurance (QA) tool. Sixty LALC volumetric-modulated arc therapy plans from 2021 were collected from 24 institutions. Plan quality was scored, with high-quality clinical (HQC) plans selected to update a KBP model originally developed in 2017. The model was validated via automated KBP planning, with 20 cases excluded from the model. Differences in dose-volume histogram metrics in the clinical plans, 2017 KBP model plans, and 2022 KBP model plans were compared. Twenty recent clinical cases not meeting consortium quality metrics were replanned with the 2022 model to investigate potential plan quality improvements. Forty-seven plans were included in the final KBP model. Compared with the clinical plans, the 2022 model validation plans improved 60%, 65%, and 65% of the lung V20Gy, mean heart dose, and spinal canal D0.03cc metrics, respectively. The 2022 model showed improvements from the 2017 model in hot spot management at the cost of greater lung doses. Of the 20 recent cases not meeting quality metrics, 40% of the KBP model-replanned cases resulted in acceptable plans, suggesting potential clinical plan improvements. A multi-institutional KBP model was updated using plans from a statewide consortium. Multidisciplinary plan review resulted in HQC model training plans and model validation resulted in acceptable quality plans. The model proved to be effective at identifying potential plan quality improvements. Work is ongoing to develop web-based training plan review tools and vendor-agnostic platforms to provide the model as a QA tool statewide.

Clonal KEAP1 mutations with loss of heterozygosity share reduced immunotherapy efficacy and low immune cell infiltration in lung adenocarcinoma.

KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation KEAP1 clonal diploid-subclonal (KEAP1 CD-SC) in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N 2550). ClonalityLOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAFTP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSKRome N 237 DFCI N 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). ClonalityLOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAFTP ratio. In the ICI-treated MSKRome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P 0.001 OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P 0.006 OS log-rank P 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.

Anti-proliferative, pro-apototic and anti-migratory properties of HDAC inhibitor PXD-101 on osteosarcoma cell lines.

The therapeutic strategies for osteosarcoma involve both surgical approach and chemotherapy, but the identification of new therapeutic targets is particularly necessary in patients with local chemo-resistance, recurrence and lung metastases. The role of epigenetic regulation in osteosarcoma is largely unknown. Thus, in this study we disclosed the effects of histone deacetylase inhibitor drug PXD-101 on human osteosarcoma (OS) cell lines with different aggressiveness, including Saos-2, HOS and 143B cell lines. XTT assays revealed that treatment of Saos-2, HOS and 143B cells with PXD-101 decreased cell viability in a concentration-dependent manner. Fluorescence-activated cell sorting (FACS) analysis showed that PXD-101 inhibited proliferation and induced cell apoptosis. Wound healing assay indicated that PXD-101 inhibited migration of osteosarcoma cells. Real-Time RT-qPCR and protein analysis highlighted reduced expression of Runx2, Osterix and Mad2, probably due to Cyclin B1 inhibition by PXD-101 treatment. To our knowledge, this is the first study that characterized the anti-tumoral effect of PXD-101 in OS cells, suggesting a potential new therapeutic approach in osteosarcoma patients.

Cytotoxicity of fibrous antigorite from New Caledonia.

Exposure to asbestos and asbestos-like minerals has been related to the development of severe lung diseases, including cancer and malignant mesothelioma (MM). A high incidence of non-occupational MM was observed in New Caledonia (France) in people living in proximity of serpentinite outcrops, containing chrysotile and fibrous antigorite. Antigorite is a magnesium silicate, which shares with chrysotile asbestos the chemical formula. To achieve information on antigorite toxicity, we investigated the physico-minero-chemical features relevant for toxicity and cellular effects elicited on murine macrophages (MH-S) and alveolar epithelial cells (A549) of three fibrous antigorites (f-Atg) collected in a Caledonian nickel lateritic ore and subjected to supergene alteration. Field Atg were milled to obtain samples suitable for toxicological studies with a similar particle size distribution. UICC chrysotile (Ctl) and a non-fibrous antigorite (nf-Atg) were used as reference minerals. A high variability in toxicity was observed depending on shape, chemical alteration, and surface reactivity. The antigorites shared with Ctl a similar surface area (16.3, 12.1, 20.3, 13.4, and 15.6 m

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate.

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.

Dephosphorylation of the EGFR protein by calcineurin at serine 10461047 enhances its stability.

The epidermal growth factor receptor (EGFR) is highly expressed or abnormally activated in several types of cancers, such as lung and colorectal cancers. Inhibitors that suppress the tyrosine kinase activity of EGFR have been used in the treatment of lung cancer. However, resistance to these inhibitors has become an issue in cancer treatment, and the development of new therapies that inhibit EGFR is desired. We found that calcineurin, a Ca

P-YGNHs sensitizes non-small cell lung cancer cells to radiotherapy via blockage of the PI3KAKT signaling pathway.

Radioresistance represents a common phenomenon found in cancer treatment. Herein, the current study sought to evaluate the effects of a nanodrug delivery system of YSAYPDSVPMMS (YSA) peptide-modified gold nanoparticles-dextran-based hydrogel loaded with paclitaxel-succinic anhydride (P-YGNHs) on non-small cell lung cancer (NSCLC) cell radiosensitivity. Firstly, utilizing the coupling reaction and layer-by-layer assembly technique, P-YGNHs was prepared. The therapeutic effects of the P-YGNHs in NSCLC cells in relation to the PI3KAKT signaling pathway were examined by assessing the colony formation, apoptosis, and reactive oxygen species (ROS) generation of A549 cells under 10 Gy X-rays irradiation. Moreover, A549 tumor-bearing mice were generated to further validate the therapeutic effect in vivo. We confirmed the successful conjugation of the nanocomposite. Under 10 Gy X-rays irradiation, P-YGNHs reduced the number of colonies of A549 cells, while inducing both cell apoptosis and ROS production. Moreover, P-YGNHs enhanced the radiosensitivity of A549 cells by inhibiting the PI3KAKT signaling pathway. In vivo fluorescence experiments validated that P-YGNHs effectively-targeted and accumulated at the tumor site in nude mice, thus augmenting the radiosensitivity of tumors without significant immune toxicity or side effects. Conclusively, our findings highlighted that P-YGNHs significantly enhanced the radiosensitivity of NSCLC cells by repressing the PI3KAKT signaling pathway.

Simultaneous quantitation of befotertinib (D-0316) and its metabolite D-0865 in human plasma by LC-MSMS method.

A sensitive and reliable method was developed to determine befotertinib (D-0316) and its metabolite D-0865 from human plasma by LC-MSMS. The samples were prepared by simple protein precipitation and 2 µL of the supernatant were chromatographed on a C18 analytical column (ACE Excel 2 Super C

Wnt Family Member 9b (Wnt9b) Is a Sensitive and Specific Marker for Triple-negative Breast Carcinoma Including Metaplastic Carcinoma.

Wnt9b was recently identified as a highly sensitive and specific marker for breast carcinomas. Due to the limited number of triple-negative breast carcinomas (TNBCs) in previous study, we further explored Wnt9bs utility in breast carcinoma, especially in TNBCs including metaplastic carcinomas. We systematically evaluated Wnt9b expression on tissue microarrays (TMAs) from 413 breast carcinomas, 208 urothelial carcinomas, 102 endometrial carcinomas, 109 cholangiocarcinomas, 192 ovarian carcinomas, 48 lung adenocarcinomas, 69 colorectal adenocarcinomas, and 78 melanomas, and whole tissue section (WTS) from 20 human epidermal growth factor receptor 2-positive, 34 nonmetaplastic TNBCs, and 67 invasive metaplastic carcinomas. The results showed Wnt9b was highly expressed in breast carcinomas (91% on TMA and 98% on WTS) and in nonmetaplastic TNBCs (91% on TMA and 97% on WTS), but almost completely negative in other tested tumor types. Wnt9b was also highly expressed in metaplastic carcinomas (80%), significantly higher than GATA3 (56%) and SOX10 (48%), but slightly lower than TRPS1 (90%). In summary, our results demonstrate that Wnt9b is a highly sensitive marker for breast carcinomas, including TNBCs and metaplastic carcinomas. Further, we compared its utility with other breast markers including TRPS1, GATA3, and SOX10 in metaplastic carcinomas.

The survival after discontinuation of EGFR-TKIs due to intolerable adverse events in patients with EGFR-mutated non-small cell lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for advanced non-small cell lung cancer (NSCLC) patients harboring the EGFR mutation. Patients experiencing intolerable adverse events (AEs) would discontinue EGFR-TKIs. This study aimed to evaluate the impact of intolerable AEs and subsequent treatment on the survival of patients who discontinued EGFR-TKIs. The data of advanced NSCLC patients treated with EGFR-TKIs as frontline treatment at Chang Gung Memorial Hospitals from June 2014 to March 2018 were retrospectively reviewed. A total of 2190 patients were enrolled and treated with frontline EGFR-TKIs. In August 2021, 114 (5.2%) patients experienced intolerable AEs requiring discontinuation of EGFR-TKIs. The time median of EGFR-TKIs discontinuation was 2.56 months. Age >65 years, females, body weight, and body surface area were associated with the occurrence of intolerable AEs for patients treated with afatinib. Patients experiencing skinparonychiamucositis and abnormal liver function test had favorable survivals results. Patients who received subsequent EGFR-TKIs treatment, experienced better progression-free survival (PFS), total PFS (from frontline line EGFR-TKIs), and overall survival (OS) compared to patients receiving chemotherapy or no treatment. Patients undergoing subsequent EGFR-TKIs had better total PFS (median, 14.9 vs. 11.3 months, p 0.013) and OS (median, 31.3 vs. 20.1 months, p 0.001) than patients who did not discontinue because of AEs. Favorable OS was validated by propensity score matching. Patients experiencing intolerable AEs during EGFR-TKI treatment should consider switching to an alternative EGFR-TKI, which increase the survival results as compared to those patients who did not experience intolerable AEs.

FBP1 induced by β-elemene enhances the sensitivity of gefitinib in lung cancer.

β-elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. In this study, the common genes involved in gefitinib resistance and β-elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT-PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of β-elemene and FBP1. Western blot analysis was used to evaluate apoptosis-related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib-resistant HCC827GR cells in nude mice. Screening analysis demonstrated that fructose-1,6-bisphosphatase (FBP1) was induced by β-elemene and downregulated in gefitinib-resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9GR and HCC827GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p-STAT3. The FBP1STAT3 axis was required for FBP1-mediated apoptosis-related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. Our research indicated that β-elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1STAT3 axis in gefitinib-resistant lung cancer cells.

Endobronchial ultrasound-guided re-biopsy of non-small cell lung cancer with acquired resistance after EGFR tyrosine kinase inhibitor treatment.

Few studies assessed the use of endobronchial ultrasound (EBUS)-guided re-biopsy for detecting the T790M mutation after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure. A total of 2996 EBUS procedures were performed during the study period (January 2019-June 2022). In total, 44 consecutive patients who underwent EBUS-guided re-biopsy (56 procedures) for detecting the T790M mutation were analyzed. The success rates and T790M mutation frequencies were analyzed according to the re-biopsy site and EBUS method. Multivariate logistic regression analyses were used to identify factors affecting the likelihood of the T790M mutation. The success rates for the mutation analyses using EBUS with a guide-sheath (EBUS-GS), EBUS guided transbronchial needle aspiration (EBUS-TBNA), and EBUS-GS with EBUS-TBNA for re-biopsy were 80.6% (2936), 93.3% (1415), and 100% (55), respectively. Patients who underwent lymph node biopsy using EBUS-TBNA had an increased rates of the T790M mutation compared with those undergoing lung biopsy using EBUS-GS (EBUS-TBNA, 60.0% EBUS-GS with EBUS-TBNA, 40.0% EBUS-GS, 11.1% p < 0.001). In multivariate analysis, the use of a first-generation EGFR-TKI (odds ratio OR, 4.29 95% confidence interval CI, 1.05-17.58 p 0.043) was associated with occurrence of the T790M mutation. Re-biopsy of the metastatic site tended to be associated with a higher T790M mutation rate. Mild hemoptysis occurred in 3.6% (256) of the patients. EBUS-guided re-biopsy can be used for detecting the T790M mutation in patients who failed EGFR-TKI therapy. The T790M mutation frequency differed according to the re-biopsy site. The use of a first-generation EGFR-TKI was an independent predictor of the T790M mutation.

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection.

Extrahepatic nucleic acid delivery using polymers typically requires the synthesis and purification of custom monomers, post-synthetic modifications, and incorporation of additional excipients to augment their stability, endosomal escape, and in vivo effectiveness. Here, we report the development of a single-component and excipient-free, polyester-based nucleic acid delivery nanoparticle platform comprising ionizable

Use of a Novel Network-Based Linchpin Score to Characterize Accessibility to the Oncology Physician Workforce in the United States.

Physician headcounts provide useful information about the cancer care delivery workforce however, efforts to track the oncology workforce would benefit from new measures that capture how essential a physician is for meeting the multidisciplinary cancer care needs of the region. Physicians are considered linchpins when fewer of their peers are connected to other physicians of the same specialty as the focal physician. Because they are locally unique for their specialty, these physicians networks may be particularly vulnerable to their removal from the network (eg, through relocation or retirement). To examine a novel network-based physician linchpin score within nationwide cancer patient-sharing networks and explore variation in network vulnerability across hospital referral regions (HRRs). This cross-sectional study analyzed fee-for-service Medicare claims and included Medicare beneficiaries with an incident diagnosis of breast, colorectal, or lung cancer from 2016 to 2018 and their treating physicians. Data were analyzed from March 2022 to October 2022. Physician characteristics assessed were specialty, rurality, and Census region. HRR variables assessed include sociodemographic and socioeconomic characteristics and use of cancer services. Oncologist linchpin score, which examined the extent to which a physicians peers were connected to other physicians of the same specialty as the focal physician. Network vulnerability, which distinguished HRRs with more linchpin oncologists than expected based on oncologist density. χ2 and Fisher exact tests were used to examine relationships between oncologist characteristics and linchpin score. Spearman rank correlation coefficient (ρ) was used to measure the strength and direction of relationships between HRR network vulnerability, oncologist density, population sociodemographic and socioeconomic characteristics, and cancer service use. The study cohort comprised 308 714 patients with breast, colorectal, or lung cancer. The study cohort of 308 714 patients included 161 206 (52.2%) patients with breast cancer, 76 604 (24.8%) patients with colorectal cancer, and 70 904 (23.0%) patients with lung cancer. In our sample, 272 425 patients (88%) were White, and 238 603 patients (77%) lived in metropolitan areas. The cancer patient-sharing network included 7221 medical oncologists and 3573 radiation oncologists. HRRs with more vulnerable networks for medical oncology had a higher percentage of beneficiaries eligible for Medicaid (ρ, 0.19 95% CI, 0.08 to 0.29). HRRs with more vulnerable networks for radiation oncology had a higher percentage of beneficiaries living in poverty (ρ, 0.17 95% CI, 0.06 to 0.27), and a higher percentage of beneficiaries eligible for Medicaid (ρ, 0.21 95% CI, 0.09 to 0.31), and lower rates of cohort patients receiving radiation therapy (ρ, -0.18 95% CI, -0.28 to -0.06 P .003). The was no association between network vulnerability for medical oncology and percent of cohort patients receiving chemotherapy (ρ, -0.03 95% CI, -0.15 to 0.08). This study found that patient-sharing network vulnerability was associated with poverty and lower rates of radiation therapy. Health policy strategies for addressing network vulnerability may improve access to interdisciplinary care and reduce treatment disparities.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I non-small cell lung cancer and breast cancer.

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II prostate cancer and colorectal cancer.

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents a retrospective study.

Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). Of 92 patients (median age 66 years (IQR 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colonrectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%) 2% had brain metastases. Apixaban 5 mg bid (n 41) or rivaroxaban 20 mg daily (n 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI 0.7-50.0) with bevacizumab and 11.7 months (95%CI 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%) 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%) 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI 76.9-NR) for KI and 86.9 months (95%CI 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

How do patients interpret and respond to a single-item global indicator of cancer treatment tolerability

There is increasing interest in patient-reported measures of cancer treatment tolerability. A global measure of bother, the FACT GP5 item (I am bothered by side effects of treatment) is potentially useful for regulatory, research, and clinical use. To understand this items appropriateness for capturing treatment tolerability, we conducted cognitive interviews on this item with 3 samples of cancer patients. Patients with ovarian cancer (Study 1 N 21 on treatment), lymphoma (Study 2 N 14 on treatment), and colorectal or lung cancer (Study 3 N 16 treatment naïve) were interviewed about GP5s understandability and relevance to their treatment side effects. What patients think about when answering GP5 was also assessed. In all studies, the interview included both structured and open-ended questions. Qualitative data were coded to extract themes and responses to structured questions were tallied. Most patients on treatment (Studies 1 and 2) reported that the GP5 item wording is appropriate (88%) and its meaning is clear (97%). They were very confident or confident in their response (97%) and stated that GP5 was relevant to their cancer experience (97%). When answering GP5, patients considered their treatment and specific side effects. A large proportion (40%) of the treatment-naïve (Study 3) patients reported that GP5 was not relevant to their cancer treatment, and the largest proportion responded to GP5 thinking of negative side effect expectancies. This study provides assurance that GP5 is a useful indicator of treatment tolerability, and is meaningful to people with cancer, especially once they have started treatment.

Impact of physical activity on postural stability and coordination in children with posterior fossa tumor randomized control phase III trial.

Posterior fossa tumor is a type of brain tumor that is located at the borders of both the brain stem and cerebellum. The cerebellum is the brain region in charge of balance and coordination. Pediatric patients diagnosed with posterior fossa tumor have been reported to fall frequently. The aim of this study is to investigate the effectiveness of balance and coordination training in these children. This randomized control clinical trial (ClinicalTrials.gov Identifier NCT04528316) was carried out between September 2020 and April 2021 at Childrens Cancer Hospital-57357. The inclusion criteria were patients with posterior fossa tumor in maintenance phase and, age between 5 and 12 years. The exclusion criteria were patients who had a genetic disorder or suffer from mental retardation, a chronic lung disease, severe cardiomyopathy, or a neuromuscular disease that does not relate to tumor. The study participants were randomly assigned into three groups Group IControl group they received Pilates core stability exercises program, Group IIPostural stability group they received the same program plus HUMAC balance program, and Group IIICoordination group they received the same program plus coordination exercises of BOT-2. The semi-parametric proportional odds model was used to compare follow-up scores of the Postural stability group vs Control, and Coordination group vs Control, while adjusting for baseline values. All tests were two sided, with alpha set to 0.05. Sixty children including 38 boys and 22 girls were enrolled in this study. In all three groups, postural stability and coordination improved significantly in terms of modified clinical test of sensory integration of balance, center of pressure, limits of stability, bilateral coordination, and upper-limb coordination. The current study supports the value of adding postural stability and coordination training to the physiotherapy plan for children with posterior fossa tumor. ClinicalTrials.gov Identifier NCT04528316 on August 27, 2020.

No survival benefit in never-smoker never-drinker patients with oral cavity cancer.

Although strongly associated with tobacco and alcohol use, many oral cavity squamous cell carcinoma (OCSCC) cases occur in patients without exposure to either, known as never-smoker, never-drinkers (NSND). We aimed to compare clinical outcomes between NSND and tobaccoalcohol-exposed populations and to define demographic characteristics of NSND. We performed a retrospective, single-institution cohort study of 672 OCSCC patients. Cox models were used to estimate differences in overall survival (OS) and recurrence-free survival (RFS) between NSND and tobaccoalcohol-exposed patients while adjusting for confounders. NSND represented 25.6% of our cohort and were older, more female, and more economically advantaged. Among NSND, oral tongue tumors dominated in younger patients, while alveolar ridge tumors dominated in elderly patients. Multivariate survival analysis revealed no differences in OS or RFS between NSND and tobaccoalcohol-exposed patients. When adjusted for independent biologic features, clinical outcomes in OCSCC are similar between NSND and tobaccoalcohol-exposed patients.

Pattern of failure and clinical value of local therapy for oligo-recurrence in locally advanced non-small cell lung cancer after definitive chemoradiation Impact of driver mutation status.

Considerable differences of treatment response and pattern of failure may exist between definitive chemoradiation (CRT) treated locally advanced non-small cell lung cancer (LA-NSCLC) patients. The clinical value of additional tyrosine kinase inhibitors (TKIs) before disease recurrence and salvage local therapy after initial recurrent disease remain controversial. Consecutive LA-NSCLC patients receiving definitive CRT and having definite results about driver mutations (EGFR, ALK and ROS1) were retrospectively reviewed. Initial recurrent disease was classified as in-field recurrence, out-of-field recurrence and distant metastasis. Recurrent disease occurred only in the brain or limited to ≤3 extra-cranial organs and ≤5 extra-cranial lesions, was defined as oligo-recurrence. Progression free survival and overall survival (OS) were calculated from diagnosis to disease progression or death, and to death, respectively. OS2 was measured from initial disease recurrence to death among patients who had recurrent disease. Of the 153 enrolled patients, 39 had driver mutations and 13 received additional TKI therapy besides definitive CRT. Patients harboring driver mutations but without additional TKI therapy had a similar PFS and significantly longer OS (p 0.032) than those without driver mutations. Additional TKI therapy prolonged PFS (p 0.021) but not OS among patients with driver mutations. No significant difference of pattern of failure was observed between patient subgroups stratified by the status of driver mutations and the usage of additional TKI therapy. Furthermore, 57 of the 95 patients with initial recurrent disease developed oligo-recurrence and salvage local therapy significantly improved OS2 (p 0.01) among patients with oligo-recurrence disease. LA-NSCLC patients receiving definitive CRT generally had similar PFS and pattern of treatment failure, regardless of driver mutation status. Additional TKI therapy besides definitive CRT could prolong PFS but not OS. The majority of recurrent disease after definitive CRT belongs to oligo-recurrence and salvage local therapy may provide survival benefit.

Impact of video-assisted thoracoscopic lobectomy versus open lobectomy for lung cancer on recovery assessed using self-reported physical function VIOLET RCT.

Lung cancer is the leading cause of cancer death. Surgery remains the main method of managing early-stage disease. Minimal-access video-assisted thoracoscopic surgery results in less tissue trauma than open surgery however, it is not known if it improves patient outcomes. To compare the clinical effectiveness and cost-effectiveness of video-assisted thoracoscopic surgery lobectomy with open surgery for the treatment of lung cancer. A multicentre, superiority, parallel-group, randomised controlled trial with blinding of participants (until hospital discharge) and outcome assessors conducted in nine NHS hospitals. Adults referred for lung resection for known or suspected lung cancer, with disease suitable for both surgeries, were eligible. Participants were followed up for 1 year. Participants were randomised 1 1 to video-assisted thoracoscopic surgery lobectomy or open surgery. Video-assisted thoracoscopic surgery used one to four keyhole incisions without rib spreading. Open surgery used a single incision with rib spreading, with or without rib resection. The primary outcome was self-reported physical function (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) at 5 weeks. Secondary outcomes included upstaging to pathologic node stage 2 disease, time from surgery to hospital discharge, pain in the first 2 days, prolonged pain requiring analgesia at > 5 weeks, adverse health events, uptake of adjuvant treatment, overall and disease-free survival, quality of life (Quality of Life Questionnaire Core 30, Quality of Life Questionnaire Lung Cancer 13 and EQ-5D) at 2 and 5 weeks and 3, 6 and 12 months, and cost-effectiveness. A total of 503 patients were randomised between July 2015 and February 2019 (video-assisted thoracoscopic surgery, Ethnic minorities were under-represented compared with the UK population (< 5%), but the cohort reflected the lung cancer population. Video-assisted thoracoscopic surgery lobectomy was associated with less pain, fewer complications and better quality of life without any compromise to oncologic outcome. Use of video-assisted thoracoscopic surgery is highly likely to be cost-effective for the NHS. Evaluation of the efficacy of video-assisted thoracoscopic surgery with robotic assistance, which is being offered in many hospitals. This trial is registered as ISRCTN13472721. This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Lung cancer is a common cause of cancer death worldwide. If the disease is caught early, the part of the lung containing the tumour can be removed in an operation called a lobectomy. The operation can be carried out through a large cut so that the surgeon has a full view of the lung, which is called open surgery, or using several small cuts and a camera, which is called video-assisted thoracoscopic (keyhole) surgery. It is thought that, as keyhole surgery is less invasive, patients recover quicker. However, to the best of our knowledge, there are no high-quality research studies that are applicable to UK practice to support this. This study was conducted so that it could be determined, based on high-quality evidence, which operation provides the best treatment and recovery for patients. Five hundred and three adults referred for lobectomy for known or suspected lung cancer from nine hospitals in the UK. Participants were randomly allocated to either receive keyhole or open surgery. Participants were followed up for 12 months. We collected information on further treatment, hospital visits, safety information and disease progression over this period. Participants were also asked to complete questionnaires about their health and recovery. For patients with early-stage lung cancer who underwent a lobectomy, keyhole surgery led to less pain, less time in hospital and better quality of life than open surgery, without having a detrimental effect on cancer progression or survival. Keyhole surgery was found to be cost-effective and to provide excellent value for money for the NHS.

PRC1 plays an important role in lung adenocarcinoma and is potentially targeted by fostamatinib.

Lung adenocarcinoma (LUAD) is one of the most common cancers in the world. Protein regulator of cytokinesis 1 (PRC1) plays a role in the tumorigenesis and development of several cancers, including LUAD. The aim of the present study is to assess the characteristics of PRC1 in LUAD in order to find a potential drug that targets PRC1. We investigated the prognostic value of PRC1 in patients with LUAD using Cox analysis of the RNA sequencing data from The Cancer Genome Atlas (TCGA) portal. A link between PRC1 and LUAD progression, cigarette smoking mutation count, aneuploidy, and hypoxia scores was assessed. The relationship between PRC1 and tumor-infiltrating immune cells in LUAD was analyzed and Gene Set Enrichment Analysis (GSEA) was used to study the PRC1-related biological process and signal pathways. Potential drugs targeting PRC1 were identified using DrugBank database and molecular docking. PRC1 expression was significantly increased in LUAD. PRC1 could be, therefore, a prognostic biomarker for predicting overall survival in LUAD. PRC1 expression was also related to cancer stage and patients smoking history. PRC1 positively correlated with mutation count, aneuploidy and hypoxia scores. It was also significantly related to tumor-infiltrating immune cells, especially the activated mast cells. GSEA revealed that PRC1 might be correlated with cell cycle, cytokinesis and p53 signaling pathway. Additionally, fostamatinib was found to be a potential drug targeting PRC1. PRC1 may have a prognostic value for patients with LUAD, and be correlated with the mutation count, aneuploidy, hypoxia and tumor-infiltrating immune cells. Fostamatinib was found to be a potential drug targeting PRC1 in LUAD.

The role of neutrophil to lymphocyte ratio in predicting lung metastasis in giant cell tumor of the extremities.

Inflammation has a vital role in tumor development and metastasis. Changes in blood count parameters have been associated with tumor prognosis. We aimed to evaluate the prognostic significance of neutrophil to lymphocyte ratio (NLR) in predicting lung metastasis of giant cell tumors of the bone (GCTB) of the extremities. 34 GCTB patients (22 males and 12 females) were included in the study. Patients were divided into two groups. The metastasis group (n 7) included GCTB patients with lung metastasis, while the non-metastasis group (n 27) included those without lung metastasis. Descriptive statistics and frequency distribution were calculated age, white blood cell (WBC), neutrophil, lymphocyte, platelets, neutrophil to lymphocyte ratio (NLR), and platelets to lymphocytes ratio (PLR). Continuous normal variables were expressed as mean ± standard deviation and compared using Students t-tests. The receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of NLR and PLR to predict lung metastasis. The factors were considered to be statistically significant at p < 0.05. There were no significant differences between the lymphocyte count (1.81 vs. 2.23 103mm3), platelet count (436 vs. 364 103mm3), and PLR values (247 vs. 190) of the two groups (p > 0.05). The WBC count (11.8 vs. 8.95 103mm3), neutrophil count (8.78 vs. 5.69 103mm3), and NLR levels (5.45 vs. 2.81) (p < 0.05) were significantly higher in the metastasis group. The presence of an NLR cut-off value of 3.7 significantly predicted the existence of lung metastasis (AUC 0.857 95%CI 0.714-1, p 0.004) with a sensitivity of 85% and specificity of 82%. NLR may serve as a promising prognostic marker for predicting lung metastasis in GCTB patients.

Use of lung ultrasound for the diagnosis and treatment of pleural effusion.

Pleural effusion affects gas exchange, hemodynamic stability, and respiratory movement, thereby increasing the failure rate of intensive care unit discharge and mortality. Therefore, it is especially important to diagnose pleural effusion quickly to make the appropriate treatment decisions. The present review discusses the role of ultrasound in the diagnosis and puncturedrainage of pleural effusions and highlights the importance of lung ultrasound techniques in this patient population. We searched on PubMed, Embase, and Cochrane Library databases for articles from establishment to October 2022 using the following keywords lung ultrasound, pulmonary ultrasound, pleural effusion, ultrasound-guided and thoracentesis. Lung ultrasound not only helps clinicians visualize pleural effusion but also to identify its different types and assess pleural effusion volume. It is also very important for thoracentesis, not only to increase safety and reduce life-threatening complications, but also to monitor the amount of fluid after drainage of pleural effusion. Lung ultrasound is a simple, noninvasive bedside technique with good sensitivity and specificity for the diagnosis and treatment of pleural effusions.

EGFR TKI resistance in lung cancer cells using RNA sequencing and analytical bioinformatics tools.

Epidermal Growth Factor Receptor (EGFR) signaling and EGFR mutations play key roles in cancer pathogenesis, particularly in the development of drug resistance. For the ∼20% of all non-small cell lung cancer (NSCLC) patients that harbor an activating mutation, EGFR tyrosine kinase inhibitors (TKIs) provide initial clinical responses. However, long-term efficacy is not possible due to acquired drug resistance. Despite a gradually increasing knowledge of the mechanisms underpinning the development of resistance in tumors, there has been very little success in overcoming it and it is probable that many additional mechanisms are still unknown. Herein, publicly available RNASeq (RNA sequencing) datasets comparing lung cancer cell lines treated with EGFR TKIs until resistance developed with their corresponding parental cells and protein array data from our own EGFR TKI treated xenograft tumors, were analyzed for differential gene expression, with the intent to investigate the potential mechanisms of drug resistance to EGFR TKIs. Pathway analysis, as well as structural disorder analysis of proteins in these pathways, revealed several key proteins, including DUSP1, DUSP6, GAB2, and FOS, that could be targeted using novel combination therapies to overcome EGFR TKI resistance in lung cancer.Communicated by Ramaswamy H. Sarma.

Retracted Overexpression of miR‑203 increases the sensitivity of NSCLC A549H460 cell lines to cisplatin by targeting Dickkopf‑1.

Following the publication of this paper, it was drawn to the Editors attention by a concerned reader that certain of the mouse images shown in Fig. 5A and the flow cytometric assay data shown in Fig. 4A and B were strikingly similar to data appearing in different form in other articles written by some of the same authors, but which had already been published elsewhere or were already under consideration for publication, prior to this papers submission to

Genome stability‑related lncRNA ZFPM2‑AS1 promotes tumor progression via miR‑3065‑5pXRCC4 in hepatocellular carcinoma.

Long noncoding RNAs (lncRNAs) have a certain link to genomic stability (GS). However, the regulatory relationship of lncRNAs and GS has not been thoroughly investigated in hepatocellular carcinoma (HCC). In the present study, samples were retrieved from The Cancer Genome Atlas with somatic mutations and lncRNA expression data. Cox regression analysis was used to identify independent prognostic factors. The RNA levels were determined by reverse transcription‑quantitative PCR and protein levels were detected by western blot analysis. Cell Counting Kit‑8 and colony‑formation assays were used to assess cell viability. Cell migration was measured by wound‑healing and Transwell assays. Cell apoptosis and cell‑cycle progression were evaluated by flow cytometry. GS was detected by alkaline comet and chromosomal aberration assays. A xenograft model and lung metastasis model were used to assess the role of zinc finger protein, FOG family member 2 antisense 1 (ZFPM2‑AS1) in tumor growth

Evaluate the Prognosis of

Bystander CD4

Tumor-specific T cells likely underpin effective immune checkpoint-blockade therapies. Yet, most studies focus on Treg cells and CD8

Vesicle-mediated transport-related genes are prognostic predictors and are associated with tumor immunity in lung adenocarcinoma.

Globally, lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths. It is a progressive disorder that arises from multiple genetic and environmental factors. Dysregulated expression of vesicle-mediated transport-related genes (VMTRGs) have been reported in several cancers. However, the prognostic significance of VMTRGs in LUAD has yet to be established. The VMTRG profiling data for 482 LUAD patients and 59 normal controls were downloaded from The Cancer Genome Altas (TCGA). Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct and optimize the risk model. Several GEO datasets were used to validate the risk model. The roles of these genes were investigated We identified 85 prognosis-associated VMTRGs that could be constructed a risk model for LUAD patients, indicating their potential importance in LUAD development. The risk model including the five VMTRGs (CNIH1, KIF20A, GALNT2, GRIA1, and AP3S1) was associated with clinical outcomes. Tumor stage and risk score were found to be independent prognostic factors for LUAD patients. The five VMTRGs were also correlated with activation of the Notch and p53 signaling pathways. The risk model was significantly associated with immune responses and with high-level expression of immune checkpoints. High-risk group patients were more sensitive to several chemotherapeutic drugs and Lapatinib. Furthermore, CNIH1 and AP3S1 promoted LUAD cell growth and migration We constructed a VMTRG-based risk model for effective prediction of prognostic outcomes for LUAD patients. The risk model was associated with immune infiltration levels. These five hub genes are potential targets for immune therapy combined with chemotherapy in LUAD.

Development of a copper metabolism-related gene signature in lung adenocarcinoma.

The dysregulation of copper metabolism is closely related to the occurrence and progression of cancer. This study aims to investigate the prognostic value of copper metabolism-related genes (CMRGs) in lung adenocarcinoma (LUAD) and its characterization in the tumor microenvironment (TME). The differentially expressed CMRGs were identified in The Cancer Genome Atlas (TCGA) of LUAD. The least absolute shrinkage and selection operator regression (LASSO) and multivariate Cox regression analysis were used to establish the copper metabolism-related gene signature (CMRGs), which was also validated in Gene Expression Omnibus (GEO) database (GSE72094). The expression of key genes was verified by quantitative real-time PCR (qRT-PCR). Then, the CMRGS was used to develop a nomogram to predict the 1-year, 3-year, and 5-year overall survival (OS). In addition, differences in tumor mutation burden (TMB), biological characteristics and immune cell infiltration between high-risk and low-risk groups were systematically analyzed. Immunophenoscore (IPS) and an anti-PD-L1 immunotherapy cohort (IMvigor210) were used to verify whether CMRGS can predict the response to immunotherapy in LUAD. 34 differentially expressed CMRGs were identified in the TCGA dataset, 11 of which were associated with OS. The CMRGS composed of 3 key genes (LOXL2, SLC31A2 and SOD3) had showed good clinical value and stratification ability in the prognostic assessment of LUAD patients. The results of qRT-PCR confirmed the expression of key CMRGs in LUAD and normal tissues. Then, all LUAD patients were divided into low-risk and high-risk groups based on median risk score. Those in the low-risk group had a significantly longer OS than those in the high-risk group (P<0.0001). The area under curve (AUC) values of the nomogram at 1, 3, and 5 years were 0.734, 0.735, and 0.720, respectively. Calibration curves comparing predicted and actual OS were close to ideal model, indicating a good consistency between prediction and actual observation. Functional enrichment analysis showed that the low-risk group was enriched in a large number of immune pathways. The results of immune infiltration analysis also confirmed that there were a variety of immune cell infiltration in the low-risk group. In addition, multiple immune checkpoints were highly expressed in the low-risk group and may benefit better from immunotherapy. CMRGS is a promising biomarker to assess the prognosis of LUAD patients and may be serve as a guidance on immunotherapy.

Human B-1 cells are important contributors to the naturally-occurring IgM pool against the tumor-associated ganglioside Neu5GcGM3.

Only few studies have described the anti-tumor properties of natural antibodies (NAbs). In particular, natural IgM have been linked to cancer immunosurveillance due to its preferential binding to tumor-specific glycolipids and carbohydrate structures. Neu5GcGM3 ganglioside is a sialic acid-containing glycosphingolipid that has been considered an attractive target for cancer immunotherapy, since it is not naturally expressed in healthy human tissues and it is overexpressed in several tumors. Screening of immortalized mouse peritoneal-derived hybridomas showed that peritoneal B-1 cells contain anti-Neu5GcGM3 antibodies on its repertoire, establishing a link between B-1 cells, NAbs and anti-tumor immunity. Previously, we described the existence of naturally-occurring anti-Neu5GcGM3 antibodies with anti-tumor properties in healthy young humans. Interestingly, anti-Neu5GcGM3 antibodies level decreases with age and is almost absent in non-small cell lung cancer patients. Although anti-Neu5GcGM3 antibodies may be clinically relevant, the identity of the human B cells participating in this anti-tumor antibody response is unknown. In this work, we found an increased percentage of circulating human B-1 cells in healthy individuals with anti-Neu5GcGM3 IgM antibodies. Furthermore, anti-Neu5GcGM3 IgMs were generated predominantly by human B-1 cells and the antibodies secreted by these B-1 lymphocytes also recognized Neu5GcGM3-positive tumor cells. These data suggest a protective role for human B-1 cells against malignant transformation through the production of NAbs reactive to tumor-specific antigens such as Neu5GcGM3 ganglioside.

Feasibility and safety of percutaneous cryoablation under local anesthesia for the treatment of malignant lung tumors a retrospective cohort study.

In our institution, computed tomography (CT)-guided percutaneous cryoablation has been performed in patients with malignant lung tumors under local anesthesia. This study aimed to examine the feasibility and safety of percutaneous cryoablation for the treatment of malignant lung tumors. From July 2002 to December 2016, 227 patients (56 with primary lung cancer and 171 with metastatic lung tumor) underwent percutaneous cryoablation for the treatment of malignant lung tumors using a cryosurgical unit at our institution. Demographic factors, duration of post-treatment hospitalization, and adverse event and mortality rates were retrospectively investigated in 366 treatment sessions targeting 609 lesions. The median diameter of the targeted tumor was 1.3 cm. All the cryoablation procedures were completed under local anesthesia, and the median duration of post-treatment hospitalization was two days. Adverse events (grade 2 or higher) were observed in 79 sessions (21.6%), with pneumothorax being the most common. In five sessions (1.4%), patients had grade 3 adverse events. There was no 30-day mortality however, there were two 60-day mortality (0.5%) due to acute exacerbation of interstitial pneumonia. In multivariate analysis, independent predictors of adverse events were comorbid interstitial pneumonia odds ratio (OR) 2.20 95% confidence interval (CI) 1.04-4.64 and no history of pulmonary resection on the treated side (OR 3.04 95% CI 1.65-5.62). Cryoablation is a feasible and safe treatment for malignant lung tumors with acceptable adverse event rates. However, the mortality risk in patients with comorbid interstitial pneumonia should be fully recognized.

Application of computed tomography-based radiomics combined with clinical factors in the diagnosis of malignant degree of lung adenocarcinoma.

As an emerging technology, radiomics is being widely used in the diagnosis of early lung cancer due to its excellent diagnostic performance. However, there is a lack of studies that apply radiomics to the diagnosis of malignancy of lung adenocarcinoma. Thus, we used computed tomography (CT)-based radiomics to construct a model for the diagnosis of high-risk lung adenocarcinoma. Data of 170 patients who underwent surgical treatment at the First Affiliated Hospital of Soochow University and had a maximum nodule diameter ≤2 cm on preoperative CT images between January 2020 and December 2021 were retrospectively analyzed. All enrolled patients were randomly divided into experimental and validation groups according to the ratio of 73. The diagnosis of lung adenocarcinoma was based on postoperative pathological results. The region of interest was delineated on preoperative CT images, and the radiomics features were extracted. The least absolute shrinkage and selection operator (LASSO) was used to screen the radiomics features thus obtaining the radiomics score (Radscore), which was the basis of the radiomics model. Based on the multivariate regression analysis, independent predictors were screened from the clinical baseline data and imaging features thus constructing clinical model. Multivariate logistic regression was used to combine independent predictors and the Radscore to form a comprehensive nomogram. The diagnostic performance of constructed models was evaluated based on receiver operating characteristic (ROC) curves and decision curve analysis (DCA). The sensitivity and specificity of the clinical model based on consolidation-to-tumor ratio (CTR), lobulated signs and vascular anomaly signs was 70.0% and 76.7% in the validation group. The radiomics model area under the curve (AUC) 0.926 95% confidence interval (CI) 0.857-0.995 and the comprehensive model (AUC 0.922 95% CI 0.851-0.992) performed better than clinical model (AUC 0.839 95% CI 0.720-0.958) in the validation group. The sensitivity and specificity of the comprehensive model was 85.0% and 80.0% in the validation group. DCA of radiomics model and comprehensive model suggested they have better net survival benefit than clinical model. Compared with clinical model, radiomics model and comprehensive model had better diagnostic performance in distinguishing malignant degree of lung adenocarcinoma.

A cross-sectional study analysis of anatomical variation in the right upper lung intersegmental vein V2a based on a 3D reconstruction technique.

This study aimed to summarize and analyze the anatomical structures of the right upper lung intersegmental vein V2a based on 3-dimensional (3D) reconstruction technology. We collected the enhanced computed tomography (CT) scans of 157 patients with pulmonary diseases, and reconstructed the right upper lung tissue structure through interactive qualitative and quantitative analysis (IQQA). According to the reconstruction results, the V2a of the right upper pulmonary intersegmental vein was returned to different veins for classification, and the subtypes were further subdivided according to the different vascular routes and the location of the pulmonary segmental bronchus. Among 157 patients, there were 4 types of V2a according to the anatomical position of the veins. In type B (15 cases, 9.6%), V2a returned to the apical vein V1. In type C (2 cases, 1.3%), V2a did not exist, while in type D (1 case, 0.6%), V2a directly flowed into the right atrium. Type A is further divided into three subtypes (A1, A2, A3) according to the type of veins returned and the anatomical location of their confluence. In subtype A1 (110139 cases, 79.1%), V2a returned to the posterior segment central vein. In subtype A2 (8139 cases, 5.8%), V2a flowed from the B2 mediastinal surface down to the interlobular part of the posterior segmental vein. In subtype A3 (21139 cases, 15.1%), V2a flowed between B1a and B2a and back to the central vein at the junction of the B2 and B3 bronchus. Type B is further divided into 3 subtypes (B1, B2, B3) according to the location of the apical posterior segmental bronchus. In B1 subtype (115 cases, 6.7%), V2a continued from the mediastinal surface of B1 back down to V1. In B2 subtype (715 cases, 46.7%), V2a continued from the medial side of the B1 lung back down to V1. In subtype B3 (715 cases, 46.7%), V2a flowed back into the central part of the posterior segmental vein. This study, supported by 3D reconstruction technology, preliminarily summarized the V2a typology and further refined the anatomical differences of each subtype.

Zhengyuan capsules for the treatment of chemotherapy-induced cancer-related fatigue in stage IIIB-IV unresectable NSCLC study protocol for a randomized, multi-center, double-blind, placebo-controlled clinical trial.

Patients with advanced non-small cell lung cancer (NSCLC) frequently experience cancer-related fatigue (CRF) during or after chemotherapy. Traditional Chinese medicine (TCM) can effectively relieve CRF, although the clinical evidence is insufficient due to the absence of extensive and rigorous clinical studies. Zhengyuan capsules have both tonifying and dispersing effects, and its ability to alleviate CRF has been verified in mice. This study aimed to provide evidence for the role of proprietary Chinese medicines in alleviating CRF in advanced NSCLC patients. A multi-center, randomized, double-blind, placebo-controlled clinical trial has been designed to evaluate the efficacy and safety of Zhengyuan capsules for CRF in stage IIIB-IV unresectable NSCLC patients undergoing chemotherapy. Thirty eligible participants will be randomized into two groups at a 11 ratio during chemotherapy using the centralized interactive web response system. All patients will receive conventional platinum-based dual-drug chemotherapy and Zhengyuan capsules or simulant for 42 consecutive days starting on the first day of the first week of chemotherapy. The primary outcome is the difference between baseline and post-treatment CRF in the two groups, which will be assessed using the Brief Fatigue Inventory (BFI) score. Secondary outcome measurements include the Revised Pipers Fatigue Scale (RPFS)-Chinese Version, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Module C30 (EORTC QLQ-C30) v3.0 combined with EORTC QLQ-LC13 (Lung Cancer 13), clinical symptom score, hematology exploratory index, and progression-free survival. And safety indicators such as blood, urine, fecal routine, liver and kidney function, coagulation, and electrocardiogram will be performed before chemotherapy. Data will be analyzed according to intention-to-treat (ITT) and per-protocol (PP) principles Empowerstats and R will be applied for statistical analysis. This trial will provide data on the efficacy and safety of Zhengyuan capsules for treating CRF in stage IIIB-IV unresectable NSCLC patients undergoing chemotherapy. It will also provide a basis for the feasibility of a large-scale clinical trial. The clinical trial was registered on 19 November 2020 through httpswww.chictr.org.cn (registration number ChiCTR2000040061).

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of

To evaluate the prompting value of thyroid transcription factor 1 (TTF-1) and Napsin A for the status of epidermal growth factor receptor ( In this study, 976 untreated primary LUADs were retrospectively reviewed. The clinical and pathological data, including age, gender, smoking history, predictive values of TTF-1 and Napsin A, A total of 362 cases (37.1%) of The positive expression of TTF-1 and Napsin A had the prompting value for EGFR mutations in patients with LUAD, and the indicators could be combined with other clinical characteristics to enhance the prediction of the

Accurate detection of lung cancer-related microRNA through CRISPRCas9-assisted garland rolling circle amplification.

MicroRNA (miRNA) is reported to be closely related to a variety of pathophysiological processes for carcinoma and considered a potential biomarker for the diagnosis of lung cancer with brain metastasis. However, developing an accurate and sensitive miRNA detection method has proven to be a challenge. The aim of the present study was to integrate the advantages of rolling circle amplification (RCA), clustered regularly interspaced short palindromic repeats (CRISPR)CRISPR-associated nucleases 9 (Cas9), and catalytic hairpin assembly (CHA) technologies to develop an miRNA detection method. In the present study, we developed a novel approach for the sensitive and accurate detection of miRNA through integrating garland RCA and CRISPRCas9-assisted signal generation. In this method, target miRNA cyclized dumbbell padlock and triggered the RCA process to form long single-stranded DNA products with a repeated hairpin structure. Double-stranded DNA sequences (dsDNA) were formed with the addition of complementary sequences. With the assistance of the Cas9 enzyme for specific recognition and cleavage of formed dsDNA, RCA products were disassembled into hairpin probes. The generated hairpin probe could be unfolded by target miRNA to initiate the CHA process for signal generation. Through integration of the RCA and CHA processes, the method demonstrated favorable detection performance. The correlation equation between the signal and concentration of target miRNA was determined to be Y312.3 × lgC 2108, with a high correlation coefficient of 0.9786. The approach also exhibited high selectivity to the mismatched miRNAs. Our method could be used in the screening, diagnosis, and prognosis of multiple diseases without complicated thermal cycling instrumentation.

A clinical risk model for assessing the survival of patients with stage IA-IIA non-small cell lung cancer after surgery.

The survival of patients with stage IA-IIA non-small cell lung cancer (NSCLC) after surgery is heterogeneous. This study aimed to construct a prognostic risk model to predict the overall survival (OS) of these patients. Data from patients (n9,914) from the Surveillance Epidemiology and End Results (SEER) database were analyzed. The cases were randomly divided into the training and the validation groups. Patients from the Shanghai Pulmonary Hospital (n270) were also included as an external cohort. Independent significant factors affecting survival in the training cohort were used to construct a nomogram. The precision was evaluated using the concordance index (C-index) and calibration plots. The X-tile software was used to confirm the optimal cut-off value to classify the patients. Sex, age at diagnosis, tumor size, visceral pleura invasion (VPI), tumor grade, and the number of examined lymph nodes were deemed independent prognostic factors and were selected to establish the nomogram. The C-indices of the nomogram for predicting OS were 0.671 95% confidence interval (CI) 0.653-0.689 in the training group, and 0.668 (95% CI 0.650-0.687) and 0.707 (95% CI 0.651-0.763) in the validation and the testing groups, respectively. The cut-off value of risk points was 106.0, which stratified the patients into high-risk and low-risk groups. The high-risk patients had shorter 5-year OS than low-risk patients (P<0.001). The established nomogram could evaluate the survival in patients with stage IA-IIA NSCLC after surgery and may provide prognostic information for clinicians to make decisions in the management of adjuvant therapy.

Diagnostic value and safety of endobronchial ultrasonography with a guide sheath transbronchial biopsy for diagnosing peripheral pulmonary lesions in patients with interstitial lung disease.

Radial endobronchial ultrasonography transbronchial biopsy with and without a guide sheath is a useful method for diagnosing peripheral pulmonary lesions (PPLs). However, the diagnostic yield and complications of radial endobronchial ultrasonography transbronchial biopsy for PPLs remains elusive in patients with interstitial lung disease (ILD). We retrospectively analysed 431 patients (69 with and 362 without ILD) who underwent radial endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) for PPLs from April 1, 2011, to March 31, 2020. We investigated the diagnostic yield and complications of the procedure for PPLs and compared them between patients with and without ILD. We also evaluated the factors contributing to successful diagnosis. The diagnostic yield of radial endobronchial ultrasonography in patients with ILD was significantly lower than in those without ILD (62.3% The presence of ILD as the background lung significantly affected the diagnostic yield of PPLs with radial EBUS-GS TBB. Regarding the complications, pneumothorax occurred more frequently in patients with ILD than in those without ILD.

Risk of adenocarcinoma in patients with a suspicious ground-glass opacity a retrospective review.

Both primary lung adenocarcinoma and benign processes can have a ground-glass opacity (GGO) appearance on imaging. This study evaluated the incidence of and risk factors for malignancy in a diverse cohort of patients who underwent resection of a GGO suspicious for lung cancer. All patients who underwent resection of a pulmonary nodule with a GGO component and suspected to be primary lung cancer at a single institution from 2001-2017 were retrospectively reviewed. Risk factors for malignancy were evaluated using multivariable logistic regression analysis that included nodule size, age, sex, and race as potential predictors. The incidence of pulmonary adenocarcinoma in the 243 patients who met inclusion criteria was 86% (n208). The most common pathologic findings in 35 patients with a benign pathology was granulomatous inflammation (n14, 40%). Risk factors for adenocarcinoma in multivariable logistic regression were age odds ratio (OR) 1.06, P0.003, GGO size (OR 2.76, P<0.001), female sex (OR 4.47, P0.002), and Asian race (OR 8.35, P0.002). In this cohort, adenocarcinoma was found in 100% (4444) of Asian females, 86% (2529) of Asian males, 84% (98117) of non-Asian females, and 77% (4153) of non-Asian males. The likelihood of adenocarcinoma in lung nodules with a ground-glass component is influenced by sex and race. Asian females with a GGO have a much higher likelihood of having adenocarcinoma than men and non-Asians. This data can be used when deciding whether to pursue nodule resection or surveillance in a patient with a GGO.

Prognostic value of lactate dehydrogenase in non-small cell lung cancer patients with brain metastases a retrospective cohort study.

At present, although there are some known molecular markers for the prognosis of non-small cell lung cancer (NSCLC) brain metastases, but there are still shortcomings in sensitivity and specificity. Lactate dehydrogenase (LDH) is one of the key enzymes involved in malignancy vital glycolytic pathway. Elevated serum LDH levels are reported significantly associated with a poor prognosis in various malignancies. However, there is currently no consensus regarding the prognostic value of LDH in NSCLC patients with brain metastases. We retrospectively analyzed 224 patients diagnosed with lung cancer brain metastases between January 2006 and June 2020 after excluding patients meeting combined with other malignancies and inaccurate clinical information. The LDH cutoff values were obtained using a restricted cubic spline (RCS) model, and the patients were divided into two groups according to the optimal cut-off value (180 UL). 107 patients with LDH ≤180 (47.77%) and 117 patients with LDH >180 (52.23%) were identified. Univariate and multivariate logistic regression analyses were performed to identify the risk factors. The overall survival (OS) time was defined as the time from the first diagnosis of brain metastases to the last follow-up or death. Of the included patients, 147 survived and 77 died. The Kaplan-Meier method was used to illustrate the OS difference between the two groups. Finally, sensitivity analysis was employed to evaluate the robustness of the results. The OS rate was significantly lower in the high LDH group versus the low LDH group (P0.009). The median survival times of the high and low LDH groups were approximately 16 and 33 months, respectively. Multivariate analysis showed that high LDH was associated with a significantly worse OS adjusted hazard ratio (aHR), 1.567 95% confidence interval (CI) 1.058 to 2.32, P0.025 with adjustment for covariables that P<0.05 in univariate analysis. Sensitivity analysis indicated that the results of this study are robust, despite potential unmeasured confounders. High level of serum LDH indicates poor prognosis for patients with NSCLC brain metastases. This finding may provide useful prognostic information for patients and clinicians to choose more aggressive treatment strategies.

Extended use of rh-endostatin improves prognosis in patients with advanced non-small cell lung cancer an analysis of retrospective study.

Rh-endostatin is a potent inhibitor of angiogenesis approved and widely used for advanced non-small cell lung cancer (NSCLC) in China. While the efficacy and safety of extended use of rh-endostatin with platinum-based chemotherapy during induced and maintenance therapy are still not very clear, and whether extended use of rh-endostatin can improve survival needs further investigation. We performed a retrospective analysis of chemotherapy-naïve patients with stage IIIB-IV or recurrent NSCLC who had been treated with first-line chemotherapy plus rh-endostatin between January 2008 and June 2018. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Cox proportional hazards regression model was used to assess the prognostic importance of risk factors (age, gender, smoking status, Eastern Cooperative Oncology Group (ECOG) performance score, stage, pathology, previous thoracic surgery, and rh-endostatin treatment cycles). A total of 105 patients, with a median of 4 cycles of chemotherapy with rh-endostatin, were eligible for analysis. The median 95% confidence interval (CI) PFS and OS for patients with extended use of rh-endostatin (≥4 cycles) and nonextended use were 8.2 (4.2-12.3) In patients with advanced NSCLC, the extended use of rh-endostatin (≥4 cycles) could provide additional survival benefits and satisfactory toxicity profiles, especially for those with squamous cell cancer, which merits further evaluation in a prospective randomized study in the future.

The association between thoracic sarcopenia and survival is gender specific in early-stage lung cancer.

Sarcopenia, as measured at the 3rd lumbar (L3) level, has been shown to prognosticate survival in cancer patients. However, many patients with early-stage non-small cell lung cancer (NSCLC) do not undergo abdominal imaging. We hypothesized that preoperative thoracic sarcopenia is associated with survival in patients undergoing lung resection for early-stage NSCLC. Patients who underwent anatomic resection for NSCLC between 2010-2019 were retrospectively identified. Exclusion criteria included induction therapy, less than 90 days of follow-up, and absence of computed tomography (CT) imaging. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5), twelfth thoracic vertebra (T12), and L3 level. Gender-specific lowest quartile values and previously defined values were used to define sarcopenia. Overall survival and disease-free survival were assessed using the Kaplan-Meier method. Overall, 221 patients met inclusion criteria with a median body mass index (BMI) of 26.5 kgm Sarcopenia at T5 is associated with worse survival in males, but not females. When using upper thoracic vertebral levels to assess for sarcopenia, it is necessary to account for gender.