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Brief report Combination of Osimertinib and Dacomitinib to mitigate primary and acquired resistance in EGFR-mutant lung adenocarcinomas.

Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKIs) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. We conducted two prospective, phase 12 trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as first-line therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% 95% CI 50% to 88%. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance study, the overall response was 14% 95% CI 1% to 58%. We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as upfront treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

Derazantinib, a fibroblast growth factor receptor inhibitor, inhibits colony-stimulating factor receptor-1 in macrophages and tumor cells and in combination with a murine programmed cell death ligand-1-antibody activates the immune environment of murine syngeneic tumor models.

Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors 1-3 (FGFRi) with similar potency against colony-stimulating factor receptor-1 (CSF1R), a protein important in the recruitment and function of tumor-associated macrophages. DZB inhibited pCSF1R in the macrophage cell line RAW264.7, and tumor cells GDM-1 and DEL, and had the same potency in HeLa cells transiently over-expressing FGFR2. DZB exhibited similar potency against pCSF1R expressed by isolated murine macrophages, but as in the cell lines, specific FGFRi were without significant CSF1R activity. DZB inhibited growth of three tumor xenograft models with reported expression or amplification of CSF1R, whereas the specific FGFRi, pemigatinib, had no efficacy. In the FGFR-driven syngeneic breast tumor-model, 4T1, DZB was highly efficacious causing tumor stasis. A murine PD-L1 antibody was without efficacy in this model, but combined with DZB, increased efficacy against the primary tumor and further reduced liver, spine and lung metastases. Immunohistochemistry of primary 4T1 tumors showed that the combination favored an antitumor immune infiltrate by strongly increasing cytotoxic T, natural killer and T-helper cells. Similar modulation of the tumor microenvironment was observed in an FGFR-insensitive syngeneic bladder model, MBT-2. These data confirm CSF1R as an important oncology target for DZB and provide mechanistic insight for the ongoing clinical trials, in which DZB is combined with the PD-L1 antibody, atezolizumab.

Immune checkpoint inhibitors for RET fusion non-small cell lung cancer hopes and challenges.

Immune ch eckpoint inhibitors (ICIs) represent a milestone in advanced nonsmall cell lung cancer (NSCLC). Nevertheless, NSCLC with known oncogenic drivers has been overlooked in most studies evaluating anti-programmed death-1programmed death ligand 1. Rearranged during transfection proto-oncogene (RET) gene fusion was identified in 1-2% of NSCLC patients. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy and good tolerability. In contrast, the activity of ICIs in RET fusion NSCLC has not been well characterized. Here, we analyzed the clinical data of ICIs and discussed the suitable time to introduce ICIs in RET fusion NSCLC. Finally, we put forward future strategies to adequately maximize the efficacy of ICIs treatment in patients with RET fusion NSCLC in the upcoming era of combination immunotherapies.

Efficacy and safety of anlotinib as maintenance therapy after induction chemotherapy in extensive-stage small-cell lung cancer.

Anlotinib has been approved as the third-line or beyond treatment regimen for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, it is indistinct whether there are survival benefits of anlotinib in the maintenance therapy of ES-SCLC. Therefore, this study aims to evaluate the efficacy and safety of anlotinib monotherapy as maintenance therapy after induction chemotherapy for patients with ES-SCLC. The median progression-free survival (mPFS) was considered to be the pivotal symbol as the primary endpoint. The median overall survival (mOS) and safety were recognized as the second endpoints. Eligible patients in stable status after first-line chemotherapy would subsequently accept oral anlotinib (12 mgd, d1-d14, every 21 days as a course). The maintenance method was continued until disease progression or unmanageable toxicity occurred. The mPFS was 7.7 months (95% CI, 7.20-8.20 months) and the mOS was 11.0 months (95% CI, 9.19-12.82 months), respectively. The most common treatment-related adverse events were hypertension (n 9 64.3%), fatigue (n 6 42.9%), followed by decreased appetite (n 5 35.7%), nausea (n 5 35.7%), weight decrease (n 4 28.6%), and rash (n 4 28.6%). There were no patients who required dose reduction because of severe adverse events. Anlotinib achieved prospective efficacy and manageable safety in the maintenance treatment of ES-SCLC. These above outcomes demonstrated that anlotinib was a tolerable and potent maintenance treatment option after induction chemotherapy in ES-SCLC.

Comorbidities and causes of death of patients with asbestosis.

Comorbidities are common and affect the prognosis of patients with interstitial lung diseases, but few previous studies have investigated patients with asbestosis. We collected comorbidities and death causes of 116 patients with asbestosis treated in Oulu University Hospital. Causes of death were confirmed by autopsy in 68% of the cases. The most common comorbidities of asbestosis patients were pleural plaques (96%) and coronary artery disease (CAD) (67%). The prevalence of rheumatoid arthritis was 8.6%. The most common underlying causes of death were asbestosis (36%), CAD (24%) and lung cancer (LC) (10%). CAD and LC were associated with shorter survival in adjusted analyses. Patients with asbestosis have multiple comorbidities. Prevention and treatment of CAD and LC may influence the prognosis of asbestosis patients.

Transcription factor ZEB1 regulates PLK1-mediated SKA3 phosphorylation to promote lung cancer cell proliferation, migration and cell cycle.

Lung cancer (LC) is one of the most common malignancies worldwide with low 5-year survival rate. The mechanism of spindle and kinetochore-associated complex subunit 3 (SKA3) in LC tumorgenesis remains largely unclear. The expression of SKA3 in LC cells was detected by quantitative PCR. Cell proliferation, migration and cell cycle were evaluated by functional assays including 5-ethynyl-2-deoxyuridine, wound healing, transwell assays and flow cytometry analysis. Bioinformatics analysis, chromatin immunoprecipitation, luciferase reporter, co-immunoprecipitation and in vitro phosphorylation assays were applied to explore the interactions between zinc finger E-box binding homeobox 1 (ZEB1) and SKA3polo-like kinase 1 (PLK1). SKA3 is highly expressed in LC cell lines and drives LC cell proliferation, migration and cell cycle. PLK1 also enhances the malignancy of LC cells. PLK1 can mediate SKA3 phosphorylation and enhance the stability of SKA3 protein, thus promoting LC progression. Besides, we found that transcription factor ZEB1 transcriptionally activates SKA3PLK1 expression, contributing to LC cell malignancy. This study demonstrated that transcription factor ZEB1 modulates PLK1-mediated SKA3 phosphorylation to accelerate LC cell growth, migration and cycle, which might offer novel insight into LC treatment.

Acquired EML4-ALK fusion and EGFR C797S in cis mutation as resistance mechanisms to osimertinib in a non-small cell lung cancer patient with EGFR L858RT790M.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR-dependent as well as EGFR-independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALKgene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR-mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.

Diagnostic importance of lung perfusionventilation scans in the evaluation of pulmonary embolism in COVID-19 patients systematic review of the literature.

To investigate the outcomes of ventilationperfusion scintigraphy on the diagnosis of pulmonary embolism in coronavirus disease 2019 (COVID-19) patients, we performed a systematic review of the available literature. PubMed and Scopus were systematically searched up to 4 June 2022, for relevant studies. We included studies on patients with COVID-19 who have performed ventilationperfusion scintigraphy for diagnosis of pulmonary embolism to describe any diagnosis outcome. Irrelevant and non-English articles were excluded. Overall, 27 articles were included in our review. The database search yielded studies from PubMed, Scopus, and studies identified through reviewing the reference list of included studies. Extracted information from the included studies could be categorized into several aspects Diagnosis of pulmonary embolism with Q single-photon emission computed tomography (SPECT) CT, Tracheobronchial uptake, Diagnostic value of VQ rather than Q at diagnosis pulmonary embolism, Different characteristics (morphological alterations) of COVID-19 in ventilation orperfusion scan, the prevalence of pulmonary embolism with Q or VQ criteria, and Design of radiotherapy planning in lung cancer patients with COVID-19. Different perfusion patterns in COVID-19 are challenging but can be alleviated by adding SPECTcomputed tomography (CT) to lung perfusion scans. Although perfusion only SPECTCT can rule out or rule in others in considerable number of patients, ventilation scan is still needed in certain patients.

Different Decellularization Methods in Bovine Lung Tissue Reveals Distinct Biochemical Composition, Stiffness, and Viscoelasticity in Reconstituted Hydrogels.

Extracellular matrix (ECM)-derived hydrogels are in demand for use in lung tissue engineering to mimic the native microenvironment of cells in vitro. Decellularization of native tissues has been pursued for preserving organotypic ECM while eliminating cellular content and reconstitution into scaffolds which allows re-cellularization for modeling homeostasis, regeneration, or diseases. Achieving mechanical stability and understanding the effects of the decellularization process on mechanical parameters of the reconstituted ECM hydrogels present a challenge in the field. Stiffness and viscoelasticity are important characteristics of tissue mechanics that regulate crucial cellular processes and their in vitro representation in engineered models is a current aspiration. The effect of decellularization on viscoelastic properties of resulting ECM hydrogels has not yet been addressed. The aim of this study was to establish bovine lung tissue decellularization for the first time via pursuing four different protocols and characterization of reconstituted decellularized lung ECM hydrogels for biochemical and mechanical properties. Our data reveal that bovine lungs provide a reproducible alternative to human lungs for disease modeling with optimal retention of ECM components upon decellularization. We demonstrate that the decellularization method significantly affects ECM content, stiffness, and viscoelastic properties of resulting hydrogels. Lastly, we examined the impact of these aspects on viability, morphology, and growth of lung cancer cells, healthy bronchial epithelial cells, and patient-derived lung organoids.

ent-Pimarane Diterpenes from the Aerial Parts of Siegesbeckia pubescens.

Five new ent-pimarane diterpenes (1-5) and five known analogs (6-10) were isolated from the aerial parts of Siegesbeckia pubescens. Their structures, including absolute configurations, were determined by comprehensive spectroscopic methods especially 1D and 2D NMR and quantum chemical electronic circular dichroism calculations. All the isolated compounds were evaluated for their cytotoxicity against human BT549, A549 and H157 cancer cell lines. Among them, compounds 1 and 2 showed mild cytotoxicity against lung cancer cell lines H157 with IC

Self-Assembled Core-Shell Nanoscale Coordination Polymer Nanoparticles Carrying a Sialyltransferase Inhibitor for Cancer Metastasis Inhibition.

Despite hypersialylation of cancer cells together with a significant upregulation of sialyltransferase (ST) activity contributes to the metastatic cascade at multiple levels, there are few dedicated tools to interfere with their expression. Although transition state-based ST inhibitors are well-established, they are not membrane permeable. To tackle this problem, herein, we design and construct long-circulating, self-assembled core-shell nanoscale coordination polymer (NCP) nanoparticles carrying a transition state-based ST inhibitor, which make the inhibitor transmembrane and potently strip diverse sialoglycans from various cancer cells. In the experimental lung metastasis and metastasis prevention models, the nanoparticle device (NCPSTI) significantly inhibits metastases formation without systemic toxicity. This strategy enables ST inhibitors to be applied to cells and animals by providing them with a well-designed nanodelivery system. Our work opens a new avenue to the development of transition state-based ST inhibitors and demonstrates that NCPSTI holds great promise in achieving metastases inhibition for multiple cancers.

FDG PETCT in a Case of Lung Adenocarcinoma With Diffuse Cavitary Intrapulmonary Metastases.

We describe FDG PETCT findings in a case of lung adenocarcinoma with diffuse cavitary intrapulmonary metastases at initial diagnosis. High-resolution CT of the chest showed the primary solid tumor in the right upper lobe and numerous cavitating metastases ranging from a few millimeters to 1 cm in the bilateral lungs. FDG PETCT showed intense activity of the primary tumor, diffuse activity of the lung metastases, and hypermetabolic metastases in the mediastinal lymph nodes and bones. Familiarity with this atypical intrapulmonary metastatic pattern of lung cancer may be helpful for the diagnosis and differential diagnosis.

PETCT Manifestations of a Case of Penicilliosis Marneffei Misdiagnosed as Lung Cancer.

Penicilliosis marneffei is an extremely rare fungal infectious disease and is especially rare in people with normal immunity. Penicilliosis marneffei restricted to the lung and involving the formation of a pulmonary tumor is difficult to distinguish from peripheral lung cancer. This kind of case has rarely been reported. We report the case of a 53-year-old man with penicilliosis marneffei misdiagnosed as lung cancer by 18F-FDG PETCT.

Development and validation of an immune-related gene signature for prognosis in Lung adenocarcinoma.

The most common type of lung cancer tissue is lung adenocarcinoma. The TCGA-LUAD cohort retrieved from the TCGA dataset was considered the internal training cohort, while GSE68465 and GSE13213 datasets from the GEO database were used as the external test cohort. The TCGA-LUAD cohort was classified into two immune subtypes using single-sample gene set enrichment analysis of the immune gene set and unsupervised clustering analysis. The ESTIMATE algorithm, the CIBERSORT algorithm, and HLA family expression levels again validated the reliability of this typing. We performed Venn analysis using immune-related genes from the immport dataset and differentially expressed genes from the subtypes to retrieve differentially expressed immune genes (DEIGs). In addition, DEIGs were used to construct a prognostic model with the least absolute shrinkage and selection operator regression analysis. A reliable risk model consisting of 11 DEIGs, including S100P, INHA, SEMA7A, INSL4, CD40LG, AGER, SERPIND1, CD1D, CX3CR1, SFTPD, and CD79A, was then built, and its reliability was further confirmed by ROC curve and calibration plot analysis. The high-risk score subgroup had a poor prognosis and a lower tumour immune dysfunction and exclusion score, indicating a greater likelihood of anti-PD-1cytotoxic T lymphocyte antigen 4 benefit.

Lung cancer-kidney crosstalk induces kidney injury, interstitial fibrosis, and enhanced cisplatin-induced nephrotoxicity.

Cancer patients represent a unique patient population with increased susceptibility to kidney disease. Drug-induced acute kidney injury (AKI) in cancer patients is a common problem. Cisplatin is a highly effective treatment used in many solid organ cancers and causes AKI in 30% of patients, increasing the risk of chronic kidney disease (CKD) development. Most preclinical cisplatin toxicity studies have been completed in mice without cancer. We believe the physiology of cancer patients is not adequately represented in preclinical models, and the objective of this study was to determine how lung cancer will alter cisplatins nephrotoxicity. A genetically engineered mouse model and a syngeneic xenograft model of lung cancer were used. The mice were divided into 4 groups, non-cancercancer, and vehiclecisplatin treatment. Mice were administered cisplatin via intraperitoneal injection once a week for four weeks. Animals were euthanized 72 hours following their final cisplatin injection. The mice with lung cancer had increased renal toxicity, injury, and fibrosis following repeated low doses of cisplatin (RLDC). Additionally, lung cancer alone induced kidney injury and fibrosis in the kidney prior to cisplatin treatment. This is the first study that we are aware of that assesses the impact of cancer on the kidney in conjunction with the nephrotoxicity of cisplatin. We believe cancer is providing the first hit to the kidney, and the subsequent damage from repeated doses of cisplatin becomes unsurmountable, leading to AKI and progression to CKD.

Smoking, Alcohol consumption, and 24 Gastrointestinal Diseases Mendelian Randomization Analysis.

Preliminary results of randomized phase II study of etoposide plus lobaplatin or etoposide plus cisplatin with concurrent thoracic radiotherapy in the treatment of limited-stage small cell lung cancer.

The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL (n 19) or EP (n 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7% and 56.5, 43.5, and 29.0%, respectively (P 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8% and 73.9, 48.4, and 48.4%, respectively (P 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% (P 0.006) and 20.1% vs. 60.9% (P 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower (P 0.038), both groups showed a similar incidence of radiation pneumonitis (P 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.

Circ0091537 promotes gefitinib chemoresistance in non-small cell lung cancer by mediating the miR-520hYAP1 network.

Chemoresistance is the leading cause of poor outcomes of non-small cell lung cancer (NSCLC). Circular RNA (circRNA) plays a vital role in NSCLC resistance progression. Our study aimed to uncover the role of circRNA PDZ domain containing 8 (circ0091537) in NSCLC with gefitinib resistance. The expression of circ0091537, microRNA-520h (miR-520h), and Yes-associated protein 1 (YAP1) mRNA were detected using quantitative real-time PCR. Cell viability and cell proliferation were assessed by MTT assay and colony formation assay. Colony formation ability was detected by colony formation assay. Cell cycle distribution and cell apoptosis were determined by flow cytometry assay. Cell migration and cell invasion were detected by transwell assay. The potential relationship between miR-520h and circ0091537 or YAP1 was verified by dual-luciferase reporter assay. Tumor formation assay in nude mice was performed to test the role of circ0091537 in vivo. Circ0091537 and YAP1 were upregulated, while miR-520h was downregulated in gefitinib-resistant NSCLC cells. Circ0091537 knockdown inhibited gefitinib resistance in NSCLC cells and then inhibited NSCLC cell growth, migration, and invasion. MiR-520h was a target of circ0091537, and miR-520h inhibition reversed the effects of circ0091537 knockdown. Moreover, YAP1 was a target of miR-520h, and circ0091537 competitively combined with miR-520h to enrich YAP1 expression. MiR-520h restoration impaired gefitinib resistance and suppressed NSCLC cell proliferation, migration, and invasion by repressing YAP1. Circ0091537 overexpression weakened gefitinib sensitivity in vivo to promote tumor growth. Circ0091537 strengthens gefitinib chemoresistance to promote NSCLC progression by mediating the miR-520hYAP1 network, suggesting that circ0091537 may be a key indicator in resistance to treatment of NSCLC.

Temporal Variation in Indoor Radon Concentrations Using Environmental Public Health Tracking Data.

Indoor radon is the second leading cause of lung cancer in the United States (US) after smoking and the number one for lung cancer in non-smokers. Understanding how indoor radon varies during the year reveals the best time to test to avoid underestimating exposure. This study looks at the temporal variation in 13 years of radon concentrations in buildings located in 46 US states and the District of Columbia (DC). In the dataset, radon concentration varies from 3.7 Bq m-3 (Becquerels per cubic meter) to 52,958.1 Bq m-3, with an overall mean of 181.4 Bq m-3. About 35.4% of tests have a radon concentration level equal to or greater than the US Environmental Protection Agency (US EPA) action level 4.0 pCi L-1 (148 Bq m-3).3 Temporal variation in radon concentrations was assessed using the overall monthly mean radon concentration. The highest concentrations were found in January (203.8 Bq m-3) and the lowest in July (129.5 Bq m-3). Higher monthly mean indoor radon concentrations were found in January, February, and October, and lower in July, August, and June. This result is consistent with findings from other studies and suggests continuing to encourage radon testing throughout the year with an emphasis on testing during the colder months.

Four-dimensional computed tomography-based ventilation imaging in intensity-modulated radiation therapy treatment planning for pulmonary functional avoidance.

To incorporate four-dimensional computed tomography (4DCT)-based ventilation imaging into intensity-modulated radiation therapy (IMRT) treatment planning for pulmonary functional avoidance. Nineteen locally advanced lung cancer patients are retrospectively studied. 4DCT images are employed to create ventilation maps for each patient via a density-change-based algorithm with mass correction. The regional ventilation is directly incorporated into the mathematical formulation of a direct aperture optimization model in IMRT treatment planning to achieve functional avoidance and a voxel-based treatment plan. The proposed functional avoidance planning and voxel-based planning are compared to the conventional treatment planning approach purely based on the anatomy of patients. Paired sample t-tests are conducted to see whether dosimetric differences among the three approaches are significant. Similar planning target volume (PTV) coverage is achieved by anatomical, functional avoidance, and voxel-based approaches. The voxel-based treatment planning performs better than both functional avoidance and anatomical planning to the lung. For a total lung, the average volume reductions in a functional avoidance plan from an anatomical plan, a voxel-based plan from an anatomical plan, and a voxel-based plan from a functional avoidance plan are 7.0% , 16.8%, and 10.6%, respectively for V We propose a treatment planning framework that directly utilizes functional images and compares voxel-based treatment planning with functional avoidance and anatomical treatment planning.

Association between PD-1 inhibitor-related adverse events and frailty assessed by frailty index in lung cancer patients.

The programmed cell death protein 1 (PD-1) inhibitor, as one of the immune checkpoint inhibitors (ICIs), is the standard treatment for advanced lung cancer. However, immune-related adverse events (irAEs) remain poorly understood toxicities. It is unclear whether frailty plays a role in the occurrence of irAEs. Thus, we assess whether irAEs occur more often in frail patients than in non-frail patients according to the Frailty Index (FI). A retrospective study was conducted. Medical records from lung cancer patients treated with PD-1 inhibitors (Sintilimab, Camrelizumab, Tislelizumab, and Pembrolizumab) at Peking University First Hospital (May 2018-June 2022). Patients were categorized into non-frail and frail groups according to a cut-point of 0.25 by FI. The FI calculation included 28 baseline variables, all of which were health deficits measured by questionnaires and body measurements. The statistical analysis included 114 advanced lung cancer patients. The median age was 66 years, and the malefemale ratio was 4.71 (9420). Approximately 39 (34%) were classified as frail. PD-1 inhibitor-related adverse events occurred in 17.5% of patients, and 6.1% experienced irAEs of grade ≥3. There was no significant difference in the occurrence of irAEs (14.7% vs. 23.1%, p 0.26), grade ≥ 3 irAEs (5.3% vs. 7.7%, p 0.93), and treatment discontinuation due to irAEs (12.0% vs. 17.9%, p 0.39) between non-frail and frail patients. However, frail patients are more likely to have more than one type of irAEs and are more possibly to have checkpoint inhibitor pneumonitis (CIP) than non-frail patients when they use PD-1 inhibitors (p < 0.05). Frail patients had a longer hospital stay (6 vs. 3 days, p 0.01). Frailty is not associated with severe irAEs, but is related to CIP. Meanwhile, it predicts more than one type of irAEs and a longer hospital stay. Frailty screening has added value to the decision-making process for frail patients eligible for PD-1 inhibitors.

Outcomes and pulmonary function after sleeve lobectomy compared with pneumonectomy in patients with non-small cell lung cancer.

Sleeve lobectomy is recommended to avoid pneumonectomy and preserve pulmonary function in patients with central lung cancer. However, the relationship between postoperative pulmonary functional loss and resected lung parenchyma volume has not been fully characterized. The aim of this study was to evaluate the relationship between pulmonary function and lung volume in patients undergoing sleeve lobectomy or pneumonectomy. A total of 61 lung cancer patients who had undergone pneumonectomy or sleeve lobectomy were analyzed retrospectively. Among them, 20 patients performed pulmonary function tests, including vital capacity (VC) and forced expiratory volume in 1 s (FEV1) tests, preoperatively and then about 6 months after surgery. VC and FEV1 ratios were calculated (measured postoperative respiratory functionpredicted postoperative respiratory function) as the standardized pulmonary functional loss ratio. Thirty-day operation-related mortality was significantly lower after sleeve lobectomy (3.2%) than pneumonectomy (9.6%). The 5-year relapse-free survival rate was 46.67% versus 29.03%, and the 5-year overall survival rate was 63.33% versus 38.71% in patients receiving sleeve lobectomy versus pneumonectomy. The VC ratio in the pneumonectomy group was better than in the sleeve lobectomy group (1.003 ± 0.117 vs. 0.779 ± 0.12 p 0.0008), as was the FEV1 ratio (1.132 ± 0.226 vs. 0.851 ± 0.063 p 0.0038). Both short-term and long-term outcomes were better with sleeve lobectomy than pneumonectomy. However, actual postoperative pulmonary function after pneumonectomy may be better than clinicians expect, and pneumonectomy should still be considered a treatment option for patients with sufficient pulmonary reserve and in whom sleeve lobectomy is less likely to be curative.

Cancer survival in the Faroe Islands over the last 50 years compared to the other Nordic countries.

As sustained development in cancer treatment protocols have led to improved survival in most areas of the world, surveillance is needed to ensure that small populations follow suit. Our study reports age-standardized relative cancer survival in the Faroe Islands compared to the other Nordic countries. We present 1- and 5-year survival estimates and corresponding 95% confidence intervals for the Faroe Islands and compare them with estimates for the Nordic countries. The data for this article has been obtained through the NORDCAN collaboration (2019 data). Age-standardized relative survival was estimated using shared R codes on individual-level data within each country. Ten-year calendar inclusion periods were used in addition to the usual 5-year calendar periods to include cancer sites with few cases, which is especially beneficial to the smaller populations. The primary findings were that 1- and 5-year survival were consistently lower in the Faroes for the summary group all sites but non-melanoma skin cancer for both women and men. Further, 5-year survival was lower for women with ovarian cancer and men with lung cancer than in other Nordic countries. Previously, breast cancer survival was low in the Faroes but has improved to a comparable level over the last few years. Colorectal cancer survival was relatively high for both sexes. The reported estimates in this article call for further research to investigate the cancers with lower survival and should call for actions to improve the survival of Faroese cancer patients.

Dose reduction of docetaxel avoids the usage of pegfilgrastim in docetaxel plus ramucirumab therapy for recurrent nonsmall cell lung cancer.

Pegfilgrastim is recommended in docetaxel plus ramucirumab (DTX RAM) therapy for recurrent nonsmall cell lung cancer (NSCLC) because of the associated frequency of febrile neutropenia (FN). However, the FN occurs less frequently when the dose of DTX is reduced because of other adverse events, such as appetite loss and oral mucositis. Twenty-two patients with recurrent NSCLC who received DTX RAM therapy at the Hiroshima Prefectural Hospital. The cut-off value which is the most unlikely to cause FN without the combined use of pegfilgrastim was set using a receiver operating characteristic (ROC) curve. This was created according to the dose of DTX and the presence or absence of the onset of FN. We compared the incidence of FN when a DTX dose above and below the cut-off value was used. The ROC curve showed that 48 mgm Pegfilgrastim can be discontinued when the dose of DTX is reduced to <48 mgm

The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer.

Lung cancer (LC) remains the leading cause of cancer-related deaths worldwide, with extremely high morbidity and mortality rates. Non-small cell lung cancer (NSCLC) is the most critical type of LC. It seriously threatens the life and health of patients because of its early metastasis, late clinical symptoms, limited early screening methods, and poor treatment outcomes. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), participate in cell proliferation, metastasis, and chemoresistance. Several previous studies have proven that ncRNAs are vital regulators of tumorigenesis. Ubiquitination plays the most crucial role in protein post-translational modification (PTM). Deubiquitination and ubiquitination form a homeostasis. In summary, ubiquitination and deubiquitination play essential roles in mediating the degradation or overexpression of a range of crucial proteins in various cancers. A growing number of researchers have found that interactions between ncRNAs and ubiquitination (or deubiquitination) play a crucial role in NSCLC. This review presents several typical examples of the important effects of ncRNAs and ubiquitination (or deubiquitination) in NSCLC, aiming to provide more creative ideas for exploring the diagnosis and treatment of NSCLC.

Stereotactic ablative radiotherapy for acquired resistance to EGFR therapy in metastatic non-small cell lung cancer.

The advent of targeted therapy has transformed the treatment paradigm and survival of patients with metastatic non-small cell lung cancer (NSCLC) with driver mutations. The development of acquired resistances during treatment with tyrosine kinase inhibitors (TKIs) impedes a prolonged survival in many patients. This fact is leading to the use of locally ablative therapies such as stereotactic ablative radiotherapy (SABR) to counter these resistances. SABR is a non-invasive treatment that can be delivered in multiple locations and has already proven effective in oligometastatic disease. Clinical evidence suggests that the combination of SABR with TKIs prolongs progression-free survival (PFS) in metastatic NSCLC patients with mutations in epidermal growth factor receptor (EGFR), with international guidelines recommending their use in unfavorable scenarios such as oligoprogressive disease. In this publication, we have reviewed the available evidence on EGFR-TKIs resistance mechanisms and the combination of SABR with TKI in metastatic NSCLC with EGFR mutations. We also describe the utility and clinical recommendations of this combination in oligometastatic and oligoprogressive disease.

A Rare Event of Liver Dysfunction on Sotorasib and Management Strategy.

Liquid Biopsy for Guiding Treatment Decisions in Advanced Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths in the United States. The 5-year survival rates are poor with traditional therapy alone. New scientific advances in technology involving the human genome, including diagnostic tools to inform on tumor-derived acquired (somatic) mutations that drive cancer formation, are essential to utilize. Targeting cancer cells paired with actionable drugs to shut off growth pathways has significantly improved patient survival. Obtaining mutational analysis can be performed via traditional methods such as tissue new advances allow comparable information obtained through liquid biopsy to inform targeted treatment decision-making. Getting tissue for additional molecular analysis can pose several challenges for patients. Liquid biopsy is a minimally invasive test (typically blood) analyzed by next-generation sequencing for tumor shed to obtain actionable information for treatment decisions. Analyses between blood and tissue consistently yield high concordance, with liquid biopsy providing faster turnaround time for results than tissue. The utility of liquid biopsy is well proven but not standardized and cannot diagnose lung cancer histopathology, which requires a tissue diagnosis.

Concomitant preoperative airflow obstruction confers worse prognosis after trans-thoracic surgery for esophageal cancer.

Airflow obstruction is a critical element of chronic airway diseases. This study aimed to evaluate the impact of preoperative airflow obstruction on the prognosis of patients following surgery for esophageal carcinoma. A total of 821 esophageal cancer patients were included and classified into two groups based on whether or not they had preoperative airflow obstruction. Airflow obstruction was defined as a forced expiration volume in the first second (FEV Patients with airflow obstruction (102821, 12.4%) had lower three-year overall (42102, 58.8%) and progression-free survival rate (47102, 53.9%) than those without airflow obstruction ( Preoperative airflow obstruction defined by FEV

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CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer.

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858RT790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

Pharmacokinetics, tissue distribution, and antitumor activity of a novel compound, NY-2, in non-small cell lung cancer.

The role of smoking and alcohol in mediating the effect of gastroesophageal reflux disease on lung cancer A Mendelian randomization study.

Observational studies have suggested a positive association between gastroesophageal reflux disease and lung cancer, but due to the existence of confounders, it remains undetermined whether gastroesophageal reflux disease (GERD) has a causal association with lung cancer. Therefore, Mendelian randomization (MR) analyses were applied to investigate the relationship between the two conditions. Two-sample Mendelian randomization analysis was utilized with summary genetic data from the European Bioinformatics Institute (602,604 individuals) and International Lung Cancer Consortium, which provides information on lung cancer and its histological subgroups. Furthermore, we used two-step Mendelian randomization and multivariable Mendelian randomization to estimate whether smoking initiation (311,629 cases and 321,173 controls) and alcohol intake frequency (

Molecular characterization based on tumor microenvironment-related signatures for guiding immunotherapy and therapeutic resistance in lung adenocarcinoma.

Combined model of radiomics and clinical features for differentiating pneumonic-type mucinous adenocarcinoma from lobar pneumonia An exploratory study.

The purpose of this study was to distinguish pneumonic-type mucinous adenocarcinoma (PTMA) from lobar pneumonia (LP) by pre-treatment CT radiological and clinical or radiological parameters. A total of 199 patients (patients diagnosed with LP 138, patients diagnosed with PTMA 61) were retrospectively evaluated and assigned to either the training cohort ( The radiomics signature, consisting of 14 selected radiomics features, showed excellent performance in distinguishing between PTMA and LP, with an AUC of 0.90 (95% CI, 0.83-0.96) in the training cohort and 0.88 (95% CI, 0.79-0.97) in the validation cohort. A nomogram model was developed based on the radiomics signature and clinical features. It had a powerful discriminative ability, with the highest AUC values of 0.94 (95% CI, 0.90-0.98) and 0.91 (95% CI, 0.84-0.99) in the training cohort and validation cohort, respectively, which were significantly superior to the clinical model alone. There were no significant differences in calibration curves from Hosmer-Lemeshow tests between training and validation cohorts ( The nomogram model based on radiomics signatures of CT images and clinical risk factors could help to differentiate PTMA from LP, which can provide appropriate therapy decision support for clinicians, especially in situations where differential diagnosis is difficult.

Nearly free silanols drive the interaction of crystalline silica polymorphs with membranes Implications for mineral toxicity.

Crystalline silica (CS) is a well-known hazardous material that causes severe diseases including silicosis, lung cancer, and autoimmune diseases. However, the hazard associated to crystalline silica is extremely variable and depends on some specific characteristics, including crystal structure and surface chemistry. The crystalline silica polymorphs share the SiO

A Novel Texture Extraction-Based Compressive Sensing for Lung Cancer Classification.

Lung cancer images require large memory storage and transmission bandwidth for sending the data. Compressive sensing (CS), as a method with a statistical approach in signal sampling, provides different output patterns based on information sources. Thus, it can be considered that CS can be used for feature extraction of compressed information. In this study, we proposed a novel texture extraction-based CS for lung cancer classification. We classify three types of lung cancer, including adenocarcinoma (ACA), squamous cell carcinoma (SCC), and benign lung cancer (N). The classification is carried out based on texture extraction, which is processed in 2 stages, the first stage to detect N and the second to detect ACA and SCC. The simulation results show that two-stage texture extraction can improve accuracy by an average of 84%. The proposed system is expected to be decision support in assisting clinical diagnosis. In terms of technical storage, this system can save memory resources. The proposed two-step texture extraction system combined with CS and K- Nearest Neighbor has succeeded in classifying lung cancer with high accuracy the system can also save memory storage. It is necessary to examine the complexity of the proposed method so that it can be analyzed further.

Environmental signals perceived by the brain abate pro-metastatic monocytes by dampening glucocorticoids receptor signaling.

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought.

Single-cell spatial landscapes of the lung tumour immune microenvironment.

Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution

Slow TCA flux and ATP production in primary solid tumours but not metastases.

Tissues derive ATP from two pathways-glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism

A national comparison between the collocated short- and long-term radon measurements in the United States.

Knowing the geographical and temporal variation in radon concentrations is essential for assessing residential exposure to radon, the leading cause of lung cancer in never-smokers in the United States. Tens of millions of short-term radon measurements, which normally last 2 to 4 days, have been conducted during the past decades. However, these massive short-term measurements have not been commonly used in exposure assessment because of the conflicting evidence regarding their correlation with long-term measurements, the gold standard of assessing long-term radon exposure. We aim to evaluate the extent to which a long-term radon measurement can be predicted by a collocated short-term radon measurement under different conditions. We compiled a national dataset of 2245 pairs of collocated short- and long-term measurements, analyzed the predictability of long-term measurements with stratified linear regression and bootstrapping resampling. We found that the extent to which a long-term measurement can be predicted by the collocated short-term measurement was a joint function of two factors the temporal difference in starting dates between two measurements and the length of the long-term measurement. Short-term measurements, jointly with other factors, could explain up to 79% (0.95 Confidence Interval CI 0.73-0.84) of the variance in seasonal radon concentrations and could explain up to 67% (0.95 CI 0.52-0.81) of the variance in annual radon concentrations. The large proportions of variance explained suggest that short-term measurement can be used as convenient proxy for seasonal radon concentrations. Accurate annual radon estimation entails averaging multiple short-term measurements in different seasons. Our findings will facilitate the usage of abundant short-term radon measurements, which have been obtained but was previously underutilized in assessing residential radon exposure. Tens of millions of short-term radon measurements have been conducted but underutilized in assessing residential exposure to radon, the greatest cause of lung cancer in non-smokers. We investigate the correlations between collocated short- and long-term measurements in 2245 U.S. buildings and find that short-term measurements can explain 75% of the variance in subsequent long-term measurements in the same buildings. Our results can facilitate the usage of massive short-term radon measurements that have been conducted to estimate the spatial and longitudinal distribution of radon concentrations, which can be used in epidemiological studies to quantify the health effects of radon.

Efficacy of combined transbronchial lung cryobiopsy and conventional forceps biopsy for lung malignancies a prospective cohort study.

There are few prospective reports of transbronchial lung cryobiopsy (TBLC) for malignant tumors in combination with forceps biopsy. We investigated the clinical parameters in which TBLC is superior to forceps biopsy. This is a prospective cohort study to analyse the efficacy of TBLC for suspected malignancy. TBLC was performed after brushing cytology and forceps biopsy, and the diagnostic yield for TBLC, brushing cytology, and forceps biopsy were examined. Adverse events were defined as those requiring additional procedures. Next-generation sequencing (NGS) analysis was performed in each case of non-small cell lung cancer. Of the 100 patients, malignancy was confirmed in 94 cases. The diagnostic yield for TBLCforceps biopsybrushing cytology was 868182% respectively, while the diagnostic yield for all procedures combined was 94%. There was no significant difference in the diagnostic yield between TBLC and forceps biopsy. When comparing the biopsy site, the diagnostic yield for TBLC at the lower lobe was significantly higher than forceps biopsy (P < 0.01). Endobronchial ultrasonography imaging using a guide-sheath did not significantly differ in the diagnostic yield of TBLC. The success rate of NGS for TBLC specimens was 100% (26 cases). Adverse events included two cases of severe bleeding. TBLC of peripheral lesions may improve the diagnostic yield when combined with forceps biopsy and brushing cytology. The diagnostic yield of TBLC was higher at the lower lobes. Furthermore, TBLC provided sufficient specimen quality for NGS.

Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPRCas9 screening.

There is currently a lack of efficacious treatments for patients with chemo-resistant small-cell lung cancer (SCLC), leading to poor prognoses. We examined a chemo-resistant SCLC cell line using genome-wide CRISPRCas9 screening and identified serinethreonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Silencing CDC7 in chemo-resistant SCLC cells decreased the IC

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer.

In the treatment of most malignancies, radiotherapy plays a significant role. However, the resistance of cancer cells to ionizing radiation (IR) is the main reason for the failure of radiotherapy, which causes tumor recurrence and metastasis. In this study, we confirmed that GPR162, an orphan receptor in the G-protein-coupled receptor family, acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes (STING), which targeted DNA damage responses, activated IRF3, accelerated the activation of type I interferon system, promoted the expression of chemokines including CXCL10 and CXCL4, and inhibited the occurrence and development of tumors. Interestingly, the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS. STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models. In addition, most solid tumors showed low expression of GPR162. And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma, liver cancer, breast cancer, etc. In summary, these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response, providing an alternative strategy for improving cancer radiotherapy.

Study protocol of KeyPemls-004 A phase 2 study of pembrolizumab in combination with plinabulin and docetaxel in previously treated patients with metastatic non-small cell lung cancer and progressive disease (PD) after immunotherapy (PD-1PD-L1 inhibitor) alone or in combination with platinum-doublet chemotherapy.

Immune checkpoint inhibitor (ICI)-based treatment regimens have become the standard of care for first-line treatment of metastatic epidermal growth factor receptor (EGFR)anaplastic lymphoma kinase (ALK) wild-type non-small cell lung cancer (NSCLC). Nevertheless, most patients inevitably develop disease progression, and the mechanisms of resistance to first-line immunotherapy are not clear. ICIs in combination with agents targeting other pathways may serve as second-line therapy options. Plinabulin is a selective immunomodulating microtubule-binding agent which inhibits the polymerization of tubulin monomers, with multiple mechanisms to inhibit tumor growth. Clinical studies have demonstrated preliminary the antitumor efficacy of this agent. Therefore, we hypothesize that a combination of plinabulin with programmed death 1 (PD-1) inhibitor and docetaxel may result in higher efficacy and fewer side effects leading to better tolerance. In this investigator-initiated, single-arm, open-label, phase II trial, metastatic NSCLC patients who acquired resistance to first-line immunotherapy-based therapy will be enrolled. Participants will receive pembrolizumab 200 mg D1, plinabulin 30 mgm This trial will provide evidence of the benefit and safety of pembrolizumab in combination with plinabulin and docetaxel in metastatic NSCLC patients who have been exposed and developed resistance to first-line PD-1PD-L1 inhibitor either as monotherapy or in combination with chemotherapy.

PARP inhibitor plus chemotherapy versus chemotherapy alone in patients with triple-negative breast cancer a systematic review and meta-analysis based on randomized controlled trials.

Chemotherapy is the standard treatment for triple-negative breast cancer (TNBC). Whether the addition of PARP inhibitors improves treatment efficacy remains controversial clinically. Thus, we performed a meta-analysis to compare the efficacy and safety of combination treatment (PC) and chemotherapy alone (CA). Relevant studies were identified through searches of 7 databases. The primary endpoints were progression-free survival (PFS) and overall survival (OS). We screened 317 studies and included seven RCTs involving 2091 patients in the final analysis. PC tended to have better efficacy than CA according to PFS (HR hazard ratio 0.83 0.75, 0.93, p 0.001), OS (HR 0.89 0.76,1.03, p 0.11) and overall response rate (ORR) (RR risk ratio 1.19 0.97,1.46, p 0.10). However, grade 3-5 AEs (RR 1.50 0.87,2.61, p 0.15) were observed in the PC group. In the PC arm, the 10 most-reported grade 3-5 AEs were neutropenia (62.8%), anemia (28.5%), thrombocytopenia (26.4%), lymphopenia (19.05%), leukopenia (16.9%), fatigue (5%), heart failure (4.76%), lung infection (4.76%), thromboembolic events (4.76%) and ventricular tachycardia (4.76%). Similar results for pathological complete response (pCR), total AEs, rate of complete response (CR), stable disease (SD) and progressive disease (PD), breast conservation rate (BCR), and drug discontinuation (DD) rate were found between the two groups. For TNBC treatment, the combination of PARP inhibitors and chemotherapy appears to be superior to chemotherapy alone with better antitumor efficacy. However, its higher rate of AEs needs to be taken seriously. More high-quality RCTs are needed to confirm these results.

The location of visceral pleural invasion in stage IB patients with non-small cell lung cancer Comparison and prognosis.

Recently, early-stage lung cancer has been drawing more attention, especially in screening and treatment. Visceral pleural invasion in stage IB cancer is considered as risk factor for poor prognosis. Herein, we aimed to study the distinction between the different locations of visceral pleural invasion. In this retrospective cohort study, we summarized 58,242 patient cases that underwent surgery from 2015 to 2018 at Shanghai Chest Hospital. Of those patients, 389 met the inclusion criteria. Patients with PL3 pleural invasion were excluded. The patients were dichotomized into the interlobar pleural and peripheral pleural groups. The outcomes measured were overall survival (OS) and recurrence-free survival (RFS) rates. According to the initial analysis, the baseline characteristics of the two groups were largely balanced. In multivariate Cox analyses, we found that the location of visceral pleural invasion was not a risk factor for prognosis in the overall population (RFS P 0.726, OS P 0.599). However, we discovered that relative to patients with peripheral pleura invasion, those with interlobar pleura invasion, PL1 invasion, lesions with greater than 3 cm solid components, and those who underwent segmentectomy had a compromised prognosis. Additionally, tumors larger than 3 cm in size with interlobar pleura invasion showed poor prognosis in patients who underwent postoperative chemotherapy. In most cases, the location of tumor invasion did not worsen the postoperative prognosis of stage IB non-small cell lung cancer patients with visceral pleural invasion. However, interlobar pleural invasion still had some potential risks compared to that of peripheral pleural invasion.

Effects of Expert-Determined Reference Standards in Evaluating the Diagnostic Performance of a Deep Learning Model A Malignant Lung Nodule Detection Task on Chest Radiographs.

Little is known about the effects of using different expert-determined reference standards when evaluating the performance of deep learning-based automatic detection (DLAD) models and their added value to radiologists. We assessed the concordance of expert-determined standards with a clinical gold standard (herein, pathological confirmation) and the effects of different expert-determined reference standards on the estimates of radiologists diagnostic performance to detect malignant pulmonary nodules on chest radiographs with and without the assistance of a DLAD model. This study included chest radiographs from 50 patients with pathologically proven lung cancer and 50 controls. Five expert-determined standards were constructed using the interpretations of 10 experts individual judgment by the most experienced expert, majority vote, consensus judgments of two and three experts, and a latent class analysis (LCA) model. In separate reader tests, additional 10 radiologists independently interpreted the radiographs and then assisted with the DLAD model. Their diagnostic performance was estimated using the clinical gold standard and various expert-determined standards as the reference standard, and the results were compared using the The LCA model (sensitivity, 72.6% specificity, 100%) was most similar to the clinical gold standard. When expert-determined standards were used, the sensitivities of radiologists and DLAD model alone were overestimated, and their specificities were underestimated (all The LCA model was most similar to the clinical gold standard for malignant pulmonary nodule detection on chest radiographs. Expert-determined standards caused bias in measuring the diagnostic performance of the artificial intelligence model.

Research progress of thyroid hormone in pulmonary fibrosis.

Pulmonary fibrosis is end-stage of variety of heterogeneous interstitial lung disease, characterizedby excessive proliferation of fibroblasts and extracellular matrix deposition and destruction of lung parenchyma. Thyroid and lung are derived from the same endodermal cells, thyroid hormone affect the occurrence、development and prognosis of the chronic obstructive pulmonary disease, lung cancer and other lung diseases, This article reviews the role and mechanism of thyroid hormone in pulmonary fibrosis in order to provide new idea for the study of the role and mechanism of thyroid hormone in silicosis. 肺纤维化是多种异质性肺间质疾病的终末期，以肌成纤维细胞的过度增殖、细胞外基质的沉积和肺实质的破坏为特征。甲状腺和肺来源于同一内胚层细胞，甲状腺激素影响慢性阻塞性肺疾病、肺癌等多种肺疾病的发生、发展和预后。本文就甲状腺激素在肺纤维化的作用和机制进行综述，以期为甲状腺激素在矽肺中的作用和机制研究提供新思路。.

Single-cell spatial landscape of immunotherapy response reveals mechanisms of CXCL13 enhanced antitumor immunity.

Immunotherapy has revolutionized clinical outcomes for patients suffering from lung cancer, yet relatively few patients sustain long-term durable responses. Recent studies have demonstrated that the tumor immune microenvironment fosters tumorous heterogeneity and mediates both disease progression and response to immune checkpoint inhibitors (ICI). As such, there is an unmet need to elucidate the spatially defined single-cell landscape of the lung cancer microenvironment to understand the mechanisms of disease progression and identify biomarkers of response to ICI. Here, in this study, we applied imaging mass cytometry to characterize the tumor and immunological landscape of immunotherapy response in non-small cell lung cancer by describing activated cell states, cellular interactions and neighborhoods associated with improved efficacy. We functionally validated our findings using preclinical mouse models of cancer treated with anti-programmed cell death protein-1 (PD-1) immune checkpoint blockade. We resolved 114,524 single cells in 27 patients treated with ICI, enabling spatial resolution of immune lineages and activation states with distinct clinical outcomes. We demonstrated that CXCL13 expression is associated with ICI efficacy in patients, and that recombinant CXCL13 potentiates anti-PD-1 response in vivo in association with increased antigen experienced T cell subsets and reduced CCR2 monocytes. Our results provide a high-resolution molecular resource and illustrate the importance of major immune lineages as well as their functional substates in understanding the role of the tumor immune microenvironment in response to ICIs.

First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations CheckMate 817.

CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (cohort A) and special populations (cohort A1 ECOG PS 2 or ECOG PS 0-1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection). Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mgkg every 6 weeks. The primary endpoint was the incidence of grade 3-4 and grade 5 immune-mediated adverse events (IMAEs adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoringintervention, reported between first dose and 30 days after the last dose) in cohort A efficacy endpoints were secondaryexploratory. In cohort A1, safetyefficacy assessment was exploratory. The most common grade 3-4 IMAEs were pneumonitis (5.1%), diarrheacolitis (4.9%), and hepatitis (4.6%) in cohort A (N391) and diarrheacolitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N198). The most common grade 3-4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively. Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0-1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate. NCT02869789.

Stability and safety of transbronchial dye mixture for preoperative localization in a porcine model.

For thoracoscopy, the usefulness of a dye mixture of indigo carmine and Lipiodol for localizing lung lesions has been reported. However, little is known about the stability and safety of this dye mixture injected on the visceral pleura through a bronchoscope. Porcine models were divided into three groups according to the detection time of the dye mixture group A with a detection time of 4 h group B, 8 h and group C, 24 h. A dye mixture of indigo carmine and Lipiodol (0.5 mL each) was sprayed onto the visceral pleura both in the ventral and dorsal regions via a spray catheter. Twelve markings were created on the visceral pleura of the porcine lung (six ventral and six dorsal) in the six porcine models. At predetermined detection times, all 12 dye markings (100%) were visible on the visceral pleura. The mean longest diameter of the dye marking in the ventral and dorsal regions was 18.8 mm and 24.3 mm, respectively. In groups B and C, pathological changes in the lymphatic system, such as lymphatic dilatations, were found minimal changes were found in group B, however, these changes with oval-shaped lymphatic cysts and Lipiodol accumulation, were more evident in group C. The dye mixture of indigo carmine and Lipiodol had reliable stability and visibility. In terms of safety, it may be necessary to check the dye mixture on the lung surface within 8 h.

Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade.

Programmed death-1 (PD-1) blockade promotes combination therapy in advanced non-small cell lung cancer (NSCLC), hypofractionated radiotherapy (HFRT) and chemotherapy combined with immunotherapy improves the outcome of prognosis in advanced NSCLC, while effective biomarkers to follow prognostic efficacy are still to be found. We enrolled 44 NSCLC patients with HFRT combined with PD-1 blockade, 13 patients with chemotherapy combined with immunotherapy, additionally collected tissue samples from 8 patients with earlystage NSCLC without therapy, and peripheral whole blood from 16 healthy donors, detected the expression differences of cytokines Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Interleukin 17A (IL-17A) in the peripheral plasma and tissues by flow cytometry, immunofluorescence, and real-time fluorescence quantitative PCR. Cultured peripheral blood mononuclear cell (PBMC) and tumor-infiltrating T cells with recombinant human IL-8 in vitro to observe the changes of immune memory T cell subtypes and apoptosis. Our results show that IL-6, IL-8, and IL-17A are highly expressed in advanced NSCLC, high levels of IL-8 are significantly associated with poor prognosis in advanced NSCLC patients treated with HFRT PD1 blockade, high circulating IL-8 in NSCLC increased apoptosis of effector memory RA (TemRA CD45RA We suggest that IL-8 can impair immune memory function in NSCLC. It is a useful biomarker to evaluate the efficacy of HFRT PD1 blockade in advanced NSCLC. Further exploration of easily available plasma biomarkers for personalized treatment of NSCLC is required.

An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers.

Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression. Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations. By combining the prognostic information of anti-tumoural CD8 Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types. Swedish Cancer Society, Lions Cancer Foundation, Selanders Foundation, P.O. Zetterling Foundation, U-CAN supported by SRA CancerUU, Uppsala University and Region Uppsala.

Eligibility to lung cancer screening among staffs of a university hospital A large cross-sectional survey.

Implementation of Lung cancer screening (LCS) programs is challenging. The ILYAD study objectives is to evaluate communication methods to improve participation rate among the Lyon University Hospital employees. In this first part of the study, we aimed to determinate the number of eligible individuals among our population of employees. In November 2020, we conducted a questionnaire based cross sectional survey among the Lyon University Hospital employees (N 26,954). We evaluated the PLCO m2012 risk prediction model and the eligibility criteria recommended by French guidelines. We assessed the proportion of eligible individuals among the responders and calculated the total eligible individuals in our hospital. Overall, 4,526 questionnaires were available for analysis. 16.0% were current smokers, and 28.2% were former smokers. Among the 50-75yo ever-smoker employees, 27% were eligible according to the French guidelines, 2.7% of all eversmokers according to a PLCO m2012 score ≥ 1.51%, and thus, 3.8% of the surveyed population were eligible to the combined criteria. The factors associated with higher eligibility among 50-75yo ever-smokers were educational level, feeling symptoms related to tobacco smoking, personal history of COPD and family history of lung cancer. Using the French guidelines criteria only, we estimated the total number of eligible individuals in the hospital at 838. In this study, we determined a theoretical number of eligible employees to LCS in our institution and the factors associated to eligibility. Secondly, we will propose LCS to all eligible employees of Lyon University Hospital with incremented information actions.

Statewide Examination of Access to Cancer Surgery During the COVID-19 Pandemic.

The COVID-19 pandemic caused interruptions in the delivery of medical care across a wide range of conditions including cancer. Trends in surgical treatment for cancer during the pandemic have not been well described. We sought to characterize associations between the pandemic and access to surgical treatment for breast, colorectal, and lung cancer in Illinois. We performed a retrospective cohort study evaluating inpatient admissions at Illinois hospitals providing surgical care for lung cancer (n 1913 cases, n 64 hospitals), breast cancer (n 910 cases, n 108 hospitals), and colorectal cancer (n 5339 cases, n 144 hospitals). Using discharge data from the Illinois Health and Hospital Associations Comparative Health Care and Hospital Data Reporting Services database, average monthly surgical case volumes were compared from 2019 to 2020. We also compared rates of cancer surgery for each cancer type, by patient characteristics, and hospital type across the three time periods using Pearson chi-squared and ANOVA testing as appropriate. Three discrete time periods were considered prepandemic (7-122019), primary pandemic (4-62020), and pandemic recovery (7-122020). Hospital characteristics evaluated included hospital type (academic, community, safety net), COVID-19 burden, and baseline cancer surgery volume. There were 2096 fewer operations performed for breast, colorectal, and lung cancer in 2020 than 2019 in Illinois, with the greatest reductions in cancer surgery volume occurring at the onset of the pandemic in April (colorectal, -48.3% lung, -13.1%) and May (breast, -45.2%) of 2020. During the pandemic, breast (-14.6%) and colorectal (-13.8%) cancer surgery experienced reductions in volume whereas lung cancer operations were more common (26.4%) compared to 2019. There were no significant differences noted in gender, race, ethnicity, or insurance status among patients receiving oncologic surgery during the primary pandemic or pandemic recovery periods. Academic hospitals, hospitals with larger numbers of COVID-19 admissions, and those with greater baseline cancer surgery volumes were associated with the greatest reduction in cancer surgery during the primary pandemic period (all cancer types, P < 0.01). During the recovery period, hospitals with greater baseline breast and lung cancer surgery volumes remained at reduced surgery volumes compared to their counterparts (P < 0.01). The COVID-19 pandemic was associated with significant reductions in breast and colorectal cancer operations in Illinois, while lung cancer operations remained relatively consistent. Overall, there was a net reduction in cancer surgery that was not made up during the recovery period. Academic hospitals, those caring for more COVID-19 patients, and those with greater baseline surgery volumes were most vulnerable to reduced surgery rates during peaks of the pandemic and to delays in addressing the backlog of cases.

Tripartite motif-containing 68-stabilized modulator of apoptosis-1 retards the proliferation and metastasis of lung cancer.

Non-small cell lung cancer (NSCLC) is a major global health threat with high incidence and mortality. Modulator of apoptosis-1 (MOAP1), also named MAP-1, belongs to the PNMA gene family and plays a key role in regulating apoptosis and tumor growth. However, its influences on NSCLC are largely unclear, and thus were explored in our present study, particularly the underlying mechanisms. Here, we initially find that MOAP1 expression is significantly decreased in NSCLC patients compared with the normal ones, and negatively correlated with the TNM and pathologic stages among patients. Additionally, MOAP1 low expression predicts a poorer prognosis than that of the NSCLC patients expressing higher MOAP1. Our in vitro studies confirm much lower MOAP1 expression in NSCLC cell lines. Of note, promoting MOAP1 expression strongly reduces the proliferation and induces apoptosis in NSCLC cells, accompanied with cell cycle arrest distributed in G0G1 phase. Moreover, we find that MOAP1 has a negative correlation with Th2 cells infiltration, but a positive correlation with the infiltration levels of eosinophils. Epithelial mesenchymal transition (EMT) process is also greatly restrained in NSCLC cells with MOAP1 over-expression, as proved by the reduced migration and invasion of cells. We further identify a positive correlation between MOAP1 and tripartite motif-containing 68 (TRIM68) in patients with NSCLC. Further analysis shows that TRIM68 directly interacts with MOAP1 and stabilizes MOAP1. Importantly, TRIM68 can activate MOAP1 by inducing the K63-linked polyubiquitination of MOAP1. Finally, animal studies verify that promoting MOAP1 efficiently suppresses tumor growth and lung metastasis in the nude mice. Collectively, our results reveal a novel mechanism through which MOAP1 stabilized by TRIM68 inhibits NSCLC development and targeting MOAP1 for its up-regulation may be a promising therapeutic strategy for NSCLC treatment.

Diagnostic Yield of Endobronchial Ultrasound-Guided Mediastinal Lymph Node Transbronchial Forceps Biopsies (EBUS-TBFB).

The diagnostic accuracy and yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is not well established in lymphoma and other mediastinal-related diseases. The objective of this study was to examine the yield of a combined technique of EBUS-TBNA and endobronchial ultrasound-guided transbronchial forceps biopsies (EBUS-TBFB) compared with each modality alone in lymphoma and other mediastinal-related diseases. This was a retrospective review of cases of mediastinal lymphadenopathy of unknown etiology accessed using TBNA and TBFB. The McNemar test was used to compare the diagnostic yield of TBNA, TBFB, and the combined technique. The combined approach yielded a definitive diagnosis in 3135 cases (88.6%). In 910 cases (90%), Hodgkins and non-Hodgkins lymphomas were diagnosed and subtyped without further need for invasive testing. All of the granulomatous inflammation cases were confirmed using the combined technique. Two cases led to adequate whole-genome sequencing of lung cancer, and one patient was diagnosed as having dedifferentiated liposarcoma despite a nondiagnostic preprocedural mediastinoscopy. There was only one procedure-related complication, a pneumomediastinum that required no further intervention. There were no significant adverse events. The combination of EBUS-TBFB and EBUS-TBNA is safe and provides a high yield in the diagnosis of mediastinal adenopathy of unknown etiology, especially lymphoma. Furthermore, the larger samples obtained from TBFB increased its sensitivity to detect granulomatous disease and provided specimens for clinical trials of malignancy when needle aspirates were insufficient.

Design and CT imaging of casper, an anthropomorphic breathing thorax phantom.

The goal of this work was to build an anthropomorphic thorax phantom capable of breathing motion with materials mimicking human tissues in x-ray imaging applications. The thorax phantom, named Casper, was composed of resin (body), foam (lungs), glow polyactic acid (bones) and natural polyactic acid (tumours placed in the lungs). X-ray attenuation properties of all materials prior to manufacturing were evaluated by means of photon-counting computed tomography (CT) imaging on a table-top system. Breathing motion was achieved by a scotch-yoke mechanism with diaphragm motion frequencies of 10-20 rpm and displacements of 1 to 2 cm. Casper was manufactured by means of 3D printing of moulds and ribs and assembled in a complex process. The final phantom was then scanned using a clinical CT scanner to evaluate material CT numbers and the extent of tumour motion. Casper CT numbers were close to human CT numbers for soft tissue (46 HU), ribs (125 HU), lungs (-840 HU) and tumours (-45 HU). For a 2 cm diaphragm displacement the largest tumour displacement was 0.7 cm. The five tumour volumes were accurately assessed in the static CT images with a mean absolute error of 4.3%. Tumour sizes were either underestimated for smaller tumours or overestimated for larger tumours in dynamic CT images due to motion blurring with a mean absolute difference from true volumes of 10.3%. More Casper information including a motion movie and manufacturing data can be downloaded from httpweb.uvic.cabazalovaCasper.

CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors.

Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.

Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy.

Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog D-Phe

Survival of Patients With Inoperable Non-Small Cell Lung Cancer With Baseline Severe Pulmonary Dysfunction Impacts of Thoracic Radiotherapy and Predictive Analysis for Acute Radiation Pneumonitis.

Currently, there is no standard treatment for patients with lung cancer with deteriorated pulmonary function. In this study, we aimed to assess the efficacy of thoracic radiotherapy for unresectable non-small cell lung cancer (NSCLC) with baseline severe pulmonary dysfunction and severe acute radiation pneumonitis (SARP). Patients were categorized into a radiotherapy group and a nonradiotherapy group, followed by analysis of clinical variables. A Cox regression was used to evaluate the impact of various factors on overall survival (OS). Each SARP factors predictive value was assessed using logistic regression, receiver operating characteristic curve, and Kaplan-Meier analyses. The median OS in the radiotherapy group was 21.6 months vs 8.9 months in the nonradiotherapy group. Cox analysis revealed that chemotherapy (HR, 0.221 95% CI, 0.149-0.329 P < .001) and radiotherapy (HR, 0.589 95% CI, 0.399-0.869 P .008) are independent prognostic factors for the current cohort. The data suggested that the ipsilateral lung V10 (ilV10, the percentage of the lung volume that received more than 10 Gy) was an independent predictor of SARP. Our findings suggested that thoracic radiotherapy might be associated with clinical benefits to inoperable NSCLC in patients with severe pulmonary dysfunction and that ilV10 may be involved in the prediction of risk for SARP in these patients.

NumbParkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation.

Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the NumbParkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the NumbParkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation.

A cuproptosis-associated long non-coding RNA signature for the prognosis and immunotherapy of lung squamous cell carcinoma.

Cuproptosis, a copper-induced mechanism of mitochondrial-related cell death, has been implicated as a breakthrough in the treatment of cancer and has become a new treatment strategy. Furthermore, long non-coding RNA (lncRNA) can change the biological activities of tumor cells. Worldwide, lung squamous cell carcinoma (LUSC) is among the most common annoying tumors. LncRNAs related to cuproptosis are not researched at LUSC. Our research intends to develop a signature on the basis of cuproptosis-associated lncRNAs, which can predict LUSC prognosis and investigate LUSC immunological features. The TCGA database was used to retrieve LUSC transcriptome, clinical, and gene mutation data. For statistical analysis, we utilized the R program. We created a signature consisting of three cuproptosis-related lncRNAs in this investigation (including AC002467.1, LINC01740, and LINC02345). Survival analyses and Receiver Operating Characteristic curves demonstrated that this signature possessed powerful predictive capability. The signatures ability to predict was confirmed by a Receiver Operating Characteristic curve and principal component analysis. Notably, the patient with a high-risk score and a high tumor mutation burden level had a lower survival time. Furthermore, the tumor immune dysfunction and exclusion analysis showed that these individuals with low-risk scores may benefit from immunotherapy. The signature constructed by three cuproptosis-associated lncRNAs may be prognostic markers of LUSC. It contributes to immunotherapy and offers LUSCs therapy a new treatment direction.

The Humeral Metastasis as the Initial Presentation of Lung Adenocarcinoma Revealed by 18F-FDG PETCT.

Lung adenocarcinoma with humeral metastasis as the initial presentation is rare. We reported FDG PETCT findings of solitary humeral metastasis from adenocarcinoma of the lung in a 57-year-old man with the right upper arm pain as the initial presentation. MRI showed bone destruction of the right humerus with a soft tissue mass, suggesting the possibility of malignancy. FDG PETCT showed that the right humeral mass had strong activity, and there were additional FDG lesions in the right armpit, left apical lung, and left adrenal gland, which was later confirmed as humeral metastasis from lung adenocarcinoma by pathological examination.

18FDG PETCT Tumoral and Neurologic Therapeutic Response in a Case of Anti-GABABR Paraneoplastic Limbic Encephalitis.

A 70-year-old man with a history of small cell lung carcinoma 2 years earlier was addressed for the suspicion of a paraneoplastic limbic encephalitis. Brain 18FDG PETCT revealed a bilateral amygdalian and hippocampal hypermetabolism, confirming a limbic encephalitis, and concurrent whole-body 18FDG PETCT showed a small cell lung carcinoma plurifocal metastatic recurrence, consistent with a paraneoplastic limbic encephalitis. 18FDG PETCT follow-up under chemotherapy revealed an almost complete normalization of brain metabolism and a partial metabolic response of the metastatic recurrence, consistent with the good clinical neurological evolution of the patient. This case highlights the clinical-metabolic imaging correlation in paraneoplastic limbic encephalitis.

Arsenic trioxide (ATO) exerts anticancer effects on lung cancer. However, the clinical use of ATO is limited due to its systemic toxicity and resistance of lung cancer cells. The present study aimed to investigate the effects of ATO, alone and in combination with The transmission electron microscope observed the tumor ultrastructure of lung cancer xenograft mice. The proliferation index of Ki-67 and the number and morphology of tumor microvessels were detected with immunohistochemical staining. The protein and mRNA expression were examined by western blot and real-time PCR assay. The in vivo results demonstrated that ATO combined with ATO combined with

Prediction of histologic types in solid lung lesions using preoperative contrast-enhanced CT.

This study aimed to develop and validate a predicting model for the histologic classification of solid lung lesions based on preoperative contrast-enhanced CT. A primary dataset of 1012 patients from Tianjin Medical University Cancer Institute and Hospital (TMUCIH) was randomly divided into a development cohort (708) and an internal validation cohort (304). Patients from the Second Hospital of Shanxi Medical University (SHSMU) were set as an external validation cohort (212). Two clinical factors (age, gender) and twenty-one characteristics on contrast-enhanced CT were used to construct a multinomial multivariable logistic regression model for the classification of seven common histologic types of solid lung lesions. The area under the receiver operating characteristic curve was used to assess the diagnostic performance of the model in the development and validation cohorts, separately. Multivariable analysis showed that two clinical factors and twenty-one characteristics on contrast-enhanced CT were predictive in lung lesion histologic classification. The mean AUC of the proposed model for histologic classification was 0.95, 0.94, and 0.92 in the development, internal validation, and external validation cohort, respectively. When determining the malignancy of lung lesions based on histologic types, the mean AUC of the model was 0.88, 0.86, and 0.90 in three cohorts. We demonstrated that by utilizing both clinical and CT characteristics on contrast-enhanced CT images, the proposed model could not only effectively stratify histologic types of solid lung lesions, but also enabled accurate assessment of lung lesion malignancy. Such a model has the potential to avoid unnecessary surgery for patients and to guide clinical decision-making for preoperative treatment. • Clinical and CT characteristics on contrast-enhanced CT could be used to differentiate histologic types of solid lung lesions. • Predicting models using preoperative contrast-enhanced CT could accurately assessment of tumor malignancy based on predicted histologic types.

Acute arterial occlusive disease due to tumor thrombus from lung metastasis of breast cancer with cartilaginous and osseous metaplasia a case report.

Tumor embolization due to venous infiltration of breast cancer pulmonary metastases is very rare. A 72-year-old female was diagnosed with triple-negative breast cancer. Neoadjuvant chemotherapy was discontinued because of progressive disease, and a right mastectomy with sentinel lymph node biopsy was performed. The pathological analysis of surgical specimens revealed carcinoma with cartilaginous andor osseous metaplasia. At 22 months after surgery, lung metastasis was observed, and 6 months after initiating treatment for lung metastases, she complained of sudden numbness in the left-lower limb with trouble walking. Ultrasonography showed an embolism in the left popliteal artery, and contrast computed tomography showed enlarged lung metastases and infiltration of the left-upper lobe disease into the left superior pulmonary vein and left atrium. Acute arterial occlusive disease in the left-lower limb caused by the tumor embolism was suspected, so an endovascular thrombectomy was performed. Tumor emboli were removed by embolectomy catheter. This report of lung metastasis from breast cancer with cartilaginous andor osseous metaplasia and acute lower-limb artery occlusion due to a tumor thrombus adds useful information to the literature on these extremely rare cases.

Non-utilisation of medical services during the COVID-19 pandemic among persons with chronic diseases.

The COVID-19 pandemic is also impacting the medical care for other diseases. The extent to which people with chronic diseases are affected by the suspension of medical services is investigated-differentiating between patient and provider perspectives. A cross-sectional study was conducted based on data from the longitudinal Hamburg City Health Study (HCHS). The study population was all HCHS participants (a sample of the population of Hamburg, 45-74 years) between April 2020 and November 2021. Utilisation of medical services was collected via the COVID-19-module of the HCHS. The chronic conditions included cardiovascular disease, kidney and lung disease, cancer and diabetes mellitus analyses were descriptive and multivariate. Of the 2047 participants, 47.9% had at least one previous illness. Of those with pre-existing conditions, 21.4% had at least one healthcare service suspended or an appointment cancelled. In addition, 15.4% stated that they decided by themselves not to attend a doctors appointment. Specialist care services (43.8% of all cancellations) were cancelled more frequently than general practitioner care (16.6%). After adjustment for age, gender and education, lung disease (OR 1.80 p < 0.008) and cancer (OR 2.33 p < 0.001) were found to be independent risk factors for appointment cancellations by healthcare providers. Of cancellations by patients, 42.2% were due to their fear of an infection with the coronavirus SARS-CoV‑2. Health policy and the media are faced with the challenge of dealing with fears of infection in the population in such a way that they do not lead to an avoidance of necessary care services. EINLEITUNG Die COVID-19-Pandemie wirkt sich auch auf die medizinische Versorgung anderer Erkrankungen aus. Differenziert zwischen patientinnen- und anbieterinnenseitigen Gründen wurde untersucht, inwieweit Personen mit chronischen Erkrankungen vom Aussetzen medizinischer Versorgungsleistungen betroffen sind. Es wurde eine Querschnittstudie auf Datenbasis der Kohortenstudie Hamburg City Health Study (HCHS) durchgeführt. Die Studienpopulation bestand aus allen HCHS-Teilnehmerinnen (Stichprobe der Bevölkerung Hamburgs, 45–74 Jahre) zwischen April 2020 und November 2021. Über das „COVID-19-Modul“ der HCHS wurde die Inanspruchnahme von Versorgungsleistungen erhoben. Als Grunderkrankungen wurden u. a. Herz-Kreislauf‑, Nieren- und Lungenerkrankungen, Krebs und Diabetes mellitus betrachtet. Die Daten wurden deskriptiv und multivariat in logistischen Regressionen ausgewertet. Von 2047 Teilnehmerinnen hatten 47,9 % mindestens eine Vorerkrankung. 21,4 % der Personen mit Vorerkrankungen hatten mindestens eine Versorgungsleistung ausgesetzt oder eine Terminabsage erhalten. 15,4 % gaben an, von sich aus auf einen Arztbesuch verzichtet zu haben. Fachärztliche Leistungen (Anteil 43,8 %) entfielen häufiger als hausärztliche (16,6 %). Nach Adjustierung für Alter, Geschlecht und Bildung erwiesen sich Lungen- (OR 1,80 p < 0,008) und Krebserkrankungen (OR 2,33 p < 0,001) als unabhängige Risikofaktoren für ärztliche Terminabsagen. 42,2 % der patientinnenseitigen Absagen erfolgten aus Angst vor einer Ansteckung mit SARS-CoV‑2. Gesundheitspolitik und Medien stehen vor der Herausforderung, mit Ängsten in der Bevölkerung vor einer Infektion so umzugehen, dass notwendige Versorgungsleistungen dadurch nicht vermieden werden.

Area-level Socioeconomic Disadvantage and Cancer Survival in Metropolitan Detroit.

Racial segregation is linked to poorer neighborhood quality and adverse health conditions among minorities, including worse cancer outcomes. We evaluated relationships between race, neighborhood social disadvantage, and cancer survival. We calculated overall and cancer-specific survival for 11,367 non-Hispanic Black (NHB) and 29,481 non-Hispanic White (NHW) individuals with breast, colorectal, lung, or prostate cancer using data from the Metropolitan Detroit Cancer Surveillance System. The area deprivation index (ADI) was used to measure social disadvantage at the census block group level, where higher ADI is associated with poorer neighborhood factors. Associations between ADI and survival were estimated using Cox proportional hazards mixed-effects models accounting for geographic grouping and adjusting for demographic and clinical factors. Increasing ADI quintile was associated with increased overall mortality for all four cancer sites in multivariable-adjusted models. Stratified by race, these associations remained among breast (NHW HR 1.16, P < 0.0001 NHB HR 1.20, P < 0.0001), colorectal (NHW HR 1.11, P < 0.0001 NHB HR 1.09, P 0.00378), prostate (NHW HR 1.18, P < 0.0001 NHB HR 1.18, P < 0.0001), and lung cancers (NHW HR 1.06, P < 0.0001 NHB HR 1.07, P 0.00177). Cancer-specific mortality estimates were similar to overall mortality. Adjustment for ADI substantially attenuated the effects of race on mortality for breast overall proportion attenuated (OPA) 47%, P < 0.0001 cancer-specific proportion attenuated (CSPA) 37%, P < 0.0001 prostate cancer (OPA 51%, P < 0.0001 CSPA 56%, P < 0.0001), and colorectal cancer (OPA 69%, P 0.032 CSPA 36%, P 0.018). Area-level socioeconomic disadvantage is related to cancer mortality in a racially diverse population, impacting racial differences in cancer mortality. Understanding the role of neighborhood quality in cancer survivorship could improve community-based intervention practices.

Subtyping of advanced lung cancer based on PD-L1 expression, tumor histopathology and mutation burden (EGFR and KRAS) a study from North India.

Immune checkpoint inhibitor (PD-L1) therapy of advanced non-small-cell lung cancer (NSCLC) has variable outcomes. Tumor subtypes based on PD-L1 expression, histopathology, mutation burden is required for patient stratification and formulation of treatment guidelines. Lung cancers (n57) diagnosed at Pathology department, VPCI (2018-2021) were retrospectively analyzed. PD-L1(SP263) expressed by tumor cells low (<1%), medium (1-49%), high (≥50%) was correlated with histopathology, microenvironment, EGFR, KRAS expression. Patients were categorized into high and low risk based on their i) gender males (n47, 30-89 years), females (n10, 45-80 years) ii) smoking history males 2647 (45.61%), females 110 (10%) iii) tumor subtyping squamous cell carcinoma 1557 (26.32%), adenocarcinoma 657 (17.54%), NSCLC-undifferentiated 2457 (42.10%), adenosquamous carcinoma 557 (8.77 %), carcinosarcoma 457 (7.02%), small cell carcinoma 157 (1.75%) iv) inflammatory tumor microenvironmentTILs 4457 (77.1%) iv) PD-L1 positivity-3157 (54.3%) v) concomitant EGFRKRAS positivity. PD-L1positive cases showed squamousundifferentiated histopathology, concomitant EGFR (920, 45%) and KRAS (815, 53.3%), smoking (2131,67.74%).PD-L1 negative cases (2657, 45.6%), were EGFR (214, 14.28%) and KRAS (619, 31.5%). The high-risk lung cancer subtypes show squamousundifferentiated histopathology, inflammatory microenvironment, male preponderance, smoking history, higher concomitant PD-L1, KRAS and EGFR positivity. Lung cancer subtyping can predict clinical responseresistance of patients prior to initiation of PD-L1 inhibitor therapies and can be used to guide therapy.

Focus on the molecular mechanisms of cisplatin resistance based on multi-omics approaches.

Cisplatin is commonly used in combination with other cytotoxic agents as a standard treatment regimen for a variety of solid tumors, such as lung, ovarian, testicular, and head and neck cancers. However, the effectiveness of cisplatin is accompanied by toxic side effects, for instance, nephrotoxicity and neurotoxicity. The response of tumors to cisplatin treatment involves multiple physiological processes, and the efficacy of chemotherapy is limited by the intrinsic and acquired resistance of tumor cells. Although enormous efforts have been made toward molecular mechanisms of cisplatin resistance, the development of omics provides new insights into the understanding of cisplatin resistance at genome, transcriptome, proteome, metabolome and epigenome levels. Mechanism studies using different omics approaches revealed the necessity of multi-omics applications, which provide information at different cellular function levels and expand our recognition of the peculiar genetic and phenotypic heterogeneity of cancer. The present work systematically describes the underlying mechanisms of cisplatin resistance in different tumor types using multi-omics approaches. In addition to the classical mechanisms such as enhanced drug efflux, increased DNA damage repair and changes in the cell cycle and apoptotic pathways, other changes like increased protein damage clearance, increased protein glycosylation, enhanced glycolytic process, dysregulation of the oxidative phosphorylation pathway, ferroptosis suppression and mRNA m6A methylation modification can also induce cisplatin resistance. Therefore, utilizing the integrated omics to identify key signaling pathways, target genes and biomarkers that regulate chemoresistance are essential for the development of new drugs or strategies to restore tumor sensitivity to cisplatin.

Mesopore-encaged active MnOx in nano-silica selectively suppresses lung cancer cells by inducing autophagy.

Autophagy induced by nanomaterials is one of the intracellular catabolic pathways that degrade and recycle the biomacromolecules and damaged organelles in cells and has emerged as a very promising pharmacological target critical to future drug development and anti-cancer therapy. Herein, we developed mesopore-encaged highly-dispersed active cluster-like MnOx in nanosilica entitled MnO-MS, with a size of around 130 nm. Our studies show that MnO-MS could not only obviously induce autophagy in both stable GFP-LC3 HeLa cells and GFP-LC3-mCherry HeLa cells but also could selectively inhibit lung cancer A549 cell growth at 11.19 μg mL

Extended Survival in Patients With Non-Small-Cell Lung Cancer-Associated Brain Metastases in the Modern Era.

Brain metastases (BM) have long been considered a terminal diagnosis with management mainly aimed at palliation and little hope for extended survival. Use of brain stereotactic radiosurgery (SRS) andor resection, in addition to novel systemic therapies, has enabled improvements in overall and progression-free (PFS) survival. To explore the possibility of extended survival in patients with non-small-cell lung cancer (NSCLC) BM in the current era. During the years 2008 to 2020, 606 patients with NSCLC underwent their first Gamma Knife SRS for BM at our institution with point-of-care data collection. We reviewed clinical, molecular, imaging, and treatment parameters to explore the relationship of such factors with survival. The median overall survival was 17 months (95% CI, 13-40). Predictors of increased survival in a multivariable analysis included age <65 years (P < .001), KPS ≥80 (P < .001), absence of extracranial metastases (P < .001), fewer BM at first SRS (≤3, P .003), and targeted therapy (P .005), whereas chemotherapy alone was associated with shorter survival (P .04). In a subgroup of patients managed before 2016 (n 264), 38 (14%) were long-term survivors (≥5 years), of which 16% required no active cancer treatment (systemic or brain) for ≥3 years by the end of their follow-up. Long-term survival in patients with brain metastases from NSCLC is feasible in the current era of SRS when combined with the use of effective targeted therapeutics. Of those living ≥5 years, the chance for living with stable disease without the need for active treatment for ≥3 years was 16%.

Treatment patterns and long-term survival outcomes for patients with stage III non-small cell lung cancer A retrospective study.

Lung cancer is the leading cause of cancer-related deaths in Australia with poor long-term survival outcomes. Stage III non-small cell lung cancer (NSCLC) is a highly heterogenous group with diverse tumor characteristics and multiple, possible treatment options. We present retrospective data on patient characteristics, treatment patterns, and long-term outcomes in stage III NSCLC patients treated at a single cancer center in New South Wales, Australia. Stage III NSCLC patients were identified from the Nepean Cancer Research Biobank. Patient demographics, cancer-related information, and long-term follow-up data were collected and analyzed. A total of 88 patients were eligible for analysis with 61% of them diagnosed as stage IIIA, 35% IIIB, and 4% IIIC. Induction chemotherapy was administered in 20% of the patients. Overall, 48% of the study population underwent surgery, and 38% underwent concurrent chemoradiotherapy (CCRT). Both median progression-free survival and overall survival (OS) were superior in stage IIIA patients in comparison to stage IIIB (and IIIC) patients (22 vs. 11 months, p .018 and 58 vs. 19 months, p .048, respectively). Patients who were younger (<65 years old), good Eastern Cooperative Oncology Group performance status (ECOG PS <2), and females had better prognosis on univariate analysis. There was a nonstatistically significant trend toward better median OS with CCRT in comparison to surgery (58 vs. 37 months, p .87). Long-term outcomes remain poor, and hence better treatment strategies are urgently needed in stage III NSCLC. Equally, more robust, prospective studies would help delineate the optimal treatment modality in these patients.

Alternative Chemotherapies Angiotensin-Converting Enzyme Inhibitors Reduce Myeloid-Derived Suppressor Cells to Benefit Older Patients with Colorectal Cancer.

Older individuals are more likely to develop solid cancers, but at the same time are more sensitive to the side effects of chemotherapy. In addition, older adults are more likely to present with chronic diseases (comorbidities) and immunosenescence that may decrease immunosurveillance against cancer. Clinical outcomes for the older patient with cancer are different from the younger patient and require different research and treatment approaches. Thus, alternative therapeutic approaches tailored specifically to the older patients are required. Colorectal cancer (CRC) has a high incidence in older individuals and is the third leading cause of cancer death globally. Anti-hypertensives are used by a large proportion of older patients and some studies have pointed to a positive impact of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on CRC outcomes. As we have previously shown in a mouse model, lung metastases express ACE and contain many infiltrating myeloid-derived suppressor cells (MDSC) particularly high levels of MDSC are also present in the blood of older patients with CRC and other cancers, and are associated with disease severity. In this Commentary, we hypothesize that one mechanism responsible for the positive impact of ACEi or ARB on the outcome of CRC is the modulation of myeloid cells contributing to their maturation to non-suppressive neutrophilsmonocytes and diverting them away from retaining an immature MDSC phenotype.

HIV and chronic lung disease.

As people living with human immunodeficiency virus (HIV, PLWH) age, aging-related comorbidities have come into focus as major challenges to their overall health. In this review, an in-depth overview of the two most commonly encountered chronic lung diseases in PLWH, chronic obstructive pulmonary disease (COPD) and lung cancer, is provided. The risk for both COPD and lung cancer remains significantly higher in PLWH compared to the HIV-uninfected population, although fortunately rates of lung cancer appear to be declining over the last two decades. Outcomes for PLWH with these conditions, though, continue to be poor with worse survival rates in comparison to the general population. PLWH still face major barriers in accessing care for these conditions, including a higher likelihood of being underdiagnosed with COPD and a lower likelihood of being referred for lung cancer screening or treatment. A lack of evidence for optimal treatment strategies for both COPD and lung cancer still hampers the care of PLWH with these conditions. COPD and lung cancer represent substantial burdens of disease in PLWH. Improved access to standard-of-care screening and treatment and greater investigation into therapeutic responses specifically in this population are recommended.

Use of Veterans Health Administration Structured Data to Identify Patients Eligible for Lung Cancer Screening.

Lung cancer screening (LCS) uptake is low. Assessing patients cigarette pack-years and years since quitting is challenging given the lack of documentation in structured electronic health record data. We used a convenience sample of patients with a chest CT scan in the Veterans Health Administration. We abstracted data on cigarette use from electronic health record notes to determine LCS eligibility based on the 2021 U.S. Preventive Services Task Force age and cigarette use eligibility criteria. We used these data as the ground truth of LCS eligibility to compare them with structured data regarding tobacco use and a COPD diagnosis. We calculated sensitivity and specificity as well as fast-and-frugal decision trees. For 50-80-year-old veterans identified as former or current tobacco users, we obtained 94% sensitivity and 47% specificity. For 50-80-year-old veterans identified as current tobacco users, we obtained 59% sensitivity and 79% specificity. Our fast-and-frugal decision tree that included a COPD diagnosis had a sensitivity of 69% and a specificity of 60%. These results can help health care systems make their LCS outreach efforts more efficient and give administrators and researchers a simple method to estimate their number of possibly eligible patients.

Extended Pulmonary Resection for T4 Non-Small Cell Lung Cancer.

Purine synthesis suppression reduces the development and progression of pulmonary hypertension in rodent models.

Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of pulmonary hypertension (PH). Proliferative cells utilize purine bases from the de novo purine synthesis (DNPS) pathways for nucleotide synthesis however, it is unclear whether DNPS plays a critical role in VSMC proliferation during development of PH. The last two steps of DNPS are catalysed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferaseinosine monophosphate cyclohydrolase (ATIC). This study investigated whether ATIC-driven DNPS affects the proliferation of pulmonary artery smooth muscle cells (PASMCs) and the development of PH. Metabolites of DNPS in proliferative PASMCs were measured by liquid chromatography-tandem mass spectrometry. ATIC expression was assessed in platelet-derived growth factor-treated PASMCs and in the lungs of PH rodents and patients with pulmonary arterial hypertension. Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in both hypoxia- and lung interleukin-6hypoxia-induced murine PH. ATIC-mediated DNPS at the mRNA, protein, and enzymatic activity levels were increased in platelet-derived growth factor-treated PASMCs or PASMCs from PH rodents and patients with pulmonary arterial hypertension. In cultured PASMCs, ATIC knockdown decreased DNPS and nucleic acid DNARNA synthesis, and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodelling and inhibited the development and progression of both hypoxia- and lung IL-6hypoxia-induced PH in mice. Targeting ATIC-mediated DNPS compromises the availability of purine nucleotides for incorporation into DNARNA, reducing PASMC proliferation and pulmonary vascular remodelling and ameliorating the development and progression of PH.

Early Detection of Cancers in the Era of Precision Oncology.

The increasing global incidence of cancer demands innovative cancer detection modalities. The current population-based early cancer detection approaches focus on several major types of cancers (breast, prostate, cervical, lung and colon) at their early stages, however, they generally do not target high-risk individuals at precancerous stages. Some cancers, such as pancreatic cancer, are challenging to detect in their early stages. Therefore, there is a pressing need for improved, accessible, noninvasive, and cost-effective early detection methods. Harnessing cell-free-based biomarker-driven strategies paves a new era of precision diagnosis for multicancer early detection. The majority of these tests are in the early stages and expensive, but these approaches are expected to become cost sensitive in the near future. This review provides an overview of early cancer detection strategies, highlighting the methods, challenges, and issues to be addressed to revolutionize and improve global early cancer detection.

Successful Retreatment with Crizotinib After Crizotinib-Induced Liver Failure in ALK-Positive Advanced Lung Adenocarcinoma A Case Report.

Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are treated with crizotinib. However, treatment with crizotinib is often discontinued owing to hepatotoxicity. Herein, we report a case of crizotinib-induced liver failure that was successfully treated. A 70-year-old woman complained of a cough with blood in her sputum and presented to our hospital in September 2020. Imaging examination revealed a mass in the middle and lower lobes of the right lung invading the right pulmonary artery and metastases to the right hilar lymph nodes and pleura. A stage IVa (cT4N1M1a) lung adenocarcinoma with ALK fusion was diagnosed. The patient received crizotinib, an ALK tyrosine kinase inhibitor and achieved partial remission. However, she suffered from acute liver failure, which led to the cessation of treatment. The patient was started on a liver protection treatment, and the liver function subsequently recovered. One year later, crizotinib was readministered at a half-dose because of disease progression, and the patient achieved stable disease without hepatotoxicity for 9 months. Therefore, the patient benefited from crizotinib without hepatotoxicity one year after acute liver failure caused by crizotinib.

Evaluation of clinical outcomes, laboratory and imaging data of patients with solid tumor infected with COVID-19 infection.

COVID-19 is associated with higher mortality rates in patients with cancer. In this study, we aimed to evaluate the clinical outcomes, and laboratory and imaging data of patients with solid tumor infected with COVID-19 infection. This is a cross-sectional retrospective study performed in 2020-2022 on 85 patients with a previous diagnosis of solid tumors infected with COVID-19. We included all patients with tumors of solid organs that were diagnosed with COVID-19 infection and required hospitalization those patients previously hospitalized for treatments and were infected with COVID-19 during hospitalization. Demographic data of patients were collected using a checklist. We collected data regarding clinical outcome (discharge, hospitalization or death), duration of hospitalization, requiring ICU admission, duration of hospitalization divided by received drugs and type of tumor and mean survival time. Furthermore, we collected laboratory data from all patients. The radiologic characteristics of patients were also extracted from their data. Breast cancer was the most common solid tumor (34.9%), followed by lung cancer (19.3%). The mortality rate was 24.1% (20 patients). The highest mortality rate in this study was for metastatic intestinal cancer to the lung (100%, one patient), followed by metastatic prostatic cancer to lung (50%, three patients). The highest hospitalization duration was for patients with glioblastoma multiform (GBM) (30 days). The mean survival time among patients with mortality was 19.15±1.80 days. The mean CT severity score of all patients was 27.53±22.90. Patients most common radiologic sign was air space consolidation (89.1%). The highest CT severity score was found in patients with stomach cancer (46.67±5.77). The mortality rate in this study was 24.1%. Based on the results of our study and previous research, special care should be provided to patients with solid tumors during the COVID-19 pandemic and in infected cases.

Ferroptosis as a Potential Cell Death Mechanism Against Cisplatin-Resistant Lung Cancer Cell Line.

Bioactive PI3-kinaseAktmTOR Inhibitors in Targeted Lung Cancer Therapy.

One of the central signaling pathways with a regulatory effect on cell proliferation and survival is AktmTOR. In many human cancer types, for instance, lung cancer, the overexpression of AktmTOR has been reported. For this reason, either targeting cancer cells by synthetic or natural products affecting the AktmTOR pathway down-regulation is a useful strategy in cancer therapy. Direct inhibition of the signaling pathway or modulation of each related molecule could have significant feedback on the growth and proliferation of cancer cells. A variety of secondary metabolites has been identified to directly inhibit the AKTmTOR signaling, which is important in the field of drug discovery. Naturally occurring nitrogenous and phenolic compounds can emerge as two pivotal classes of natural products possessing anticancer abilities. Herein, we have summarized the alkaloids and flavonoids for lung cancer treatment together with all the possible mechanisms of action relying on the AktmTOR pathway down-regulation. This review suggested that in search of new drugs, phytochemicals could be considered as promising scaffolds to be developed into efficient drugs for the treatment of cancer. In this review, the terms AktmTOR, Alkaloid, flavonoid, and lung cancer were searched without any limitation in search criteria in Scopus, PubMed, Web of Science, and Google scholar engines.

Immunotherapy in Cancer Management A Literature Review of Clinical Efficacy of Pembrolizumab in the Non-small Cell Lung Cancer Treatment.

An Unusual Case of Two Paraneoplastic Neurological Syndromes in a Patient With Lung Cancer.

Paraneoplastic immune-mediated disorders have been well described in the literature. However, it is still relatively rare. The incidence has increased over the past decade due largely to the discovery of more autoantibodies. With a better understanding of the pathophysiology of different autoantibodies and clinical phenotypes, we are often able to diagnose clinically some specific paraneoplastic autoimmune neurological syndromes. We may also predict the response to treatment based on the autoantibody class. We are presenting a very unusual case of two completely different paraneoplastic syndromes with two different autoantibodies, gamma-aminobutyric acid-B (GABA

Colorectal Adenocarcinoma Metastasis to the Hard Palate An Uncommon Site of Metastasis for a Common Malignancy.

Colorectal adenocarcinoma (CRC) most commonly metastasizes to the peritoneum, liver, lung, and bone. Metastasis to the oral cavity is uncommon. Here, we report the case of a 74-year-old man who presented with a few months of chewing and swallowing difficulty, shoulder pain, and weight loss of 30 pounds. On oral exam, he was noted to have a 5 cm fixed hard palate mass. Primary hard palate malignancy was initially suspected. Biopsy of the mass confirmed adenocarcinoma with an immunohistochemical pattern suggestive of colorectal origin. He was later found to have extensive skeletal metastasis. Palliative radiotherapy to the hard palate region was initiated, followed by palliative systemic chemotherapy. We have found only three other published cases of rectal adenocarcinoma with hard palate metastasis.

Proton Therapy With Concurrent Chemotherapy for Thoracic Esophageal Cancer Toxicity, Disease Control, and Survival Outcomes.

When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung andor heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy CRT) with or without surgery. We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected. Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube. Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity.

Epidemiology and Histopathology of Nasopharyngeal Neoplasms in Iran.

This study aimed to study the trend, histologic pattern, geographical distribution, and characteristics of nasopharyngeal carcinoma (NPC) and nasopharyngeal neoplasms (NPN) from 2003 to 2017 in Iran. The Ministry of Health and Medical Education collected NPN cases from the corresponding university in each province and stored them in Iran National Cancer Registry (INCR) database. The Joinpoint program calculated the average annual percent change (AAPC) and its 95% confidence interval (CI). The jump model minimized the interfering effect of INCR transformation. 3653 NPN cases were reported between 2003-2010 and 2014-2017, with a mean age of 49.04 ± 18.31 years and a male-to-female ratio of 2.15. The age-standardized incidence rate (ASIR) per 100,000 person-years was 0.30 for females and 0.68 for males in 2017. Although the ASIR100,000 of NPN raised from 0.35 to 0.49 during 2003-2017, the trend was constant with an AAPC of -2% (95% CI -4.8% to 0.9%). The age-specific incidence rate was highest in the older than 70 population (1.56100,000). NPC formed 77.1% of NPNs and showed a constant pattern (AAPC CI -5.7% to 0.2%), in contrast to the significant increase of non-keratinizing squamous cell carcinoma (AAPC CI 2.3%to 24.5%). Nasopharynx cancer is rare in Iran, and NPC incidence remained constant from 2003 to 2017, unlike previously reported rising trend. However, non-keratinizing squamous cell carcinoma exhibited a significant increase, and future studies are needed to examine the role of the Epstein-Barr virus on this growth rate.

Generalizability of Machine Learning Models Quantitative Evaluation of Three Methodological Pitfalls.

To investigate the impact of the following three methodological pitfalls on model generalizability ( The authors used retrospective CT, histopathologic analysis, and radiography datasets to develop machine learning models with and without the three methodological pitfalls to quantitatively illustrate their effect on model performance and generalizability. F1 score was used to measure performance, and differences in performance between models developed with and without errors were assessed using the Wilcoxon rank sum test when applicable. Violation of the independence assumption by applying oversampling, feature selection, and data augmentation before splitting data into training, validation, and test sets seemingly improved model F1 scores by 71.2% for predicting local recurrence and 5.0% for predicting 3-year overall survival in head and neck cancer and by 46.0% for distinguishing histopathologic patterns in lung cancer. Randomly distributing data points for a patient across datasets superficially improved the F1 score by 21.8%. High model performance metrics did not indicate high-quality lung segmentation. In the presence of a batch effect, a model built for pneumonia detection had an F1 score of 98.7% but correctly classified only 3.86% of samples from a new dataset of healthy patients. Machine learning models developed with these methodological pitfalls, which are undetectable during internal evaluation, produce inaccurate predictions thus, understanding and avoiding these pitfalls is necessary for developing generalizable models.

Alveolar Hemorrhage Following Positron Emission TomographyComputed Tomography in 2 Separate Episodes 5 Months Apart.

BACKGROUND Positron emission tomographycomputed tomography (PETCT) has become one of the most prominent modalities worldwide for the diagnosis and surveillance of malignancies. Current clinical imaging guidelines report adverse reactions following PETCT, especially due to contrast-induced toxicities, such as contrast-induced nephropathy and other rare reactions attributed to a hypersensitivity immune response, such as bronchospasm. Other rare lung toxicities were reported in a few case reports. Herein, we report repeated episodes of alveolar hemorrhage, a novel adverse response to PETCT, occurring on 2 separate occasions 5 months apart. CASE REPORT A 57 year-old female patient with breast carcinoma managed by mastectomy, adjuvant chemotherapy, irradiation, and hormonal therapy presented with massive alveolar hemorrhage following PETCT performed for surveillance 13 years after completion of chemotherapy and irradiation. An additional episode of massive alveolar hemorrhage occurred 5 months later following PETCT, with respiratory failure requiring mechanical ventilation. Fluorine-18 fluorodeoxyglucose (¹⁸F FDG) and iohexol were used for imaging on both occasions. Common causes of alveolar hemorrhage, including malignancy, were excluded. CONCLUSIONS The repeated episodes immediately following PETCT and the earlier and more intense respiratory failure following the second event raise the possibility of an immune-mediated alveolar hemorrhage in response to either the administration of iodinated radiocontrast agent or to ¹⁸F FDG.

SLERT, as a novel biomarker, orchestrates endometrial cancer metastasis via regulation of BDNFTRKB signaling.

Recent evidence suggests that the box HACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA), SLERT, plays a critical role in gene regulation. However, its role in cancer remains undetermined. Herein, we explored its implication in human endometrial cancer (EC). EC plasma and tissue samples were collected for the detection of SLERT expression using qRT-PCR method. The functional investigation was tested by CCK-8 and transwell assays. Luciferase reporter, RNA pull-down, and immunoprecipitation (RIP) assays were used to determine the regulatory network involved in SLERT. The in vivo effect of SLERT was tested by caudal vein lung metastasis model. Stable knockdown of SLERT significantly inhibited EC cell (KLE and AN3CA) migration and invasion, while it did not affect cell viability. SLERT induced epithelial-mesenchymal transition (EMT) via elevating N-cadherin and Vimentin and downregulating E-cadherin. Further investigation showed that SLERT directly binds to METTL3, increasing the m Our findings, for the first time, uncover the metastasis-promoting effect of SLERT in EC via in vitro and in vivo evidence, providing a potential therapeutic target for metastatic EC treatment.

Conversion surgery for advanced hepatocellular carcinoma after combination treatment of lenvatinib and camrelizumab a case report.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with high morbidity and mortality. Conversion therapy can improve surgical resection rate and prolong survival time for patients with advanced HCC. We show that combination therapy with lenvatinib and camrelizumab is a novel approach to downstage unresectable HCC. A 49-year-old man was diagnosed with massive HCC with hilar lymph node and lung metastases. Since radical resection was not feasible, lenvatinib and camrelizumab were administered as first-line therapy. After 10 cycles of camrelizumab and continuous oral administration of lenvatinib, the tumor exhibited striking shrinkage in volume indicating a partial radiological response, accompanied by a reduction in the alpha-fetoprotein levels, followed by salvage resection. Intriguingly, an improvement in predictive biomarkers, like lactate dehydrogenase (LDH) and neutrophil-to-lymphocyte ratio (NLR), was observed. Notably, the pathological examination found high levels of necrosis in the resected tumor, and flow cytometry analysis indicated a significant increase in the ratio of CD5 and CD5- B lymphocytes in the peripheral blood. After the treatment, the overall survival period was over 24 months, and no recurrence was observed 17-month post-surgery. A combination of lenvatinib and camrelizumab may be a new conversion therapy for initially unresectable HCC to resectable HCC, thus contributing to improve the disease prognosis. In addition, the combination regimen could cause an activated immune response, and LDH, NLR, and CD5 B-cell levels might be predictors for immunotherapy efficacy.

Secreted proteins MDK, WFDC2, and CXCL14 as candidate biomarkers for early diagnosis of lung adenocarcinoma.

Early diagnosis of lung adenocarcinoma (LUAD), one of the most common types of lung cancer, is very important to improve the prognosis of patients. The current methods cant meet the requirements of early diagnosis. There is a pressing need to identify novel diagnostic biomarkers. Secretory proteins are the richest source for biomarker research. This study aimed to identify candidate secretory protein biomarkers for early diagnosis of LUAD by integrated bioinformatics analysis and clinical validation. Differentially expressed genes (DEGs) of GSE31210, gene expression data of early stage of LUAD, were analyzed by GEO2R. Upregulated DEGs predicted to encode secreted proteins were obtained by taking the intersection of the DEGs list with the list of genes encoding secreted proteins predicted by the majority decision-based method (MDSEC). The expressions of the identified secreted proteins in the lung tissues of early-stage LUAD patients were further compared with the healthy control group in mRNA and protein levels by using the UALCAN database (TCGA and CPTAC). The selected proteins expressed in plasma were further validated by using Luminex technology. The diagnostic value of the screened proteins was evaluated by receiver operating characteristic (ROC) analysis. Cell counting kit-8 assay was carried out to investigate the proliferative effects of these screened proteins. A total of 2183 DEGs, including 1240 downregulated genes and 943 upregulated genes, were identified in the GSE31210. Of the upregulated genes, 199 genes were predicted to encode secreted proteins. After analysis using the UALCAN database, 16 molecules were selected for further clinical validation. Plasma concentrations of three proteins, Midkine (MDK), WAP four-disulfide core domain 2 (WFDC2), and C-X-C motif chemokine ligand 14 (CXCL14), were significantly higher in LUAD patients than in healthy donors. The area under the curve values was 0.944, 0.881, and 0.809 for MDK, WFDC2, and CXCL14, 0.962 when combined them. Overexpression of the three proteins enhanced the proliferation activity of A549 cells. MDK, WFDC2, and CXCL14 were identified as candidate diagnostic biomarkers for early-stage LUAD and might also play vital roles in tumorigenesis.

An integrated multi-omics analysis of sleep-disordered breathing traits implicates P2XR4 purinergic signaling.

Sleep Disordered Breathing (SDB) is a common disease associated with increased risk for cardiometabolic, cardiovascular, and cognitive diseases. How SDB affects the molecular environment is still poorly understood. We study the association of three SDB measures with gene expression measured using RNA-seq in multiple blood tissues from the Multi-Ethnic Study of Atherosclerosis. We develop genetic instrumental variables for the associated transcripts as polygenic risk scores (tPRS), then generalize and validate the tPRS in the Womens Health Initiative. We measure the associations of the validated tPRS with SDB and serum metabolites in Hispanic Community Health StudyStudy of Latinos. Here we find differential gene expression by blood cell type in relation to SDB traits and link P2XR4 expression to average oxyhemoglobin saturation during sleep and butyrylcarnitine (C4) levels. These findings can be used to develop interventions to alleviate the effect of SDB on the human molecular environment.

Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma.

Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.

Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples.

Spatially resolved transcriptomics has enabled precise genome-wide mRNA expression profiling within tissue sections. The performance of methods targeting the polyA tails of mRNA relies on the availability of specimens with high RNA quality. Moreover, the high cost of currently available spatial resolved transcriptomics assays requires a careful sample screening process to increase the chance of obtaining high-quality data. Indeed, the upfront analysis of RNA quality can show considerable variability due to sample handling, storage, andor intrinsic factors. We present RNA-Rescue Spatial Transcriptomics (RRST), a workflow designed to improve mRNA recovery from fresh frozen specimens with moderate to low RNA quality. First, we provide a benchmark of RRST against the standard Visium spatial gene expression protocol on high RNA quality samples represented by mouse brain and prostate cancer samples. Then, we test the RRST protocol on tissue sections collected from five challenging tissue types, including human lung, colon, small intestine, pediatric brain tumor, and mouse bonecartilage. In total, we analyze 52 tissue sections and demonstrate that RRST is a versatile, powerful, and reproducible protocol for fresh frozen specimens of different qualities and origins.

Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer.

Fibroblasts are poorly characterised cells that variably impact tumour progression. Here, we use single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry (CIBERSORTx) to identify and characterise three major fibroblast subpopulations in human non-small cell lung cancer adventitial, alveolar and myofibroblasts. Alveolar and adventitial fibroblasts (enriched in control tissue samples) localise to discrete spatial niches in histologically normal lung tissue and indicate improved overall survival rates when present in lung adenocarcinomas (LUAD). Trajectory inference identifies three phases of control tissue fibroblast activation, leading to myofibroblast enrichment in tumour samples initial upregulation of inflammatory cytokines, followed by stress-response signalling and ultimately increased expression of fibrillar collagens. Myofibroblasts correlate with poor overall survival rates in LUAD, associated with loss of epithelial differentiation, TP53 mutations, proximal molecular subtypes and myeloid cell recruitment. In squamous carcinomas myofibroblasts were not prognostic despite being transcriptomically equivalent. These findings have important implications for developing fibroblast-targeting strategies for cancer therapy.