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Rotenoids and isoflavones from the leaf and pod extracts of Millettia brandisiana Kurz.

Phytochemical investigations of the leaf and pod extracts of Millettia brandisiana Kurz led to the isolation and identification of four previously undescribed rotenoids, (-)-(6aS,12aS)-millettiabrandisins A-C and (-)-(6aS,12aS)-6-deoxyclitoriacetal, two previously undescribed isoflavones, millettiabrandisins D and E, and 20 known compounds. The structures of previously undescribed compounds were determined on the basis of NMR and MS data. The absolute configurations of (-)-(6aS,12aS)-millettiabrandisins A-C were determined from the comparison of their experimental and calculated ECD spectra. (-)-(6aR,12aR)-12a-Hydroxy-α-toxicarol was also confirmed by X-ray crystallographic data. Some isolated compounds were evaluated for their cytotoxicity against three cancer cell lines, including lung cancer (A549), colorectal cancer (SW480), and leukemic cells (K562). Of these, α-toxicarol displayed the best cytotoxicity against lung cancer (A549) and leukemic cells (K562) with the IC

Combining structure-based pharmacophore modeling and machine learning for the identification of novel BTK inhibitors.

Brutons tyrosine kinase (BTK) is a critical enzyme which is involved in multiple signaling pathways that regulate cellular survival, activation, and proliferation, making it a major cancer therapeutic target. We applied the novel integrated structure-based pharmacophore modeling, machine learning, and other in silico studies to screen the Korean chemical database (KCB) to identify the potential BTK inhibitors (BTKi). Further evaluation of these inhibitors on three different human cancer cell lines showed significant cell growth inhibitory activity. Among the 13 compounds shortlisted, four demonstrated consistent cell inhibition activity among breast, gastric, and lung cancer cells (IC50 below 3 μM). The selected compounds also showed significant kinase inhibition activity (IC50 below 5 μM). The current study suggests the potential of these inhibitors for targeting BTK malignant tumors.

NTRK3 gene fusion in an adult ganglioglioma illustrative case.

Gangliogliomas are well-differentiated, slow-growing glioneuronal neoplasms frequently reported to harbor upregulating alterations in the mitogen-activated protein kinase pathway, particularly serine-threonine protein kinase B-RAF alterations. Fusions involving neurotrophin tyrosine receptor kinase (NTRK) genes have rarely been reported in ganglioglioma. Similarly, echinoderm microtubule-associated protein-like (EML) 4 gene fusion has been described in lung cancer, but none has been reported in ganglioglioma. This report discusses the care of a 72-year-old man presenting with medication-refractory, left-sided focal seizures who was found to have a nongadolinium-enhancing, T2-hyperintense, right frontoparietal lesion. The patient received resection, and histological analysis found a World Health Organization grade I ganglioglioma, with genetic analysis demonstrating an EML4-NTRK3 gene fusion protein. To our knowledge, this is the first report of an NTRK3 fusion, EML4-NTRK3, in an adult ganglioglioma, which is otherwise mostly associated with BRAF alterations and activation of the mitogen-activated protein kinase signaling pathway. Further studies are needed to elucidate the function of the resultant fusion protein and determine whether it may serve as a future therapeutic target.

Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo.

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Magnetic-field-modulated radiotherapy (MagMRT) in inhomogeneous medium and its potential applications.

Not Available.

Proporcionar recomendaciones para la detección temprana de pacientes con alto riesgo de desarrollar cáncer de pulmón (CP) en el primer nivel de atención y su referencia oportuna. Material y métodos. Se realizó una búsqueda detallada de la evidencia científica disponible para responder las preguntas de investigación clínica y se utilizó el Panel Delphi modificado para lograr un consenso entre expertos. Se generaron 14 recomendaciones siguiendo los estándares de una GPC. Conclusión. El CP representa un problema de salud pública en México por ello, esta guía establece recomendaciones que apoyan la toma de decisiones sobre la detección precoz y la referencia de pacientes con sospecha de CP en el primer nivel de atención.

Prioritizing Pregnant Women for Coronavirus Disease 2019 Vaccination in African Countries.

Coronavirus disease 2019 (COVID-19) in pregnancy is associated with excess maternal and infant morbidity and mortality in both African and higher-resource settings. Furthermore, mounting evidence demonstrates the safety and efficacy of COVID-19 vaccination for pregnant women and infants. However, national guidelines in many African countries are equivocal or lack recommendations on COVID-19 vaccine in pregnancy. We summarize key data on COVID-19 epidemiology and vaccination among pregnant African women to highlight major barriers to vaccination and recommend 4 interventions. First, policymakers should prioritize pregnant women for COVID-19 vaccination, with a target of 100% coverage. Second, empirically supported public health campaigns should be sustainably implemented to inform and support pregnant women and their healthcare providers in overcoming vaccine hesitancy. Third, COVID-19 vaccination for pregnant women should be expanded to include antenatal care, obstetricsgynecology, and targeted mass vaccination campaigns. Fourth, national monitoring and evaluation of COVID-19 vaccine uptake, safety, surveillance, and prospective outcomes assessment should be conducted.

Lung cancer subtype diagnosis using weakly-paired multi-omics data.

Cancer subtype diagnosis is crucial for its precise treatment and different subtypes need different therapies. Although the diagnosis can be greatly improved by fusing multiomics data, most fusion solutions depend on paired omics data, which are actually weakly paired, with different omics views missing for different samples. Incomplete multiview learning-based solutions can alleviate this issue but are still far from satisfactory because they (i) mainly focus on shared information while ignore the important individuality of multiomics data and (ii) cannot pick out interpretable features for precise diagnosis. We introduce an interpretable and flexible solution (LungDWM) for Lung cancer subtype Diagnosis using Weakly paired Multiomics data. LungDWM first builds an attention-based encoder for each omics to pick out important diagnostic features and extract shared and complementary information across omics. Next, it proposes an individual loss to jointly extract the specific information of each omics and performs generative adversarial learning to impute missing omics of samples using extracted features. After that, it fuses the extracted and imputed features to diagnose cancer subtypes. Experiments on benchmark datasets show that LungDWM achieves a better performance than recent competitive methods, and has a high authenticity and good interpretability. The code is available at httpwww.sdu-idea.cncodes.phpnameLungDWM. Supplementary data are available at Bioinformatics online.

Patterns of metastases progression- The linear parallel ratio.

Linear and parallel are the two leading models of metastatic progression. In this study we propose a simple way to differentiate between them. While the linear model predicts accumulation of genetic and epigenetic alterations within the primary tumor by founder cells before spreading as waves of metastases, the parallel model suggests preclinical distribution of less advanced disseminated tumor cells with independent selection and expansion at the ectopic sites. Due to identical clonal origin and time of dispatching, linear metastases are expected to have comparable diameters in any specific organ while parallel metastases are expected to appear in variable sizes. Retrospective revision of chest CT of oncological patients with lung metastases was performed. Metastasis number and largest diameters were recorded. The sum number of metastases with a similar diameter (c) and those without (i) was counted and the linearparallel ratio (LPR) was calculated for each patient using the formula (∑c-∑i)(∑c∑i). A LPR ratio of 1 implies pure linear progression pattern and -1 pure parallel. 12,887 metastases were measured in 503 patients with nine malignancy types. The median LPR of the entire group was 0.71 (IQR 0.14-0.93). In carcinomas of the pancreas, prostate, and thyroid the median LPR was 1. Median LPRs were 0.91, 0.65, 0.60, 0.58, 0.50 and 0.43 in renal cell carcinomas, melanomas, colorectal, breast, bladder, and sarcomas, respectively. Metastatic spread of thyroid, pancreas, and prostate tumors is almost exclusively by a linear route. The spread of kidney, melanoma, colorectal, breast, bladder and sarcoma is both linear and parallel with increasing dominance of the parallel route in this order. These findings can explain and predict the clinical and genomic features of these tumors and can potentially be used for evaluation of metastatic origin in the individual patient.

Ectopic papillary thyroid carcinoma mimicking distant metastatic tissue.

We report a case of a 50-year-old woman presenting with a solid nodule in each lung. She was previously suspected of having lung cancer and distant pulmonary metastasis on the basis of imaging findings. Surgical pathology revealed that the left lung nodule was adenocarcinoma, but the contralateral nodule was papillary thyroid carcinoma (PTC). We subsequently performed total thyroidectomy, and the histological findings of the resected specimen showed no suspicious tumor tissue. Overall, the results led to a diagnosis of ectopic intrapulmonary PTC with synchronous lung adenocarcinoma. Ectopic intrapulmonary PTC is a rare but true phenomenon that may be easily mistaken for pulmonary metastasis in daily practice. It is important to improve the recognition of ectopic intrapulmonary thyroid tumors to avoid misdiagnosis.

Recalibrating Risk Prediction Models by Synthesizing Data Sources Adapting the Lung Cancer PLCO Model for Taiwan.

Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. Using Taiwanese multiple data sources, we formed an age-matched case-control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011-2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40 pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). The adapted PLCOT models had high predictive performance. The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Sudden unexpected death in a 17-year-old boy due to unacknowledged adamantinoma-like Ewing sarcoma.

A 17-year-old male with no previous medical history was admitted 2 days before his death to a local hospital after mild dyspnea. Electrocardiography, chest radiography, and blood analysis revealed no abnormalities. Blood oxygen saturation was 99%, and SARS-CoV-2 nasopharyngeal swabs tested negative thus, he was discharged without prescriptions. After 2 days, the subject died suddenly during a pool party. Forensic autopsy was performed analyzing all anatomical districts. Cardiac causes were fully excluded after deep macroscopic and microscopic evaluation lung and brain analyses showed no macroscopic pathology. Finally, a large subglottic solid mass was detected. The whitish neoplasm showed an aggressive invasion pattern to the thyroid and adjacent deep soft tissues and occluded the trachea. High-power microscopy showed sheets of small, uniform cells with scant cytoplasm round nuclei and small, punctate nucleoli, with immunohistochemical expression of CK8-18, AE1AE3, and CD99. Using FISH analysis, the break-apart molecular probes (EWSR1 (22q12) Break - XL, Leica Biosystem, Nussloch, Germany) showed distinct broken red and green fluorochromes, diagnostic of Ewing sarcoma. The neoplasm was characterized as adamantinoma-like Ewing sarcoma, and the mechanism of death was identified as airway obstruction. The rarity of the case resides in the circumstances of death, which pointed to the possibility of sudden unexpected death due to heart disease, but an oncological cause and the underlying mechanism were finally diagnosed. The best method to perform autopsies is still complete, extensive, and systematic macroscopic sampling of organs and districts followed by histopathological analysis, in addition to immunohistochemical and molecular investigations in those cases in which they are necessary. In fact, when neoplasms are detected, the application of advanced techniques such as immunohistochemistry and molecular diagnostics is fundamental to accurately certify death.

Proteasomal deubiquitylase activity enhances cell surface recycling of the epidermal growth factor receptor in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) represents a top therapeutic target in the treatment of non-small cell lung cancer. EGFR expression is intricately modulated by receptor endocytosis, during which EGFR ubiquitylation and deubiquitylation play fundamental roles to govern receptor fate. This study aims to uncover novel aspects of the endocytic regulation of EGFR trafficking by deubiquitylases. The expression and ubiquitylation of EGFR in non-small cell lung cancer cells treated with deubiquitylase inhibitors were assessed by immunoblotting, immunoprecipitation and mass spectrometry analyses. The intracellular EGFR distribution was investigated using immunofluorescence and confocal microscopy assays, and colocalizations with endocytic compartments were examined using GFP-tagged Rab proteins as markers. The influence of the proteasomal deubiquitylase inhibitor b-AP15 on EGF- and HSP90 inhibitor-induced EGFR downregulation was evaluated by immunoblotting. The anticancer effects of b-AP15 were assessed by cell proliferation, colony formation and flow cytometry assays, as well as xenograft animal models. We found that b-AP15 caused a dramatically enhanced ubiquitylation of EGFR in lung cancer cells. Treatment with b-AP15 decreased cell surface EGFR levels and accumulated EGFR on recycling endosomes marked with Rab4A and Rab11A. b-AP15 effectively repressed EGF- and HSP90 inhibitor-induced EGFR degradation. Lung cancer cells exposed to b-AP15 showed markedly reduced cell propagation and significantly increased cell apoptosis. Furthermore, b-AP15 effectively inhibited tumor xenograft growth in nude mice. Proteasomal USP14 and UCHL5 act collectively to promote cell surface recovery of EGFR. Inhibition of proteasomal deubiquitylase activity induces increased EGFR ubiquitylation and retention on recycling endosomes. The USP14 and UCHL5 dual inhibitor b-AP15 elicits potent tumor-suppressive effects to deter cell proliferation and induce apoptotic cell death in lung cancer.

Lung cancer surgery after COVID-19 infection in a patient with severe interstitial pneumonia and restrictive ventilatory impairment.

The spread of COVID-19 infection increased the number of patients who underwent pulmonary resection for lung cancer after COVID-19 infection. It is unclear how previous infection with COVID-19 affects perioperative complications and acute exacerbation of interstitial pneumonia after surgery in patients with interstitial pneumonia. An 80-year-old man was referred to our hospital because of a tumor in his left lung. Chest computed tomography showed a 28-mm nodule in the lower lobe of the left lung and usual interstitial pneumonia in bilateral lungs. Bronchoscopic examination was performed, which diagnosed squamous cell carcinoma. Pulmonary function testing revealed restrictive ventilatory impairment, and we planned to perform basal segmentectomy of the left lung. However, before the planned surgery, the patient contracted symptomatic COVID-19. Chest computed tomography revealed ground-glass opacities owing to COVID-19. The patient was admitted for surgery 7 weeks after COVID-19 infection. Preoperatively, pulmonary function testing was repeated, which revealed decreased % vital capacity (%VC) and % diffusing capacity for carbon monoxide (%DLco). The 6-min walk test indicated a distance of 500 m, and the percutaneous oxygen saturation at the end of the test was 94%. Basal segmentectomy of the left lung was performed by video-assisted thoracoscopic surgery. The patients postoperative course was favorable, and he was discharged without the need for oxygen inhalational therapy 12 days after the surgery. Pathological examination of the resected specimen revealed usual interstitial pneumonia in the non-cancerous areas of the lung. Additionally, the infiltration of immature fibroblasts in the alveoli and perivascular infiltration of inflammatory cells were observed, which were consistent with fibrotic change after inflammation owing to COVID-19. Three months after the surgery, the patient was alive without recurrence or acute exacerbation of the interstitial pneumonia. Pulmonary function testing 6 weeks after surgery revealed decreased %VC and %DLco. Testing 12 weeks after surgery revealed persistently decreased %VC and improved %DLco (Table 1). Table 1 Pulmonary function test results before and after COVID-19 infection and 6 and 12 weeks after surgery VC (ml) %VC (%) %DLco (%) Before COVID-19 infection 2070 71.9 74.9 7 weeks after COVID-19 infection 1700 59.6 51.9 6 weeks after surgery 1500 52.6 53.1 12 weeks after surgery 1510 53.0 61.7 %VC % vital capacity, %DLco % diffusing capacity for carbon monoxide CONCLUSION We successfully performed basal segmentectomy of the left lung for lung cancer 7 weeks after COVID-19 infection in a patient with severe interstitial pneumonia and restrictive ventilatory impairment.

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer A Multicentric Retrospective French Study.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected. Overall, 104 patients were included. Most patients had adenocarcinoma (n 102, 98%) with an exon 19 EGFR deletion (n 54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15% n 4) and EGFR C797S mutation (11% n 3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%). We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Short-term outcomes of colorectal cancer surgery in older patients a novel nomogram predicting postoperative morbi-mortality.

To analyze short-term outcomes of curative-intent cancer surgery in all adult patients diagnosed with colorectal cancer undergoing surgery from January 2010 to December 2019 and determine risk factors for postoperative complications and mortality. Retrospective study conducted at a single tertiary university institution. Patients were stratified by age into two groups < 75 years and ≥ 75 years. Primary outcome was the influence of age on 30-day complications and mortality. Independent risk factors for postoperative adverse events or mortality were analyzed, and two novel nomograms were constructed. Of the 1486 patients included, 580 were older (≥ 75 years). Older subjects presented more comorbidities and tumors were located mainly in right colon (45.7%). After matching, no between-group differences in surgical postoperative complications were observed. The 30-day mortality rate was 5.3% for the older and 0.8% for the non-older group (p < 0.001). In multivariable analysis, the independent risk factors for postoperative complications were peripheral vascular disease, chronic pulmonary disease, severe liver disease, postoperative transfusion, and surgical approach. Independent risk factors for 30-day mortality were age ≥ 80 years, cerebrovascular disease, severe liver disease, and postoperative transfusion. The model was internally and externally validated, showing high accuracy. Patients aged ≥ 75 years had similar postoperative complications but higher 30-day mortality than their younger counterparts. Patients with peripheral vascular disease, chronic pulmonary disease, or severe liver disease should be informed of higher postoperative complications. But patients aged ≥ 80 suffering cerebrovascular disease, severe liver disease, or needing postoperative transfusion should be warned of significantly increased risk of postoperative mortality.

Effect of Antigen Retrieval on Genomic DNA From Immunodissected Samples.

Immunohistochemical (IHC) staining is an established technique for visualizing proteins in tissue sections for research studies and clinical applications. IHC is increasingly used as a targeting strategy for procurement of labeled cells via tissue microdissection, including immunodissection, computer-aided laser dissection (CALD), expression microdissection (xMD), and other techniques. The initial antigen retrieval (AR) process increases epitope availability and improves staining characteristics however, the procedure can damage DNA. To better understand the effects of AR on DNA quality and quantity in immunodissected samples, both clinical specimens (

Contextualizing the Role of Volumetric Analysis in Pulmonary Nodule Assessment

Pulmonary nodules are managed on the basis of their size and morphologic characteristics. Radiologists are familiar with assessing nodule size by measuring diameter using manually deployed electronic calipers. Size may also be assessed with 3D volumetric measurements (referred to as volumetry) obtained with software. Nodule size and growth are more accurately assessed with volumetry than on the basis of diameter, and the evidence supporting clinical use of volumetry has expanded, driven by its use in lung cancer screening nodule management algorithms in Europe. The application of volumetry has the potential to reduce recommendations for imaging follow-up of indeterminate solid nodules without impacting cancer detection. Although changes in scanning conditions and volumetry software packages can lead to variation in volumetry results, ongoing technical advances have improved the reliability of calculated volumes. Volumetry is now the primary method for determining size of solid nodules in the European lung cancer screening position statement and British Thoracic Society recommendations. The purposes of this article are to review technical aspects, advantages, and limitations of volumetry and, by considering specific scenarios, to contextualize the use of volumetry with respect to its importance in morphologic evaluation, its role in predicting malignancy in risk models, and its practical impact on nodule management. Implementation challenges and areas requiring further evidence are also highlighted.

Retracted MicroRNA‑433 reduces cell proliferation and invasion in non‑small cell lung cancer via directly targeting E2F transcription factor 3.

Following the publication of this paper, it was drawn to the Editors attention by a concerned reader that certain of the cell migration and invasion assay data shown in Figs. 2C, 4C and 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to

Cytotoxicity and apoptosis induction of the marine

Cancer is still an area of continuous research for finding more effective and selective agents, so our study aimed to explore new anticancer medicines from Cone snails venoms as marine natural products with promising biological activities. Venoms from seven cone snails collected from two locations on the Red Sea coast (Marsa Alam (Ma) and Hurghada (Hu)) were extracted and subjected to SDS for protein concentrations. The venoms of

Alectinib rescue therapy in advanced ALK rearranged lung adenocarcinoma a case report.

Alectinib is a highly selective tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that is approved as first-line treatment in adult patients with ALK-positive non-small cell lung cancer (NSCLC) and as second-line in patients previously treated with crizotinib, and has been shown in the literature to significantly prolong progression-free survival compared to chemotherapy in patients with advanced non-small cell lung cancer. The authors describe a clinical case of a 24-year-old woman with malignant massive pleural effusion caused by ALK rearranged pulmonary adenocarcinoma with pleural and pericardial metastasis, in which, despite a dramatic clinical debut, the correct and timely management of the diagnostic and therapeutic path allowed for extraordinary therapeutic success.

Differences in the performance of adjuvant chemotherapy between hemodialysis and nonhemodialysis patients.

The survival of hemodialysis (HD) patients with cancer is poor, which may be caused by undertreatment due to renal dysfunction. Particularly, adjuvant chemotherapy after surgery may be considered optional because of its preventive nature. This study investigated the current frequency of administration of adjuvant chemotherapy to HD patients compared with non-HD patients in Japan. We used data from the Hospital-Based Cancer Registries national database linked to health services utilization data to analyze cases of newly diagnosed colon cancer, gastric cancer, breast cancer, and non-small cell lung cancer (NSCLC) at the stages where adjuvant chemotherapy is generally required. We compared the performance rate of adjuvant chemotherapy and the adjuvant chemotherapy regimens between HD and non-HD patients from October 2011 to December 2017. Of the 99,761 patients who underwent curative surgery, 1207 (1%) were HD patients. HD patients received adjuvant chemotherapy less frequently than non-HD patients (24% vs. 63%, p < 0.001). After adjusting for potential confounders, HD remained negatively related to adjuvant chemotherapy administration for all four cancer types. Among all patients who received adjuvant chemotherapy 0(N 61,873), HD patients were less likely to receive standard regimens and chemotherapy requiring dose adjustment than non-HD patients (88% vs. 95%, p < 0.001 and 92% vs. 98%, p < 0.001, respectively). This trend was particularly pronounced among patients with gastric cancer. HD patients were less likely to receive adjuvant chemotherapy with standard regimens than non-HD patients.

Financial toxicity of patients with lung cancer in China Results from a National Survey Study.

To develop a comprehensive understanding of financial toxicity (FT) among patients with lung cancer in China and the major factors affecting FT. Drawing from a national cross-sectional survey, which used the validated comprehensive score for financial toxicity (COST) questionnaire, we estimated the prevalence and degree of FT. Patient coping actions were investigated. Pearsons chi tests and multinomial logistic regression were used to evaluate the predictors of FT in patients with lung cancer. The median score of FT was 20 (scored on a range of 0-44, with lower scores indicating more severe toxicity). Altogether, 77% of the sample patients had FT (COST <26), 54.5% had mild FT (COST 14-25), and 22.5% had moderate and severe FT (COST 0-13). Living in the less-developed western region of China, being male, having a lower educational level, lower annual family income, and advanced stage or worse self-reported health status were significantly related to higher FT than their counterparts (p < 0.05). Patients with higher FT tended to have a lower level of medical compliance, a higher risk of incurring debts, and reduced living expenditures relative to those with lower FT. Despite Chinas remarkable progress in the past two decades with regard to Universal Healthcare Coverage, FT still presents a serious challenge for patients with lung cancer. Keen attention must be paid to reducing the disproportionate high financial risks of patients with low socioeconomic status.

Sex difference in response to non-small cell lung cancer immunotherapy an updated meta-analysis.

Studying sex differences in the efficacy of immunotherapy may contribute to the practice of the precision medicine, especially in non-small cell lung cancer (NSCLC), a kind of cancer with sexual bimorphism. Published randomized controlled trials (RCTs), published by PubMed, Medline, Embase, and Scopus, before 15 June 2022, testing immunotherapy (CTLA-4 or PD-1L1 inhibitor alone, combination or with chemotherapy) versus non-immunotherapy (receiving chemotherapy or placebo only) were included to assess different efficacy between males and females. The primary endpoint was overall survival (OS). This meta-analysis was registered with PROSPERO (CRD42022298439). Sixteen RCTs, involving 10,155 patients with advanced NSCLC, was collected in this meta-analysis. The pooled HR comparing immunotherapy vs non-immunotherapy were 0.76 (95%CI 0.71-0.81) for males and 0.74 (95%CI 0.63-0.87) for females. The pooled HRs comparing immune-checkpoint inhibitors (ICIs) plus chemotherapy versus chemotherapy were 0.79 (95%CI 0.70-0.89) for males and 0.63 (95%CI 0.42-0.92) for females. The pooled HRs comparing ICIs versus chemotherapy were 0.74 (95%CI 0.67-0.81) for males and 0.83 (95%CI 0.73-0.95) for females. In squamous NSCLC, the pooled HRs comparing immunotherapy vs non-immunotherapy were 0.73 (95%CI 0.58-0.91) for males and 0.74 (95%CI 0.37-1.48) for females. In non-squamous NSCLC, the pooled HRs comparing immunotherapy versus non-immunotherapy were 0.62 (95%CI 0.71-0.94) for males and 0.59 (95%CI 0.39-0.89) for females. Compared to chemotherapy, immunotherapy can improve the prognosis of patients with advanced NSCLC. Meanwhile, there are sex differences in the efficacy of immunotherapy.KEY MESSAGECompared to chemotherapy, immunotherapy can improve the prognosis of patients with advanced NSCLC.The most interesting thing in this study is that immunotherapy showed significant sex differences in the treatment of squamous NSCLC.

Anticancer and antibacterial flavonoids from the callus of

A new flavonoid angelioue (1) together with five known compounds cuminatanol (2), myricetin (3), epigallocatechin (4), taxifolin (5) and dihydromyricetin (6) was isolated from the callus extract of

Application of the international system for reporting serous fluid cytopathology on reporting various body fluids experience of a tertiary care hospital.

Cytological examination of effusion sample is a preliminary and minimally invasive method for the diagnosis of body fluids. Recently, the International System For Reporting Serous Fluid Cytopathology (ISRSFC) and the Indian Academy of Cytologist (IAC) have published guidelines for reporting effusion cytology and calculating the risks of malignancy (ROMs) for each defined category. We report our 2 years of experience in reclassifying and assessing the feasibility of applying ISRFSC and IAC categories to effusion fluid and to provide an estimate of the risk of malignancy for each diagnostic category. Cytological reports of patients from January 2019 to December 2020 were retrieved and reclassified into a five-tiered classification scheme as per ISRSFC guidelines. Cellblock and immunohistochemistry were performed in selected cases. Clinico radiological and histopathological information were obtained and correlated with the cytological findings wherever available. In the study, 652 cases were included during the 2 years. Out of these, 328 (50.3%) were women and 314 (47.3%) were men. Patients ages ranged between 2 92 years with a mean age of 47.4 years. There were 366 (56.1%) cases of ascitic fluid followed by 262 (40.1%) cases of pleural fluid and 24 (3.8%) cases of pericardial fluid in the analysis. Of all the cases, 13 (2%) were non-diagnostic (ND), 464 (71.6%) were negative for malignant (NFM) cells, 16 (2.4%) were atypia of uncertain significance, 31 (4.7%) were suspicious of malignancy, and 125 (19.3%) were malignant. Cellblock was prepared in 65 cases. Lung cancer followed by breast cancer was the most common malignancies involving the pleural effusion and ovarian cancer was the most common cause of peritoneal effusion. ROM for each diagnostic category was 23% for ND, 25% for NFM, 56% for the atypical category, 80.6% in suspicious, and 90% were for positive for malignancy category. The use of a five-tiered system as per the ISRFC and IAC guidelines are feasible for the standardized reporting of effusion samples, thus avoiding subjective variation of reporting.

Cytomorphology of pituitary carcinoma metastatic to liver diagnosed by fine-needle aspiration A rare case report and review of literature.

Pituitary carcinomas (PCs) are rare entities constituting about 0.1-0.2% of all pituitary neoplasms. They are diagnosed by the presence of craniospinal or systemic metastasis in pituitary adenomas (PAs). The distant metastatic sites include liver, followed by bone, lung, and lymph nodes. The diagnosis of PC is rarely made on fine-needle aspiration cytology (FNAC) with only six cases reported till date hence, the cytologic features are not well defined. Herein, we report a case of PA having high Ki-67 proliferation index and p53 expression, presenting with liver lesion 6 weeks post-surgery and diagnosed on FNA. Detailed cytomorphologic features are defined and compared. We emphasize that FNAC, along with clinic-radiologic correlation, is a cost-effective, safe, and diagnostically accurate method of diagnosing PC metastases.

Oncogenic role of TWF2 in human tumors A pan-cancer analysis.

To develop effective medicines, researchers must first understand the common and distinct mechanisms that drive oncogenic processes in human cancers. TWF1 and TWF2 belong to the actin-depolymerizing factor homology family. TWF1 has been identified as an important gene in lung, breast, and pancreatic cancer in recent investigations. TWF2s role in cancer remains largely unknown, no comprehensive pan-cancer studies have been conducted. We utilized the The Cancer Genome Atlas and Gene Expression Omnibus datasets to investigate the role of TWF2 in different types of cancers. TWF2 transcription in cancers and the number of TWF2 mutations were examined as part of our study. We also examined the possible functional pathways involved in TWF2-mediated oncogenicity. Our pan-cancer analysis provided a complete overview of the oncogenic effects of TWF2 in a wide range of human malignancies.

Intrapatient variability of 18F-FDG uptake in normal tissues.

To investigate the effect of serum glucose level and other confounding factors on the variability of maximum standardized uptake value (SUVmax) in normal tissues within the same patient on two separate occasions and to suggest an ideal reference tissue. We retrospectively reviewed 334 18F-FDG PETCT scans of 167 cancer patients including 38 diabetics. All patients had two studies, on average 152 ± 68 days apart. Ten matched volumes of interest were drawn on the brain, right tonsil, blood pool, heart, lung, liver, spleen, bone marrow, fat, and iliopsoas muscle opposite third lumber vertebra away from any pathological 18F-FDG uptake to calculate SUVmax. SUVmax of the lungs and heart were significantly different in the two studies ( The liver, muscle, and splenic activities showed satisfactory testretest stability and can be used as reference activities. The spleen and muscle appear to be more optimal reference than the liver, as it is only associated with the injected dose of 18F-FDG.

Scoping Review of 5 Common Occupational Cancers and Their Related Exposures.

Evaluation of Progression-Free Survival and Overall Survival of Epidermal Growth Factor Receptor-Positive Metastatic Lung Adenocarcinoma Patients Treated with Erlotinib.

miR-378 associated with proliferation, migration and apoptosis properties in A549 cells and targeted NPNT in COPD.

microRNAs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). However, the underlying molecular mechanisms are largely unclear. The goal of this study was to investigate the roles of miR-378 in alveolar epithelial type II cells and identify molecular mechanisms which contribute to the pathogenesis of COPD. Human alveolar epithelial (A549) cells were cultured in Dulbeccos Modified Eagle Medium. Cell proliferation was studied by using a cell counting kit-8 (CCK-8) and colony formation assays. Cell apoptosis and cell cycle were analyzed by flow cytometry and wound healing and Transwell were used to analyze the cell migration and. We performed bioinformatics analysis including target gene prediction, gene ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment and construction of protein-protein interaction (PPI) network. The expression of miR-378 and NPNT from publically available expression microarray of COPD lung tissues was analyzed. Overexpression of miR-378 significantly increases cell proliferation, migration, and suppress apoptosis. GO analysis demonstrated that the miR-378 involved in transcription, vascular endothelial growth factor receptor signaling pathway, phosphatidylinositol 3-kinase signaling, cell migration, blood coagulation, cell shape, protein stabilization and phosphorylation. Pathway enrichment showed that the 1,629 target genes of miR-378 were associated with mTOR, ErbB, TGF-β, MAPK, and FoxO signaling pathways. Notably, miR-378 directly targets Nephronectin in A549 cells, and miR-378 was upregulated while NPNT was downregulated in COPD lung tissue samples. These findings suggest that miR-378 can regulate the proliferation, migration, and apoptosis of A549 cells and target NPNT. miR-378 increased in COPD lung tissues while NPNT decreased, and might prove a potential target for novel drug therapy.

The Association Between Gastroesophageal Reflux Disease and Non-Small Cell Lung Cancer A Retrospective Case-Control Study.

Lung cancer is a leading cause of mortality in the USA. Non-small cell lung cancer (NSCLC) contributes to 85% of all lung cancers. It is the most prevalent subtype amongst non-smokers, and its incidence has risen in the last 20 years. In addition, gastroesophageal reflux disease (GERD) has been associated with several lung pathologies, namely idiopathic pulmonary fibrosis and asthma. We aimed to investigate the association between GERD and NSCLC by performing a retrospective, multicenter, case-control study. This is the first study of this nature to be carried out in the USA. Data were retrieved from 17 Northwell health care facilities in the New York area between the years 2010 and 2018. Inclusion criteria were patients > 18 years of age with NSCLC (large cell, adenocarcinoma, and squamous cell). They were appropriately matched with controls based on age, gender, weight, comorbidities, and medication use. Our exposure group had a diagnosis of GERD based on the International Classification of Diseases, Ninth10th Revision (ICD 910) codes and endoscopic, in addition to histological evidence if present. We excluded patients with secondary lung cancers, esophageal adenocarcinoma, other primary malignancies, Barretts esophagus, and smokers. Logistic regression was conducted to determine the adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between NSCLC and GERD. A total of 1,083 subjects were included in our study 543 (50%) patients were diagnosed with NSCLC. In this population, GERD was twice as prevalent compared to controls (20.4% vs. 11.6%, P < 0.001). Multivariate analysis demonstrated that GERD was associated with a higher risk of NSCLC compared to matched controls (OR 1.86, 95% CI 1.26 - 2.73). In addition, GERD patients treated with either antihistamines or proton pump inhibitors did not demonstrate an overall reduced risk of NSCLC (OR 1.01, 95% CI 0.48 - 2.12). Our study demonstrates that GERD is associated with a higher risk of NSCLC, irrespective of GERD treatment. We postulate that GERD patients suffer from chronic micro-aspirations leading to a prolonged inflammatory state within the lung parenchyma, triggering specific proliferative signaling pathways that may lead to malignant transformation.

CYP1B1 Gene Polymorphism Based on Health Monitoring and Nursing Methods after Minimally Invasive Surgery for Lung Cancer.

The rapid development of science and technology has become an indispensable part of human life. Minimally invasive lung cancer surgery, that is, thoracoscopic surgery and da Vinci robotic surgery, has many advantages over previous surgeries, there is no need to make a large incision in the chest, the patient after such surgery, and recovery is also better and can also reduce the incision of the operation. Therefore, with the rapid development of science and technology today, how to detect changes in patients health and establish an intelligent health monitoring system has become a development trend. This paper proposes to apply health monitoring in CYP1B1 gene polymorphism and nursing after clinical treatment of minimally invasive lung cancer surgery, after analyzing the societys demand for real-time health monitoring in this paper. It also studies the health monitoring system based on the advantages of smart phones. The system is suitable for the Android operating system and can monitor the temperature, weight, and other data of the human body. The experimental results show that the data value of the information displayed by the android software has a high degree of matching with the measured value, which basically keeps floating around 80, and the data consistency is strong.

Imaging with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and We report an unusual case of metastatic brain tumors without accumulation of FDG or MET, contrasting with high FDG uptake in the primary lung lesion. The brain lesions were identified as adenocarcinoma with a more mucus-rich background, contributing to the indistinct accumulation of both FDG and MET. Histopathological characteristics can affect both MET and FDG accumulation, leading to findings contradicting those of the primary lesion.

The Influence of Influenza Virus Infections in Patients with Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a common disease and is preventable and treatable. A previous study showed that influenza virus infections were also associated with the risk of acute exacerbation in patients with COPD, and other studies showed that the influenza virus might increase the risk of stroke. However, studies on the influence of influenza infection among COPD patients are limited. In this study, we review the role of influenza infection in contributing to mortality, pneumonia, respiratory failure, COPD acute exacerbation, and ischemic stroke among COPD patients. We performed a population-based cohort study of COPD patients using data from Taiwan between January 1, 2011, and December 31, 2019. We excluded patients with lung cancer, lung transplantation and asthma. We also excluded patients who lacked COPD medication prescriptions and those treated with anti-influenza drugs without flu diagnosis records. Patients with missing or incomplete data were also excluded from the study cohort. After 11 matching by age, sex, COPD duration, diagnosed years and comorbidities, we enrolled 10,855 cases and controls for further analysis. The risks of pneumonia, respiratory failure, COPD acute exacerbation, and ischemic stroke were 1.770 (95% CI1.638-1.860 P<0.0001), 1.097 (95% CI1.008-1.194 P0.0319), 1.338 (95% CI1.248-1.435 P<0.0001), and 1.134 (95% CI1.039-1.239, P0.0051), respectively, in the influenza infection group compared with COPD patients without influenza infection. Influenza infections are linked to an increased risk of ischemic stroke, pneumonia, respiratory failure, and COPD acute exacerbation among COPD patients. In conclusion, patients with COPD need to be closely monitored after having an influenza infection.

Bone Metastasis As the Initial Presentation of a Hidden Bronchogenic Carcinoma.

Primary malignant bone tumours are on the whole rare, while secondary bone tumours are much more common. Up to 40% of bone metastases are associated with lung cancer. This case report highlights a rare presentation of metastatic bone disease as the initial presentation of a primary lung malignancy and only very few cases were mentioned in literature with the same presentation of no clinical signs of the primary lung pathology, except for an unexpected radiological finding of a suspicious lung lesion. An 85-year-old gentleman presented with a progressive lower backache radiating to both lower limbs over a period of 4 weeks associated with difficulty in walking, significant weight loss, and decreased appetite. A skeletal survey showed only spondylolisthesis. However, no clinical improvement was noticed with conventional therapy. Examination of the respiratory, gastrointestinal, and genitourinary systems was normal. Ultrasonography of the abdomen and pelvis, and the findings of the colonoscopy did not add anything. During the third week of follow-up, the patient reported unbearable severe pain in the left arm. A plain radiograph revealed a pathological fracture of the humerus. Secondary bone metastasis was suspected. Although the patient was a non-smoker and there were no clinical signs of underlying lung disease, a simple plain chest radiograph, unexpectedly, showed a suspicious right lower lobe lesion. Therefore, a contrast-enhanced computerized tomography (CT) scan for the chest, abdomen, and pelvis was done which revealed a right lower lobe lesion of bronchogenic carcinoma with distant metastasis. Unfortunately, the patient died after 3 weeks of palliative therapy when he was admitted to the hospital with acute renal failure and septic shock. Bone metastases in lung cancer predict a poor prognosis and short-term survival. The diagnosis of such a challenging presentation requires a high index of suspicion. If the patient had been sent for a plain chest radiograph at first, lots of time and effort could be saved in reaching the diagnosis without the need for further sophisticated or invasive diagnostic procedures.

Deregulation of PRDM5 promotes cell proliferation by regulating JAKSTAT signaling pathway through SOCS1 in human lung adenocarcinoma.

PRDM5 is considered a tumor suppressor in several types of solid tumors and is involved in multiple cellular processes. However, target genes regulated by PRDM5 in lung cancer and its potential mechanism are poorly defined. Survival analysis was conducted using Kaplan-Meier estimates based on the online databases. RNA-sequencing and bioinformatics analysis were performed to identify the differentially expressed genes in PRDM5-overexpressed A549 cells. We observed deregulated PRDM5 in several lung adenocarcinoma cell lines and its association with a poor prognosis. PRDM5 overexpression inhibited the proliferation of lung adenocarcinoma cells in vitro and suppressed tumor growth in a xenograft model. PRDM5 upregulated the promoter activity of SOCS1, which then inhibited the phosphorylation of JAK2 and STAT3. Our study suggests that the low expression of PRDM5 promotes the proliferation of lung adenocarcinoma cells by downregulating SOCS1 and then upregulating the JAK2STAT3 signaling pathway.

Expert consensus on the diagnosis and treatment of NTRK gene fusion solid tumors in China.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first tumor agnostic drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA andor RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Comparison of n-butyl-2-cyanoacrylate and polyvinyl alcohol particles for bronchial artery embolisation in primary lung cancer a retrospective cohort study.

Bronchial artery embolisation (BAE) is an effective treatment option to control haemoptysis in primary lung cancer. However, no studies have investigated optimal embolisation material for BAE in lung cancer patients. Thus, this study aimed to compare the safety and efficacy of BAE performed using n-butyl-2-cyanoacrylate (NBCA) and polyvinyl alcohol (PVA) particles in primary lung cancer patients to determine which embolic material is better for patients with haemoptysis. This retrospective study was approved by the institutional review board, and consent was waived. The rates of hemostasis, complications, procedure time, dose-area product, and haemoptysis-free survival were retrospectively compared between primary lung cancer (non-small cell n 111 and small cell n 11) patients who underwent BAE using NBCA (n 58) or PVA particles (n 64) between January 2004 and December 2019. Predictors of recurrent haemoptysis were analysed using the Cox proportional hazard regression model. Among 122 patients (mean age, 66 ± 10 years range 32-86 years 103 men), more patients in the NBCA group (81.0% 47 of 58) achieved complete hemostasis than did patients in the PVA group (53.1% 34 of 64) (P 0.002). No major complications were observed in either group. The procedure time (36.4 ± 21.6 vs. 56.3 ± 27.4 min, P < 0.001) was shorter, and the dose-area product (58.6 ± 64.0 vs. 233.5 ± 225.0 Gycm BAE using NBCA showed significantly superior initial hemostasis with longer haemoptysis-free survival, shorter procedure time, and reduced radiation dose than BAE using PVA particles. The PVA use and coagulopathy were independent predictors of recurrent haemoptysis. Retrospectively registered.

Survival by Number and Sites of Resections of Recurrence after First Curative Resection of Colorectal Liver Metastases.

Recurrence after curative hepatectomy for colorectal liver metastases (CRLM) is common. We sought to determine if number and sites of resections of recurrence after hepatectomy for CRLM impact survival. The study included patients who underwent resection of recurrence following complete curative-intent resection of CRLM during 1998-2016 at two academic medical centers in Houston, USA, and Rome, Italy. The survival impacts of number and sites of resections of recurrence were evaluated. Patients with synchronous extrahepatic disease at curative CRLM resection were excluded. Among 2163 patients who underwent curative hepatectomy, 1456 (67.3%) developed a recurrence. Four hundred seventy-eight patients underwent one (322478 67.4%) or two or more (156478 32.6%) resections of recurrence. The 5-year overall survival (OS) rate was higher in patients with resected than unresected recurrence (70.2% vs. 24.0% p < 0.001). In patients who underwent only one resection of recurrence, the 5-year OS rate differed by location (lung, 81.6% liver, 64.3% other, 54.1%). In patients who underwent two or more resections of recurrence, the 5-year OS rate was similar for liver-only resection (87.5%) and resection of liver and other sites (66.1%) (p 0.223) and for liver-only resection and other-sites-only resection (80.7%) (p 0.258) 5-year OS rate by site of first resection of recurrence did not differ between liver (78.5%) and lung (81.8%) (p 0.502) but was worse for other sites (61.1%) than for lung (p 0.045). When recurrence after initial CRLM resection is resectable, the ability to undergo resection was associated with improved survival and can be considered as an option regardless of the number of recurrence and resection. Sites of resection of recurrence impact survival and should be considered.

Clinical and Dosimetric Predictors for Postoperative Cardiopulmonary Complications in Esophageal Squamous Cell Carcinoma Patients Receiving Neoadjuvant Chemoradiotherapy and Surgery.

Neoadjuvant chemoradiotherapy followed by esophagectomy is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). This study explored correlations of clinical factors and dose-volume histogram (DVH) parameters with postoperative cardiopulmonary complications and predicted their risk by establishing a nomogram model. Clinical and DVH parameters of ESCC patients who underwent trimodality treatment from 2002 to 2020 were collected. Postoperative cardiopulmonary complications were recorded. Logistic regression analysis was applied, and a nomogram model was constructed. Area under the receiver operating characteristic (AUC) curve, calibration curve, and decision curve analyses were performed to evaluate the performance of the nomogram. Of the 307 ESCC patients enrolled in this study, 65 (21.2%) experienced pulmonary complications and 57 (18.6%) experienced cardiac complications. The following six risk factors were identified as independent risk factors for pulmonary complications by multivariate logistic regression analyses in the integrated model male sex (odds ratio OR, 3.26 95% confidence interval CI, 1.27-9.70 P 0.021), post-radiation therapy (RT) forced expiratory volume in 1 s (FEV1) (OR, 0.51 95% CI 0.28-0.90 P 0.023), mean lung dose (MLD) (OR, 1.13 95% CI 1.01-1.28 P 0.041), and pre-RT monocyte (OR, 8.36 95% CI 1.23-11.7 P 0.03). The AUC of this integrated model was 0.705 (95% CI 0.64-0.77). The paclitaxel and cisplatin (TP) concurrent chemotherapy regimen was the independent predictor of cardiac complication (OR, 2.50 95% CI 1.22-5.55 P 0.016). For ESCC patients who underwent trimodality treatment, male sex, post-RT FEV1, MLD, and pre-RT monocyte were confirmed as significant predictors of postoperative pulmonary complications. A nomogram model including six risk factors was further established. The independent predictor of cardiac complication was TP concurrent chemotherapy.

In vitro and in vivo low-dose exposure of simulated cooking oil fumes to assess adverse biological effects.

Cooking oil fumes (COFs) represent a major indoor environmental pollutant and exhibit potent mutagenic or carcinogenic health effects caused by containing various heterocyclic aromatic amines (HAAs) and long-chain aldehydes. Despite some evaluation of the cumulative exposure of COFs to cancer cells under high concentration were evaluated, their biological adverse effects with low-dose exposure to healthy cells had been inadequately investigated. Herein, we firstly scrutinized the three selected typically toxic compounds of heterocyclic amine 2-amino-1-methyl-6-phenylimidazo4,5-bpyridine (PhIP), 3,8-dimethylammidazo4,5-fquinoxalin-2-amine (MeIQx) and trans, trans-2,4-decadienal (TDA)) emitted from COFs. In vitro studies revealed that the PhIP, MeIQx and TDA aerosol particles were negligible toxicity to cancer cells (A549 and HepG-2) but strong cytotoxicity to normal healthy cells (HelF and L02) under 0.5-4 μgmL low dose exposure based on the reactive oxygen species (ROS) mechanism. In vivo studies demonstrated that PhIP caused significant lung and liver damage after exposure to PhIP for 30 days with mice. These results indicated the direct proof of healthy cell damage even at low-dose exposure to HAAs and aldehydes.

Plasma autoantibodies IgG and IgM to PD1PDL1 as potential biomarkers and risk factors of lung cancer.

Antibodies targeting programmed cell death-1 (PD1) and its ligand (PDL1) have transformed current cancer therapy while little is known about the expression of anti-PD1PDL1 autoantibodies between lung cancer (LC) patients and normal controls (NC). The expression level of anti-PD1PDL1 IgG and IgM was detected in plasma of 325 LC and 324 NC by indirect enzyme-linked immune sorbent assay (ELISA). Western blot and indirect immunofluorescence (IIF) were used to verify the ELISA results. The association analysis was used to evaluate the odds ratio (OR) of LC. The expression of anti-PD1PDL1 IgG in LC samples was significantly higher than NC (P < 0.001 and P < 0.05, respectively). The positive rate of anti-PD1PDL1 IgG in LC was significantly higher than NC and significant difference was also shown in LC samples of different clinical characteristics, such as clinical stage, nodules diameter, lymph node metastasis and distant metastasis (P < 0.001). Moreover, PD1PDL1 expression in tissues showed no significant relation with that in plasma (P > 0.05). Anti-PD1PDL1 IgG were the risk factors related to LC (OR (95% CI) 22.433 (5.426-92.745) and 5.051 (1.316-19.386)), while anti-PD1PDL1 IgM were the risk factors for LC with ≤ 60 years (OR (95% CI) 6.122 (1.365-27.455) and 7.664 (1.715-34.251)) and anti-PD1 IgM was also the risk factor for male LC cases(OR (95% CI) 6.948 (1.076-44.868)). Plasma anti-PD1PDL1 IgG and IgM might serve as potential biomarkers and risk predictors for LC.

Diagnostic accuracy and safety of CT-guided percutaneous lung biopsy with a coaxial cutting needle for the diagnosis of lung cancer in patients with UIP pattern.

This study aimed to assess the diagnostic accuracy and safety of CT-guided percutaneous core needle biopsy (PCNB) with a coaxial needle for the diagnosis of lung cancer in patients with an usual interstitial pneumonia (UIP) pattern of interstitial lung disease. This study included 70 patients with UIP and suspected to have lung cancer. CT-guided PCNB was performed using a 20-gauge coaxial cutting needle. The diagnostic accuracy, sensitivity, specificity, and percentage of nondiagnostic results for PCNB were determined in comparison with the final diagnosis. PCNB-related complications were evaluated. Additionally, the risk factors for nondiagnostic results and pneumothorax were analyzed. The overall diagnostic accuracy, sensitivity, and specificity were 85.7%, 85.5%, and 87.5%, respectively. The percentage of nondiagnostic results was 18.6% (1370). Two or less biopsy sampling was a risk factor for nondiagnostic results (p 0.003). The overall complication rate was 35.7% (2570), and pneumothorax developed in 22 patients (31.4%). A long transpulmonary needle path was a risk factor for the development of pneumothorax (p 0.007). CT-guided PCNB using a coaxial needle is an effective method with reasonable accuracy and an acceptable complication rate for the diagnosis of lung cancer, even in patients with UIP.

Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast.

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPECPPAR-γ link for BC treatment.

Elevated Expression of ADAP2 is Associated With Aggressive Behavior of Human Clear-Cell Renal Cell Carcinoma and Poor Patient Survival.

Clear cell renal cell carcinoma (ccRCC) is the most common and lethal cancer of the adult kidney. ADAP2 is a GTPase-activating protein was upregulated in clear cell renal cell carcinoma. The role of ADAP2 in ccRCC progression is unknown. ADAP2 expression in ccRCC cell lines and tissues was examined via real-time PCR, Western blot and IHC. MTS, colony formation and transwell assay to explore the role of ADAP2 in ccRCC. ADAP2 in growth and metastasis of ccRCC were evaluated in vivo through ccRCC xenograft tumor growth, lung metastatic mice model. The prognostic role of ADAP2 was evaluated by survival analysis. ADAP2 mRNA was expressed at significantly higher levels in 23 pairs of ccRCC tissues than in normal kidney tissues (P < 0.01). Immunohistochemical analysis of 298 ccRCC tissues revealed elevated ADAP2 expression as an independent unfavorable prognostic factor for the overall survival (P 0.0042) and progression-free survival (P 0.0232) of patients. The KaplanMeier survival curve showed that patients with a higher expression of ADAP2 showed a significantly lower overall survival rate and disease-free survival rate. Moreover, high expression of ADAP2 at the mRNA level was associated with a worse prognosis for overall survival (P 0.0083) in The Cancer Genome Atlas (TCGA) cohort. In vivo and in vitro functional study showed that overexpression of ADAP2 promotes ccRCC cell proliferation and metastasis ability, whereas knockdown of ADAP2 inhibited cell proliferation, colony formation, migration and invasion. ADAP2 is a novel prognostic marker and could promotes tumor progression in ccRCC.

Ginsenoside Rd ameliorates muscle wasting by suppressing the signal transducer and activator of transcription 3 pathway.

The effects of some drugs, aging, cancers, and other diseases can cause muscle wasting. Currently, there are no effective drugs for treating muscle wasting. In this study, the effects of ginsenoside Rd (GRd) on muscle wasting were studied. Tumour necrosis factor-alpha (TNF-α)interferon-gamma (IFN-γ)-induced myotube atrophy in mouse C2C12 and human skeletal myoblasts (HSkM) was evaluated based on cell thickness. Atrophy-related signalling, reactive oxygen species (ROS) level, mitochondrial membrane potential, and mitochondrial number were assessed. GRd (10 mgkg body weight) was orally administered to aged mice (23-24 months old) and tumour-bearing (Lewis lung carcinoma LLC1 or CT26) mice for 5 weeks and 16 days, respectively. Body weight, grip strength, inverted hanging time, and muscle weight were assessed. Histological analysis was also performed to assess the effects of GRd. The evolutionary chemical binding similarity (ECBS) approach, molecular docking, Biacore assay, and signal transducer and activator of transcription (STAT) 3 reporter assay were used to identify targets of GRd. GRd significantly induced hypertrophy in the C2C12 and HSkM myotubes (average diameter 50.8 ± 2.6% and 49.9% ± 3.7% higher at 100 nM, vs. control, P ≤ 0.001). GRd treatment ameliorated aging- and cancer-induced (LLC1 or CT26) muscle atrophy in mice, which was evidenced by significant increases in grip strength, hanging time, muscle mass, and muscle tissue cross-sectional area (1.3-fold to 4.6-fold, vs. vehicle, P ≤ 0.05 P ≤ 0.01 P ≤ 0.001). STAT3 was found to be a possible target of GRd by the ECBS approach and molecular docking assay. Validation of direct interaction between GRd and STAT3 was confirmed through Biacore analysis. GRd also inhibited STAT3 phosphorylation and STAT3 reporter activity, which led to the inhibition of STAT3 nuclear translocation and the suppression of downstream targets of STAT3, such as atrogin-1, muscle-specific RING finger protein (MuRF-1), and myostatin (MSTN) (29.0 ± 11.2% to 84.3 ± 30.5%, vs. vehicle, P ≤ 0.05 P ≤ 0.01 P ≤ 0.001). Additionally, GRd scavenged ROS (91.7 ± 1.4% reduction at 1 nM, vs. vehicle, P ≤ 0.001), inhibited TNF-α-induced dysregulation of ROS level, and improved mitochondrial integrity (P ≤ 0.05 P ≤ 0.01 P ≤ 0.001). GRd ameliorates aging- and cancer-induced muscle wasting. Our findings suggest that GRd may be a novel therapeutic agent or adjuvant for reversing muscle wasting.

Level of knowledge on low-dose CT lung cancer screening in Sichuan province, China a cross-sectional study.

Low-dose CT (LDCT) can help determine the early stage of lung cancer and reduce mortality. However, knowledge of lung cancer and lung cancer screening among community residents and medical workers, and potential factors that may affect medical institutions to set up LDCT are limited. A cross-sectional study was conducted in Sichuan province, China, in 2021. Community residents, medical workers and medical institutions were randomly selected, and participants responded to related questionnaires. Knowledge of lung cancer and LDCT lung cancer screening was evaluated. Data analyses were performed using SAS V.9.4. A total of 35 692 residents, 6350 medical workers and 81 medical institutions were recruited 4.05% of the residents were very familiar with lung cancer and 37.89% were (completely) unfamiliar. Characteristics, such as age and level of education, were significantly related to residents who were very familiar with lung cancer. Furthermore, 22.87% of the residents knew that LDCT can effectively screen for early-stage lung cancer, which was correlated with smoking (OR 1.1300 95% CI 1.0540 to 1.2110 p0.006) and family history of cancer (OR 1.2210 95% CI 1.1400 to 1.3080 p<0.0001) 66.06% of medical workers believed that LDCT can detect early-stage lung cancer. Technicians and nurses were less knowledgeable than doctors about whether LDCT can effectively screen for early-stage lung cancer (OR 0.6976 95% CI 0.5399 to 0.9015 p0.0059 and OR 0.6970 95% CI 0.5718 to 0.8496 p0.0004, respectively). Setting up LDCT in medical institutions was related to grade, administrative rank, number of hospital beds that opened and total number of medical workers. The knowledge of lung cancer in residents is relatively low, and the knowledge of LDCT in screening (early-stage) lung cancer needs to be improved both in residents and medical workers. Possible factors that affect medical institutions to set up LDCT may need to be incorporated.

The Yorkshire Kidney Screening Trial (YKST) protocol for a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal pathology within a trial of community-based CT screening for lung cancer.

Kidney cancer (renal cell cancer (RCC)) is the seventh most common cancer in the UK. As RCC is largely curable if detected at an early stage and most patients have no symptoms, there is international interest in evaluating a screening programme for RCC. The Yorkshire Kidney Screening Trial (YKST) will assess the feasibility of adding non-contrast abdominal CT scanning to screen for RCC and other abdominal pathology within the Yorkshire Lung Screening Trial (YLST), a randomised trial of community-based CT screening for lung cancer. In YLST, ever-smokers aged 55-80 years registered with a general practice in Leeds have been randomised to a Lung Health Check assessment, including a thoracic low-dose CT (LDCT) for those at high risk of lung cancer, or routine care. YLST participants randomised to the Lung Health Check arm who attend for the second round of screening at 2 years without a history of RCC or abdominal CT scan within the previous 6 months will be invited to take part in YKST. We anticipate inviting 4700 participants. Those who consent will have an abdominal CT immediately following their YLST thoracic LDCT. A subset of participants and the healthcare workers involved will be invited to take part in a qualitative interview. Primary objectives are to quantify the uptake of the abdominal CT, assess the acceptability of the combined screening approach and pilot the majority of procedures for a subsequent randomised controlled trial of RCC screening within lung cancer screening. YKST was approved by the North West-Preston Research Ethics Committee (21NW0021), and the Health Research Authority on 3 February 2021. Trial results will be disseminated at clinical meetings, in peer-reviewed journals and to policy-makers. Findings will be made available to participants via the study website (www.YKST.org). NCT05005195 and ISRCTN18055040.

Impact of prolonged isolation on adolescents with drug-susceptible tuberculosis in Lima, Peru a qualitative study.

Patients with tuberculosis (TB) generally are instructed to isolate at the beginning of treatment in order to prevent disease transmission. The duration of isolation varies and may be prolonged (ie, lasting 1 month or more). Few studies have examined the impact of isolation during TB treatment on adolescents, who may be more vulnerable to its negative effects. This study took place from 2018 through 2019 in Lima, Peru, where the Ministry of Health mandates the exclusion of patients with TB from educational institutions for at least 2 months. Using semi-structured guides, we conducted individual in-depth interviews with adolescents who received treatment for drug-susceptible TB, their primary caregivers and health providers. We performed thematic analysis of the transcribed interviews. We interviewed 85 participants 34 adolescents, 36 caregivers and 15 healthcare workers. At the time of their TB diagnoses, 28 adolescents were in secondary, postsecondary, vocational or military school. Adolescents with drug-susceptible TB were prescribed home isolation usually for 2 (and occasionally for 1) months. Consequently, they could neither attend school nor socialise with family members or friends. Two primary themes emerged from the interviews. First, as a result of their exclusion from school, most adolescents fell behind academically and had to repeat a semester or academic year. Second, absence from school, separation from friends and loved ones, and reinforcement of TB-related stigma (arising from fear of TB transmission) harmed adolescents mental health. Prolonged isolation led to educational setbacks and emotional trauma among adolescents with TB. Prolonged isolation is not supported by current evidence on TB transmission and is problematic from a human rights perspective, as it violates adolescents rights to education and freedom of movement. Isolation recommendations should be re-evaluated to align with data on TB transmission and the principles of patient-centred care.

Correlations of switchsucrose nonfermentable complex mutations with clinical outcomes in advanced non-small cell lung cancer.

The switchsucrose nonfermentable complex mutations (SWISNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWISNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-L1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWISNF alterations and clinical outcomes in each cohort. In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWISNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n 146), patients with co-mutations of SWISNF and Kirsten rat sarcoma oncogene (KRAS) (SWISNFmutKRASmut, n 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m hazard ratio HR, 0.31 95% confidence intervals CI, 0.11-0.83 p 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach NR vs. 6.3 m HR, 0.36, 95% CI, 0.15-0.82 p 0.016). In cohort 2 (n 205), ARID1A-mut (n 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m HR, 0.47, 95% CI, 0.27-0.94 p 0.023). In advanced NSCLC, patients with SWISNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.

Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.

While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (mV), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for gt90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections.

Wedge Resection vs Lobectomy for Clinical Stage IA Non-Small Cell Lung Cancer With Occult Lymph Node Disease.

Sublobar resection is increasingly performed for stage Ia non-small cell lung cancer, but pathologic lymph node upstaging remains a common clinical scenario. This study compares the long-term prognosis of patients with clinical stage Ia disease and occult lymph node disease undergoing wedge resection vs lobectomy. The National Cancer Database was queried for patients treated with wedge resection or lobectomy for clinical stage Ia (cT1N0) non-small cell lung cancer and who were pathologically upstaged with either pN1pN2 disease. Overall survival (OS) was compared by extent of resection using inverse probability treatment weighting-adjusted Cox regression analyses. Of 5437 clinical stage Ia patients included, 3408 (62.7%) were found to have occult pN1 and 2029 (37.3%) to have occult pN2. Of 5437 patients, 93.5% (5082) were treated with lobectomy and 6.5% (355) underwent wedge resection. Lobectomy was associated with improved OS compared with wedge resection for patients with occult pN1 disease (median OS, 70.0 months 95% CI, 66.6-77.4 vs 36.4 months 95% CI, 24.2-45.6 P < .001) but not for pN2 disease (median OS, 48.2.1 months 95% CI, 43.8-52.9 vs 43.7 months 95% CI, 31.2-62.4 P 0.24). On inverse probability treatment weighting-adjusted multivariable analysis, adjusting for demographics, comorbidities, margin status, and pathologic T and N stage, lobectomy remained associated with improved survival (adjusted hazard ratio, 0.73 95% CI, 0.60-0.89 P .0016). Lobectomy is associated with improved survival in clinical stage Ia non-small cell lung cancer patients with occult lymph node disease. These data may aid the decision for completion lobectomy for patients with unanticipated N1 lymph node upstaging.

Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells.

Non-small cell lung carcinomas (NSCLCs), especially lung adenocarcinomas (LUADs), harbor several driver mutations against which highly effective tyrosine kinase inhibitors (TKIs) are available. Although TKIs are generally effective against certain NSCLCs, primary or acquired resistance almost always develops. Driver mutations include RET fusion (∼1-2% of NSCLC cases) and MET exon 14 skipping mutation (METΔex14 ∼3-4%). Surprisingly, the LUAD cell line LC-2ad with CCDC6-RET fusion thrived independently of RET signaling, and Hs-746T cells harboring METΔex14 plus amplification survived MET silencing. However, these two cell lines were highly sensitive to dual silencing of the representative anti-apoptotic BCL2 family members BCL2L1 and MCL1, undergoing extensive apoptosis in monolayer or 3D on-top culture systems. Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.

Influence of esomeprazole on the bioavailability of afatinib A pharmacokinetic cross-over study in patients with non-small cell lung cancer.

Afatinib is an oral small-molecule kinase inhibitor (SMKI) approved for treatment of metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) driver mutation. Although oral administration is convenient, most SMKIs experience pH-dependent solubility. A drug-drug interaction between afatinib and proton-pump inhibitors (PPIs) has, however, never been studied in humans. Hence, we performed a randomized, three-period cross-over study. Afatinib (30 mg or 40 mg) was administered without PPI (period A), concomitantly with esomeprazole (period B) and three hours after esomeprazole intake (period C). Primary objective was the area under the curve (AUC

Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma A systematic review and meta-analysis.

To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular carcinoma (HCC) and to explore the predictive performance of tumour mutation burden (TMB). We conducted a systematic literature search to identify clinical trials. Meta-analysis and subgroup analyses were performed to estimate the benefits of combination regimens with PD-1PD-L1 inhibitors for patients with advanced HCC and compare the effectiveness of PD-1PD-L1 inhibitors and sorafenib as first-line therapy. Individualized analysis and Kaplan-Meier were used to assess the prognostic value of TMB. A total of 29 studies with 5396 patients were included. ICIs combination therapy had higher ORR (26 % vs 15 %) and DCR (73 % vs 55 %), longer PFS (5.5 vs 3.1 months) and OS (15.9 vs 12.6 months) compared to monotherapy. Anti-PD-1PD-L1 agents provided improved ORR, DCR, PFS and OS compared to sorafenib. The overall ORs of ORR and DCR in subgroup analysis were 3.49 (95 % CI 2.36-5.17, p < 0.01) and 1.60 (95 % CI 1.15-2.21, p < 0.01). The overall HRs of PFS and OS were 0.68 (95 % CI 0.48-0.96, p 0.03) and 0.73 (95 % CI 0.62-0.85, p < 0.01). PD-1PD-L1 inhibitors plus anti-VEGF agents had an advantage in DCR (0.80 vs 0.48, meta-regression - 0.32, P < 0.001), but an equal ORR (0.29 vs 0.26) compared to dual immune checkpoint inhibitors. The total OS in Dua-ICIs were 16.5 months (95 % CI 14.2-18.7), yet not reached in the major studies of ICI plus anti-VEGF regimen. In individualized analysis, the 1-year OS was superior for patients who had high-TMB (>10, mutationsMb) than moderate-TMB (1-10, mutationsMb 28 % vs 15 %, P 0.025). Immune checkpoint inhibitors combination therapy improved clinical outcomes in the management of advanced hepatocellular carcinoma. However, the overall objective response rate still did not exceed 30%. PD-1PD-L1 inhibitors plus anti-angiogenic agents and dual immunotherapy provided significantly increased survival over sorafenib, which also pose new challenges for future research, and more appropriate and guided control regimens are required. Also, TMB may be a promising prognostic biomarker for immunotherapy in HCC. However, the validation of prospective and large sample studies is needed.

Tumor Mutational Burden by Whole-Genome Sequencing in Resected NSCLC of Never Smokers.

Data are scarce about tumor mutational burden (TMB) as a biomarker in never smokers with non-small cell lung cancer (NSCLC). TMB was assessed by whole-genome sequencing (WGS) and compared with in silico reduced whole-exome sequencing (WES) and targeted commercial next-generation sequencing (NGS) gene panels in 92 paired tumor-normal samples from never smokers who underwent NSCLC resection with curative intent. Analyses were performed to test for association with survival after surgery and to identify the optimal prognostic TMB cutoff. Tumors of never smokers with NSCLC had low TMB scores (median 1.57 mutationsMb range, 0.13-17.94). A TMB cutoff of 1.70 mutationsMb was associated with a 5-year overall survival of 58% in the high-TMB (42% of cases) compared with 86% in low-TMB patients (Wald P 0.0029). TMB scores from WGS and WES were highly correlated (Spearman ρ 0.93, P < 2.2e-16). TMB scores from NGS panels demonstrated high intraindividual fluctuations and identified high-TMB patients with 65% concordance in average compared with WGS. In resected NSCLC of never smokers, high TMB was associated with worse prognosis. WES provided a good estimate of TMB while targeted NGS panels seem to lack adequate depth and resolution in the setting of low mutation burden. TMB is a prognostic indicator of survival in resected NSCLC from individuals who never smoked. In this setting of low mutation counts, TMB can be accurately measured by WGS or WES, but not NGS panels.

TGFB2-AS1 inhibits triple-negative breast cancer progression via interaction with SMARCA4 and regulating its targets

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells in vitro and dramatically decreases tumorigenic frequency and lung metastasis in vivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWISNF chromatin remodeling complex, and results in transcriptional repression of its target genes including

Economic burden of brain metastases in non-small cell lung cancer patients in South Korea A retrospective cohort study using nationwide claims data.

Brain metastases (BM) are common in patients with non-small cell lung cancer (NSCLC). However, the pure economic burden of BM is unknown. This study aimed to evaluate the impact of BM on healthcare costs and resource utilization in patients with NSCLC by comparing patients with and without BM. This was a retrospective cohort analysis of South Korean health insurance review and assessment claims data. Patients with stage IIIB or IV NSCLC were identified (March 1, 2013 to February 28, 2018). We compared their two-year and per-patient-per-month (PPPM) healthcare costs and resource utilization with 13 propensity score-matched patients without the condition. A generalized linear model was used to estimate the impact of BM and other covariates on healthcare costs. After propensity score matching with the 33 402 newly diagnosed cases of stage IIIB or IV NSCLC, 3435 and 10 305 patients were classified as having or not having BM, respectively. Mean healthcare costs were significantly greater in patients with BM for both the two years (US$ 44 692 vs. US$ 32 230, p < .0001) and PPPM (US$ 3510 vs. US$ 2573, p < .0001). The length of hospital stay was longer in patients with BM (79.15 vs. 69.41 days for two years, p < .0001 7.69 vs. 6.86 days PPPM, p < .0001), and patients with BM had more outpatient visits (50.61 vs. 46.43 times for two years, p < .0001 3.64 vs. 3.40 times PPPM costs, p < .0001). The costs of drugs, radiologyradiotherapy, and admission comprised the majority of PPPM costs and were higher in patients with BM. The generalized linear model analysis suggested that patients with BM had significantly increased healthcare costs (by 1.29-fold, 95% confidence interval 1.26-1.32). BM is a significant economic burden for patients with NSCLC. Therefore, it is important to prevent BM in patients with NSCLC to reduce their economic burden.

A pan-cancer bioinformatic analysis of the carcinogenic role of SMARCA1 in human carcinomas.

SMARCA1is a mammalian imitation switch (ISWI) gene that encodes for SNF2L. SNF2L is involved in regulating cell transition from a committed progenitor state to a differentiated state. Although many papers have detailed the correlation between SMARCA1 and different cancers, no pan-cancer analysis has been conducted to date. We started by exploring the potential carcinogenic role of SMARCA1 across 33 carcinomas using the cancer genome atlas (TCGA) and the genotype-tissue expression (GTEx) databases. The expression of SMARCA1 was significantly elevated in some tumor types but not in others. There was a distinct relationship between SMARCA1 expression and patient prognosis. S116 phosphorylation levels were up-regulated in both lung adenocarcinoma and uterine corpus endometrial carcinoma. The expression level of SMARCA1 was positively correlated with cancer-associated fibroblasts infiltration in a number of tumors, such as colon adenocarcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma. It was also associated with CD8 T-cell infiltration in head and neck squamous cell carcinoma and lung adenocarcinoma. Furthermore, SMARCA1 is involved in chromatin remodeling and protein processing-associated mechanisms. Our study presents an initial assessment and illustration of the carcinogenic role of SMARCA1 in different carcinomas.

Cancer risk associated with cytomegalovirus infection among solid organ transplant recipients in the United States.

Cytomegalovirus (CMV) is among the most common viral infections after solid organ transplantation (SOT). Associations of CMV with cancer risk among SOT recipients have been incompletely evaluated. The authors used linked data from the US SOT registry and 32 cancer registries. Poisson regression was used to compare cancer incidence across CMV risk groups based on donor (D) and recipient (R) immunoglobulin G (IgG) serostatus high risk (R-negativeD-positive), moderate risk (R-positive), and low risk (R-negativeD-negative). In total, 247,318 SOT recipients were evaluated during 2000-2017 (R-negativeD-positive, 20.3% R-positive, 62.9% R-negativeD-negative, 16.8%). CMV-seropositive recipients were older, more raciallyethnically diverse, and had lower socioeconomic status than CMV-seronegative recipients. Compared with R-negativeD-negative recipients, recipients in the R-negativeD-positive and R-positive groups had a lower incidence of diffuse large B-cell lymphoma (DLBCL R-negativeD-positive adjusted incidence rate ratio aIRR, 0.74 95% confidence interval CI, 0.59-0.91 R-positive aIRR, 0.83 95% CI, 0.69-1.00). CMV serostatus modified the association between Epstein-Barr virus (EBV) status and DLBCL (p .0006) DLBCL incidence was increased for EBV R-negativeD-positive recipients (aIRR, 3.46 95% CI, 1.50-7.95) among CMV R-negativeD-negative recipients but not among the other CMV risk groups. Compared with recipients who were CMV R-negativeD-negative, those who were R-negativeD-positive had a lower incidence of small intestine cancer (aIRR, 0.23 95% CI, 0.09-0.63), and R-positive recipients had a higher incidence of lung cancer (aIRR, 1.24 95% CI, 1.05-1.46). CMV status was not associated with risk for other cancers. CMV status was not associated with risk for most cancers among SOT recipients. The inverse association with DLBCL may reflect the protective effects of CMV prophylaxis or treatment with off-target efficacy against EBV infection (the major cause of lymphoma in SOT recipients).

ALK-rearranged Mesenchymal Neoplasms A Report of 9 cases Further Expanding the Clinicopathologic Spectrum of Emerging Kinase Fusion Positive Group of Tumors.

Anaplastic lymphoma kinase (ALK) fusions are oncogenic drivers in diverse cancer types. Although well established in inflammatory myofibroblastic tumor (IMT) and epithelioid fibrous histiocytoma (EFH), ALK rearrangements also occur in the emerging family of kinase fusion-positive mesenchymal neoplasms. We investigated 9 ALK-rearranged mesenchymal neoplasms (exclusive of IMT and EFH) arising in 6 males and 3 females with a wide age range of 10 to 78 years old (median 42 years). Tumors involved superficial and deep soft tissue (6) and viscera (3). Three were myxoid or collagenous low-grade paucicellular tumors with haphazardly arranged spindled cells. Three were cellular tumors with spindled cells in intersecting short fascicles or solid sheets. Three cases consisted of uniform epithelioid cells arranged in nests or solid sheets, with prominent mitotic activity and necrosis. Band-like stromal hyalinization was present in 6 cases. All tumors expressed ALK four were positive for S100 and five were positive for CD34, while all were negative for SOX10. By targeted RNA sequencing, the breakpoints involved ALK exon 20 the 5 partners included KLC1, EML4, DCTN1, PLEKHH2, TIMP3, HMBOX1, and FMR1. All but two patients presented with localized disease. One patient had distant lung metastases another had diffuse pleural involvement. Of the six cases with treatment information, five were surgically excised one also received neoadjuvant radiation therapy (RT), and one received RT and an ALK inhibitor. Of the four patients with follow-up (median 5.5 months), one remained alive with stable disease and three were alive without disease. We expand the clinicopathologic spectrum of ALK-fused mesenchymal neoplasms, including a low-grade malignant peripheral nerve sheath tumor-like subset and another subset characterized by epithelioid and high-grade morphology.

α-cyanoacrylate rapid medical adhesive (medical EC glue) localization of pulmonary nodules guided by computed tomography before thoracoscopic surgery.

Lung cancer screening by low-dose CT to identify the nature of pulmonary nodule. The purpose of this study was to evaluate the role of preoperative medical EC glue localization of pulmonary nodules of uncertain nature by minimally invasive surgical resection. From December 2017 to December 2019, 18 patients (12 women, 6 men median age 54 years)with pulmonary nodules were located using medical EC glue under the guidance of preoperative CT and then resected under video thoracoscopy at Air Force Medical Center of PLA. The clinical characteristics were retrospectively collected to evaluate the effectiveness, safety and feasibility of the operation. The mean value of the maximum diameter of pulmonary nodules on CT images before operation was 10.8 mm. Average depth was 10.3 mm (1.0-39.5 mm). Among 18 nodules, 8 were pure ground glass nodules, 3 were solid nodules and 7 were partial solid nodules. The diagnosis rate of medical glue localization under the guidance of CT after operation was 100%. Postoperative pathological diagnosis showed that there were 10 cases of primary lung adenocarcinoma, 1 case of invasive lung adenocarcinoma, 3 cases of adenocarcinoma in situ, 1 case of metastatic adenocarcinoma, and 3 cases of benign nodules. No obvious serious complications were found after localization. This study suggests that CT-guided percutaneous medical EC glue localization is a reliable, safe, feasible and practical method for undiagnosed pulmonary nodules, and can significantly improve the rate of resection of small pulmonary nodules. Furthermore, it was considered be more reasonable to remove pulmonary nodules and maximize the preservation of lung function.

Indirect Clinical Validation of a Programmed Death-Ligand 1 Laboratory-Developed Test for GastricGastroesophageal Junction Adenocarcinoma with 22C3 Antibody Concentrate.

The PD-L1 IHC 22C3 pharmDx used on the Dako Autostainer Link 48 (ASL48) staining platform is an established method for assessing programmed death-ligand 1 (PD-L1) expression in tumor tissue and determining patient eligibility for pembrolizumab treatment however, the availability of this platform is limited in Europe and Asia. The aims of this study were to develop and optimize protocols for the PD-L1 22C3 antibody concentrate with multiple immunohistochemistry staining platforms and to validate these protocols using PD-L1 combined positive score (CPS) with a cut-off of ≥ 1 in gastric or gastroesophageal junction adenocarcinoma. The 22C3 antibody concentrate was tested and optimized protocols were developed for use with three staining platforms Dako ASL48, Ventana BenchMark ULTRA, and Leica BOND-MAX. Tumor specimens (N 120) from patients with gastric or gastroesophageal junction adenocarcinoma were used for the validation study these specimens were evaluated independently by three pathologists for PD-L1 CPS as a continuous variable and using a cut-off of ≥ 1. PD-L1 IHC 22C3 pharmDx used on the Dako ASL48 platform served as the reference or gold standard. The intraclass correlation coefficient of CPS as a continuous variable between the gold standard and each staining platform assessed was 0.910-0.989. When CPS was dichotomized based on a cut-off of ≥ 1, depending on the pathologist and the platform used, positive percentage agreement was 81-99% and negative percentage agreement was 90-100%. Interobserver agreement using the gold standard showed substantial agreement (κ 0.779). The PD-L1 22C3 antibody concentrate can potentially be used with the laboratory-developed test on three commercially available immunohistochemistry staining platforms to determine PD-L1 expression in tumor samples from patients with gastric or gastroesophageal junction adenocarcinoma.

SARS-CoV-2 Diverges from Other Betacoronaviruses in Only Partially Activating the IRE1αXBP1 Endoplasmic Reticulum Stress Pathway in Human Lung-Derived Cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed to be essential for viral replication. We examined the master UPR sensor IRE1α kinaseRNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found that human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.

Electrochemical sensor propelled by exonuclease III for highly efficient microRNA-155 detection.

MicroRNA-155 is highly expressed in tumor cells such as lung cancer, liver cancer and lymphoma. As such, it is increasingly used for the early diagnosis and monitoring of cancer diseases. Herein, we designed an electrochemical sensor propelled by exonuclease III, which is coupled with multiple signal amplification strategies for highly efficient microRNA-155 detection. In the presence of miRNA-155, a DNA hairpin probe with exposed bases at both ends was found to form a flat end, which can be hydrolyzed by exonuclease III. The produced single-stranded DNA enters the next cycle for further cleavage to produce another single-stranded DNA. The end product can trigger a hybridization chain reaction on the electrode surface, which is used for electrochemical detection with methylene blue as an electrochemical signaling indicator. Under optimal reaction conditions, there is good linear correlation between the logarithm of the target concentration and the current signal, with the concentration ranging from 0.1 fM to 0.1 nM. The detection limit is as low as 0.035 fM. Overall, the strategy for miRNA detection offers good prospects for early cancer screening.

EGFR, the Lazarus target for precision oncology in glioblastoma.

The Lazarus effect is a rare condition that happens when someone seemingly dead shows signs of life. The epidermal growth factor receptor (EGFR) represents a target in the fatal neoplasm glioblastoma (GBM) that through a series of negative clinical trials has prompted a vocal subset of the neuro-oncology community to declare this target dead. However, an argument can be made that the core tenets of precision oncology were overlooked in the initial clinical enthusiasm over EGFR as a therapeutic target in GBM. Namely, the wrong drugs were tested on the wrong patients at the wrong time. Furthermore, new insights into the biology of EGFR in GBM vis-à-vis other EGFR-driven neoplasms, such as non-small cell lung cancer, and development of novel GBM-specific EGFR therapeutics resurrects this target for future studies. Here, we will examine the distinct EGFR biology in GBM, how it exacerbates the challenge of treating a CNS neoplasm, how these unique challenges have influenced past and present EGFR-targeted therapeutic design and clinical trials, and what adjustments are needed to therapeutically exploit EGFR in this devastating disease.

Impact of segmentectomy and lobectomy on non-lung cancer death in early-stage lung cancer patients.

This study aimed to analyse the risk of death from non-lung cancer after segmentectomy or lobectomy for early-stage lung cancer. A total of 1385 patients underwent lobectomy or segmentectomy for clinical stage 0-I primary lung cancer, with no evidence of recurrence after surgery, between January 2008 and December 2018. Risk factors for non-lung cancer deaths (NLCD) were analysed using multivariable logistic regression analysis. The overall survival (OS) of patients with low and high comorbidities who underwent lobectomy and segmentectomy was compared using a log-rank test. Patients with NLCD (n 126) were more likely to have undergone lobectomy than patients with non-recurrence survival (n 1259). Multivariable analysis revealed that age (≥65 years), smoking index (≥600), body mass index (≤18.5 kgm2), interstitial pneumonia, values for percentage of predicted vital capacity (≤9.4%) and lobectomy were risk factors for NLCD. Patients who underwent segmentectomy had significantly better 5-year OS than those who underwent lobectomy, after propensity score matching (94.6% vs 90.4%, P 0.027). Patients with high comorbidities (patients with ≥2 of the following risks age ≥65 years, smoking index ≥600, body mass index ≤18.5 kgm2, Charlson Comorbidity Index ≥1, values for percentage of predicted vital capacity ≤96.4%) who underwent segmentectomy had a better 5-year OS than those who underwent lobectomy (92.8% vs 87.8%, P 0.016). However, there was no difference in 5-year OS between segmentectomy and lobectomy in patients with low comorbidities (98.5% vs 97.4%, P 0.867). The impact of lobectomy and segmentectomy on NLCD depends on the extent of the patients comorbidities.

Anti-programmed death ligand 1 immunotherapy in patients with limited-stage small cell lung cancer a real-world exploratory study.

The aim of this study was to investigate the safety and efficacy of anti-programmed death ligand 1 (PD-L1) immunotherapy plus chemoradiotherapy for patients with limited-stage small cell lung cancer (LS-SCLC) in clinical practice. Patients with LS-SCLC treated with anti-PD-L1 (atezolizumabdurvalumab) plus chemoradiotherapy (CRT) as the initial treatment at three general hospitals between March 2020 and December 2021 were retrospectively analysed. 12 propensity score matching for controls that receive CRT only was performed. Clinical data (age, sex, history of cancer treatment, adverse events, etc.) were collected to evaluate toxicity, progression-free survival (PFS) and objective response rate (ORR). Researchers used univariate Chi-squared analyses to determine if anti-PD-L1 immunotherapy had a significant association with toxicity or ORR. Kaplan-Meier survival analysis, and the log-rank test were used to compare survival curves between the two groups. In the anti-PD-L1 plus CRT and CRT groups, 15 and 30 patients were analyzed median follow-up was 16.39 months and 16.64 months, respectively. Incidence of toxicity between the two groups was similar and there were no new safety signals. Anti-PD-L1 immunotherapy significantly improved PFS (

Discovering significant evolutionary trajectories in cancer phylogenies.

Tumors are the result of a somatic evolutionary process leading to substantial intra-tumor heterogeneity. Single-cell and multi-region sequencing enable the detailed characterization of the clonal architecture of tumors and have highlighted its extensive diversity across tumors. While several computational methods have been developed to characterize the clonal composition and the evolutionary history of tumors, the identification of significantly conserved evolutionary trajectories across tumors is still a major challenge. We present a new algorithm, MAximal tumor treeS TRajectOries (MASTRO), to discover significantly conserved evolutionary trajectories in cancer. MASTRO discovers all conserved trajectories in a collection of phylogenetic trees describing the evolution of a cohort of tumors, allowing the discovery of conserved complex relations between alterations. MASTRO assesses the significance of the trajectories using a conditional statistical test that captures the coherence in the order in which alterations are observed in different tumors. We apply MASTRO to data from nonsmall-cell lung cancer bulk sequencing and to acute myeloid leukemia data from single-cell panel sequencing, and find significant evolutionary trajectories recapitulating and extending the results reported in the original studies. MASTRO is available at httpsgithub.comVandinLabMASTRO. Supplementary data are available at Bioinformatics online.

Reporting and management of incidental lung findings on computed tomography beyond lung nodules.

Non-nodular incidental lung findings can broadly be categorised as airway- or airspace-related abnormalities and diffuse parenchymal abnormalities. Airway-related abnormalities include bronchial dilatation and thickening, foci of low attenuation, emphysema, and congenital variants. Diffuse parenchymal abnormalities relate to the spectrum of diffuse parenchymal lung diseases cover a spectrum from interstitial lung abnormalities (ILAs) and pulmonary cysts to established diffuse parenchymal lung abnormalities such as the idiopathic interstitial pneumonias and cystic lung diseases. In this review, we discuss the main manifestations of these incidental findings, paying attention to their prevalence and importance, descriptors to use when reporting, the limits of what can be considered normal, and conclude each section with some pragmatic reporting recommendations. We also highlight technical and patient factors which can lead to spurious abnormalities.

A novel dictionary learning-based approach for Ultrasound Elastography denoising.

Ultrasound Elastography is a late-model Ultrasound imaging technique mainly used to diagnose tumors and diffusion diseases that cant be detected by traditional Ultrasound imaging. However, artifact noise, speckle noise, low contrast and low signal-to-noise ratio in images make disease diagnosing a challenging task. Medical images denoising, as the first step in the follow-up processing of medical images, has been concerned by many people. With the widespread use of deep learning technique in the research field, dictionary learning method are once again receiving attention. Dictionary learning, as a traditional machine learning method, requires less sample size, has high training efficiency, and can describe images well. In this work, we present a novel strategy based on K-clustering with singular value decomposition (K-SVD) and principal component analysis (PCA) to reduce noise in Ultrasound Elastography images. At this stage of dictionary training, we implement a PCA method to transform the way dictionary atoms are updated in K-SVD. Finally, we reconstructed the image based on the dictionary atoms and sparse coefficients to obtain the denoised image. We applied the presented method on datasets of clinical Ultrasound Elastography images of lung cancer from Nanjing First Hospital, and compared the results of the presented method and the original method. The experimental results of subjective and objective evaluation demonstrated that presented approach reached a satisfactory denoising effect and this research provides a new technical reference for computer aided diagnosis.

Assessment of clinical utility and predictive potential of pre-chemotherapy soluble urokinase plasminogen activator receptor - observational single center study.

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 - 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 - 1.13 p 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ngmL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state.

Autophagy-linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS-CoV-2 entry into human cells.

Better understanding on interactions between SARS-CoV-2 and host cells should help to identify host factors that may be targetable to combat infection and COVID-19 pathology. To this end, we have conducted a genome-wide CRISPRCas9-based loss-of-function screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate many findings from previous screens that used full SARS-CoV-2 viruses, but also unveil two novel critical host factors the lysosomal efflux transporter SPNS1 and the plasma and lysosomal membrane protein PLAC8. Functional experiments with full SARS-CoV-2 viruses confirm that loss-of-function of these genes impairs viral entry. We find that PLAC8 is a key limiting host factor, whose overexpression boosts viral infection in eight different human lung cancer cell lines. Using single-cell RNA-Seq data analyses, we demonstrate that PLAC8 is highly expressed in ciliated and secretory cells of the respiratory tract, as well as in gut enterocytes, cell types that are highly susceptible to SARS-CoV-2 infection. Proteomics and cell biology studies suggest that PLAC8 and SPNS1 regulate the autophagolysosomal compartment and affect the intracellular fate of endocytosed virions.

The Value of Adenosine Deaminase 2 in the Detection of Tuberculous Pleural Effusion A Meta-Analysis and Systematic Review.

Adenosine deaminase 2 (ADA

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells.

In this report, we provide evidence showing diminished expression of the mineral dust-induced gene (mdig), a previously identified oncogenic gene, in human triple negative breast cancer (TNBC). Using a mouse model of orthotopic xenograft of the TNBC MDA-MB-231 cells, we demonstrate that mdig promotes the growth of primary tumors but inhibits metastasis of these cells

Anthocyanin Encapsulated Nanoparticles as a Pulmonary Delivery System.

Anthocyanins are known for their therapeutic efficacy for many human diseases, including cancer. After ingestion, anthocyanins degrade due to oxidation and enzymatic breakdown, resulting in reduced therapeutic efficacy. Direct delivery to target tissues and entrapment of anthocyanins increases their stability, bioavailability, and therapeutic efficacy. The objective of the present study was to develop a direct delivery system of anthocyanins into pulmonary tissues via encapsulated nanocarriers. A cyanidin-3-

Immune Effect of T Lymphocytes Infiltrated by Tumors on Non-Small-Cell Lung Cancer.

Lung cancer is increasing every year and it has high morbidity and mortality. Antitumor immunotherapy is a new method for the treatment of lung cancer. Currently, tumor immunotherapy mainly includes classical immunotherapy and immune-targeted therapy To explore the influence of tumor T-lymphocyte (T-cell) infiltration in non-small-cell lung cancer (NSCLC) patients, 100 NSCLC patients diagnosed and treated in Changde Second Peoples hospital were recruited. Patients were followed up for 3 years. The subjects were divided into a survival group (group S) and a death group (group D). The patients pathological tissue sections were made, and the degree of T-cell infiltration was counted by HE (Hematoxylin and eosin) staining. The infiltration degree was graded, and the positive rate of T-cell subsets was calculated by immunohistochemical staining. The 3-year positive rate was 48%, with 48 cases in group S and 52 cases in group D. The positive rate of HE staining of group S was 100%, including 0 cases of grade 0, 5 cases of grade 1 (10.42%), 16 cases of grade 2 (33.33%), and 27 cases of grade 3 (56.25%). The positive rate of group D was 86.54%, including 4 cases of grade 0 (8.89%), 10 cases of grade 1 (22.22%), 25 cases of grade 2 (55.56%), and 6 cases of grade 3 (13.33%). The total number of T-cell infiltrates in group S was much higher than that in group D (

Human Cardiac Pericytes are Susceptible to SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19) is associated with serious cardiovascular complications, with incompletely understood mechanism(s). Pericytes have key functions in supporting endothelial cells and maintaining vascular integrity. We demonstrate that human cardiac pericytes are permissive to SARS-CoV-2 infection in organotypic slice and primary cell cultures. Viral entry into pericytes is mediated by endosomal proteases, and infection leads to upregulation of inflammatory markers, vasoactive mediators, and NF-κB-dependent cell death. Furthermore, we present evidence of cardiac pericyte infection in COVID-19 myocarditis patients. These data demonstrate that human cardiac pericytes are susceptible to SARS-CoV-2 infection and suggest a role for pericyte infection in COVID-19.

Perspectives of Participation in Daily Life From Cancer Survivors A Qualitative Analysis.

To characterize how survivors of cancer define participation. Cross-sectional qualitative study. Participants were enrolled from a large academic medical center in the Midwestern United States. Interviews were conducted over Zoom or phone. Survivors of cancer (N40) with brain, breast, colorectal, or lung cancer (n10 per group). Participants were purposively sampled to maximize variation in the study sample. Participant ages ranged from 26-83 years, with a mean age of 55 years. Seventy percent of participants were receiving active cancer treatment at the time of the interview. Not applicable. Participant perspectives gathered from 1-on-1 semistructured interviews. Qualitative description and thematic analysis were used to analyze interview transcripts and develop themes from the data. Survivors described participation as doing valued activities and highlighted 4 common aspects (1) control (2) social connection (3) engaging in various contexts and (4) cultivation of joy and purpose. Fully participating in life involved being able to do what they want to do without restrictions or limitations. Survivors perspectives of control outlined how competence, choice, adaptations, and locus of control influence broader feelings of control and participation. Interviews highlighted that participation remains central to daily life among survivors of cancer. Rehabilitation researchers and clinicians need to establish a standard and comprehensive definition of participation. Rehabilitation providers need to consistently evaluate how participation is affected among survivors of cancer and use measures that include core aspects of participation identified in this study and previous research. Comprehensively defining participation will improve the design and selection of measurement tools and support comprehensive assessment of survivor experiences.

Effects of high-quality nursing care on quality of life, survival, and recurrence in patients with advanced nonsmall cell lung cancer.

Postoperative nursing can improve the quality of life (QoL) and functional prognosis for lung cancer patients. The purpose of this study was to evaluate the effects of high-quality nursing on inflammation and prognosis in postoperative patients with advanced nonsmall cell lung cancer (NSCLC). A total of 372 patients with NSCLC were enrolled between the May 2014 and June 2016. Patients were randomly received high-quality nursing (n 192) or normal nursing (n 180). Symptom management, QoL, hospital stay, inflammatory score, survival time, recurrence rate, symptoms, anxiety, depression scale and psychological distress were assessed at baseline and 5-year follow up. High-quality nursing significantly shortened hospital stay, improved postoperative inflammation, symptom management, QoL compared to patients received normal nursing. Compare with normal nursing, high-quality nursing decreased anxiety, depression scale and psychological distress for postoperative patients with advanced NSCLC. Outcomes showed that high-quality nursing increased the survival time and decreased recurrence rate for postoperative patients with advanced NSCLC. In conclusion, data in the current study indicate that high-quality nursing can decrease inflammation and improve prognosis for the postoperative patients with NSCLC.

Prediction of lung squamous cell carcinoma immune microenvironment and immunotherapy efficiency with pyroptosis-derived genes.

Lung squamous cell carcinoma (LUSC) is a common subtype of lung cancer that exhibits diverse pyroptosis regulatory patterns. Studies have highlighted the significance of pyroptosis in cancer invasion and immune responses. We aimed to explore the signatures of pyroptosis-related genes and their immune relevance in LUSC. Using The Cancer Genome Atlas (TCGA)-LUSC cohort and 5 gene expression omnibus (GEO) datasets, we performed consensus clustering based on 41 pyroptosis-related genes, and single sample gene set enrichment analysis (ssGSEA) was employed to calculate the infiltration levels of distinct clusters. A pyroptosis scoring scheme using the principal component analysis (PCA) method was used to quantify pyroptosis regulation in patients with LUSC and predict their prognosis. Four pyroptosis clusters were identified among 833 LUSC samples, which were associated with different Kyoto encyclopedia of genes and genome (KEGG) signaling pathways and tumor microenvironment infiltration features, and were highly consistent with 4 reported immune phenotypes immune-responsive, immune-non-functional, immune-exclusion, and immune-ignorance. We then divided the patients into high- and low-pyroptosis score subgroups, and patients with higher scores were characterized by prolonged survival and attenuated immune infiltration. Moreover, higher scores were correlated with male patients, higher microsatellite instability, lower immune checkpoint inhibitor expression (such as CTLA-4 and GAL-9), and high mutation rates of typical mutated genes (e.g., TP53 and TTN). In particular, patients with lower pyroptosis scores showed better immune response to immune checkpoint inhibitor treatment. Pyroptosis regulatory patterns in the immune microenvironment can predict the clinical outcomes of patients with LUSC. Accurately quantifying the pyroptosis of individual patients will strengthen the understanding of heterogeneity within the LUSC tumor microenvironment infiltration areas.

Nitrogen dioxide increases the risk of disease progression in idiopathic pulmonary fibrosis.

Air pollution affects clinical course and prognosis of idiopathic pulmonary fibrosis (IPF). However, the effect of individual exposure to air pollutants on disease progression is unclear. We aimed to identify the effect of individual exposure to nitrogen dioxide (NO The serial lung function data of 946 IPF patients (mean age 65.4 years, male 80.9%) were analysed. Individual-level long-term exposures to NO Overall, 547 patients (57.8%) experienced progression during a median follow-up of 1.0 year (interquartile range 0.4-2.6 years). In the primary model, a 10-ppb increase in NO Our data suggest that increased individual exposure to NO

An ensemble learning with active sampling to predict the prognosis of postoperative non-small cell lung cancer patients.

Lung cancer is the leading cause of cancer death worldwide. Prognostic prediction plays a vital role in the decision-making process for postoperative non-small cell lung cancer (NSCLC) patients. However, the high imbalance ratio of prognostic data limits the development of effective prognostic prediction models. In this study, we present a novel approach, namely ensemble learning with active sampling (ELAS), to tackle the imbalanced data problem in NSCLC prognostic prediction. ELAS first applies an active sampling mechanism to query the most informative samples to update the base classifier to give it a new perspective. This training process is repeated until no enough samples are queried. Next, an internal validation set is employed to evaluate the base classifiers, and the ones with the best performances are integrated as the ensemble model. Besides, we set up multiple initial training data seeds and internal validation sets to ensure the stability and generalization of the model. We verified the effectiveness of the ELAS on a real clinical dataset containing 1848 postoperative NSCLC patients. Experimental results showed that the ELAS achieved the best averaged 0.736 AUROC value and 0.453 AUPRC value for 6 prognostic tasks and obtained significant improvements in comparison with the SVM, AdaBoost, Bagging, SMOTE and TomekLinks. We conclude that the ELAS can effectively alleviate the imbalanced data problem in NSCLC prognostic prediction and demonstrates good potential for future postoperative NSCLC prognostic prediction.

Transcription factor AP2 enhances malignancy of non-small cell lung cancer through upregulation of USP22 gene expression.

Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. A luciferase reporter driven by a promoter region of USP22 gene was selectively constructed to screen against a customized siRNA library targeting 89 selected transcription factors to identify potential transcription factors (TFs) that regulate USP22 expression in human non-small cell lung cancers (NSCLC). Association of identified TFs with USP22 and potential role of the TFs were validated and explored in NSCLC by biological assays and immunohistochemistry analysis. Luciferase reporter assays revealed that SP1 and activating transcription factor 3 (ATF3) inhibit USP22 transcription, while transcription factor AP-2 AlphaBeta (TFAP2A2B) and c-Myc promote USP22 transcription. Binding site-directed mutagenesis and chromosome immunoprecipitation (ChIP) assays validated AP2α and AP2β are novel TFs of USP22. Furthermore, overexpression of AP2A and AP2B significantly upregulates USP22 expression, and its target Cyclin D1, concurrently enhances the proliferation, migration, and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. Moreover, AP2 protein level correlated with USP22 protein in human NSCLC tissues. Our findings indicate AP2α and AP2β are important transcription factors driving USP22 gene expression to promote the progression of NSCLC, and further support USP22 as a potential biomarker and therapeutic target for lung cancer. Video Abstract.

EPHA5 mutation was associated with adverse outcome of atezolizumab treatment in late-stage non-small cell lung cancers.

The aim of the study was to investigate predictive value of gene mutation for atezolizumab treatment response from OAK and POPLAR cohorts. Several public databases were used for analyzing gene mutation type of EPHA5 and association with alterations of other genes. Survival analysis was performed for patients receiving atezolizumab from OAK and POPLAR cohorts. EPHA5 mutation have high frequency to harbor TP53 and KEAP1 mutations. The bTMB value has significant difference between EPHA5 mutant and wild-type cases. Patients with EPHA5 mutation got worse survival compared to those without gene mutations receiving atezolizumab (P 0.0186). EPHA5 mutant NSCLC may represent a subpopulation which showed worse response after treatment of atezolizumab compared to wild-type ones.

Combining a nanoparticle-mediated immunoradiotherapy with dual blockade of LAG3 and TIGIT improves the treatment efficacy in anti-PD1 resistant lung cancer.

While improvements in immunoradiotherapy have significantly improved outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to immunoradiotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of immunoradiotherapy. We combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors PD1, LAG3, and TIGIT, and tested the treatment efficacy in an anti-PD1-resistant lung cancer model in mice. 129 SvEv mice were inoculated with fifty thousand αPD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected into the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 µg), αLAG3 (200 µg), and αTIGIT (200 µg) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. This nanoparticle-mediated combination therapy is effective at controlling the growth of irradiated and distant unirradiated tumors, enhancing animal survival, and is the only one that led to the destruction of both tumors in approximately 30% of the treated mice. Corresponding with this improved response is robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment. Our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune checkpoint receptors and provide a pre-clinical rationale for investigating its translation into human patients.

Translation of a tissue epigenetic signature to circulating free DNA suggests BCAT1 as a potential noninvasive diagnostic biomarker for lung cancer.

Lung cancer patients are diagnosed at late stages when curative treatments are no longer possible thus, molecular biomarkers for noninvasive detection are urgently needed. In this sense, we previously identified and validated an epigenetic 4-gene signature that yielded a high diagnostic performance in tissue and invasive pulmonary fluids. We analyzed DNA methylation levels using the ultrasensitive digital droplet PCR in noninvasive samples in a cohort of 83 patients. We demonstrated that BCAT1 is the candidate that achieves high diagnostic efficacy in circulating DNA derived from plasma (area under the curve 0.85). Impact of potentially confounding variables was also explored.

Optimizing the endoscopic diagnosis of mediastinal lymphadenopathy a glimpse on cryobiopsy.

Etiological diagnosis of mediastinal lymphadenopathy represents a daily challenge. Endosonography (transesophageal and transbronchial ultrasound-guided needle aspiration) is the recommended technique in the first diagnostic work-up and in the mediastinal staging of lung cancer. Despite a good sensitivity, limited amount of collected tissue may hamper molecular assessment in advanced lung cancer and in the diagnosis of lymphoproliferative disorders, fibrotic sarcoidosis, and mycobacterial lymphadenitis. Cryobiopsy, a bronchoscopic technique based on cooling, crystallization, and subsequent collection of tissue, has been successfully employed in the diagnosis of interstitial lung diseases. Cryoprobes provide larger amount of tissue than conventional bronchoscopic sampling tools and might potentially prevent the need for invasive surgical procedures. New applications of the technique (e.g., bronchoscopic diagnosis of peripheral pulmonary lesions and mediastinal lymph nodes) have been recently described in few reports. In a recent issue of the Journal, Genova et al. described five patients who underwent endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) followed by ultrasound-guided transbronchial cryobiopsy of mediastinal lymphadenopathy for a suspected malignancy. The authors discussed about the potential added value of mediastinal cryobiopsy on a correct histopathological and molecular assessment in patients with malignancies. EBUS-cryobiopsy could be a promising technique in the diagnostic pathway of mediastinal lymphadenitis. However, cryobiopsy is now available only in few selected centres. The learning curve of the technique adapted to mediastinal ultrasound-guided sampling, the optimal sampling strategy, its true diagnostic accuracy in patients with malignant and benign diseases, as well as its safety, are still largely unclear. Mediastinal cryobiopsy could be complementary rather than alternative to conventional endosonography. Rapid on-site evaluation of EBUS-TBNA could guide subsequent sampling with cryoprobes in case of poor collection of biological material or in case of suspected lymphoproliferative disorders. Further studies should investigate its diagnostic yield, in comparison or in combination with conventional endosonography, in large cohorts of patients with malignant or benign mediastinal lymphadenopthies.

Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC A multicenter pooled analysis.

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

The evolutionary dynamics of extrachromosomal DNA in human cancers.

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

YAP 5-methylcytosine modification increases its mRNA stability and promotes the transcription of exosome secretion-related genes in lung adenocarcinoma.

YAP is a transcriptional co-activator with critical roles in tumorigenesis. However, its upstream regulatory mechanism, especially how its mRNA stability is regulated, remains to be further studied. Here, we validated that YAP expression was higher in lung adenocarcinoma (LUAD) tissues compared to adjacent normal tissues, and found that YAP m

Soft skin-interfaced mechano-acoustic sensors for real-time monitoring and patient feedback on respiratory and swallowing biomechanics.

Swallowing is a complex neuromuscular activity regulated by the autonomic nervous system. Millions of adults suffer from dysphagia (impaired or difficulty swallowing), including patients with neurological disorders, head and neck cancer, gastrointestinal diseases, and respiratory disorders. Therapeutic treatments for dysphagia include interventions by speech-language pathologists designed to improve the physiology of the swallowing mechanism by training patients to initiate swallows with sufficient frequency and during the expiratory phase of the breathing cycle. These therapeutic treatments require bulky, expensive equipment to synchronously record swallows and respirations, confined to use in clinical settings. This paper introduces a wireless, wearable technology that enables continuous, mechanoacoustic tracking of respiratory activities and swallows through movements and vibratory processes monitored at the skin surface. Validation studies in healthy adults (n 67) and patients with dysphagia (n 4) establish measurement equivalency to existing clinical standard equipment. Additional studies using a differential mode of operation reveal similar performance even during routine daily activities and vigorous exercise. A graphical user interface with real-time data analytics and a separate, optional wireless module support both visual and haptic forms of feedback to facilitate the treatment of patients with dysphagia.

Therapeutic targets and biomarkers of tumor immunotherapy response versus non-response.

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

Protocol of an iterative qualitative study to develop a molecular testing decision aid for shared decision-making in patients with lung cancer after surgery.

Although molecular testing is crucial for many patients with lung cancer, the decision to carry out molecular testing is not easy to make in actual clinical scenarios. Using a specific decision aid (DA) to conduct shared decision-making (SDM) may help ameliorate this problem. However, no DA currently exists for lung cancer molecular testing (DALCMT). We aim to develop an evidence-based, iteratively refined DA, which may facilitate SDM and improve the quality of SDM. After considering the Ottawa Decision Support Framework, International Patient Decision Aid Standards and Food and Drug Administration guidance about methods to identify what is important to patients, semistructured interviews with qualitative research methods will be used to generate the decision-making needs of patients with lung cancer diagnosed with lung adenocarcinoma by intraoperative frozen pathological sections. Input will be provided by patients and other stakeholders, including thoracic surgeons, nurses, hospital administrators, molecular testing company staff and insurance company staff. Then, a modified Delphi method will be used to develop the DALCMT V.1.0 (DALCMT 1.0). Structured interviews with qualitative research methods will be used in the cognitive debriefing (alpha tests) and field testing (beta tests) to revise and improve the DALCMT from version 1.0 to the final version, version 3.0. Descriptive statistics will be used to summarise the baseline characteristics of the patients and other stakeholders. Qualitative data will be analysed using the three steps of grounded theory generate a codebook, update the codebook and create a comprehensive list of related items. Ethics Committee for Medical Research and New Medical Technology of Sichuan Cancer Hospital approved this study. This protocol is based on the latest version 1.0, dated 31 October 2021. The study was also approved by the Ethics Committees of The Third Peoples Hospital of Chengdu, Zigong First Peoples Hospital and Jiangyou Peoples Hospital. The results of this study will be presented at medical conferences and published in peer-reviewed journals. NCT05191485.

ALK inhibitors in ALK-rearranged non-small cell lung cancer with and without brain metastases systematic review and network meta-analysis.

To systematically evaluate the efficacy and safety of anaplastic lymphoma kinase (ALK) inhibitors in ALK-rearranged positive non-small cell lung cancer (NSCLC) with brain metastases, and update the overall survival (OS) outcomes of the second-generation and third-generation ALK (ALK-2 The study is in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Randomised controlled trials (RCTs) published up to 3 November 2021 were retrieved from PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov. RCTs from any country and healthcare setting. Patients with advanced ALK-positive NSCLC with or without brain metastases. The interventions were ALK-2 Primary outcomes included median progression-free survival and median OS. Secondary outcomes included systemic objective response rate, intracranial response rate and rate of grade ≥3 adverse events (AEs). A total of 12 RCTs involving 3156 patients were analysed. Compared with ALK-1 Treatment with ALK-2 CRD42021292245.

A cell-laden hydrogel as prophylactic vaccine and anti-PD-L1 amplifier against autologous tumors.

Immune checkpoint blockade (ICB) can elicit anti-cancer response against tumors growing at normal organs while sparing adjacent tissues. However, many orthotopic tumors respond poorly to ICB therapy due to the lack of pre-existing immune effector cells. Here, we describe a vaccine strategy that induces protective immunity and benefits ICB therapy. An injectable hydrogel platform that forms scaffold subcutaneously was applied to deliver autologous cancer cells undergoing oncolysis (ACCO) as immunogenic antigen source and toll-like receptor 9 agonists (CpG) as additional adjuvant. When administered as a prophylactic, the hydrogel-based vaccine, denoted as (ACCOCpG)Gel, successfully built a durable and tumor antigen-specific immune memory against subsequent challenges with orthotopic engraftment of autologous tumors including melanoma, colon carcinoma, and lung carcinoma. Although the vaccination did not completely prevent tumor occurrence, tumors orthotopically established in vaccinated mice acquired significant enhancement in tumor-infiltrating CD8 T cells and intratumoral PD-L1 expression, which ameliorated the immune status and rendered the originally irresponsive tumors responsible to anti-PD-L1 therapy. Further treatment with PD-L1 blockade therapy efficiently delayed the tumor growth and prolonged the survival of these orthotopic cancer models. Thus, without the need for precisely delivering immunoactivatory agents to tumor or locally remodeling tumor microenvironment, priming intractable or inaccessible tumors for subsequent ICB therapy could be achieved by prophylactic vaccination with (ACCOCpG)Gel. These findings highlighted (ACCOCpG)Gel as a generalized framework of protective vaccine strategy that could be broadly applicable to potentiate ICB therapy against multiple types of orthotopic tumors growing in different regions.

LPCAT1 functions as an oncogene in cervical cancer through mediating JAK2STAT3 signaling.

Cervical cancer is a major gynecological tumor worldwide. Unfortunately, the molecular mechanisms involved in cervical cancer tumorigenesis still requires more clarification. Lysophosphatidylcholine acyltransferase 1 (LPCAT1), an enzyme involved in phosphatidylcholine metabolism, has been reported to regulate the proliferation, epithelial-mesenchymal transition (EMT) and recurrence of malignancies. Here in our study, we found that LPAT1 was over-expressed in clinical cervical cancer tissues, and its high expression was closely correlated with poor outcomes of patients. We further showed that LPCAT1 knockdown remarkably restrained the proliferation, migration and invasion of cervical cancer cells, while it significantly induced apoptosis. RNA-seq and bioinformatics assays initially showed that interleukin-6signal transducer and activator of transcription 3 (IL-6STAT3) pathway was a key mechanism for LPCAT1 to regulate cervical cancer progression. LPCAT1 silence strongly decreased IL-6, p-Janus kinase 2 (JAK2) and p-STAT3 expression levels in cervical cancer cells. Similarly, the expression levels of IL-6STAT3 target genes were also highly down-regulated in cervical cancer cells with LPCAT1 deletion. Importantly, we found that human recombinant IL-6 addition considerably abolished the function of LPCAT1-knockdown to suppress the proliferation and EMT process in cervical cancer cells, accompanied with mitigated apoptotic cell death. Furthermore, our animal experiment results validated that stable LPCAT1 deletion efficiently reduced the tumor growth rates of xenograft mouse models and lung metastasis in vivo. Collectively, all our findings revealed that LPCAT1 may be a promising alternative prognostic biomarker and therapeutic target for cervical cancer through regulating JAK2STAT3 signaling pathway.

Primary Thoracic Endografting for T4 Lung Cancer Aortic Involvement.

The aim of the study was to present the results in patients with a T4 thoracic tumor with aortic involvement who were treated with a thoracic endograft before surgical resection. All consecutive patients undergoing a thoracic endograft procedure before an oncologic resection between January 2012 and December 2019 were reviewed in a single-center retrospective study. Included patients had either a T4 lung tumor or a mediastinal tumor invading the thoracic aorta. Nine patients were included 7 with T4 lung cancer, 1 with sarcoma, and 1 patient with thymoma. Median follow-up was 25 months (range, 22-47 months). There were no endograft-related complications. All but 1 patient had an R0 oncologic resection. Eight patients were alive and free from recurrence at the last follow-up. Use of thoracic stent grafting before surgical resection for patients with a thoracic tumor invading the aorta is a feasible option that obviates the need for extracorporeal circulation and its associated morbidity. This technique could be an alternative strategy in the treatment of tumors invading the thoracic aorta.