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PD-1 blockade augments CD8

No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1 Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8

Mutated HRAS activates YAP1-AXL signaling to drive metastasis of head and neck cancer.

The survival rate for head and neck cancer (HNC) patients diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts (PDXs), and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.

Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study.

Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC however, the efficacy of these agents in patients with brain metastases remains unclear. To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases. This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled. The eligible patients were randomly assigned (11) to receive gefitinib plus chemotherapy or gefitinib alone. The primary end point was intracranial PFS secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. A total of 161 patients (87 54.0% women mean SD age, 55 9.8 years range, 26-80 years) were enrolled and randomized to receive gefitinib (n 81) or gefitinib plus chemotherapy (n 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36 95% CI, 0.25-0.53 P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3 95% CI, 14.4-18.2 months vs 9.5 95% CI, 8.3-10.8 months P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0% 95% CI, 77.0%-93.0% vs 63.0% 95% CI, 52.2%-73.7% P .002) and overall objective response rate (80.0% 95% CI, 71.0%-89.0% vs 64.2% 95% CI, 53.5%-74.9% P .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months hazard ratio, 0.65 95% CI, 0.43-0.99 P .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. ClinicalTrials.gov Identifier NCT01951469.

A reliable mouse model of liver and lung metastasis by injecting esophageal cancer stem cells (CSCs) through tail-vein injection.

Esophageal Squamous Cell Carcinoma (ESCC) is a highly aggressive tumor with increased metastatic potential. Recent evidence suggests that esophageal CSCs have a crucial role in tumor initiation, progression, and resistance to conventional anti-cancer therapies. The study aimed to develop mouse model to mimic the late steps of the metastasis process using a tail-vein injection of esophageal CSCs. The sphere formation assay was used to enrich CSCs. For analysis of tumorigenicity, YM-1 adherent cells and enriched CSCs were injected subcutaneously into dorsal flank of nude mice. The expression of SLUG, E-cad, and CTHRC1 genes was examined by Real-Time qRT-PCR and immunohistochemistry (IHC) methods. To assess the metastatic potential of adherent YM-1 cells and their enriched CSCs, we injected the cells into the tail vein of nude mice. Our findings showed the up-regulation of SLUG and down-regulation of E-cad in the esophageal CSC-derived tumors (ECSCTs) compared to adherent cells-derived tumors. There was no statistically significant difference between CTHRC1 gene expressions in both groups of tumors. IHC staining confirmed the higher expression of SLUG protein in ECSCTs compared to adherent cell-derived tumors. Enriched CSCs were able to metastasize to the lungs and livers after three months, but, metastasis of adherent cells wasnt observed. Our study showed esophageal CSCs injected through the tail-vein injection can migrate and metastasize to the lung and liver after three months. The developed metastatic mouse model can be a valuable and relevant model to investigate the molecular and cellular mechanisms of metastasis and develop successful targeted therapies against ESCC. The present study is one of the few studies that investigate the metastasis of esophageal cancer stem cells (ESCC type) through injection into the tail vein of nude mice.

Comparable efficacy and safety of COVID-19 vaccines for patients receiving tegafur-uracil as postoperative adjuvant chemotherapy.

Many effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed, but a weaker response in individuals undergoing anticancer treatment has been reported. This study evaluates the immunogenic status and safety of SARS-CoV-2 vaccines for patients with non-small-cell lung cancer (NSCLC), receiving tegafur-uracil (UFT) as postoperative adjuvant chemotherapy. The subjects of this prospective study were 40 patients who underwent surgery for NSCLC and received SARS-CoV-2 vaccines postoperatively. We compared the antibody titers of SARS-CoV-2 vaccines and the adverse events between patients who received adjuvant UFT and patients who did not. The mean anti-S1 IgG titers were not significantly different between the UFT and without-UFT groups (mean optimal density, 0.194 vs. 0.205 P 0.76). Multivariate analysis identified the period after the second vaccination as an independent predictor of anti-S1 IgG titer (P 0.049), but not the UFT status (with or without-UFT treatment P 0.47). The prevalence of adverse events did not differ significantly between the groups, and no severe adverse events occurred. The efficacy and safety of the SARS-CoV-2 vaccines for NSCLC patients who received postoperative adjuvant UFT chemotherapy were comparable to those for NSCLC patients who did not receive postoperative adjuvant UFT chemotherapy. This study was registered with the University Hospital Medical Information Network (UMIN) in Japan (UMIN000047380).

Griseofulvin Radiosensitizes Non-Small Cell Lung Cancer Cells and Activates cGAS.

Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non-small cell lung cancer (NSCLC). Griseofulvin (GF FDA approved treatment) inhibits CC, and combined with radiation therapy (RT) resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and RT resulted in a significant tumor growth delay. Both GF and RT treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased RT efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, RT and immunotherapy could be a promising strategy to treat NSCLC.

Surgical outcome of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy.

Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous surgery. In this study, we retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without prior ipsilateral lobectomy. Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy.

Test performance metrics for breast, cervical, colon and lung cancer screening a systematic review.

Multiple quality metrics have been recommended to ensure consistent, high-quality execution of screening tests for breast, cervical, colorectal and lung cancers. However, minimal data exist evaluating the evidence base supporting these recommendations and the consistency of definitions and concepts included within and between cancer types. We performed a systematic review for each cancer type using MEDLINE, Embase and CINAHL from 2010 to April 2020, to identify guidelines from screening programs or professional organizations containing quality metrics for tests used in breast, cervical, colorectal and lung cancer screening. We abstracted metrics definitions, target performance levels, and related supporting evidence for test completeness, adequacy (sufficient visualization or collection), accuracy, and safety. We identified 11 relevant guidelines with 20 suggested quality metrics for breast cancer, 5 guidelines with 9 metrics for cervical cancer, 13 guidelines with 18 metrics for colorectal cancer, and 3 guidelines with 7 metrics for lung cancer. These included 54 metrics related to adequacy (6), test completeness (3), accuracy (33), and safety (12). Target performance levels were defined for 30 metrics (56%). Ten (19%) were supported by evidence, all from breast and colorectal cancer, with no evidence cited to support metrics from cervical and lung cancer screening. Considerably more guideline-recommended test performance metrics exist for breast and colorectal cancer screening than cervical or lung cancer. The domains covered are inconsistent among cancers and few targets are supported by evidence. Clearer evidence-based domains and targets are needed for test performance metrics. PROSPERO 2020 CRD42020179139.

Risk of death from liver cancer in relation to long-term exposure to fine particulate air pollution in Taiwan.

According to the International Agency for Research on Cancer (IARC), airborne fine particulate matter (PM

Expression and predictive significance of FHL1 and SLIT3 in surgically resected lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. However, predictive biomarkers for early efficacy and prognosis evaluation in patients with surgically resected LUAD are not completely explained. Differentially expressed genes (DEGs), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were identified between thirteen LUAD tissues and five normal lung tissues were analyzed by RNA sequencing (RNA-Seq). The expression of DEGs was confirmed by qRT-PCR and a validated cohort from GEPIA. Protein-protein interaction (PPI) network of the top 5% DEGs was constructed by STRING and visualized in Cytoscape. Immunofluorescence results were acquired from clinical specimens from LUAD patients. The expression of FHL1 was analyzed by ImageJ. Survival analysis was performed using the GEPIA dataset. Consistent with the RNA-Seq data, validation of DEGs expression by qRT-PCR and GEPIA cohort showed that FHL1 and SLIT3 were down-regulated in LUAD patient tissues compared with non-tumor tissues. Moreover, FHL1 was significantly reduced in LUAD cell lines compared to the bronchial epithelium cell line (P<0.01). However, SLIT3 was elevated in A549 and H1299 cells (wide type EGFR) (P<0.05) while decreased in HCC827 and PC9 cells (mutant EGFR) compared to BESA-2B cells (P<0.01). PPI network revealed the most significant cluster with 10 nodes and 43 edges. Immunofluorescent staining also showed that the expression of FHL1 was lower in LUAD tissues compared with that in normal lung tissues (P<0.01). The expressions of SLIT3 and FHL1 were positively correlated. Specifically, the higher expression level of SLIT3 and FHL1 independently predicted a better prognosis (P<0.01 or P<0.05). Our findings provide two novel candidates, FHL1 and SLIT3, for prognostic evaluation and treatments after surgery.

Real-world study of next-generation sequencing diagnostic biomarker testing for patients with lung cancer in Japan.

Our previous real-world studies raised concerns that sequential biomarker testing may lead to increased time to treatment when compared with simultaneous single biomarker testing. The Oncomine Dx target test (ODxTT), a next-generation sequencing-based multiplex biomarker panel test approved in Japan in 2019, is expected to improve time to treatment due to changes in testing methods. This retrospective observational study examined data claims for reimbursement submitted for patients with lung cancer in Japan between June 1, 2019, and March 31, 2020. To evaluate the change in testing prevalence over time and associated improvements in time to treatment (TTT), descriptive statistics were used to characterize biomarker testing patterns and rates and evaluate the TTT in the time following the approval of ODxTT considering transitions over time during the evaluation period. EGFR and programmed death ligand 1 (PD-L1) were the most tested biomarkers in overall single and simultaneous single testing in the 6177 patients in this study. Individual single biomarker testing gradually decreased over time, except testing for PD-L1, which remained constant. The use of ODxTT gradually increased in this period. TTT was decreased from 29 to 22 days with ODxTT, in contrast with single biomarker tests (median, 21-23 days overall). These results indicate that biomarker testing frequency has changed in Japanese clinical practice during the study and that the use of ODxTT has increased over time, which potentially contributed to the shortening of TTT.

CT features of rounded atelectasis in chronic inflammatory pleural effusions in cats and dogs.

Rounded atelectasis is well described in human medicine as focal lung deformation and collapse secondary to inflammatory pleural effusions and pleuritis. Specific CT features (round to ovoid soft tissue pulmonary attenuations, creation of an acute angle with the adjoining visceral pleura, and the presence of perinodular comet tail signs) support the diagnosis of rounded atelectasis in humans so that further diagnostic workup is not necessary in defining the nodules. In this retrospective case series, we described the CT characteristics of rounded atelectasis in eight cats and three dogs diagnosed with restrictive pleuritis secondary to either a chylothorax or pyothorax. Thirty-six soft tissue attenuating pulmonary nodular lesions were identified on CT. Comet tail signs, consisting of bundles of bronchi and vessels coalescing into the pulmonary nodules, were associated with 92% of the nodules (3336), and 92% of the nodules abutted and created an acute angle with the pleura (3336). Other prevalent features included location in gravity-dependent regions of the lung lobes (3336, 92%), blurred hilar margins with sharper pleural margins of the nodules (3336, 92%), presence of air bronchograms (3036, 83%), homogeneous contrast-enhancement (2336, 64%), and volume loss of the affected lung lobe (2236, 61%). Pulmonary malignant neoplasms were not found cytologically (611 patients) or histologically (511 patients). To avoid a misdiagnosis of neoplasia, veterinary radiologists should be aware of the CT features of rounded atelectasis and consider it as a differential for pulmonary nodular lesions in patients with concurrent inflammatory pleural effusion and pleuritis.

Awareness and knowledge of risk factors associated with oral cancer among military personnel in Nigeria.

The military lifestyle has been reported to increase the risk of this population group to the development of oral cancer. This study aimed to determine the awareness and knowledge of oral cancer in a population of soldiers to acquire data for establishing an educational program for units of the Nigerian Army in oral cancer prevention and monitoring. The study was conducted in the dental center of 82 Division Military Hospital, Nigerian Army, Enugu, Nigeria. A cross-sectional survey was performed using a pre-tested self-administered questionnaire. Questions relating to oral cancer awareness, knowledge of causes, and relationship to certain habits, treatment options, and desirability of screening opportunities for oral cancer were asked. Soldiers attending the military hospital, dental center, were chosen randomly for the study. Three hundred soldiers were surveyed. The mean age of those surveyed was 37.5 and had spent an average of 11-15 years in the Army. The majority of the soldiers (80.7%) have heard of cancer the types most known were breast (75%), skin (30%), and lung cancer (28.3%). Of the 300 soldiers surveyed, 15.3% knew about oral cancer, with 41.3% of these able to identify cigarette smoking and (26%) alcohol consumption as possible risk factors associated with oral cancer. The majority believed that cancer was caused by some form of supernatural phenomenon. Oral cancer awareness is low among soldiers in the Nigerian Armed Forces, and strategies to increase awareness should be developed.

Diagnostic value of LungPoint navigation combined with EBUS-GS ROSE in peripheral pulmonary nodules.

Recently, there has been a surge to develop new devices and techniques for the diagnosis of peripheral pulmonary lesions such as the combination of LungPoint navigation and endobronchial ultrasound with a guide sheath (EBUS-GS). The present study aimed to explore the diagnostic value of LungPoint navigation in combination with EBUS-GS and rapid on-site evaluation (ROSE) particularly for peripheral pulmonary nodules. Patients (n108) with pulmonary nodules (10 mm ≤ nodal diameter ≤30 mm) presenting to Henan Provincial Peoples Hospital were detected using chest computed tomographic (CT) scanning and bronchoscopy. All patients were evaluated using LungPoint navigation, EBUS-GS and ROSE techniques to evaluate the positive rate of combined diagnosis using the three methods. A total of 108 patients participated in this study and successfully underwent all the three procedures. Of these, 82 patients were accurately diagnosed, making the overall diagnostic rate of 75.9 per cent for combined LungPoint navigation, EBUS-GS, and ROSE analyses. Further subgroup analysis of the diagnostic rate of the three combined techniques were conducted based on the size of the nodules which showed a diagnostic rate of 65.3 per cent for 10 mm ≤ nodule diameter ≤20 mm and 85.7 per cent for 20 mm ≤ nodal diameter ≤30 mm. Of the 108 patients, 85 had solid nodules and 23 had ground-glass nodules the positive rate of diagnosis of solid nodules was the highest. The patients ultimately were diagnosed with lung cancer with a positive rate of 83.5 per cent. The sensitivity, specificity and positive and negative predicted values for ROSE were 90.3, 78.3, 84.8 and 83.6 per cent, respectively. The combined use of the three techniques can effectively shorten the duration of the total diagnosis period and improve the safety of diagnosis without affecting the detection rate.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog 本研究以探索与免疫检查点抑制剂（ICIs）效果有关联的基因突变亚型为目标，进行了系统文献检索（电子数据库截至2021年5月31日）。与肿瘤基因特征相关联的主要结局事件包括：总生存期、无进展生存期、客观反应率、持久临床获益。我们从14项研究中总计提取了1546个有基因突变数据的肺癌患者，发现ICIs治疗在

Neoadjuvant Therapy and Factors Influencing Survival in Locally Advanced Non-Small Cell Lung Cancer.

We aimed to investigate the effectiveness of neoadjuvant therapy (NAT) and clinicopathological characteristics in locally advanced non-small cell lung cancer (NSCLC) (IIIA-IIIB), as well as the influence of the post-NAT treatment modalities on survival. This study included patients who presented to the Dicle University Medical Oncology Clinic and received NAT for a diagnosis of locally advanced NSCLC between 2004 and 2020. Clinicopathological and radiological data of the 57 patients whose data could be retrieved from the hospital archive system were retrospectively reviewed. Patients overall survival (OS) and failure-free survival (FFS) times and the factors influencing these times were evaluated. This study included a total of 57 patients consisting of five (8.8%) females and 52 (91.2%) males. The median patient age at diagnosis was 58 (30-75) years. All patients had received four courses of chemotherapy during the neoadjuvant period. When the factors influencing OS were evaluated, the post-NAT modality was found to have a statistically significant effect on survival. FFS times were 12, 13, and 16 months in the chemotherapy, chemoradiotherapy, and surgery arms, respectively (log-rank p0.035). FFS was longer in those who underwent surgery (Hazard ratio (HR) 0.33, 95 % CI 0.14-0.77, (p0.01)). OS times were 20, 21, and 55 months in the chemotherapy, chemoradiotherapy, and surgery arms, respectively (log-rank p0.05). OS was longer in the arm undergoing surgery compared to the other arms (HR 0.36, 95% CI 0.14-0.87, (p0.02)). Five-year survival rates for the chemotherapy, chemoradiotherapy, and surgery arms were 14.3%, 21.4%, and 40%, respectively. This study shows that achieving an operable status is the most important indicator of survival and that patients undergoing surgery have a marked advantage in OS and FFS compared with patients receiving chemoradiotherapy or palliative chemotherapy.

Precision oncology provides opportunities for targeting KRAS-inhibitor resistance.

Novel inhibitors targeting Kirsten rat sarcoma virus homolog (KRAS) KRAS

Brain metastases in Japanese NSCLC patients prognostic assessment and the use of osimertinib and immune checkpoint inhibitors-retrospective study.

The Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed. We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results. The median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS 34.2 and 17.6 months with and without osimertinib, respectively (p 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months). We confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

The chromatin-associated RNAs in gene regulation and cancer.

Eukaryotic genomes are prevalently transcribed into many types of RNAs that translate into proteins or execute gene regulatory functions. Many RNAs associate with chromatin directly or indirectly and are called chromatin-associated RNAs (caRNAs). To date, caRNAs have been found to be involved in gene and transcriptional regulation through multiple mechanisms and have important roles in different types of cancers. In this review, we first present different categories of caRNAs and the modes of interaction between caRNAs and chromatin. We then detail the mechanisms of chromatin-associated nascent RNAs, chromatin-associated noncoding RNAs and emerging m

Development and validation of an integrative pan-solid tumor predictor of PD-1PD-L1 blockade benefit.

Anti-PD-1 and PD-L1 (collectively PD-L1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients 26 tumor types IRS-High or -Low groups). In the 248 patient validation cohort (248 patients 24 tumor types non-pembrolizumab PD-L1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio aHR 0.52, p 0.003 OS aHR 0.49, p 0.005) TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumabchemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-HighTMB-Low. The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications. Therapies activating the immune system (checkpoint inhibitors) have revolutionized the treatment of patients with advanced cancer, however new molecular tests may better identify patients who could benefit. Using treatment data and clinical molecular test results, we report the development and validation of Immunotherapy Response Score (IRS) to predict checkpoint inhibitor benefit. Across patients with more than 20 advanced cancer types, IRS better predicted checkpoint inhibitor benefit than currently available tests. Data from >20,000 patients showed that IRS identifies 8% of patients with advanced cancer who may dramatically benefit from checkpoint inhibitors but would not receive them today based on currently available tests. Our approach may help clinicians to decide which patients should receive checkpoint inhibitors to treat their disease.

TASL, TADE, and DAROC consensus for the screening and management of hepatitis C in patients with diabetes.

Diabetes mellitus (DM) and hepatitis C virus (HCV) infection are prevalent diseases globally and emerging evidence demonstrates the bidirectional association between the two diseases. Direct-acting antivirals (DAAs) for HCV have a high treatment success rate and can significantly reduce the risks of short and long-term complications of HCV infection. However, despite the evidence of the association between diabetes and HCV and the benefits of anti-HCV treatment, previously published guidelines did not focus on the universal HCV screening for patients with diabetes and their subsequent management once confirmed as having HCV viremia. Nonetheless, screening for HCV among patients with diabetes will contribute to the eradication of HCV infection. Thus, the three major Taiwan medical associations of diabetes and liver diseases endorsed a total of 14 experts in the fields of gastroenterology, hepatology, diabetology, and epidemiology to convene and formulate a consensus statement on HCV screening and management among patients with diabetes. Based on recent studies and guidelines as well as from real-world clinical experiences, the Taiwan experts reached a consensus that provides a straightforward approach to HCV screening, treatment, and monitoring of patients with diabetes.

Lung SBRT treatment planning a study of VMAT arc selection guided by collision check software.

To evaluate the effects of arc geometry on lung stereotactic body radiation therapy (SBRT) plan quality, using collision check software to select safe beam angles. Thirty lung SBRT cases were replanned 10Gy x 5 using 4 volumetric modulated arc therapy (VMAT) geometries coplanar lateral (cpLAT), coplanar oblique (cpOBL), noncoplanar lateral (ncpLAT) and noncoplanar oblique (ncpOBL). Lateral arcs spanned 180° on the affected side whereas the 180° oblique arcs crossed midline to spare healthy tissues. Couch angles were separated by 30° on noncoplanar plans. Clearance was verified with Radformation CollisionCheck software. Optimization objectives were the same across the four plans for each case. Planning target volume (PTV) coverage was set to 95% and then plans were evaluated for dose conformity, healthy tissue doses, and monitor units. Clinically treated plans were used to benchmark the results. The volumes of the 25%, 50% and 75% isodoses were smaller with noncoplanar than coplanar arcs. The volume of the 50% isodose line relative to the PTV (CI50%) was as follows clinical 3.75±0.72, cpLAT 3.39 ± 0.37, cpOBL 3.36 ± 0.34, ncpLAT 3.02 ± 0.21 and ncpOBL 3.02 ± 0.22. The Wilcoxon signed rank test with Bonferroni correction showed p < 0.005 in all CI50% comparisons except between the cpLat and cpObl arcs and between the ncpLat and ncpObl arcs. The best lung sparing was achieved using ncpObl arcs, which was statistically significant (p < 0.001) compared with the other four plans at V12.5Gy, V13.5Gy and V20Gy. Chest wall V30Gy was significantly better using noncoplanar arcs in comparison to the other plan types (p < 0.001). The best heart sparing at V10Gy from the ncpOBL arcs was significant compared with the clinical and cpLat plans (p < 0.005). Arc geometry has a substantial effect on lung SBRT plan quality. Noncoplanar arcs were superior to coplanar arcs at compacting the dose distribution at the 25%, 50% and 75% isodose levels, thereby reducing the dose to healthy tissues. Further healthy tissue sparing was achieved using oblique arcs that minimize the pathlength through healthy tissues and avoid organs at risk. The dosimetric advantages of the noncoplanar and oblique arcs require careful beam angle selection during treatment planning to avoid collisions during treatment, which may be facilitated by commercial software.

Association between tobacco product use and asthma among US adults from the Population Assessment of Tobacco and Health (PATH) Study waves 2-4.

Research on cigarettes and adult asthma offers mixed findings, perhaps due to overlap with chronic obstructive pulmonary disease (COPD) and inadequate adjustment for other smoke exposures. Associations between other tobacco products, including e-cigarettes, and asthma are also understudied. Using Population Assessment of Tobacco and Health Study waves 2-4 (20142015-20162017) data, we assessed the relation between tobacco product use and asthma in persons unlikely to have COPD. Prospective study of 10 267 adults aged 18-39 years without COPD diagnoses. Past-month tobacco use at wave 2 was modelled first as combustible versus non-combustible use and second as specific product categories (former, cigarettes, e-cigarettes, cigars, hookah, smokeless tobacco). Outcomes included lifetime asthma prevalence at wave 2, incidence (waves 3 and 4) and Asthma Control Test score (lowerworse). Multivariable regressions adjusted for predictors of asthma, including other smoke exposures cigarette pack-years, secondhand smoke and marijuana use. Sensitivity analyses examined findings when persons >39 years and those with both COPD and asthma were added, and when smoke exposure adjustments were removed. No product, including cigarettes and e-cigarettes, was associated with prevalence or incidence of asthma. Among people with asthma at wave 2, combustible tobacco (beta-0.86, 95% CI (-1.32 to -0.39)) and cigarettes (beta-1.14, 95% CI (-1.66 to -0.62)) were associated with worse asthma control. No tobacco product was associated with asthma control over time. In sensitivity analyses, tobacco use became associated with incident asthma as adults >39 years and those with asthmaCOPD were added, and as adjustments for other smoke exposures were omitted. Although cigarette use was associated with worse asthma control, there were no longitudinal associations between combustible tobacco or e-cigarette use and new onset or worsening asthma in these preliminary analyses. Research on tobacco and asthma should exclude COPD and adjust for smoking history and other smoke exposures.

Epigenetic age and lung cancer risk in the CLUE II prospective cohort study.

Epigenetic age, a robust marker of biological aging, has been associated with obesity, low-grade inflammation and metabolic diseases. However, few studies have examined associations between different epigenetic age measures and risk of lung cancer, despite great interest in finding biomarkers to assist in risk stratification for lung cancer screening. A nested case-control study of lung cancer from the CLUE II cohort study was conducted using incidence density sampling with 11 matching of controls to lung cancer cases ( We did not observe associations between the three epigenetic age acceleration measurements and risk of lung cancer overall however, inverse associations for the two Hannum age acceleration measures (intrinsic and extrinsic) were observed in men and among younger participants, but not in women or older participants. We did not observe effect modification by time from blood draw to diagnosis. Findings from this study do not support a positive association between three different biological age acceleration measures and risk of lung cancer. Additional studies are needed to address whether epigenetic age is associated with lung cancer in never smokers.

Novel Algorithm for the Estimation of Cancer Incidence Using Claims Data in Japan A Feasibility Study.

We developed algorithms to identify patients with newly diagnosed cancer from a Japanese claims database to identify the patients with newly diagnosed cancer of the sample population, which were compared with the nationwide cancer incidence in Japan to assess the validity of the novel algorithms. We developed two algorithms to identify patients with stomach, lung, colorectal, breast, and cervical cancers diagnosis only (algorithm 1), and combining diagnosis, treatments, and medicines (algorithm 2). Patients with newly diagnosed cancer were identified from an anonymized commercial claims database (JMDC Claims Database) in 2017 with two inclusionsexclusion criteria selecting all patients with cancer (extract 1) and excluding patients who had received cancer treatments in 2015 or 2016 (extract 2). We estimated the cancer incidence of the five cancer sites and compared it with the Japan National Cancer Registry incidence (calculated standardized incidence ratio with 95% CIs). The number of patients with newly diagnosed cancer ranged from 219 to 17,840 by the sites, algorithms, and exclusion criteria. Standardized incidence ratios were significantly higher in the JMDC Claims Database than in the national registry data for extract 1 and algorithm 1, extract 1 and algorithm 2, and extract 2 and algorithm 1. In extract 2 and algorithm 2, colorectal cancer in male and stomach, lung, and cervical cancers in females showed similar cancer incidence in the JMDC and national registry data. The novel algorithms are effective for extracting information about patients with cancer from claims data by using the combined information on diagnosis, procedures, and medicines (algorithm 2), with 2-year cancer-treatment history as an exclusion criterion (extract 2).

Are circulating endothelial cells the next target for transcriptome-level pathway analysis in ARDS

Acute Respiratory Distress Syndrome (ARDS) has had no mortality-improving pharmacological intervention despite 50 years of high-caliber research due to its heterogeneity.(1) For the field to advance, better definitions for ARDS subgroups that more uniformly respond to therapies are needed.(2-6) A plethora of high quality clinical research has uncovered the next generation of soluble biomarkers that provide the predictive enrichment necessary for trial recruitment, however plasma-soluble markers do not specify the damaged organ of origin nor do they provide insight into disease mechanisms. In this Perspective, we make the case for querying the transcriptome of circulating endothelial cells (CECs), which when shed from vessels after inflammatory insult, become heralds of site-specific inflammatory damage. We review the application of CEC quantification to multiple disease phenotypes (including myocardial infarction, vasculitides, cancer and ARDS), in each case supporting the association of CEC number with disease severity. We also argue for the utility of single-cell RNA transcriptomics to the understanding of cell-specific contributions to disease pathophysiology, and its potential to uncover novel insight on signals contributing to CEC shedding in ARDS.

Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858RT790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (

Dosimetric impact of 3D motion-compensated SPECT reconstruction for SIRT planning.

In selective internal radiation therapy, Twenty-nine patients with liver cancer or hepatic metastases treated by radioembolization were included in this study. The biodistribution of The mean amplitude of the liver was 9.5 ± 2.7 mm. Medians of PDD were closed to zero for all VOI except for lungs (6.4%) which means that the motion compensation overestimates the absorbed dose to the lungs compared to the 3D reconstruction. The smallest lesions had higher PDD than the largest ones. Between 3D and 3Dcomp reconstructions, means of differences in lung dose and TN ratio were not statistically significant, but in some cases these differences exceed 1 Gy (431) and 8% (231). The absolute differences in activity were on average 3.1% ± 5.1% and can reach 22.8%. The correction of respiratory motion mainly impacts the lung and tumor doses but only for some patients. The largest dose differences are observed for the smallest lesions.

NOTCH3 missense mutations as predictor of long-term response to gemcitabine in a patient with epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) as a very rare malignant vascular tumor belongs to the heterogenous group of soft-tissue sarcomas. Depending on the clinical course of the disease, interdisciplinary treatment concepts are required, including surgery, radiotherapy and systemic cancer therapy. However, due to its uncommonness, standard treatment options are lacking so far, especially in advanced disease with distant metastases. Here we report on an unusual case of a patient with metastasized EHE showing long-term response to second line treatment with gemcitabine over almost 2 decades. Cancer genome sequencing of the patients tumor tissue detected a NOTCH3 missense mutation which could provide an explanation for these clinical findings. NOTCH3 is known to be a mediator of resistance towards gemcitabine-based cancer treatment, at least in pancreatic cancer and non-small cell lung cancer. The observation that this missense mutation of NOTCH3 is associated with an increased response to treatment with gemcitabine in EHE can be used prospectively to assess NOTCH3 as potential biomarker for predicting therapy response to gemcitabine.

Real-world outcomes in non-small-cell lung cancer patients with MET Exon 14 skipping mutation and brain metastases treated with capmatinib.

Combination of serum ACSL4 levels and low-dose 256-slice spiral CT exhibits the potential in the early screening of lung cancer.

The prognosis of lung cancer is related to the stage of the disease at the time of detection, and early diagnosis can prolong survival time. In this prospective observational cohort research, we aimed to analyze the diagnostic performance of the combined application of ACSL4 and low-dose 256-slice spiral computed tomography (CT) to lung cancer. This prospective observational cohort research enrolled a total of 512 patients with pulmonary nodules (PN) who were found with PN by CT. All patients were divided into 2 groups through biopsy operation, including 449 patients with benign PN and 63 patients with malignant PN. Both groups were scanned with a Philips Brilliance 256iCT machine. Imaging features of PN were recorded. All images of the nodules were used for data measurement and image analysis by the Lung Nodule Assessment analysis software. The serum ACSL4, carcinoembryonic antigen (CEA), cytokeratin 19 fragment 21-1 (CYFRA21-1), neuron-specific enolase, carbohydrate antigen 199 (CA199) and carbohydrate antigen 125 (CA125) levels were measured by enzyme-linked immunosorbent assay method. The demographic data and clinical data, including age, sex, body mass index, smoke condition, TNM stage, lymph node metastasis and distant metastasis were collected. All the patients were followed for 5 years. Statistical analysis was conducted using SPSS software with P < .05 as statistically different. The diameter of nodules, the proportion of burr signs and smoking status, and the serum levels of CEA, CYFRA21-1, CA199, CA125 were significantly higher in malignant nodules group compared with the benign nodules group. Serum ACSL4 levels of malignant nodules group (19.33 ± 6.92 ngmL) were remarkably lower than the benign nodules group (25.34 ± 3.78 ngmL). ACSL4 was negatively correlated with CEA, CYFRA21-1, CA199, and CA125. ACSL4 was associated with the clinical outcomes in malignant PN patients and lower ACSL4 predicted poor clinic outcomes and prognosis. In addition, ACSL4 combined with low-dose 256-slice spiral CT had satisfactory diagnostic value for lung cancer. In summary, our results showed that combination application of ACSL4 and low-dose 256-slice spiral CT might be a potential method for the early screening of lung cancer.

Can 99 Tc m -3PRGD 2 (α ν β 3 ) and 18 F-FDG dual-tracer molecular imaging change the therapeutic strategy for progressive refractory differentiated thyroid cancer Case report.

The management of radioiodine refractory differentiated thyroid cancer (RAIR-DTC) represents a major challenge in thyroid cancer. The American Thyroid Association guidelines recommend the use of tyrosine kinase inhibitors (TKIs) for RAIR-DTC that does not respond to conventional treatment. Currently, imaging modalities that predict the response to TKI treatment based on morphological and functional features are lacking. we report a case of a patient with progressive RAIR lung metastases who underwent 2-deoxy-2- 18 Ffluoro-D-glucose and 99technetiumm-three polyethylene glycol spacers-arginine-glycine-aspartic acid ( 99 Tc m -3PRGD 2 ) dual-tracer imaging and investigate the value of this imaging strategy for determining subsequent therapeutic schedules. A 52-year-old man with advanced RAIR-DTC and progressive lung metastasis. After TKI treatment sorafenib lost its clinical benefits, the patients therapeutic response was evaluated as progressive disease. 2-deoxy-2- 18 Ffluoro-D-glucose PETCT and 99 Tc m -3PRGD 2 SPECTCT were performed. There were multiple FDG-positive lesions in the lung. However, 99 Tc m -3PRGD 2 SPECTCT showed only 1 lesion in the right middle pulmonary lobe with arginine-glycine-aspartic positivity. RAIR-DTC. Radiofrequency ablation was performed for only the lesion with RDG and FDG positivity. The patient quickly achieved partial response. This case indicates that for progressive RAIR metastases, patients can benefit more from prioritizing treatment for lesions that are both arginine-glycine-aspartic and FDG positive.

AI Improves Nodule Detection on Chest Radiographs in a Health Screening Population A Randomized Controlled Trial.

Background The impact of artificial intelligence (AI)-based computer-aided detection (CAD) software has not been prospectively explored in real-world populations. Purpose To investigate whether commercial AI-based CAD software could improve the detection rate of actionable lung nodules on chest radiographs in participants undergoing health checkups. Materials and Methods In this single-center, pragmatic, open-label randomized controlled trial, participants who underwent chest radiography between July 2020 and December 2021 in a health screening center were enrolled and randomized into intervention (AI group) and control (non-AI group) arms. One of three designated radiologists with 13-36 years of experience interpreted each radiograph, referring to the AI-based CAD results for the AI group. The primary outcome was the detection rate, that is, the number of true-positive radiographs divided by the total number of radiographs, of actionable lung nodules confirmed on CT scans obtained within 3 months. Actionable nodules were defined as solid nodules larger than 8 mm or subsolid nodules with a solid portion larger than 6 mm (Lung Imaging Reporting and Data System, or Lung-RADS, category 4). Secondary outcomes included the positive-report rate, sensitivity, false-referral rate, and malignant lung nodule detection rate. Clinical outcomes were compared between the two groups using univariable logistic regression analyses. Results A total of 10 476 participants (median age, 59 years IQR, 50-66 years 5121 men) were randomized to an AI group (

Drug reactions with eosinophilia and systemic symptoms induced by immune checkpoint inhibitors an international cohort of 13 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), drug reactions with eosinophilia and systemic symptoms (DRESS) have been very rarely reported. The objective of this study is to better define the clinical and histologic features, treatment and prognosis of ICI-related DRESS. This retrospective case series was conducted between 01 January 2015 and 31 December 2021 by the dermatology departments of five international networks involved in drug reactions. Inclusion criteria were age ≥18 years old, DRESS with Regiscar score ≥4 (probable or certain) and ICI as a suspect drug. Clinical, biologic and follow-up data were extracted from the medical charts. Thirteen patients were included. The median time to onset was 22 days (3-11). No patients had a high-risk drug introduced in the past 3 months. A majority of patients presented fever (92%), diffuse exanthema (77%) and facial edema (69%). Biologic features included hypereosinophilia in eight patients (61.5%), hyperlymphocytosis in 3 (23%), elevated liver function tests in 11 (85%, grade 1 or 2 in most cases) and renal involvement in 5 (38%). Two patients (15%) had lung involvement. PCR evidence of viral replication was detected in five patients (38.5%). Treatment involved discontinuation of the suspect ICI and systemic steroids with variable dose and duration regimens. Among the four patients in which ipilimumab nivolumab combination therapy was initially suspected, one was rechallenged with nivolumab monotherapy with good tolerance. Five patients were switched to another anti-PD-1 plus low-dose systemic steroids, with good tolerance in four cases. No patient died because of DRESS. DRESS induced by ICI are rare and of moderate severity. A consensus for management is still pending.

A Signature Constructed Based on the Integrin Family Predicts Prognosis and Correlates with the Tumor Microenvironment of Patients with Lung Adenocarcinoma.

As an important element in regulating the tumor microenvironment (TME), integrin plays a key role in tumor progression. This study aimed to establish prognostic signatures to predict the overall survival and identify the immune landscape of patients with lung adenocarcinoma based on integrins. The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus datasets were used to obtain information on mRNA levels and clinical factors (GSE72094). The least absolute shrinkage and selection operator (LASSO) model was used to create a prediction model that included six integrin genes. The nomogram, risk score, and time-dependent receiver operating characteristic analysis all revealed that the signatures had a good prognostic value. The gene signatures may be linked to carcinogenesis and TME, according to a gene set enrichment analysis. The immunological and stromal scores were computed using the ESTIMATE algorithm, and the data revealed, the low-risk group had a higher score. We discovered that the B lymphocytes, plasma, CD4 T, dendritic, and mast cells were much higher in the group with low-risk using the CiberSort. Inflammatory processes and several HLA family genes were upregulated in the low-risk group. The low-risk group with a better prognosis is more sensitive to immune checkpoint inhibitor medication, according to immunophenoscore (IPS) research. We found that the patients in the high-risk group were more susceptible to chemotherapy than other group patients, according to the prophetic algorithm. The gene signatures could accurately predict the prognosis, identify the immune status of patients with lung adenocarcinoma, and provide guidance for therapy.

Gene Variations of Chemokine and Chemokine Receptor CXCL12CXCR4 in Lung Cancer.

Lung cancer is the most common type of cancer in the world and about 1 million people die from lung cancer every year in the world. Inflammation is an important factor in the onset, progression and metastasis of lung cancer. The most important regulators of inflammation are chemokines and chemokine receptors. Chemokines induce the proliferation of cancer cells and prevent their apoptosis. Chemokines may indirectly affect tumor growth by inducing growth and release of angiogenic factors from cells in the tumor microenvironment. CXCL12CXCR4 are chemokine and chemokine receptors predicted to be involved in lung cancer pathogenesis. This study aimed to determine the relationship between CXCL12CXCR4 gene variations and CXCL12 serum levels in disease pathogenesis in lung cancer. For this purpose, DNA samples isolated from 90 lung cancer patients (36 squamous cell carcinomas, 18 small cell carcinomas and 36 adenocarcinomas) and 90 control individuals were genotyped by PCR-RFLP method for CXCL12 (rs1801157) and CXCR4 (rs2228014). CXCL12 protein levels were determined from serum samples by the enzyme-linked immuno-sorbent assay (ELISA) method. Results were evaluated using IBM SPSS Statistics 21 software and FINNETI program. As a result, there was no significant difference between the genotype frequencies of the CXCL12 rs1801157 variant and the risk of lung cancer (P 0.396). CXCR4 rs2228014 genotypes were significantly associated with lung cancer risk (P < 0.001). Lung cancer patients had significantly elevated serum CXCL12 levels than controls (P < 0.001). In conclusion, the rs2228014 variants localized on the chemokine receptors CXCR4 gene was found to be closely related to lung cancer risk.

Stromal Interaction Molecule 1 (STIM1) is a Potential Prognostic Biomarker and Correlates with Immune Infiltrates in Solid Tumors.

Increasing evidence has shown that stromal interaction molecule 1 (STIM1), a key subunit of store-operated Ca2 entry (SOCE), is closely associated with tumor growth, development, and metastasis. However, there is no report of a comprehensive assessment of STIM1 in pan-cancer. This study aimed to perform a general analysis of STIM1 in human tumors, including its molecular characteristics, functional mechanisms, clinical significance, and immune infiltrates correlation based on pan-cancer data from The Cancer Genome Atlas (TCGA). Gene expression analysis was investigated using TCGA RNA-seq data, the Tumor Immune Estimation Resource (TIMER). Phosphorylation analysis was undertaken using the Clinical Proteomic Tumor Analysis Consortium (CP-TAC) and the PhosphoNET database. Genetic alterations of STIM1 were analyzed using cBioPortal. Prognostic analysis was via the R package survival function and the Kaplan-Meier plotter. Functional enrichment analysis was via by the R package cluster Profiler function. The association between STIM1 and tumor-infiltrating immune cells and immune markers was by the R package GSVA function and TIMER. STIM1 was differentially expressed and associated with distinct clinical stages in multiple tumors. The phosphorylation of STIM1 at S673 is highly expressed in clear cell renal carcinoma and lung adenocarcinoma tumors compared to normal tissues. STIM1 genetic alterations correlate with poor prognosis in several tumors, including ovarian cancer and lung squamous cell carcinomas. High STIM1 expression is associated with good or poor prognosis across diverse tumors. Overall survival (OS) analysis indicated that STIM1 is a favorable prognostic factor for patients with BRCA, KIRC, LIHC, LUAD, OV, SARC, and UCEC, and is a risk prognostic factor for BLCA, KIRP, STAD, and UVM. There is a close correlation between STIM1 expression and immune cell infiltration, immune-regulated genes, chemokines, and immune checkpoints in a variety of tumors. STIM1 functions differently in diverse tumors, playing an oncogenic or antitumor role. Moreover, It may serve as a prognostic biomarker and an immunotherapy target across multiple tumors.

Isolated bronchoplastic procedure for typical carcinoid of the left lung.

Lung carcinoids (LC) comprise neuroendocrine lung tumors of low (typical carcinoid) and intermediate (atypical carcinoid) grade of malignancy accounting for less than 2% of all lung neoplasms. In Europe, annual incidence of LC varies from 0.2 to 2 per 100 000. This value increased dramatically over the past 30 years. One of the causes is improvement of diagnostic methods. Compared to aggressive high-grade neuroendocrine lung cancer, natural course of early-stage LC is usually indolent. Therefore, surgery with preservation of as much normal lung tissue as possible is preferable for resectable tumors. Nevertheless, the number of isolated bronchial resections with preservation of the entire lung tissue is relatively small, and these procedures remain technically complex interventions. We present isolated resection of interlobular spur, lower medial wall of distal part of the left main bronchus and proximal part of the lower lobular bronchus for typical carcinoid with monobronchial anastomosis and preservation of the entire lung parenchyma. Карциноиды легких (КЛ) — совокупность нейроэндокринных опухолей легких низкой (типичный карциноид) и промежуточной (атипичный карциноид) степени злокачественности, составляют <2% всех новообразований легких. Заболеваемость КЛ, которая в Европе варьирует от 0,2 до 2 случаев на 100 000 населения в год, за последние 30 лет резко возросла, в том числе в результате совершенствования методов диагностики. По сравнению с агрессивным поведением нейроэндокринного рака легкого высокой степени злокачественности естественное течение КЛ ранних стадий, как правило, индолентное, поэтому хирургическое вмешательство с сохранением как можно большего количества нормальной легочной ткани является эталонным стандартом лечения резектабельных опухолей. Вместе с тем доля изолированной резекции бронхов с сохранением всей легочной ткани относительно невелика, и они по-прежнему остаются редкими, технически сложными вмешательствами. Представляем клиническое наблюдение изолированной резекции шпоры долевых бронхов, нижнемедиальной стенки дистального отдела левого главного бронха и проксимального отдела нижнего долевого бронха по поводу типичного карциноида с наложением монобронхиального анастомоза и сохранением всей легочной паренхимы.

Diagnosis and treatment of bronchopleural fistula after anatomical lung resections.

To assess the factors causing air leakage after anatomical lung resections and present a rational tactical approach for timely establishing the cause and level of bronchial fistula. We analyzed 723 patients who underwent anatomical lung resection (pneumonectomy - 136 patients, anatomical lobectomy and segmentectomy - 513, video-assisted anatomical resection - 74 patients). In 506 (69.9%) cases, complete lung inflation after surgery was observed within 24-48 hours. Persistent air discharge for more than 3 days was observed in 141 (19.5%) patients. Prolonged air leakage for more than 7 postoperative days occurred in 50 (6.9%) patients. Air discharge for more than 10 days was considered abnormal and observed in 20 (2.8%) patients. Redo surgeries were performed in 49 patients with bronchopleural fistula at the level of segmental bronchi. Forty-two patients after primary thoracoscopy and 6 ones after primary thoracotomy underwent video-assisted resection of the lung with bronchopleural fistula after previous surgery. In 11 patients, re-thoracotomy was performed middle lobectomy after previous right-sided upper lobectomy in 2 patients, lung resection after previous segmentectomy in 8 cases and atypical resection of bulla after previous right-sided lower lobectomy in 1 case. Surgical approach for persistent postoperative air leakage involves various surgical interventions. The best option is minimally invasive thoracoscopic procedure. This method is valuable to visualize bronchopleural fistula, eliminate air leakage, additionally reinforce pulmonary suture and perform targeted adequate drainage of the pleural cavity. Оценить факторы, вызывающие просачивание воздуха через линию швов бронха после анатомических резекций легких, и на этом основании представить рациональный тактический подход, который направлен на своевременное установление причины и уровня бронхиального свища. Изучены результаты хирургического лечения 723 пациентов, которым выполнена анатомическая резекция легких. Объем оперативного вмешательства был следующим пневмонэктомия — у 136 пациентов, анатомическая лоб- и сегментэктомия — у 513, видеоторакоскопически ассистированная анатомическая резекция — у 74. В 506 (69,9%) наблюдениях полное расправление легкого после операции зафиксировано в течение 24—48 ч. Сохранение сброса воздуха >3 сут отмечено у 141 (19,5%) пациента, что расценено как затянувшееся. Продленное просачивание воздуха >7 сут в послеоперационном периоде наблюдали у 50 (6,9%) пациентов. Отделение воздуха по дренажам в сроки >10 сут считали патологическим, что зарегистрировано у 20 (2,8%) пациентов. Повторные операции выполнены у 49 больных с признаками бронхоплеврального свища на уровне сегментарных бронхов. У 42 пациентов после первичной видеоторакоскопии и у 6 — после первичной торакотомии выполнена видеоассистированная аппаратная резекция легкого с бронхоплевральным свищом в зоне предыдущей операции. У 11 пациентов выполнена реторакотомия у 2 — средняя лобэктомия (ранее им произведена верхняя лобэктомия справа), у 8 пациентов, перенесших ранее сегментэктомии, — аппаратная резекция легкого, у 1 — атипичная резекция буллы после нижней лобэктомии справа. Хирургический подход к лечению пациентов с явлениями просачивания воздуха в послеоперационном периоде предполагает различные по объему оперативные вмешательства. Лучшим вариантом является миниинвазивное хирургическое пособие — видеоторакоскопия, которая позволяет непосредственно визуализировать зону бронхоплеврального свища, осуществить аэростаз, выполнить дополнительные мероприятия по укреплению легочного шва, прицельное адекватное дренирование плевральной полости.

Research Progress on Gene Synthesis and Anticancer and Lipid-lowering Mechanism of Monacolin K.

Monacolin K (MK), also known as lovastatin (LOV), is a secondary metabolite synthesized by Monascus in the later stage of fermentation and is the main component of functional red yeast rice (RYR). The structure of MK is similar to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and it can competitively bind to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), thus reducing the level of blood lipids. MK can affect the expression of MAPK, PI3KAKT, and NF-κB pathway, prepare conjugates with other compounds, and enhance the sensitivity of cancer cells to chemotherapeutic drugs so as to induce apoptosis of acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, and liver cancer. Combined with the synthetic route of MK, this paper summarizes the latest lipid-lowering and anticancer mechanism of MK, and provides a reference for the application of MK in medicine.

Efficacy and safety of first-line treatments for patients with advanced anaplastic lymphoma kinase mutated, non-small cell cancer A systematic review and network meta-analysis.

This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC). A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed. The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best Prbest, 90% surface under the cumulative ranking curve SUCRA, 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib hazard ratio (HR), 0.31 95% confidence interval (CI), 0.20-0.47) lorlatinib vs. chemotherapy HR, 0.17 95% CI, 0.12-0.23 crizotinib vs. lorlatinib HR, 3.6 95% CI, 2.4-5.2 and brigatinib vs. lorlatinib HR, 1.7 95% CI, 1.0-2.8). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%). For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit. Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non-small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.

Characteristics and 6-Month Mortality of Medical Oncology Patients With Incidental and Symptomatic Pulmonary Embolism A Single-Institutional Retrospective Longitudinal Analysis.

This study aimed to identify clinical characteristics of cancer patients with incidental pulmonary embolism (IPE) and assess the variables associated with 30-day mortality in cancer patients with PE including symptomatic pulmonary embolism (SPE) and IPE. 6-Month mortality rate in cancer patients with SPE and IPE were also compared. We retrospectively analyzed electronic medical records of cancer patients with newly diagnosed PE between January 2016 and June 2021. We compared clinical and radiological characteristics in cancer patients with IPE and SPE and identified variables associated with the overall 30-day mortality on multivariate analysis. All patients were followed up for 6 months and survival analysis was performed by use of Kaplan-Meier. Five hundred and nine eligible cancer patients with pulmonary embolism were identified during the study period. IPE is associated with lower BMI, colorectal and pancreas cancers, stage IIIIV of cancer, recent antiangiogenic therapy, central venous catheter (CVC) and chronic cardiac or respiratory disease compared to SPE. The factors associated with 30-day mortality included poor performance status, lungpleura or upper gastrointestinal cancers, stage IIIIV of cancer, previous VTE, oxygen saturation < 95%, lactic acid > 2 mmoll and bilateral PE. The overall survival in patients with IPE at 6-month follow-up was similar to those diagnosed with SPE. The present study has allowed the identification of factors associated with 30-day mortality in cancer patients with IPE and SPE. We also found similar mortality rate in cancer patients with IPE compared with patients with SPE at 6-month follow-up.

Sintilimab plus chemotherapy for first-line treatment of advanced or metastatic nonsquamous non-small-cell lung cancer network meta-analysis.

Sintilimab is an immunotherapy drug that was successfully developed and tested in China to treat a kind of lung cancer that has spread, called advanced non-squamous non-small-cell lung cancer (NSCLC). The ORIENT-11 clinical study showed that adding sintilimab to two types of chemotherapy (pemetrexed and platinum) as the first treatment for people in China with advanced non-squamous NSCLC was safe and effective in reducing the risk of cancer spreading, growing or getting worse, compared with chemotherapy alone. Our study combined and analyzed the results from 11 clinical studies to look at how well sintilimab with chemotherapy may work compared with immunotherapy drugs approved in the USA. The results showed that sintilimab with chemotherapy is as effective and safe as immunotherapy drugs approved in the USA to treat people with advanced non-squamous NSCLC. These results may help doctors and payers when deciding how to treat people with this disease.

Alignment, segmentation and neighborhood analysis in cyclic immunohistochemistry data using CASSATT.

Cyclic immunohistochemistry (cycIHC) uses sequential rounds of colorimetric immunostaining and imaging for quantitative mapping of location and number of cells of interest. Additionally, cycIHC benefits from the speed and simplicity of brightfield microscopy, making the collection of entire tissue sections and slides possible at a trivial cost compared to other high dimensional imaging modalities. However, large cycIHC datasets currently require an expert data scientist to concatenate separate open-source tools for each step of image pre-processing, registration, and segmentation, or the use of proprietary software. Here, we present a unified and user-friendly pipeline for processing, aligning, and analyzing cycIHC data - Cyclic Analysis of Single-Cell Subsets and Tissue Territories (CASSATT). CASSATT registers scanned slide images across all rounds of staining, segments individual nuclei, and measures marker expression on each detected cell. Beyond straightforward single cell data analysis outputs, CASSATT explores the spatial relationships between cell populations. By calculating the log odds of interaction frequencies between cell populations within tissues and tissue regions, this pipeline helps users identify populations of cells that interact-or do not interact-at frequencies that are greater than those occurring by chance. It also identifies specific neighborhoods of cells based on the assortment of neighboring cell types that surround each cell in the sample. The presence and location of these neighborhoods can be compared across slides or within distinct regions within a tissue. CASSATT is a fully open source workflow tool developed to process cycIHC data and will allow greater utilization of this powerful staining technique.

Cholesterol-Amino-Phosphate (CAP) Derived Lipid Nanoparticles for Delivery of Self-Amplifying RNA and Restoration of Spermatogenesis in Infertile Mice.

Male infertility caused by genetic mutations is an important type of infertility. Currently, there is no reliable method in the clinic to address this medical need. The emergence of mRNA therapy provides a possible strategy for restoring mutant genes in the reproductive system. However, effective delivery of mRNA to spermatocytes remains a formidable challenge. Here a series of cholesterol-amino-phosphate (CAP) lipids are reported by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results demonstrate that CAP-derived lipid nanoparticles (CAP LNPs) can deliver RNA including traditional mRNA and self-amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and treat male infertility caused by the Dmc1 gene mutation. Notably, the delivery efficiency of CAP LNPs is significantly higher than that of the MC3 and ALC-0315 LNPs, which is consistent with the design of CAP molecules. More importantly, a single injection of CAP LNPs-saRNA can produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Overall, this study proves the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation.

circrac GTPase-Activating Protein 1 Facilitates Stemness and Metastasis of Non-Small Cell Lung Cancer via Polypyrimidine Tract-Binding Protein 1 Recruitment to Promote Sirtuin-3-Mediated Replication Timing Regulatory Factor 1 Deacetylation.

Circular RNAs have been identified as diagnostic and therapeutic targets for various tumors. The expression of circrac GTPase-activating protein 1 (circRACGAP1) is reported to drive the development of non-small cell lung cancer (NSCLC). This study further explored the potential mechanism of circRACGAP1-mediated development of NSCLC. The circRACGAP1 level was detected by quantitative RT-PCR. Sphere formation, CD133-positive cell percentage, and expression of octamer-binding transcription factor 4, Sox2, Nanog, and CD133 were detected to evaluate stemness of NSCLC. Migration and invasion were determined using wound healing and transwell assays. Protein expression was measured using Western blotting. The molecular mechanism was evaluated using RNA pull-down, RNA immunoprecipitation, and coimmunoprecipitation assays. In vivo tumor growth and metastasis were determined in nude mice. circRACGAP1 was highly expressed in NSCLC and was associated with stemness marker Sox2 expression. The stemness, metastasis, and epithelial mesenchymal transformation were repressed in circRACGAP1-depleted NSCLC cells. Mechanistically, circRACGAP1 recruited RNA-binding protein polypyrimidine tract-binding protein 1 to enhance the stability and expression of sirtuin-3 (SIRT3), which subsequently led to replication timing regulatory factor 1 (RIF1) deacetylation and activation of the Wntβ-catenin pathway. circRACGAP1 overexpression counteracted SIRT3 or RIF1 knockdown-mediated inhibition in stemness and metastasis of NSCLC cells. The in vivo tumor growth and metastasis were repressed by circRACGAP1 depletion. Patients with NSCLC with a higher serum exosomal circRACGAP1 level had a lower overall survival rate. In conclusion, circRACGAP1 facilitated stemness and metastasis of NSCLC cells through the recruitment of polypyrimidine tract-binding protein 1 to promote SIRT3-mediated RIF1 deacetylation. Our results uncover a novel regulatory mechanism of circRACGAP1 in NSCLC and identify circRACGAP1 as a promising therapeutic target.

Research advances in non-terminal respiratory unit adenocarcinoma of the lung.

肺腺癌根据组织学起源分为终末呼吸单位型腺癌和非终末呼吸单位型腺癌。非终末呼吸单位型腺癌从临床病理特征、组织学结构、免疫表型、分子表型以及预后均显著不同于终末呼吸单位型腺癌，且临床上相对少见。本文就非终末呼吸单位型肺腺癌的组织学特点、发生途径、分子特征等多方面进行综述，总结非终末呼吸单位型腺癌的病变特点，以提高病理医师对该病研究进展的认识，从而能为患者选择更合适的治疗方案提供理论依据，改善患者预后。.

Pathological research progress on spread of lung cancer through air spaces.

气腔播散（spread through air spaces）是肺癌组织中一种特殊的肿瘤侵袭模式，2015年WHO肺癌病理分类中正式提出该概念。气腔播散见于多种组织类型的肺癌，表现为主瘤体边界外的气腔内出现肿瘤细胞簇。近年来，气腔播散成为肺癌病理研究的热点之一。大量临床研究表明，气腔播散与肺癌的术后复发和预后关系密切，尤其对早期肺癌临床治疗术式选择具有指导意义，提高病理医师对气腔播散现象的认识有助于肺癌的精准诊断。目前对气腔播散的研究仍然有待进一步深入和细化，包括鉴别人为因素可能造成的假象、气腔播散的分级诊断标准、术中冷冻切片诊断以及气腔播散形成的分子机制等。本文将阐述气腔播散的相关概念、病理学特征、对临床诊疗的影响以及尚存的病理学问题等，以增强临床实践中病理医师对肺癌气腔播散的认知与重视。.

Pulmonary granular cell tumors a clinicopathological analysis of five cases.

Application of the WHO Classification of Thoracic Tumors (2021) grading system in invasive pulmonary adenocarcinoma and its correlation with the targeted genes variations.

Clinicopathological features of patients with RET fusion-positive non-small cell lung cancer.

Gene mutation profiles and clinicopathological features of patients with non-small cell lung cancer harboring KRAS G12C mutation a single-center retrospective study.

Advances of pathological diagnosis of lung cancer based on clinical needs.

Pathological diagnosis of lung cancer keep updating and developing, in order to meet the clinical needs in the era of precision medicine. It mainly involves the advances of histological subtype classification, molecular testing for targeted therapy, biomarkers detection for immunotherapy and the pathological evaluation for neoadjuvant therapy. Nowadays, pathological diagnosis of lung cancer present a multidisciplinary model including clinical medicine, radiology and pathology. It is gradually moving towards standardization with expection to provide better guidance for clinical treatment and prognosis. 为满足肿瘤精准治疗时代的临床需求，肺癌的病理诊断也在不断更新和发展，主要体现在肺癌组织学分类的不断更新、用于指导靶向药物治疗的分子检测、免疫治疗相关标志物的检测及新辅助治疗后病理评估方面的进展。新时代肺癌病理诊断体现了临床-影像-病理等多学科诊断模式，正在逐步走向规范化、精准化，以期更好地为临床提供治疗及预后指导。.

Combined KRAS

Efforts to improve the anti-tumor response to KRAS

Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis.

Oncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP (

In situ modeling of acquired resistance to RTKRAS pathway targeted therapies.

Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Preclinical studies that identify synergistic combinations enhance therapeutic efficacy to target intrinsic resistance, however, methods to study acquired resistance in cell culture are lacking. Here, we describe a novel in situ resistance assay (ISRA), performed in a 96-well culture format, that models acquired resistance to RTKRAS pathway targeted therapies. Using osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show acquired resistance can be reliably modeled across cell lines using objectively defined osimertinib doses. Similar to patient populations, isolated osimertinib-resistant populations showed resistance via enhanced activation of multiple parallel RTKs so that individual RTK inhibitors did not re-sensitize cells to osimertinib. In contrast, inhibition of proximal RTK signaling using the SHP2 inhibitor RMC-4550 both re-sensitized resistant populations to osimertinib and prevented the development of osimertinib resistance as a primary therapy. Similar, objectively defined drug doses were used to model resistance to additional RTKRAS pathway targeted therapies including the KRASG12C inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.

Iris metastasis as resistance mechanism to atezolizumab, carboplatin, and etoposide but responds to additional irinotecan and anlotinib in a small cell lung cancer patient.

Small cell lung cancer (SCLC) is an aggressive malignancy associated with poor prognosis. Metastasis to sites outside the chest at the time of initial diagnosis, such as bone, brain, and liver metastasis have been found in most SCLC patients. Iris metastases from SCLC have rarely been previously reported, and often cause eye pain and blindness in patients. Here, we report a patient with SCLC who presented with iris metastasis in the right eye and metastasis in the left adrenal gland due to disease progression on first-line therapy, which subsequently caused pain and blindness in the right eye. The patient was treated with second-line irinotecan combined with anlotinib and atezolizumab and did not receive any local treatment in the right eye. After only one cycle of treatment, the iris metastases in the right eye were smaller than before, and the visual acuity in the right eye recovered. At the same time, her left adrenal metastases were also significantly smaller than before. Our case suggests that systemic therapy with effective treatment options can similarly improve iris metastases in patients.

Upregulation of long intergenic non-coding RNA LINC00326 inhibits non-small cell lung carcinoma progression by blocking Wntβ-catenin pathway through modulating the miR-657dickkopf WNT signaling pathway inhibitor 2 axis.

Long intergenic non-coding RNA 326 (LINC00326) modulates hepatocarcinogenic lipid metabolism. However, the ability of LINC00326 to modulate the highly aggressive non-small cell lung carcinoma (NSCLC) is unknown. Here, LINC00326 in NSCLC was investigated, together with its effects on tumor malignancy and the underlying mechanisms of action. LINC00326 levels in tumor tissues and cell lines were measured by Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and RNA fluorescence in situ hybridization (FISH). Proliferation and apoptosis were assessed in cell lines by Cell Counting Kit-8 (CCK-8), EdU staining assays and flow cytometry, respectively, and tumor growth was measured in mouse models. Possible microRNA targets of LINC00326 were predicted by bioinformatics and verified by RNA pull-down and immunoprecipitation and luciferase reporter assays. Western blotting was used to evaluate the expression of Wntβ-catenin-associated proteins. LINC00326 was downregulated in tumor tissues and cell lines. Knockdown of LINC00326 stimulated NSCLC cell proliferation and suppressed apoptosis in vitro, as well as enhancing xenograft tumor growth. LINC00326 sponged miR-657, and dickkopf WNT signaling pathway inhibitor 2 (DKK2) was found to be directly targeted by miR-657, with LINC00326 positively regulating its expression through sponging miR-657. The actions of LINC00326 knockdown on proliferation and apoptosis were reversed by stimulation of the miR-657DKK2 axis. Furthermore, overexpression of miR-657 mitigated DKK2 inhibition on Wntβ-catenin signaling. LINC00326miR-657DKK2 axis signaling blocked tumor-associated functions in NSCLC cells through the targeting Wntβ-catenin pathway. This suggests that this pathway could be a target for NSCLC treatment.

Differential treatment responses to immune checkpoint inhibitor (ICI) therapy in a case of multiple primary malignancies the programmed death ligand-1 (PD-L1) negative ureteral and lung metastasis from a clear cell renal cell carcinoma appearing after robotic-assisted partial nephrectomy progressed after ICI therapy, while synchronous PD-L1-positive primary lung squamous cell carcinoma responded very well to ICI therapy a case report.

Renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are representative malignancies that respond well to immune checkpoint inhibitors (ICIs). Research has been conducted to identify biomarkers, such as programmed death ligand-1 (PD-L1), that would allow the response to ICI therapy to be predicted however, the complex tumor immune system consisting of both host and tumor factors may also exert an influence. Computed tomographic imaging (CT) incidentally revealed a left renal mass, and a left pulmonary nodule with multiple lymph node metastases (LNMs). Firstly, video-assisted thoracic surgery revealed a lung tumor invading the chest wall. Histologically, the findings of the tumor were consistent with squamous cell carcinoma (SCC), and immunohistochemistry (IHC) showed positive PD-L1 expression. The renal tumor was excised by robotic-assisted partial nephrectomy (RAPN). Histologically, the renal tumor showed the features of clear cell carcinoma (CCC). Four months after the RAPN, CT revealed left hydronephrosis caused by an enhancing ureteral tumor. Then, multiple right lung metastases appeared, and the left lung tumor increased. Following treatment including atezolizumab, the primary lung SCC and the multiple LNMs almost disappeared completely, while the ureteral and right lung metastases showed progression. The ureteral metastasis was resected by left open nephroureterectomy. Histology of the ureteral tumor revealed features consistent with CCC. Histological examination of the multiple right lung metastases that were resected by partial lobectomy via a small thoracic incision also revealed features consistent with CCC. Two months after nephroureterectomy, a solitary left lung metastasis was treated by nivolumab and ipilimumab. Six months after nephroureterectomy, the patient died of RCC. Further studies of specimens revealed that the tumor cells in the primary RCC and the ureteral and lung metastases showed negative results of IHC for PD-L1. The responses to ICI therapy of concomitant RCC and NSCLC were quite different. The PD-L1 expression status in individual tumors in cases of multiple primary malignancies (MPMs) may directly predict the response of each malignancy to ICI therapy, because the host immune system, which may affect the response to ICI therapy, could be the same in MPMs.

Deep learning model integrating positron emission tomography and clinical data for prognosis prediction in non-small cell lung cancer patients.

Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of lung cancers are non-small cell lung cancer (NSCLC), accounting for approximately 85% of all lung cancer types. The Cox proportional hazards model (CPH), which is the standard method for survival analysis, has several limitations. The purpose of our study was to improve survival prediction in patients with NSCLC by incorporating prognostic information from F-18 fluorodeoxyglucose positron emission tomography (FDG PET) images into a traditional survival prediction model using clinical data. The multimodal deep learning model showed the best performance, with a C-index and mean absolute error of 0.756 and 399 days under a five-fold cross-validation, respectively, followed by ResNet3D for PET (0.749 and 405 days) and CPH for clinical data (0.747 and 583 days). The proposed deep learning-based integrative model combining the two modalities improved the survival prediction in patients with NSCLC.

Role of chest CT scan in patients with preexisting cancer and COVID-19 pneumonia.

Detection of COVID-19 in cancer patients is challenging due to probable preexisting pulmonary infiltration caused by many infectious and non-infectious etiologies. We evaluated chest CT scan findings of COVID-19 pneumonia in cancer patients and explored its prognostic role in mortality. We studied 266 COVID-19 patients with a history of cancer diagnosis between 2020 and 2022. Chest CT images were reported based on Radiological Society of North America (RSNA) structural report and the CT score and pattern of involvement were noted. We used multivariate logistic regression models to determine the association between CT scan findings and mortality of the cancer COVID-19 patients. The mean age was 56.48 (± 18.59), and 53% were men. Gastrointestinal (29.3%), hematologic (26.3%), and breast (10.5%) cancers were the most frequent types of cancer. The prevalence of atypical or indeterminate findings in the chest CT was 42.8%. Most radiologic findings were consolidation mixed with ground-glass opacity (44.4%), pleural effusion (33.5%), and pure ground-glass opacity (19.5%). The risk of death was higher among those who had typical chest CT for COVID-19 (OR 3.47 95% CI 1.14-8.98) and those who had a severity of score higher than 18 (OR 1.89 95% CI 1.07-3.34). Also, presence of consolidation (P value 0.040), pleural effusion (P value 0.000), centrilobular nodules (P value 0.013), and architectural distortion (P value 0.005) were associated with a poorer prognosis. Less than half of COVID-19 patients with a history of cancer had typical imaging features of COVID-19. Radiologists should be aware of atypical, rare, or subtle chest CT findings in patients with pre-existing cancer.

Diagnosis value of

The diagnosis of pulmonary hamartoma (PH) based on computed tomography (CT) is a challenge, especially in patients with atypical imaging characteristics. This study was aimed at summarizing the imaging characteristic of Patients diagnosed with PH who had undergone PET-CT from literature pertaining were retrospectively analyzed, which were cases of publications from the Cochrane Library, PubMed, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI) and Wanfang databases, from 2008 to June 2022. The other 20 cases of the collection were patients from our hospital from 2008 to June 2022. Patients symptoms, imaging characteristics of chest CT, PET-CT characteristics, the reason for PET-CT and the complications were analyzed. In this retrospective study, a total of 216 patients were diagnosed with PH and had been examined by PET-CT. 20 of the cases were patients of our hospital from January 2008 to June 2022. The other cases were collected from the literature. The mean diameter of most PH lesions is 1.7 ± 1.0 cm. The mean maximum standardized uptake value (SUVmax) of the PH lesions was 1.2 ± 1.1. Most of their SUVmax were lower than internationally recognized cut-off value (SUVmax 2.5). PET-CT was superior to CT in the diagnosis of PH but there was a correlation of between CT diagnosis and PET-CT diagnosis for the PH lesions. In order to draw the Receiver operating characteristic (ROC), we selected 29 patients with a clear SUVmax value of their PH lesion, and 29 lung cancer patients with clear SUVmax value in our hospital were collected as a control group. ROC curve analysis showed that the area under curve (AUC) of SUVmax was 0.899, and the optimal diagnostic threshold was SUVmax > 2.65. PET-CT could distinguish PH from malignant lesions with a sensitivity of 89.66% by applying a SUVmax of 2.65 as a cut-off in this study. PET-CT might be a useful tool to diagnose PH, which shows a better diagnostic sensitivity than CT. But PET-CT can not be used as a single diagnostic approach, which should be combined with other methods and the patients history to make the most correct diagnosis.

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model.

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.

Regulation of immunological tolerance by the p53-inhibitor iASPP.

Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8

Path planning for percutaneous lung biopsy based on the loose-Pareto and adaptive heptagonal optimization method.

Lung cancer has is highly prevalent worldwide and is the leading cause of cancer-related deaths. In the clinic, a biopsy sample of the lesion is taken to determine whether a lung mass is benign or malignant. CT-guided percutaneous lung biopsy is a minimally invasive intervention and is commonly used to diagnose lung cancer. Path planning before surgery plays a crucial role in percutaneous lung biopsy. Traditionally, path planning for lung biopsy is performed manually by physicians based on CT images of the patient, which demands knowledge and extensive clinical experience of the operating physicians. In this work, a computer-assisted path planning system for percutaneous lung biopsy is proposed based on clinical objectives. Five constraints are presented to remove unqualified skin entry points and determine a feasible entry region based on clinical criteria. Inspired by the Pareto principle and the concept of geometric weighting, the loose-Pareto and adaptive heptagonal optimization (LPHO) method is introduced to plan the optimal puncture path. CT images of 29 patients were collected from Zigong First Peoples Hospital. Retrospective experiments and test experiments were conducted to evaluate the effectiveness of the algorithm. The planning paths obtained using the proposed method were clinically feasible for 89.7% of patients, demonstrating the applicability and robustness of the system in surgical path planning for lung biopsy.

Deciphering the modulatory role of apigenin targeting oncogenic pathways in human cancers.

Cancer is a complicated malignancy controlled by numerous intrinsic and extrinsic pathways. There has been a significant increase in interest in recent years in the elucidation of cancer treatments based on natural extracts that have fewer side effects. Numerous natural product-derived chemicals have been investigated for their anticancer effects in the search for an efficient chemotherapeutic method. Therefore, the rationale behind this review is to provide a detailed insights about the anticancerous potential of apigenin via modulating numerous cell signaling pathways. An ingestible plant-derived flavonoid called apigenin has been linked to numerous anticancerous potential in numerous experimental and biological studies. Apigenin has been reported to induce cell growth arrest and apoptotic induction by modulating multiple cell signaling pathways in a wider range of human tumors including those of the breast, lung, liver, skin, blood, colon, prostate, pancreatic, cervical, oral, and stomach. Oncogenic protein networks, abnormal cell signaling, and modulation of the apoptotic machinery are only a few examples of diverse molecular interactions and processes that have not yet been thoroughly addressed by scientific research. Thus, keeping this fact in mind, we tried to focus our review towards summarizing the apigenin-mediated modulation of oncogenic pathways in various malignancies that can be further utilized to develop a potent therapeutic alternative for the treatment of various cancers.

Treatment patterns and outcomes among patients with small-cell lung cancer (SCLC) in Europe a retrospective cohort study.

Describe characteristics, treatment patterns and clinical outcomes of patients with small-cell lung cancer (SCLC). Retrospective chart review study defining several cohorts (1) limited-stage disease (LD) SCLC initiating 1L therapy (1 L LD-SCLC), (2) extensive-stage disease (ED) SCLC initiating 1L therapy (1L ED-SCLC) and (3) patients initiating 2L therapy. 39 physicians (medical oncologists, thoracic oncologists andor pulmonologists) from France, Italy and the UK. Patients >18 years of age with a confirmed diagnosis of LD-SCLC or ED-SCLC and a full oncology medical history. Patients included initiated a 1L (2013-2015) or 2L (2013-2016) treatment (chemotherapy andor radiotherapy-RT). Overall survival (OS) and progression-free survival (PFS). 231 patients in 1L LD-SCLC, 308 in 1L ED-SCLC and 225 with relapserefractory SCLC initiating 2L treatment were included. The proportion of men was higher across all groups (56.8% to 68.5%) and mean age at time of diagnosis was 66.0 and 65.4 years in 1L LD-SCLC and 2L ED-SCLC cohorts. The majority of patients in LD-SCLC 1L group received chemotherapy with RT (76.2%). Patients initiating 2L therapy predominantly received chemotherapy alone (79.6%).Median OS in 1 L patients was 17.3 months in LD-SCLC and 8.8 months in ED-SCLC. Median PFS was 11.6 months in LD-SCLC and 6.1 months in ED-SCLC patients. Median OS in patients initiating 2L treatment was 6.6 months. OS from start of 2L treatment was lower in patients initially diagnosed with ED (5.1 months) than in patients initially diagnosed with LD (9.3 months) (p<0.0001). OS and PFS were assessed from the start of 1L or 2L therapy, depending on the cohort. Despite the availability of a high number of treatments and combinations, the prognosis of SCLC is still unsatisfactory, especially for those patients diagnosed with ED-SCLC, indicating high unmet need in this patient population.

Inflammasome-independent NLRP3 function enforces ATM activity in response to genotoxic stress.

NLRP3 is a pattern recognition receptor with a well-documented role in inducing inflammasome assembly in response to cellular stress. Deregulation of its activity leads to many inflammatory disorders including gouty arthritis, Alzheimer disease, and cancer. Whereas its role in the context of cancer has been mostly explored in the immune compartment, whether NLRP3 exerts functions unrelated to immunity in cancer development remains unexplored. Here, we demonstrate that NLRP3 interacts with the ATM kinase to control the activation of the DNA damage response, independently of its inflammasome activity. NLRP3 down-regulation in both broncho- and mammary human epithelial cells significantly impairs ATM pathway activation, leading to lower p53 activation, and provides cells with the ability to resist apoptosis induced by acute genotoxic stress. Interestingly, NLRP3 expression is down-regulated in non-small cell lung cancers and breast cancers, and its expression positively correlates with patient overall survival. Our findings identify a novel non-immune function for NLRP3 in maintaining genome integrity and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways to maintain cell integrity.

Lung cancer resection after immunochemotherapy vs. chemotherapy in oligometastatic NSCLC.

Background Neoadjuvant immunochemotherapy is currently being tested in pivotal trials for stage I-III NSCLC. The impact of immunochemotherapy in patients with oligometastastic disease remains undefined. This study aimed to compare the outcomes of radical treatment after the neoadjuvant course of immunochemotherapy versus chemotherapy. Methods We retrospectively analyzed patients with oligometastastic disease who were treated with immunochemotherapy or chemotherapy combined with local ablation of metastases and radical primary tumor resection between 2017 and 2021. Group A included eight patients with immunochemotherapy Group B included seven patients with chemotherapy. Descriptive statistical analysis included the characteristics of the patients, tumors, and outcomes. Results There was no difference in postoperative morbidity rates between the groups (p0.626). The 30-day mortality in both groups was 0%. The median overall survival for Group A was not reached, with a median follow-up time of 25 (range13-35) months the median overall survival for Group B was 26 (range5-53) months. In Group A, all patients remained alive in contrast, in Group B, four patients died (p0.026). There was no local thoracic recurrence in either group. In Group B, recurrent disease was identified significantly more often (12.5% vs. 85.75%p0.009). The rates of complete and major pathologic response were 37.5% and 0% in Group A and 42.85% and 14.25% in Group B, respectively. Conclusion Despite the small patient number and short-term results, the progression-free and overall survival in patients with oligometastastic disease after local therapy for metastases and primary tumor resection following neoadjuvant course of immunochemotherapy might be promising compared to chemotherapy.

CEMIP promotes small cell lung cancer proliferation by activation of glutamine metabolism via FBXW7c-Myc-dependent axis.

Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitroin vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation. Mechanistically, beyond as a scaffold protein, CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.

Risk Model-Based Lung Cancer Screening A Cost-Effectiveness Analysis.

In their 2021 lung cancer screening recommendation update, the U.S. Preventive Services Task Force (USPSTF) evaluated strategies that select people based on their personal lung cancer risk (risk model-based strategies), highlighting the need for further research on the benefits and harms of risk model-based screening. To evaluate and compare the cost-effectiveness of risk model-based lung cancer screening strategies versus the USPSTF recommendation and to explore optimal risk thresholds. Comparative modeling analysis. National Lung Screening Trial Surveillance, Epidemiology, and End Results program U.S. Smoking History Generator. 1960 U.S. birth cohort. 45 years. U.S. health care sector. Annual low-dose computed tomography in risk model-based strategies that start screening at age 50 or 55 years, stop screening at age 80 years, with 6-year risk thresholds between 0.5% and 2.2% using the PLCOm2012 model. Incremental cost-effectiveness ratio (ICER) and cost-effectiveness efficiency frontier connecting strategies with the highest health benefit at a given cost. Risk model-based screening strategies were more cost-effective than the USPSTF recommendation and exclusively comprised the cost-effectiveness efficiency frontier. Among the strategies on the efficiency frontier, those with a 6-year risk threshold of 1.2% or greater were cost-effective with an ICER less than $100 000 per quality-adjusted life-year (QALY). Specifically, the strategy with a 1.2% risk threshold had an ICER of $94 659 (model range, $72 639 to $156 774), yielding more QALYs for less cost than the USPSTF recommendation, while having a similar level of screening coverage (person ever-screened 21.7% vs. USPSTFs 22.6%). Risk model-based strategies were robustly more cost-effective than the 2021 USPSTF recommendation under varying modeling assumptions. Risk models were restricted to age, sex, and smoking-related risk predictors. Risk model-based screening is more cost-effective than the USPSTF recommendation, thus warranting further consideration. National Cancer Institute (NCI).

Rural Disparities in Lung Cancer-directed Surgery A Medicare Cohort Study.

The primary objective of this study was to determine the influence of rural residence on access to and outcomes of lung cancer-directed surgery for Medicare beneficiaries. Lung cancer is the leading cause of cancerrelated death in the United States and rural patients have 20% higher mortality. Drivers of rural disparities along the continuum of lung cancercare delivery are poorly understood. Medicare claims (2015-2018) were used to identify 126,352 older adults with an incident diagnosis of nonmetastatic lung cancer. Rural Urban Commuting Area codes were used to define metropolitan, micropolitan, small town, and rural site of residence. Multivariable logistic regression models evaluated influence of place of residence on 1) receipt of cancer-directed surgery, 2) time from diagnosis to surgery, and 3) postoperative outcomes. Metropolitan beneficiaries had higher rate of cancer-directed surgery (22.1%) than micropolitan (18.7%), small town (17.5%), and isolated rural (17.8%) (P < 0.001). Compared to patients from metropolitan areas, there were longer times from diagnosis to surgery for patients living in micropolitan, small, and rural communities. Multivariable models found nonmetropolitan residence to be associated with lower odds of receiving cancer-directed surgery and MIS. Nonmetropolitan residence was associated with higher odds of having postoperative emergency department visits. Residence in nonmetropolitan areas is associated with lower probability of cancer-directed surgery, increased time to surgery, decreased use of MIS, and increased postoperative ED visits. Attention to timely access to surgery and coordination of postoperative care for nonmetropolitan patients could improve care delivery.

Principles of Lung Cancer Metastasis to Brain.

Lung cancer is a disease associated with significant morbidity and mortality on a global setting. This form of cancer commonly gives raise to metastatic lesions the brain, which can further worsen outcomes. In this focused review, we discuss an overview of lung cancers that metastasize to the brain known risk factors means of detection and diagnosis and options for treatment including a comparison between surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy. These interventions are still being assessed by clinical trials and continue to be modified through evidence-based practice.

The pulmonary surgical apgar score for lung cancer surgery predicts postoperative complications and long-term survival.

The surgical Apgar score, calculated using three intraoperative variables (blood loss, lowest mean arterial pressure, and lowest heart rate), is associated with mortality in cancer surgery. The original score has less applicability in lung cancer surgery therefore, we innovated the modified pulmonary surgical Apgar score with additional intraoperative oxygen saturation representing pulmonary parenchymal damage and cardiopulmonary dynamics. We retrospectively analyzed the data of 691 patients who underwent surgery for primary lung cancer between 2015 and 2019 at a single institute. We analyzed the utility of the pulmonary surgical Apgar score compared with the original surgical Apgar score. Postoperative complications were observed in 57 (8.2%) and seven (1.0%) of the 691 patients who were stratified as grade ≥III and V, respectively, according to the Clavien-Dindo classification. We compared the fitness of the score in predicting postoperative complications the calculated c-index (0.622) was slightly higher than the original c-index (0.604 P 0.398). Patients were categorized into three groups based on their scores as follows 0-6 points (n 59), 7-9 points (n 420), and 10-12 points (n 212). Univariable and multivariable analyses demonstrated that a lower score was an independent negative risk factor for postoperative complications (odds ratio, 3.53 P 0.02). Patients with lower scores had a considerably poor 5-year overall survival (64.6%) (P 0.07). The pulmonary surgical Apgar score predicts postoperative complications and long-term survival in patients with lung cancer undergoing surgery and may be utilized for postoperative management.

Two new sarasinosides from marine sponge

Two new sarasinosides designated as 5,8-epoxysarasinoside (

Feiyiliu Mixture sensitizes EGFR

Single-cell analysis reveals the COL11A1

Combinational antitumor strategies of exosomes as drug carriers Mini review.

Cancer therapies have made tremendous progress in the last decade, but monotherapy still has apparent limitations and lacks therapeutic efficacy. Thus, the simultaneous administration of multiple drugs has been widely explored and has shown better outcomes. Exosomes, deriving from almost all living cells, are natural nanocarriers designed to deliver drugs to tumor sites. Therefore, combinational antitumor therapies based on exosomes, such as engineered exosomes and different combinations of chemotherapeutic agents, therapeutic nucleic acids, photosensitizers, immunotherapy and phytochemicals, have considerable prospects and potential for clinical translation. Here, we summarize current strategies of cancer combination therapy in exosomes and propose opportunities and challenges in the future.

ABI3BP is a prognosis biomarker related with clinicopathological features and immunity infiltration of lung tumor.

Dysregulated lipid metabolism in lymphangioleiomyomatosis pathogenesis as a paradigm of chronic lung diseases.

A chronic inflammatory condition characterizes various lung diseases. Interestingly, a great contribution to inflammation is made by altered lipids metabolism, that can be caused by the deregulation of the mammalian target of rapamycin complex-1 (mTORC1) activity. There is evidence that one of mTOR downstream effectors, the sterol regulatory element-binding protein (SREBP), regulates the transcription of enzymes involved in the

Perioperative systemic therapies for non-small-cell lung cancer Recent advances and future perspectives.

The mainstay of treatment for early-stage non-small-cell lung cancer (NSCLC) is surgical resection. Traditionally, chemotherapy has been used perioperatively in locally extensive disease to improve the oncologic outcomes of surgery, with a 5-year absolute survival benefit of approximately 5%. In recent years, immunotherapy and molecular targeted therapy have shown excellent results in the treatment of locoregionally advanced and metastatic NSCLC, replacing chemotherapy as first-line treatment in certain cases. Consequently, researchers have been increasingly investigating the use of immunotherapy or targeted therapy in combination with surgery for the treatment of early-stage disease. This growing research interest has resulted in several published and ongoing studies of various size and design. In this mini review, we provide a succinct and up-to-date overview of recently published, phase 3 randomized clinical trials on adjuvant and neoadjuvant immunotherapy or targeted therapy for NSCLC. We subsequently discuss some important unresolved clinical issues, including the optimal duration of treatment, scheduling with respect to surgery, and potential combinations of different systemic therapies. Finally, we reference large, randomized, phase 3 studies that are currently in progress and may give answers to those and other clinical questions.

Case Report A papillary thyroid microcarcinoma patient with skip lymph node metastasis and multiple distant metastasis.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Papillary thyroid microcarcinoma (PTMC) is defined as PTC with a diameter less than 1 centimeter. Most lymph nodes of PTC patients have metastasized to the central neck, and a few lymph nodes have metastasized to the lateral neck. Skip lymph node metastasis, that is, lateral cervical lymph node metastasis without central lymph node metastasis, is even less common. Additionally, distant metastasis of PTMC is also rare, mainly occurring in the lung and bone. Here, we reported a case of PTMC patient with skip lymph node metastasis and multiple distant metastasis. The patient presented with a huge shoulder mass and the primary tumor was found to originate from the thyroid. However, the patient only suffered with PTMC

Outcome following nivolumab treatment in patients with advanced non-small cell lung cancer and comorbid interstitial lung disease in a real-world setting.

Up to 10% of patients with advanced non-small cell lung cancer (aNSCLC) have pre-existing interstitial lung disease (ILD). These patients are usually excluded from immunotherapy clinical trials. Consequently, knowledge on outcomes following nivolumab treatment in these patients remains limited. The primary objective of this study was to evaluate survival outcome following nivolumab treatment in ILD patients with pre-treated aNSCLC in the real-world setting. The study included all patients with aNSCLC recorded in the French hospital database, starting nivolumab in 2015-2016. Patients were stratified by pre-existing ILD and three subgroups were studied auto-immune or granulomatous (AIG) ILD, other known causes ILD and idiopathic ILD. Time to discontinuation of nivolumab treatment time to treatment duration (TTD) and overall survival (OS) were estimated using Kaplan-Meier survival analysis. Of 10,452 aNSCLC patients initiating nivolumab, 148 (1.4%) had pre-existing ILD. Mean age at nivolumab initiation was 64.6 ± 9.4 years in ILD and 63.8 ± 9.6 years in non-ILD. Compared to non-ILD, patients in the ILD group were more frequently men ( In this large cohort of aNSCLC patients with ILD, outcomes are similar to those obtained in the non-ILD population. Immunotherapy could be beneficial for these patients.

Long Noncoding RNA LINC01426 Sequesters microRNA-519d-5p to Promote Non-Small Cell Lung Cancer Progression by Increasing ETS1 Expression Retraction.

This retracts the article DOI 10.2147CMAR.S277113..

LncRNA

Non-coding RNA played one pivotal role in NSCLC in terms of pathogenesis and progression. We aimed to determine the LncRNA, which can be one new potential target for NSCLC treatment and its possible mechanisms from Jan 2017 to Aug 2020. Gene An axis of lncRNA

Combined analysis of gut microbiome and serum metabolomics reveals novel biomarkers in patients with early-stage non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer and is one of the most fatal cancers worldwide. Recently, the International Association for the Study of Lung Cancer (IASLC) proposed a novel grading system based on the predominant and high-grade histological patterns for invasive pulmonary adenocarcinoma (IPA). To improve outcomes for NSCLC patients, we combined serum metabolomics and fecal microbiology to screen biomarkers in patients with early-stage NSCLC and identified characteristic microbial profiles in patients with different grades of IPA. 26 genera and 123 metabolites were significantly altered in the early-stage NSCLC patients.

Inheritance and innovation of the diagnosis of peripheral pulmonary lesions.

As the leading cause of cancer-related deaths worldwide, early detection and diagnosis are crucial to reduce the mortality of lung cancer. To date, the diagnosis of the peripheral pulmonary lesions (PPLs) remains a major unmet clinical need. The urgency of diagnosing PPLs has driven a series of development of the advanced bronchoscopy-guided techniques in the past decades, such as radial probe-endobronchial ultrasonography (RP-EBUS), virtual bronchoscopy navigation (VBN), electromagnetic navigation bronchoscopy (ENB), bronchoscopic transparenchymal nodule access (BTPNA), and robotic-assisted bronchoscopy. However, these techniques also have their own limitations. In this review, we would like to introduce the development of diagnostic techniques for PPLs, with a special focus on biopsy approaches and advanced guided bronchoscopy techniques by discussing their advantages, limitations, and future prospects.

Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach.

The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic small molecules could pave the way for the development of a new cancer therapeutic pathway. Using multiple linear regression (MLR)-quantitative structure-activity relationship (QSAR) and artificial neural network (ANN)-QSAR modeling techniques, we look at the quantitative relationship between the biological inhibitory activity of 40 small molecules derived from cyclohexane-1,3-dione and their topological, physicochemical, and electronic properties against NSCLC cells. In this regard, screening methods based on QSAR modeling with density-functional theory (DFT) computations, in silico pharmacokineticpharmacodynamic (ADME-Tox) modeling, and molecular docking with molecular electrostatic potential (MEP) and molecular mechanics-generalized Born surface area (MM-GBSA) computations were used. Using physicochemical (stretch-bend, hydrogen bond acceptor, Connolly molecular area, polar surface area, total connectivity) and electronic (total energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels) molecular descriptors, compound

Intracranial Remote Metastasis from Adenoid Cystic Cancer of Parotid Gland Case Report and Review of Literature.

Adenoid cystic carcinoma is rare, locally aggressive salivary gland tumor. It has indolent course, multiple local recurrences and delayed distant metastasis in lung, bone, liver and soft tissues which are detected up to a maximum of 5.5 years after local-regional resection of the primary tumor. Intracranial remote metastasis of ACCs is extremely rare, and very few cases have been reported in the literature. Here we report a rare case of intracranial remote metastasis of ACC of the parotid gland developed after 15 years of primary curative surgery, emphasizing long term follow up on these cases.

Identification of novel biomarkers for lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second most common subtype of lung cancer, accounting for a majority of lung cancer-related deaths. Detection or diagnosis of cancer at an early stage is an unmet clinical need that is being actively explored. In this study, we aimed to identify potential biomarkers for LUSC, by screening expression status of all human genes against LUSC patient samples available with The Cancer Genome Atlas (TCGA). This led to the identification of several genes that are upregulated in LUSC. Further analysis revealed that many of these genes also show higher expression at the protein level not only in lung cancer but also in other cancers. Additionally, some of these genes show stage-dependent higher expression and are associated with statistically significant poor survival of LUSC patients. As per our results, more than 60 genes are overexpressed in LUSC at the level of mRNA and some at the protein level. Thus, we identified genes such as The online version contains supplementary material available at 10.1007s13205-023-03489-z.

Prognosis comparison between small cell carcinoma of ovary and high-grade serous ovarian cancer A retrospective observational cohort study.

Small cell carcinoma of ovary (SCCO) is a rare and aggressive cancer primarily reported in the form of case reports. Due to limited epidemiological and prognostic analyses based on large populations, SCCO has varied considerably without prognostic models and a recognized first-line treatment strategy. The study aimed to compare the clinical characteristics, treatment methods, and prognosis of SCCO and high-grade serous ovarian cancer (HGSOC), the most prevalent subtype of ovarian cancer, in a large sample and develop a predictive model for these two subtypes. Data from the Surveillance, Epidemiology, and End Results program were analyzed for patients with SCCO or HGSOC from 2000 to 2017. Clinical, demographic, and treatment characteristics were compared between the two groups. Propensity-score matching, Cox risk regression analysis, and Kaplan-Meier survival curves were used to assess the data. Finally, a nomogram was developed to predict the patient survival time. A total of 32,185 women, including 31,979 (99.4%) diagnosed with HGSOC and 206 (0.6%) diagnosed with SCCO, were identified. Age ≤ 51 years, single, median house income less than $70,000, early stage, and unilateral disease were more common characteristics of patients with SCCO than those with HGSOC. Patients with SCCO were more likely to receive radiotherapy (6.8% vs. 0.8%, p <0.001) and have tumors ≥ 141 mm (38.3% vs. 9.7%, p <0.001) than patients with HGSOC. The independent risk factors for SCCO patients included older age at diagnosis, advanced stage, surgery, radiotherapy, chemotherapy, larger tumor size, and bilateral tumor. Overall and cancer-specific survival rates were significantly lower for SCCO than more malignant HGSOC. Prognostic models and nomograms had been constructed to predict the individual survival rates of patients with SCCO and HGSOC. Patients with SCCO presented with the early-stage disease more frequently than patients with HGSOC and had decreased overall and cancer-specific survival rates.

Exosome-based cancer vaccine for prevention of lung cancer.

Our earlier work has shown that a unique stem cell-based vaccine that comprises of murine embryonic stem cells (ESCs) and murine fibroblasts expressing the immunostimulant granulocyte-macrophage colony stimulating factor (GM-CSF) successfully protects mice from the outgrowth of an implantable form of murine lung cancer. The use of live ESCs raises the potential risks of inducing teratomas and autoimmunity. We have attempted to improve the safety and utility of this prophylactic vaccine by employing exosomes derived from murine ESCs engineered to produce GM-CSF (ES-exoGM-CSF vaccine). We have previously reported that ES-exoGM-CSF immunization does protect mice from the outgrowth of an implantable form of murine lung cancer. Here, we have investigated the cancer prevention efficacy of ES-exoGM-CSF vaccine in an experimental metastasis model of murine lung cancer, in which Lewis lung carcinoma (LLC) cells were administered into female C57BL6 mice (8 weeks of age) through tail vein injection and subsequently LLC tumors were established in lungs. Our objective is to test the anti-cancer efficacy of ES-exoGM-CSF vaccine in a mouse model of metastatic lung cancer. Our studies indicate that vaccination of mice with ES-exoGM-CSF vaccine inhibited the growth of metastatic lung tumors. ES-exoGM-CSF vactionation reduced lung tumor burden from 1.86% in non-vaccinated, LLC-challenged mice to 0.036% in corresponding vacinnated mice. Importantly, control exosomes without GM-CSF failed to provide protection against metastasized pulmonary tumors. The efficacy of ES-exoGM-CSF vaccination was associated with a decrease in the frequencies of tumor-infiltrating immunosuppressive immune cells, including T regulatory cells, myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages, as well as an increase in effector cytokine production from intra-tumoral CD8 Overall, our research provides a novel strategy for developing a cell-free prophylactic vaccine against lung tumors.

LncRNA LINC01833 is a Prognostic Biomarker and Correlates with Immune Infiltrates in Patients with Lung Adenocarcinoma by Integrated Bioinformatics Analysis.

Due to the absence of accurate tools for early detection and successful treatment, lung adenocarcinoma (LUAD) is one of the most aggressive tumors with high morbidity and mortality globally. It is absolutely necessary to investigate the process behind its development and search for new biomarkers that could aid in the early detection of LUAD. There is a correlation between the immune microenvironment of the tumor and the prognosis of lung cancer as well as the efficacy of immunotherapy. Long noncoding RNAs (lncRNAs) have been identified as potential prognostic biomarkers linked to immunological activities. In this study, we identified 1 downregulated lncRNA and 76 upregulated lncRNAs in LUAD samples from TCGA datasets. Among the 77 dysregulated lncRNAs, our attention focused on lncRNA LINC01833 (LINC01833). When compared with nontumor specimens, the level of expression of LINC01833 was shown to be significantly elevated in LUAD samples. In addition, the data of the ROC study revealed that LUAD patients with high LINC01833 expression had an AUC value of 0.840 (95% confidence interval 0.804 to 0.876). There was a correlation between high LINC01833 expression and an advanced clinical stage. Patients who had a high expression of LINC01833 were shown to have a lower overall survival rate (

Dietary patterns and breast cancer risk, prognosis, and quality of life A systematic review.

Statistics indicate that the morbidity of breast cancer is increasing globally, and its (overall figures) incidence has now surpassed that of lung cancer for the first time. The relation between a whole dietary pattern, rather than of a single food or nutrient, and breast cancer (BC) should be examined for findings to capture the complexities of diet and the potential for synergism between dietary components. Hence, the effects of dietary patterns on breast cancer have recently attracted increasing attention. To systematically review the effects of dietary patterns on breast cancer risk, prognosis, and quality of life in survivors. This systematic review was conducted following PRISMA guidelines and was registered in PROSPERO. Data from Ovid, China Biomedical Literature Database, Wanfang Data Knowledge Service Platform, CNKI, PubMed, Weipu, The Cochrane Library, Duxiu Data, ProQuest, Embase, Web of Science, and Scopus Database were retrieved and evaluated. A total of 47 studies that investigated the association between eating patterns and breast cancer were identified. Ten studies evaluated the effect of the model on treatment outcome and prognosis of breast cancer and two cross-sectional studies examined the influence of dietary patterns on quality of life. The resulting favorable dietary patterns were shown to regulate metabolic biomarkers, antioxidants, anti-inflammatory agents, and protective genes, and inhibit cell proliferation and invasion. Numerous studies have examined the effects of healthy eating, plant-based, anti-inflammation, low-fat, and other favorable dietary patterns in relation to breast cancer. However, few studies reported significant associations and the studies had limitations, suggesting that the current findings should be interpreted with caution. httpswww.crd.york.ac.ukprospero, CRD4202 2350171.

Exploration of the Long Noncoding RNAs Involved in the Crosstalk between M2 Macrophages and Tumor Metabolism in Lung Cancer.

Complex regulation exists between tumor metabolism and M2 macrophages. Long noncoding RNAs (lncRNAs) are famous for their wide regulatory role. This study aimed to identify the lncRNAs involved in the crosstalk between tumor metabolism and M2 macrophages. The Cancer Genome Atlas was responsible for the public data. R software was responsible for the analysis of public data. Based on the input expression profile, we quantified the M2 macrophage infiltration using the CIBERSORT algorithm and found that M2 macrophages were a risk factor for lung cancer. Also, we found that M2 macrophages were correlated with multiple metabolism pathways. Then, 67 lncRNAs involved in both M2 macrophages and related metabolism pathways were identified. A prognosis signature based on AC027288.3, AP001189.3, FAM30A, GAPLINC, LINC00578, and LINC01936 was established, which had good prognosis prediction ability. The clinical parameters and risk score were combined into a nomogram plot for better prediction of the patients prognosis. A high fit of actual survival and nomogram-predicted survival was found using the calibration plot. Moreover, in low-risk patients, immunotherapy was more effective, while cisplatin and docetaxel were more effective in high-risk patients. Biological enrichment analysis indicated pathways of notch signaling, TGF- Our result can provide new insights into the interaction between M2 macrophages and tumor metabolism, as well as the involved lncRNAs, which can provide the direction for future studies.

Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early‑stage lung cancer.

The early diagnosis of lung cancer is closely associated with the decline of mortality. A panel consisting of seven lung cancer-related autoantibodies (7-AABs) has been shown to be a reliable and specific indicator for the early detection of lung cancer, with a specificity of 90% and a positive predictive value of 85%. However, its low sensitivity and negative predictive value limit its wide application. To improve its diagnostic value, the diagnostic efficiencies of 7-AABs in combination with non-specific tumor markers were retrospectively investigated for the detection of early-stage lung cancer. A total of 217 patients with small lung nodules who presented with ground-glass opacity or solid nodules as well as 30 healthy controls were studied. The concentrations of 7-AABs and heat shock protein 90a (HSP90a) were assessed using ELISA. Automated flow fluorescence immune analysis was used for the assessment of CEA, CYFRA21-1, CA199 and CA125 levels. The results showed that 7-AABs HSP90a possessed a remarkably improved diagnostic efficiency for patients with small pulmonary nodules or for patients with lung nodules of different types, which suggested that 7-AABs in combination with HSP90a could have a high clinical value for the improvement of the diagnostic efficiency of early-stage lung cancer.

Retracted Effects of the Training of Aerobic Function on Clinical Symptoms and Quality of Life in Patients with Medium and Advanced Lung Cancer.

This retracts the article DOI 10.115520226753959..

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes.

Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an

Efficacy of immunotherapy in

Immunotherapy has improved the clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC). However, in patients with Kirsten rat sarcoma viral oncogene homolog ( In this retrospective cohort study, we extracted the clinical, molecular, and pathologic data from the electronic health records of patients with advanced Between January 2018 and November 2020, 793 patients were identified with stage IIIB-IV NSCLC and a total of 122 patients with In the Chinese population of patients with

Functional and postoperative outcomes after high-intensity interval training in lung cancer patients A systematic review and meta-analysis.

The study evaluated the effects of high-intensity interval training (HIIT) on postoperative complications and lung function in patients with lung cancer compared to usual care. We searched electronic databases in April 2022, including PubMed, Embase, the Cochrane Library, Web of Science, and the China National Knowledge Infrastructure (CNKI). Two authors independently applied the Cochrane Risk of Bias tool to assess the quality of RCTs. The postoperative complications, length of hospitalization, and cardiopulmonary functions from the studies were pooled for statistical analysis. A total of 12 randomized controlled trials were eligible for inclusion and were conducted in the meta-analysis. HIIT significantly increased VO HIIT may enhance VO PROSPERO, CRD42022335441.