Non-invasive prediction for pathologic complete response to neoadjuvant chemoimmunotherapy in lung cancer using CT-based deep learning: a multicenter study.

Neoadjuvant chemoimmunotherapy has revolutionized the therapeutic strategy for non-small cell lung cancer (NSCLC), and identifying candidates likely responding to this advanced treatment is of important clinical significance. The current multi-institutional study aims to develop a deep learning model to predict pathologic complete response (pCR) to neoadjuvant immunotherapy in NSCLC based on computed tomography (CT) imaging and further prob the biologic foundation of the proposed deep learning signature. A total of 248 participants administrated with neoadjuvant immunotherapy followed by surgery for NSCLC at Ruijin Hospital, Ningbo Hwamei Hospital, and Affiliated Hospital of Zunyi Medical University from January 2019 to September 2023 were enrolled. The imaging data within 2 weeks prior to neoadjuvant chemoimmunotherapy were retrospectively extracted. Patients from Ruijin Hospital were grouped as the training set (n = 104) and the validation set (n = 69) at the 6:4 ratio, and other participants from Ningbo Hwamei Hospital and Affiliated Hospital of Zunyi Medical University served as an external cohort (n = 75). For the entire population, pCR was obtained in 29.4% (n = 73) of cases. The areas under the curve (AUCs) of our deep learning signature for pCR prediction were 0.775 (95% confidence interval [CI]: 0.649 - 0.901) and 0.743 (95% CI: 0.618 - 0.869) in the validation set and the external cohort, significantly superior than 0.579 (95% CI: 0.468 - 0.689) and 0.569 (95% CI: 0.454 - 0.683) of the clinical model. Furthermore, higher deep learning scores correlated to the upregulation for pathways of cell metabolism and more antitumor immune infiltration in microenvironment. Our developed deep learning model is capable of predicting pCR to neoadjuvant chemoimmunotherapy in patients with NSCLC.

[18F]FDG PET-CT radiomics signature to predict pathological complete response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer: a multicenter study.

OBJECTIVES: This study aims to develop and validate a radiomics model based on 18F-fluorodeoxyglucose positron emission tomography-computed tomography ([18F]FDG PET-CT) images to predict pathological complete response (pCR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: One hundred eighty-five patients receiving neoadjuvant chemoimmunotherapy for NSCLC at 5 centers from January 2019 to December 2022 were included and divided into a training cohort and a validation cohort. Radiomics models were constructed via the least absolute shrinkage and selection operator (LASSO) method. The performances of models were evaluated by the area under the receiver operating characteristic curve (AUC). In addition, genetic analyses were conducted to reveal the underlying biological basis of the radiomics score. RESULTS: After the LASSO process, 9 PET-CT radiomics features were selected for pCR prediction. In the validation cohort, the ability of PET-CT radiomics model to predict pCR was shown to have an AUC of 0.818 (95% confidence interval [CI], 0.711, 0.925), which was better than the PET radiomics model (0.728 [95% CI, 0.610, 0.846]), CT radiomics model (0.732 [95% CI, 0.607, 0.857]), and maximum standard uptake value (0.603 [95% CI, 0.473, 0.733]) (p < 0.05). Moreover, a high radiomics score was related to the upregulation of pathways suppressing tumor proliferation and the infiltration of antitumor immune cell. CONCLUSION: The proposed PET-CT radiomics model was capable of predicting pCR to neoadjuvant chemoimmunotherapy in NSCLC patients. CLINICAL RELEVANCE STATEMENT: This study indicated that the generated 18F-fluorodeoxyglucose positron emission tomography-computed tomography radiomics model could predict pathological complete response to neoadjuvant chemoimmunotherapy, implying the potential of our radiomics model to personalize the neoadjuvant chemoimmunotherapy in lung cancer patients. KEY POINTS: • Recognizing patients potentially benefiting neoadjuvant chemoimmunotherapy is critical for individualized therapy of lung cancer. • [18F]FDG PET-CT radiomics could predict pathological complete response to neoadjuvant immunotherapy in non-small cell lung cancer. • [18F]FDG PET-CT radiomics model could personalize neoadjuvant chemoimmunotherapy in lung cancer patients.

Characterization of fatty acid metabolism-related lncRNAs in lung adenocarcinoma identifying potential novel prognostic targets.

Lung adenocarcinoma (LUAD), a malignant respiratory tumor with an extremely poor prognosis, has troubled the medical community all over the world. According to recent studies, fatty acid metabolism (FAM) and long non-coding RNAs (lncRNAs) regulation have shown exciting results in tumor therapy. In this study, the original LUAD patient data was obtained from the TCGA database, and 12 FAM-related lncRNAs (AL390755.1, AC105020.6, TMPO-AS1, AC016737.2, AC127070.2, LINC01281, AL589986.2, GAS6-DT, AC078993.1, LINC02198, AC007032.1, and AL021026.1) that were highly related to the progression of LUAD were finally identified through bioinformatics analysis, and a risk score model for clinical reference was constructed. The window explores the immunology and molecular mechanism of LUAD, aiming to shed the hoping light on LUAD treatment.

A novel LUAD prognosis prediction model based on immune checkpoint-related lncRNAs.

Lung adenocarcinoma (LUAD) is a malignant disease with an extremely poor prognosis, and there is currently a lack of clinical methods for early diagnosis and precise treatment and management. With the deepening of tumor research, more and more attention has been paid to the role of immune checkpoints (ICP) and long non-coding RNAs (lncRNAs) regulation in tumor development. Therefore, this study downloaded LUAD patient data from the TCGA database, and finally screened 14 key ICP-related lncRNAs based on ICP-related genes using univariate/multivariate COX regression analysis and LASSO regression analysis to construct a risk prediction model and corresponding nomogram. After multi-dimensional testing of the model, the model showed good prognostic prediction ability. In addition, to further elucidate how ICP plays a role in LUAD, we jointly analyzed the immune microenvironmental changes in LAUD patients and performed a functional enrichment analysis. Furthermore, to enhance the clinical significance of this study, we performed a sensitivity analysis of common antitumor drugs. All the above works aim to point to new directions for the treatment of LUAD.

Sintilimab plus chemotherapy achieved symptom relief in stage IV lung squamous cell carcinoma with superior vena cava syndrome: a case report.

Lung cancer is the second most common and mortality disease in the world. Most patients with lung cancer are already at the advanced stage when diagnosed. There are multiple treatments for advanced lung cancer. Among them, immunotherapy plus chemotherapy has gradually become the first-line treatment. Lung cancer has multiple complications, superior vena cava syndrome (SVCS) is a common complication of patients with advanced lung cancer. The current treatments include radiotherapy, chemotherapy, and stent implantation. Stent implantation has the disadvantages of invasiveness and poor efficacy. Immunotherapy, as an emerging treatment for tumors, has shown significant advantages in treating patients with advanced lung cancer. However, the treatment of advanced lung cancer with SVCS using immunotherapy has rarely been reported. Here, we reported a 48-year-old male patient with stage IV (T4N3M1) lung squamous cell carcinoma. After receiving 1 cycle (3 weeks) of comprehensive treatment with sintilimab plus chemotherapy, the tumor mass shrank by 30% to achieve partial response (PR), collateral circulation was formed, and most of the symptoms caused by SVCS disappeared. After 3 cycles of treatment, the tumor shrank by nearly 90%, and the superior and inferior vena cava opened larger than before. Our case provides a novel treatment strategy for such patients.

Characterization of the metabolites of trans-resveratrol-3-O-glucoside in monkeys and dogs.

In this study, a liquid chromatography-tandem multi-stage mass spectrometry (LC/MSn) method was established to characterize the metabolites of TRG in monkeys and dogs. A total of seven metabolites of TRG besides the prototype were found, which were identified as TR (M1), TRN (M2), trans-resveratrol-4'-O-glucuronide (M2'), trans-resveratrol-3-O-glucoside-4'-O-glucuronide (M3), trans-resveratrol-3-O-glucoside-5-O-glucuronide (M3'), trans-resveratrol-3-sulfate (M4) and trans-resveratrol-4'-sulfate (M4'). Additionally, the metabolic pathways of TRG in monkeys and dogs were proposed. There were also species differences of metabolism of TRG between monkeys and dogs.

Screening and evaluation of the role of immune genes of brain metastasis in lung adenocarcinoma progression based on the TCGA and GEO databases.

BACKGROUND: Brain metastasis was one of the factors leading to the poor long-term prognosis of patients with lung adenocarcinoma (LUAD). METHODS: The expression levels of immune genes in LUAD and LUAD brain metastases tissues were analyzed in GSE161116 dataset using the GEO2R, and the levels of differential immune genes in normal lung and LUAD tissues were verified. The biological functions and signaling mechanisms of the differential immune genes were explored via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Cox regression analysis was used to screen the prognostic factors of LUAD patients, and a risk model was constructed. The role of the model was checked in the development of LUAD via receiver operating characteristic analysis, gene set enrichment analysis, and Cox regression analysis. RESULTS: Differentially expressed genes (DEGs) in brain metastasis were involved in the adaptive immune response, B cell differentiation, leukocyte migration, NF-kB signaling pathway, among others. The expression levels of TNFRSF11A, MS4A2, IL11, CAMP, MS4A1, and F2RL1 were independent factors affecting the poor prognosis of LUAD patients via Cox regression analysis and Akaike information criterion. In the constructed risk model, the overall survival of LUAD patients in the high-risk group was poor. The risk model was significantly related to the gender, clinical stage, T stage, lymph node metastasis, and survival status of LUAD patients. In addition, the risk model score was an independent risk factor that affected the poor prognosis of LUAD patients. TNFRSF11A, CAMP, F2RL1, IL11, MS4A1, and MS4A2 of the risk factors had diagnostic significance in LUAD brain metastasis and LUAD. The risk model participated in cytokinetic process, cell cycle, citrate cycle TCA cycle, etc. The risk model score was correlated with the levels of B cells memory, mast cells resting, macrophages M0, mast cells activated, neutrophils, eosinophils, T cells gamma delta, and immune cell markers. CONCLUSIONS: The risk model based on the LUAD brain metastasis immune factors TNFRSF11A, MS4A2, IL11, CAMP, MS4A1, and F2RL1 was related to the diagnosis, poor prognosis, and immune infiltrating cells of LUAD patients, and is expected to provide a reference for the development of treatment strategies for LUAD patients.

Porcupine inhibitor LGK­974 inhibits Wnt/ß­catenin signaling and modifies tumor­associated macrophages resulting in inhibition of the malignant behaviors of non­small cell lung cancer cells.

Tumor­associated macrophages (TAMs) are critical components of the tumor microenvironment that are tightly associated with malignancies in human cancers, including lung cancer. LGK­974, a small molecular inhibitor of Wnt secretion, was reported to block Wnt/ß­catenin signaling and exert anti­inflammatory effects by suppressing pro­inflammatory gene expression in cancer cells. Although it was reported that Wnt/ß­catenin was critical in regulating TAMs, it is still largely unknown whether LGK­974 regulates tumor malignancies by regulating TAMs. The present study firstly verified that the polarization of TAMs was regulated by LGK­974. LGK­974 increased M1 macrophage functional markers and decreased M2 macrophage functional markers. The addition of Wnt3a and Wnt5a, two canonical Wnt signaling inducers, reversed the decrease in M1 macrophage functional markers, including mannose receptor, IL­10 and Arg1, by activating Wnt/ß­catenin signaling. Conditioned medium from LGK­974­modified TAMs inhibited the malignant behaviors in A549 and H1299 cells, including proliferation, colony formation and invasion, by blocking Wnt/ß­catenin signaling. LGK­974­modified TAMs blocked the cell cycle at the G1/G0 phase, which was reversed by the addition of Wnt3a/5a, indicating that LGK­974 regulates the microenvironment by blocking Wnt/ß­catenin signaling. Taken together, the results indicate that LGK­974 indirectly inhibited the malignant behaviors of A549 and H1299 cells by regulating the inflammatory microenvironment by inhibiting Wnt/ß­catenin signaling in TAMs.

Evaluation of clinical value and potential mechanism of MTFR2 in lung adenocarcinoma via bioinformatics.

BACKGROUND: Mitochondrial fission regulator 2 (MTFR2) was involved in the progression and development of various cancers. However, the relationship between MTFR2 with lung adenocarcinoma (LUAD) had not been reported. Herein, this study analyzed the clinical significance and potential mechanisms of MTFR2 in LUAD via bioinformatics tools. RESULTS: We found that the level of MTFR2 was increased, and correlated with sex, age, smoking history, neoplasm staging, histological subtype and TP53 mutation status in LUAD patients. Kaplan-Meier survival analysis showed LUAD patients with increased MTFR2 had a poor prognosis. In addition, univariate COX regression analysis showed neoplasm staging, T stage, distant metastasis and MTFR2 level were risk factors for the prognosis of LUAD. A total of 1127 genes were coexpressed with MTFR2, including 840 positive and 208 negative related genes. KEGG and GSEA found that MTFR2 participated in the progression of LUAD by affecting cell cycle, DNA replication, homologous recombination, p53 signaling pathway and other mechanisms. The top 10 coexpressed genes, namely CDK1, CDC20, CCNB1, PLK1, CCNA2, AURKB, CCNB2, BUB1B, MAD2L1 and BUB1 were highly expressed, and were associated with poor prognosis in LUAD. CONCLUSIONS: Consequently, we elucidated MTFR2 was a biomarker for diagnosis and poor prognosis in LUAD, and might participate in the progression of LUAD via affecting cell cycle, DNA replication, homologous recombination and p53 signaling pathway.

Bilateral secondary pulmonary tuberculosis complicated with bilateral chylothorax: a case report.

A 26-year-old female was admitted to the emergency department of thoracic surgery complaining of chest tightness, shortness of breath, and a history of bilateral tuberculosis. A chest Computed Tomography (CT) scan showed bilateral pleural effusion. After that, the patient was implanted with bilateral intercostal drainage tubes. Further analysis of the pleural effusion was conducted to confirm the diagnosis of bilateral chylothorax. We initiated conservative treatment consisting of fasting and total parenteral nutrition. After the failure of conservative treatment, the patient underwent ligation of the thoracic duct by right-sided thoracotomy combined with talc slurry. On the first day postoperatively, the right pleural effusion had decreased significantly, while the left pleural effusion had not. Subsequently, talc slurry was injected into the left thoracic drainage tube of the patient. Bilateral pleural effusion was significantly reduced. Re-examination chest X-ray showed the disappearance of pleural effusion, and the patient was discharged good healthy. Chest X-rays were reexamined one month postoperatively, and the patient's lung was well dilated, with no recurrence of pleural effusion. In this case, it was shown that conservative treatment is the first choice for chylothorax. However, if this proves to be ineffective, early surgical treatment should be considered. Early diagnosis and timely surgical intervention are the key factors to improve the prognosis of patients.

Thoracic endometriosis: a case report and review of the literature.

Thoracic endometriosis is characterized by the presence of normal functioning endometrial tissues in normal pleural, diaphragm, or lung parenchyma, and main clinical symptoms include pneumothorax, menstrual hemothorax, menstrual hemoptysis, and pulmonary nodules. Chest X-ray (CXR), computed tomography (CT), magnetic resonance imaging (MRI), bronchoscopy, and surgical biopsy could be applied to the diagnosis of TE. Both drug therapy and surgical treatment were widely used to treat this disease, but no theory was used to guide the choice of treatment options. This paper introduces a case of menstrual hemoptysis due to endometriosis, and the final surgical treatment was chosen. The patient recovered well postoperatively and reported no hemoptysis during 2 months of follow-up. Reexamination of the chest through CT showed no ground-glass lesions or pulmonary exudative lesions. We make the following recommendations for patient selection when considering a surgical approach to the treatment of TE. Patients for whom surgery should be considered are those who (I) do not respond to drug therapy or relapse once drug therapy is withdrawn, (II) cannot tolerate drug therapy or who may wish to get pregnant in the near future (III) have limited lesions which are able to be completely removed during surgery. Patients in whom surgery is not recommended include those who have extensive lesions which cannot be surgically removed, including those with diaphragm or pleural involvement as the diseased tissues must be completely removed to avoid recurrence, and those who are unfit for surgery.

Compression of superior vena cava and azygos vein by a giant mediastinal mature cystic teratoma: a case report.

Teratoma is a common type of mediastinal tumor, often located in the anterior mediastinum. Mediastinal teratomas often occur in young and middle-aged people, and account for 5-21.5% of mediastinal tumors. Mature cystic teratoma is a common type of mediastinal teratoma, its onset is slow, and most patients are asymptomatic. In a few patients, the tissue around the mediastinum is invaded or there is malignant transformation, which results in chest pain, chest tightness, a cough, and other symptoms. In this case, the patient had a giant teratoma, compressing large blood vessels and nerves, complicated by pleural and pericardial effusion. The 21-year-old female patient was misdiagnosed with tuberculous disease because of chronic cough and expectoration. Her initial symptoms improved after anti-tuberculosis treatment; however, an imaging examination showed that the lesion had enlarged some 9 months later. Surgery was performed at our hospital, as the tumor was squeezing blood vessels, and the trachea was seriously adhering to the surrounding tissue. To avoid damage to the peripheral blood vessels and nerves, many residual tissues were retained after the operation. The post-operative pathology results confirmed that the patient had a mature mediastinal cystic teratoma. One year after the operation, there was no recurrence, the peripheral blood vessels had basically returned, and the patient did not have any nerve injury. Effusion caused by mediastinal teratoma should be carefully differentiated from tuberculous diseases to avoid unnecessary damage to patients during treatment. Separation can be difficult in benign mediastinal tumors with severe adhesion. To avoid the trauma caused by the excessive separation of a tumor, it is our view that part of the residual tissue should be retained and left to be absorbed naturally.

Hypoxia modifies the polarization of macrophages and their inflammatory microenvironment, and inhibits malignant behavior in cancer cells.

Macrophages are a heterogeneous group of phagocytes that play critical roles in inflammation, infection and tumor growth. Macrophages respond to different environmental factors and are thereby polarized into specialized functional subsets. Although hypoxia is an important environmental factor, its impact on human macrophage polarization and subsequent modification of the inflammatory microenvironment have not been fully established. The present study aimed to elucidate the effect of hypoxia exposure on the ability of human macrophages to polarize into the classically activated (pro-inflammatory) M1, and the alternatively activated (anti-inflammatory) M2 phenotypes. The effect on the inflammatory microenvironment and the subsequent modification of A549 lung carcinoma cells was also investigated. The presented data show that hypoxia promoted macrophage polarization towards the M2 phenotype, and modified the inflammatory microenvironment by decreasing the release of proinflammatory cytokines. Modification of the microenvironment by proinflammatory M1 macrophages under hypoxia reversed the inhibition of malignant behaviors within the proinflammatory microenvironment. Furthermore, it was identified p38 signaling (a major contributor to the response to reactive oxygen species generated by hypoxic stress), but not hypoxia-induced factor, as a key regulator of macrophages under hypoxia. Taken together, the data suggest that hypoxia affects the inflammatory microenvironment by modifying the polarization of macrophages, and thus, reversing the inhibitory effects of a proinflammatory microenvironment on the malignant behaviors of several types of cancer cell.

Effects of RNA silencing of matrix metalloproteinase-2 on the growth of esophageal carcinoma cells in vivo.

Esophageal carcinoma is one of the most common malignancies in China. Previous studies reported that matrix metalloproteinases (MMPs) have important roles in the progression and invasion of numerous types of solid tumors. Among the MMPs, MMP-2 has been closely associated with tumor growth and invasion. In the present study, a short hairpin RNA (shRNA) lentiviral expression vector targeting the MMP-2 gene was constructed in order to observe the inhibitory effect of MMP-2 gene silencing on the growth of the KYSE150 esophageal carcinoma cell line in vivo. Three small hairpin RNA sequences targeting MMP-2 were designed and cloned into lentiviral vectors. Following transfection of the lentiviral vectors into KTSE150 cells, MMP-2 mRNA and protein expression levels were examined by reverse transcription-quantitative polymerase chain reaction and western blotting, and the growth rate of cells was analyzed by MTT assays. Subsequently, tumor growth was assessed in nude mice. Lentivirus-mediated RNA interference effectively inhibited the expression of MMP-2 mRNA and protein in KYSE150 esophageal carcinoma cells, and suppressed the growth of esophageal carcinoma cells in vivo. The results of the present study suggested that lentivirus-mediated gene therapy targeting MMP-2 may be an attractive strategy for the treatment of esophageal carcinoma and justifies the performance of further studies on the application of lentivirus vectors to cancer gene therapy.

Ursodeoxycholic acid induces autophagy via LC3B to suppress hepatocellular carcinoma in vivo and in vitro.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a common cancer worldwide. Researchers have found that UDCA can be used to inhibit the growth of tumors. Microtubule-associated protein light chain 3B (LC3B) is an important reglator of autophagosomes. No researches have been published on the relationship of UDCA and LC3B. METHODS: A Cell Counting Kit-8 cell viability assay, cell migration assay, quantitative reverse transcription PCR (qRT-PCR) and western blot were conducted for the SMMC-7721 and HepG2 cell lines. Hematoxylin-eosin (HE) staining and immunohistochemistry (IHC) were used to analyze nude mice with 7721 xenograftes. The expression of LC3B was evaluated both in vivo and in vitro. RESULTS: Our studies demonstrated that UDCA reduced the viability of the primary HCC cell lines 7721 and HepG2 (Student's t-test, P<0.05) and inhibited the migration of 7721 cells (Student's t-test, P<0.05). UDCA also increased the expression of LC3B and p53 in vitro (Student's t-test, P<0.05). Additionally, UDCA inhibited the growth of tumors (Student's t-test, P<0.05) and promoted the expression of LC3B in nude mice. CONCLUSION: Our data showed that UDCA promoted the expression of LC3B, with suppressed HCC in vivo and in vitro.

Nefopam for the prevention of perioperative shivering: a meta-analysis of randomized controlled trials.

BACKGROUND: Shivering is a frequent complication following surgery and anaesthesia. A large variety of studies have been reported that nefopam may be efficacious for the prevention and treatment of perioperative shivering. Regrettably, there is still no conclusion of the efficacy and safety of nefopam for the prevention of perioperative shivering. The aim of this analysis is to evaluate the efficacy of nefopam for the prevention of perioperative shivering in patients undergoing different types of anaesthesia compared with placebo group and other active interventions. METHODS: PubMed, EMBASE, Cochrane Central Register of Control Trials were systematically searched for potentially relevant trials. Trial quality and extracted data were evaluated by two authors independently. Dichotomous data on the absence of shivering was extracted and analysed by using relative risk (RR) with 95% confidence interval (CI). Continuous outcome was abstracted and analysed by using weighted mean difference (WMD) with 95% confidence interval (CI). Outcome data was analysed by using random effect model or fixed effect model in accordance with heterogeneity. RESULTS: Compared with placebo, prophylactic administration of nefopam significantly reduced the risk of perioperative shivering not only in the patients under general anaesthesia but also neuraxial anaesthesia (RR 0.08; 95% CI 0.05-0.13). As compared with clonidine, nefopam was more efficacious in the prevention of perioperative shivering (RR 0.34; 95% CI 0.17-0.70). Nefopam has no influence on the extubation time (WMD 0.92; 95% CI -0.15-1.99). CONCLUSION: Our analysis has demonstrated that nefopam is associated with the decrease of risk of perioperative shivering following anaesthesia without influencing the extubation time.