Primary Mediastinal Large B-Cell Lymphoma Achieved by Non-Cautery Assisted Transbronchial Mediastinal Cryobiopsy.

Transbronchial mediastinal cryobiopsy is a novel sampling strategy that shows improved diagnostic utility for mediastinal lesions, particularly in rare tumors and benign disorders, as compared to standard endobronchial ultrasound-guided transbronchial needle aspiration. During this procedure, electrocautery incision is frequently needed to advance the cryoprobe through the airway into the mediastinal lesion, which however results in increased operative difficulty and prolonged procedural time. Here we present a case of mediastinal large B-cell lymphoma successfully diagnosed by transbronchial mediastinal cryobiopsy without cautery-induced airway incision.

Endobronchial Ultrasound-Guided Transbronchial Incision and Drainage in the Treatment of Mediastinal Abscess.

Mediastinal abscess, mostly resulting from esophageal perforation or cardiothoracic surgery, is a serious condition carrying high morbidity and mortality. Antibiotic therapy alone normally did not achieve a satisfactory outcome, due to poor circulation of abscess that hampers drug delivery. Surgical intervention for debridement and drainage is recommended, but it poses a high risk in patients with poor health status and could lead to various complications. Recent studies proposed endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an effective alternative to surgery; however, repeated TBNA procedures are usually needed for complete clearance of the lesion, thus causing increased patient suffering and medical expenses. Here, we present the first case of successful application of EBUS-guided transbronchial incision and drainage, which provides a novel, safe, and effective treatment for patient with mediastinal abscess unwilling or unsuitable to undergo surgical intervention.

MicroRNA profile of tumorigenic cells during carcinogenesis of lung adenocarcinoma.

To obtain microRNA (miRNA) profile and clarify their biological function in tumorigenic Sca-1(+) CD34(+) cells during carcinogenesis of lung adenocarcinoma. After intranasal infection with recombinant Adeno-Cre viruses (AdV-Cre), lung adenocarcinoma was identified pathologically in Lox-stop-lox Kras (LSL-Kras) G12D mice. Sca-1(+) CD34(+) cells were sorted by flow cytometry and tested for tumor-initiating ability, self-renewal and tumorigenicity. MiRNA profiles were obtained using microarray and further confirmed by real-time RT-PCR (qRT-PCR). MiRNA functions were predicted bioinformatically, and miR-294 function was verified to explore its role in tumor migration and invasion. Lung adenocarcinoma was induced in LSL-Kras G12D mice within 30 days. In vivo, the tumorigenicity of Sca-1(+) CD34(+) cells was 25 times stronger than Sca-1(-) CD34(-) cells. During tumorigenesis of lung adenocarcinoma, the expression of 145 miRNAs in Sca-1(+) CD34(+) cells increased and 72 miRNAs decreased (P < 0.01). Four successively up-regulated miRNAs (miR-15a*, miR-203, miR-294 and miR-295*) and three successively down-regulated ones (miR-19b, miR-483 and miR-615-5p) were identified. Among them, miR-294 could constitutively bind to 3'-UTR of matrix metalloproteinase 3 (MMP3), and down-regulate MMP3 protein expression. MiR-294 also significantly inhibited migration and invasion of Lewis lung cancer cells. MiRNAs are characteristically expressed in tumor-initiating Sca-1(+) CD34(+) cells of lung adenocarcinoma, and may play important roles during the carcinogenesis of lung adenocarcinoma.

Transbronchial needle aspiration combined with cryobiopsy in the diagnosis of mediastinal diseases: a multicentre, open-label, randomised trial.

BACKGROUND: Transbronchial mediastinal cryobiopsy is a novel sampling technique for mediastinal disease. Despite the possibility of lung cancer misdiagnosis, the improved diagnostic yield of this approach for non-lung-cancer lesions compared with standard endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) highlights its diagnostic potential as a complementary technique to conventional biopsy. We aimed to evaluate the safety profile and added value of the combined use of transbronchial mediastinal cryobiopsy and standard EBUS-TBNA for the diagnosis of mediastinal diseases. METHODS: We conducted an open-label, randomised trial at three hospital sites in Europe and Asia. Eligible patients were aged 15 years or older, with at least one mediastinal lesion of 1 cm or longer in the short axis that required diagnostic bronchoscopy. Participants were randomly assigned (1:1) using a block randomisation scheme generated by a computer (block size of four participants based on a random table from an independent statistician) to the combined use of EBUS-TBNA and transbronchial mediastinal cryobiopsy (combined group) or EBUS-TBNA alone (control group). Because of the nature of the intervention, neither participants nor investigators were masked to group assignment. The coprimary outcomes were differences in procedure-related complications and diagnostic yield (defined as the proportion of participants for whom mediastinal biopsy led to a definitive diagnosis), assessed in the full analysis set, including all the patients who met the eligibility criteria and had a biopsy. A fully paired, intraindividual diagnostic analysis in participants who had both needle aspiration and mediastinal cryobiopsy was conducted, in addition to interindividual comparisons. This trial is now complete and is registered with ClinicalTrials.gov, NCT04572984. FINDINGS: Between Oct 12, 2020, and Sept 9, 2021, 297 consecutive patients were assessed for eligibility and 271 were enrolled and randomly assigned to the combined group (n=136) or the control group (n=135). The addition of cryobiopsy to standard sampling significantly increased the overall diagnostic yield for mediastinal lesions, as shown by both interindividual (126 [93%] of 136 participants in the combined group vs 109 [81%] of 135 in the control group; risk ratio [RR] 1·15 [95% CI 1·04-1·26]; p=0·0039) and intraindividual (126 [94%] of 134 vs 110 [82%] of 134; RR 1·15 [95% CI 1·05-1·25]; p=0·0026) analyses. In subgroup analyses in the intraindividual population, diagnostic yields were similar for mediastinal metastasis (68 [99%] of 69 participants in the combined group vs 68 [99%] of 69 in the control group; RR 1·00 [95% CI 0·96-1·04]; p=1·00), whereas the combined approach was more sensitive than standard needle aspiration in benign disorders (45 [94%] of 48 vs 32 [67%] of 48; RR 1·41 [95% CI 1·14-1·74]; p=0·0009). The combined approach also resulted in an improved suitability of tissue samples for molecular and immunological analyses of non-small-cell lung cancer. The incidence of adverse events related to the biopsy procedure did not differ between trial groups, as grade 3-4 airway bleeding occurred in three (2%) patients in the combined group and two (1%) in the control group (RR 0·67 [95% CI 0·11-3·96]; p=1·00). There were no severe complications causing death or disability. INTERPRETATION: The addition of mediastinal cryobiopsy to standard EBUS-TBNA resulted in a significant improvement in diagnostic yield for mediastinal lesions, with a good safety profile. These data suggest that this combined approach is a valid first-line diagnostic tool for mediastinal diseases. FUNDING: National Natural Science Foundation of China.

Novel molecular beacons to monitor microRNAs in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer death worldwide. There is no effective early diagnostic technology for lung cancer. microRNAs (miRNAs) are noncoding RNA molecules which regulate the process of cell growth and differentiation in human cancers. Hsa-miR-155 (miR-155), highly expressed in non-small-cell lung cancer (NSCLC), can be used as a diagnostic marker for NSCLC. Dynamic observation of miR-155 is critical to diagnose NSCLC. A novel molecular beacon (MB) of miR-155 was designed to image the expression of miR-155 in NSCLC. Then miR-155 was detected in vitro by laser confocal microscopy and in vivo by stereomicroscope imaging system, respectively. The present study demonstrated that intracellular miR-155 could be successfully and quickly detected by novel miR-155 MBs. As a noninvasive monitoring approach, MBs could be used to diagnose lung cancer at early stage through molecular imaging.

The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Clinical and laboratory studies have suggested that multi-targeting approaches against neoplastic cells could help to increase patient survival and might reduce the emergence of cells that are resistant to single-target inhibitors. Artesunate (ART) is one of the most potent and rapidly acting antimalarial agents known, and it also exerts a profound cytotoxic activity toward cancer cells and reverses multi-drug resistance. In the present study, we found that artesunate inhibited NSCLC A549 cell growth and proliferation, induced apoptosis and suppressed tumor growth in a dose-dependent manner in A549 cells and a mouse xenograft model. Furthermore, artesunate down-regulated the expression of epidermal growth factor receptor (EGFR), Akt and ATP-binding cassette subfamily G member 2 (ABCG2) at the mRNA and protein levels in vitro and in vivo. In conclusion, artesunate is an effective anti-cancer drug that may enhance the effectiveness of other anticancer drugs and may reverse multi-drug resistance by suppressing the transcription of ABCG2, which inhibits drug efflux.

Somatosensory stimulation treatments for postoperative analgesia of mixed hemorrhoids: Protocol for a systematic review and network meta-analysis.

BACKGROUND: Pain after hemorrhoidal surgery bothers both clinicians and patients. Somatosensory stimulation treatments have shown promising effect on the pain after hemorrhoidal surgery, but the comparative effectiveness between them has not been studied. We aim to determine the relative effectiveness among these treatments on pain relief after hemorrhoidal surgery by using network meta-analysis. METHOD: We will search the following electronic databases: MEDLINE, EMBASE, the Cochrane library, Chinese Biomedicine database (CBM), China National Knowledge Infrastructure (CNKI). We will include randomized controlled trials (RCTs) that examine the effect of somatosensory stimulation treatments on pain after hemorrhoidal surgery. The primary outcome will be the responder rate after treatment. The secondary outcomes will include the assessments with pain intensity scales (visual analog scale, numeric rating scale, or other scales) on day 1 to 7 after surgery. Two independent reviewers will extract needed information from eligible trials using standardized electronic forms. Network meta-analysis will be performed using a frequentist framework based on electrical network theory. The relative effectiveness of the treatments will be ranked by using P score, which is the mean probability of a treatment ranking the best in all treatments. Meta-regression will be performed to assess the impact of surgery type, anesthesia methods, and funding source on the treatment ranking. The quality of the eligible RCTs will be evaluated by the Cochrane risk of bias tool. ETHICS AND DISSEMINATION: The result of this network meta-analysis will clarify which is the relatively best somatosensory-stimulation treatment in relieving postoperative pain caused by hemorrhoidal surgery, and the review will, therefore, guide the management of postoperative pain after hemorrhoidal surgery for clinicians and patients. This review does not require ethical approval and will be reported in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018115558.

Monitoring microRNAs using a molecular beacon in CD133+/ CD338+ human lung adenocarcinoma-initiating A549 cells.

Lung cancer is the most common causes of cancer-related deaths worldwide, and a lack of effective methods for early diagnosis has greatly impacted the prognosis and survival rates of the affected patients. Tumor-initiating cells (TICs) are considered to be largely responsible for tumor genesis, resistance to tumor therapy, metastasis, and recurrence. In addition to representing a good potential treatment target, TICs can provide clues for the early diagnosis of cancer. MicroRNA (miRNA) alterations are known to be involved in the initiation and progression of human cancer, and the detection of related miRNAs in TICs is an important strategy for lung cancer early diagnosis. As Hsa-miR-155 (miR-155) can be used as a diagnostic marker for non-small cell lung cancer (NSCLC), a smart molecular beacon of miR-155 was designed to image the expression of miR-155 in NSCLC cases. TICs expressing CD133 and CD338 were obtained from A549 cells by applying an immune magnetic bead isolation system, and miR-155 was detected using laser-scanning confocal microscopy. We found that intracellular miR- 155 could be successfully detected using smart miR-155 molecular beacons. Expression was higher in TICs than in A549 cells, indicating that miR-155 may play an important role in regulating bio-behavior of TICs. As a non-invasive approach, molecular beacons could be implemented with molecular imaging to diagnose lung cancer at early stages.

Factors associated with the need of biventricular mechanical circulatory support in children with advanced heart failure.

OBJECTIVES: Postimplantation right ventricular dysfunction is associated with increased morbidity and mortality in ventricular assist device (VAD) recipients. This study aimed to determine the preoperative risk factors for severe right heart failure needing biventricular mechanical circulatory support in children with end-stage heart failure. METHODS: We reviewed data from 84 children supported with long-term VADs at the German Heart Institute Berlin between January 1999 and October 2010. Right ventricular assist device (RVAD) support was needed for 24 (29%) patients, and the other 60 (71%) were implanted with left ventricular assist devices (LVADs). RESULTS: The median age at implantation was 7 years (12 days-18 years), and the median support time was 41 days (1-432 days). Of the 84 patients, the overall survival to transplantation or recovery of ventricular function was 69%. Compared with children implanted with LVAD, patients receiving biventricular support had significantly higher postoperative mortality (P = 0.04). The multivariate logistic regression indicated that decreased milrinone use was the only preoperative factor independently associated with increased requirement for biventricular support (odds ratio: 0.1, 95% confidence interval: 0.04-0.64, P = 0.01). Children treated with milrinone preoperatively showed improved survival after implantation (P = 0.04). CONCLUSIONS: Paediatric patients needing biventricular support had significantly higher postoperative mortality. Preoperative milrinone use might decrease the risk of severe right ventricular failure requiring additional RVAD insertion and improve postimplantation survival in children with advanced heart failure.

Increased treatment-related mortality with additional cisplatin-based chemotherapy in patients with nasopharyngeal carcinoma treated with standard radiotherapy.

BACKGROUND AND PURPOSES: We performed a meta-analysis of randomized controlled trials (RCTs) to determine the overall risk of treatment-related death associated with additional cisplatin-based chemotherapy in patients with nasopharyngeal carcinoma treated with standard radiotherapy. MATERIAL AND METHODS: Eligible studies included RCTs in which cisplatin-based chemotherapy in combination with radiotherapy was compared with radiotherapy alone. Statistical analyses were conducted to calculate the summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effects models based on the heterogeneity of included studies. RESULTS: A total of 2829 patients from 13 RCTs were included in this study. The overall incidence for treatment-related death in chemoradiotherapy and radiotherapy treated patients was 1.7% and 0.8%. Compared to radiotherapy alone, radiotherapy plus cisplatin-based chemotherapy significantly increased the risk of treatment-related mortality. On subgroup analyses, no difference was found in treatment-related mortality between different timings of chemotherapy and chemotherapeutic agents. Adding cisplatin-based chemotherapy was associated with higher incidences of severe acute toxicity. CONCLUSIONS: Cisplatin-based chemotherapy plus radiotherapy increased the risk of treatment-related death and severe acute toxicity, compared with radiotherapy alone. Better management of treatment toxicity might improve the therapeutic gain in patients with nasopharyngeal carcinoma.

Identification of a cancer stem-like population in the Lewis lung cancer cell line.

OBJECTIVE: Although various human cancer stem cells (CSCs) have been defined, their applications are restricted to immunocompromised models. Developing a novel CSC model which could be used in immunocompetent or transgenic mice is essential for further understanding of the biomolecular characteristics of tumor stem cells. Therefore, in this study, we analyzed murine lung cancer cells for the presence of CSCs. METHODS: Side population (SP) cells were isolated by fluorescence activated cell sorting, followed by serum-free medium (SFM) culture, using Lewis lung carcinoma cell (LLC) line. The self-renewal, differentiated progeny, chemosensitivity, and tumorigenic properties in SP and non-SP cells were investigated through in vitro culture and in vivo serial transplantation. Differential expression profiles of stem cell markers were examined by RT-PCR. RESULTS: The SP cell fraction comprised 1.1% of the total LLC population. SP cells were available to grow in SFM, and had significantly enhanced capacity for cell proliferation and colony formation. They were also more resistant to cisplatin in comparison to non-SP cells, and displayed increased tumorigenic ability. Moreover, SP cells showed higher mRNA expression of Oct-4, ABCG2, and CD44. CONCLUSION: We identified SP cells from a murine lung carcinoma, which possess well-known characteristics of CSCs. Our study established a useful model that should allow investigation of the biological features and pharmacosensitivity of lung CSCs, both in vitro and in syngeneic immunocompetent or transgenic/knockout mice.

Aberrant microRNAs expression in CD133⁺/CD326⁺ human lung adenocarcinoma initiating cells from A549.

Increasing evidence demonstrates that miRNAs are involved in the dysregulation of tumor initiating cells (TICs) in various tumors. Due to a lack of definitive markers, cell sorting is not an ideal separation method for lung adenocarcinoma initiating cells. In this study, we combined paclitaxel with serum-free medium cultivation (inverse-induction) to enrich TICs from A549 cells, marked by CD133/CD326, defined features of stemness. We next investigated aberrant microRNAs in this subpopulation compared to normal cells with miRNA microarray and found that 50 miRNAs exhibited a greater than 2-fold change in expression. As further validation, 10 miRNAs were chosen to perform quantitative RT-PCR on the A549 cell line and primary samples. The results suggest that aberrant expression of miRNAs such as miR-29ab, miR-183, miR-17-5p and miR-127-3P may play an important role in regulating the bio-behavior of TICs.

Glucose-insulin-potassium therapy in adult patients undergoing cardiac surgery: a meta-analysis.

Glucose-insulin-potassium (GIK) has long been used as adjuvant treatment for patients with serious cardiovascular disease. Although many studies have reported their results based on GIK therapy in the setting of heart surgery, the outcomes remain controversial and inconclusive. The aim of this meta-analysis of randomized controlled trials (RCTs) was to determine the clinical effects of GIK in adult cardiac surgery patients. Electronic databases and manual bibliographical searches were conducted. A meta-analysis of all RCTs comparing GIK with control in heart surgery was performed. Data for all-causes mortality (within 2 months after surgery), perioperative myocardial infarction, postoperative inotropic support, atrial fibrillation, cardiac index, durations of intensive unit care stay and total hospital stay were extracted, and we summarized the combined results of the data of the RCTs as relative risk (RR), with 95% confidence intervals (CIs). A total of 33 RCTs including 2113 patients were assessed in this study. GIK infusion was associated with significantly fewer perioperative myocardial infarctions (RR = 0.63, 95% CI 0.42-0.95), less inotropic support requirement (RR = 0.66, 95% CI 0.45-0.96), better postoperative cardiac index (weighted mean difference (WMD) = 0.43, 95% CI 0.31-0.55), and reduced length of stay in the intensive care unit (WMD = -7.96, 95% CI -13.36 to -2.55). Further analysis showed that diabetic patients were benefited from GIK with glycemic control, but not GIK infusion without glucose control. GIK significantly reduced myocardial injury and improved hemodynamic performance in patients undergoing cardiac surgery. Glycemic control with GIK might be required for cardiac surgery patients with diabetes.

Warm versus cold cardioplegia for heart surgery: a meta-analysis.

Much controversy persists regarding the optimal techniques for myocardial protection during heart surgery. Numerous studies have compared warm cardioplegia with cold cardioplegia for myocardial preservation, but the outcomes were inconclusive. The aim of this meta-analysis of randomised controlled trials (RCTs) was to compare the beneficial and harmful effects of warm and cold cardioplegia during heart surgery. Electronic databases and manual bibliographical searches were conducted. A meta-analysis of all RCTs comparing warm cardioplegia to cold cardioplegia perfusion during cardiac surgery was performed. Data for clinical events (in-hospital death, myocardial infarction (MI), low output syndrome, postoperative use of intra-aortic balloon pump, stroke and atrial fibrillation), postoperative cardiac index, postoperative creatine kinase-MB (CK-MB) and cardiac troponin release were extracted, and we summarised the combined results of the data of the RCTs as relative risk (RR), with 95% confidence intervals. A total of 41 RCTs including 5,879 patients were assessed in this study. We found that there was no statistical difference between patients receiving warm cardioplegia and cold cardioplegia in the incidences of clinical events. Warm cardioplegia was associated with improved postoperative cardiac index. CK-MB and cardiac troponin concentrations after surgery were significantly lower in the warm group as compared with the cold group. Using warm cardioplegia for myocardial protection during heart surgery resulted in similar incidences of clinical events, significant improvement in postoperative cardiac index and reduction in postoperative enzyme release as compared with cold cardioplegia.