Exudative pleural effusion of an unclear aetiology remains a diagnostic challenge. Ultrasonic elastography-guided pleural biopsy (UEPB) offers a higher diagnostic yield than conventional ultrasound-guided pleural biopsy; however, its role relative to semi-rigid thoracoscopy remains unclear. This trial is designed to determine whether UEPB is non‑inferior to semi-rigid thoracoscopy in diagnostic yield when used as the initial diagnostic procedure, and to further quantify the proportion of patients in whom semi-rigid thoracoscopy could be avoided by adopting a UEPB-first diagnostic strategy. In this multicentre, open-label, parallel-group, non-inferiority, randomised controlled trial conducted at five sites in China, 420 patients with exudative pleural effusion of unknown aetiology and negative cytology will be randomly assigned 1:1 to either initial UEPB (with semi-rigid thoracoscopy reserved for non-diagnostic cases) or immediate semi-rigid thoracoscopy. The primary outcome is the overall diagnostic yield of the allocated diagnostic strategy, defined as the proportion of participants in whom a specific histopathological diagnosis is stablished through the protocol-defined biopsy procedures within the allocated diagnostic pathway. A non-inferiority margin of − 5

INTRODUCTION:Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). However, the learning curve associated with this technique remains unclear. METHODS:This retrospective analysis included the first 100 patients suspected of having ILD for whom TBLC was performed by six physicians (three chief physicians and three attending physicians) across three centers in China. The diagnostic yield, procedural information, and complications were compared between consecutive groups of patients. Logistic regression was employed to analyze the median diagnostic yields across ten subgroups of operative experience, categorized in intervals of 10 patients, to delineate the learning curve. RESULTS:The overall multidisciplinary discussion (MDD)-based diagnostic rate for ILD after TBLC was 75% (450 of 600 procedures). The diagnostic yield increased with time. Learning curves revealed that chief physicians achieved proficiency after approximately 60 procedures and attending physicians after approximately 90. The sample biopsy was larger for chief physicians than for attending physicians (median, 19 mm2 vs. 15.25 mm2, p < 0.001). The complication rates were acceptable, with no significant difference between the chief and attending physicians over their first 100 procedures. CONCLUSION:TBLC is a safe and effective diagnostic approach for ILD, but operators require extensive training to achieve proficiency. Senior physicians reached competency earlier than junior colleagues (after several dozen procedures), underscoring the importance of structured training programs and standardized protocols for facilitating safe implementation.

The combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) has played a significant role in the improvement of tumor therapy, but the increased incidence of pneumonitis has greatly limited its application. To identify potential intervention targets, we analyzed risk factors for pneumonitis after combination therapy with ICIs and TRT. Overall, 335 patients who received TRT and ICI therapy concurrently or sequentially were included in our study. Pneumonitis was assessed and the related factors were analyzed. After combined TRT and ICI therapy, among the 335 patients, 219 (65.4

BACKGROUND:Traditional thoracic ultrasound-guided pleural biopsy (TUSPB) is considered the initial method for histological diagnosis; however, its sensitivity for detecting malignant pleural effusion (MPE) is limited. Ultrasound elastography can be used to differentiate MPE from benign diseases by evaluating pleural stiffness. This study aimed to investigate whether ultrasonic elastography-guided pleural biopsy (UEPB) offers diagnostic accuracy superior to that of TUSPB for pleural effusions. METHODS:In this multicentre, randomised trial (ClinicalTrials.gov: NCT05781659), patients with pleural effusion of unknown origin were enrolled and randomised (1:1) to undergo either UEPB or TUSPB. The primary outcome measured was the sensitivity of UEPB in diagnosing MPE; the secondary outcomes were the diagnostic rate of the two methods in patients with different pleural thicknesses and the safety of UEPB. RESULTS:In total, 232 patients with pleural effusion were enrolled, 228 of whom were included in the analysis. The sensitivity for detecting MPE was significantly greater in the UEPB group than in the TUSPB group (85.00% (51/60) versus 63.16% (36/57); p=0.007). Patients in the UEPB group had a significantly greater diagnostic yield than those in the TUSPB group (87.83% (101/115) versus 76.99% (87/113); p=0.032). For patients with MPE and a pleural thickness ≤5 mm who did not have pleural nodules, UEPB had a significantly greater sensitivity than TUSPB (80.49% (33/41) versus 50.00% (15/30); p=0.007). The rates of procedure-related complications were similar between the UEPB and TUSPB groups (6.36% versus 8.33%; p=0.552). CONCLUSION:UEPB was superior to TUSPB in the diagnosis of MPE with a similar safety profile.

Abstract Rationale and objectives Bleeding is a major complication of transbronchial lung cryobiopsy (TBLC), and pre-placing a bronchial balloon is one of the clinical practices used to prevent it, but with very weak evidence, which should be confirmed. This study aimed to conduct whether pre-placing a bronchial balloon in TBLC for diagnosing interstitial lung disease (ILD) is more safety. Materials and methods In this prospective, single-center, randomized controlled trial, patients with suspected ILD were enrolled and randomly assigned to pre-placed balloon and none-pre-placed balloon groups. The primary outcome was incidence of moderate bleeding in each group. The secondary endpoints were the incidence of severe bleeding, pneumothorax, and other procedural complications. Results Exactly 250 patients were enrolled between August 2019 and March 2022, with 125 in each group. There were no significant differences in severe bleeding between the none-pre-placed balloon group and pre-placed balloon group (1.6% vs. 0.8%; adjusted p = 0.520), while more moderate bleeding occurred in the none-pre-placed balloon group (26.4% vs. 6.4%, adjusted p = 0.001), as well as more use of hemostatic drug (28.0% vs. 6.4%, adjusted p = 0.001). Three patients in the none-pre-placed balloon group used the bronchial balloon. More samples could be acquired in the pre-placed balloon group than in the none-pre-placed balloon group (3.8 ± 0.9 vs. 3.1 ± 0.9, p < 0.001). There were no significant differences in multidisciplinary discussion (MDD) between the two groups (89.6% vs. 91.2%, adjusted p = 0.182). Conclusion A pre-placed bronchial balloon can reduce the incidence of moderate bleeding and increase the confidence of the bronchoscopists. However, it had no effect on increasing the diagnostic rate of MDD and reducing severe bleeding. Registration number: NCT04047667 (www.clinicaltrials.gov identifier).

Rationale: The diagnostic yield of traditional ultrasound-guided pleural biopsy remains unsatisfactory, particularly when the pleural thickness is ⩽5 mm and/or no pleural nodules are detected. Pleural ultrasound elastography (UE) has a better diagnostic yield than traditional ultrasound for malignant pleural effusion (MPE). However, studies on UE-guided pleural biopsies are lacking. Objectives: To evaluate the feasibility and safety of UE-guided pleural biopsy. Methods: In this multicenter prospective single-arm trial, patients with pleural effusion whose pleural thickness was ⩽5 mm with no pleural nodules were enrolled between July 2019 and August 2021. The diagnostic yield of UE-guided pleural biopsy for pleural effusion and its sensitivity for detecting MPE were evaluated. Results: Ninety-eight patients (mean age, 62.4 ± 13.2 yr; 65 men) were prospectively enrolled. The diagnostic yield of UE-guided pleural biopsy for making any diagnosis was 92.9% (91/98), and its sensitivity for MPE was 88.7% (55/62). In addition, its sensitivity for pleural tuberculosis was 69.6% (16/23). The rate of postoperative chest pain was acceptable, and there was no pneumothorax. Conclusions: UE-guided pleural biopsy is a novel technique for diagnosing MPE with good diagnostic yield and sensitivity. Clinical trial registered with https://www.chictr.org.cn (ChiCTR2000033572).

Abstract Background Primary CNS anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) is extremely rare and only few cases have been reported. Due to its rarity, the clinicopathologic features and the prognosis of primary CNS ALK + ALCL have not been well characterized. Methods We retrospectively analyzed the clinicopathologic and prognostic features of 3 cases of primary CNS ALK + ALCLs among 337 cases of primary CNS lymphomas during the past 14 years in our cancer center with review of an additional 20 cases from the literature. Results Primary CNS ALK + ALCL accounted for 0.9% (3/337) of all primary CNS lymphomas during the study period in our cancer center. The ages of patients ranged from 4 to 43 years, with a median age of 18 years. There was a predominance of males, with the male-to-female ratio of 6.7:1. Most (87%, 20/23) of cases had intracerebral mass(es), and among these cases, 25% (5/20) of cases were accompanied by involvement of spinal cord and (or) leptomeninges; rare cases (3/23,13%) were confined to the spinal cord and (or) leptomeninges. A solitary mass and multiple tumors were present in 56.5% (13/23) and 43.5% (10/23) of cases, respectively. Of the 22 patients with survival data, 31.8% (7/22) of patients died of the disease during the follow-up period (median follow-up, 24 months; range, 0.5–87 months). The 2-year overall survival (OS) of patients with primary CNS ALK + ALCL was 69%. Patients under 18-years old had worse 2-year overall survival, but the difference did not reach statistical significance (p = 0.115). No statistical significance was found between patients with solitary mass and multiple tumors (p = 0.940). Conclusions Primary CNS ALK + ALCL is an extremely rare disease and tends to occur in young adults with a male preponderance. Patients with this disease have relatively favorable outcome than other types of primary CNS lymphomas. Accurate diagnosis, as well as timely and optimal treatment for patients with this disease is important.

To the Editor: Osteosarcoma (OS) is the most common malignant primary bone tumor majorly affecting children, adolescents, and young adults. Statistic studies showed that up to 20% of OS patients have clinically detectable metastatic tumor at presentation, and >85% of metastases occurs in the lung. Thus, identifying risk factors that reflect the biological characteristics and survival of OS could lead to better interventions for patients.

Background: The diagnostic yields of traditional ultrasound-guided pleural biopsy remain unsatisfactory, especially when the pleural thickness is ≤ 5 mm and/or no pleural nodules are detected. Pleural ultrasound elastography has a better diagnostic yield than traditional ultrasound for malignant pleural effusion (MPE). However, studies of ultrasound elastography-guided pleural biopsy (UEPB) are lacking. This study was designed to assess the diagnostic yield and safety of UEPB for diagnosing MPE.Methods: We prospectively enrolled patients with pleural effusion whose pleural thickness ≤ 5 mm and no pleural nodules into the UEPB group or flexible thoracoscopy (FT) group between July 2019 and October 2021. UEPB diagnostic yield for pleural effusion and sensitivity for MPE were compared with those of FT.Findings: Ninety-eight patients (mean age, 62·4±13·2 years; 65 men) in the UEPB group and 116 patients (mean age, 61·1±12·8 years; 62 men) in the FT group were prospectively enrolled. The diagnostic yield of UEPB was 92 ·9% (91/98), and the sensitivity of UEPB for MPE was 88·7% (55/62). There was no difference in diagnostic yield between the UEPB and FT groups for all diagnoses (92·2%, 107/116, p =0·865) or MPE (88·5%, 69/78, p =0·963). However, the rate of postoperative chest pain was lower in the UEPB group, and there was no pneumothorax in the UEPB group.Interpretation: Elastography-guided pleural biopsy is a novel technique for diagnosing malignant pleural effusion with a good diagnostic yield and sensitivity. Elastography-guided pleural biopsy is comparable to flexible thoracoscopy regarding diagnostic yield for malignant pleural effusion but is less invasive.Trial Registration Details: This study was registered at www.chictr.org.cn (ChiCTR2000033572).Funding Information: This research was supported by the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (No. 2020-PT320-001) and the Elite Medical Professionals Project of China-Japan Friendship Hospital (NO. ZRJY2021-BJ08).Declaration of Interests: The authors declare no commercial or financial relationships that could be construed as a potential conflict of interest.Ethics Approval Statement: This study was approved by the Institutional Ethical Review Board of the First Hospital of China Medical University and China-Japan Friendship Hospital (reference numbers: 2019-143-2 and 2021-136-K94), and written informed consent was obtained from all patients.

Background: Met proto-oncogene (MET) exon 14 skipping mutations are tumor drivers in approximately 3% of lung cancer patients. The antitumor efficacy of ensartinib, a novel multi-kinase inhibitor, against non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations was investigated in this study. Methods: The MET-mutant binding affinity and antitumor activity of ensartinib were assessed in vitro and in vivo. Preliminary therapeutic activity of ensartinib in patient-derived organoids was observed. To explore clinical activity, 17 NSCLC patients with MET exon 14 skipping mutations were treated with ensartinib at 225 mg qd. Results: Molecular dynamic simulations revealed that ensartinib exhibited favorable binding to c-MET. Ensartinib was highly effective in inhibiting the kinase activity of the MET exon 14 deletion protein (IC50 = 7.9 nM). Furthermore, ensartinib potently suppressed the MET pathway and the growth of Hs746T cells that were subcutaneously implanted into mice. Most importantly, of 17 patients with 14 different types of MET exon 14 skipping mutations undergoing ensartinib treatment, 1 (6%) showed a complete response, 11 (65%) achieved a partial response, and 4 (24%) exhibited stable disease. Thus, the objective response rate (ORR) was 71% and the disease control rate (DCR) was 94%, and the ORR in MET-TKI naive patients was even higher (12/15, 80%). In 2 patients with brain metastasis without prior brain radiation, we observed one partial response in the brain, while in the other patient the brain lesions were stable for 6 months. The most frequently reported adverse events were rash, peripheral edema, and nausea; however, no fatal adverse events occurred. Conclusions: These results provide the first evidence that ensartinib exhibits both preclinical and clinical antitumor activity against MET exon 14 skipping mutations with the potential of strong intracranial efficacy and warrant further evaluation in a planned phase II study thus providing more options to patients with MET exon 14 skipping mutations. Updated data including duration of response, PFS and and OS will be provided at the time of the presentation with additional few months of follow up. Citation Format: Yang Xia, Fen Lan, Jing Zhao, Hua-Hao Shen, Giovanni Selvaggi, Wen Li. Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4131.

Background: Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related death in women worldwide. Pyroptosis and long noncoding RNAs (lncRNAs) have been demonstrated to play vital roles in the tumorigenesis and development of BC. However, the clinical significance of pyroptosis-related lncRNAs in BC remains unclear. Methods: Using the mRNA and lncRNA profiles of BC obtained from TCGA dataset, a risk model based on the pyroptosis-related lncRNAs for prognosis was constructed using univariate and multivariate Cox regression model, and least absolute shrinkage and selection operator. Patients were divided into high- and low-risk groups based on the risk model, and the prognosis value and immune response in different risk groups were analyzed. Furthermore, functional enrichment annotation, therapeutic signature, and tumor mutation burden were performed to evaluate the risk model we established. Moreover, the expression level and clinical significance of the selected pyroptosis-related lncRNAs were further validated in BC samples. Results: 3,364 pyroptosis-related lncRNAs were identified using Pearson's correlation analysis. The risk model we constructed comprised 10 pyroptosis-related lncRNAs, which was identified as an independent predictor of overall survival (OS) in BC. The nomogram we constructed based on the clinicopathologic features and risk model yielded favorable performance for prognosis prediction in BC. In terms of immune response and mutation status, patients in the low-risk group had a higher expression of immune checkpoint markers and exhibited higher fractions of activated immune cells, while the high-risk group had a highly percentage of TMB. Further analyses in our cohort BC samples found that RP11-459E5.1 was significantly upregulated, while RP11-1070N10.3 and RP11-817J15.3 were downregulated and significantly associated with worse OS. Conclusion: The risk model based on the pyroptosis-related lncRNAs we established may be a promising tool for predicting the prognosis and personalized therapeutic response in BC patients.

The ADAURA study aims to explore the optimal adjuvant strategy in patients with resectable stage IB-IIIA non-small cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor (EGFR) mutations. The improved disease-free survival (DFS) observed in the osimertinib group was rather impressive with HR as low as 0.20. Very recently, an exploratory analysis of adjuvant chemotherapy use and outcomes have been reported, the HR of DFS in patients with adjuvant chemotherapy was further improved to 0.16. We thus have pretty high expectations for the survival data. Notably, previous studies, such as SELECT and ADJUVANT trails, assessing adjuvant first-generation EGFR-TKI in NSCLC, only showed delayed recurrence without altering the disease prognosis. In the ADAURA study, whether dramatic DFS advantage would be translated into survival benefit would be determined by some key points. First, to figure out the contribution of adjuvant chemotherapy in the osimertinib group. Current evidence has demonstrated the value of the adjuvant osimertinib compared to placebo, at least in terms of DFS, no matter in the adjuvant chemotherapy group or no adjuvant chemotherapy group (Table 1). The HR of DFS in patients with adjuvant

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

Abstract BackgroundThe involvement of gastrointestinal (GI) symptoms in the progression of illness in COVID-19 patients has not been illustrated, with the association between GI symptoms and illness severity remaining controversial. The present study aimed to evaluate the association between GI symptoms and the illness progression, severity, and prognosis in COVID-19 patients.MethodsThis study retrospectively recruited consecutive patients with laboratory-confirmed COVID-19 from three hospitals in Wuhan. The severity of illness was classified as non-severe and severe for analyses. The primary outcome was the association between GI symptoms and progression from non-severe to severe illness (PNTS) in COVID-19 patients. ResultsOf the 934 COVID-19 patients (mean age 59.3 years; 43.7% males), the prevalence of overall and specific GI symptoms at/prior to admission were 59.9% and 13.0%, respectively. Patients with GI symptoms were associated with increased risk of fever (56.1% vs. 48.1%; P=0.02), increased IL-6 (18.2% vs. 11.7%; P=0.04), ground-glass opacity (56.8% vs. 43.1%; P<0.001), bilateral pneumonia (80.4% vs. 72.3%; P=0.005), secondary infections (12.6% vs. 6.5%;, P=0.003), and hypoalbuminemia (26.2% vs. 18.4%; P=0.01). Patients with GI symptoms had a higher risk for PNTS (2.9% vs. 0.6%; P=0.02), even after full adjustments (OR, 6.50; (95%CI:1.34-31.6); P=0.02), but comparable risk for severe illness or deaths. GI symptoms and the specific GI symptoms were identified as the independent risk factors for PNTS.Conclusions The occurrence of GI symptoms is proved to be an independent risk factor for PNTS, which might be a predicting indicator in the prevention of illness deterioration at an early stage.

Objective To explore the effect and significance of clinical pathway guided teaching in the residency standard training program of respiratory medicine. Methods Total 47 resident physicians were selected and divided into clinical pathway group and control group from March 2014 to November 2014. The pathway group (n=24) was introduced into the teaching guided by clinical pathway management. The control group (n=23) was taught by traditional teaching method. All physicians were tested for the basic theory and the ability of case analysis after 4 weeks training. The ability of chemotherapy strategy ordered by residents independently and correctly was assessed each week during training. A satisfaction questionnaire survey was conducted to evaluate the effectiveness and satisfaction of teaching guided by clinical pathway. GraphPad Prism 5.0 was used and T test was done for comparison of data between groups. Results The medical records about basic theory and case analysis in the pathway group was higher than those in the control group with significant statistical difference (P<0.05). The records of resident physicians who could issue orders for chemotherapy independently and correctly were (70.75±2.79), (81.43±1.91), (85.23±1.3), (90.62±2.34) in the pathway group and (69.65±2.06), (77.11±2.21), (80.3±1.96), (87.78±2.21) in the control group at each week time point. There was statistical increase of the records in the pathway group than in the control group since the second week time point (P<0.05) The overall satisfaction of the pathway group was 95.84%(23/24), and the teaching satisfaction was higher than that of the control group(91.29%, 21/23). Pathway group doctors believe that the relevant teaching effectively improve the level of their knowledge , experience and ability. Conclusions The teaching method guided by clinical pathway is help-ful to standardize the teaching behavior, develop the standardized medical behavior of resident physicians, improve their clinical working ability efficiently, promote the relationship between teaching and studying, which is worth application in the residency standard training program of respiratory medicine.

Background Though the possibility of using malignant pleural effusions (MPEs) as alternatives for metastatic pleural tumor tissues (MPTTs) in epidermal growth factor receptor (EGFR) mutation test has been examined, due to the lack of studies comparing the results in matching MPEs and MPTTs, the clinical value of MPEs for advanced adenocarcinoma patients with pleural effusions is not confirmed. Methods EGFR mutation statuses in matching MPTTs, MPE supernatants and cell blocks, of 41 patients with advanced lung adenocarcinoma as diagnosed by thoracoscopy were analyzed using amplification refractory mutation system (ARMS). Results EGFR mutations were detected in 46.3% (19/41) of MPTTs, 43.9% (18/41) of MPE supernatants and 56.3% (18/32) of MPE cell blocks by ARMS analysis. Generally, the same EGFR statuses were identified in both MPTTs and matching MPE cell blocks of 81.3% patients (26/32), whereas MPTTs and matching MPE supernatants of 87.8% (36/41) patients shared the same EGFR status. Compared with EGFR mutation detection in MPTTs, the sensitivity of EGFR mutation detection in MPE-cell blocks was 87.5% (14/16), specificity was 75.0% (12/16), while the sensitivity of EGFR mutation detection in MPE-supernatants was 84.2% (16/19), specificity was 90.9% (20/22). Conclusions The high concordance of EGFR mutation statuses between MPEs and MPTTs in lung adenocarcinoma patients with pleural metastasis as determined by ARMS analysis suggests that MPEs, particularly MPE supernatants, may be substitutes for MPTTs in EGFR mutation test.

The reform of standardized training for resident physicians in Shanghai will help to train personnel at all levels of clinical medicine and promote the sustainable development of health.The residents participated in training have characteristics of wide range of sources,uneven,bilateral choice,and strong liquidity.The key need to be resolved is how to improve the effect of training.According to the situation of training base,this paper describes how to use a variety of training methods to improve the effects of training in respiratory specialist.