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Objectives Afatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the toxicity associated with this agent often leads to dose modifications. The aim of this study was to assess the efficacy, safety and plasma concentrations of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC. Patients and Methods This was a multicenter, single-arm, open-label, phase II trial involving treatment-naive patients with advanced EGFR mutation-positive NSCLC. From March 2017 to September 2018, 53 patients were enrolled from 21 institutions in Japan. Patients initially received afatinib 20 mg/day orally. For patients in whom the tumor progressed within stable disease, the investigators were able to increase the afatinib dose (10 mg increments). The primary endpoint was progression-free survival (PFS). The threshold and expected median PFS was 9.2 and 13.8 months, respectively. Additionally, the correlation of the plasma concentration of low-dose afatinib with clinical outcome and adverse events were evaluated. Results The median age of patients was 70 years (range: 37–85 years); 28 patients (52.8%) were females. The median duration of the follow-up was 20.8 months. The median PFS, and overall survival were 12.6 months (90% confidence interval [CI]: 9.7–14.3 months), and not reached, respectively. The primary endpoint was met. The objective response rate and disease control rate were 66.0% (95% CI: 51.7–78.5) and 92.5% (95% CI: 81.8–97.9), respectively. Grade ≥ 3 adverse events occurred in 12 patients (22.6%), including diarrhea in four patients (7.5%). The rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib. Conclusion Based on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC.

Background Homeless persons are those who carry out their activities of daily living in city parks and other facilities. Little is known about homeless patients with lung cancer in Japan. Therefore, we characterized the clinical features and outcomes of homeless people in metropolitan Tokyo. Methods Between January 2014 and August 2018, 2,068 homeless patients were admitted to the homeless patient care unit at Tokyo Saiseikai Central Hospital. Of these, 13 patients were treated for primary lung cancer. We retrospectively analyzed the patients' clinical characteristics, including their age, gender, treatment, and outcome, obtained from the hospital's electronic medical records. Results A total of 13 patients were treated for lung cancer. The median age was 66.2 (range, 51-77) years old. Twelve patients (92.3%) were smokers. All of the patients were men and had advanced lung cancer. Of these, four patients had adenocarcinoma, four had squamous carcinoma, and four had other histologies. Ten patients received chemotherapy, and 3 received chemoradiotherapy (carboplatin, n=8; cisplatin, n=2, immune check point inhibitor, n=2; other, n=1). Of the patients on first-line treatment, 58% discontinued treatment, with 71% doing so willfully. The median overall survival was 7.5 (1-44) months. During the study, nine patients died in the hospital, and four were lost to follow up. Conclusion It is difficult for homeless patients to continue chemotherapy, and they often quit therapy willfully. Therefore, it is necessary to develop an education and health insurance support system to ensure treatment continuity in a good social environment.

Background As far as we know, there are no reports comparing the safety and cough frequency of transnasal bronchoscopy (TNB) with transoral bronchoscopy (TOB). Methods The subjects were 50 patients who underwent either TNB or TOB and completed the pain score questionnaire between May and November 2020. Complications, pain scores, and cough frequency (times per minute) were compared between the patients with TNB and TOB. A surgical mask was worn over the mouthpiece during the examination. Results Thirty-two and 18 patients underwent TNB and TOB, respectively. Between the two groups, there were no significant differences in examination time and frequency of serious complications. In pain scores, there were no significant differences in terms of anesthesia suffering, several pains during the examination, and availability of re-examination. The TNB group did not feel the prolonged examination time compared to the TOB group (p=0.04). Cough frequency was lower in the TNB group than in the TOB group (0.36 vs 0.73, p=0.027). Moreover, cough frequency in the 25 TNB patients who underwent thin bronchoscopy was significantly lower (0.19 vs 0.73, p0.01). Conclusions TNB with a surgical mask was well tolerated and safe. Cough frequency in the transnasal thin bronchoscopy was extremely low, suggesting aerosol reduction can be expected.

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

Background Precision medicine in non-small cell lung cancer requires attainment of a sufficient amount of high-quality tumor tissue. Transbronchial cryobiopsy has emerged as a new diagnostic method for non-neoplastic lung disease with a better potential to assess morphology compared with conventional methods. However, the influence of cryobiopsy on specimen quality, particularly detection of protein expression, is unknown. We performed a comparative immunohistochemical study in specimens obtained by cryobiopsy versus conventional sampling to evaluate the feasibility of cryobiopsy for lung cancer diagnosis. Methods Pairs of artificial biopsy specimens, collected using a cryoprobe or conventional scalpel, were obtained from 43 surgically resected primary lung tumors. Formalin-fixed, paraffin-embedded blocks were prepared in an ISO15189-certified laboratory. Immunohistochemical staining of thyroid transcription factor-1, p40, Ki67 and programmed death-ligand 1 (22C3) was performed. The H-scores for thyroid transcription factor-1 and p40, labeling index for Ki67 and tumor proportion score for programmed death-ligand 1 were assessed. Pearson’s correlation coefficients between two sampling types were calculated. Results The thyroid transcription factor-1 and p40 H-scores showed perfect correlations between the cryobiopsy and conventional scalpel-obtained specimens (R2 = 0.977 and 0.996, respectively). Ki67 labeling index and PD-L1 tumor proportion score also showed strong correlations between the two sample types (R2 = 0.896 and 0.851, respectively). Five cases (11.6%) exhibited differences in tumor proportion score category between sample types, potentially because of intratumoral heterogeneity. Conclusions Immunohistochemical expression of certain tumor markers showed a high concordance between cryobiopsy and conventional scalpel sampling. Cryobiopsy is feasible for pathological diagnostics including PD-L1 evaluation.

Photodynamic therapy (PDT) with Talaporfin sodium (Talaporfin) is an effective and safe treatment for central-type early-stage lung cancer (CELC) that is associated with less skin photosensitivity. However, PDT is mostly performed in hospital for the purpose of light shading management in Japan. It is expected that it will be possible to perform PDT with Talaporfin (Talaporfin-PDT) as a day treatment with ≥14 days of shading management at home. This study aimed to confirm the safety of Talaporfin-PDT as day treatment.We retrospectively investigated the occurrence of adverse events among consecutive patients who received PDT for CELC in a day treatment setting in the Respiratory Endoscopy Division of our institution between January 2010 and February 2020.A total of 12 patients (16 treatments) received day treatment of Talaporfin-PDT. Among the 12 patients, one patient (one treatment) was followed at another hospital. No severe adverse events after treatment were observed among the remaining 11 patients (15 treatments). Mild photosensitivity on a photosensitivity test was observed in 3 (3 treatments) of the 11 patients (15 treatments) but no major photosensitivity was observed. This photosensitivity was a temporary reaction.Talaporfin-PDT for CELC was safely performed as a day treatment.

Immunotherapy using immune checkpoint inhibitors (ICIs) has improved the prognosis of many cancers, including lung cancer. The mechanisms of development of immune-related adverse events (irAEs) after treatment with ICIs are not completely understood. Because ICIs can exacerbate opportunistic infections by altering immune conditions, potential opportunistic infections such as those caused by Epstein–Barr virus (EBV) may be involved in the development of irAEs. However, there is a lack of clinical findings that indicate the relationship between irAEs and potential opportunistic infections. Herein, we present the case of a 67-year-old man with advanced lung adenocarcinoma who developed encephalitis after the third cycle of pembrolizumab administration. Polymerase chain reaction using cerebrospinal fluid and blood samples revealed positive results for EBV. An autopsy examination revealed lymphocyte infiltration in the area surrounding the EBV-infected cells in the brain. Our case suggests that immune reconstitution occurred after the administration of ICIs, followed by an enhanced immune response to EBV that resulted in fatal encephalitis. Additional findings regarding the interaction between irAEs and opportunistic infections should be acquired to confirm this speculation.

Simple Summary Next-generation sequencing (NGS) with specimens obtained through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been used to identify cancer-related genes among patients with lung cancer. However, the reported success rates vary, and the clinical factors associated with successful NGS remain unclear. We retrospectively reviewed consecutive patients with non-small-cell lung cancer who underwent EBUS-TBNA for NGS (OncomineTM Dx Target Test). The numbers of punctures and core tissues, as well as computed tomography (CT) and EBUS findings, were evaluated. The success rate of NGS was 83.3% (130/156). The cut-off value for the number of core tissues was 4, and the sensitivity and specificity for successful NGS were 73.8% and 61.5%, respectively. CT and EBUS findings were not associated with successful NGS. In logistic regression analysis, the number of core tissues (≥4) was the sole predictor of successful NGS. Bronchoscopists should obtain sufficient core tissues for successful NGS using EBUS-TBNA specimens. Abstract The success rate of next-generation sequencing (NGS) with specimens obtained through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) among patients with lung cancer as well as the related clinical factors remain unclear. We aimed to determine the optimal number of punctures and core tissues during EBUS-TBNA for NGS in patients with non-small-cell lung cancer (NSCLC) as well as the association of chest computed tomography (CT) and EBUS findings with successful NGS. We retrospectively reviewed 156 consecutive patients with NSCLC who underwent EBUS-TBNA for NGS (OncomineTM Dx Target Test). Using the receiver operating characteristic curve, we calculated the optimal numbers of punctures and core tissues for NGS and evaluated CT and EBUS findings suggestive of necrosis and vascular pattern within the lesion. The success rate of NGS was 83.3%. The cut-off value for the number of core tissues was 4, and the sensitivity and specificity of successful NGS were 73.8% and 61.5%, respectively. Logistic regression analysis revealed that the number of core tissues (≥4) was the sole predictor of successful NGS. CT and EBUS findings were not associated with successful NGS. Bronchoscopists should obtain sufficient core tissues for successful NGS using EBUS-TBNA specimens.

BACKGROUND Malignant pleural mesothelioma (MPM) is rarely an asbestos-related cancer with a poor prognosis that is difficult to distinguish from some benign conditions by using conventional biopsy techniques. The purpose of this study was to evaluate the utility of a novel biopsy technique using a cryoprobe during flex-rigid pleuroscopy for diagnosing MPM. METHODS Consecutive patients who underwent pleural cryobiopsy during flex-rigid pleuroscopy from June through November 2017 to diagnose the cause of pleural effusion were collected. From these, cases ultimately diagnosed as MPM were selected. Pleural biopsies were performed by using conventional instruments followed by a cryoprobe. The obtained samples were histologically examined and compared with regard to the quality (sample size, tissue depth, and crush rate), immunohistochemical (IHC) staining, and p16 by fluorescence in situ hybridization (FISH). RESULTS In total, five patients ultimately diagnosed as MPM were enrolled. The sample collected was significantly larger for cryobiopsy than conventional biopsy (18.9 mm2 vs. 6.7 mm2, P < 0.001). Full-thickness biopsies were achieved in four cases by using cryobiopsy compared with one case by conventional biopsy. Moreover, the crush rate was significantly less for cryobiopsy than conventional biopsy (9% vs. 35%, P < 0.001). The results of IHC staining and p16 by FISH were similar between biopsy techniques. Cryobiopsy successfully led to accurate diagnosis of MPM in all cases, whereas conventional biopsy was diagnostic in one case. No severe complications developed after either biopsy technique. CONCLUSION Cryobiopsy during flex-rigid pleuroscopy is a feasible and convenient biopsy technique that supports precise diagnosis of MPM.

Background and objective Due to the outbreak of coronavirus disease 2019 (COVID-19), the Japanese Society of Respiratory Endoscopy recommended the omission of throat anesthesia using Jackson’s spray prior to bronchoscopy for preventing aerosol generation. In this survey, we investigated the tolerability of patients toward the omission of anesthesia using Jackson’s spray before bronchoscopy. Methods Group A patients received throat anesthesia with 5 mL of 4% lidocaine using Jackson’s spray prior to bronchoscopy and were then administered pethidine hydrochloride and midazolam intravenously. Group B patients did not receive anesthesia using Jackson’s spray before bronchoscopy. They were administered pethidine hydrochloride and midazolam and were then administered 8% lidocaine several times into the pharynx. A patient distress questionnaire, classified as a five-graded score, was administered to each group after bronchoscopy. Results Seventy patients participated in this study: 39 patients in Group A and 31 patients in Group B. There were no significant differences in their backgrounds. In the questionnaire survey, the distress caused by pre-examination anesthesia in Group A was significantly higher than in Group B (3.03 ± 1.25 vs. 1.23 ± 0.62; p < 0.0001), and no significant differences were observed in the other questions during bronchoscopy. Conclusion This study demonstrates the tolerability of patients toward the omission of throat anesthesia using Jackson’s spray prior to bronchoscopy, which is recommended for preventing infection, including COVID-19.

A 76-year-old man was admitted to our hospital with Guillain-Barré syndrome (GBS), presenting with facial palsy, dysarthria, and dysphagia as Grade 3 immune-related adverse events (irAEs) due to pembrolizumab administration for Stage IV lung adenocarcinoma. Although prednisolone (1 mg/kg) was started for GBS due to the irAE, dark erythema and skin eruptions appeared on the patient’s torso. Then erosion was observed on 18% of the body surface area and skin biopsy was performed. Finally, the patient was diagnosed with Stevens-Johnson syndrome/toxic epidermal necrosis overlap. Intravenous immunoglobulin therapy was started, and the skin symptoms improved, with the erosion becoming epithelial. He died of aspiration pneumonia related to GBS, although his neurological symptoms had improved after steroid and intravenous immunoglobulin therapy. This is the first reported case of pembrolizumab-induced GBS and Stevens–Johnson syndrome/toxic epidermal necrosis overlap. It is necessary to be careful that the possibility of other severe irAEs may occur simultaneously.

The treatment of lung cancer is one of the major challenges in the field of oncology. According to statistics from the National Cancer Center of China in 2015, lung cancer has the highest incidence and mortality, with 733,300 new cases and 610,200 deaths across the country (1). About 85% of lung cancers are non-small cell lung cancer (NSCLC), of which 30% to 40% are considered resectable tumors, including most stage I-II and a small portion of stage IIIA tumors (2). Very early-stage NSCLC (IA) can be cured by surgery. However, more than 50% of NSCLC patients who undergo surgical treatment will relapse or metastasize within 5 years. Even if there is no lymph node metastasis and the primary

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL. The patient was a 71-year-old female admitted to our hospital with hypoxia. On admission, chest computed tomography revealed a ground-glass opacity. Interstitial pneumonia associated with systemic scleroderma was suspected because of positive anti-centromere antibody. Thereafter, steroid pulse therapy and plasma exchange were performed. Although ground-glass opacity improved, bilateral pleural effusion appeared, so we performed a random skin biopsy because of her elevated serum lactate dehydrogenase and soluble interleukin-2 receptor levels. The patient was diagnosed with IVLBCL with symptoms improving after 6 cycles of rituximab plus chemotherapy treatment.

A 66-year old man with non-smoking history was diagnosed with pulmonary pleomorphic carcinoma of the right lower lobe. The carcinoma metastasized to the brain, lungs, pleura, and mediastinal lymph nodes. It was positive for epidermal growth factor receptor (EGFR) L858R mutation, and tumor cells highly expressed programmed death-ligand 1(PD-L1). Atezolizumab was initiated as the fourth treatment. After three days, he developed cardiac tamponade and immediately underwent pericardial drainage. Computed tomography showed bilateral ground-glass opacity (GGO), significant worsening of multiple lung metastases, and increased size of metastatic lesions. Newly developed metastasis was noted in the lung, and the patient's respiratory condition rapidly deteriorated. He died of respiratory failure on day 13 after atezolizumab administration. The autopsy showed widespread metastasis in all lobes of the bilateral lungs, cardiac tamponade due to carcinomatous pericarditis, carcinomatous lymphangiopathy, and multiple lung metastases, which were thought to be comprehensively the cause of death. These symptoms suggested hyperprogressive disease (HPD). Hence, we report the first case of HPD following atezolizumab therapy for pulmonary pleomorphic carcinoma with EGFR mutation.

BackgroundFungal infections are rarely reported as a complication of bronchial thermoplasty (BT) in patients without immunosuppressive comorbidity.Case presentationA 19-year-old woman college student was admitted to our hospital owing to uncontrolled severe asthma despite using the maximum dose of steroid inhalation. She experienced asthmatic attacks more frequently while cheerleading, which is an extracurricular activity. She received BT because she wanted to continue cheerleading. After the second BT session, she developed more sputum and cough. During the third session, white secretion and saccular bronchodilation appeared in the left lower bronchus. Aspergillus fumigatus was detected in the culture of the bronchial lavage sample, and saccular bronchodilation in the affected bronchus was observed on computed tomography (CT). Five months after the start of oral itraconazole, her subjective symptoms as well as her CT findings improved. Her asthma condition improved enough for the patient to continue cheerleading without exacerbation.ConclusionsIt is necessary to consider the possibility of respiratory tract infections including fungal infections after BT. Detailed observations of the entire bronchus and sample collection for microbial culture are highly recommended.

Background Bronchoscopy is important to diagnose lung cancer. However, some patients who undergo bronchoscopic procedures develop respiratory tract infections. Little is known about the proportion of pathogen-positive results in bacterial cultures from diagnostic bronchoscopy samples in patients with suspected lung cancer. This study aimed to determine the rate of positive bacterial cultures after diagnostic bronchoscopy in patients with suspected lung cancer and the relationship among culture results, clinical characteristics, and respiratory tract infections. Methods We retrospectively reviewed the medical records of all immunocompetent patients who underwent bronchoscopy and had culture and histological samples for the diagnosis of peripheral pulmonary lesions from September 2012 to August 2014 at the National Cancer Center in Tokyo. We analyzed data and classified radiological lesions into the following categories: calcifications, cavitations, low-density areas, margin irregularities, and satellite nodules. Results The study population consisted of 328 patients (median age, 69 years). We found that 65.9% of patients had malignant lesions and 4.2% of patients had positive cultures for pathogenic bacteria. The number of calcifications (p = 0.002, 95% CI: 2.17–41.10) was significantly higher in patients with positive bacterial isolates, according to the multivariate analysis, and bacterial culture positivity was not associated with the development of respiratory complications after bronchoscopy. Of the three patients with respiratory complications, all presented with cavitations. Conclusion Because of the low prevalence of positive bacterial cultures in patients with suspected lung cancer, bacterial culture may be limited to specific patients, such as those with calcifications. Lesions with cavitation warrant close monitoring.

Background Malignant pleural effusion is a commonly seen complication of malignancies such as lung and breast cancers. In Western countries, talc is frequently used as a standard therapeutic agent (pleurodesis agent) with the aim of alleviating symptoms including dyspnea and chest pain. Talc is not recognized as a pleurodesis agent in Japan. The aim of this study was to verify the efficacy and safety of sterilized talc (NPC-05) for the introduction of talc in Japan. Methods The study was a single-arm, open-label, investigator-initiated trial conducted jointly at six institutions. The subjects were 30 patients with malignant pleural effusions. A solution of 4 g NPC-05 suspended in 50 ml physiological saline was instilled into the pleural space to perform pleurodesis. Results The efficacy of NPC-05 for pleural adhesion 30 days after pleurodesis was 83.3% (25/30 cases). Amelioration of dyspnea and pain (chest pain) was seen. Commonly seen adverse effects were increased C-reactive protein (CRP) and fever. Nearly all adverse events were phenomena previously reported as adverse effects of talc. No acute respiratory distress syndrome (ARDS) or other serious side effects occurred. Conclusion The efficacy and safety of NPC-05 for malignant pleural effusion in Japanese patients was verified, and the clinical outcomes with talc were confirmed to be the same as previously reported in other countries. There is thought to be a high level of need for this agent in the treatment of malignant pleural effusion in Japan.

Background Endobronchial ultrasound-guided transbronchial needle aspiration is a standard method for obtaining specimens of mediastinal and hilar lesions. Several types of needles of various sizes and materials are available. This study aimed to compare the quality of specimens collected using two needles, cobalt chromium and stainless steel for endobronchial ultrasound-guided transbronchial needle aspiration. Methods This retrospective study included data of patients who underwent EBUS-TBNA with a 22-gauge needle made from either stainless steel (41 lesions, 121 punctures) or cobalt chromium (47 lesions, 145 punctures). Histological data per puncture, diagnostic yield per lesion, procedure time and complication rates were compared. Results There were no significant differences between the groups in the baseline characteristics of the patients or lesions or in the complication rates. The rate of diagnostic histological specimens in each sample (71.0% vs. 58.7%, P = 0.039), fewer samples with cartilage alone (1.4% vs. 6.6%, P = 0.047) and fewer samples containing cartilage (7.6% vs. 16.5%, P = 0.034) were seen in the cobalt chromium needle group than in the stainless steel needle group. In both groups, the rate of specimens that only contained blood clots in each sample and diagnostic yield per lesion were similar, but the procedure time was significantly shorter (22 min vs. 26 min, P = 0.007) in the cobalt chromium needle group. Conclusion Compared with stainless steel needles, cobalt chromium needle for EBUS-TBNA showed lower cartilage contamination and a higher ratio of obtaining diagnostic specimens in each sample. Bronchoscopists should consider using the optimal needle gauges and materials for collecting adequate specimens.

Non-small cell lung cancer (NSCLC) is the most common and fatal tumor worldwide, with 2.1 million new cases and 1.77 million deaths per year (1). With the wider application of examination approaches and the improvement of health awareness, higher proportions of surgically resectable early and mid-stage lung cancers have been detected. In overall, only 50% of patients have been cured after radical resection. In other cases, however, NSCLC is highly active and recurrence and/or metastasis can easily occur after surgery. In these patients, systemic therapy as a postoperative adjuvant therapy is required to eliminate or reduce residual micro-lesions to lower the risk of recurrence; meanwhile, the patients should be closely monitored to detect early recurrence. EGFR mutation is a major mutation type in lung cancer, and is seen in about 40% of lung cancer cases in Asia (2). Compared with wild types and other mutation types, EGFR-mutant NSCLC has its unique biological properties and drug susceptibilities, and thus requires specific diagnosis and treatment strategies. This expert consensus aims to review the current evidence and provide recommendations on key issues. A consensus and guideline development panel, with its members including top thoracic surgeons and oncologists all around the world, was established to decide the methodologies, processes, levels of evidence, and related recommendations. The panel members proposed the core clinical issues in the consensus document and wrote and submitted the outlines to the panel for approval. The panel carried out a problem-oriented literature search for articles published since 1997 in Chinese and foreign databases. The level of evidence was defined using the following criteria: Categories of Evidence and Consensus, Category 1: based upon high-level evidence, there is uniform consensus that the intervention is appropriate; Category 2A: based upon lower-level evidence, there is uniform consensus that the intervention is appropriate; Category 2B: based upon lower-level evidence, there is consensus that the intervention is appropriate; Category 3: based upon any level of evidence, there is major disagreement that the intervention is appropriate. The strength of recommendations was classified as strong or weak according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system (3), and the recommendation statement was composed based on the real-world evidence. A “strong” recommendation generally refers to recommendations based on high-level evidence with consistency between clinical behavior and outcome expectancy; in contrast, a “weak” recommendation is typically based on low-level evidence with uncertainty between clinical behavior and outcome expectancy. After the first draft had been completed, all the panel members were involved in revising and finalizing this document.