Recurrent pleural effusion as a rare manifestation after prolonged PD1 inhibitor (camrelizumab)-based immunotherapy: A case report.

Immune-related adverse events (irAEs) pose a significant challenge for the widespread adoption of immuno-oncology therapies, but their symptoms can vary widely. In particular, the relationship between irAEs and pleural effusion (PE) in patients with advanced non-small cell lung cancer (NSCLC) remains unclear. In this report, we present the case of an advanced NSCLC patient who developed persistent PE despite receiving camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) and chemotherapy as first-line treatment. While the patient's tumor biomarkers decreased after multiple cycles of treatment, the PE persisted despite negative findings on cytology and pleural biopsy. Additionally, the use of anti-angiogenic drugs failed to alleviate the PE. Screening for rheumatic connective tissue markers and tuberculosis yielded negative results, but intrathoracic dexamethasone injections in two doses resulted in a significant reduction of the PE. This case suggests that PE may represent a rare type of irAE that should be monitored for during prolonged immuno-oncology therapy.

Education level has an effect on the recovery of total knee arthroplasty: a retrospective study.

OBJECTIVE: This study aimed to observe the relationship between education level and outcomes after total knee arthroplasty (TKA). METHODS: One thousand two hundred sixty four patients after TKA in our hospital from April 2016 to April 2020 were reviewed. These patients were divided into 4 groups (A who were illiterate, B who had elementary school degree, C who had junior high school degree, D who had senior high school degree or higher) by the educational level, which was blinded to the observers. The postoperative outcomes of KSS score, pain, joint extension and flexion function were observed 1 year after discharged from hospital. RESULTS: Among 1253 patients met the inclusion criteria, the average age was 68.63 years, the average body mass was 57.73 kg. There are no distinctions among 4 groups one day after the surgery. However, the outcomes of the follow up were that, the KSS score was: 77.84 ± 10.635; 80.70 ± 8.956; 87.92 ± 8.123;91.27 ± 8.262, with significant differences (P < 0.05). The mean VAS scores were: 1.97 ± 1.60; 2.07 ± 1.66; 1.197 ± 1.5265, 1.044 ± 1.4662. Patients in Group C and D had significantly less pain than that in Group A and B (P < 0.05). The knee flexion range of motion (ROM) was: 91.21 ± 11.69°; 91.77 ± 11.95°; 102.12 ± 11.38°; 109.96 ± 10.64°, Group D performed best, with significant differences (P < 0.05). The knee extension ROM were: - 2.41 ± 4.49°; - 0.91 ± 2.82°; - 0.83 ± 2.87°; - 0.35 ± 1.60°, with significant difference between Group D and the others (P < 0.05). CONCLUSION: Education level affects the outcomes such as VAS score, KSS score, the extension and flexion ROM of the knee after TKA. The patients with higher education level have better outcomes.

Case Report: Nintedanib for Pembrolizumab-Related Pneumonitis in a Patient With Non-Small Cell Lung Cancer.

Pembrolizumab, an immune checkpoint inhibitor (ICI) approved for advanced non-small cell lung cancer (NSCLC) treatment, has shown superior survival benefits. However, pembrolizumab may lead to severe immune-related adverse events (irAEs), such as checkpoint inhibitor-related pneumonitis (CIP). The routine treatment of CIP was based on systemic corticosteroids, but the therapies are limited for patients who are unsuitable for steroid therapy. Here, we present the first successful treatment of nintedanib for pembrolizumab-related pneumonitis in a patient with advanced NSCLC.

[Locking plate external fixation combined with membrane induction technology for the treatment of open and comminuted tibial fractures with bone defects].

OBJECTIVE: To explore clinical effect of locking plate external fixation combined with membrane induction technology in treating open and comminuted tibial fractures with bone defects. METHODS: Totally 92 patients of open and comminuted tibial fractures with bone defects were chosen form January 2018 to July 2019, and randomly divided into external fixation group and internal fixation group, 46 patients in each group. In external fixation group, there were 29 males and 17 females, aged from 25 to 62 years old, with an average of (37.45±10.92) years old;according to AO classification, 15 patients were type A, 22 patients were type B and 9 patients were type C;according to Gustilo classification, 21 patients were typeⅡ, 10 patients were type ⅢA, 10 patients were type ⅢB, 5 patients were type Ⅲ C;treated by fracture reduction with locking plate external fixation. In internal fixation group, there were 31 males and 15 females, aged from 23 to 60 years old, with an average of(36.88±10.64) years old;according to AO classification, 18 patients were type A, 20 patients were type B and 8 patients were type C; according to Gustilo classification, 22 patients were typeⅡ, 11 patients were type ⅢA, 7 patients were type ⅢB, 6 patients were type Ⅲ C;treated by traditional open reduction with plate internal fixation. Operation time, intraoperative blood loss, incision length, hospital stay, fracture healing time and lower limb full weight-bearing time and postoperative complications between two groups were observed and compared, bone mineral density, osteocalcin, blood calcium and phosphorus before operation and 1 month after operation. RESULTS: All patients were followed up from 12 to 18 months with an average of (14.92±2.46) months. Operation time, intraoperative blood loss, incision length, hospital stay, fracture healing time and lower limb full weight-bearing time of external fixation group were significantly better than that of internal fixation group(P<0.05). Postoperative bone mineral density, osteocalcin, blood calcium and phosphorus at 1 month in external group were higher than that of internal fixation group (P<0.05). Four patients in external fixation group occurred complications, 13 patients in internal fixtaion group, and occurrence rate of complications in external fixation group (8.70%) was lower than that of internal fixtaion group (28.26%)(χ2=4.618, P=0.032). CONCLUSION: Locking plate external fixation combined with membrane induction technology in treating open and comminuted tibial fractures with severe post-traumatic bone defects has advantages of less trauma, reliable fixation, shorter fracture healing time, and could improve bone metabolic activity with less postoperative complications.

Case Report: Neoadjuvant and Adjuvant Crizotinib Targeted Therapy in Stage IIIA-N2 ALK-Positive Non-Small-Cell Lung Cancer.

The treatment of anaplastic lymphoma kinase (ALK)-positive locally advanced non-small-cell lung cancer (NSCLC) is challenging because there is no randomized controlled trial has been reported. The value of neoadjuvant and adjuvant targeted therapy remains unclear. Herein, we show that systemic treatment with ALK inhibitor crizotinib before surgery can provide the potential to cure the initially inoperable tumor. A 27-year-old man was diagnosed with a stage IIIAcT3N2M0 (7thUICC/AJCC) upper left lung adenocarcinoma harboring EML4-ALK fusion gene. Clinically, the patient had a large primary lesion adjacent to the pericardium and regional lymph node metastasis at the ipsilateral mediastinum. Poor tumor response was observed after 3 cycles of chemotherapy (gemcitabine plus cisplatin), and upon multidisciplinary discussion, the patient was started with 250 mg crizotinib twice daily. Successive clinical examinations showed a progressive reduction of the lesions. After 2 months of therapy, the patient was downstaged to cT2aN2M0, then video-assisted thoracic surgery was performed and the final histopathological stage was ypT2aN2M0. The treatment with crizotinib (250 mg, qd) was continued more than 30 months post surgery and stopped until intracranial oligometastasis. The patient's overall survival (OS) time is 68 months at last follow-up. This case presented here supports the use of neoadjuvant and adjuvant treatment with ALK inhibitors in ALK positive locally advanced NSCLC.

Erratum to risk factors and predictors associated with the severity of COVID-19 in China: a systematic review, meta-analysis, and meta-regression.

[This corrects the article DOI: 10.21037/jtd-20-1743.].

Anlotinib Plus S-1 for Patients with EGFR Mutation-Negative Advanced Squamous Cell Lung Cancer with PS Scores of 2-3 After Progression of Second-Line or Later-Line Treatment.

OBJECTIVE: The study aimed to analyze the efficacy and safety of combination regimen of anlotinib and S-1 for Chinese patients with EGFR mutation-negative advanced squamous cell lung cancer (SqCLC) with poor performance status (PS,2-3) after progression of second-line or later-line chemotherapy. METHODS: Clinical data of 70 SqCLC patients with PS scores of 2-3 treated in the First Affiliated Hospital of Guangzhou Medical University between January 1, 2018 to September 31, 2019 who failed second- or more-line treatment were analysed retrospectively. The patients were divided into two treatment groups: anlotinib (12mg) plus S-1 (25mg) combination group and anlotinib (12mg) monotherapy group. The efficacy and adverse reactions of the two groups were compared. RESULTS: In terms of the short-term efficacy, there were no significant differences in objective response rate (ORR) (20.0% vs 10.0%, p = 0.464) and disease control rate (DCR) (75.0% vs 60.0%, p = 0.181) between the two groups. As for the long-term efficacy, there was no significant difference in progression-free survival (PFS) between the two groups (3.87±0.29 months vs 3.00±0.24 months, p=0. 11). The overall survival (OS) of patients in the combination group was longer than S1 group (8.07±0.56 months vs 6.17±0.42 months, p=0.022). CONCLUSION: Advanced SqCLC patients with higher PS scores still benefit from anlotinib and S-1 combination regimen, even after they failed second-line or later-line systemic treatment.

Clinical features, treatment, and survival outcome of primary pulmonary NUT midline carcinoma.

OBJECTIVE: NUT midline carcinoma (NMC), a rare type of squamous cell carcinoma, is genetically characterised by NUT midline carcinoma family member 1 (NUTM1) gene rearrangement. NMC can arise from the lungs; however, there is no standard for the management of primary pulmonary NMC. This study aimed to confirm the clinical features and report the treatments, especially with immune checkpoint inhibitors (ICIs), and outcomes of patients with primary pulmonary NMC. METHODS: A retrospective review of patients with primary pulmonary NMC was performed in the First Affiliated Hospital of Guangzhou Medical University between January 2015 and December 2018. Clinical manifestations as well as radiographic and pathological findings were recorded. Whole-exome sequencing (WES), a predictor for ICI response, was used to determine the tumour mutational burden (TMB). Treatments, especially by immune checkpoint blockade, and patient survival were analysed. RESULTS: Seven patients with primary pulmonary mass (four men and three women) with a mean age of 42 years (range, 23-74) who were diagnosed with NMC according to NUT immunohistochemistry staining were included for analysis. One patient had a rare fusion of CHRM5-NUTM1 by tumour sequencing. A wide range of TMB (1.75-73.81 mutations/Mbp) was observed. The initial treatments included chemotherapy (5/7, 71.4%), surgery (1/7, 14.3%), and radiotherapy (1/7, 14.3%). Five patients (5/7, 71.4%) received ICIs (programmed cell death protein 1 [PD1]/programmed cell death ligand 1 [PDL1] monoclonal antibody) as second- or higher-line treatments. The median overall survival (OS) was 4.1 months (range, 1.5-26.7 months). CONCLUSIONS: Patients with primary pulmonary NMC have a poor prognosis and chemotherapy is often preferred. Checkpoint immunotherapy is a good option as the second- or higher-line treatment. TMB seems to be not associated with OS.

Risk factors and predictors associated with the severity of COVID-19 in China: a systematic review, meta-analysis, and meta-regression.

Since December 2019, the pneumonia cases infected with 2019 novel coronavirus have appeared, posing a critical threat to global health. In this study, we performed a meta-analysis to discover the different clinical characteristics between severe and non-severe patients with COVID-19 to find the potential risk factors and predictors of this disease's severity, as well as to serve as a guidance for subsequent epidemic prevention and control work. PubMed, Cochrane Library, Medline, Embase and other databases were searched to collect studies on the difference of clinical characteristics of severe and non-severe patients. Meta-analysis was performed using RevMan 5.3 software, and the funnel plots could be made to evaluate the publication bias. P>0.05 means no statistical significance. Furthermore, a meta-regression analysis was performed by using Stata 15.0 to find the potential factors of the high degree of heterogeneity (I2>50%). Sixteen studies have been included, with 1,172 severe patients and 2,803 non-severe patients. Compared with non-severe patients, severe patients were more likely to have the symptoms of dyspnea, hemoptysis, and the complications of ARDS, shock, secondary infection, acute kidney injury, and acute cardiac injury. Interestingly, the former smokers were more prevalent in severe cases as compared to non-severe cases, but there was no difference between the two groups of 'current smokers'. Except for chronic liver disease and chronic kidney disease, the underlying comorbidities of hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease (COPD), malignancy, cerebrovascular disease, and HIV can make the disease worse. In terms of laboratory indicators, the decreased lymphocyte and platelet count, and the increased levels of white blood cell (WBC), D-dimer, creatine kinase, lactate dehydrogenase, procalcitonin, alanine aminotransferase, aspartate aminotransferase, and C-reactive protein were more prevalent in severe patients. Meta-regression analysis showed that patient age, gender, and proportion of severe cases did not significantly impact on the outcomes of any clinical indexes that showed high degree of heterogeneity in the meta-analysis. In conclusion, the severity of COVID-19 could be evaluated by, radiologic finding, some symptoms like dyspnea and hemoptysis, some laboratory indicators, and smoking history, especially the ex-smokers. Compared with non-severe patients, severe patients were more likely to have complications and comorbidities including hypertension, cardiovascular disease etc., which were the risk factors for the disease to be severer, but the chronic liver disease and chronic kidney disease were not associated the severity of COVID-19 in China.

Incidence and risk of thromboembolism associated with bevacizumab in patients with non-small cell lung carcinoma.

BACKGROUND: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is effective for the treatment of advanced non-small cell lung cancer (NSCLC). However, severe adverse events (AEs) have been reported in NSCLC patients treated with bevacizumab. Currently, the contribution of Bevacizumab to thromboembolism is still controversial. We conducted a study to determine the overall risk and incidence of thromboembolism with bevacizumab in NSCLC patients. METHODS: Electronic databases such as the PubMed, Web of Science and Cochrane Library were searched for related trials. Statistical analyses were conducted to calculate the overall incidence rates, odds ratios (ORs), and 95% confidence intervals (CIs) by using either random-effect or fixed-effect models depending on the heterogeneity. We also used trial sequence analysis (TSA) to verify the pooled result. RESULTS: A total of 3,555 subjects from nine studies were included. The overall incidence of thromboembolism events in NSCLC patients treated with bevacizumab was 4.8% (95% CI: 1.9-7.7%). Without bevacizumab, this incidence was 2.9% (95% CI: 0.6-5.1%). Bevacizumab use was associated with a significantly increased risk in thromboembolism events (OR =1.74; 95% CI: 1.15-2.62; P=0.008). Subgroup analysis based on the doses showed that bevacizumab administered at 15 mg/kg (OR =1.81; 95% CI: 1.14-2.86; P=0.012), but not 7.5 mg/kg (OR =1.32; 95% CI: 0.78-2.24; P=0.296), increased the risk of thromboembolism. CONCLUSIONS: Bevacizumab is associated with a significantly increased risk of thromboembolism development in NSCLC patients. It may have dose-toxicity relationship and low dose of bevacizumab may be a better choice for NSCLC patients, with equal efficacy and low hazard of thromboembolism events.

Case report: dermatomyositis associated with lung cancer with heterogeneous morphology.

Dermatomyositis (DM) complicated with non-small cell lung cancer (NSCLC) is not rare, and could rapidly develop into severe lung cancer [performance-status score (PS) between 2 and 4]. Moreover, tumor has remarkable heterogeneity, and it is not possible to properly target treatments in cases of relapse without knowing pathological diagnosis. We retrospectively analyzed the diagnosis and treatment of a patient with DM complicated with NSCLC, which developed into severe lung cancer with heterogeneity of the tumor during chemotherapy. In this report, we addressed that in patients with severe lung cancer, both the cancer and factors associated with exacerbation should be simultaneously managed to reduce the PS score and avoid unnecessary delay. A second biopsy is important for proper management of the tumor with heterogeneity.

Combretastatin A-4 efficiently inhibits angiogenesis and induces neuronal apoptosis in zebrafish.

Cis-stilbene combretastatin A-4 (CA-4) and a large group of its derivant compounds have been shown significant anti-angiogenesis activity. However the side effects even the toxicities of these chemicals were not evaluated adequately. The zebrafish model has become an important vertebrate model for evaluating drug effects. The testing of CA-4 on zebrafish is so far lacking and assessment of CA-4 on this model will provide with new insights of understanding the function of CA-4 on angiogenesis, the toxicities and side effects of CA-4. We discovered that 7-9 ng/ml CA-4 treatments resulted in developmental retardation and morphological malformation, and led to potent angiogenic defects in zebrafish embryos. Next, we demonstrated that intraperitoneal injection of 5, 10 and 20 mg/kg CA-4 obviously inhibited vessel plexus formation in regenerated pectoral fins of adult zebrafish. Interestingly, we proved that CA-4 treatment induced significant cell apoptosis in central nervous system of zebrafish embryos and adults. Furthermore, it was demonstrated that the neuronal apoptosis induced by CA-4 treatment was alleviated in p53 mutants. In addition, notch1a was up-regulated in CA-4 treated embryos, and inhibition of Notch signaling by DAPT partially rescued the apoptosis in zebrafish central nervous system caused by CA-4.

Effect of tiotropium on neural respiratory drive during exercise in severe COPD.

BACKGROUND: Studies have shown that tiotropium once daily reduces lung hyperinflation and dyspnea during exercise and improves exercise tolerance in patients with COPD. Mechanisms underlying the effects of the muscarinic receptor antagonist tiotropium on COPD have not been fully understood. OBJECTIVE: In this study, we investigated whether improvement in neural respiratory drive is responsible for reducing dyspnea during exercise and improving exercise tolerance in COPD. METHODS: Twenty subjects with severe COPD were randomized into two groups: no treatment (Control, n = 10, 63.6 ± 4.6 years, FEV1 29.6 ± 13.3%pred) or inhaled tiotropium 18 µg once daily for 1 month (n = 10, 66.5 ± 5.4 years, FEV1 33.0 ± 11.1%pred). All subjects were allowed to continue their daily medications other than anti-cholinergics during the study. Constant cycle exercise with 75% of maximal workload and spirometry were performed before and 1 month after treatment. Diaphragmatic EMG (EMGdi) and respiratory pressures were recorded with multifunctional esophageal catheter. Efficiency of neural respiratory drive, defined as the ratio of minute ventilation (VE) and diaphragmatic EMG (VE/EMGdi%max), was calculated. Modified British Medical Research Council Dyspnea Scale (mMRC) was used for the evaluation of dyspnea before and after treatment. RESULTS: There was no significant difference in spirometry before and after treatment in both groups. Diaphragmatic EMG decreased significantly at rest (28.1 ± 10.9% vs. 22.6 ± 10.7%, P < 0.05) and mean efficiency of neural respiratory drive at the later stage of exercise increased (39.8 ± 2.9 vs. 45.2 ± 3.9, P < 0.01) after 1-month treatment with tiotropium. There were no remarkable changes in resting EMGdi and mean efficiency of neural respiratory drive post-treatment in control group. The score of mMRC decreased significantly (2.5 ± 0.5 vs. 1.9 ± 0.7, P < 0.05) after 1-month treatment with tiotropium, but without significantly difference in control group. CONCLUSION: Tiotropium significantly reduces neural respiratory drive at rest and improves the efficiency of neural respiratory drive during exercise, which might account for the improvement in exercise tolerance in COPD.

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma.

OBJECTIVE: The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy. PATIENTS AND METHODS: One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy. RESULTS: The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001). CONCLUSIONS: Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.

Efficiency of neural drive during exercise in patients with COPD and healthy subjects.

BACKGROUND: It is unknown whether efficiency of neural drive as expressed by a ratio of ventilation to the diaphragm electromyogram (EMGdi) in patients with COPD differs from that of healthy subjects during exercise and whether maximal neural drive is exhibited at the point of exercise termination. METHODS: We studied 12 male patients with COPD (mean ± SD age, 62.8 ± 10.3 years; FEV(1), 28.1 ± 10.2% predicted) and 12 age- and sex-matched healthy subjects (age, 61.1 ± 7.2 years, FEV(1), 101.5 ± 11.9% predicted). EMGdi was recorded from a multipair esophageal electrode during a constant work (80% of maximal oxygen consumption derived from a previous incremental exercise test) treadmill exercise. Minute ventilation and oxygen consumption were also measured. RESULTS: Root mean square (RMS) of the EMGdi increased initially and reached a plateau at submaximal drive during constant load exercise in both patients with COPD and healthy subjects. The ratio of ventilation to EMGdi remained stable during exercise in healthy subjects from beginning to the end (100% ± 70% at the beginning and 100% ± 39% at the end, P > .05), whereas the ratio decreased gradually during exercise in patients with COPD (from 85% ± 66% to 42% ± 13%, P < .05). CONCLUSIONS: Efficiency of neural drive decreases in patients with COPD during treadmill exercise. Neural respiratory drive reached a submaximal plateau during constant load exercise in both healthy subjects and patients with COPD, indicating that it may not be the only factor determining exercise capacity.