Serum sphingolipids aid in diagnosing adult HIV-negative patients with pulmonary cryptococcosis: a clinical cohort study.

Background: Pulmonary cryptococcosis (PC) contributes to the ongoing global disease burden in human immunodeficiency virus (HIV)-negative populations. Since some PC patients are misdiagnosed under existing diagnostic guidelines, new diagnostic markers are needed to improve diagnostic accuracy and therapeutic efficacy and reduce disease risk. Methods: Our previously established sphingolipidomic approach was employed to explore the use of serum sphingolipids (SPLs) in diagnosing HIV-negative patients with PC. A clinical cohort of PC, pulmonary aspergillosis (PA), and tuberculosis (TB) patients and healthy controls was assessed to identify SPL biomarkers. Results: A total of 47 PC, 27 PA, and 18 TB patients and 40 controls were enrolled. PC and TB patients had similar clinical features, laboratory test results and radiological features, excluding plural effusion. The serum ceramide [Cer (d18:1/18:0)] level showed a significant increase in PC patients compared to controls and PA and TB patients (P<0.05). Cer (d18:1/18:0) was identified as a specific diagnostic biomarker for PC. The optimal cut-off value of greater than 18.00 nM showed a diagnostic sensitivity of 76.60% and a specificity of 95.00% and better distinguished PC patients from PA and TB patients. Furthermore, the serum Cer (d18:1/18:0) level gradually decreased after 3 and 6 months of treatment, suggesting the prediction potential for therapeutic efficacy of this biomarker. In addition, Cer (d18:1/18:0) analysis presented a higher sensitivity than the cryptococcal antigen (CrAg) assay. Conclusions: This is the first study to report the use of the SPL Cer (d18:1/18:0) as a serum biomarker for diagnosing Cryptococcus spp. infection in HIV-negative patients.

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.

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.

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.

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.

CYP1A1 MspI polymorphisms and lung cancer risk: an updated meta-analysis involving 20,209 subjects.

Published data describing the association between CYP1A1 MspI gene polymorphism and lung cancer risk are inconclusive. To determine a more conclusive relationship, we performed an updated meta-analysis of all eligible studies and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung cancer, gender and smoking status of case and control populations. A total of 51 studies comprising 20,209 subjects were included in the analysis. A significantly elevated lung cancer risk was associated with two variant genotypes (for TT vs CC: OR=1.24, 95% CI=1.11-1.40; for CT and TT combined vs CC: OR=1.19, 95% CI=1.12-1.27) in the overall population. In the stratified analysis, significantly higher risks associated with lung cancer were found in Asians, Caucasians, lung SCC, lung AC and the male population. In contrast, negligible risks were found in the mixed population, lung SCLC and the female population. Additionally, a significant association was found in the smoker population, whereas no association was found in non-smoker populations. This meta-analysis suggests that the MspI polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility, and that there is an interaction between the CYP1A1 polymorphism and smoking. However, the associations vary in different ethnic populations, histological types of lung cancer and the gender of case and control populations.

Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been implicated in tumorigenesis and metastasis, and it presumably mediates the proliferation of endothelial cells and promotes vascular permeability. However, the prognostic value of VEGF overexpression in patients with lung cancer remains controversial. METHODS: Survival data from published studies were aggregated following a methodological assessment. A systematic review of eligible studies with meta-analysis was performed to quantitatively review the correlation of VEGF overexpression with survival in patients with lung cancer. RESULTS: We conducted a final analysis of 5386 patients from 51 studies. The studies were categorized by histology, disease stage, patient race, VEGF isoform, and laboratory techniques used. Combined hazard ratios suggested that VEGF overexpression had an unfavorable impact on survival of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). However, VEGFC and vascular endothelial growth factor receptor 3 (VEGFR3)/flt-1 overexpression did not significantly correlate with survival in patients with NSCLC. In stage I-III NSCLC with VEGF, the hazard ratio (95% confidence interval) was 1.46 (1.38-1.54) overall, 1.35 (1.24-1.46) in Asian patients, 1.61 (1.49-1.73) in non-Asian patients, 1.41 (1.17-1.65) in SCLC, 1.27 (1.06-1.47) in adenocarcinoma, 1.57 (1.43-1.70) in stage I NSCLC, 1.46 (1.38-1.55) in NSCLC by immunohistochemistry, 1.52 (1.23-1.81) in NSCLC by reverse transcription-polymerase chain reaction, 1.22 (0.96-1.47) in NSCLC with VEGFC, and 1.58 (0.96-2.20) in NSCLC with VEGFR3/flt-1. The data collected were not sufficient to determine the prognostic value of VEGF in patients with squamous cell lung carcinomas. CONCLUSION: VEGF overexpression indicates a poor prognosis for patients with NSCLC and SCLC; VEGFC and VEGFR3/flt-1 overexpression was not significantly correlated with survival for patients with NSCLC.

[Effect of heparin upon inflammatory reaction of endotoxin-induced acute lung injury in rat].

OBJECTIVE: To investigate the effects of heparin upon inflammatory reaction and associated mechanism of endotoxin-induced acute lung injury (ALI) in rat. METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into three equal groups namely: ALI group, heparin treatment group and normal control group. The ALI rats were induced by injecting endotoxin intravenously and sacrificed at 4 h after model establishment. The lung histology was scored by a modification of Smith technique. The albumin permeability of pulmonary microvascular (P(alb)) was measured by single nuclide tracer technique. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and von Willebrand factor (vWF) levels of serum were determined using commercial enzyme-linked immunosorbent assay kits. The expressions of lung tissue extacellular signal-regulated kinases (ERK)-1/2, P38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinases (JNK) were determined by Western blotting. RESULTS: The Smith lung injury score in heparin treatment group and ALI group were (5.00 +/- 1.26) and (8.00 +/- 1.09) respectively. The values were significantly higher than that of normal control group (0.67 +/- 0.52, both P < 0.01). However, the Smith lung injury score in heparin treatment group was significantly lower than that of ALI group (P < 0.01). The P(alb), TNF-alpha, IL-6 and vWF of heparin treatment group were (0.28 +/- 0.04), (1.92 +/- 0.35) microg/L, (1.22 +/- 0.13) ng/ml and (24.9 +/- 4.0) U/L respectively. The values were significantly higher than those of normal control group [0.20 +/- 0.02, (0.51 +/- 0.09) microg/L, (0.23 +/- 0.05) ng/ml and (14.0 +/- 3.0) U/L respectively, all P < 0.01] but significantly lower than those of ALI group [(0.38 +/- 0.04), (2.77 +/- 0.37) microg/L, (1.62 +/- 0.13) ng/ml and (31.8 +/- 7.5) U/L respectively, all P < 0.01]. The lung tissue levels of phospho-ERK1/2 and phospho-P38 MAPK expressions of heparin treatment group were markedly higher than those of normal control group, whereas markedly lower than those of ALI group. There was no marked difference of phospho-JNK expression in all three groups. CONCLUSION: Heparin markedly inhibits the expressions of phospho-ERK1/2 and phospho-P38 MAPK, down-regulates the inflammatory reaction, attenuates the endothelial permeability of pulmonary vasculature and significantly improves endotoxin-induced lung injury in rats.

Antithrombin-III without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase.

BACKGROUND: Antithrombin-III (AT-III), the major inhibitor of thrombin in plasma, also has anti-inflammation property and might have positive effect on sepsis. The present study aimed to investigate the effects of AT-III on inflammatory reaction and pulmonary protection in endotoxin-induced acute lung injury (ALI) rat. METHODS: Sixty male Sprague-Dawley rats were randomly assigned equally to normal control group, ALI group, AT-III treatment group, AT-III + heparin treatment group, and heparin treatment group. The pulmonary vascular permeability index (PVPI) was measured by single nuclide tracer technique. The activity of AT-III in plasma was determined by the method of synthetic chromogenic substrata. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels in serum were determined by enzyme-linked immunosorbent assay. The expressions of lung tissue mitogen-activated protein kinases (ERK1/2, P38 and JNK MAPK) were determined by Western blotting. RESULTS: Rats had significantly improved lung histopathology in the AT-III treatment group and heparin treatment group compared with the ALI group. The PVPI of the ALI group was 0.38 + or - 0.04, significantly higher than that of the normal control group (0.20 + or - 0.02, P < 0.01), AT-III treatment group (0.30 + or - 0.04, P < 0.01) and heparin treatment group (0.28 + or - 0.04, P < 0.01) respectively. There were no significant differences of PVPI in the ALI group and AT-III + heparin treatment group. The activity of AT-III in plasma in the ALI group was (76 + or - 8)%, significantly lower than that of the normal control group ((96 + or - 11)%, P < 0.05) and AT-III treatment group ((105 + or - 17)%, P < 0.05) respectively. The serum levels of TNF-alpha and IL-6 of the ALI group were (2.770 + or - 0.373) microg/L and (1.615 + or - 0.128) ng/ml respectively, significantly higher than those of the normal control group ((0.506 + or - 0.093) microg/L and (0.233 + or - 0.047) ng/ml respectively, all P < 0.01), AT-III treatment group ((1.774 + or - 0.218) microg/L and (1.140 + or - 0145) ng/ml respectively, all P < 0.01) and heparin treatment group ((1.924 + or - 0.349) microg/L and (1.223 + or - 0.127) ng/ml respectively, all P < 0.01). The lung tissue levels of phospho-ERK1/2 and phospho-P38 MAPK expressions were markedly higher in the ALI group than in the normal control group, AT-III treatment group and heparin treatment group respectively. CONCLUSIONS: AT-III without concomitant heparin inhibited the activation of ERK1/2 and P38 MAPK, down-regulated the levels of downstream cytokines TNF-alpha and IL-6, relieved endothelial permeability, and improved the ALI in endotoxin-induced rats. It might be helpful to administrate AT-III alone, not with concomitant heparin, to those patients with ALI and sepsis.