Almonertinib-induced interstitial lung disease in a lung adenocarcinoma patient complicated with interstitial lung abnormality.

BACKGROUND: With the use of targeted drugs in lung cancer patients, targeted drug-induced interstitial lung disease (ILD) has attracted more and more attention. The incidence, time, and severity of different targeted drug-induced ILD vary. Almonertinib/HS-10296 is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Post-marketing safety and effectiveness of almonertinib have been confirmed. The reported adverse events of almonertinib were mainly an increase in creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase, and onset of rash. Almonertinib-induced ILD is rare. CASE REPORT: This paper reported the case of a patient with lung adenocarcinoma complicated with interstitial lung abnormality (ILA). Gene detection showed L858R mutation in exon 21 of the EGFR gene. After operation, almonertinib (110 mg per day) was prescribed. 3 months later, ILD was found by chest CT due to dyspnea. MANAGEMENT AND OUTCOME: Subsequently, almonertinib was stopped. With the administration of intravenous glucocorticoid and oxygen inhalation, the patient's dyspnea was significantly regressed and lung lesions regressed on follow-up chest CT done after discharge. DISCUSSION: This case suggested that we should pay attention to the existence of ILD/ILA before using targeted drugs. The use of targeted drugs should be more strictly controlled and monitored in patients with previous ILA or ILD. This paper also reviewed the relevant literature on the drug characteristics and summarized the risk factors of ILD caused by EGFR-TKI.

A prognostic analysis of antisynthetase syndrome-related interstitial lung disease.

OBJECTIVE: To analyze prognostic factors of antisynthetase syndrome (ASS)-related interstitial lung disease (ILD). METHODS: We retrospectively collected the data of 77 inpatients with ASS-ILD at our hospital from January 1, 2018, to January 1, 2021. The improvement/stability group and deterioration/death group were defined according to their follow-up outcome. Clinical data of the 2 groups were compared. Univariate analysis was adopted to screen the possible prognostic factors and then logistic regression was used for multivariate analysis. RESULT: After 6 to 42 months of follow-up, 52 patients (67.5%) were classified into the improvement/stability group, and 25 patients (32.5%) were classified into the deterioration/death group. According to the multivariate stepwise logistic regression analysis, respiratory failure (odds ratio [OR] = 6.71, 95% CI: 1.64-27.38, P = .008) and elevated muscle enzymes (OR = 4.31, 95% CI: 1.03-18.05, P = .045) were found to be independent risk factors, while mechanic's hands (OR = 0.06, 95% CI: 0.01-0.37, P = .003) and anti-Jo-1 antibody (OR = 0.24, 95% CI: 0.06-0.93, P = .039) were protective factors. CONCLUSION: The prognostic assessment of ASS-ILD patients should be emphasized. Patients with a poor prognosis should be identified early based on their risk factors to guide clinical management decisions.

Clinical Characteristics and Prognostic Analysis of Microscopic Polyangiitis With Diffuse Alveolar Hemorrhage.

OBJECTIVE: To analyze the clinical features and prognostic factors of microscopic polyangiitis (MPA) with diffuse alveolar hemorrhage (DAH). METHODS: We conducted a retrospective study of 92 patients diagnosed with MPA with DAH at the First Affiliated Hospital of Chongqing Medical University between March 1, 2012, and March 12, 2018. The cumulative survival rate was analyzed by the Kaplan-Meier method, and survival curves were drawn. A Cox hazard model was used to determine the prognostic factors for survival by univariate and multivariate analysis. RESULTS: The mean age at the onset of MPA with DAH was 66.32 years. Among the 92 MPA with DAH patients with follow-up visits, 41 (44.57%) were critically ill and 79 (85.87%) had pulmonary and renal involvement. The cumulative survival rates of the 92 patients at 1, 3, and 5 years were 63.7%, 51.2%, and 47.3%, respectively, and the median survival time was 46 months. In the multivariate analysis, age > 65 years (HR 4.30, 95% CI 1.94-9.55), sCr > 500 µmol/L (HR 2.04, 95% CI 1.05-3.97), PaO2/FiO2 < 300 mmHg (HR 4.10, 95% CI 1.97-8.53), and lung involvement area ≥ 50% (HR 2.93, 95% CI 1.40-6.13) were independent prognostic factors (P < 0.05). CONCLUSION: The incidence and mortality of DAH are high in MPA patients. Age > 65 years, sCr > 500 µmol/L, PaO2/FiO2 < 300 mmHg, and lung involvement area ≥ 50% are independent prognostic factors for MPA with DAH.

Current and emerging treatment options for lung cancer in patients with pre-existing connective tissue disease.

An association between connective tissue disease (CTD) and lung cancer has been claimed in accumulating studies. However, the management of lung cancer with CTD is challenging because the pre-existing CTDs have proved to be significant risk factors for treatment-related toxicity, resulting in poor survival. In this review, we summarize the available information related to the treatment for lung cancer with CTD, discuss risk factors for treatment-related toxicities and management recommendations, which attempts to approach lung cancer with comorbid CTD systematically. Preliminary data show that: i) limited studies have focused on the effect of traditional therapeutic modalities, such as surgical treatment and chemotherapy; ii) with the development of the modern radiation techniques, radiotherapy would be well tolerated in this challenging clinical situation, but a cautious decision should be made for patients with CTD associated interstitial lung disease (ILD); iii) for patients with inactive CTD, immunotherapy was shown to have excellent local control with acceptable toxicity; iv) little information is available on the effects of tyrosine kinase inhibitors because of acute exacerbation (AE) of ILD risks; v) antiangiogenic therapy might be useful in preventing the progression in both lung cancer and CTD without increasing the AE-ILD risk; vi) Nintedanib would be a potentially promising novel therapy since it has recently been developed with promising results for both lung cancer and CTD-ILD. Further large-scale, randomized, controlled studies are still required to develop better therapeutic management for patients with lung cancer and pre-existing CTD.

[Tristetraprolin inhibits autophagy in cultured lung cancer cells via the nuclear factor-κB pathway].

OBJECTIVE: To explore the expression of the RNA-binding protein tristetraprolin in lung adenocarcinoma cells and its molecular mechanism for inhibiting autophagy. METHODS: Quantitative real-time PCR and Western blotting were performed to detect the expression of autophagy-related genes (including Beclin1, LC3-Ⅱ/LC3-Ⅰ and SQSTM1/p62) in cultured lung adenocarcinoma cells at 24, 48 and 72 h after transient transfection with a tristetraprolin-overexpressing plasmid and the empty plasmid. The effects of transfection with the tristetraprolin-overexpressing plasmid and empty plasmids in the presence or absence of tumor necrosis factor-α (TNF-α) on the expressions of nuclear factor-κB (NF-κB) p65, c-rel, and p50 were examined in lung adenocarcinoma cells using immunofluorescence assay and Western blotting. The cells were also transfected with the IκBα-mut plasmid and the tristetraprolin-overexpressing plasmid, either alone or in combination, and the changes in the expressions of tristetraprolin and autophagy-related genes were detected using RT-qPCR and Western blotting. RESULTS: The expressions of tristetraprolin were significantly reduced at both the mRNA and protein levels in lung adenocarcinoma cells (P < 0.001). Overexpression of tristetraprolin in the cells significantly lowered the expressions of autophagy-related genes Beclin1 and the ratio of LC3-Ⅱ/LC3-Ⅰ at the mRNA and protein levels (P < 0.001), obviously lowered the expressions of NF-κB p65 and c-rel, and almost totally blocked the nuclear translocation of NF-κB p65 and c-rel (P < 0.05); the expression of p50, however, did not undergo significant changes in response to tristetraprolin overexpression (P > 0.05). The inhibitory effect of tristetraprolin overexpression on autophagy was abrogated by transfection of the cells with IκBα-mut plasmid, which blocked the NF-κB signaling pathway. Co-transfection of the cells with IκBα-mut also attenuated the inhibitory effect of tristetraprolin overexpression on Beclin1 and the LC3-Ⅱ/LC3-Ⅰ ratio at both the mRNA and protein levels (P < 0.05). CONCLUSIONS: The expression of tristetraprolin is low in lung adenocarcinoma cells. Tristetraprolin overexpression causes inhibition of autophagy in lung adenocarcinoma cells possibly by blocking NF-κB p65 and c-rel nuclear translocation.

The RNA binding protein tristetraprolin down-regulates autophagy in lung adenocarcinoma cells.

Tristetraprolin (TTP) is the most well-known member of RNA-binding zinc-finger protein that play a significant role in accelerating mRNA decay. Increasingly studies have reported that TTP was functioned as a tumor suppressor gene in several types of carcinomas, while its underlying mechanism is not clear yet. In the current study, we found that TTP overexpression decreased cell proliferation and increased cell death in lung adenocarcinoma cells, with the cell cycle arrest at the S phase. Remarkably, instead of inducing cell apoptosis directly, TTP overexpression alters cell autophagy. Our studies demonstrate that TTP overexpression has no effect on apoptosis related genes, but decreases the expression of autophagy-related genes, including Beclin 1 and LC3II. The level of autophagy flux assessed by infection with the mGFP-RFP-LC3 adenovirus construction has been blocked by TTP overexpression. Moreover, the autophagic vacuoles number detected by transmission electron microscopy decreased with TTP expression up-regulation. Our results indicate, for the first time, that TTP suppresses cell proliferation and increases cell death through cell autophagy pathway in lung cancer cells. Our study provides a new angle of view for TTP function as a tumor suppressor which could be targeted in tumor treatment.

The role of circulating tumor cells in evaluation of prognosis and treatment response in advanced non-small-cell lung cancer.

PURPOSE: Non-small-cell lung cancer (NSCLC) lacks validated biomarkers to predict the prognosis and treatment response. This study investigated whether circulating tumor cells (CTCs) detectable could reminder high risk of distant metastasis, provide prognostic information, and early indicate the response to the conventional therapy in patients with advanced NSCLC. PATIENTS AND METHODS: In this single-center prospective study, blood samples for CTC analysis were obtained from 59 patients with previously untreated, stage III or IV NSCLC both before and after administration of two cycles of chemotherapy. CTCs took in peripheral blood were measured by Cell Search detect technique. RESULTS: Carcino-embryonic antigen and count of metastatic sites were positively related to CTC count analyzed by multiple linear regression (P < 0.05). The median overall survival was 11.2 months (95% CI: 10.37-12.03 months) for the baseline CTC ≥ 2 group compared with 8.3 months (95% CI: 7.72-8.88 months) for the CTC < 2 group (log-rank test P < 0.05). Similarly, patients with CTC ≥ 2 at baseline had a significantly shorter median PFS (4.3 months, 95% CI: 3.7-4.9 months) compared with patients with CTC < 2 (6.2 months, 95% CI: 5.59-6.82 months) (log-rank test P < 0.05). For the disease control (stable disease, partial response, or complete response), group CTC value before treatment did not present difference with that after therapy compared by pared-samples T test (t = 1.455, P = 0.154), similar to the result of progressed group (progressive disease) (t = -0.987, P = 0.335). The CTC value of progressed group was higher than that of disease control group either at baseline or post chemotherapy. CONCLUSION: These data provide an evidence of positive correlation between CTC counts with CEA, as well as count of metastatic sites. Meanwhile, CTCs could be an effective predictor of distant metastasis and poor prognosis. In this study, CTCs are poorly related to treatment response. Whether CTCs could be a predictor of curative effect in advanced NSCLC should be validated by more researches in the future.

Circulating tumor cells in lung cancer: detection methods and clinical applications.

Circulating tumor cells (CTCs) are tumor cells that have disseminated from primary and metastatic sites, and circulate in the bloodstream. Advanced immunological and molecular-based methods can be used to detect and analyze the cells with the characteristics of tumor cells, and can be detected and analyzed in the blood of cancer patients. The most commonly used methods in lung cancer combine the processes of immunomagnetic enrichment and immunocytochemical detection, morphology-based enrichment coupled with reverse transcriptase polymerase chain reaction (RT-PCR), and RT-PCR alone. CTC analysis is considered a liquid biopsy approach for early diagnosis, risk stratification, evaluation of curative efficacy, and early detection of lung cancer relapse. In this review, we discuss the present techniques for analyzing CTCs, and the restrictions of using these methods in lung cancer. We also review the clinical studies in lung cancer and discuss the underlying associations between these studies and their future applications to this disease.

Effects of ubiquitin-conjugating enzyme 2C on invasion, proliferation and cell cycling of lung cancer cells.

The aims of this study were to investigate the influence of ubiquitin- conjugating enzyme E2C (UBE2C) on biological behavior of lung cancer cells. Using MTT, flow cytometry and invasion assays, we detected UBE2C expression and evaluated its biological properties in these cells, including effects on proliferation, the cell cycle profile and invasive capability. Compared with control cells, the UBE2C transfected cells demonstrated increased cellular proliferation (p<0.05). UBE2C transfected cells also had a lower percentage in G1 phase and a higher percentage in S phase (p<0.05). Importantly, the UBE2C transfected cells had a notable enhancement of cell numbers penetrating the basement membrane compared with the control group (p<0.05). Ectopic up- regulation UBE2C promoted the growth of lung cancer cells in vivo. Furthermore, we found UBE2C increased the expression of cyclin D1 and MMP-2. These results show UBE2C may represent a potential therapeutic target for lung cancer.

Protocol-directed versus physician-directed weaning from noninvasive ventilation: the impact in chronic obstructive pulmonary disease patients.

BACKGROUND: Noninvasive ventilation (NIV), a technique widely used in intensive care units (ICUs), eliminates the need for many patients in respiratory failure to undergo intubation. However, few articles have described how to wean patients from NIV. Herein, we put forward a protocol to be performed by respiratory therapists to wean patients from NIV. METHODS: A prospective, randomized, controlled trial was performed in a respiratory ICU of a teaching hospital. Respiratory therapists screened patients daily. In the protocol-directed weaning group, the weaning attempt was initiated according to the protocol. In the physician-directed weaning group, the weaning attempt was initiated according to physicians' orders. RESULTS: At randomization, patients in the two groups had similar clinical characteristics. A total of 73 patients were successfully weaned from NIV (37 in the protocol-directed group and 36 in the physician-directed group). The preponderance of them (64%) was chronic obstructive pulmonary disease patients. Compared with physician-directed weaning, protocol-directed weaning reduced the duration of NIV (4.4 ± 2.5 days vs. 2.6 ± 1.5 days, respectively, p < 0.001) and the duration of the ICU stay (8.1 ± 5.5 days vs. 5.8 ± 2.7 days, respectively, p = 0.02). In the protocol-directed group, the successful weaning rate was 57%, 27%, 13%, 0%, and 3% on the 1st, 2nd, 3rd, 4th, and 5th days after randomization, respectively. CONCLUSIONS: Protocol-directed weaning reduces the duration of NIV and the duration of the ICU stay. LEVEL OF EVIDENCE: II.

Dual-mode weaning strategy for difficult-weaning tracheotomy patients: a feasibility study.

BACKGROUND: Tracheotomy patients who are difficult to wean from ventilation consume a substantial portion of intensive care unit (ICU) resources. These patients also typically undergo a long period of mechanical ventilation (MV) and have a high mortality rate. The efficacy of a dual-mode weaning strategy (alternation of invasive and noninvasive MV) in tracheotomy patients who are difficult to wean is unknown. METHODS: We performed this prospective, randomized, controlled trial in a 17-bed respiratory ICU from July 2009 to October 2011. After tracheotomy, patients who failed for 3 consecutive days in a spontaneous breathing trial were enrolled (n = 32) and randomly allocated to either the dual-mode (n = 15) or conventional (n = 17) weaning group. RESULTS: Compared with the conventional group, patients in the dual-mode group had a shorter duration of MV during the entire study (median 38 days, interquartile range [IQR]: 28-53 vs 59, IQR: 39-88, P = 0.03) and after randomization (median 10 days, IQR: 4-21 vs 37, IQR: 16-51, P < 0.01). They also had a shorter ICU stay (median 44 days, IQR: 32-54 vs 72, IQR: 52-102, P = 0.01), a lower mortality rate during weaning (1 of 15 vs 7 of 17, P = 0.04), and a lower rate of pulmonary infection after randomization (3 of 15 vs 12 of 17, P < 0.01). CONCLUSIONS: Dual-mode weaning is a promising strategy for treating tracheotomy patients who are difficult to wean. In a small cohort of patients with tracheotomies, we demonstrated that dual-mode weaning reduced the total duration of MV and ICU stay; we recommend additional studies to assess its effect on pulmonary infections and mortality.

Protocadherin 10 is frequently downregulated by promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer.

PURPOSE: Protocadherin 10 (PCDH10), a homophilic cell adhesion member of the protocadherin family, plays important roles in calcium-dependent cell-cell adhesion and signal transduction. PCDH10 expression is downregulated in a number of different malignances, predominantly through promoter methylation-driven silencing. This study was designed to investigate PCDH10 expression and promoter methylation status in non-small cell lung cancer (NSCLC), and biological effects of PCDH10 in lung cancer cells. METHODS: The mRNA levels and promoter methylation status of PCDH10 were examined by RT-PCR and methylation-specific PCR (MSP) in lung cancer cell lines as well as primary lung tissue samples, and the clinical correlation of PCDH10 promoter methylation in NSCLC was further analyzed. The effects of PCDH10 re-expression in lung cancer cell lines was determined by cell proliferation, colony formation, and wound healing assays. RESULTS: PCDH10 expression was downregulated or silenced in 4/8 lung cancer cell lines but could be restored by treatment with 5-aza-2'-deoxycytidine and trichostatin A. PCDH10 was also downregulated in NSCLC tissues compared to their corresponding adjacent tissues. Promoter methylation of PCDH10 was observed in 50% (20/40) of the NSCLC tissues but not in tumor-adjacent or normal tissues, and PCDH10 promoter methylation was statistically related to smoking. Ectopic expression of PCDH10 in silenced cells can reduce lung cancer cell proliferation and migration. CONCLUSION: PCDH10 is frequently downregulated by promoter methylation and may serve as a tumor suppressor gene (TSG) in NSCLC.

[A clinical study on efficacy of gemcitabine and carboplatin versus paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer].

BACKGROUND: To evaluate the efficacy and toxicity of gemcitabine and carboplatin (GC) versus paclitaxel and carboplatin (TC) in the treatment of non-small cell lung cancer (NSCLC). METHODS: A total of 64 patients with advanced NSCLC diagnosed by pathology were randomly divided into two groups. Gemcitabine and carboplatin were administrated to the patients in GC group (n=30), and paclitaxel and carboplatin in the TC group (n=34), 28 days as a cycle. All patients received at least two cycles. RESULTS: The overall response rate was 53.3% in the GC group and 58.8% in the TC group (P > 0.05). The main toxicities were well tolerated and consisted of leukopenia, nausea, vomiting and peripheral neuritis, which occurred more frequently in the TC group than in the GC group (P < 0.05). CONCLUSIONS: Both of the two regimens of gemcitabine plus carboplatin and paclitaxel plus carboplatin are feasible, well tolerated and effective in the treatment of NSCLC, and the former may be safer than the latter.