Clinical and chest CT features of immune checkpoint inhibitor-related pneumonitis / 中华肿瘤杂志

Objective: To explore the clinical and chest computed tomography (CT) features and the outcome of immune checkpoint inhibitor-related pneumonitis (CIP). Methods: Clinical and chest CT data of 38 CIP patients with malignant tumors from the Cancer Hospital, Chinese Academy of Medical Sciences between August 2017 and April 2021 were retrospectively reviewed, and the outcomes of pneumonitis were followed up. Results: The median time from the administration of immune checkpoint inhibitors (ICIs) to the onset of CIP was 72.5 days in 38 patients with CIP, and 22 patients developed CIP within 3 months after the administration of ICIs. The median occurrence time of CIP in 24 lung cancer patients was 54.5 days, earlier than 119.0 days of non-lung cancer patients (P=0.138), with no significant statistical difference. 34 patients (89.5%) were accompanied by symptoms when CIP occurred. The common clinical symptoms were cough (29 cases) and dyspnea (27 cases). The distribution of CIP on chest CT was asymmetric in 31 cases and symmetrical in 7 cases. Among the 24 lung cancer patients, inflammation was mainly distributed ipsilateral to the primary lung cancer site in 16 cases and diffusely distributed throughout the lung in 8 cases. Ground glass opacities (37 cases) and consolidation (30 cases) were the common imaging manifestations, and organizing pneumonia (OP) pattern (15 cases) was the most common pattern. In 30 CIP patients who were followed up for longer than one month, 17 cases had complete absorption (complete absorption group), and 13 cases had partial absorption or kept stable (incomplete absorption group). The median occurrence time of CIP in the complete absorption group was 55 days, shorter than 128 days of the incomplete absorption group (P=0.022). Compared with the incomplete absorption group, there were less consolidation(P=0.010) and CIP were all classified as hypersensitivity pneumonitis (HP) pattern (P=0.004) in the complete absorption group. Conclusions: CIP often occurs within 3 months after ICIs treatment, and the clinical and CT findings are lack of specificity. Radiologic features may have a profound value in predicting the outcome of CIP.

Epidermal growth factor receptor genotype in plasma DNA and outcome of chemotherapy in the Chinese patients with advanced non-small cell lung cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The genotype of epidermal growth factor receptor (EGFR) is associated with tyrosine kinase inhibitor and effectiveness of therapy, but its role in cytotoxic chemotherapy is still unknown. Previous studies indicated that certain EGFR mutations were associated with response and progression free survival following platinum based chemotherapy. Our recent studies have identified that EGFR genotypes in the tumour tissues were not associated with response to the first-line chemotherapy in Chinese patients with advanced non-small cell lung cancer (NSCLC). In this study, we investigated associations of EGFR genotypes from plasma of patients with advanced NSCLC and response to first-line chemotherapy and prognosis.</p><p><b>METHODS</b>We enrolled 145 advanced NSCLC patients who had received first-line chemotherapy in our department. We examined plasma EGFR genotypes for these patients and associations of EGFR mutations with response to chemotherapy and clinical outcomes.</p><p><b>RESULTS</b>There were 54 patients with known EGFR mutations and 91 cases of wild types. No significant difference was detected in the response rate to first-line chemotherapy between mutation carriers and wild-type patients (37.0% vs. 31.9%). The median survival time and 1-, 2-year survival rates were higher in mutation carriers than wild-types (24 months vs. 18 months, 85.7% vs. 65.7% and 43.7% vs. 25.9%, P = 0.047). Clinical stage (IV vs. IIIb), response to the first-line chemotherapy (partial vs. no) and EGFR genotype were independent prognostic factors.</p><p><b>CONCLUSION</b>Plasma EGFR mutations in the Chinese patients with advanced NSCLC is not a predictor for the response to first-line chemotherapy, but an independent prognostic factor indicating longer survival.</p>

Critical role of deltaDNMT3B4/2 in regulating RASSF1A promoter-specific DNA methylation in non-small cell lung cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>DeltaDNMT3B (a new DNMT3B subfamily) expression is initiated through a novel promoter. We identified at least 7 transcription variants of deltaDNMT3B as a result of alternative pre-mRNA processing. The aim of this study was to detect the expression pattern of deltaDNMT3B variants in non-small cell lung cancer (NSCLC) and to explore the role of deltaDNMT3B variants in regulating the promoter-specific DNA methylation.</p><p><b>METHODS</b>Specific polymerase chain reaction (PCR) primer sets were designed to distinguish individual deltaDNMT3B variants according to their splicing patterns. The expressions of seven deltaDNMT3B variants were measured in 13 cell lines, 109 NSCLC patients, and the corresponding normal lung tissues using reverse transcription-PCR (RT-PCR). The status of the p16 and RASSF1A promoter methylations in the tumors was detected using a methylation specific PCR (MSP). The relationships of the expression patterns of the deltaDNMT3B variants were analyzed by observing the status of p16 and RASSF1A promoter methylations in the tumors. The siRNA and the anti-sense oligo-dioxynucleotide specifically targeting the junction of exon 5 and 7 of deltaDNMT3B were designed and transfected by lipofectmane 2000 into H1299 and H358 cell lines. RASSF1A promoter methylation from cells treated by siRNA-deltaDNMT3B4/2 was detected using MSP and Bisulfite sequencing, and Western blotting was used to detect the protein expression of DNMT3B and ADNMT3B. Cell growth and cell cycle distribution were measured by applying real-time cell growth analysis and flowcytometry, respectively.</p><p><b>RESULTS</b>ADNMT3B variants, not DNMT3B, were the predominant transcripts in both NSCLC cell lines and primary tumors. The expression of deltaDNMT3B4 strongly correlated to the promoter methylation status of RASSF1A in a primary NSCLC. The knockdown of deltaDNMT3B4/2 by RNA-interference or anti-sense approaches resulted in a complete demethylation of RASSF1A promoter with the reactivation of a RASSF1A gene expression in less than 12 hours, but no effect resulted from the p16(INK4a) promoter in the NSCLC cell lines.</p><p><b>CONCLUSIONS</b>These results demonstrate an important role of deltaDNMT3B4/2 in the maintenance of promoter-specific DNA methylation in a cell type specific manner and provide a novel cell model for the study of the regulation of replication-independent DNA methylation.</p>