Background
Significant improvement in survival outcome with the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has been shown in advanced non-small cell lung cancer (NSCLC) ...patients compared with chemotherapy. However, the full spectrum of toxic events of PD-1/PD-L1 inhibitors was not well characterized. We conducted a comprehensive meta-analysis to state the safety profile of PD-1/PD-L1 inhibitors in NSCLC, and identify the exact incidence and relative risk (RR) of both summary and detailed AEs.
Materials and methods
Electronic databases (PubMed, EMBASE and the Cochrane library databases) and major conference proceedings were systematically searched for all clinical trials in lung cancer using PD-1/PD-L1 inhibitors. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients reporting all-grade (1–4) or high-grade (3–4) AEs toxic symptoms, hematologic toxicities, and immune-related AEs (irAEs), treatment discontinuation due to toxicities, or toxic deaths. The pooled incidence, RR, and corresponding 95% confidence interval (CI) of toxicity outcomes were calculated.
Results
A total of 4413 patients from 8 RCTs (3 with nivolumab; 2 with atezolizumab, and 3 with pembrolizuma) were included. In terms of summary toxic events, PD-1/PD-L1 inhibitors had a significantly lower risk of any all-grade AEs (66.20 vs. 86.08%; RR 0.77) and high-grade AEs (14.26 vs. 43.53%; RR 0.32), treatment discontinuation (5.94 vs. 13.92%; RR 0.44), and toxic deaths (0.48 vs. 1.12%; RR 0.45) than chemotherapy. With regard to detailed toxic events, the risk of toxic symptoms (including all-grade fatigue, nausea, constipation, diarrhea and peripheral sensory neuropathy; high-grade fatigue, anorexia, diarrhea and peripheral sensory neuropathy) and hematologic toxicities (including all-grade and high-grade neutropenia, thrombocytopenia, and anemia) from PD-1/PD-L1 inhibitors was significantly lower than from chemotherapy. However, there was a small but significantly increased risk of irAEs, including all-grade rash, pruritus, colitis, hypothyroidism, hyperthyroidism, ALT/AST elevations and pneumonitis, as well as high-grade pneumonitis.
Conclusion
PD-1/PD-L1 inhibitors are generally safer and better tolerated than chemotherapy for patients with NSCLC with regard to summary toxic events, detailed toxic symptoms and hematologic toxicities. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and several of them can be severe and even life-threatening. Clinicians should be aware of the risk of these AEs, as they may have a potentially negative impact on the patients’ quality of life and survival outcome.
The COVID-19 outbreak is becoming a public health emergency. Data are limited on the clinical characteristics and causes of death. A retrospective analysis of COVID-19 deaths were performed for ...patients' clinical characteristics, laboratory results, and causes of death. In total, 56 patients (72.7%) of the decedents (male-female ratio 51:26, mean age 71 ± 13, mean survival time 17.4 ± 8.4 days) had comorbidities. Acute respiratory failure (ARF) and sepsis were the main causes of death. Increases in C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer and lactic acid and decreases in lymphocytes were common laboratory results. Intergroup analysis showed that (1) most female decedents had cough and diabetes. (2) The proportion of young- and middle-aged deaths was higher than elderly deaths for males, while elderly decedents were more prone to myocardial injury and elevated CRP. (3) CRP and LDH increased and cluster of differentiation (CD) 4+ and CD8+ cells decreased significantly in patients with hypertension. The majority of COVID-19 decedents are male, especially elderly people with comorbidities. The main causes of death are ARF and sepsis. Most female decedents have cough and diabetes. Myocardial injury is common in elderly decedents. Patients with hypertension are prone to an increased inflammatory index, tissue hypoxia and cellular immune injury.
Since no report on the genetic characteristics of RET fusions in female patients with lung cancer is available, this study revealed the genetic and prognostic characteristics of female patients with ...lung cancer harboring RET fusion gene for the first time.
The molecular portfolios of 1,652 patients with lung cancer who underwent targeted next-generation sequencing for screening candidate oncogenic drivers in their histological specimens from January 2016 to December 2018 were investigated in this study.
RET fusions were identified in 23 cases, 15 females 2.2% (15/685) and eight males 0.9% (8/902). The most common fusions were KIF5B-RET in females 80% (12/15) and CCDC6-RET in males 50% (4/8), along with some rare RET fusions, including SLC39A8-RET, ITIH2-RET, FYCO1-RET and SLC25A36-RET in females, and MIR3924-RET, ZBTB41-RET and ITGA8-RET in males. Interestingly, the highly positive, moderate positive, and negative rates of PD-L1 staining in females were 33.3%, 8.3% and 58.3%, respectively; whereas those in males were 0%, 57.1% and 42.9%. Additionally, the progression-free survival (PFS) of stage IV patients was comparatively shorter in females, shown by the medians of 4.0 months in females and 6.0 months in males (P = 0.029). A 43-year-old female patient with metastatic lung adenocarcinoma, who harbored KIF5B-RET fusion and had highly positive PD-L1 staining, received nivolumab as second-line treatment. A partial response was achieved and remained for more than five months.
Unique genetic characteristics and poor prognosis are found in female patients with lung cancer harboring RET fusion gene. Immune checkpoint inhibitors are a potential option for patients with high expression of PD-L1.
Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of lung cancer, but the benefit population is limited and there is a lack of effective predictive markers of efficacy. ...Tissue-resident memory T cells (TRM) reside in tissues and exert anti-tumor effects by expressing the integrins CD103, CD49a or C-type lectin CD69 and immune checkpoint receptors. TRM expressing programmed cell death 1 (PD-1) is enriched with transcriptional products associated with cytotoxicity and enhances T cell (antigen) receptor (TCR)-mediated cytotoxicity. TRM is a promising biomarker for predicting the efficacy and prognosis of immunotherapy in lung cancer patients. This review will describe the progress of TRM research in lung cancer. .
Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell lung cancer (NSCLC), it is now understood that ...drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and demonstrated that treatment with EGFR-TKI heightened the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor 3 (M3R). Importantly, we showed that aberrant ACh metabolism in patients with NSCLC played a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a therapeutic strategy--targeting the ACh/M3R/WNT axis--for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.
Purpose
This study aimed to determine the molecular features and clinical outcomes of young patients with non-small cell lung cancer (NSCLC) harboring
ALK
fusion genes.
Methods
We interrogated the ...genomic profile of 1652 patients with lung cancer who underwent targeted next-generation sequencing to screen for candidate oncogenic drivers using histological specimens acquired from January 2016 to December 2018.
Results
ALK
fusions were identified in 101 NSCLC patients, and 52 of them were diagnosed before the age of 50 years (52/367, 14.2%). Of the 52 patients with early-onset disease, 22 (42.3%) were male and 43 (82.7%) never smoked; the median patient age was 44 years (range 28–50 years). The most frequently occurring
ALK
fusion partner was
EML4
, which was identified in 80.8% (42/52) of young patients. Compared to the older patients, patients with early-onset disease were more likely to harbor
EML4-ALK
variant 1 (38.5% vs. 14.3%;
P
= 0.007). We also identified rare
ALK
fusions, including
CHRNA7-ALK
,
TACR1-ALK
,
HIP1-ALK, DYSF-ALK
and
ITGAV-ALK
, in patients with early-onset disease, and patients with these fusions responded well to crizotinib treatment. A statistically significant difference was observed in progression-free survival (PFS) between the young patients and older patients who received crizotinib as the first-line therapy (17.5 months vs 9.0 months,
P
= 0.048). However, the median PFS of young patients harboring concurrent
TP53
mutations was only 6.2 months.
Conclusion
Unique genetic characteristics were found in
ALK
-rearranged NSCLC patients with early disease onset, and these patients responded better to crizotinib and had longer PFS compared to patients with later disease onset. However, patients with concomitant
TP53
mutations may not have a significant response to treatment.
...56 patients who received ALK-TKI treatment were enrolled Supplementary Figure 1, http://links.lww.com/CM9/B791. ...most uncommon ALK fusions detected by DNA-based NGS may generate transcripts and ...proteins, and these cases may respond to ALK-TKIs as those involving canonical fusions do. ...non-canonical ALK fusion detected by DNA-based NGS was not validated at the RNA or protein level. ...we provide knowledge of the impact of non-canonical ALK fusion on efficacy based on different generations of ALK-TKIs and whether brain metastasis is present at baseline.
Epidemiological and demographic data, the discharge diagnosis as recorded by the 10th edition of the International Classification of Diseases, and the respiratory tract microbiological examination ...results were obtained from the electronic medical records of West China Hospital. 2 A multicenter randomized clinical study of outpatient health care personnel wearing either N95 respirators or medical masks found no significant difference in the incidence of laboratory-confirmed influenza. 4 Wu et al5 reported a significant decline in TB detection during the COVID-19 pandemic (from March 27 to May 28, 2020), but they indicated that this may have been due to a reduction in people seeking health care because of the insufficient and delayed provision of TB services. COVID-19 protective measures alone, such as wearing face masks and maintaining hand hygiene, cannot effectively reduce TB morbidity. ...the current study found no change in the proportion of TB in hospitalized patients.
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