Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non‐small‐cell lung cancer (NSCLC). ...Next‐generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real‐world clinical data using the Oncomine Dx Target Test Multi‐CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%‐83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36‐6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.
The mutation identification success rate for all four genes was 80.1%. Surgical resection was associated with the highest success rate. Multivariate analysis showed a significant difference for surgical resection alone.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation–positive lung cancer. However, clinical data and reliable prognostic ...biomarkers are insufficient.
We performed a retrospective multicentre cohort study for 538 EGFR mutation–positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS).
The median observation period was 14.7 months (interquartile range 11.4–20.0). The median PFS was 20.5 months (95% confidence interval CI 18.6−not reached). Multivariate analysis showed that sex (male) (hazard ratio HR 1.99, 95% CI 1.35–2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11–2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03–2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04–2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01–2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70–5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1–49% (HR 1.66, 95% CI 1.05–2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17–4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05–2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%).
During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.
•Osimertinib is standard treatment for advanced EGFR mutation-positive lung cancer.•Clinical data and reliable prognostic biomarkers remain insufficient.•Tumour PD-L1 expression level is associated with progression-free survival.•Adverse events are a common reason for treatment discontinuation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT).
We conducted a multicentre, ...retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT.
In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% 95% confidence interval: 2.3%–3.5%). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non–small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months.
HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.
•This is the largest EGFR-mutated lung cancer retrospective cohort study.•We analysed 74 patients with histologic transformation (HT).•The incidence rate of HT was lower (2.8%) than previously reported.•Cytotoxic agents are likely to be effective in patients with HT.•None of the patients achieved 1-year PFS with immune checkpoint inhibitor therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This ...study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC.
Methods
We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis.
Results
Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24–4.85,
P
= 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio OR: 1.09, 95% CI 1.05–1.14,
P
< 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01–1.19,
P
= 0.023) levels were independent risk factors.
Conclusion
Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related ...pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data currently are lacking.
What is the prevalence of osimertinib-induced DRP in first-line settings? What are the characteristics, clinical impact, and risk factors of osimertinib-induced DRP?
We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest CT scans and clinical information during osimertinib exposure were collected until June 2020. The primary end point was DRP incidence identified through central review.
A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) had a diagnosis of DRP (all grades), and 21 patients (4.6%) had a diagnosis of grade 3 or more DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT scan patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and nonspecific interstitial pneumonia were found in 30, 21, 18, 9, and two patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio, 1.72; 95% CI, 1.01-2.89; P = .046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not affect treatment efficacy negatively.
For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.
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Psb28 is an extrinsic protein of photosystem II (PSII), which is conserved among photosynthetic organisms from cyanobacteria to higher plants. A unicellular cyanobacterium, Synechocystis sp. PCC ...6803, has two homologs of Psb28, Psb28-1 and Psb28-2. However, the role of these proteins remains poorly understood. In this study, we disrupted the psb28-1 (sll1398) and psb28-2 (slr1739) genes in wild-type Synechocystis sp. PCC 6803 and examined their photosynthetic properties to elucidate the physiological role of Psb28 in photosynthesis. We also disrupted the psb28-1 gene in a dgdA mutant defective in the biosynthesis of digalactosyldiacylglycerol, in which Psb28-1 significantly accumulates in PSII. The disruption of the psb28-1 gene in the wild-type resulted in growth retardation under high-light conditions at high temperatures with a low rate of restoration of photodamaged photosynthetic machinery. Similar phenomena were observed at normal growth temperatures in the psb28-1/dgdA double mutant. In contrast, disruption of psb28-2 in the wild-type and dgdA mutant did not affect host strain phenotype, suggesting that Psb28-2 does not contribute to the recovery of PSII. In addition, protein analysis using strains expressing His-tagged Psb28-1 revealed that Psb28-1 is mainly associated with the CP43-less PSII monomer. In the dgdA mutant, the CP43-less PSII monomer accumulated to a greater extent than in the wild-type, and its accumulation caused greater accumulation of Psb28-1 in PSII. These results demonstrate that Psb28-1 plays an important role in PSII repair through association with the CP43-less monomer, particularly at high temperatures.
► psb28 mutants were constructed in the cyanobacterium Synechocystis sp. PCC 6803. ► Growth of psb28-1 mutant was retarded at high temperatures. ► psb28-1 mutant had a low rate of restoration of photosynthetic activities. ► psb28-2 mutant did not show significant phenotype. ► Psb28-1 is involved in recovery of photosystem II at high temperatures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The bacterial density of Pseudomonas aeruginosa is closely related to its pathogenicity. We evaluated the effect of airway P. aeruginosa density on the clinical course of mechanically ventilated ...patients and the therapeutic efficacy of antibiotics.
We retrospectively analyzed data of mechanically ventilated ICU patients with P. aeruginosa isolated from endotracheal aspirates. Patients were divided into three groups according to the peak P. aeruginosa density during ICU stay: low (≤ 10
cfu/mL), moderate (10
‒10
cfu/mL), and high (≥ 10
cfu/mL) peak density groups. The relationship between peak P. aeruginosa density and weaning from mechanical ventilation, risk factors for isolation of high peak density of P. aeruginosa, and antibiotic efficacy were investigated using multivariate and propensity score-matched analyses.
Four-hundred-and-sixty-one patients were enrolled. Patients with high peak density of P. aeruginosa had higher inflammation and developed more severe respiratory infections. High peak density of P. aeruginosa was independently associated with few ventilator-free days on day 28 (P < 0.01) and increased ICU mortality (P = 0.047). Risk factors for high peak density of P. aeruginosa were prolonged mechanical ventilation (odd ratio OR 3.07 95% confidence interval CI 1.35‒6.97), non-antipseudomonal cephalosporins (OR 2.17, 95% CI 1.35‒3.49), hyperglycemia (OR 2.01, 95% CI 1.26‒3.22) during ICU stay, and respiratory diseases (OR 1.9, 95% CI 1.12‒3.23). Isolation of commensal colonizer was associated with lower risks of high peak density of P. aeruginosa (OR 0.43, 95% CI 0.26‒0.73). Propensity score-matched analysis revealed that antibiotic therapy for patients with ventilator-associated tracheobronchitis improved weaning from mechanical ventilation only in the high peak P. aeruginosa group.
Patients with high peak density of P. aeruginosa had worse ventilator outcome and ICU mortality. In patients with ventilator-associated tracheobronchitis, antibiotic therapy was associated with favorable ventilator weaning only in the high peak P. aeruginosa density group, and bacterial density could be a good therapeutic indicator for ventilator-associated tracheobronchitis due to P. aeruginosa.
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