•We identified clinically significant AEs in 35% of 75 NSCLC patients.•We evaluated AEs and germline variations by target-gene panel sequencing.•These AEs were associated with nonsynonymous SNVs in ...EPHX1 and TCF7L2.•Germline multi-gene information might be useful for predicting AEs.•These strategies are helpful for better precision medicine in the clinic.
Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations.
DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher’s exact test.
We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs.
Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.
Epidermal growth factor receptor (EGFR) mutations, especially deletional mutations in exon 19 (DEL) and L858R, predict gefitinib sensitivity in patients with non-small cell lung cancer (NSCLC). In ...this study, we validated EGFR mutation detection using high-resolution melting analysis (HRMA) and evaluated the associations between EGFR mutations and clinical outcomes in advanced NSCLC patients treated with gefitinib on a larger scale.
The presence of DEL or L858R was evaluated using HRMA and paraffin-embedded tissues and/or cytologic slides from 212 patients. In 66 patients, the results were compared with direct sequencing data.
HRMA using formalin-fixed tissues had a 92% sensitivity and a 100% specificity. The analysis was successfully completed in 207 patients, and DEL or L858R mutations were detected in 85 (41%) patients. The response rate (78% versus 8%), time-to-progression (median, 9.2 versus 1.6 months), and overall survival (median, 21.7 versus 8.7 months) were significantly better in patients with EGFR mutations (P < 0.001). Even among the 34 patients with stable diseases, the time-to-progression was significantly longer in patients with EGFR mutations. Patients with DEL (n = 49) tended to have better outcomes than those with L858R (n = 36); the response rates were 86% and 67%, respectively (P = 0.037), and the median time-to-progression was 10.5 and 7.4 months, respectively (P = 0.11).
HRMA is a precise method for detecting DEL and L858R mutations and is useful for predicting clinical outcomes in patients with advanced NSCLC treated with gefitinib.
Background
Currently used biomarkers for immunotherapy are inadequate because they are only based on tumor properties. In view of microenvironment changes by tumors, host immunity should be ...considered, which may result in identifying more accurate and easily detectable biomarkers for daily clinical practice. Here, we assessed serum immune‐modulating factor levels for the response to anti‐PD‐1 antibodies during the first cycle in non‐small cell lung cancer (NSCLC) patients.
Methods
Serum was collected from patients with advanced NSCLC treated with nivolumab or pembrolizumab at several time points during the first cycle. We applied the enzyme‐linked immunosorbent assays (ELISAs) and multiplex assays to measure the levels of immune modulators.
Results
A total of 40 patients treated with nivolumab and 26 patients treated with pembrolizumab were studied. By ELISA, serum perforin, but not granzyme B, was measured in all samples. By multiplex assay, 10 immune modulators, including granzyme B, were measured in some, but not all, samples. Serum baseline perforin levels were strongly associated with increased progression‐free survival (PFS) and overall survival (OS) times. Sequential changes in perforin levels during the first cycle were weakly associated with the clinical outcome.
Conclusions
Serum baseline perforin levels may be used to predict the prognosis of NSCLC patients treated with anti‐PD‐1 antibody therapy.
Key points
To identify a useful predictive marker for anti‐PD‐1 antibody therapy, using blood samples might be helpful.
Serum baseline perforin levels were closely associated with prognosis with anti‐PD‐1 antibody therapy in non‐small cell lung cancer.
This study demonstrates immune‐modulator changes in serum during the first cycle of anti‐PD‐1 antibody therapy in non‐small cell lung cancer. Serum baseline perforin levels were found to be closely associated with clinical outcome with anti‐PD‐1 antibody therapies.
The cathepsin inhibitor Cystatin A (CSTA) has antiapoptotic properties linked with neoplastic changes in squamous cell epithelium, where it has been proposed as a diagnostic and prognostic marker of ...lung cancer. Notably, cystatin A is upregulated in dysplastic epithelium, prompting us to hypothesize that it might be modulated in chronic obstructive pulmonary disease (COPD), a small airway epithelial (SAE) disorder that is a risk factor for non-small cell lung cancer (NSCLC) in a subset of smokers. Here we report that genetic variation, smoking, and COPD can all elevate levels of CSTA expression in lung small airway epithelia, with still further upregulation in squamous cell carcinoma (SCC), an NSCLC subtype. We examined SAE gene expression in 178 individuals, including healthy nonsmokers (n = 60), healthy smokers (n = 82), and COPD smokers (n = 36), with corresponding large airway epithelium (LAE) data included in a subset of subjects (n = 52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were found to associate with its expression in SAE. Levels were higher in COPD smokers than in healthy smokers, who, in turn, had higher levels than nonsmokers. CSTA gene expression in LAE was also smoking-responsive. Using publicly available NSCLC expression data we also found that CSTA was upregulated in SCC versus LAE and downregulated in adenocarcinoma versus smoke-exposed SAE. All phenotypes were associated with different proportional expression of CSTA to cathepsins. Our findings establish that genetic variability, smoking, and COPD all influence CSTA expression, as does SCC, supporting the concept that CSTA may make pivotal contributions to NSCLC pathogenesis in both early and late stages of disease development.
Background
Osimertinib is recommended for non‐small cell lung cancer (NSCLC) patients with EGFR mutation; however, it is unclear whether body size variables affect the efficacy of osimertinib in such ...patients. This study assessed the potential effect of body surface area (BSA) and body mass index (BMI) on osimertinib chemotherapy in patients with T790M‐positive advanced NSCLC who progress on prior EGFR‐tyrosine kinase inhibitors (TKIs).
Methods
We conducted a prospective observational cohort study. Median BSA and BMI were used as cut‐off values to evaluate the impact of body size variables on osimertinib chemotherapy.
Results
The median BSA and BMI of 47 patients were 1.50 m2 and 21.5 kg/m2, respectively. Clinical outcomes did not significantly differ between the high and low BSA groups, with response rates of 59.1% and 56.0% (P = 0.83) and progression‐free survival (PFS) of 7.6 and 9.1 months (P = 0.69), respectively. Similarly, there were no significant differences between the high and low BMI groups relative to response rates, which were 60.8% and 54.1% (P = 0.64), respectively, and PFS, which was 7.6 months in both groups (P = 0.38). No significant differences were observed among toxicity profiles in relation to BSA or BMI. Multivariate analysis identified better performance status, young age, and EGFR exon 19 deletion as independent favorable predictors of PFS.
Conclusion
The efficacy of osimertinib does not significantly vary relative to body size variables of patients with T790M‐positive NSCLC who progress on prior EGFR‐TKIs.
Epidermal growth factor receptor (EGFR) mutations, especially in-frame deletions in exon 19 (DEL) and a point mutation in exon 21 (L858R), predict gefitinib sensitivity in patients with non-small ...cell lung cancer (NSCLC). In this study, we verified the accuracy of EGFR mutation analysis in small samples by high-resolution melting analysis (HRMA), which is a rapid method using PCR amplification with a dye to analyze the melting curves in NSCLC.
We designed a prospective study to compare the sensitivity and specificity of HRMA and DNA sequencing with laser capture microdissection. Eligible patients with lung lesions were screened by bronchoscopy or percutaneous needle biopsy to histologically confirm the diagnosis, followed by surgical resection of the NSCLC. Small diagnostic specimens were analyzed for EGFR mutations by HRMA, and the surgically resected specimens were examined for mutations by HRMA and DNA sequencing.
The analyses for EGFR mutations were conducted in 52 eligible cases of the 92 enrolled patients. EGFR mutations were detected in 18 (34.6%) patients. The results of HRMA from surgically resected specimens as well as DNA sequencing revealed 100% sensitivity and specificity. On the other hand, the sensitivity and specificity of HRMA from the small diagnostic specimens were 83.3% and 100%, respectively.
In this study, we showed that HRMA is a highly accurate method for detecting DEL and L858R mutations in patients with NSCLC, although it is necessary to consider the identification of patients with a false-negative result when the analysis is conducted using small samples.
The arc of Riolan (AOR) is an anastomosis between the middle and left colic arteries. Aneurysms of the AOR are very rare visceral artery aneurysms. A 44-year-old man presented with abdominal pain and ...loss of consciousness. Computed tomography and angiography showed hemorrhagic ascites around the liver and spleen. An irregularly dilated artery was visible within a hematoma in the upper left region of the abdomen, consistent with a ruptured pseudoaneurysm of the AOR. Transcatheter arterial embolization was performed with microcoils. The patient's abdominal pain disappeared after embolization, and no symptoms of intestinal ischemia were observed. To our knowledge, this is the first case of an AOR aneurysm with AOR dilation due to dissection of the celiac artery that was successfully treated by coil embolization.
Background
The standard treatment for patients with unresectable locally advanced (LA) non‐small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). Consolidation therapy with durvalumab after CRT ...demonstrated survival benefits and was approved in Japan in July 2018. The use of immune checkpoint inhibitors (ICIs) is entering routine oncological practice, and here we investigate the feasibility of concurrent CRT for LA‐NSCLC patients based on the PACIFIC criteria.
Methods
We performed a retrospective study to evaluate the feasibility and efficacy of concurrent CRT prior to the approval of durvalumab. We assessed consecutive patients with LA‐NSCLC treated with CRT between January 2012 and June 2018.
Results
We analyzed a total of 108 consecutive patients who received radical thoracic radiotherapy and concurrent platinum‐based chemotherapy. Of those patients, 105 (97%) completed the planned radiotherapy. Radiation pneumonitis was observed in 93 patients (85%), with a median of 130 days (range: 41–317 days) from the initiation of radiation to the onset of the complication. Among the patients, 74 (69%) were considered eligible for consolidation therapy with durvalumab. The overall response rate was 64%, and the two‐year survival rate was 63%. Patients who received an ICI after relapse were associated with significantly better survival than those who did not receive an ICI (two‐year survival rate: 87% vs. 41%, respectively; P = 0.001).
Conclusions
Prior to the approval of durvalumab, the clinical application of ICIs improved the outcome of patients with relapsed NSCLC after CRT for LA‐NSCLC. The management of radiation pneumonitis remains a challenge following the approval of durvalumab.
Despite recent advances in mechanistic understanding and controlled‐synthesis methodologies regarding synthetic supramolecular assemblies, it has remained challenging to capture the molecular‐level ...phenomena in real time, thus hindering further progress in this research field. In this study, we applied high‐speed atomic‐force microscopy (AFM), which has extraordinary spatiotemporal resolution (1 nm and sub‐100 ms), to capture dynamic events occurring during synthetic molecular self‐assembly. High‐speed AFM permitted the visualization of unique dynamic behavior, such as seeded growth and self‐repair in real time. Furthermore, scanning‐probe AFM permitted the site‐specific manipulation and functionalization of a molecular self‐assembly. This powerful combination of bottom‐up and top‐down approaches at the molecular level should enable targeted syntheses of unprecedented functional nanoarchitectures.
Auf Trab: Durch Hochgeschwindigkeits‐AFM konnten das induzierte Wachstum und die Selbstreparatur supramolekularer Polymere in Echtzeit verfolgt werden. Rastersondenmikroskopie ermöglichte die ortsspezifische Manipulation und Funktionalisierung einer molekularen Selbstorganisation (siehe Bild). Diese Kombination von „Bottom‐up”‐ und „Top‐down”‐Ansätzen auf molekularer Ebene soll eine gezielte Synthese von funktionalen Nanoarchitekturen ermöglichen.
•Hybrid approach using standard and finite-volume lattice Boltzmann methods.•Efficient aeroacoustic simulation for low-speed turbomachines.•Computations on Cartesian and body-fitted grids with the ...direct forcing method.•The hybrid method simulated flow and acoustic fields around a crossflow fan.
In this study, we developed a hybrid approach using the lattice Boltzmann method (LBM) and finite-volume lattice Boltzmann method (FVLBM) to perform efficient aeroacoustic simulations with moving boundaries. An entire domain, including the flow and acoustic fields, was computed using the standard LBM with a Cartesian grid. Local domains around the moving objects were computed using the FVLBM with body-fitted grids. These simulations were coupled using the direct forcing method to consider moving boundaries. The hybrid method was validated for several problems including turbulent flows and flow-induced sounds under low-Mach-number conditions. These validation problems covered flows with Reynolds numbers up to 2.0×105 and Mach numbers less than 0.2. In the simulations of the aeolian tone generated from stationary and rotating cylinders, the hybrid method results were consistent with those of the conventional methods. In the simulation of the turbulent flow and broadband sound of the isolated airfoil, the hybrid method was 15 times faster than the standard LBM and produced results consistent with the experimental results. Furthermore, the application of a cross-flow fan demonstrated that the hybrid method successfully simulated the flow and acoustic fields around the rotor.
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