The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Coronaviruses have large positive-strand RNA genomes that are 5' capped and 3' polyadenylated. The 5'-terminal two-thirds of the genome contain two open reading frames (ORFs), 1a and 1b, that ...together make up the viral replicase gene and encode two large polyproteins that are processed by viral proteases into 15-16 nonstructural proteins, most of them being involved in viral RNA synthesis. ORFs located in the 3'-terminal one-third of the genome encode structural and accessory proteins and are expressed from a set of 5' leader-containing subgenomic mRNAs that are synthesized by a process called discontinuous transcription. Coronavirus protein synthesis not only involves cap-dependent translation mechanisms but also employs regulatory mechanisms, such as ribosomal frameshifting. Coronavirus replication is known to affect cellular translation, involving activation of stress-induced signaling pathways, and employing viral proteins that affect cellular mRNA translation and RNA stability. This chapter describes our current understanding of the mechanisms involved in coronavirus mRNA translation and changes in host mRNA translation observed in coronavirus-infected cells.
Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.
CheckMate 331 is a ...randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).
Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.
Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.
•The primary endpoint of OS with nivolumab versus chemotherapy as second-line treatment of SCLC was not met.•Crossing of the survival curves indicates higher long-term survival with nivolumab in a subset of patients.•Post hoc analyses suggest patients with baseline LDH ≤ ULN and those without liver metastases may benefit from nivolumab.•The safety profile of nivolumab was consistent with prior studies and more favorable than that of chemotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the ...efficacy of nivolumab for patients with CUP.
Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1.
Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% 95% confidence interval (CI), 11.2% to 37.1%, with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed.
Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
•Nivolumab demonstrated clinical benefits in a statistically assessable number of patients with CUP.•Objective response rate was 22.2% in previously treated patients with CUP, which met the study primary endpoint.•Benefits were more apparent in patients with known biomarkers for ICIs, but also observed in those without such markers.•No differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin.•Nivolumab could be an additional therapeutic option for these unmet medical needs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We investigated effects of low-dose X-ray irradiation on eggshells radical production. Eggshells irradiated by low-dose X-ray produced stable radicals. The stable radicals at the central ...region of the spectrum are the carbonates and CO2*− signals. The electron spin resonance (ESR) signals increase with increasing absorbed dose. The estimated radical concentration (spin number) was approximately 3.6 × 1012 (spins/g) at 10-Gy dose using various known concentrations of TEMPOL (4-hydroxy-2, 2, 6, 6-tretramethylpiperidin-1-oxyl) aqueous solutions. The stable radicals in irradiated eggshells were recognized at the low-level dose (0.10 Gy). In addition, no significant dose rate (0.5-1.5 Gy/min) dependence was found for the radical production.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
High-speed photography is a powerful tool for studying fast dynamics in photochemistry, spintronics, phononics, fluidics and plasma physics. Currently, the pump-probe method is the gold standard for ...time-resolved imaging, but it requires repetitive measurements for image construction and therefore falls short in probing non-repetitive or difficult-to-reproduce events. Here, we present a motion-picture camera that performs single-shot burst image acquisition without the need for repetitive measurements, yet with equally short frame intervals (4.4 trillion frames per second) and high pixel resolution (450 × 450 pixels). The principle of this method--'motion picture femtophotography'--is all-optical mapping of the target's time-varying spatial profile onto a burst stream of sequentially timed photographs with spatial and temporal dispersion. To show the camera's broad utility we use it to capture plasma dynamics and lattice vibrational waves, both of which were previously difficult to observe with conventional methods in a single shot and in real time.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives
We aimed to investigate the relationship between the ability to press Process Lead (PL) in the oral cavity and the tongue pressure and recommended diet form for elderly individuals in ...nursing homes, using PL normalized physical properties.
Design
Cross-sectional observation study.
Setting
Geriatric facilities.
Participants
A 100 elderly individuals aged between 67–96 years.
Measurements
PL was pressed between the tongue and palate to evaluate its deformation. The thickness was set at 6, 9, and 18 mm. The tongue pressure was measured with a JMS tongue pressure manometer. The number of chewing cycles until an 18-mm thick PL was first swallowed was measured (PL chewing test). The diet was set to level 4, and the recommended form was evaluated by video endoscopic evaluation of swallowing (VE). The results of the PL pressing test and correlations between PL chewing test, tongue pressure, and diet level were statistically examined.
Results
The tongue pressure was significantly decreased in groups that could not press the PL. The PL pressing test and recommended diet form showed a significant correlation, and the elderly with difficulty in pressing the PL had a lower diet level. In addition, the diet level decreased with decreased PL chewing test performance in those without molar occlusion.
Conclusions
The PL pressing and chewing tests may aid in ascertaining the appropriate diet level. In the future, we would like to verify the usefulness of these tests in determining the diet level of elderly people requiring long-term care at the time of entering the facility.
Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 ...that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
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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
POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and ...biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have ...now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer.
We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS).
Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027).
Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments.
The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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