The value of disease-free survival (DFS) and osimertinib in adjuvant non-small-cell lung cancer (NSCLC): an international Delphi consensus report.

BACKGROUND: Rates of disease recurrence and death following surgery remain high in early-stage non-small-cell lung cancer (NSCLC), despite adjuvant treatment and curative intent. Recently, osimertinib showed overwhelming evidence for disease-free survival (DFS), as demonstrated by an overall reduction in the risk of disease recurrence or death in the adjuvant setting of 80% versus control in the ADAURA study (stage IB-IIIA; hazard ratio 0.20; 99.12% confidence interval 0.14-0.30; P < 0.001). However, due to the early unblinding of ADAURA and lack of mature overall survival data, there is a need to qualitatively confirm consensus on the clinical and patient relevance of DFS. MATERIALS AND METHODS: We conducted a modified Delphi panel study consisting of two rounds of surveys, followed by a consensus meeting. An international panel of experts in the field of NSCLC and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (n = 13) was asked to rate agreement and comment on a list of pre-defined statements covering key consensus gaps. Statements were eliminated or updated between surveys, depending on the level of agreement. A final list of agreed-upon statements was drafted in the consensus meeting. RESULTS: Consensus was reached on 32 qualitative statements, with topics including unmet needs in early-stage NSCLC, the value of DFS, and the value of osimertinib. Crucially, DFS was agreed to be a clinically and patient-relevant endpoint in adjuvant NSCLC. The relevance of DFS was found to relate to the ability of an adjuvant therapy, such as osimertinib, to keep patients in the clinically valuable curative intent setting, while preventing the burden associated with distant and locoregional recurrence, and progressive disease. CONCLUSIONS: Addressing the need for measures that reflect clinical benefit is essential to continue improving outcomes for NSCLC patients. To that end, this work provides a qualitative framework for clinicians to consider the clinical and patient relevance of DFS in adjuvant NSCLC and the benefit demonstrated in ADAURA thus far.

Incidence and mortality of nasopharyngeal carcinoma: interim analysis of a cluster randomized controlled screening trial (PRO-NPC-001) in southern China.

BACKGROUND: Previous mass screening studies have shown that IgA antibodies against Epstein-Barr Virus (EBV) can facilitate early detection of nasopharyngeal carcinoma (NPC), but the impact of EBV-antibody screening for NPC-specific mortality remains unknown. PATIENTS AND METHODS: A prospective, cluster randomized, controlled trial for NPC screening (PRO-NPC-001) was conducted in 3 selected towns of Zhongshan City and 13 selected towns of Sihui City in southern China beginning in 2008. Serum samples of the screening group were tested for two previously selected anti-EBV antibodies. Subjects with serological medium risk were subsequently retested annually for 3 years, and those with serological high risk were referred to otorhinolaryngologists for diagnostic check-up. An interim analysis was carried out to evaluate the primary end points of the NPC-specific mortality and the early diagnostic rate, and the secondary end point of the NPC incidence, through linkage with the database of Zhongshan City. RESULTS: Among 70 296 total subjects, 29 413 screened participants (41.8% of the total subjects) in the screening group and 50 636 in the control group, 153 (43.3 per 100 000 person-year), 62 (55.3 per 100 000 person-year) and 99 (33.1 per 100 000 person-year) NPC cases were identified. The early diagnostic rates of NPC were significantly higher in the participants (79.0%, P < 0.0001) and the screening group (45.9%, P < 0.0001) compared with the control group (20.6%). Although no differences were found between NPC-specific mortality of the screening group and the control group [relative risk (RR)= 0.82, 95% confidence interval (CI) 0.37-1.79], lower NPC-specific mortality was noticed among participants from the screening group versus the control group (RR = 0.22, 95% CI 0.09-0.49). CONCLUSION: IgA antibodies against EBV can identify high-risk population and was effective in screening for early asymptomatic NPC. Although the mortality reduction was not significant in the primary end point, we noted encouraging evidence of a mortality reduction in screening participants in this interim analysis. CLINICAL TRIAL NUMBER: NCT00941538.

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Enhancing protein fluorescence detection through hierarchical biometallic surface structuring.

The enhancement of bovine serum albumin (BSA) fluorescence detection using a hierarchical laser-induced periodic surface structure (LIPSS) at the TC4 titanium alloy substrate was experimentally demonstrated. The hierarchical structure, including microgrooves, submicrometer LIPSS, and nanoparticles, has been achieved by a femtosecond laser. Due to the surface plasmon polariton induced by the LIPSS and localized surface plasmon resonance induced by nanoparticles, the enhancement factor of BSA fluorescence detection reached 74. Further, a good linear relationship between the concentration of copper ion inside and BSA fluorescence intensity was found in the range between 5 and 35 µg/mL. Our method explores a simple, reproducible, and pollution-free technique for surface-enhanced fluorescence.

ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma.

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.

Mantidis ootheca induces vascular relaxation through PI3K/AKT-mediated nitric oxide-cyclic GMP-protein kinase G signaling in endothelial cells.

Mantidis ootheca (Sang Piao Xiao) is well known mantis eggs in a foamy pouch. The purpose of the present study was to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of the aqueous extract of Mantidis ootheca (AMO) in rat aorta and vascular endothelial cells. AMO was examined for its vascular relaxant effect in isolated phenylephrine-precontracted rat thoracic aortic rings. The roles of the nitric oxide (NO) signaling in the AMO-induced effects were tested in human umbilical vein endothelial cells (HUVECs). HUVEC treated with AMO produced higher amount of NO compared to control. However, AMO-induced increases in NO production were blocked by pretreatment with NG-nitro-L-arginine methylester (L-NAME) or wortmannin. AMO increased in phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt in HUVECs, which were attenuated by a NOS and Akt inhibitors. In aortic ring, AMO-induced dose-dependent relaxation of phenylephrine-precontracted aorta was abolished by removal of functional endothelium. Pretreatment with L-NAME, 1H-[1,2,4]-oxadiazolo-[4,3-alpha]-quinoxalin-1-one (ODQ), and KT5823 inhibited the AMO-induced vasorelaxation. Similarly, wortmannin and LY-294002, an inhibitors of the phosphatidylinositol 3-kinase (PI3K), an upstream signaling molecule of eNOS, attenuated the AMO-induced vasorelaxation. Moreover, AMO-induced increases in cGMP production were blocked by pretreatment with L-NAME or ODQ. The vasorelaxant effect of AMO was attenuated by tetraethylammonium, 4-aminopyridine, and glibenclamide. We conclude that AMO relaxed vascular smooth muscle via endothelium-dependent activation of PI3K/Akt-mediated NO-cGMP-PKG signaling pathway and possible involvement of K+ channel.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Dual-wavelength passively Q-switched Nd:GYSGG laser by tungsten disulfide saturable absorber.

A dual-wavelength passively Q-switched Nd:GYSGG laser using vacuum evaporating tungsten disulfide (WS2) as a saturable absorber was demonstrated for the first time to the best of our knowledge. The WS2 saturable absorber was prepared simply by evaporating nanometer WS2 powders onto a quartz substrate in a vacuum. By inserting the WS2 saturable absorber into the laser cavity, stable Q-switched laser operation was achieved with a maximum average output power of 367 mW, a pulse repetition rate of 70.7 kHz, the shortest pulse width of 591 ns, and pulse energy of about 1.05 µJ. By vacuum evaporation method, a high-quality WS2 saturable absorber can be produced, and it seems to be a suitable method for fabrication of 2D transition metal dichalcogenides.

Fabrication of Laser-reduced Graphene Oxide in Liquid Nitrogen Environment.

Porous structure of reduced graphene oxide (rGO) plays an important role in developing flexible graphene-based devices. In this work, we report a novel methodology for reduction of freestanding graphite oxide (GO) sheet by picosecond pulse laser direct writing in liquid nitrogen. Non-agglomerate and porous structure of rGO is fabricated successfully due to frozen effect during laser processing. Compared with laser-irradiated rGO developed in N2 gas at ambient environment, the frozen rGO developed in liquid N2 shows better ordered structure with less defects, crack-free morphology as well as better electron supercapacitor performance including 50-60 Ω/sq in sheet electrical resistance. Mechanism of cryotemperature photoreduction GO is also discussed.

Modulation of photonic nanojets generated by microspheres decorated with concentric rings.

A novel design of decorating microsphere surface with concentric rings to modulate the photonic nanojet (PNJ) is investigated. By introducing the concentric ring structures into the illumination side of the microspheres, a reduction of the full width at half maximum (FWHM) intensity of the PNJ by 29.1%, compared to that without the decoration, can be achieved numerically. Key design parameters, such as ring number and depth, are analyzed. Engineered microsphere with four uniformly distributed rings etched at a depth of 1.2 µm and width of 0.25 µm can generate PNJ at a FWHM of 0.485 λ (λ = 400nm). Experiments were carried out by direct observation of the PNJ with an optical microscope under 405 nm laser illumination. As a result, shrinking of PNJ beam size of 28.0% compared to the case without the rings has been achieved experimentally. Sharp FWHM of this design can be beneficial to micro/nanoscale fabrication, optical super-resolution imaging, and sensing.

High aspect ratio SiNW arrays with Ag nanoparticles decoration for strong SERS detection.

Well-ordered silicon nanowires (SiNWs) are applied as surface-enhanced Raman scattering (SERS) substrates. Laser interference lithography is used to fabricate large-area periodic nanostructures. By controlling the reaction time of metal assisted chemical etching, various aspect ratios of SiNWs are generated. Ag nanoparticles are decorated on the substrates via redox reaction to allow a good coverage of Ag over the SiNWs. As the height of the SiNWs increases, the light scattering inside the structures is enhanced. The number of the probing molecules within the detection volume is increased as well. These factors contribute to stronger light-matter interaction and thus lead to higher SERS signal intensity. However, the light trapping effect is more significant for higher SiNWs, which prevents the detection of the SERS signals. An optimized aspect ratio ∼5:1 (1 µm height and 200 nm width) for the SiNW array is found. The well-ordered SiNWs demonstrate better SERS signal intensity and uniformity than the randomly arranged SiNWs.

Hybrid phase-change plasmonic crystals for active tuning of lattice resonances.

Tunable lattice resonances are demonstrated in a hybrid plasmonic crystal incorporating the phase-change material Ge2Sb2Te5 (GST) as a 20-nm-thick layer sandwiched between a gold nanodisk array and a quartz substrate. Non-volatile tuning of lattice resonances over a range Δλ of about 500 nm (1.89 µm to 2.27 µm) is achieved experimentally via intermediate phase states of the GST layer. This work demonstrates the efficacy and ease of resonance tuning via GST in the near infrared, suggesting the possibility to design broadband non-volatile tunable devices for optical modulation, switching, sensing and nonlinear optical devices.

Enhancement of laser-induced rear surface spallation by pyramid textured structures on silicon wafer solar cells.

Pulsed laser ablation is increasingly being applied to locally open the rear dielectric layer of advanced silicon wafer solar cell structures, such as aluminum local back surface field solar cells. We report that the laser ablation process on the rear surface of the solar cell at a relatively low laser fluence can cause undesirable spallation at the front surface which is textured with random upright pyramids. This phenomenon is attributed to the enhancement of the surface spallation effect by up to 3 times due to the confinement of the pressure waves at the tips of these random pyramids. Laser ablation at different laser focus positions and laser fluences is carried out to achieve optimized laser processing of the solar cells.

An efficacy analysis for nasopharyngeal carcinoma screening of different screening intervals.

OBJECTIVE: To evaluate the impact of different screening intervals on screening for nasopharyngeal carcinoma (NPC). METHODS: A Markov model was constructed, based on the natural history of NPC. The 5-year mortality rate of NPC was the major measurement to evaluate the efficacies of 16 screening strategies. Parameters for the model were derived from published literature. RESULTS: Screening reduced the 5-year mortality rate for NPC by 20.4 - 43.3%, compared with the equivalent rate without screening. The 5 year mortality rate and the NPC pick-up rate with strategy A1 (annual screening) were 23.6% and 83.9%, respectively. Compared with strategy A1, strategy B1 (annual screening for seropositive subjects; biennial screening for seronegative subjects) had a similar 5-year mortality rate (24.0%) and a slightly smaller NPC pick-up rate (81.7%), but led to a 39.3% reduction in total screenings. Compared with all other strategies excluding strategy A1, strategy B1 achieved the lowest 5-year mortality rate and the largest NPC pick-up rate. CONCLUSIONS: Strategy B1 had the highest efficacy for NPC screening.

Enhancement of laser-induced rear surface spallation by pyramid textured structures on silicon wafer solar cells.

Pulsed laser ablation is increasingly being applied to locally open the rear dielectric layer of advanced silicon wafer solar cell structures, such as aluminum local back surface field solar cells. We report that the laser ablation process on the rear surface of the solar cell at a relatively low laser fluence can cause undesirable spallation at the front surface which is textured with random upright pyramids. This phenomenon is attributed to the enhancement of the surface spallation effect by up to 3 times due to the confinement of the pressure waves at the tips of these random pyramids. Laser ablation at different laser focus positions and laser fluences is carried out to achieve optimized laser processing of the solar cells.

Lattice resonances in antenna arrays for liquid sensing in the terahertz regime.

Terahertz antenna arrays supporting narrow lattice resonances are proposed as an alternative sensor-on-chip approach to liquid sensing. An array of metallic rectangular antennas fabricated on a polyethylene naphthalate (PEN) substrate is used to demonstrate the sensing of a number of fluids. Good agreement is shown between experiment and simulation with Q-factors of around 20 and a figure-of-merit (FOM) of 3.80 being achieved. Liquid sensing with antenna arrays is simple both in terms of fabrication and setup. The working frequency can be tuned with a suitable choice of substrates and array parameters. The nature of the lattice resonance means that the whole sample is used to provide the conditions required for resonance occurrence, eliminating the need to preferentially locate the sample in small areas of high field concentration. The antenna arrays could also potentially be coupled with a microfluidic system for in situ sensing or used in a reflection setup.

Influence of plasmon destructive interferences on optical properties of gold planar quadrumers.

Arrays of planar symmetric gold quadrumers consisting of a central nano-disc surrounded by three similar nano-discs belonging to the D(3h) point group were designed and fabricated. Since the geometrical configuration of quadrumers is the same as planar trigonal molecules, nano-discs can play the roles of artificial atoms to study the coupling trends among them. The plasmonic properties of the nano-disc structures are investigated by reflection spectrum measurement and finite-difference time-domain calculation with good agreement. Plasmon interaction among the nano-discs is also studied via a mass-spring coupled oscillator model. A pronounced Fano resonance (FR) is observed for the fabricated nano-discs with inter-disk gaps of around 18 nm during light irradiation at normal incidence. Although the obtained FR is independent of the excitation polarization, the near-field energy spatial distribution can be flexibly tuned by the polarization direction. This has potential applications in nano-lithography, optical switching and nonlinear spectroscopy.

Broadband multi-layer terahertz metamaterials fabrication and characterization on flexible substrates.

Microscopic split-ring-resonator (SRR) arrays are fabricated on 100 µm thick polyethylene naphthalate (PEN) films by femtosecond laser micro-lens array (MLA) lithography. The transmission properties of these metamaterials are characterized by THz Time Domain Spectroscopy (THz-TDS). Tunable resonance responses can be achieved by changing SRR structural design parameters. By stacking 2D PEN metamaterial films with different frequency responses together, a broadband THz filter with full width at half maximum (FWHM) of 0.38 THz is constructed. The bandwidth of the resonance response increases up to 4.2 times as compared to the bandwidths of single layer metamaterials. Numerical simulation reveals that SRR layers inside the multi-layer metamaterials are selectively excited towards specific frequencies within the broadband response. Meanwhile, more than one SRR layers respond to the chosen frequencies, resulting in the enhancement of the resonance properties. The multi-layer metamaterials provide a promising way to extend SRR based metamaterial operating region from narrowband to broadband with a tunable feature.