Effect of drug interactions with non-vitamin-K oral anticoagulants on thromboembolic events in patients with nonvalvular atrial fibrillation.

Introduction: Few real-world studies have investigated drug-drug interactions (DDIs) involving non-vitamin-K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation (NVAF). The interactions encompass drugs inducing or inhibiting cytochrome P450 3A4 and permeability glycoprotein. These agents potentially modulate the breakdown and elimination of NOACs. This study investigated the impact of DDIs on thromboembolism in this clinical scenario. Method: Patients who had NVAF and were treated with NOACs were selected as the study cohort from the National Health Insurance Research Database of Taiwan. Cases were defined as patients hospitalised for a thromboembolic event and who underwent a relevant imaging study within 7 days before hospitalisa-tion or during hospitalisation. Each case was matched with up to 4 controls by using the incidence density sampling method. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer or inhibitor or both with NOACs was identified. The effects of these interactions on the risk of thromboembolic events were examined with univariate and multivariate conditional logistic regressions. Results: The study cohort comprised 60,726 eligible patients. Among them, 1288 patients with a thromboembolic event and 5144 matched control patients were selected for analysis. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer resulted in a higher risk of thromboembolic events (adjusted odds ratio [AOR] 1.23, 95% confidence interval [CI] 1.004-1.51). Conclusion: For patients with NVAF receiving NOACs, the concurrent use of cytochrome P450 3A4/ permeability glycoprotein inducers increases the risk of thromboembolic events.

Accumulation and bio-oxidation of arsenite mediated by thermoacidophilic Cyanidiales: innate potential biomaterials toward arsenic remediation.

Addressing geogenic and anthropogenic arsenic (As) pollution is critical for environmental health. This study explored arsenite [As(III)] removal using Cyanidiales, particularly Cyanidium caldarium (Cc) and Galdieria partita (Gp), under acidic to neutral pH, and determined As(III) detoxification mechanisms in relation to As speciation and protein secondary structure in Cyanidiales. Regarding As(III) sorption amounts, Cc outperformed Gp, reaching 83.2 mg g-1 of removal at pH 5.0. Wherein, 23.5 % of sorbed As on Cc presented as arsenate [As(V)] complexation with polysaccharides, alongside other predominant species including As(III)-cysteine (41.2 %) and As(III)-polysaccharides (35.3 %) complexes. This suggested that As(III) was directly transported into cells, rather than As(V). Coupled with the formation of As(III)-cysteine complexes within cells, these mechanisms may be key to efficiently accumulating As(III) in Cyanidiales during the 6-h incubation. These results highlight the potential of Cyanidiales for sustainable As(III) remediation and provide new insights into managing As(III) toxicity.

Global Seasonal Activities of Respiratory Syncytial Virus Before the Coronavirus Disease 2019 Pandemic: A Systematic Review.

Varied seasonal patterns of respiratory syncytial virus (RSV) have been reported worldwide. We conducted a systematic review on articles identified in PubMed reporting RSV seasonality based on data collected before 1 January 2020. RSV seasonal patterns were examined by geographic location, calendar month, analytic method, and meteorological factors including temperature and absolute humidity. Correlation and regression analyses were conducted to explore the relationship between RSV seasonality and study methods and characteristics of study locations. RSV seasons were reported in 209 articles published in 1973-2023 for 317 locations in 77 countries. Regular RSV seasons were similarly reported in countries in temperate regions, with highly variable seasons identified in subtropical and tropical countries. Longer durations of RSV seasons were associated with a higher daily average mean temperature and daily average mean absolute humidity. The global seasonal patterns of RSV provided important information for optimizing interventions against RSV infection.

Intercorrelated Ferroelectricity and Bulk Photovoltaic Effect in Two-Dimensional Sn2P2S6 Semiconductor for Polarization-Sensitive Photodetection.

A two-dimensional (2D) ferroelectric semiconductor, which is coupled with photosensitivity and room-temperature ferroelectricity, provides the possibility of coordinated conductance modulation by both electric field and light illumination and is promising for triggering the revolution of optoelectronics for monolithic multifunctional integration. Here, we report that semiconducting Sn2P2S6 crystals can be achieved in a 2D morphology using a chemical vapor transport approach with the assistant of space confinement and experimentally demonstrate the robust ferroelectricity in atomic-thin Sn2P2S6 nanosheet at room temperature. The intercorrelated programming of ferroelectric order along out-of-plane (OOP) and in-plane (IP) directions enables a tunable bulk photovoltaic (BPV) effect through multidirectional electrical control. By combining the capability of anisotropic in-plane optical absorption, a highly integrated Sn2P2S6 optoelectronic device vertically sandwiched with graphene electrodes yields the polarization-dependent open-circuit photovoltage with a dichroic ratio of 2.0 under 405 nm light illumination. The reintroduction of ferroelectric Sn2P2S6 to the 2D asymmetric semiconductor family provides possibilities to hardware implement of the self-powered polarization-sensitive photodetection and spotlights the promising applications for next-generation photovoltaic devices.

Genetic Basis and Evolution of Structural Color Polymorphism in an Australian Songbird.

Island organisms often evolve phenotypes divergent from their mainland counterparts, providing a useful system for studying adaptation under differential selection. In the white-winged fairywren (Malurus leucopterus), subspecies on two islands have a black nuptial plumage whereas the subspecies on the Australian mainland has a blue nuptial plumage. The black subspecies have a feather nanostructure that could in principle produce a blue structural color, suggesting a blue ancestor. An earlier study proposed independent evolution of melanism on the islands based on the history of subspecies divergence. However, the genetic basis of melanism and the origin of color differentiation in this group are still unknown. Here, we used whole-genome resequencing to investigate the genetic basis of melanism by comparing the blue and black M. leucopterus subspecies to identify highly divergent genomic regions. We identified a well-known pigmentation gene ASIP and four candidate genes that may contribute to feather nanostructure development. Contrary to the prediction of convergent evolution of island melanism, we detected signatures of a selective sweep in genomic regions containing ASIP and SCUBE2 not in the black subspecies but in the blue subspecies, which possesses many derived SNPs in these regions, suggesting that the mainland subspecies has re-evolved a blue plumage from a black ancestor. This proposed re-evolution was likely driven by a preexisting female preference. Our findings provide new insight into the evolution of plumage coloration in island versus continental populations, and, importantly, we identify candidate genes that likely play roles in the development and evolution of feather structural coloration.

A novel endoscopic nasopharyngectomy by low-temperature plasma radiofrequency ablation in localized recurrent nasopharyngeal carcinoma.

OBJECTIVE: Endoscopic nasopharyngectomy (ENPG) with en bloc resection has been well accepted in resectable localized recurrent nasopharyngeal carcinoma (rNPC), but it is a difficult technique to master for most otorhinolaryngology head and neck surgeons. Ablation surgery is a new and simplified method to remove tumors. We designed a novel method using low-temperature plasma radiofrequency ablation (LPRA) and evaluated the survival benefit. METHODS: A total of 56 localized rNPC patients were explained in detail and retrospectively analyzed. The surgery method was ablated from the resection margin to the center of the tumor. The postmetastatic overall survival (OS), local relapse-free survival (LRFS) rate, progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: All surgeries were successfully performed without any severe postoperative complications or deaths. The median operation time of ablation and harvested NSFF respectively were 29 min (range, 15-100 min) and 101 min (range, 30-180 min). The average number of hospital days postoperation was 3 days (range, 2-5 days). All cases (100.0%) had radical ablation with negative resection margins. The nasopharyngeal defects were completely re-epithelialized in 54 (96.4%) patients. As of the data cutoff (September 3, 2023), the median follow-up time was 44.3 months (range, 17.1-52.7 months, 95% CI: 40.4-48.2). The 3-year OS, LRFS, PFS and DMFS of the entire cohort were 92.9% (95% CI: 0.862-0.996), 89.3% (95% CI: 0.813-0.973), 87.5% (95% CI: 0.789-0.961), and 92.9% (95% CI: 0.862-0.996), respectively. Cycles of radiotherapy were independent risk factors for OS (p = 0.003; HR, 32.041; 95% CI: 3.365-305.064), LRFS (p = 0.002; HR, 10.762; 95% CI: 2.440-47.459), PFS (p = 0.004; HR, 7.457; 95% CI: 1.925-28.877), and DMFS (p = 0.002; HR, 34.776; 95% CI: 3.806-317.799). CONCLUSION: Radical endoscopic nasopharyngectomy by using low-temperature plasma radiofrequency ablation is a novel, safe and simplified method to master and disseminate for treating resectable rNPC. However, further data and longer follow-up time are needed to prove its efficacy.

Generating Multi-Carbon Products by Electrochemical CO2 Reduction via Catalytically Harmonious Ni/Cu Dual Active Sites.

Despite the unique advantages of single-atom catalysts, molecular dual-active sites facilitate the C-C coupling reaction for C2 products toward the CO2 reduction reaction (CO2 RR). The Ni/Cu proximal dual-active site catalyst (Ni/Cu-PASC) is developed, which is a harmonic catalyst with dual-active sites, by simply mixing commercial Ni-phthalocyanine (Ni-Pc) and Cu-phthalocyanine (Cu-Pc) molecules physically. According to scanning transmission electron microscopy (STEM) and transmission electron microscopy (TEM) energy dispersive spectroscopy (EDS) data, Ni and Cu atoms are separated, creating dual-active sites for the CO2 RR. The Ni/Cu-PASC generates ethanol with an FE of 55%. Conversely, Ni-Pc and Cu-Pc have only detected single-carbon products like CO and HCOO- . In situ X-ray absorption spectroscopy (XAS) indicates that CO generation is caused by the stable Ni active site's balanced electronic state. The CO production from Ni-Pc consistently increased the CO concentration over Cu sites attributed to subsequent reduction reaction through a C-C coupling on nearby Cu. The CO bound (HCOO- ) peak, which can be found on Cu-Pc, vanishes on Ni/Cu-PASC, as shown by in situ fourier transformation infrared (FTIR). The characteristic intermediate of *CHO instead of HCOO- proves to be the prerequisite for multi-carbon products by electrochemical CO2 RR. The work demonstrates that the harmonic dual-active sites in Ni/Cu-PASC can be readily available by the cascading proximal active Ni- and Cu-Pc sites.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Neuro-inspired optical sensor array for high-accuracy static image recognition and dynamic trace extraction.

Neuro-inspired vision systems hold great promise to address the growing demands of mass data processing for edge computing, a distributed framework that brings computation and data storage closer to the sources of data. In addition to the capability of static image sensing and processing, the hardware implementation of a neuro-inspired vision system also requires the fulfilment of detecting and recognizing moving targets. Here, we demonstrated a neuro-inspired optical sensor based on two-dimensional NbS2/MoS2 hybrid films, which featured remarkable photo-induced conductance plasticity and low electrical energy consumption. A neuro-inspired optical sensor array with 10 × 10 NbS2/MoS2 phototransistors enabled highly integrated functions of sensing, memory, and contrast enhancement capabilities for static images, which benefits convolutional neural network (CNN) with a high image recognition accuracy. More importantly, in-sensor trajectory registration of moving light spots was experimentally implemented such that the post-processing could yield a high restoration accuracy. Our neuro-inspired optical sensor array could provide a fascinating platform for the implementation of high-performance artificial vision systems.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma treated with PD-1 blockade: data from a multicohort phase 2 study.

Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Fosaprepitant Weekly vs Every 3 Weeks for the Prevention of Concurrent Chemoradiotherapy-Induced Nausea and Vomiting: A Pilot Randomized Clinical Trial.

Importance: Unlike substantial evidence in the prevention of chemotherapy-induced nausea and vomiting (CINV), research in the prevention of nausea and vomiting caused by concurrent chemoradiotherapy (CCRT) is currently lacking. Objective: To compare the efficacy and safety of fosaprepitant weekly vs every 3 weeks for the prevention of nausea and emesis caused by CCRT among patients with nasopharyngeal carcinoma. Design, Setting, and Participants: This pilot randomized clinical trial was conducted at a single cancer center from November 24, 2020, to July 26, 2021, among patients with nasopharyngeal carcinoma who had achieved CINV control after 2 to 3 cycles of induction chemotherapy. Efficacy analyses were performed in the intention-to-treat population. Data were analyzed on November 4, 2022. Interventions: Eligible patients were randomly assigned (1:1) to receive fosaprepitant either weekly or every 3 weeks. Main Outcomes and Measures: The primary end point was the proportion of patients with sustained complete response (defined as no emesis and no rescue therapy) during CCRT. Secondary end points were sustained no emesis, no nausea, no significant nausea, mean time to first emetic episode, quality of life, and 1-year progression-free survival (PFS). Results: A total of 100 patients (mean [SD] age, 46.6 [10.9] years; 83 [83.0%] male) who had achieved CINV control after induction chemotherapy were randomly assigned to receive fosaprepitant weekly (50 patients) or every 3 weeks (50 patients). There was no significantly significant difference in cumulative risk of emesis or rescue therapy in the group that received weekly fosaprepitant compared with those who received fosaprepitant every 3 weeks (subhazard ratio, 0.66 [95% CI, 0.43-1.02]; P = .06). The proportion of patients with sustained no emesis (38% vs 14%; P = .003) or no significant nausea (92% vs 72%; P = .002) was significantly higher in the group that received fosaprepitant weekly vs those who received fosaprepitant every 3 weeks. Treatments were well tolerated. Patients in the weekly group had improved scores for multiple quality-of-life measures. There was no significant difference in survival outcomes between groups (91.8% vs 93.7%; P = .99). In the mean brainstem dose subgroups, a possible treatment interaction effect was observed in sustained complete response (mean brainstem dose ≥36 Gy: hazard ratio [HR], 0.32 [95% CI, 0.15-0.69]; mean brainstem dose <36 Gy: HR, 0.95 [95% CI, 0.55-1.63]) and sustained no emesis (mean brainstem dose ≥36 Gy: HR, 0.21 [95% CI, 0.08-0.53]; mean brainstem dose <36 Gy: HR, 0.73 [95% CI, 0.41-1.28]). Conclusions and Relevance: In this pilot randomized clinical trial, there was no statistically significant difference in the complete response primary end point, but patients receiving weekly fosaprepitant were less likely to experience emesis compared with those who received fosaprepitant every 3 weeks, especially in the subgroup with a mean brainstem dose of 36 Gy or more. Weekly fosaprepitant was well tolerated and improved quality of life of patients without compromising survival. Trial Registration: ClinicalTrials.gov Identifier: NCT04636632.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

Two-dimensional semiconducting SnP2Se6 with giant second-harmonic-generation for monolithic on-chip electronic-photonic integration.

Two-dimensional (2D) layered semiconductors with nonlinear optical (NLO) properties hold great promise to address the growing demand of multifunction integration in electronic-photonic integrated circuits (EPICs). However, electronic-photonic co-design with 2D NLO semiconductors for on-chip telecommunication is limited by their essential shortcomings in terms of unsatisfactory optoelectronic properties, odd-even layer-dependent NLO activity and low NLO susceptibility in telecom band. Here we report the synthesis of 2D SnP2Se6, a van der Waals NLO semiconductor exhibiting strong odd-even layer-independent second harmonic generation (SHG) activity at 1550 nm and pronounced photosensitivity under visible light. The combination of 2D SnP2Se6 with a SiN photonic platform enables the chip-level multifunction integration for EPICs. The hybrid device not only features efficient on-chip SHG process for optical modulation, but also allows the telecom-band photodetection relying on the upconversion of wavelength from 1560 to 780 nm. Our finding offers alternative opportunities for the collaborative design of EPICs.

Synaptic plasticity realized by selective oxidation of TiS3 nanosheet for neuromorphic devices.

Memristive devices operating analogous to biology synapses demonstrate great potential for neuromorphic applications. Here, we reported the space-confined vapor synthesis of ultrathin titanium trisulfide (TiS3) nanosheets, and subsequent laser manufacturing of a TiS3-TiOx-TiS3 in-plane heterojunction for memristor applications. Due to the flux-controlled migration and aggregation of oxygen vacancies, the two-terminal memristor demonstrates reliable "analog" switching behaviors, in which the channel conductance can be incrementally adjusted by tuning the duration and sequence of programming voltage. The device allows the emulation of basic synaptic functions, featuring excellent linearity and symmetry in conductance change during long-term potentiation/depression processes. The small asymmetric ratio of 0.15 enables it to be integrated into a neural network for the pattern recognition task with a high accuracy of 90%. The results demonstrate the great potential of TiS3-based synaptic devices for neuromorphic applications.

Van der Waals Heterostructure Mid-Infrared Emitters with Electrically Controllable Polarization States and Spectral Characteristics.

Modern infrared (IR) microscopy, communication, and sensing systems demand control of the spectral characteristics and polarization states of light. Typically, these systems require the cascading of multiple filters, polarization optics, and rotating components to manipulate light, inevitably increasing their sizes and complexities. Here, we report two-terminal mid-infrared (mid-IR) emitters, in which tuning the polarity of the applied bias can switch their emission peak wavelengths and linear polarization states along two orthogonal orientations. Our devices are composed of two back-to-back p-n junctions formed by stacking anisotropic light-emitting materials, black phosphorus and black arsenic-phosphorus with MoS2. By controlling the crystallographic orientations and engineering the band profile of heterostructures, the emissions of two junctions exhibit distinct spectral ranges and polarization directions; more importantly, these two electroluminescence (EL) units can be independently activated, depending on the polarity of the applied bias. Furthermore, we show that when operating our emitter under the polarity-switched pulse mode, the time-averaged EL exhibits the characteristics of broad spectral coverage, encompassing the entire first mid-IR atmospheric window (λ: 3-5 µm), and electrically tunable spectral shapes.

Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance.

It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study.

PURPOSE: Immune checkpoint inhibitors combined with antiangiogenic therapy reportedly have potential synergistic antitumor activity. We investigated the activity and safety of this regimen for recurrent/metastatic nasopharyngeal carcinoma (NPC). METHODS: This single-arm, Simon two-stage study enrolled patients with recurrent/metastatic NPC who were refractory to at least first-line systemic therapy and treatment-naive to immune checkpoint inhibitors. The patients received camrelizumab 200 mg once every 3 weeks and apatinib 250 mg once per day. The primary end point was the objective response rate. Key secondary end points included disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, and all were included in the efficacy and safety analysis set. The objective response rate was 65.5% (95% CI, 51.9 to 77.5), and the disease control rate was 86.2% (95% CI, 74.6 to 93.9). The median duration of response was not reached, and the median progression-free survival was 10.4 months (95% CI, 7.2 to 13.6), with a median follow-up duration of 12.4 months (range, 2.1-19.9 months). Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 34 (58.6%) patients, with the most common being hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), AST elevation (10.3%), and creatine phosphokinase elevation (10.3%). Sixteen (27.6%) patients discontinued apatinib treatment before progression because of unbearable TRAEs, and the most common complication was nasopharyngeal necrosis (9/16; 56.3%). Recurrent nasopharyngeal lesions (odds ratio, 5.94 [95% CI, 1.45 to 24.24]) and reirradiation (odds ratio, 5.33 [95% CI, 1.15 to 24.79]) were significantly positively correlated with nasopharyngeal necrosis. CONCLUSION: Camrelizumab plus apatinib had promising antitumor activity in patients with refractory recurrent/metastatic NPC who failed first-line therapy. Moderate to severe TRAEs were experienced by 58.6%, including nasopharyngeal necrosis associated with local recurrence and a history of reirradiation.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Early detection of the initial stages of LED light-triggered non-alcoholic fatty liver disease by wax physisorption kinetics-Fourier transform infrared imaging.

Light-emitting diodes (LEDs), particularly in the blue waveform range, are regarded as a major source of circadian rhythm dysregulation. A circadian rhythm dysregulation induced by blue LEDs is associated with non-alcoholic fatty liver disease (NAFLD). Hepatocellular accumulation of lipids is a key event in the early stages of NAFLD. Kupffer cells (KCs) have been reported to be lost in the early onset of NAFLD followed by an inflammatory reaction that alters the liver response to lipid overload. This study focused on the detection of the initial stages (subpathological stages) of LED light-triggered NAFLD. Mice were exposed to either blue or white LED irradiation for 44 weeks. Synchrotron radiation-based Fourier-transform infrared microspectroscopy (SR-FTIRM) and wax physisorption kinetic-Fourier transform infrared (WPK-FTIR) imaging were used to evaluate the ratio of lipid to protein and the glycosylation of glycoprotein, respectively. Immunohistopathological studies on KCs and circadian-related proteins were performed. Although liver biopsy showed normal pathology, an SR-FTIRM study revealed a high hepatic lipid-to-protein ratio after receiving LED illumination. The results of WPK-FTIR demonstrated that a high inflammation index was found in the high irradiance of the blue LED illumnation group. These groups showed a decrease in KC number and an increase in Bmal1 and Reverbα circadian protein expression. These findings provide explanations for the reduction of KCs without subsequent inflammation. A significant reduction of Per2 and Cry1 expression is correlated with the findings of WPK-FTIR imaging. WPK-FTIR is a sensitive method for detecting initiative stages of NAFLD induced by long-term blue LED illumination.