Monolithic three-dimensional tier-by-tier integration via van der Waals lamination.

Two-dimensional (2D) semiconductors have shown great potential for monolithic three-dimensional (M3D) integration due to their dangling-bonds-free surface and the ability to integrate to various substrates without the conventional constraint of lattice matching1-10. However, with atomically thin body thickness, 2D semiconductors are not compatible with various high-energy processes in microelectronics11-13, where the M3D integration of multiple 2D circuit tiers is challenging. Here we report an alternative low-temperature M3D integration approach by van der Waals (vdW) lamination of entire prefabricated circuit tiers, where the processing temperature is controlled to 120 °C. By further repeating the vdW lamination process tier by tier, an M3D integrated system is achieved with 10 circuit tiers in the vertical direction, overcoming previous thermal budget limitations. Detailed electrical characterization demonstrates the bottom 2D transistor is not impacted after repetitively laminating vdW circuit tiers on top. Furthermore, by vertically connecting devices within different tiers through vdW inter-tier vias, various logic and heterogeneous structures are realized with desired system functions. Our demonstration provides a low-temperature route towards fabricating M3D circuits with increased numbers of tiers.

Epitaxial Growth of Two-Dimensional MoO2-MoSe2 Metal-Semiconductor Heterostructures for Schottky Diodes.

The metal-semiconductor interface fabricated by conventional methods often suffers from contamination, degrading transport performance. Herein, we propose a one-pot chemical vapor deposition (CVD) process to create a two-dimensional (2D) MoO2-MoSe2 heterostructure by growing MoO2 seeds under a hydrogen environment, followed by depositing MoSe2 on the surface and periphery. The ultraclean interface is verified by cross-sectional scanning transmission electron microscopy and photoluminescence. Along with the high work function of semimetallic MoO2 (Ef = -5.6 eV), a high-rectification Schottky diode is fabricated based on this heterostructure. Furthermore, the Schottky diode exhibits an excellent photovoltaic effect with a high open-circuit voltage of 0.26 eV and ultrafast photoresponse, owing to the naturally formed metal-semiconductor contact with suppressed pinning effect. Our method paves the way for the fabrication of an ultraclean 2D metal-semiconductor interface, without defects or contamination, offering promising prospects for future nanoelectronics.

MOF Derivatives with Gradient Structure Anchored on Carbon Foam for High-Performance Electromagnetic Wave Absorption.

The impedance matching and high loss capabilities of composites with homogeneous distribution are limited owing to high addition and lack of structural design. Developing composites with heterogeneous distribution can achieve strong and wide electromagnetic (EM) wave absorption. However, challenges such as complex design and unclear absorption mechanisms still exist. Herein, a novel composite with a heterogeneous distribution gradient is successfully constructed via MOF derivatives Co@ nitrogen-doped carbon (Co@NC) anchored on carbon foam (CF) matrix (MDCF). Notably, the concentration of MOF can easily control the gradient structure. In particular, the morphologies of MOF derivatives on the surface of CF undergo a transition from the collapse of the inner layer to the integrity of the outer layer, accompanied by a continuous reduction in the size of Co nanoparticles. Correspondingly, enhanced interface polarization from the core-shell of Co@NC and good impedance matching of MDCF can be obtained. The optimized MDCF exhibits the minimum reflection loss of -68.18 dB at 2.01 mm and effective absorption bandwidth covering the entire X-band. Moreover, MDCF exhibits lightweight characteristics, excellent compressive strength, and low radar cross-section reduction. This work highlights the immense potential of composites with heterogeneous distribution for achieving high-performance EM wave absorption.

AcEXPA1, an α-expansin gene, participates in the aluminum tolerance of carpetgrass (Axonopus compressus) through root growth regulation.

KEY MESSAGE: AcEXPA1, an aluminum (Al)-inducible expansin gene, is demonstrated to be involved in carpetgrass (Axonopus compressus) root elongation under Al toxicity through analyzing composite carpetgrass plants overexpressing AcEXPA1. Aluminum (Al) toxicity is a major mineral toxicity that limits plant productivity in acidic soils by inhibiting root growth. Carpetgrass (Axonopus compressus), a dominant warm-season turfgrass widely grown in acidic tropical soils, exhibits superior adaptability to Al toxicity. However, the mechanisms underlying its Al tolerance are largely unclear, and knowledge of the functional genes involved in Al detoxification in this turfgrass is limited. In this study, phenotypic variation in Al tolerance, as indicated by relative root elongation, was observed among seventeen carpetgrass genotypes. Al-responsive genes related to cell wall modification were identified in the roots of the Al-tolerant genotype 'A58' via transcriptome analysis. Among them, a gene encoding α-expansin was cloned and designated AcEXPA1 for functional characterization. Observed Al dose effects and temporal responses revealed that Al induced AcEXPA1 expression in carpetgrass roots. Subsequently, an efficient and convenient Agrobacterium rhizogenes-mediated transformation method was established to generate composite carpetgrass plants with transgenic hairy roots for investigating AcEXPA1 involvement in carpetgrass root growth under Al toxicity. AcEXPA1 was successfully overexpressed in the transgenic hairy roots, and AcEXPA1 overexpression enhanced Al tolerance in composite carpetgrass plants through a decrease in Al-induced root growth inhibition. Taken together, these findings suggest that AcEXPA1 contributes to Al tolerance in carpetgrass via root growth regulation.

Realizing On/Off Ratios over 104 for Sub-2 nm Vertical Transistors.

Vertical transistors hold promise for the development of ultrascaled transistors. However, their on/off ratios are limited by a strong source-drain tunneling current in the off state, particularly for vertical devices with a sub-5 nm channel length. Here, we report an approach for suppressing the off-state tunneling current by designing the barrier height via a van der Waals metal contact. Via lamination of the Pt electrode on a MoS2 vertical transistor, a high Schottky barrier is observed due to their large work function difference, thus suppressing direct tunneling currents. Meanwhile, this "low-energy" lamination process ensures an optimized metal/MoS2 interface with minimized interface states and defects. Together, the highest on/off ratios of 5 × 105 and 104 are realized in vertical transistors with 5 and 2 nm channel lengths, respectively. Our work not only pushes the on/off ratio limit of vertical transistors but also provides a general rule for reducing short-channel effects in ultrascaled devices.

Highly Stable HfO2 Memristors through van der Waals Electrode Lamination and Delamination.

Memristors have attracted considerable attention in the past decade, holding great promise for future neuromorphic computing. However, the intrinsic poor stability and large device variability remain key limitations for practical application. Here, we report a simple method to directly visualize the origin of poor stability. By mechanically removing the top electrodes of memristors operated at different states (such as SET or RESET), the memristive layer could be exposed and directly characterized through conductive atomic force microscopy, providing two-dimensional area information within memristors. Based on this technique, we observed the existence of multiple conducting filaments during the formation process and built up a physical model between filament numbers and the cycle-to-cycle variation. Furthermore, by improving the interface quality through the van der Waals top electrode, we could reduce the filament number down to a single filament during all switching cycles, leading to much controlled switching behavior and reliable device operation.

In Situ Defect Engineering of Controllable Carrier Types in WSe2 for Homomaterial Inverters and Self-Powered Photodetectors.

WSe2 has a high mobility of electrons and holes, which is an ideal choice as active channels of electronics in extensive fields. However, carrier-type tunability of WSe2 still has enormous challenges, which are essential to overcome for practical applications. In this work, the direct growth of n-doped few-layer WSe2 is realized via in situ defect engineering. The n-doping of WSe2 is attributed to Se vacancies induced by the H2 flow purged in the cooling process. The electrical measurements based on field effect transistors demonstrate that the carrier type of WSe2 synthesized is successfully transferred from the conventional p-type to the rarely reported n-type. The electron carrier concentration is efficiently modulated by the concentration of H2 during the cooling process. Furthermore, homomaterial inverters and self-powered photodetectors are fabricated based on the doping-type-tunable WSe2. This work reveals a significant way to realize the controllable carrier type of two-dimensional (2D) materials, exhibiting great potential in future 2D electronics engineering.

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

Genetic structure of an endangered species Ormosia henryi in southern China, and implications for conservation.

BACKGROUND: The evergreen broadleaved forest (EBLF) is an iconic vegetation type of East Asia, and it contributes fundamentally to biodiversity-based ecosystem functioning and services. However, the native habitat of EBLFs keeps on decreasing due to anthropogenic activities. Ormosia henryi is a valuable rare woody species in EBLFs that is particularly sensitive to habitat loss. In this study, ten natural populations of O. henryi in southern China were sampled, and then genotyping by sequencing (GBS) was applied to elucidate the standing genetic variation and population structure of this endangered species. RESULTS: In ten O. henryi populations, 64,158 high-quality SNPs were generated by GBS. Based on these markers, a relatively low level of genetic diversity was found with the expected heterozygosity (He) ranging from 0.2371 to 0.2901. Pairwise FST between populations varied from 0.0213 to 0.1652, indicating a moderate level of genetic differentiation. However, contemporary gene flow between populations were rare. Assignment test and principal component analysis (PCA) both supported that O. henryi populations in southern China could be divided into four genetic groups, and prominent genetic admixture was found in those populations located in southern Jiangxi Province. Mantel tests and multiple matrix regression with randomization (MMRR) analyses suggested that isolation by distance (IBD) could be the possible reason for describing the current population genetic structure. In addition, the effective population size (Ne) of O. henryi was extremely small, and showed a continuous declining trend since the Last Glacial Period. CONCLUSIONS: Our results indicate that the endangered status of O. henryi is seriously underestimated. Artificial conservation measures should be applied as soon as possible to prevent O. henryi from the fate of extinction. Further studies are needed to elucidate the mechanism that leading to the continuous loss of genetic diversity in O. henryi and help to develop a better conservation strategy.

Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

Establishment of a high-fidelity patient-derived xenograft model for cervical cancer enables the evaluation of patient's response to conventional and novel therapies.

BACKGROUND: Recurrent or metastatic cervical cancer (r/m CC) often has poor prognosis owing to its limited treatment options. The development of novel therapeutic strategies has been hindered by the lack of preclinical models that accurately reflect the biological and genomic heterogeneity of cervical cancer (CC). Herein, we aimed to establish a large patient-derived xenograft (PDX) biobank for CC, evaluate the consistency of the biologic indicators between PDX and primary tumor tissues of patients, and explore its utility for assessing patient's response to conventional and novel therapies. METHODS: Sixty-nine fresh CC tumor tissues were implanted directly into immunodeficient mice to establish PDX models. The concordance of the PDX models with their corresponding primary tumors (PTs) was compared based on the clinical pathological features, protein biomarker levels, and genomic features through hematoxylin & eosin staining, immunohistochemistry, and whole exome sequencing, respectively. Moreover, the clinical information of CC patients, RNA transcriptome and immune phenotyping of primary tumors were integrated to identify the potential parameters that could affect the success of xenograft engraftment. Subsequently, PDX model was evaluated for its capacity to mirror patient's response to chemotherapy. Finally, PDX model and PDX-derived organoid (PDXO) were utilized to evaluate the therapeutic efficacy of neratinib and adoptive cell therapy (ACT) combination strategy for CC patients with human epidermal growth factor receptor 2 (HER2) mutation. RESULTS: We established a PDX biobank for CC with a success rate of 63.8% (44/69). The primary features of established PDX tumors, including clinicopathological features, the expression levels of protein biomarkers including Ki67, α-smooth muscle actin, and p16, and genomics, were highly consistent with their PTs. Furthermore, xenograft engraftment was likely influenced by the primary tumor size, the presence of follicular helper T cells and the expression of cell adhesion-related genes in primary tumor tissue. The CC derived PDX models were capable of recapitulating the patient's response to chemotherapy. In a PDX model, a novel therapeutic strategy, the combination of ACT and neratinib, was shown to effectively inhibit the growth of PDX tumors derived from CC patients with HER2-mutation. CONCLUSIONS: We established by far the largest PDX biobank with a high engraftment rate for CC that preserves the histopathological and genetic characteristics of patient's biopsy samples, recapitulates patient's response to conventional therapy, and is capable of evaluating the efficacy of novel therapeutic modalities for CC.

Comparison of the Montreux definition with the Berlin definition for neonatal acute respiratory distress syndrome.

To compare the similarities and differences between the Montreux definition and the Berlin definition in terms of the prevalence, mortality, and complications of neonatal acute respiratory distress syndrome (ARDS). We retrospectively analyzed the data of neonates with respiratory failure treated in a neonatal intensive care unit (NICU) between 1 November 2019 and 31 December 2021. In total, 554 infants had neonatal ARDS (524 infants, Montreux definition; 549 infants, Berlin definition). The prevalence (3.1% vs. 3.3%, p = 0.438) and mortality (18.9% vs.18.0%, p = 0.716) of neonatal ARDS did not differ between the definitions. Among the 519 infants meeting both definitions, key clinical outcomes did not differ between the definitions such as ventilation duration, NICU stay, complication rates, and antibiotic use, except for nitric oxide inhalation. The Montreux and Berlin definitions identified an additional 5 and 30 patients, respectively, not captured by the other definition. The rate of inhaled nitric oxide treatment (20.0% vs. 0%, p = 0.013), air leaks (20.0% vs. 0%, p = 0.013), and invasive ventilation duration (110.00 vs.0.00 h, p = 0.002) significantly differed between the above two groups. Sixty-two patients had moderate and severe ARDS according to the Montreux and Berlin definitions, respectively. The rates of adverse outcomes (e.g., mortality, invasive ventilation time) among these patients were similar to the rates among patients with moderate ARDS according to both definitions than among patients with severe ARDS according to both definitions.  Conclusion: The prevalence, mortality, and most complications of neonatal ARDS were similar between the Montreux and Berlin definitions, which mainly differed in terms of the severity of neonatal ARDS. What is Known: • The Montreux definition was first proposed for the diagnosis of neonatal acute respiratory distress syndrome and was established in 2017. To date, the Montreux definition has not been compared with other diagnostic definitions of ARDS. What is New: • The study suggests that perinatal lung disease need not be excluded in the diagnosis of neonatal ARDS, and that the Montreux definition is more applicable to neonates, taking into account their specific physiological characteristics.

Realization of Ultra-Scaled MoS2 Vertical Diodes via Double-Side Electrodes Lamination.

Schottky diode is the fundamental building blocks for modern electronics and optoelectronics. Reducing the semiconductor layer thickness could shrink the vertical size of a Schottky diode, improving its speed and integration density. Here, we demonstrate a new approach to fabricate a Schottky diode with ultrashort physical length approaching atomic limit. By mechanically laminating prefabricated metal electrodes on both-sides of two-dimensional MoS2, the intrinsic metal-semiconductor interfaces can be well retained. As a result, we demonstrate the thinnest Schottky diode with a length of 2.6 nm and decent rectification behavior. Furthermore, with a diode length smaller than the semiconductor depletion length, the carrier transport mechanisms are investigated and explained by thickness-dependent and temperature-dependent electrical measurements. Our study not only pushes the scaling limit of a Schottky diode but also provides a general double-sided electrodes integration approach for other ultrathin vertical devices.

[Genetic analysis of a patient with familial hypercholesterolemia due to variant of LDLR gene].

OBJECTIVE: To analyze variant of LDLR gene in a patient with familial hypercholesterolemia (FH) in order to provide a basis for the clinical diagnosis and genetic counseling. METHODS: A patient who had visited the Reproductive Medicine Center of the First Affiliated Hospital of Anhui Medical University in June 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was applied to the patient. Candidate variant was verified by Sanger sequencing. Conservation of the variant site was analyzed by searching the UCSC database. RESULTS: The total cholesterol level of the patient was increased, especially low density lipoprotein cholesterol. A heterozygous c.2344A>T (p.Lys782*) variant was detected in the LDLR gene. Sanger sequencing confirmed that the variant was inherited from the father. CONCLUSION: The heterozygous c.2344A>T (p.Lys782*) variant of the LDLR gene probably underlay the FH in this patient. Above finding has provided a basis for genetic counseling and prenatal diagnosis for this family.

Strain-Plasmonic Coupled Broadband Photodetector Based on Monolayer MoS2.

2D Semiconductors are promising in the development of next-generation photodetectors. However, the performances of 2D photodetectors are largely limited by their poor light absorption (due to ultrathin thickness) and small detection range (due to large bandgap). To overcome the limitations, a strain-plasmonic coupled 2D photodetector is designed by mechanically integrating monolayer MoS2 on top of prefabricated Au nanoparticle arrays. Within this structure, the large biaxial tensile strain can greatly reduce the MoS2 bandgap for broadband photodetection, and at the same time, the nanoparticles can significantly enhance the light intensity around MoS2 with much improved light absorption. Together, the strain-plasmonic coupled photodetector can broaden the detection range by 60 nm and increase the signal-to-noise ratio by 650%, representing the ultimate optimization of detection range and detection intensity at the same time. The strain-plasmonic coupling effect is further systematically characterized and confirmed by using Raman and photoluminescence spectrophotometry. Furthermore, the existence of built-in potential and photo-switching behavior is demonstrated between the strained and unstrained region, constructing a self-powered homojunction photodetector. This approach provides a simple strategy to couple strain effect and plasmonic effect, which can provide a new strategy for designing high-performance and broadband 2D optoelectronic devices.

Loss of function mutation in DNAH7 induces male infertility associated with abnormalities of the sperm flagella and mitochondria in human.

Male infertility is an increasingly serious health problem affecting couples of reproductive age. Mutations in axoneme-associated genes cause male infertility. Dynein arm proteins are essential in sustaining normal axonemes and promote flagellar motility. However, the function of DNAH7 in male fertility in vivo remains unclear. Herein, we showed that DNAH7 disruption in humans results in male infertility, which was characterised by multiple morphological abnormalities of sperm flagella. The axoneme structure of the sperm from a DNAH7-deficient patient revealed the loss of inner dynein arms. Moreover, the mitochondria of the sperm flagella detached and dispersed outside the axoneme, leading to abnormalities in the mitochondrial sheath in the mid-piece region. Live birth was achieved via intracytoplasmic sperm injection. Thus, DNAH7 is critical for axoneme and mitochondrial development in human sperm. These findings further clarify the spectrum of DNAH7 biology and provide new insights for diagnosing infertility and treating patients harbouring DNAH7 mutations.

Identifying optimal candidates for postoperative adjuvant therapy among regional persistent/recurrent nasopharyngeal carcinoma patients after neck dissection.

PURPOSE: To analyze the clinical outcomes of patients with regional persistent/recurrent nasopharyngeal carcinoma (NPC) who received neck dissection, and to evaluate the clinical benefit of postoperative adjuvant therapy (PAT) based on patients' positive lymph node counts (PLNs), extracapsular spread (ECS) and preoperative plasma EBV DNA levels. METHODS: From 2003 to 2017, 342 patients with regional persistent/recurrent NPC were included in this study. All patients were treated with neck dissection and 76 patients received PAT. Progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were compared between groups using propensity score matching (PSM). RESULTS: 152 patients without PAT treatment and 76 patients with PAT treatment were selected by the PSM. There was no significant difference in 2-year PFS (52.4% vs. 61.3%, P = 0.371), 2-year OS (91.9% vs. 90.5%, P = 0.097) or 2-year LRFS (66.3% vs. 67.9%, P = 0.872) between the two groups. However, the application of PAT brought survival benefits to patients in terms of 2-year DMFS (76.5% vs. 84.7%, P = 0.020). PLN, ECS and preoperative EBV DNA level remained independent risk factors for poorer PFS. Accordingly, patients were divided into low-risk and high-risk groups using receiver operating characteristic (ROC) curve; the 2-year PFS rates for two risk groups were 73.4% and 59.1% (P < 0.0001) respectively. The results showed that low-risk patients didn't benefit from the addition of PAT. However, the 2-year DMFS rate was significantly improved in high-risk PAT-treated patients than those treated by neck dissection alone (83.7% vs. 71.7%, P = 0.023). CONCLUSIONS: PLNs, ECS and preoperative EBV DNA level are associated with the prognosis of patients with regional persistent/recurrent NPC. High-risk patients identified by PLNs, ECS and preoperative EBV DNA level may benefit from the addition of PAT after neck dissection.

Prognostic significance of AKR1C4 and the advantage of combining EBV DNA to stratify patients at high risk of locoregional recurrence of nasopharyngeal carcinoma.

BACKGROUND: Distinguishing patients at a greater risk of recurrence is essential for treating locoregional advanced nasopharyngeal carcinoma (NPC). This study aimed to explore the potential of aldo-keto reductase 1C4 (AKR1C4) in stratifying patients at high risk of locoregional relapse. METHODS: A total of 179 patients with locoregionally advanced NPC were grouped by different strategies; they were: (a) divided into two groups according to AKR1C4 expression level, and (b) classified into three clusters by integrating AKR1C4 and Epstein-Barr virus (EBV) DNA. The Kaplan-Meier method was used to calculate locoregional relapse-free survival (LRFS), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The Cox proportional hazards model was used to determine potential prognostic factors, and a nomogram was generated to predict 3-year and 5-year LRFS. RESULTS: A significant difference in the 5-year LRFS was observed between the high and low AKR1C4 expression groups (83.3% vs. 92.7%, respectively; p = 0.009). After integrating AKR1C4 expression and EBV DNA, the LRFS (84.7%, 84.5%, 96.9%, p = 0.014) of high-, intermediate-, and low- AKR1C4 and EBV DNA was also significant. Multivariate analysis indicated that AKR1C4 expression (p = 0.006) was an independent prognostic factor for LRFS. The prognostic factors incorporated into the nomogram were AKR1C4 expression, T stage, and EBV DNA, and the concordance index of the nomogram for locoregional relapse was 0.718. CONCLUSIONS: In conclusion, high AKR1C4 expression was associated with a high possibility of relapse in NPC patients, and integrating EBV DNA and AKR1C4 can stratify high-risk patients with locoregional recurrence.

First-Line Immunochemotherapy Versus Palliative Chemotherapy Plus Definitive Radiation Therapy for de novo Metastatic Nasopharyngeal Carcinoma: A Matched Cohort Study.

BACKGROUND: The combined use of immune checkpoint inhibitors (ICIs) with palliative chemotherapy (PCT) is a promising first-line treatment for de novo metastatic nasopharyngeal carcinoma (mNPC). However, the efficacy of ICIs with PCT vs PCT with definitive radiation therapy (DRT) remain unclear. METHODS: Patients with mNPC who received first-line immunochemotherapy (ICI + PCT) or PCT + DRT were included. Propensity score matching (PSM) was applied to balance potential confounders between patients who did and did not undergo DRT (at a ratio of 1:1). Progression free survival (PFS) and overall survival (OS) were compared between the 2 groups using a log-rank test and Cox proportional hazard model. RESULTS: Among all participants, 149 received ICI + PCT. After PSM, 149 patients were included in the PCT + DRT group. First-line immunochemotherapy was associated with significantly improved PFS (median 9.0 months vs 12.0 months, P < .001) and OS (median 12.5 months vs 19.9 months, P < .001). Subgroup analysis revealed that tumor response to immunochemotherapy, metastatic organs, and number of metastatic sites potentially affected the efficacy of DRT after first-line immunochemotherapy. CONCLUSION: Compared with PCT + DRT, first-line immunochemotherapy was associated with improved PFS and OS in patients with mNPC but not in patients with unfavorable tumor response and metastasis involving the liver, distant nodes, or multiple sites.

Determining the suitability of definitive radiation therapy in patients with metastatic nasopharyngeal carcinoma based on PET/CT: a large cohort study.

OBJECTIVES: To determine patients with de novo metastatic nasopharyngeal carcinoma (mNPC) who would benefit from receiving definitive radiation therapy (DRT) along with their pre-existing palliative chemotherapy (PCT) by evaluating their post-PCT Deauville scores and EBV DNA. METHODS: A total of 570 mNPC patients, treated with PCT or PCT+DRT, were studied. EBV DNA levels, along with post-PCT Deauville scores, were used to stratify risk based on the recursive partitioning analysis (RPA). RESULTS: Significant differences were observed in the survival rates of patients with Deauville scores of 1-3 and 4-5 (2-year progression-free survival (PFS): 23.4% versus 8.5%, p < 0.001; 2-year overall survival (OS): 56.8% versus 18.8%, p < 0.001). RPA yielded three distinct groups in the increasing order of risk (Deauville scores of all RPA I-II were within the range of 1-3): (1) RPA I: EBV DNA levels at a pretreatment concentration ≤ 4000 copies/mL and undetectable post-PCT; (2) RPA II: EBV DNA levels either at a pretreatment concentration > 4000 copies/mL or at a pretreatment concentration ≤ 4000 copies/mL and detectable post-PCT; (3) RPA III: Deauville scores 4-5. While patients in RPA I and RPA II had significantly PFS rates when treated with PCT+DRT than when treated with PCT alone (RPA I: 72.7% versus 13.4%, RPA II: 37.8% versus 6.3%), those in RPA III did not experience such PFS benefits (6.5% versus 9.7%). CONCLUSION: PCT+DRT might improve the survival rates in mNPC patients in the low- and mid-risk strata but not those of patients in the high-risk strata. KEY POINTS: We use the Deauville scores and the concentrations of the Epstein-Barr virus (EBV) DNA to determine those patients with de novo metastatic NPC who would benefit from radiation therapy.