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Wai Tong Ng,1,2 Barton But,2 Horace CW Choi,3 Remco de Bree,4 Anne WM Lee,1,2 Victor HF Lee,1,2 Fernando López,5,6 Antti A Mäkitie,7– 9 Juan P Rodrigo,5,6 Nabil F Saba,10 Raymond KY Tsang,11 Alfio Ferlito12 1Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 2Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 3Department of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 4Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; 5Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, 33011, Spain; 6Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Madrid, 28029, Spain; 7Department of Otorhinolaryngology - Head and Neck Surgery, HUS Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 8Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 9Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; 10Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 11Division of Otorhinolaryngology, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 12Coordinator of the International Head and Neck Scientific Group, Padua, ItalyCorrespondence: Barton ButDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of ChinaTel +852 2255 4352Fax +852 2872 6426Email bbut@hku.hkIntroduction: Nasopharyngeal carcinoma (NPC) is endemic to Eastern and South-Eastern Asia, and, in 2020, 77% of global cases were diagnosed in these regions. Apart from its distinct epidemiology, the natural behavior, treatment, and prognosis are different from other head and neck cancers. With the growing trend of artificial intelligence (AI), especially deep learning (DL), in head and neck cancer care, we sought to explore the unique clinical application and implementation direction of AI in the management of NPC.Methods: The search protocol was performed to collect publications using AI, machine learning (ML) and DL in NPC management from PubMed, Scopus and Embase. The articles were filtered using inclusion and exclusion criteria, and the quality of the papers was assessed. Data were extracted from the finalized articles.Results: A total of 78 articles were reviewed after removing duplicates and papers that did not meet the inclusion and exclusion criteria. After quality assessment, 60 papers were included in the current study. There were four main types of applications, which were auto-contouring, diagnosis, prognosis, and miscellaneous applications (especially on radiotherapy planning). The different forms of convolutional neural networks (CNNs) accounted for the majority of DL algorithms used, while the artificial neural network (ANN) was the most frequent ML model implemented.Conclusion: There is an overall positive impact identified from AI implementation in the management of NPC. With improving AI algorithms, we envisage AI will be available as a routine application in a clinical setting soon.Keywords: machine learning, neural network, deep learning, prognosis, diagnosis, auto contouring

Milliwatt average power terahertz quantum cascade lasers (THz-QCLs, 2 THz to 5 THz) have been developed for spectroscopy and as local oscillators for heterodyne receivers. Novel DFB THz-QCLs have been fabricated and show single-mode operation. The narrow line widths of

The first application of a commercial Terahertz quantum cascade laser (QCL) system for high resolution spectroscopy of supersonic beams is presented. The QCLs exhibited continuous linear voltage tuning over a 2 GHz range about a center frequency of 3.762 THz with ∼1 ppm resolution. A sensitivity of ∼1 ppm fractional absorption was measured with a single pass optical system. Multipass operation at the quantum noise limit of the stressed photoconductor detector would produce a 100-fold improvement.

Importance: Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential., Objective: To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC., Design, Setting, and Participants: This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9)., Main Outcomes and Measures: The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping., Results: Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects., Conclusion and Relevance: The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Dyspnea, a prevalent and debilitating symptom in patients with advanced lung cancer, negatively affects symptom burden and prognosis. Physical activity has emerged as a promising non-pharmacological intervention for managing dyspnea., Objectives: This study compared the effectiveness of two widely-recognized physical activity modalities, namely Tai Chi (TC) and aerobic exercise (AE) for treating dyspnea in patients with advanced lung cancer., Methods: Patients with advanced lung cancer (n=226) were randomized into TC, AE, or control groups. There was no baseline dyspnea requirement for patients. The AE group received two 60-minute supervised sessions and home-based exercises per month, the TC group received 60-minute sessions twice weekly, and the control group received exercise guidelines for 16 weeks. The primary outcome (sleep quality) of the study has been previously reported. In this secondary analysis, we focused on dyspnea outcomes, including overall and lung cancer-specific dyspnea. Assessments were conducted at baseline (T0), 16 weeks (T1), and one year (T2)., Results: Compared to the control group, TC significantly improved overall dyspnea at T1 (between-group difference, -8.69; P=0.03) and T2 (between-group difference, -11.45; P=0.01), but not AE. Both AE (between-group difference, -11.04; P=0.01) and TC (between-group difference, -14.19; P<0.001) significantly alleviated lung cancer-specific dyspnea at T2 compared with the control group., Conclusion: Both TC and AE alleviate dyspnea severity in patients with advanced lung cancer, and continuous exercise can yield substantial improvements. Due to its multi-component nature, Tai Chi has a greater effect on dyspnea., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Lymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer., Material and Methods: Patients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts., Results: A total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher., Conclusion: This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control., Methods: A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR)., Results: Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66-76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1-67.8) in this cohort. In multivariable analysis, a GARD threshold (GARD T ) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARD T (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66-74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %)., Conclusion: GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This systematic review examines the role of dosimetric parameters in predicting temporal lobe necrosis (TLN) risk in nasopharyngeal carcinoma (NPC) patients treated with three-dimensional conformal RT (3D-CRT), intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). TLN is a serious late complication that can adversely affect the quality of life of NPC patients. Understanding the relationship between dosimetric parameters and TLN can guide treatment planning and minimize radiation-related complications. A comprehensive search identified relevant studies published up to July 2023. Studies reporting on dosimetric parameters and TLN in NPC patients undergoing 3D-CRT, IMRT, and VMAT were included. TLN incidence, follow-up duration, and correlation with dosimetric parameters of the temporal lobe were analyzed. The review included 30 studies with median follow-up durations ranging from 28 to 110 months. The crude incidence of TLN varied from 2.3 % to 47.3 % and the average crude incidence of TLN is approximately 14 %. Dmax and D1cc emerged as potential predictors of TLN in 3D-CRT and IMRT-treated NPC patients. Threshold values of >72 Gy for Dmax and >62 Gy for D1cc were associated with increased TLN risk. However, other factors should also be considered, including host characteristics, tumor-specific features and therapeutic factors. In conclusion, this systematic review highlights the significance of dosimetric parameters, particularly Dmax and D1cc, in predicting TLN risk in NPC patients undergoing 3D-CRT, IMRT, and VMAT. The findings provide valuable insights that can help in developing optimal treatment planning strategies and contribute to the development of clinical guidelines in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Cancer-related cognitive impairment is prevalent in metastatic lung cancer survivors. This study aimed to compare the effectiveness of aerobic exercise and Tai Chi on perceived cognitive function and the mediating role of psychoneurological symptoms with perceived cognitive impairment., Methods: In a subgroup of a parent randomized clinical trial, participants who reported cognitive impairment underwent a 16-week aerobic exercise (n = 49), Tai Chi (n = 48), and control (n = 54) groups. Measures included perceived cognitive function and psychoneurological symptoms (sleep disturbance, fatigue, anxiety, and depression) assessed at baseline (T0), 16-week (T1), and 1 year (T2)., Results: Participants in Tai Chi showed significant improvements compared to aerobic exercise and control groups in perceived cognitive function at T1 (AE: between-group difference, 6.52; P < 0.001; CG: 8.34; P < 0.001) and T2 (AE: between-group difference, 3.55; P = 0.05; CG: 5.94; P < 0.001). Sleep disturbance, fatigue, anxiety, and depression at month 12 explained 24%, 31%, 32%, and 24% of the effect of the intervention on cognitive function at month 12, respectively. Only anxiety at month 4 explained 23% of the intervention effect at month 12., Conclusions: Tai Chi demonstrated beneficial effects on cognitive function in advanced lung cancer survivors with perceived cognitive impairment. Improvement in cognitive function was mediated by reducing sleep disturbance, fatigue, anxiety, and depression, highlighting the importance of addressing these symptoms in future interventions to improve cognitive function, with anxiety playing a significant role at an earlier stage., Implications for Cancer Survivors: Tai Chi is a potentially safe complementary therapeutic option for managing cognitive impairment in this vulnerable population., Trial Registration: ClinicalTrials.gov identifier: NCT04119778; retrospectively registered on 8 October 2019., (© 2024. The Author(s).)

This study reviews national-level policies regulating cross-border healthcare in mainland China after it acceded to the World Trade Organization (WTO). Policy documents from official websites of the State Council and 19 ministries were screened, from which 487 policy documents were analyzed. WTO's five modes of trade and WHO's six building blocks of healthcare system were used to guide the analysis of policymaking patterns, charting of policy evolution process, identification of key policy areas, differentiation of 29 detailed policy themes, and identification of major countries/regions involved in cross-border healthcare. The findings lead to four policy recommendations: (1) to establish a national-level committee to govern cross-border healthcare, (2) to build an information system to comprehensively integrate various information on cross-border healthcare consumption and provision, (3) to take more proactive policy actions in healthcare internationalization, and (4) to carry out reform experiments in key sub-national regions to fully explore various possibilities in developing and regulating cross-border healthcare., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

Importance: Sleep disturbances prevalent among patients with advanced lung cancer can aggravate physical and psychological symptoms, contributing to decreased quality of life and survival., Objective: To compare the effectiveness of 2 physical activities of different modalities and intensities, namely aerobic exercise (AE) and tai chi (TC), on subjective sleep quality, physical and psychological outcomes, and survival in patients with advanced lung cancer., Design, Setting, and Participants: This assessor-blinded, randomized clinical trial was conducted in 3 public hospitals in Hong Kong between December 19, 2018, and September 7, 2022. A total of 226 patients with advanced lung cancer were recruited and randomized 1:1:1 to AE, TC, or the control group., Interventions: For 16 weeks, the AE group received two 60-minute supervised group exercise sessions and home-based exercises per month, and the TC group received 60-minute group sessions twice weekly. The control group received physical activity guidelines., Main Outcomes and Measures: The primary outcome was subjective sleep quality. Secondary outcomes included objective sleep measures, anxiety, depression, fatigue, quality of life, physical function, circadian rhythm, and 1-year survival. Assessments were conducted at baseline, 16 weeks (T1), and 1 year (T2)., Results: The 226 participants had a mean (SD) age of 61.41 (8.73) years, and 122 (54.0%) were female. Compared with the control group, participants in the AE and TC groups showed statistically significant improvements in subjective sleep quality from baseline to T1 (AE: between-group difference, -2.72; 95% CI, -3.97 to -1.46; P < .001; TC: between-group difference, -4.21; 95% CI, -5.48 to -2.94; P < .001) and T2 (AE: between-group difference, -1.75; 95% CI, -3.24 to -0.26; P = .02; TC: between-group difference, -3.95; 95% CI, -5.41 to -2.49; P < .001), psychological distress, physical function, step count, and circadian rhythm. The TC group had a statistically significant greater improvement in sleep than the AE group at T1 (between-group difference, -1.49; 95% CI, -2.77 to -0.22; P = .02) and T2 (between-group difference, -2.20; 95% CI, -3.57 to -0.83; P < .001). Participants in the TC group showed statistically significant improvement in survival compared with the control group., Conclusions and Relevance: In this randomized clinical trial, AE and TC improved sleep, psychological distress, physical function, and circadian rhythm, with TC demonstrating greater benefits on sleep and survival. Both exercises, but particularly TC, can be incorporated into lung cancer survivorship care., Trial Registration: ClinicalTrials.gov Identifier: NCT04119778.

Background: The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients., Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety., Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P  = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR., Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning., Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA., Competing Interests: All the authors declare no potential conflicts of interest., (© 2023 The Author(s).)

Background and Objective: Nasopharyngeal carcinoma (NPC) with de novo distant metastasis (M1) is classified as stage IVB in the 8th edition of the staging system jointly adopted by the American Joint Committee on Cancer and the International Union against Cancer Control. Patients with M1 disease generally have a relatively short life expectancy. This review discusses the personalized and intensified treatment strategies for de novo metastatic NPC., Methods: A literature search was conducted on PubMed to identify peer-reviewed publications on subdivisions of M1 disease and treatment of de novo metastatic NPC. Clinicaltrials.gov and Chinese Clinical Trial Register were searched to identify ongoing clinical trials evaluating systemic or local therapy of previously untreated metastatic NPC., Key Content and Findings: M1 encompasses a diverse group of diseases. Several important factors, including tumor burden, EBV-DNA levels, location of involvement, the number of metastasis, and treatment strategies, influence the prognosis of NPC patients. Researchers have attempted to define M1 subcategorization to reflect the underlying risk profile and tailor personalized treatment. Recent advancements have brought new hope for this otherwise incurable condition. In the era of immunotherapy, checkpoint inhibitors have become the first-line systemic treatment for metastatic NPC in JUPITER-02, CAPTAIN-1st, and RATIONALE-309. Additionally, the value of radical locoregional radiation therapy and ablative treatment to distant metastatic sites should not be overlooked in patients with de novo metastatic diseases. Locoregional radiation with concurrent chemotherapy, maintenance chemotherapy, and radical local treatment to metastatic sites are emerging as potential treatment options., Conclusions: Given the diversity of metastatic NPC, a multimodality approach incorporating chemotherapy, immunotherapy, locoregional radiation and ablative treatment to metastatic sites has been shown to improve overall control. Further research is needed to determine the efficacy and optimal duration of maintenance therapy.

Competing Interests: MLKC reports personal fees from Astellas, Janssen, Bayer, Pfizer, BeiGene, MSD, Varian, IQVIA, Telix Pharmaceuticals; personal fees and non-financial support from AstraZeneca; non-financial support from Decipher Biosciences and MedLever; consulting fees from immunoSCAPE; is a co-inventor of the patent of a High Sensitivity Lateral Flow Immunoassay For Detection of Analyte in Sample (10202107837T), Singapore; and serves on the Board of Directors of Digital Life Line that owns the licensing agreement of the patent, outside the submitted work. MLKC is supported by the National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSAINV20nov-0021), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, and the Kua Hong Pak Head and Neck Cancer Research Programme. All other authors declare no competing interests.

Background and Purpose: Physiological changes in tumour occur much earlier than morphological changes. They can potentially be used as biomarkers for therapeutic response prediction. This study aimed to investigate the optimal time for early therapeutic response prediction with multi-parametric magnetic resonance imaging (MRI) in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemo-radiotherapy (CCRT)., Material and Methods: Twenty-seven NPC patients were divided into the responder (N = 23) and the poor-responder (N = 4) groups by their primary tumour post-treatment shrinkages. Single-voxel proton MR spectroscopy ( 1 H-MRS), diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI were scanned at baseline, weekly during CCRT and post-CCRT. The median choline peak in 1 H-MRS, the median apparent diffusion coefficient (ADC) in DW-MRI, the median influx rate constant (K trans ), reflux rate constant (K ep ), volume of extravascular-extracellular space per unit volume (V e ), and initial area under the time-intensity curve for the first 60 s (iAUC60) in DCE-MRI were compared between the two groups with the Mann-Whitney tests for any significant difference at different time points., Results: In DW-MRI, the percentage increase in ADC from baseline to week-1 for the responders (median = 11.39%, IQR = 18.13%) was higher than the poor-responders (median = 4.91%, IQR = 7.86%) (p = 0.027). In DCE-MRI, the iAUC60 on week-2 was found significantly higher in the poor-responders (median = 0.398, IQR = 0.051) than the responders (median = 0.192, IQR = 0.111) (p = 0.012). No significant difference was found in median choline peaks in 1 H-MRS at all time points., Conclusion: Early perfusion and diffusion changes occurred in primary tumours of NPC patients treated with CCRT. The DW-MRI on week-1 and the DCE-MRI on week-2 were the optimal time points for early therapeutic response prediction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

In nature, cyclopropylcarbinyl cation is often involved in cationic cascade reactions catalyzed by natural enzymes to produce a great number of structurally diverse natural substances. However, mimicking this natural process with artificial organic catalysts remains a daunting challenge in synthetic chemistry. We report a small molecule-catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities (up to 99% enantiomeric excess). In the presence of a chiral SPINOL-derived N -triflyl phosphoramide catalyst, the dehydration of prochiral cyclopropylcarbinols occurs rapidly to generate symmetrical cyclopropylcarbinyl cations, which are subsequently trapped by thione-containing nucleophiles. A subgram-scale experiment and multiple downstream transformations of the sulfide products are further pursued to demonstrate the synthetic utility. Notably, a few heteroaromatic sulfone derivatives could serve as "covalent warhead" in the enzymatic inhibition of severe acute respiratory syndrome coronavirus 2 main protease.

Background: The integration of next-generation sequencing (NGS) comprehensive gene profiling (CGP) into clinical practice is playing an increasingly important role in oncology. Therefore, the HKU-HKSH Multi-disciplinary Molecular Tumour Board (MTB) was established to advance precision oncology in Hong Kong. A multicenter retrospective study investigated the feasibility of the HKU-HKSH MTB in determining genome-guided therapy for treatment-refractory solid cancers in Hong Kong., Methods: Patients who were presented at the HKU-HKSH MTB between August 2018 and June 2022 were included in this study. The primary study endpoints were the proportion of patients who receive MTB-guided therapy based on genomic analysis and overall survival (OS). Secondary endpoints included the proportion of patients with actionable genomic alterations, objective response rate (ORR), and disease control rate (DCR). The Kaplan-Meier method was used in the survival analyses, and hazard ratios were calculated using univariate Cox regression., Findings: 122 patients were reviewed at the HKU-HKSH MTB, and 63% (n = 77) adopted treatment per the MTB recommendations. These patients achieved a significantly longer median OS than those who did not receive MTB-guided therapy (12.7 months vs. 5.2 months, P = 0.0073). Their ORR and DCR were 29% and 65%, respectively., Interpretation: Our study demonstrated that among patients with heavily pre-treated advanced solid cancers, MTB-guided treatment could positively impact survival outcomes, thus illustrating the applicability of NGS CGPs in real-world clinical practice., Funding: The study was supported by the Li Shu Pui Medical Foundation. Dr Aya El Helali was supported by the Li Shu Pui Medical Foundation Fellowship grant from the Li Shu Pui Medical Foundation. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report., Competing Interests: All authors declare no competing interests., (© 2023 The Authors.)

A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)-based approaches to screen for early stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program., (© The Author(s) 2023. Published by Oxford University Press.)

Aims: The protracted COVID-19 pandemic has overwhelmed health systems globally, including many aspects of cancer control. This has underscored the multidimensional nature of cancer control, which requires a more comprehensive approach involving taking a wider perspective of health systems. Here, we investigated aspects of health system resilience in maintaining cancer services globally during the COVID-19 pandemic. This will allow for health systems to be resilient to different types of system stressors/shocks in the future, to allow cancer care to be maintained optimally., Materials and Methods: Using the World Health Organization health system framework (capturing aspects of service delivery, health workforce, information, medical products, vaccines and technologies, financing and governance and leadership), we carried out a comparative analysis of the impact of COVID-19 and the synthesis of the findings in responses in cancer care in 10 countries/jurisdictions across four continents comprising a wide diversity of health systems, geographical regions and socioeconomic status (China, Colombia, Egypt, Hong Kong SAR, Indonesia, India, Singapore, Sri Lanka, UK and Zambia). A combination of literature and document reviews and interviews with experts was used., Results: Our study revealed that: (i) underlying weaknesses of health systems before the pandemic were exacerbated by the pandemic (e.g. economic issues in low- and middle-income countries led to greater shortage of medication and resource constraints compounded by inadequacies of public financing and issues of engagement with stakeholders and leadership/governance); (ii) no universal adaptive strategies were applicable to all the systems, highlighting the need for health systems to design emergency plans based on local context; (iii) despite the many differences between health systems, common issues were identified, such as the lack of contingency plan for pandemics, inadequate financial policies for cancer patients and lack of evidence-based approaches for competing priorities of cancer care/pandemic control., Conclusion: We identified four key points/recommendations to enhance the resilient capacity of cancer care during the COVID-19 pandemic and other system stressors: (i) effective pandemic control approaches in general are essential to maintain the continuity of cancer care during the emergency health crises; (ii) strong health systems (with sufficient cancer care resources, e.g. health workforce, and universal health coverage) are fundamental to maintain quality care; (iii) the ability to develop response strategies and adapt to evolving evidence/circumstances is critical for health system resilience (including introducing systematic, consistent and evidence-based changes, national support and guidance in policy development and implementation); (iv) preparedness and contingency plans for future public health emergencies, engaging the whole of society, to achieve health system resilience for future crises and to transform healthcare delivery beyond the pandemic., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: MLKC reports personal fees from Astellas, Janssen, Bayer, Pfizer, MSD, Varian, IQVIA, Telix Pharmaceuticals, and AstraZeneca, personal fees and non-financial support from BeiGene, non-financial support from Decipher Biosciences and MedLever, consultancy for immunoSCAPE, and is a co-inventor of the patent for a high-sensitivity lateral flow immunoassay for the detection of analyte in a sample (10202107837T) and serves on the Board of Directors of and owns stocks in Digital Life Line Pte, which owns the licensing agreement of the patent, outside the submitted work. VHFL reports personal fees and grants from AstraZeneca and personal fees from AQUILAB, Amgen, Boston Scientific, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, and Takeda, outside the submitted work. AWML declares no competing interests. Editorial note: the Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations.

Background: Post-radiation primary hypothyroidism is a common late complication in head and neck cancer (HNC) survivors. No radiation dose-volume constraint of the thyroid gland has been externally validated for predicting long-term thyroid function outcomes., Materials and Methods: This external validation study evaluated the diagnostic properties of 22 radiation dose-volume constraints of the thyroid gland proposed in the literature. Radiation dosimetric data from 488 HNC patients who underwent neck irradiation from January 2013 to December 2015 at two tertiary oncology centers were reviewed. The diagnostic metrics of candidate constraints were computed by inverse probability of censoring weighting and compared using time-dependent receiver operating characteristic (ROC) curves with death designated as a competing event. Multivariable regression analyses were performed using the Fine-Gray sub-distribution hazard model., Results: Over a median follow-up period of 6.8 years, 205 (42.0 %) patients developed post-radiation primary hypothyroidism. The thyroid volume spared from 60 Gy (VS60) had the largest area under ROC curve of 0.698 at 5 years after radiotherapy. Of all evaluated constraints, VS60 at a cutoff value of 10 cc had the highest F-score of 0.53. The 5-year hypothyroidism risks of patients with thyroid VS60 ≥ 10 cc and < 10 cc were 14.7 % and 38.2 %, respectively (p < 0.001). The adjusted sub-hazard ratio for post-radiation primary hypothyroidism for VS60 < 10 cc was 1.87 (95 % confidence interval, 1.22-2.87; p < 0.001)., Conclusion: Thyroid VS60 is the best radiation dose-volume parameter to predict the long-term risk of primary hypothyroidism in patients with HNC who underwent neck irradiation. VS60 ≥ 10 cc is a robust constraint that limits the 5-year primary hypothyroidism risk to less than 15 % and should be routinely employed during radiotherapy optimization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Radiotherapy is the primary treatment modality for nasopharyngeal carcinoma (NPC). Successful curative treatment requires optimal radiotherapy planning and precise beam delivery that maximizes locoregional control while minimizing treatment-related side effects. In this article, we highlight considerations in target delineation, radiation dose, and the adoption of technological advances with the aim of optimizing the benefits of radiotherapy in NPC patients.

Objectives: Evidence to support Epstein-Barr virus (EBV)-directed population nasopharyngeal carcinoma (NPC) screening has been growing. Familial aggregation is a well-recognized phenomenon in endemic regions. This systematic review summarizes the role of EBV-directed screening in individuals with a positive family history (FH+) of NPC., Methods: We searched four electronic databases from their inception to October 2021. We included studies on individuals with FH+ of NPC who had undergone EBV-directed investigations, with no restriction in the testing methods or analytic techniques. The primary and secondary outcomes were EBV positivity rates and NPC incidence rates, respectively. Meta-analyses were performed using the random-effect model., Results: Ten cross-sectional studies (n = 7436) and three cohort studies (n = 4306) were included. The pooled relative risk (RR) of EBV positivity between individuals with and without FH+ of NPC were 2.79 (95 % CI 1.37-5.68, p = 0.005) for viral capsid antigen (VCA) IgA, 3.09 (95 % CI 0.65-14.83, p = 0.16) for Epstein-Barr nuclear antigen (EBNA1) IgA, and 1.76 (95 % CI 1.04-2.96, p = 0.03) for combined EBNA1/VCA IgA. In the three cohort studies, the NPC incidence rates ranged from 90.2 to 266 per 100 000 person-years with high proportions of early-stage diseases. FH+ individuals who were EBV-positive had a 2.5 to 30.7-fold risk of NPC development compared to their EBV-negative counterparts., Conclusion: Family members of NPC patients had significantly higher EBV positivity rates than the general population. FH+ individuals who are EBV-positive had high risks of developing NPC. Familial screening using EBV serology may facilitate early NPC detection in endemic areas., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Purpose: Functional imaging has an established role in therapeutic monitoring of cancer treatments. This study evaluated the correlations of tumour permeability parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumour cellularity derived from apparent diffusion coefficient (ADC) in nasopharyngeal carcinoma (NPC)., Material and Methods: Twenty NPC patients were examined with DCE-MRI and RESOLVE diffusion-weighted MRI (DW-MRI). Tumour permeability parameters were quantitatively measured with Tofts compartment model. Volume transfer constant (K trans ), volume of extravascular extracellular space (EES) per unit volume of tissue (V e ), and the flux rate constant between EES and plasma (K ep ) from DCE-MRI scan were measured. The time-intensity curve was plotted from the 60 dynamic phases of DCE-MRI. The initial area under the curve for the first 60 s of the contrast agent arrival (iAUC60) was also calculated. They were compared with the ADC value derived from DW-MRI with Pearson correlation analyses., Results: Among the DCE-MRI permeability parameters, K ep had higher linearity in inverse correlation with ADC value (r = -0.69, p = <0.05). K trans (r = -0.60, p=<0.05) and iAUC60 (r = -0.64, p = <0.05) also had significant inverse correlations with ADC. V e showed a significant positive correlation with ADC (r = 0.63, p = <0.05)., Conclusions: Nasopharyngeal tumour vascular permeability parameters derived from DCE-MRI scan were correlated linearly with tumour cellularity measured by free water diffusability with ADC. The clinical implementations of these linear correlations in the quantitative assessments of therapeutic response for NPC patients may be worth to further explore., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background/purpose: A systematic review and meta-analysis were performed to better understand the benefits of particle beam therapy for nasopharyngeal cancer (NPC) treatment. The survival outcomes and toxicity of primary and recurrent NPC patients treated with proton or carbon ion beam therapy were investigated., Method: PubMed, Scopus, and Embase were searched between 1 January 2007 to 3 November 2021. The inclusion and exclusion criteria included studies with either primary or recurrent NPC patients, sample size of ≥10 patients, and proton or carbon ion beam therapy as interventions. Twenty-six eligible studies with a total of 1502 patients were included. We used a random-effect meta-analysis to examine the impact of particle beam therapy on primary NPC patients and qualitatively described the results among recurrent patients. The primary outcome was overall survival (OS), while secondary outcomes included progression-free survival (PFS), local control (LC) and toxicity., Results: The pooled OS at 1-year, 2-year and 3-year and 5-year for primary NPC patients who received particle beam therapy were 96 % (95 % confidence interval (CI) = 92 %-98 %), 93 % (95 % CI = 83 %-97 %), 90 % (95 % CI = 73 %-97 %) and 73 % (95 % CI = 52 %-87 %) respectively. The pooled 1-year and 2-year PFS, and LC for these patients were above 90 %. For locally recurrent NPC patients, the 1-year OS rate ranged from 65 % to 92 %, while the 1-year LC rate ranged from 80 % to 88 %. Both proton and carbon ion beam therapy were generally safe among primary and recurrent patients, with ≥G3 late toxicity rates of 20 % or less. Approximately a 5 % mortality rate was reported among recurrent patients., Conclusions: This systematic review and meta-analysis demonstrated particle beam therapy has great potential in treating NPC, yielding excellent survival outcomes with low toxicity. However, further investigations are needed to assess the long-term outcomes and cost-effectiveness of this newer form of radiotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Purpose: The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking., Experimental Design: 742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied., Results: Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA-B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41-0.91] and 0.67 (95% CI, 0.48-0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses., Conclusions: Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored., (©2022 American Association for Cancer Research.)

Endoscopic endonasal surgery has been demonstrated to be effective in the treatment of selected cases of sinonasal cancers. However, in cases of locally advanced neoplasms, as well as recurrences, the most appropriate approach is still debated. The present review aims to summarize the current state of knowledge on the utility of open approaches to resect sinonasal malignant tumours. Published comparative studies and meta-analyses suggest comparable oncological results with lower morbidity for the endoscopic approaches, but selection biases cannot be excluded. After a critical analysis of the available literature, it can be concluded that endoscopic surgery for selected lesions allows for oncologically safe resections with decreased morbidity. However, when endoscopic endonasal surgery is contraindicated and definitive chemoradiotherapy is not appropriate, craniofacial and transfacial approaches remain the best therapeutic option., (© 2022. The Author(s).)

Background: We conducted this study to evaluate if a reduced cumulative dose of induction and concurrent cisplatin conferred similar favorable outcomes when compared to trial NPC-0501., Methods: Newly diagnosed nasopharyngeal carcinoma (NPC) with stage III-IVA were prospectively recruited from January 2015 to September 2019. Induction chemotherapy (IC) consisted of cisplatin 80mg/m 2 on day 1 and capecitabine 1000mg/m 2 twice daily from day 1 to 14 every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy (CCRT) with 2 cycles of cisplatin 100mg/m 2 given every 3 weeks. Tumor response was evaluated according to RECIST v1.1. Acute and late adverse events (AEs) were graded with CTCAE v4.0 and Late Radiation Morbidity Scoring of the RTOG, respectively., Results: 135 patients were recruited. At 16 weeks after CCRT, all 130 patients who completed the entire course of radiotherapy (RT) had a complete response upon final assessment. With a median follow-up of 36.2 months, 22 treatment failures and 8 deaths were observed. The 3-year progression-free survival, overall survival, locoregional recurrence-free survival, and distant recurrence-free survival were 83.7%, 94.1%, 94.1%, and 85.9%, respectively. Our survival data outcomes were similar to those reported in the cisplatin and capecitabine (PX) induction arm of the 0501 trial. 103 patients (76.3%) reported acute grade 3-4 AEs. Two patients (1.5%) had late grade 3-4 complications, numerically fewer than those reported in the NPC-0501 trial., Conclusions: Induction PX and concurrent cisplatin with a reduced cumulative cisplatin dose yield survival outcomes comparable to those reported in the NPC-0501 trial with excellent tolerability. Therefore, a reduced cumulative dose of cisplatin is a promising treatment scheme for nasopharyngeal carcinoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Yang, Ng, Helali, Lee, Ma, Liu, Li, Shen, Huang, Zha, Zhou, Lee and Chen.)

Purpose: To propose a refined M1 classification in de novo metastatic nasopharyngeal carcinoma (NPC) based on pooled data from two academic institutions., Methods: Previously untreated de novo M1 NPC patients prospectively treated at The University of Hong Kong (N = 69) and Fujian Cancer Hospital (N = 114) between 2007 and 2016 were recruited and randomized in a 2:1 ratio to generate training (N = 120) and validation (N = 63) cohorts, respectively. Multivariable analysis (MVA) was performed for the training and validation cohorts to identify anatomic prognostic factors for overall survival (OS). Recursive partitioning analysis (RPA) was performed which incorporated the anatomic prognostic factors identified in the MVA to derive Anatomic-RPA groups which stratified OS in the training cohort, and were then validated in the validation cohort., Results: Median follow-up for the training and validation cohorts was 27.2 and 30.2 months with 3-year OS of 51.6% and 51.1%, respectively. MVA revealed that co-existing liver-bone metastases was the only factor prognostic for OS in both the training and validation cohorts. Anatomic-RPA separated M1 disease into M1a (no co-existing liver-bone metastases) and M1b (co-existing liver-bone metastases) with median OS 39.5 and 23.7 months, respectively (p = 0.004) in the training cohort. RPA for the validation cohort also confirmed good segregation with co-existing liver-bone metastases with median OS 47.7 and 16.0 months, respectively (p = 0.008)., Conclusion: Our proposal to subdivide de novo M1 NPC into M1a (no co-existing liver-bone metastases) vs. M1b (co-existing liver-bone metastases) provides better OS segregation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)