To explore psycho-oncologists’ knowledge of cancer-related fatigue and their self-efficacy to intervene for fatigue. We further aimed to examine the role of fatigue in psycho-oncological training and derive specific suggestions for improvements.U tests. A logistic regression analysis was performed to identify variables linked to fatigue guideline knowledge.For this cross-sectional survey study, psycho-oncologists working in Germany were systematically recruited via an address directory or invited by training institutes or colleagues. The online survey encompassed questions on knowledge of fatigue guidelines and interventions, self-efficacy, counseling, and fatigue in professional training. Data were analyzed descriptively and using Mann-Whitney Seventy two percent of the 144 surveyed psycho-oncologists stated not knowing any fatigue-specific guidelines. Those unaware of guidelines reported a lower self-efficacy to intervene for fatigue. However, despite low knowledge of the guidelines, more than 80% of the participants felt well informed about fatigue and reported high self-efficacy. Most participants were aware of the empirical evidence for psychotherapeutic interventions (95%); everyday physical activity, e.g., taking a walk (98%); yoga (82%); and mindfulness-based interventions (82%). Knowledge gaps existed concerning the evidence of resistance/endurance training for treating fatigue. Knowing that resistance/endurance training is an effective treatment was related to an increased frequency to recommend it to patients. Suggestions to improve training for psycho-oncologists included raising awareness earlier in the career path and offering multidisciplinary trainings for fatigue.To improve fatigue-related guideline knowledge among psycho-oncologists and enhance implementation into clinical practice multidisciplinary trainings are needed. Psycho-oncologists should play an important role in fatigue management.Clinicaltrials.gov, identifier: NCT04921644. Registered in June 2021.The online version contains supplementary material available at 10.1007/s00520-023-07882-5. According to the National Comprehensive Cancer Network (NCCN) cancer-related fatigue (CRF) is a “distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” . AlthougAccording to the NCCN, multidisciplinary teams, including physicians, nurses, and psychologists, are most appropriate to ensure implementation of CRF guidelines in clinical practice . ParticuClinicaltrials.gov, identifier: NCT04921644) investigating the current management of CRF in Germany. The online survey among psycho-oncologists was conducted between December 2021 and September 2022 and aimed to assess the psycho-oncologists’ perspective on CRF management. Individuals were eligible for participation if they worked as psycho-oncologists in Germany seeing at least one cancer patient per week for at least 1 year, had Internet access, and sufficient German language skills to understand the survey. The German Cancer Society (DKG) prescribes the following qualifications to be approved as a psycho-oncologist: masters’ (or comparable) degree in psychology, medicine or social pedagogy, training in psychotherapy, and advanced training in psycho-oncology certified by the DKG [This cross-sectional, observational study was part of the large-scale LIFT project  . The stuAfter providing informed consent, participants completed the online survey, which took approximately 15 min. Items were self-developed, based on an Australian questionnaire  and had U tests were performed to clarify relationships between subgroups. For Mann-Whitney U tests, Pearson’s r was calculated, with |r| > .1 indicating small, |r| > .3 moderate, and |r| > .5 large effects. All statistical analyses were carried out using IBM SPSS version 29.0.0.0, with p ≤ .05 (two-tailed) considered statistically significant.Sample characteristics and answers to CRF-related questions are presented descriptively. Associations between sociodemographic/professional characteristics and CRF guideline knowledge were explored using a logistic regression model in which CRF guideline knowledge served as binary outcome variable. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Variables considered as potentially relevant, based on theoretical considerations or previously performed univariate analyses, were simultaneously included in the model, i.e., age, gender, and leading position. Additionally, Mann-Whitney n = 123) was directly invited by study personnel to participate after having been systematically drawn from the address directory of the CIS (response rate: 34%). Additionally, 15 participants learned about the study by colleagues and the remaining six via mailing lists of the training institute for psycho-oncology.Of the 162 psycho-oncologists who had provided informed consent, 18 were excluded due to missing data. Thus, the final sample consisted of 144 psycho-oncologists of which the majority . Female gender  decreased the likelihood of reporting knowledge of CRF guidelines, while higher age increased the likelihood . Adding further predictors like working experience did not significantly improve the model.The logistic regression analysis revealed a significant association between leading position and guideline knowledge, with psycho-oncologists in leading positions being more likely to know guidelines . Likewise, perceived CRF-related knowledge was greater in psycho-oncologists who knew guidelines than in the subgroup who did not .To enable the following analysis, three individuals who indicated “unable to judge” in the self-efficacy item were excluded. Significantly higher levels of self-efficacy were found in psycho-oncologists who knew CRF-specific guidelines when compared to those who did not .Eighty four percent stated to often or almost always recommend psychotherapeutic interventions to patients showing signs of CRF  or even comprehensively (39%) during advanced psycho-oncological training. Psycho-oncologists’ suggestions to improve education and training for CRF are presented in Fig. In this study, we investigated psycho-oncologists’ knowledge and self-efficacy to intervene for CRF. Furthermore, we assessed the role of CRF in education and training in order to identify concrete steps to improve CRF knowledge among psycho-oncologists.Overall, we revealed knowledge gaps regarding CRF among psycho-oncologists. The majority was not aware of CRF-specific guidelines, and recommendations of the NCCN and ESMO guidelines for CRF were well known to only 4% and 1%, respectively. Similar to our findings, a Canadian study demonstrated HCPs’ low familiarity with CRF-specific guidelines . In our Furthermore, a lack of knowledge emerged concerning the evidence of exercise training (resistance/endurance training) for treating CRF, with 7% stating that the evidence is unclear and 13% even assuming the evidence to be against exercise training. This resulted in a reluctance to recommend this measure to patients with CRF. Since exercise training is one of the most convincing interventions for CRF, this finding is alarming . HoweverNumerous previous studies have also reported substantial CRF-related knowledge deficits in HCPs. For example, an Australian research group found that 28% of the surveyed HCPs were not able to mention any effective treatment for CRF . A consiHowever, most psycho-oncologists in our study were aware of the empirical evidence for everyday physical activity, psychosocial interventions, mindfulness-based interventions, and yoga. Given that more psycho-oncologists thought that the evidence for yoga is rather high, but not very high and that not even half of the participants often/almost always recommended yoga to patients, show, however, that there is still room for improvement. This finding corroborates results of a previous study in which mind-body interventions were rarely recommended . Yet, paHCPs’ knowledge deficits, together with gaps in the patient-provider-communication and systemic barriers such as a lack of time and reimbursement, presumably contribute to the knowledge-to-practice gap in CRF management , 14. TheDespite systematic recruitment procedures and a response rate of 34%, a selection bias cannot be excluded. However, it can be assumed that particularly those who are highly motivated and interested in CRF participated in the survey. Actual knowledge gaps in the population of psycho-oncologists might thus be even more pronounced than the knowledge gaps identified in this study. Additionally, low numbers of cases in subgroups did not allow for more comprehensive analyses. Thus, our analyses should be considered explorative, and further possible determinants of CRF-related knowledge should be examined.A lack of CRF guideline knowledge associated with lower CRF-related self-efficacy gives rise to the importance of thorough CRF-specific trainings. This is also illustrated by the fact that a significant number of psycho-oncologists in our study were not aware of the scientific evidence for exercise training or even suspected detrimental effects. Therefore, professional trainings early in the career path, e.g., during psychotherapy training, should be offered to raise awareness for the relevance of CRF. Further trainings should take place in a multidisciplinary setting, focus on the provision of up-to-date information on CRF, and include practical elements. Our study showed that psycho-oncologists rarely recommend interventions outside their discipline, e.g., exercise training, making clear that regular exchange between different professions, not only in trainings but also in daily clinical practice, is crucial. These results underline NCCN guideline recommendations saying that multidisciplinary teams are best suited to achieve progress in CRF management . MultidiA majority of psycho-oncologists are not aware of CRF-specific guidelines. Furthermore, due to knowledge gaps concerning exercise training, a considerable number of patients have presumably not received this highly effective treatment option. Consequently, to promote implementation of CRF guidelines by improving HCPs’ knowledge, it is important to provide up-to-date information within multidisciplinary trainings. Further research into barriers of CRF management and strategies to resolve them is warranted.ESM 1(PDF 126 kb)ESM 2(PDF 107 kb)ESM 3(PDF 79.9 kb)


LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed. Among them, the fundamental issue is to define the proper similarity between transcriptional profiles. Traditionally, such similarity has been defined in an unsupervised way. However, due to the high dimensionality and the existence of high noise in high-throughput data, similarity defined in the traditional way lacks robustness and has limited performance. To this end, we present DrSim, which is a learning-based framework that automatically infers similarity rather than defining it. We evaluated DrSim on publicly available in vitro and in vivo datasets in drug annotation and repositioning. The results indicated that DrSim outperforms the existing methods. In conclusion, by learning transcriptional similarity, DrSim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery. The source code and manual of DrSim are available at https://github.com/bm2-lab/DrSim/.Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as connectivity map (CMap) and library of integrated network-based cellular signatures ( Then, the query signature is used to calculate similarities with compound perturbation profiles  to indicate whether exposure to a specific compound is able to reverse or induce the phenotype of interest. In this process, the fundamental issue is to define the proper similarity between the query signature and the reference signature. Although various similarity methods, including Cosine Compound perturbation-based transcriptional profiles in connectivity map (CMap) and library of integrated network-based cellular signatures (LINCS) have been successfully applied in drug discovery, such as elucidating the mechanisms of action (MOAs) for little-known compounds or suggesting new indications for existing drugs i.e., elucidating MOAs for less well-understood drugs, and 2) drug repositioning, i.e., proposing new indications for existing drugs in vitro and in vivo datasets in drug annotation and repositioning. Our comprehensive test results indicated that DrSim outperforms the existing methods. Taken together, by learning transcriptional similarity, DrSim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery with a conceptual improvement.To this end, we present similarity learning for drug discovery (DrSim), which is a learning-based framework that automatically infers similarity rather than defining it. Basically, there are two main applications of such perturbation-based transcriptional profiles for phenotypic drug discovery: 1) drug annotation, DrSim comprises three main steps: data preprocessing, model training, and similarity calculation .Figure 1In our current study, for illustration purposes, LINCS is used as the data resource since it holds the largest-scale compound reference signatures P is obtained. 2) By applying LDA to the dimensionality-reduced signatures, a transformation matrix L is learned based on the signature labels indicating similarities and dissimilarities between them. The label of a signature is the compound that induces the signature. The transformation matrix L that fits the relationships between signatures will project signatures into another space, in which signatures belonging to the identical class stay close to each other (intraclass similarity) while signatures belonging to different classes stay away from each other (interclass dissimilarity). In summary, the basic conception of LDA is to learn an optimal metric L that aims at maximizing intraclass similarity and interclass dissimilarity. 3) The transformed references (TRs) belonging to the identical compound are median centered to obtain the transformed median-centered reference  metric learning algorithm A and B [nce TMR; C.P and L matrices, its similarities to TMRs are calculated by cosine similarity  metric after applying DrSim to all the signatures having no less than 10 replicates in the 22 subset datasets P < 0.05).Before evaluating the performance of DrSim, we demonstrated the rationale of the designed workflow to make sure that it is appropriate for drug annotation and drug repositioning based on transcriptional data. First, we evaluate whether the similarity learned by DrSim brings signatures with the same label close together, while separating signatures with different labels. More specifically, we employ t-distributed stochastic neighbor embedding (t-SNE) to visualize the distribution of query and reference signatures before and after applying DrSim. The parameter n_components of t-SNE is set to 2. Other parameters are set as default values. For illustration purposes, only signatures having the most replicates in MCF7 at 24 h are selected as an example. The selected signatures are split into queries and references at a ratio of 3:7, followed by applying DrSim. As shown in Second, we visualized the distribution of similarities between reference signatures and query signatures before and after applying DrSim. As shown in i.e., the total number of bottom- and top-ranked differentially expressed genes in the six methods, was set to 200 as commonly used i.e., drug annotation and drug repositioning, based on publicly available in vitro and in vivo transcriptional dataset.To demonstrate the advantage of DrSim, we compared it against six other commonly used methods, including Cosine, KS, GSEA, XSum, XCos, and sscMap. NFFinder The MOA describes how a drug produces its effect on the body. Compound perturbation-based transcriptional profiles have often been applied for drug annotation to uncover MOAs of less well-understood drugs. For example, the expression signature induced by thioridazine was found to have a strong similarity to those induced by DNA inhibitors, demonstrating that thioridazine exerts its anti-tumor activity by inhibiting DNA replication Compound-induced profiles are usually heterogeneous. For example, expression profiles in LINCS are measured by L1000 technology due to cost constraints i.e., drug repositioning or repurposing, is significant for pharmaceutical study and is evolving as a method to reduce the cost of drug discovery i.e., in vitro datasets, in vivo datasets, and in vivo datasets with real-world evidence. We investigated whether DrSim can suggest effective compounds for query signatures that are derived from the phenotype of interest in the three datasets. The drug repositioning benchmark workflow comprises three steps: calculation of disease query signature, compound scoring, and calculation of precision -approved drugs against diseases was compared. Three kinds of cancer were analyzed, i.e., lung adenocarcinoma (LUAD), breast invasive carcinoma (BRCA), and prostate adenocarcinoma (PRAD), based on the availability of FDA-approved drug reference signatures on these cancers . It should be noted that AD patient-derived cell lines are not available in LINCS. Therefore, the signatures on the nine cancer cell lines in LINCS were used as references. Following the benchmark workflow described above in the “drug repositioning” section, 1) query signatures were collected by comparing cancer and AD patient expression profiles to the corresponding normal tissue expression profiles  and the reference signatures on those drugs, BRCA and LUAD patients were analyzed  designing a more efficient similarity-learning algorithm to characterize transcriptional similarity, and 2) identifying more efficient signatures through the genome-wide transcriptome. For example, using key pathway signatures to characterize the causality of diseases https://hub.docker.com/r/bm2lab/drsim/. The usage and manual of DrSim are available at GitHub https://github.com/bm2-lab/DrSim/. The usage and manual of DrSim are also available at BioCode at National Genomics Data Center https://ngdc.cncb.ac.cn/biocode/tools/BT007273/.Docker version of DrSim can be installed at Zhiting Wei: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Validation, Writing - review & editing. Sheng Zhu: Data curation, Formal analysis, Methodology, Validation. Xiaohan Chen: Formal analysis, Visualization. Chenyu Zhu: Investigation, Visualization. Bin Duan: Investigation, Methodology. Qi Liu: Conceptualization, Writing - original draft, Validation, Writing - review & editing. All authors have read and approved the final manuscript.The authors declare that they have no competing interests.


All subgroups also maintained significant differences stratified by continents , analysis technique , and sample source . Conclusion: Cord blood leptin levels were significantly higher in GDM compared to controls. Further research is needed to clarify its role as a predictive biomarker of subsequent metabolic diseases in mothers with GDM and offspring.Background: The literature provides limited evidence of cord blood leptin levels in gestational diabetes mellitus (GDM), with contradictory and inconsistent results with respect to their possible implications for maternal, perinatal, and future complications. Methods: MEDLINE/PubMed, Embase, Scopus, and Web of Science databases were searched in order to investigate the state of evidence on the association of leptin profile in cord blood during perinatal complications in GDM. We critically assessed the risk of bias using the Newcastle-Ottawa scale. Meta-analyses were performed, and heterogeneity and publication bias were analyzed. Results: sixteen primary-level studies were included, recruiting 573 GDM and 1118 control pregnant women. Cord blood leptin levels were significantly higher in GDM participants compared to controls  = 0.37 to 0.80,  It is known that many biological parameters are modified by gestational diabetes mellitus (GDM) and could potentially be used as predictors. About 1–14% of all pregnancies are complicated with GDM, which, classically, is defined as an intolerance to carbohydrates that begins, or is first recognized, during pregnancy and resolves after delivery . GDM is Fetal growth is the result of complex interactions between the placental, fetal, and maternal environments, and is controlled by genetic, hormonal, and nutritional factors. Nevertheless, the hormonal mechanisms involved in fetal growth are not fully understood. Both GDM as well as obesity/overweight during pregnancy are risk factors for hormonal neonatal and harmful anthropometric outcomes ,7. PreviWhile the role of maternal leptin profile in the development of GDM and its maternal-fetal complications has been extensively evaluated by primary studies and higher-level of evidence-based research, such as a recent meta-analysis published by our group , currentThis systematic review and meta-analysis strictly complied with the pertinent PRISMA reporting checklist and with the MOOSE statement, specifically designed for meta-analyses of observational studies ,18, and www.crd.york.ac.uk/PROSPERO (accessed and registered on 26 July 2020), CRD42020194274 code) [A methodological study protocol was a priori designed with the aim of potentially reducing the risk of bias, improving transparency, precision, and, in summary, the integrity of the present study. It was also registered in the PROSPERO international prospective register of systematic reviews (74 code) .MEDLINE (through PubMed), Embase, Web of Science, and Scopus databases were searched for studies published before March 2022 (upper limit), with no lower date limits. The search strategy was driven by combining pertinent thesaurus terms  with free terms, and built to maximize sensitivity. The following syntax was implemented in MEDLINE and adapted for the rest of databases : (“DiabeInclusion criteria: (1) Primary-level studies without publication date or language restrictions, or without follow-up, geographical areas, or patients’ age limits; (2) GDM patients were compared to controls (non-GDM pregnant women); (3) Cord plasma or serum leptin profile levels assessment; (4) Observational studies, regardless of their prospective/retrospective nature or their cross-sectional/longitudinal design.in vitro); (3) Studies that do not investigate the disease of interest , do not study cord leptin profile, or without a control group; (4) Insufficient essential data to analyze means ± standard deviations (SD); (5) Data from overlapping populations.Exclusion criteria: (1) Withdrawal papers, interventional studies, meta-analyses, reviews, letters, editorials, meeting abstracts, personal comments, book chapters, and case reports; (2) Preclinical studies . Discrepancies among both researchers were resolved by consensus with a third author (P.R.-G.). Articles were selected in two stages: first, piloting the titles with abstracts of the retrieved registers; and second, full-text reading the potential sample, excluding those that did not really meet the review eligibility criteria.Two authors (M.d.M.R.-R. and C.L.-T.) separately extracted the datasets of interest from the chosen articles by using Excel software . Data were gathered on the study authors, year of publication, geographical area, publication language, sample size, study design, source of sample (serum/plasma), cord leptin profile determination  in GDM and controls, diagnostic criteria for GDM, criteria for control sampling, personal and family risk of diabetes, gestational age, control of risk factors during pregnancy , glycosylated hemoglobin (A1cHb), fetal and maternal outcomes, follow-up period, and assessment of patient drop-out rate.The Newcastle-Ottawa quality assessment scale (NOS) was used in order to assess the risk of bias (RoB) . RoB crip < 0.05). Statistical heterogeneity was assessed using the Cochran’s Q test  and quantified through the I2 statistic , which estimates what proportion of the variance in observed effects reflects variation in true effects rather than sampling error [p < 0.10 considered significant) and funnel plot construction [Mean ± SD cord blood leptin profile levels were managed from the study sample in order to contrast the GDM group vs. controls. Standardized mean differences (SMDs)—estimated by Cohen’s d method—with 95% confidence intervals (CI) were computed and adopted as effect size metrics based on the expected methodological heterogeneity, mainly due to variations in leptin determination methods and heterogeneous laboratory protocols. If only medians with an interquartile range and/or maximum-minimum ranges were available, means ± SDs were estimated following Luo et al.  and Wan ng error . Preplanng error . Weightetruction ,29. Stattruction .The flow diagram in n = 16 primary-level studies) are summarized in The characteristics of our study sample , moderate (37.5%), and high (25%) overall RoB. The most frequent potential biases were an inadequate description of fetal or maternal outcomes and the failure to report follow-up period information. In this regard, the RoB with respect to the follow-up and drop-out rates was elevated in 81.3% of the studies. It is worth highlighting the relevance of declaring the lost to the follow-up, which is essential data to evaluate any differences in obstetric and perinatal outcomes and on the subsequent follow-up and development of complications in both the child and the mother.p < 0.001), showing significant heterogeneity , by analysis technique , by sample source . Finally, the primary-level studies showing a low risk of bias also maintained this significant difference and harbored a large effect size .Analysis of subgroups. All subgroups maintained the precedent significant differences after subgroup meta-analyses were carried out , stratifUnivariable meta-regression analyses. The effect of the remaining study covariates on cord blood leptin levels among patients with GDM compared to controls showed no significant differences .Sensitivity analysis. The precedent overall results did not substantially vary after the sequential repetition of meta-analyses, omitting one study each time . This suEgger = 0.02) revealed the presence of small-study effects, thus publication bias could not be potentially ruled out.Small-study effects analysis. The visual inspection analysis of the asymmetry of the funnel plot constructed  and the p < 0.001). This finding is consistent with previous studies in this regard [This systematic review with meta-analysis has included 16 primary-level studies and 1691 patients. It is shown that cord leptin profile levels were significantly higher in women with GDM than in the control group . It means that these higher-quality primary-level studies identified the highest differences in cord blood leptin levels between pregnant women with GDM and controls. This fact increases the quality of the evidence of the results reported in our meta-analysis, which could even be underestimated in the studies reporting a small effect size and harboring a higher risk of bias. Therefore, future studies focused on this topic should consider the potential biases and recommendations reported in this systematic review and meta-analysis to improve and standardize future research.According to our risk of bias (RoB) analysis, which was carried out using the Newcastle-Ottawa Quality Assessment Scale (NOS tool), all the studies included in our systematic review were not methodologically designed with the same rigor. A meta-analysis stratified by overall risk of bias revealed that the subgroup of studies designed with better methodological quality  achieved better meta-analytic performance. (SMD = 0.93, 95%CI = 0.57 to 1.30, a priori planned and performed for all meta-analyses. In addition, more homogeneous subgroups were observed after stratified meta-analyses, with some subgroups yielding consistent non-heterogeneous results. Another possible limitation is the suspicion of publication bias, which could not be ruled out in this meta-analysis. The current tendency to publish positive results as a priority is an inherent obstacle to the editorial process that is difficult to overcome in biomedicine. Regardless, the SMD reported in our meta-analysis for cord leptin levels was considerably higher in GDM versus controls, and the sensitivity analyses performed without relevant variation in the magnitude of the effect support, in summary, the stability and robustness of our results.To the best of our knowledge, this is the first systematic review and meta-analysis about cord leptin levels in GDM. A potential limitation of our meta-analysis is the existence of a moderate degree of statistical heterogeneity. It should be noted that clinical and methodological heterogeneity was expected, so random-effects models were Our meta-analysis evidences higher cord blood leptin levels in women with GDM compared to controls. However, given the few papers reporting clinical-metabolic variables, a more comprehensive analysis of the possible involvement of cord blood leptin in the pathophysiology of GDM and maternal-fetal outcomes in these patients has not been possible. Thus, it is not yet known the possible importance of higher levels of cord leptin in maternal-fetal outcomes. The limitations of the current methods of fetal anthropometric assessment or prevention strategy for GDM demonstrate the need to discover early predictors of GDM to establish intervention and prevention strategies in high-risk women. Further studies are needed to evaluate the role of cord leptin and other biomolecule levels in the future development of T2DM and other metabolic diseases in GDM mothers and offspring.


In view of the global aging population and growing need of palliative care, innovative intervention for effective symptom management is of urgent need. Flourishing-Life-Of-Wish Virtual Reality Therapy (FLOW-VRT) is a brief, structured, manualized, and personalized psychological intervention with theoretical foundations based on stress coping theory, self-determination theory, flow theory, and attention restoration theory. With a specific focus on relaxation, FLOW-VRT-Relaxation intends to facilitate adaptive end-of-life coping through delivering personalized relaxation. This paper reports a case study of the application of FLOW-VRT-Relaxation, and discusses its therapeutic potential as a cost-effective method for reducing palliative symptoms by addressing patient's unmet needs. The case study is a 51-year-old Chinese female, diagnosed with advanced cervix cancer, and presented with unmet psychological  and physical needs  before FLOW-VRT-Relaxation. To address her unmet needs, FLOW-VRT-Relaxation was delivered by a registered clinical psychologist specialized in palliative care. Need assessment was first conducted, followed by a 10-min VR travel of Japan as her own choice. Relaxation was verbally coached during VR. Right after VR, consolidation with psychological components including psychoeducation, cognitive and emotional processing, and reminiscence intervention were delivered. The patient showed improvement in physical and psychological symptoms, lower sense of loneliness and engulfment, as well as enhanced peace after FLOW-VRT-Relaxation. The current findings provide encouraging initial support for the feasibility, acceptability, and therapeutic potential of using FLOW-VRT-Relaxation as a cost-effective, scalable and personalized VR relaxation for patients under palliative care. It is hoped that with its optimal use, FLOW-VRT-Relaxation can serve as an alternative therapeutic tool that effectively improves the end-on-life care. SubstThanks to the advanced technology, there has been a revolution in mental health care that addresses the shortcoming and limitations of traditional treatment approach. Immersive virtual reality (VR), which is increasingly adopted in regular clinical practices, has been identified as a potentially revolutionary tool for psychological treatment of various mental disorders . SimilarUnderlying explanations for VR's treatment effect among palliative care patients have been preliminarily explored. The first possible reason relates to the concepts of distraction. A pilot study conducted by Lloyd and Haraldsdottir  reportedDespite the preliminary exploration of VR studies among palliative care patients, there remains a significant research and clinical gap. Nwosu et al.  reportedFlourishing-Life-Of-Wish Virtual Reality Therapy (FLOW-VRT®) specially designed for patients under palliative care was developed in the current study. FLOW-VRT is a brief, structured, manualized, and personalized psychological intervention with theoretical foundations based on flow theory , she complained about pain and tiredness still. She showed acceptance to current palliative status, aiming for minimal physical and emotional suffering during end-of-life stage. She expressed her long-standing wish of travelling to Japan where she had not visited before, and likely would not be possible to visit in the future. The main objective of the palliative care team was to minimize her suffering looking specifically at her physical, psychological, social and spiritual challenges. She had never used VR technology prior to the study.2.2.The first author of this paper (Woo) delivered FLOW-VRT-Relaxation to Ms. W. Woo is a registered clinical psychologist under Hong Kong Institute of Clinical Psychologist, and certified thanatologist under Association of Death Education and Counselling. She was also a candidate of the Doctor of Psychology  in the University of Hong Kong. She was chiefly responsible for the delivery of psychological services in a palliative care unit of a rehabilitation hospital.2.3.https://www.youtube.com/watch?v=Awz-wNJ_bk0&list=PLztGxkyfoE6_TbFMscEDAbfdDEdV2InD3&index=9&t=13s). Meta Quest 2 as the head-mounted display was used for her virtual exposure.The current case study used a within-subject design. Need assessment was first conducted using a need assessment schedule. The schedule was developed in current study to optimize the use of VR by assessing patient's needs for relaxation. A list of most popular VR relaxation content, which were the results of surveyIn order to facilitate the exploration of the virtual environment, a semi-structured protocol consisting of verbal cues and questions was followed during VR experience. This protocol included verbal instructions and questions such as: “Please relax and look around you”; “What are you looking at?”; and “How do you feel now?”. Ms. W was allowed to express freely her thoughts and emotions with reassurance at first, after which she was verbally coached on relaxation exercise. The VR lasted for 10 min.After VR, consolidation with psychological components was delivered. It aimed to enhance self-esteem, facilitate adaptive coping, and build resilience. It included (1) psychoeducation, i.e., elaborating on the relationship between physiological response and mood; (2) cognitive and emotional processing on the virtual experience; and (3) reminiscence intervention that facilitated sharing on her recollections associated with the VR travel.The baseline assessment was taken right before the need assessment, while the post-intervention assessment was conducted immediately after the consolidation. The whole session was delivered by the registered clinical psychologist, who is also the principal investigator of the current study.2.4.Chinese version of the Edmonton Symptom Assessment System (CESAS) ( (CESAS) , 33 was  (CESAS) .UCLA Loneliness Short , and to avoid overloading patients by keeping a realistic questionnaire length. Its Chinese version (https://www.facit.org/measures/FACIT-Sp-12) with granted license was used in this study.ng Scale  is a valng Scale –42. Each version  , but also her psychological need of wish fulfillment in her end-of-life stage.The current study has several limitations. Since it is impossible to make broad scientific conclusions based on the results of a single patient , case stAnother limitation is that the patient was receiving medical treatment that might have led to improved symptoms. The use of a within-subjects design measuring outcomes right before and after FLOW-VRT-Relaxation was designed to isolate the effects of FLOW-VRT-Relaxation. Furthermore, since the death of patients under palliative care can be imminent, i.e., within a few hours or days , the preDespite limitations, the current findings provide encouraging initial support for the feasibility, acceptability, and clinical potential of using FLOW-VRT-Relaxation under palliative care. With appropriate trainings, future implementation leaders may help increase the accessibility of such cost-effective psychological interventions in wider populations across different settings. It is hoped that with its optimal use, FLOW-VRT-Relaxation can serve as an alternative therapeutic tool that effectively improves the end-on-life care by addressing patients' physical and psychological needs.


Vision is the most crucial sensory system for human beings to process external information. The retina, optic nerve, and visual pathway  are all necessary for the complete transmission of visual information. Numerous eye conditions, including glaucoma, diabetic retinopathy, optic neuritis, and hereditary optic neuropathy result in vision loss, and as a result, they remain a key field of study for both clinical and pre-clinical research. Multimodal imaging techniques, such as optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and functional magnetic resonance imaging (fMRI), give essential biological indicators in the diagnosis of ophthalmic diseases. In fact, combining imaging with artificial intelligence (AI) may enhance diagnostic precision and accuracy, detect imaging biomarkers, develop cutting-edge tools that will impact clinical practice and benefit patient outcomes.Application of multimodal imaging combined with artificial intelligence in eye diseases” included 19 articles. It covered a range of AI applications in fundus images, OCT, anterior segment images, infrared videos from eye movement recorders, and steady-state visual evoked potentials (SSVEPs) in order to classify eye diseases, or to find neuroimaging indicators. Other papers reviewed the literature, identified indicators from animal model studies, and determined the prognostic factors of transnasal endoscopic optic decompression. In this editorial, we give an overview of these studies and group them according to the study design.This Research Topic on “Chen et al. developed an attention-aware retinal atrophy segmentation network based on UNet structure called ARA-Net. To deal with blurred boundaries and irregular shapes of the retinal atrophic region, they proposed a novel skip self-attention (SSA) connection block. They also proposed a multi-scale feature flow (MSFF) between the SSA connection blocks, greatly enhancing the self-attention mechanism's capacity. The Pathological Myopia (PALM) dataset has been used to validate the proposed method, which performs noticeably better than other methods. A new deep learning model called MyopiaDETR was put up by Li M. et al. for the diagnosis of pathological myopia (PM) using 2D fundus image data. The architecture of Detection Transformer (DETR) allows it to effectively tackle the issue of morphology irregularity. An attentional feature pyramid network (FPN) increases the difference in feature intensity the between foreground and background. The experimental results show that their model outperforms other state-of-the-art object detectors in terms of localization and classification performance on the iChallenge-PM dataset.Retinal atrophy is a crucial assessment indicator as it is correlated with the severity of myopia. For 2D fundus images, Huang et al. introduces GABNet, a novel lightweight classification network model based on the global attention block (GAB) for OCT. By using their method, classification accuracy is increased over the EfficientNetV2B3 network model by 3.7%. Gan, Wu, et al. proposed an AI method based on multifeature fusion to enable automatic macular edema (ME) classification on spectral domain OCT (SD-OCT) images. With an accuracy of 93.8%, the support vector machine (SVM) model performed the best when compared to other classification models.Gan, Liu, et al. and Li, Huang, Peng developed AI segmentation platforms with a deep transfer-learning algorithm and multi-feature fusion by using anterior segment images for automatic cortical cataract staging and fungal keratitis diagnosis, respectively. One is based on a method of automatic segmentation, whereas the other is based on a method of manual segmentation. While the automatic segmentation platform can stage cataracts and diagnose fungal keratitis more quickly, the manual segmentation platform can do so more accurately. In addition, Gan, Chen, et al. developed an AI model based on ensemble DL that was combined with four benchmark models  for identifying pterygium that need to be surgically removed. The ensemble DL model exceed all other models in terms of accuracy and area under the curve (AUC).Li and Yang demonstrated that torsional nystagmus can be recognized by deep learning networks models. They used convolution neural network to extract the frame features of the infrared video sequence from eye movement recorders, and classified the obtained vector sequence.Wan, Li, et al. proposed a transformer–based EEGformer analysis model to capture the electroencephalogram (EEG) characteristics in a unified manner. Across three EEG datasets  the EEGformer achieves the best classification performance. This finding suggests that the rationality of model architecture and learning EEG characteristics in a unified manner can improve model classification performance. Another study by Wan, Cheng, et al. propose a deep neural network called GDNet-EEG for SSVEP stimulation frequency recognition that uses group depth-wise convolutional filtering to extract regional characteristics from raw EEG data. The findings show that GDNet-EEG surpasses the existing deep learning models to process EEG data on two publicly available SSVEPs datasets  and their merged dataset.For SSVEPs, Ji, Wang, et al. used the amplitude of low-frequency fluctuation (ALFF) in conjunction with sliding window approach to assess the changes of dynamic neural activity in patients with retinal detachment. Based on dALFF values, the overall accuracies of SVM classification were good under three different time windows. In patients with primary angle-closure glaucoma, Li, Huang, Peng, Liang, et al. identified changes in functional connectivity (FC) with primary visual cortex (V1), and found the increased FC between V1 and calcarine. However, the discrimination of PACG from healthy controls (HC) was poor when utilizing the SVM method and the dFC map as the classification feature.For resting-state fMRI, Ji, Huang, et al. explore differences in static FC (sFC) and dynamic FC (dFC) alteration patterns in the V1 among patients with high myopia and HCs via seed-based FC analysis. This disturbance suggests that patients with high myopia could exhibit impaired cognitive and emotional processing functions, top-down control of visual attention, and visual information processing functions. Pang et al. compared retinal OCT and optic nerve diffusion tensor imaging (DTI) parameters in patients with non-functioning pituitary adenoma (NFPA). The degree of adverse changes in OCT and DTI parameters was found to be stronger in the severe compression group than that in the mild compression group. Moreover, the fractional anisotropy (FA) value of the optic chiasma has a high diagnostic ability for visual pathway impairment. A literature review by Wang et al. described the use of DTI technology in glaucoma in humans and animal models, with the advancement of DTI technology and its coupling with artificial intelligence, DTI represents a potential future for MRI technology in glaucoma research.Wu et al. for measuring AL in Sprague Dawley rats. They found that Quantel A-B scan might be more accurate than OD-1 A scan. AL and refractive error (RE) are both influenced by gender. Duan et al. employed OCT to assess the changes in retina thickness after shape deprivation in myopic mice, and found considerably thinner retina, nerve fiber layer, inner nuclear layer, and outer nuclear layer. In addition, Shi et al. found epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) may have a role in the choroidal thickness regulation by using guinea pig model for myopia.Accurate axial length (AL) measurement is crucial for developing animal models of myopia. The accuracy of Quantel A-B scan, OD-1 A scan, and vernier caliper were compared by Tu et al. investigate the clinical effectiveness and prognostic variables of trans nasal endoscopic optic decompression in the treatment of traumatic optic neuropathy. The prognosis is highly dependent on the presence of residual light perception and the timing of surgery within 7 days.Last but not least, As we draw to a close, we wish to emphasize the need of making more efforts to enhance the technical, clinical, and preclinical advances described in this Research Topic. In future, with the aid of AI, it will be feasible to provide a comprehensive description of eye diseases by integrating data from multidimensional modalities, as well as those from patients and animal models. Furthermore, it is hoped that the existing large-scale image dataset will be useful in this regard.ZW: Writing—original draft. YC: Writing—review and editing. VK: Writing—review and editing. XH: Writing—review and editing.


Acute stroke management is critically time-sensitive and challenging. Blood-based biomarkers that can differentiate acute ischemic stroke (IS) from hemorrhagic stroke (HS) can greatly facilitate triage and early management. Admission blood samples obtained within 6 h of stroke symptom onset were analyzed in a derivation/validation design. GFAP, N-FL, NT-proBNP, copeptin, neutrophils (%), NLR, and platelet counts were assessed in the derivation cohort. The informative markers and the derived cutoff values were evaluated in the validation cohort. GFAP > 703 pg/mL showed a PPV of 76.9% and NPV of 95.8% for differentiating HS from IS. Multiple logistic regression analysis showed that GFAP and NT-proBNP were independent variables associated with IS and HS differentiation. Furthermore, applying a combined cutoff (GFAP > 703 pg/mL and NT-proBNP ≤ 125 pg/mL) for HS detection increased the PPV in both the derivation and validation cohorts . GFAP and NT-proBNP levels were validated as informative blood biomarkers in the differentiation of IS and HS and using a combination of GFAP and NT-proBNP is suggested as a feasible strategy to differentiate stroke subtypes in the hyperacute phase of stroke. Stoke remains the second leading cause of death worldwide , with AsUnfortunately, treatment options for acute stoke remains limited, and their efficacy depends on the time between symptom onset and treatment. The two main subtypes of stroke are ischemic stroke (IS)  and hemorrhagic stroke (HS) (remaining 15%) , the latThe aim of this study was to compare the diagnostic efficacy of selected blood-based biomarkers in differentiating between IS and HS and validate the suggested markers and their cutoff values using a derivation–validation study. To assess the diagnostic efficacy of blood-based biomarkers in the hyperacute phase of stroke, early samples from patients presenting with symptoms suggestive of stroke to a single tertiary hospital within 6 h from symptom onset were enrolled.All stroke patients included in this study were admitted to the emergency department of Seoul St. Mary’s Hospital from October 2021 to February 2023, and all presented within 6 h from the onset of symptoms. Medical records of the patients were retrospectively reviewed, and data regarding patient demographics, final stroke diagnosis, stroke severity, and stroke etiology were retrieved. Stroke diagnosis was determined according to the World Health Organization criteria, based on neurological assessment  and neurg for 10 min at 20 °C. The residual plasma samples were aliquoted into cryotubes and stored at −80 °C until biomarker measurement.Eligibility was determined based on the following criteria: (1) ≥19 years old; (2) present to the emergency department with suspected stroke; (3) have blood drawn as part of standard care at admission before intravenous thrombolysis; and (4) have sufficient residual samples to facilitate subsequent biomarker measurements. Plasma samples were anticoagulated using ethylenediaminetetraacetic acid and centrifuged at 2000× Samples collected between October 2021 and May 2022 were used as a derivation cohort to select the most informative biomarkers and their cut-off values. In the derivation cohort, differences in blood-based biomarkers (neutrophil (%), neutrophil–lymphocyte ratio (NLR) and platelet count, glial fibrillary acidic protein (GFAP), neurofilament light chain (NF-L), N-terminal pro B-type natriuretic peptide (NT-proBNP), and copeptin) between IS and HS were assessed. Additionally, using the area under the receiver operating characteristic curve (AUC) analysis and plotting, ideal cut-off values were derived.Samples collected from June 2022 to February 2023 were used as a validation cohort. Using the validation cohort, the ideal cut-off values of informative markers  derived from the derivation cohort were validated.GFAP and NF-L levels were measured using single-molecule array (SiMoA) methodology, as previously described . MeasureNT-proBNP was measured using an electrochemiluminescence immunoassay using the Elecsys proBNP II reagent  on the cobas e 801 immunoassay analyzer (Roche). Copeptin was measured using a colorimetric immunoassay using a human copeptin ELISA kit  and the SpectraMax 190 Absorbance Microplate Reader , according to the manufacturer’s instructions. All measurements were performed without knowledge of the patients’ clinical diagnoses.Other blood-based biomarkers (neutrophil (%), neutrophil–lymphocyte ratio (NLR), and platelet count) were retrieved from the medical records. The study protocol was approved by the Institutional Review Board (IRB) and Ethics Committee of Seoul St. Mary’s Hospital.Categorical variables are expressed as numbers (percentages), and continuous variables are expressed as medians and interquartile ranges (IQRs) for non-normally distributed data. Normality was assessed using the D’Agostino–Pearson normality test, and because most variables did not follow a normal distribution, medians were used for intergroup comparisons between patients with IS and HS.p value < 0.05) from the derivation cohort. AUC analysis was performed for each biomarker and biomarker combination. Suggestions for optimal cutoff values were derived from AUC analysis and plotting. Statistical analyses were performed using MedCalc  and SAS , and a two-tailed p value < 0.05 was considered statistically significant.In the derivation cohort, univariate analyses were performed using the chi-squared test and Mann–Whitney U test for categorical and continuous variables, respectively. A logistic regression model was developed using statistically significant variables on univariate analysis (p < 0.001). The patients with IS had a higher frequency of atrial fibrillation (AF) and hypertension  than those with HS. The median last known well (LKW) to sampling time was 188 (IQR: 85–597) min. There was no significant difference in the median sampling time from the LKW between the IS and HS groups.In the derivation cohort, 73 samples from patients with acute stroke-like symptoms were included; the final clinical diagnoses were IS in 51 patients (69.9%) and HS in 22 patients (30.1%). The baseline characteristics of the derivation cohort are presented in p < 0.001; p < 0.001]. No significant intergroup differences were found for NF-L and copeptin concentrations, or other biomarkers including neutrophils (%), neutrophil-to-lymphocyte ratio (NLR), and platelet counts. When statistically significant univariate variables were included in the logistic regression analysis, only GFAP and NT-proBNP remained in the model and were independently associated with IS and HS differentiation (The GFAP (IQR) concentration was significantly higher in patients with HS compared with IS , whereas the median NT-proBNP (IQR) concentration was significantly lower in patients with HS compared with IS . In addition, there were no significant differences in the GFAP and NT-proBNP levels for both HS and IS subgroups between the derivation and the validation cohort. Additional logistic regression analysis of the whole cohort repeatedly demonstrated GFAP and NT-proBNP as independent variables of IS and HS differentiation . There were no significant differences in baseline characteristics between the derivation and the validation cohort . Of the ntiation . In the ntiation .This study assessed the diagnostic efficacy of selected blood-based biomarkers, including GFAP, NF-L, NT-proBNP, copeptin, neutrophils (%), NLR, and platelet counts, in differentiating IS and HS in the hyperacute phase of stroke. From the derivation cohort, the GFAP and NT-proBNP levels were identified as informative biomarkers in distinguishing IS and HS in patients presenting within 6 h of symptom onset, while NF-L, copeptin, and other markers did not show clinical value.GFAP is an intermediate filament found exclusively in astrocytes ; the difIn contrast, NF-L is a neuronal intermediate filament that is a major component of the axonal cytoskeleton . NF-L isAlthough not a brain-specific marker, NT-proBNP levels have been suggested as an optimal biomarker for cardioembolic stroke diagnosis in the acute phase ,19,20,21In acute stroke management, tPA is the treatment of choice for IS, after excluding ICH, and the benefits of tPA are time dependent, with the early initiation of a tPA resulting in better outcomes . HoweverNevertheless, the results of this study should be interpreted with caution, considering the following limitations. The number of patients recruited for this study was relatively small. Therefore, further studies are required to validate the gain in specificity by combining GFAP and NT-proBNP levels in larger patient cohorts. Furthermore, we did not perform serial biomarker measurements. Therefore, we were unable to collect data on the dynamic pattern of each biomarker, which might have provided additional information regarding its diagnostic performance. Finally, we are aware that variability among different GFAP assays may affect diagnostic accuracy, and to justify the implementation of GFAP in prehospital POC testing, improvements in the sensitivity of POC assays will be mandatory.In conclusion, our study confirms the role of GFAP and NT-proBNP in the differentiation of IS and HS during the hyperacute stage of stroke. Additionally, this study provides compelling evidence of combining GFAP with NT-proBNP to improve diagnostic specificity and exclude ICH. Conversely, NF-L, copeptin, and NLR did not demonstrate clinical utility in differentiation between IS and HS. The measurements of blood GFAP and NT-proBNP assessment represent a relatively simple method and can significantly improve the discriminatory accuracy diagnosis of stroke subtypes in particular, in an emergency environment where imaging equipment is not provided. Future studies involving larger cohorts are required to validate the GFAP and NT-proBNP combined algorithm; however, our study validates the diagnostic utility of blood-based biomarkers in the differentiation of IS and HS in the hyperacute phase of stroke.


In order to avoid side effects from treatment, patients suffering from breast cancer with a lower risk of relapse might forgo radiation therapy to the whole breast or endocrine therapy after surgery. In this analysis, we compared these two options regarding the risk of breast cancer relapse with the help of direct trials and a network that analyzed one of the two options. We found that both treatment options have similar long-term cancer outcomes and should be considered equally effective.n = 1059) and nine studies randomizing overall 7207 patients additionally to BCS only and BCS + WBI + ET resulting in a four-arm comparison. In the network analysis, LR was significantly lower in the BCS + WBI group in comparison with the BCS + ET group . We did not find any differences in OS  and BCSS . Further, we found a lower distant metastasis-free interval, a higher rate of contralateral breast cancer and a reduced mastectomy-free interval in the BCS + WBI-arm. Using the EBCTCG data, OS and BCSS were not significantly different between BCS + ET and BCS + WBI after 10 years  . Conclusion: Evidence from direct and indirect comparison suggests that BCS + WBI might be an equivalent de-escalation strategy to BCS + ET in low-risk breast cancer. Adverse events and quality of life measures have to be further compared between these approaches.Background: Multiple randomized trials have established adjuvant endocrine therapy (ET) and whole breast irradiation (WBI) as the standard approach after breast-conserving surgery (BCS) in early-stage breast cancer. The omission of WBI has been studied in multiple trials and resulted in reduced local control with maintained survival rates and has therefore been adapted as a treatment option in selected patients in several guidelines. Omitting ET instead of WBI might also be a valuable option as both treatments have distinctly different side effect profiles. However, the clinical outcomes of BCS + ET vs. BCS + WBI have not been formally analyzed. Methods: We performed a systematic literature review searching for randomized trials comparing BCS + ET vs. BCS + WBI in low-risk breast cancer patients with publication dates after 2000. We excluded trials using any form of chemotherapy, regional nodal radiation and mastectomy. The meta-analysis was performed using a two-step process. First, we extracted all available published event rates and the effect sizes for overall and breast-cancer-specific survival , local (LR) and regional recurrence, disease-free survival, distant metastases-free interval, contralateral breast cancer, second cancer other than breast cancer and mastectomy-free interval as investigated endpoints and compared them in a network meta-analysis. Second, the published individual patient data from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) publications were used to allow a comparison of OS and BCSS. Results: We identified three studies, including a direct comparison of BCS + ET vs. BCS + WBI ( Multiple randomized trials have established breast-conserving surgery (BCS), adjuvant systemic therapy and whole breast irradiation (WBI) as the standard in early-stage breast cancer treatment. A meta-analysis by The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) provided robust evidence that adjuvant WBI after breast-conserving surgery improves local control and overall survival . A subseWhile achieving gratifying oncological results with this approach, recent efforts have focused on treatment de-intensification in presumed low-risk patients .One suggested option for treatment de-intensification might be to omit radiation therapy. This was put forward in order to allow an omission of the seldom, but possibly debilitating, long-term side effects of radiation therapy, which can include arm and breast symptoms, breast tissue fibrosis, lung and heart toxicity, as well as second malignancies of the contralateral breast, lung and the irradiated skin . FurtherAdjuvant endocrine therapy (ET) has been discussed in the literature as a favorable treatment option compared with adjuvant WBI. Several trials that randomized patients to adjuvant endocrine therapy with or without WBI ,7,8,9,10As part of a treatment de-intensification, one could also consider the omission of a long-term ET and confining adjuvant treatment to whole breast radiation alone. This would avoid debilitation side effects of ET, such as arthralgia, osteopenia as well as vaginal dryness, and could allow patients to benefit from specific advantages of WBI . The present paper addresses the comparison of both treatments in randomized trials.We conducted a systematic literature search of the electronic database PubMed for randomized controlled trials comparing adjuvant endocrine therapy to radiation therapy in breast cancer after breast-conserving surgery in accordance with the published PRISMA guidelines  on 4 AprWe included randomized trials for early-stage breast cancer, comparing any type of ET to WBI. In order to minimize heterogeneity and maximize the homogeneity of the compared study populations, only low-risk populations were included. Eligibility criteria included T-Stage T1-2, node-negative disease and breast-conserving surgery. We excluded trials using mastectomy and preoperative or adjuvant chemotherapy. We also excluded trials that used regional nodal irradiation as we consider these patients to be at a higher risk for local and distant recurrence. All studies had to have published 5-year results after 1 January 2000.In order to expand the analysis using a direct as well as an indirect comparison, we also searched for trials with the same inclusion criteria treating patients with breast-conserving surgery, endocrine therapy and whole breast irradiation (BCS + ET + WBI) and surgery alone (BCS). This allowed multiple comparisons in a network meta-analysis.The study endpoints were local recurrence (LR), regional recurrence (RR), distant metastasis-free interval (DMFI), disease-free survival (DFS), overall survival (OS), breast cancer-specific survival (BCSS), non-breast cancer death (NBCD), contralateral breast cancer (CBC), mastectomy-free interval (MFI) and secondary non-breast cancer (SNBC). LR was defined according to study protocols, including invasive as well as non-invasive ipsilateral breast cancer recurrence in four studies ,21,22,23Because the results of the mastectomy rates in the NSABP B-21 trial were reported to be not statistically different, we assumed an equal distribution over the treatment groups .Additionally, we also pooled the published individual patient data from the EBCTCG meta-analyses for the available endpoints BCSS and OS for the three trials in the direct comparison of BCS + WBI and BCS + ET ,22,26,27p-value of 0.05.Analysis of the studies includes patients’ characteristics as well as a description of the endpoints. Study-relevant events were extracted from the available publications, and hazard ratios, as well as odds ratios, were chosen as the appropriate comparison. Events were extracted as either the first or any event. Meta-analysis of the hazard ratios and odds ratios was performed using the inverse variance heterogeneity model. Statistical significance was set at a level of 95% resulting in a two-sided p-values. The search protocol was registered in the PROSPERO database with ID 418361.The Microsoft Excel plug-in MetaXl V5.3  was used to analyze and pool the data. The figures were created using Microsoft Excel for Microsoft Office 365 Pro Plus . Due to the possible heterogeneity of the study populations, the inverse variances of the heterogeneity model (ivhet) by Doi et al. were chosen as the comparison method . This men = 1059 patients) [n = 7207 patients). The resulting network is shown in The results of the systematic literature review are shown in atients) ,22,26,27The SweBCG91RT trial was included in a modified cohort. In this analysis, only HR+ Her2− patients without any adjuvant systemic therapy were included .The median follow-up of the included trials was between 5.0–15.6 years, including low-risk tumors with mainly tamoxifen as endocrine therapy. In all network analyses, all H values were below 3, showing minimal network inconsistency.Funnel plots for the direct analysis did not show any publication bias.p = 0.137). The indirect comparisons within the network analysis show a significantly better local control with BCS + WBI . Within the network, the addition of WBI to BCS + ET results in a significant reduction in LR . The omission of ET leads to a higher number of LR .The analysis of the endpoint local recurrence is shown in p = 0.634). Within the network analysis, the trimodal therapy (BCS + ET + WBI) improves disease-free survival . Compared with BCS + ET, the omission of ET results in a significant reduction of DFS .According to p = 0.785) (p < 0.001).The direct comparison of overall survival between BCS + WBI and BCS + ET shows no statistically significant difference  . Similarp = 0.011). Distant metastases are statistically more likely in the BCS + WBI arm in the network comparison . These differences are not evident in the direct comparison. BCSS is lower after BCS alone when ET is omitted . BCS + WBI, in contrast to BCS + ET, results in a lower risk of dying for other reasons than breast cancer  in the network analysis. This observation was not seen in the direct comparison. In the treatment arms without ET, we observe significantly more contralateral breast cancers. Other secondary cancers are not significantly different in all comparisons. The mastectomy-free interval is improved by the addition of WBI compared with BCS + ET.We observed significant differences in regional recurrences with the addition of WBI to BCS + ET . Likewise, breast cancer death also does not significantly differ between the two treatments .The comparisons of adjuvant WBI compared to adjuvant ET from the individual patient meta-analysis published by the EBCTCG  shows noThe oncological results of randomized trials assessing whole breast irradiation and endocrine therapy after breast-conserving surgery show in the direct and network comparison that both treatment options provide equally effective de-escalation strategies for women with low-risk breast cancer. The addition of WBI in the treatment paradigm improved local control and reduced the need for subsequent mastectomy after local recurrence. Non-breast cancer deaths might also be lower after BCS + WBI compared with BCS + ET. However, contralateral breast tumor recurrences were higher when omitting ET. The combination therapy of surgery, WBI and ET resulted in superior outcomes in LR and DFS but not OS or BCSS.The results of this meta-analysis are mirrored by multiple databases and retrospective institutional analyses. These trials unanimously show no differences in both de-escalation strategies in terms of survival with favorable tendencies of local control with BCS + RT ,40,41,42On the other hand, possible adverse events from whole breast radiotherapy include acute skin toxicity and fatigue as well as late toxicity with the risk of subcutaneous fibrosis, breast edema, breast pain, telangiectasia and secondary cancers ,58,59,60Due to limited adverse event data in the trials directly comparing WBI and ET, a formal analysis of adverse events could not be performed. The authors reported hot flashes, deep vein thrombosis and pulmonary embolisms associated with tamoxifen . ChanginGiven the similar efficacy regarding DFS and OS, a detailed analysis to identify subgroups that might benefit from WBI or ET would be highly desirable. Unfortunately, information on specific patient groups was only available in the NSAPB B21 trial. In this analysis, the comparison of BCS + RT vs. BCS + ET resulted in statistically superior efficacy in local control for the age group 60–69 (HR = 0.31) and regardless of estrogen receptor status (HR = 0.31 and HR = 0.41) after WBI .Radiation therapy schedules and treatment volumes have also changed considerably since the time when the included trials were conducted. First, current radiation schedules are shorter, with the majority of women treated with hypofractionated schedules consisting of 15–16 daily fractions. For these schedules, there is a high degree of certainty that they are equieffective with associated lower risks for acute and late adverse events ,61,62. MA surprising result in this analysis is the observation that patients undergoing WBI compared with ET alone had higher rates of distant metastases. When the trials were separately analyzed by the method of how the distant relapse events were scored , we observed higher DM rates only in the trials that reported DMs as first events. Given that WBI reduces local recurrences as the most common disease event, distant events would not be counted in patients that already suffered local relapses . This woThe observed higher incidence of CBCs leads to the question of whether lack of endocrine therapy or the addition of WBI results in increased risk. As we detected the increase in the comparison of BCS + WBI to BCS + ET and not in the comparison of BCS + ET + WBI vs. BCS + ET, our results indicate the conclusion that the lack of ET and not the addition of WBI is mainly responsible for the increase in CBC.The subsequent costs for the patients, health care system and providers are also important to consider when comparing different adjuvant treatment options. Multiple analyses demonstrated that radiotherapy was cost-effective in comparison to sole endocrine therapy after BCS ,76,77. HLimitations of the network part of the meta-analysis include that the comparisons are not based on individual patient data. However, trial-based analyses have also been demonstrated to provide equal results, which is also shown in our analysis in the comparison of OS and BCSS . Here, tGiven the timeframe when the trials were conducted, the estimation of low risk was based on clinical features such as tumor stage and grading. Not all trials obtained information on the hormone receptor and Her2 receptor status , which mAs mentioned before, multiple efforts are currently ongoing to identify a subgroup of patients who can safely omit WBI ,16,17,18Based on the direct meta-analysis of three randomized trials as well as a network comparison, breast-conserving surgery with whole breast radiotherapy or endocrine therapy are equally effective de-escalation strategies in low-risk breast cancer in terms of disease-free and overall survival.


We aimed to test early feasibility, acceptability, and signals of improvement after the 8-week individually delivered asynchronous, web-based mind-body program (NF-Web) modeled after the synchronous group-based live video program .n = 14, cohort 2 n = 14) completed baseline and posttest .Two cohorts  completed baseline  and posttests . Video lesson (58.0%) and homework (70.9%) completion were fair to good. Satisfaction , credibility , and expectancy  were good to excellent. Participation was associated with statistically significant pre-to-post positive changes in quality of life  and emotional distress . Pain intensity and interference did not improve significantly (p > 0.05) after participation.Enrolled participants  was feasible.•Participation was associated with pre/post QoL and emotional distress improvements.•Psychosocial web-programs for rare illnesses may be useful and warrant attention. The three NF types are biomedically district disorders, with individuals experiencing varying degrees of physical symptoms burden, including disabling and disfiguring cutaneous tumors, gait issues, and learning disabilities in NF1, hearing loss and tinnitus in NF2, and chronic pain in schwannomatosis  . UnfortuVery few NF-specific psychosocial treatment options exist and there are limited mental health providers trained to deliver these treatments . To addrDespite this program's success, we quickly learned about important barriers that prevented individuals from participating in live video groups. In fact, roughly 1/3 participants expressing interest in the live video program trial program could not participate due to specific barriers  includinNF-Web,” adapted directly from the live video, group-based 3RP-NF resiliency program ). Taken together, these initial findings are promising – specifically that NF-Web is a feasible and acceptable program for adults with NF and could be a potential treatment option in the future, especially for participants who cannot or prefer not to participate in the live video trial.This is the first study to examine early feasibility, acceptability, and signals of improvement of an individually delivered asynchronous web-based treatment based on the 3RP-NF for adults with NF. NF-Web met all a priori feasibility  benchmarks (Fair to Excellent [>50%]) similar to our prior small sample psychosocial trials ,19,20,28Within-group improvements in secondary outcomes, including QoL and emotional distress, were consistent with our previous feasibility trials in NF and suggest that NF-Web demonstrates signals of improvement for psychosocial outcomes ,29. ThesOur study limitations included a small sample size, no comparison group, a mostly homogeneous sample , and a lack of power to compare findings by demographics . These limitations are similar to other pilot studies , includiAdditionally, given the similarity of NF-Web to online courses with videos, homework assignments, and quizzes, a possible limitation may be that participants who do not prefer this medium for learning and skill acquisition may have been detoured from participating. Anecdotal accounts from this sample (exit interviews) suggest that those choosing to participate in NF-Web did not experience these aspects of the program as deterrent, however when considering this program for a wider audience other program methods may be explored. Relatedly, our sample had a relatively high number of patients with learning disabilities which may impact the generalizability of these findings.Despite using multiple modalities , future studies may benefit from inquiring how one's learning disabilities and/or differences impact their participation in technology-based interventions. Also, the GCPS was used for assessing pain intensity, which deviates from the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS)-recommended measures. Last, we did not systematically measure engagement in the NF-Web program during the 8 weeks as part of this study. With the social support aspect being the most notable difference between the two programs (live video and web-based), future studies will attempt to examine how key aspects of the NF-Web program  can facilitate engagement and how other methods of participation  can be encouraged. Despite these limitations, our study strengths included early feasibility testing a novel web-based program for an underserved population which appeared to increase enrollment, participation, accessibility, as well as retention throughout the study course.4.2Web-based programs are valuable for individuals who prefer to learn skills on their own timeline, have barriers to live video participation, and who may also have apprehensions about interacting with others during treatment. Although these do not impact other important reasons for limited participation , offering multiple program types in various modalities, we can increase accessibility to psychosocial care and make these kinds of programs sustainable in a time of limited mental health resources across the world. Long-term, multiple forms of the same evidence-based treatment can complement one another and can even supplement one another if needed .4.3Overall, NF-Web demonstrates early feasibility and acceptability for participants who are looking for a point of entry into these psychosocial interventions who may not be ready to commit to the live video or in-person group options. Having a web-version of this program provides more support to this underserved and in-need population of adults with rare illnesses. Clinicians can work with patients to decide which treatment modality fits their needs best and address barriers they may experiences when seeking psychosocial care. The next phases of this study will work to address the above limitations and plan to include a comparison group to examine between group effects for NF-Web.All authors declare that they have no conflicts of interest or competing interests related to this manuscript.NF Northeast, NF Midwest, Texas Neurofibromatosis Foundation, and the 10.13039/100001545Children's Tumor Foundation.Dr. Ethan Lester was directly supported by foundation grants-in-aid (early career) from All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.Informed consent was obtained from all individual participants included in the study.Description of authors' contribution to the work:Lester: Conceptualization, Data curation, Formal analysis, Funding aquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review and editing.Fishbein: Project administration, Writing - original draft, Writing - review and editing.Peterson: Writing - original draft, Writing - review and editing.Vranceanu: Writing - original draft, Writing - review and editing, Methodology, Supervision.


Head and neck squamous cell carcinoma (HNSCC) is a leading cause of morbidity and mortality globally. Despite significant advances in well-established treatment techniques, prognosis for advanced-stage HNSCC remains poor. Recent, accumulating evidence supports a role for immunotherapy in HNSCC treatment. Radiation therapy (RT), a standard treatment option for HNSCC, has immunomodulatory and immunostimulatory effects that may enhance the efficacy of immunotherapy. In several cancer types, combining RT and immunotherapy has been shown to improve tumor response rates, increase survival, and reduce toxicity compared to traditional chemotherapy and radiation therapy. This review provides a timely overview of the current knowledge on the use of RT and immunotherapy for treating HNSCC. It highlights the potential advantages of combining these therapies, such as improved tumor response rates, increased survival, and reduced toxicity. The review also discusses the challenges that need to be addressed when redefining the standard of care in HNSCC, and proposes further research to optimize treatment combinations, minimize radiation-induced toxicity, and identify suitable patient populations for treatment. Head and neck squamous cell carcinomas (HNSCC) continue to be a leading cause of morbidity and mortality worldwide, with over 700,000 new cases annually and 350,000 deaths globally . RoughlyThe subsite of disease, stage, histology, and patient comorbidities dictate appropriate treatment recommendations. LA disease is often treated with multimodality therapy. For patients with locoregionally advanced disease, definitive concurrent chemoradiation therapy versus surgical resection with adjuvant radiation therapy with or without chemotherapy is the standard of care. Radiation therapy is commonly delivered via intensity-modulated radiation therapy (IMRT) using contemporary computer-based planning and radiation delivery with or without simultaneous integrated boost (SIB) or dose painting, assigning different dose levels to different anatomic areas. If a patient undergoes surgical resection, adjuvant radiation therapy with or without concurrent cisplatin chemotherapy is recommended if adverse pathologic features are noted ,8,9,10. Over the last two decades, there has been a dramatic increase in the interest in and development of immunotherapy as an oncologic weapon. Some types of cancer cells are immunogenic, allowing them to constantly mutate with select clones, developing the ability to evade immune-mediated recognition and destruction ,15. SeveTwo examples of these targets are the programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). When PD-1 on T-cells binds to programmed death-ligand 1 (PD-L1) on cancer cells, T-cells are unable to kill other cells, including cancer cells. Anti-PD1 and anti-PD-L1 therapy interrupt PD-1 engagement via its ligand, allowing for the continued activation of T-cells and immune-mediated anti-cancer response . SimilarImmune checkpoint inhibitors targeting PD-1/PD-L1 complex have shown promising results in several cancer types including melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), and head and neck cancer . Two triRadiation therapy may enhance the efficacy of immunotherapy through its immunomodulatory and immunostimulatory effects. The abscopal effect refers to a phenomenon observed in radiation therapy wherein localized radiation treatment not only affects the targeted tumor, but also triggers a systemic immune response, leading to the regression or control of distant, untreated tumors. It occurs when radiation-induced cell death releases tumor-specific antigens and danger signals, which activate immune cells, such as T cells and natural killer cells, to recognize and attack cancer cells throughout the body. Radiation can also induce in situ vaccination by triggering the killing of tumor cells and generating a systemic immune response . IonizinGiven the discrete molecular landscapes between HPV-positive and HPV-negative HNSCC, several studies have looked at the correlation between HPV status and the effect of immunotherapy . ExpressThe aim of this narrative review is to synthesize the current literature to date regarding the use of immunotherapy with radiation therapy in the treatment of HNSCC. This manuscript highlights current ongoing trials for LA HNSCC and recurrent or metastatic HNSCC, and postulates future directions within this field.The potential role of radioimmunotherapy in the locally advanced (LA) setting can be generally classified into (i) the addition of IO to definitive chemo-RT/RT, or (ii) IO + RT in perioperative (neoadjuvant and adjuvant) settings. The IO agents under investigation as monotherapy or in combination with immunotherapy regiments include drugs targeting PD-1, PD-L1, and CTLA-4. Disappointingly, initial results from phase II/III studies assessing definitive IO + RT have been largely negative. For example, NRG-HN004 evaluated the efficacy of concurrent and adjuvant durvalumab compared to standard RT with cetuximab. RT with durvalumab led to significantly worse locoregional failure (LRF) and did not signal improved progression-free survival (PFS) in patients with a contraindication to cisplatin .However, ongoing trials in the neoadjuvant setting supported by pre-clinical evidence may help define a new role for IO agents in LA HNSCC. Below, we highlight initial results from major phase III studies and ongoing trials that may identify new approaches to incorporate radioimmunotherapy in this setting .Phase III trials testing addition of IO to definitive chemo-RT/RT regimens in LA HNSCC include JAVELIN Head and Neck 100, GORTEC-REACH, NRG-HN005, KEYNOTE-412, and EA3161. Trials are summarized in JAVELIN Head and Neck 100 is a trial testing addition of 12-month avelumab versus placebo in 697 patients with LA HNSCC that received cisplatin-based chemo-RT. Initial results showed an HR of 1.21  and 1.31  for progression-free survival (PFS) and OS, respectively. The trial was prematurely discontinued because the boundary for futility had been crossed. On subgroup analysis, patients with tumors that had PD-L1 high expression (CPS ≤ 25%) showed a trend of potential benefit, with an HR of 0.59  .NRG-HN005 aims to evaluate the effectiveness and safety of de-intensified radiation therapy in combination with either chemotherapy using cisplatin or immunotherapy using nivolumab in treating patients with early-stage, HPV-positive, non-smoking associated oropharyngeal cancer. The study will compare the two treatments’ efficacies in terms of PFS and OS, as well as their safety profile. The trial will provide valuable insights into the potential of de-intensified radiation therapy combined with chemotherapy or immunotherapy as a treatment option for patients with oropharyngeal cancer .p = 0.15). [GORTEC-REACH is a trial involving two patient cohorts: cisplatin-fit and cisplatin-unfit. The trial assessed weekly cetuximab and avelumab concurrent with radiation followed by avelumab for 12 months in both cohorts versus the standard of care. The standard of care for the cisplatin-fit cohort was cisplatin-based chemoradiation, and for the cisplatin-unfit cohort was cetuximab and radiation. Radiation therapy was delivered at a dose of 70 Gy over 6.5 weeks. The primary endpoint of PFS was not met for either cohort. For the cisplatin-fit cohort, PFS HR was 1.27 , with a futility boundary for efficacy crossed favoring the standard of care, cisplatin. For the cisplatin-unfit cohort, PFS HR at 2 years was 0.85 (= 0.15). KEYNOTE 412 is a trial examining the efficacy of adding concurrent and adjuvant pembrolizumab to cisplatin-based chemoradiation versus placebo. The trial enrolled 804 patients, and on final analysis for primary end point , the results showed a favorable trend, but no statistically significant benefit for pembrolizumab arm HR 0.83 . A subset analysis of PD-L1 positive (CPS ≥ 1) patients at 36 months showed an EFS of 58% in the pembrolizumab arm vs. 51.8% in the control arm; overall survival was 71.4% vs. 70.2%, respectively. In the PD-L1 high-expression (CPS ≥ 20) subgroup, neither median EFS or OS were reached in either arm .EA3161 is a trial testing whether maintenance immunotherapy (nivolumab) following definitive treatment with radiation and chemotherapy (cisplatin) results in significant improvement in OS and PFS for patients with intermediate-risk HPV-positive oropharynx cancer that has spread to nearby tissue or lymph nodes .Together, these trials show some potential benefits in specific patient subgroups including PD-L1 positive patients. Ongoing trials NRG-HN005 and EA3161 aim to evaluate outcomes associated with de-intensification of radiation therapy and addition of nivolumab for HPV-positive oropharynx cancer.Several phase III trials are currently ongoing to test adjuvant radioimmunotherapy following definitive local/regional surgery. Trials are summarized in The advantages of the use of IO in the neoadjuvant setting have been previously reviewed ,44; thesClinically, several phase III studies have begun to assess IO for LA HNSCC in the neoadjuvant setting. KEYNOTE-689 MK-3475-689) is a trial assessing neoadjuvant pembrolizumab prior to surgery with standard-of-care adjuvant treatment and continued pembrolizumab for LA HPV-negative HNSCC. Patients in this trial received two doses of neoadjuvant pembolizumab, which notably were able to induce higher levels of pathological response versus one dose in initial phase II studies . The sec5-689 is IO for LA HNSCC clearly offers several advantages, including the administration of treatment during a phase of higher tumor antigen levels with intact gross disease and the ability to assess the pathological response to treatment in resected tissue. Clinical trials are ongoing to assess the benefits of neoadjuvant IO followed by surgery and adjuvant treatment, as well as treatment escalation in specific patient populations. Although initial results are pending, these studies hold promise in advancing the neoadjuvant treatment approach for LA HNSCC, and may provide valuable insights into optimizing patient outcomes.For the treatment of recurrent and metastatic cancer, the combination of immunotherapy and radiotherapy is being actively investigated. Previous and ongoing studies are investigating the synergistic and therapeutic effects of this treatment combination. One preclinical study investigated the immune-mediated mechanism behind the abscopal effect, which refers to the reduction in tumor growth outside the area targeted by radiation. They found that enhancing the number of dendritic cells, a type of immune cell, using Flt3-Ligand (Flt3-L), in combination with radiation therapy, resulted in impaired growth of both the irradiated tumor and the non-irradiated tumor in mice. This effect was shown to be tumor-specific and dependent on the presence of T cells, suggesting the involvement of the immune system in mediating the abscopal effect induced by radiation . Due to For metastatic disease, this treatment combination has been shown to be well tolerated. A phase I trial investigating SBRT and pembrolizumab to treat metastatic cancer illustrated that patients tolerate the combination with approximately 9.7% of patients experiencing grade 3 colitis, hepatitis, and pneumonitis . SimilarThere is conflicting evidence as to the benefit of combining immunotherapy and radiation for the treatment of metastatic HNSCC. A phase II prospective clinical trial illustrated that SBRT combined with PD-1 receptor inhibitor pembrolizumab improved the overall response rate (ORR) in patients with NSCLC . HoweverThe use of both radiotherapy and immunotherapy has shown great promise as a treatment strategy for patients with LA and recurrent/metastatic HNSCC. Several studies have explored the combined synergistic and therapeutic effects of these treatments, providing various mechanistic rationales for their effectiveness. Based on several phase II/III clinical trials, it appears that adding immunotherapy to radiation is a safe option. Overall, further research is needed to optimize the use of radioimmunotherapy for HNSCC, and to identify the patients who are most likely to benefit from this treatment. Ongoing trials are exploring various immunotherapeutic agents in order to determine the optimal timing, dose, sequence, and therapeutic agent for the combination of RT and immunotherapy in HNSCC treatment. Further research is needed to establish the optimal dose, fractionation, target volume, and field size for RT combined with immunotherapy.Optimal immunotherapeutic agent selection and sequencing with RT are active areas of investigation. Results from several ongoing clinical trials could guide these decisions for the treatment of patients with HNSCC. Patients with HPV-LA HNSCC are receiving neoadjuvant durvalumab and concurrent SBRT prior to surgical resection in the phase I trial NCT03635164 . PatientFor both metastatic and recurrent HNSCC, there are several ongoing clinical trials investigating radiotherapy techniques. Immunotherapy and brachytherapy are being studied for patients with recurrent HNSCC in NCT04340258. Perioperative pembrolizumab and Cesium-131 will be administered to patients prior to salvage surgery in this phase I/II trial. Cesium-131, a low-energy gamma isotope, will be placed at the time of surgery, and will deliver 60–70 Gy to the area of disease .De-escalation has been a major theme in HNSCC RT. This shift aims to achieve effective cancer treatment while minimizing the potential toxicity associated with traditional high-dose radiation regimens. The radiobiological rationale for de-escalation stems from a better understanding of tumor biology and the dose–response relationship. Studies have shown that certain tumors may exhibit a phenomenon called the “dose–response plateau,” where further increasing the radiation dose beyond a certain threshold may not significantly improve local control. Additionally, normal tissues surrounding the tumor have a finite tolerance to radiation, beyond which the risk of toxicity increases. By de-escalating radiation therapy, it is possible to achieve a balance between effective tumor control and minimizing the risk of treatment-related side effects.Several clinical trials have provided valuable insights into the efficacy and safety of de-escalation strategies. The RTOG 9003 trial, for instance, evaluated the impact of decreasing radiation dose in patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma. The trial demonstrated that reducing radiation dose while concurrently administering chemotherapy yielded similar outcomes compared to standard-dose radiation therapy, while reducing treatment-related toxicity. To achieve de-escalation, alternative fractionation and hypofractionation techniques have gained prominence. These approaches involve delivering higher radiation doses per fraction over a shorter treatment period, thereby reducing the overall treatment duration. QUADSHOT is a radiation therapy technique that allows for 14 Gy to be given in four fractions, given twice daily, at least 6 h apart, over two days . QUADSHOThe toxicity from RT for head and neck cancer is dose-dependent. As such, target dose and volume reduction are important potential strategies to mitigate toxicity. The REWRITe trial (GORTEC 2018-02) is investigating treatment of LA HNSCC with durvalumab and RT without prophylactic neck irradiation. RT is given at a dose of 69.96 Gy in 33 fractions to the macroscopic tumor volume, and a second optional dose is given to the immediately adjacent nodal level, at a dose of 52.8 Gy, in 33 fractions. There is also a paucity of data to guide patient selection for radioimmunotherapy regimens. The location, stage, and extent of the tumor ought to play a crucial role in patient selection. Radioimmunotherapy may be considered for patients with LA or recurrent HNSCC who have not responded adequately to standard therapies or have limited treatment options. The patient’s overall health and functional status are important considerations. Biomarkers are under investigation in an effort to predict which patients are most likely to respond to immunotherapy. There are several types of biomarkers that are being investigated for their potential use in predicting response to immunotherapy in HNSCC patients, including tumor mutational burden, PD-L1 expression, tumor-infiltrating lymphocytes, immune gene structures, and circulating tumor DNA . Such biFinally, there is a need for long-term follow-up studies to evaluate the efficacy and toxicity of radioimmunotherapy for HNSCC. This can help determine the durability of response and potential long-term toxicities associated with this treatment.In conclusion, the combination of radiotherapy and immunotherapy is a potential treatment strategy for patients with LA and recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Clinical studies have explored the synergistic effects of these treatments, with several phase II/III trials indicating the safety and potential efficacy of adding immunotherapy to radiation. However, further research is required to optimize the use of radioimmunotherapy and identify the patients who are most likely to benefit. Ongoing clinical trials are investigating different immunotherapeutic agents, treatment sequencing, and optimal radiation techniques to guide decision-making in HNSCC treatment. De-escalation strategies, such as alternative fractionation and hypofractionation, have also emerged to balance effective tumor control with reduced treatment-related toxicity. Biomarker research is underway to identify predictive markers for immunotherapy response, but more extensive investigation is needed. Long-term follow-up studies are necessary to assess treatment durability and long-term toxicities associated with radioimmunotherapy in HNSCC. Through continued research and the refinement of protocols, radioimmunotherapy holds the potential to improve outcomes for patients with HNSCC, while minimizing treatment-related side effects.