Background: The coronavirus (COVID-19) pandemic has increased the burden for the medical systems around the world. In Hong Kong, the pandemic not only affects the local populations, but also the healthcare workers. Healthcare workers, especially nurses, involving in COVID-19 treatments are highly susceptible to adverse psychological outcomes . Studies have shown that socio-demographic characteristics, COVID-19-specific worries, and work settings-related variables are associated with healthcare workers' well-being during the COVID-19 pandemic. However, relevant studies for nurses in Hong Kong are limited. This study examined the psychosocial correlates of anxiety symptoms among nurses in Hong Kong.Methods: Nurses  working in hospitals and community settings were recruited through nursing associations in Hong Kong between August 8, 2020 and September 22, 2020. They were invited to complete a cross-sectional survey measuring their anxiety symptoms, sociodemographic characteristics, COVID-19-specific worries, and satisfaction with work and workplace pandemic-control guidelines.Results: 17.2% of nurses reported moderate to severe levels of anxiety symptoms. Results from hierarchical regressions found that higher COVID-19-specific worries  , higher perceived stigma of being a healthcare worker , and lower work satisfaction  were associated with higher anxiety symptoms.Conclusion: A moderate proportion of nurses in Hong Kong did report levels of anxiety symptoms amid the COVID-19 pandemic. Futures studies could focus on the contributing factors of anxiety symptoms to design for effective strategies to promote nurses' well-being during pandemic situations. The Coronavirus pandemic (COVID-19) has become an international public health emergency, posing continuous threats to lives and healthcare systems worldwide. Since the first reported case on January 23, 2020, Hong Kong has reported 12,063 COVID-19 cases and 212 deaths as of August 23, 2021  and the Middle East Respiratory Syndrome (MERS), perceived stigma has been found to be a significant contributor of poor psychological well-being among healthcare workers  can be associated with well-being among healthcare workers. Studies have found that individuals who are satisfied with work are more likely to find meaning in nature of work, which facilitate well-being during the COVID-19 pandemic  were associated with higher anxiety symptoms.n = 16,500), the labor union of nurses in Hong Kong, were approached and invited to this study using their email contacts. The self-administered questionnaire was distributed to the nurses in an internet-based link along with an invitation email. An information sheet about the study was included at the beginning of the questionnaire, followed by an electronic consent form. The participants who agreed to join the study filled in the questionnaire on their own electronic devices. A reminder for participation into the survey was sent 2 weeks after the first invitation email. Responses from 1,566 participants were collected via the online platform. Among them, 56 did not fulfill the eligibility criteria . Therefore, only 1,510 valid responses representing working nurses included both worked as full-time or part-time in health care settings were retained in the analyses.The nurses working in either public or private service provision in different settings  were eligible for this study. Those who were nursing trainees and retired nurses were excluded from the study sample. All registered members of the Association of Hong Kong Nursing Staff , characteristics of this sample were matched to nurse population in Hong Kong according to the latest statistics from Department of Health . The study protocol was approved by the Research Ethics Committee (CUHK-NTEC CREC) at the first author's institution (Protocol no. CRE-2020.073).not at all to 3 as nearly every day), a higher sum score from all items  indicated more frequent anxiety symptoms. The Chinese version of the GAD-7 has been shown to be reliable and valid in community populations in Hong Kong, with a cut-off point of ≥10 indicating at least a moderate level of anxiety  was used to measure participant's levels of anxiety over the last 2 weeks , higher item scores represented higher COVID-19-related worries.Three items were specifically developed to measure participants' worries about the consequences of getting COVID-19 . On a 5-point scale , a higher sum score represented higher perceived stigma of being a healthcare worker. A similar scoring method was also used in another study measuring perceived stigma among healthcare workers in Columbia  my family/relatives, (2) my neighbors, and (3) friends at social gatherings. On a dichotomous scale . A higher score indicated a higher level of job satisfaction. Prior research has supported the validity of this single item measure in predicting health outcomes among employees in different countries , on a 5-point scale . A higher mean score from the item responses represented a higher level of satisfaction of workplace pandemic control guidelines. We also conducted a supplementary exploratory factor analysis to examine the dimensionality of the items. One factor was extracted through principal component analysis with orthogonal rotation, explaining 79.8% of variances in satisfaction with workplace pandemic control guidelines. Those results supported that this concept was suitable to be represented in a single dimension for the subsequent regression analysis. The Cronbach's alpha of the scale in this sample was 0.94.Five items were developed to measure participants' satisfaction with pandemic control guidelines at their workplace. Participants were asked to rate their level of satisfaction toward the different aspects of the workplace pandemic control guidelines , on a 5-point scale  and job-context variables  were measured.Descriptive statistics and Pearson correlations among the major variables were computed. Internal consistencies of the scales were indicated by their corresponding Cronbach's alphas. Hierarchical regressions were conducted to examine the associations between the independent variables and anxiety symptoms. The sequence of entering independent variables followed the suggestions from prior studies on individuals' well-being in response to emerging infectious diseases and other traumatic events  in the association between the independent variables and anxiety symptoms in the hierarchical regression analysis, we needed at least 515 participants to achieve a statistical power of 0.95 at p = 0.05 (G*Power 3.1.2). With our sample size , we should be able to detect the expected effect size with sufficient statistical power.Expecting a small-to-medium effect size (Most of the participants were aged between 30 and 39 (36.8%) and married (50.7%). On average, they have been working in the profession for around 8.9 years (SD = 8.60). About one-fifth of the participants were specifically taking care for diagnosed and suspected cases of patients with COVID-19 (‘dirty team”) (18.5%) and reporting at least a moderate level of anxiety (GAD ≥ 10) (17.2%) .rs ranged from 0.12 to 0.39, p < 0.05) , and working in the “dirty team” were correlated with more anxiety symptoms . Those variables were included as covariates in the subsequent regression analysis. Other socio-demographic variables reported non-significant correlations with anxiety symptoms .The correlation analysis results showed that higher levels of COVID-19-specific worries , higher perceived stigma, lower work satisfaction, and lower satisfaction with workplace pandemic control guidelines were correlated with higher anxiety symptoms ( < 0.05) . Regardip < 0.01) and working in the “dirty team”  were significantly associated with higher anxiety symptoms. In Block 2, higher levels of worries about contracting COVID-19 from work, about family members contracting COVID-19 due to their nursing duties, and about insufficient protective equipment at workplace  were significantly associated with higher anxiety symptoms. In Block 3, higher perceived stigma of being a healthcare worker was associated with higher anxiety symptoms , explaining an additional 3.7% of variance. In Block 4, work-related coping resources variables explained an additional 3.8% of the variance in anxiety symptoms. Only work satisfaction was associated with lower anxiety symptoms . With all the independent variables, the overall model explained 30.4% of variances in anxiety symptoms  ≥ 4, supporting the absence of multicollinearity. In Block 1, the background variables explained 3.3% of variance in anxiety symptoms. Specifically, younger age . Using the same measurement scale, our sample reported a comparable prevalence of probable anxiety (GAD-7 ≥10) with healthcare workers in India  were independently contributing to anxiety symptoms among the nurses in Hong Kong. Similar findings have been reported in healthcare workers in other countries, including China  and healthcare workers are generally highly respected professions in Hong Kong Schoeb, , perceivConsistent with some prior studies (Hamama-Raz et al., Even satisfaction of workplace pandemic control guidelines was bivariately correlated with fewer anxiety symptoms, it did not emerge as a significant contributor after accounting for other variables. It implied that COVID-19 worries, and work satisfaction might be even more important factors associated with anxiety symptoms among the nurses. To better understand how working environment might affect healthcare workers' adjustments to the COVID-19, it will still be important to further examine other aspects of work settings and arrangements and their contributions to those workers' well-being. For example, a previous study showed that satisfaction with the workload and the capability of participating in decision making were associated with fewer anxiety symptoms, whereas satisfaction with monetary compensation was associated with lower perceived stress among public health doctors in Korea (Han et al., This study had several limitations. First, it was a cross-sectional study so that the tested relationships were not causal. Future studies could examine how the changes in the independent variables could predict anxiety symptoms temporally using longitudinal designs. Second, all of the measures were self-reported, which might be subject to recall bias. However, the use of self-reported measures is common among many studies conducted during the COVID-19 pandemic (Salari et al., This study highlighted that COVID-19 worries, perceived stigma, and work satisfaction might be prominent contributors to anxiety symptoms among those nurses. The World Health Organization recommends that healthcare workers should maintain self-care, be attentive to their own mental health problems, and reflect on how their experiences may influence themselves and their loved ones. Identifying and instituting effective treatment strategies to improve psychological outcomes for nurses is essential. Practically, our findings also implied that alleviating COVID-19 worries, addressing stigma toward healthcare workers, and increasing work satisfaction might be important intervention strategies to reducing anxiety symptoms among the nurses amid the COVID-19 pandemic. Development of digital interventions targeting at healthcare workers' well-being has also been emerging. Recently in the United Kingdom, a free digital education package has been developed to provide valuable information to enhance healthcare workers' skills in coping with social stigma, self-care, and social support seeking during the pandemic (Blake et al., A moderate proportion of nurses in Hong Kong did report at least moderate levels of anxiety symptoms amid the COVID-19 pandemic. This study highlighted that COVID-19 worries, perceived stigma, and work satisfaction were the important contributors to anxiety symptoms among those nurses. We hope our findings could help tailoring intervention strategies to promote nurses' well-being during pandemic situations.lywong@cuhk.edu.hk.The datasets presented in this article are not readily available because their containing information that could compromise the privacy of research participant. The datasets are available from the corresponding author on reasonable request. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.NY and EW conceptualized the study and led on the manuscript writing. AC and NY collected and analyzed the data. E-kY and SW provided feedback on drafts of the manuscript. All authors approved the final manuscript draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Repetitive transcranial magnetic stimulation (rTMS) is an innovative method in the treatment of borderline personality disorder (BPD). We hypothesized that prefrontal rTMS in patients with BPD leads to improved BPD symptoms and that these effects are associated with brain connectivity changes.Fourteen patients with BPD received 15 sessions of individually navigated prefrontal rTMS over the right dorsolateral prefrontal cortex. Clinical effects were measured by the Borderline Symptom List 23, UPPS-P, the Difficulties in Emotion Regulation Scale (DERS), the Zung Self-Rating Anxiety Scale (SAS), and the Montgomery and Åsberg Depression Rating Scale (MADRS). Effects of rTMS on brain connectivity were observed with a seed correlation analysis on resting-state fMRI and with a beta series correlation analysis on Go/No Go tasks during fMRI. Assessments were made before and immediately after the treatment.The assessments after rTMS showed significant reductions in two subscales of UPPS-P, and in DERS, SAS, and MADRS. The brain connectivity analysis revealed significant decreases in amygdala and insula connectivity with nodes of the posterior default mode network . Connectivity changes were observed both in the resting state and during inhibition. The decrease of amygdala-pDMN connectivity was positively correlated with reduced depression and lack of premeditation after rTMS.Despite the study limitations , our findings suggest a possible neural mechanism of rTMS effect in BPD, reduced amygdala connectivity with the pDMN network, which was positively associated with symptom reduction. Borderline personality disorder (BPD) is a serious mental disorder characterized by instability of affect, self-image, and relationships, and by marked impulsivity including self-harm and recurrent suicidal behavior . TreatmeOn the neural level, BPD patients show impairment in multiple networks. Patients with BPD have been reported to show increased involvement of the posterior default mode network , 7 and iRepetitive transcranial magnetic stimulation  is a potentially innovative method in the treatment of BPD. rTMS was used in patients with BPD in nine studies with a total sample of 72 BPD patients –22; two In this study, patients with BPD underwent high-frequency rTMS of the right DLPFC (rDLPFC). High-frequency rTMS leads to increased cortex excitability, and patients with BPD have been found to have decreased activation predominantly in right DLPFC as compared to healthy controls . Also, SWe hypothesized that prefrontal rTMS in patients with BPD can lead to improved symptoms, specifically to enhanced impulse control and emotion regulation and, based on previous studies, to decreased anxiety and depression. We hypothesized that these effects are associated with brain connectivity changes induced by prefrontal rTMS. We focused on exploring changes in brain connectivity in three regions of interest: the DLPFC, a brain area crucial for emotion and impulse regulation , 26 and M = 23.57, SD = 4.73 years) underwent a prefrontal rTMS protocol. The inclusion criteria were: 5 out of 9 criteria for BPD according to DSM-5 , an established measure for BPD symptom severity . Impulsi3, FoV (224 × 224 mm), Flip Angle (FA) = 8°, 240 sagittal slices]. We used a gradient-echo echoplanar-imaging sequence sensitive to BOLD contrast for acquisition of one task-free and four task fMRI sessions (GNG task) with the following task-free/task parameters: TR = 750/2,280 ms, TE = 35 ms, voxel size = 3 × 3 × 3 mm3, FoV (192 × 192 mm), FA = 46°/75°, multiband factor = 4/1, 39/40 transversal slices, 380/153 scans.Functional MRI was done immediately before and after the rTMS protocol with 3T Magnetom Siemens Prisma machine  at the Central European Institute of Technology (CEITEC) in Brno, Czech Republic. The acquisition sequence was three-dimensional magnetization-prepared rapid gradient echo [3D inversion recovery; anatomical T1; 3D MP-RAGE; Repetition time (TR) = 2,300 ms, Echo time (TE) = 2.33 ms, voxel size = 1 × 1 × 1 mmWe adapted the GNG task according to the task design from Albares et al. . In the The rDLPFC was targeted individually by stereotactic neuronavigation , fMRI data analysis for neuronavigation was performed in SPM12. The rDLPFC anatomical mask was derived from the Destrieux neuroanatomic atlas  from FreWe used the DuoMAG XT magnetic stimulator (Deymed Diagnostic) with a 70BF air-cooled coil. The patients underwent 15 stimulation sessions at 110% of their individual resting motor threshold (RMT) over a period of 3 weeks with one session each working day. One stimulation session contained 1,500 pulses  divided into 10 trains with 10 Hz frequency . The RMT was measured before the first stimulation session and defined according to the Rossini-Rothwell method .t-tests and non-parametric Wilcoxon rank test due to small sample size.Behavioral and self-reported data analysis was performed in jamovi software v1.6 . DiffereAll functional datasets were preprocessed in SPM12 software  running p (FWE) <0.05 with an initial cut-off of p < 0.001.We employed beta series correlation analysis (BSCA)  to invest-test was used to assess the stimulation effects. Group results were corrected for multiple testing with cluster-level inference at p (FWE) <0.05 with an initial cut-off of p < 0.001.We used seed correlation analysis (SCA) to analyze connectivity in task-free data with identical seeds as used for BSCA. Before SCA, we filtered low-frequency drifts using high-pass with a cutoff of 1/128 Hz. We also filtered the confounder signals from WM and CSF and the effect of 24 movement regressors. A paired To see whether the observed changes in brain connectivity were associated with changes in the scales measuring BPD symptoms, we performed Spearman correlations between the changes in brain connectivity (T2-T1) and changes in symptom measures . A positive correlation means that the higher the decrease of brain connectivity, the higher the decrease in measured symptom. A negative correlation means that the higher the decrease of brain connectivity, the lower the decrease in measured symptom. The results were not corrected for multiple comparisons due to the exploratory nature of this analysis and the small sample size.RTMS was well-tolerated without any major side effects. Four patients reported headache after the stimulation, usually at the beginning of our protocol, which disappeared spontaneously without any medication after a short time.According to the self-reported measures , rTMS let = 5.00, p = 0.025), 78 voxels; In the resting state after rTMS vs. before rTMS, we found a decrease in connectivity of the left amygdala with a cluster comprising the right precuneus and superior parietal lobule [peak 27 −70 37 , 374 voxels; t = 5.96, p = 0.017), 67 voxels; t = 5.41, p = 0.014), 70 voxels; t = 5.11, p = 0.010), 74 voxels; In the GNG task, specifically in the NoGo vs. Go contrast and after vs. before rTMS, we found decreased connectivity of the left amygdala with a cluster comprising the left parietal lobule, precuneus, and middle and posterior parts of cingulate gyrus [peak −15 −67 13  and Lack of Premeditation . We observed another negative correlation of decreased Lack of Perseverance  and decreased left insula connectivity with the right precuneus in the inhibition condition.We observed two trend associations of connectivity change and symptom change . DecreasThis is the first study reporting both behavioral and neural effects of prefrontal rTMS in a sample of patients with BPD. We used high-frequency stimulation of rDLPFC based on the literature about fronto-limbic dysfunction in BPD  which underlies affective dysregulation and impulsivity , 11, 48.Regarding the performance in inhibition in the GNG task, the number of NoGo errors was low both before and after rTMS, and it did not significantly change. A small number of mistakes is normal in equiprobable tasks such as the one used in our study , 49. RegIn both the resting state and inhibition conditions, we found decreased left amygdala connectivity with the precuneus (PCN), posterior cingulate cortex (PCC), and parietal lobules (PL) after rTMS. These regions are parts of the posterior default mode network (pDMN), which is associated with self-related  and future-oriented reflection and thinking and emotional and attributional evaluation of situations , 51.Previous studies reported increased involvement of pDMN in patients with BPD as compared to healthy controls, suggesting higher self-referential thinking , 7. IncrImportantly, decreased amygdala connectivity with pDMN (in resting state only) was positively correlated with decreased depressive symptoms and with decreased lack of thinking before acting and planning (Lack of Premeditation). This means that the larger the decrease in amygdala-pDMN connectivity in the resting state after rTMS as compared to before rTMS, the greater the improvement in depressive symptoms and premeditation ability. Thus, our results are consistent with previous literature reporting positive associations of amygdala-pDMN connectivity and borderline or depressive symptoms. Decreasing amygdala-pDMN connectivity seems to be beneficial in patients with BPD and was achieved after the prefrontal rTMS protocol in our study.In the inhibition condition, we found decreased connectivity of the PCN and PCC with the left insula after rTMS as compared to before rTMS. Again, there was a decrease of pDMN areas connectivity. The insula processes interoceptive information to engage externally oriented attention and internal cognitive control, helps with integrating information from the limbic system, and is a major part of the inhibition network , 58, 59.In our study, we found a negative correlation of decreased insula-pDMN connectivity in the inhibition condition and symptom reduction—specifically with reduced Lack of Perseverance. Though previous studies suggest that decreasing insula-pDMN connectivity could be beneficial in patients with BPD, our data did not support the hypothesis that reduction in this connectivity is positively associated with symptom changes in patients with BPD. Moreover, it should be noted that we found the decrease of pDMN-insula connectivity only in inhibition condition and not in resting state. Thus, the effect might be more situation specific or task related than general, while previous studies usually report increased pDMN-insula connectivity in resting state or during pain processing.Overall, previous studies suggest that increased connectivity of pDMN with the amygdala and insula is associated with increased self-referential and self-attributional thinking, especially in negatively perceived situations. These connectivity increases are then associated with symptoms commonly associated with BPD, such as depressive mood, risk-taking, and suicidality with pDMN-amygdala connectivity, and dissociation and disturbed pain processing with pDMN-insula connectivity. Increased connectivity in both cases have been linked to adverse experiences in childhood. Our study reported decreased pDMN-amygdala and pDMN-insula connectivity and decreased BPD symptoms. We observed decreased pDMN-amygdala connectivity both in the resting state and during an inhibition task. This result suggests that negative self-referential thinking was decreased during resting and during a task activity focused on impulse control. We found that symptom reduction was positively correlated with decreased amygdala-pDMN connectivity, but negatively correlated with insula-pDMN connectivity. Thus, the reduction of negative self-referential thinking associated with reduced pDMN connectivity with the amygdala seems to be a beneficial effect for patients with BPD and a candidate mechanism of the rTMS effect in patients with BPD.per se. First, it is possible that the effects are induced by factors other than the intervention, including a placebo effect. Double-blind sham-controlled studies are needed to shed more light on this possibility. Second, prefrontal rTMS might actually induce distant beneficial brain changes, which would correspond with the hypothesis that the precise stimulation site might not be a crucial parameter at all. Third, it is possible that the current study did not have sufficient power to show prefrontal connectivity changes, and replication on a higher sample is needed. Moreover, medication in patients with BPD might influence the results since limbic hyperactivity has been found to be moderated by medication status in BPD patients .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The use of checkpoint inhibitors in advanced and metastatic renal cell carcinomas (RCCs) has rapidly evolved over the past several years. While immune-oncology (IO) drug therapy has been successful at resulting in improved responses and survival, combination therapies with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors have further improved outcomes. This article reviews the landmark trials that have led to the approval of IO therapies, including the Checkmate 214 trial and combination IO/VEGF TKI therapies with Checkmate 9ER, CLEAR, and Keynote-426, and it includes a discussion on promising therapies moving in the future. Cancers of the kidney and renal pelvis are the sixth most common cancers among men and the ninth most common cancers in women. There will be an estimated number of 76,080 new cases of and 13,780 deaths from these cancers in 2021  resultedEarly-stage disease is primarily treated with surgical resection via a partial or radical nephrectomy . AdjuvanThere are several prognostic models that have been proposed for the risk classification of metastatic ccRCC. The most commonly used classification systems in contemporary trials are the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic RCC Database Consortium (IMDC) models. The MSKCC model established serum lactate dehydrogenase level (LDH), hemoglobin, Karnofsky performance status, corrected serum calcium level, and time from diagnosis to treatment as predictors of outcome based on retrospective data . The IMDIn this review, we examine the evolving role of immunotherapy in the treatment of advanced clear cell renal cell carcinoma (ccRCC) and summarize the findings of key clinical trials over the past quarter century. We will conclude with a discussion on what the RCC treatment landscape may look like in the future.For many years, interferon alfa (IFN-α) and high-dose interleukin-2 (IL-2) were the mainstays of advanced RCC treatment. Treatment options have been limited to cytokine-based regimens because ccRCC is notoriously insensitive to traditional cytotoxic chemotherapy. Though cytokine-based treatments are highly effective in a small subset of patients, response rates are generally low. Responses, if any, are often at the expense of inconvenient drug administration and significant toxicity . Two newIn the RECORD-1 trial, everolimus, a novel mTOR inhibitor, was compared with placebo in advanced ccRCC patients who had progressed on prior VEGFR tyrosine kinase inhibitor (TKI) therapy. In the final analysis, treatment with everolimus improved the median PFS by 3 months compared to placebo. The median overall survival (OS) for everolimus and placebo was similar, 14.8 months and 14.4 months, respectively. However, once the survival data were corrected to account for crossover (80% of patients in the placebo arm had crossed over to the everolimus arm), a 1.9-fold increase in overall survival was demonstrated with everolimus .These early clinical trials established the use of VEGF pathway inhibitors as first-line treatment and mTOR inhibitors as second-line treatment for advanced ccRCC.Renal cell carcinoma is one of the most immune-infiltrated tumors, which makes the use of ICIs attractive . SimilarThe CheckMate 025 trial was one of the first studies to investigate the use of an ICI in advanced ccRCC in the second-line setting. This was a phase 3, randomized, open-label study comparing nivolumab versus everolimus. Patients in this study had already received systemic treatment targeting the VEGF pathway (such as sunitinib or sorafenib). There was a statistically significant difference in OS between the two groups. The patients in the nivolumab group had a median OS of 25 months versus 19.6 months in the everolimus group . The subAs the use of ICIs gained traction based on the results of the aforementioned ccRCC studies, there was increased interest in combining ICIs with VEGFR TKIs in the treatment of advanced ccRCC  with a VEGFR TKI (axitinib) with sunitinib in patients with advanced ccRCC in the first-line setting. After a median follow-up of 12.8 months, the median PFS was 15.1 months in the axitinib plus pembrolizumab group and 11.1 months in the sunitinib group. The 12-month OS rate was nearly 90% in the combination treatment arm versus 78.3% in the sunitinib arm. There was also a significant improvement in ORR, 59.3% versus 35.7%, in the investigational and sunitinib arms, respectively. Treatment with axitinib plus pembrolizumab was favored in patients across all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups. Moreover, the combination regimen proved to be beneficial over sunitinib irrespective of tumor PD-L1 expression .p = 0.005), but there was no statistically significant OS benefit of L+E compared to sunitinib. Objective response rates as determined by an independent review committee for each treatment arm were 71%, 53.5%, and 36.1% in the L+P, L+E, and S arms, respectively [The CLEAR trial compared two different combination regimens with standard-of-care sunitinib monotherapy, the results of which were reported at the 2021 ASCO Genitourinary Cancers Symposium. Patients randomized to the investigational treatment arms received lenvatinib, an oral multi-kinase inhibitor, with either pembrolizumab (L+P) or everolimus (L+E). Each of these treatment arms were evaluated against sunitinib (S) with PFS as the primary endpoint analyzed. A statistically significant improvement in PFS was reported with both combination treatment arms compared to the S arm. The median PFS was 23.9 months in the L+P group, 14.7 months in the L+E group, and 9.2 months in the S group. OS was significantly improved with L+P compared to S , and the 12-month OS probability was 85.7% in the combination treatment arm versus 75.6% in the sunitinib arm. ORR was significantly improved with combination therapy, 55.7% versus 27.1% in those who were treated with sunitinib [CheckMate 9ER is a phase 3, randomized, open-label trial that evaluated the use of cabozantinib, an oral multi-kinase inhibitor with multiple targets , in combination with nivolumab in untreated advanced ccRCC patients. Outcomes were compared to the control group who received standard-of-care sunitinib monotherapy, and the findings from this trial were published in March 2021. At a median follow-up of 18.1 months, the median PFS was 16.6 months for the cabozantinib plus nivolumab treatment arm versus 8.3 months in the sunitinib arm. Combination therapy with cabozantinib plus nivolumab appeared to result in a statistically significant improvement in PFS , temporary holding of ICI therapy, or low-dose systemic corticosteroid administration. Grade 3 or 4 usually requires higher-dose systemic corticosteroids in addition to holding or permanently discontinuing ICI. Often, toxicity profiles can overlap between ICI and TKI agents. For example, both nivolumab and cabozantinib can cause diarrhea via different mechanisms, making this particular side effect challenging to manage in a patient who is on this combination treatment regimen. The real-world treatment of advanced RCC has become complicated given the compelling data reported across all of the aforementioned first-line trials in the past three years. That said, it is a good problem to have several treatment regimens to choose from. It is unlikely we will have data comparing these first-line regimens head-to-head in a single prospective trial to determine which regimen is truly superior; therefore, it is reasonable to offer any of these regimens to an advanced ccRCC patient in the clinical setting. In addition, these different trials set different primary endpoints. Some primarily evaluated progression-free survival as the primary endpoint (for Checkmate 9ER and CLEAR), others used dual primary endpoints such as Keynote 426 or, specifically, the PD-L1 population of patients, in Javelin Renal 101. The choice of therapy, in our opinion, is contingent upon a number of factors including the presence of comorbid conditions  and patient preference as it relates to the treatment schedule and potential toxicities. The management of toxicities can be complicated as there is an overlap of the potential side effects that can occur in TKIs and ICI, for example, diarrhea. When a patient develops diarrhea while on a combination ICI+TKI regimen, it is often difficult to ascertain whether or not it is an immune-mediated toxicity that requires systemic steroids versus simply holding or discontinuing either one or both drugs. Therefore, one could justify a preference for offering nivolumab plus ipilimumab  in the first-line setting based on the CheckMate 214 trial in the appropriate patient as the management of immune-mediated side-effects is more straightforward. On the other hand, adequate resources for education of patients and clinicians, who may not often see such oncology patients who develop autoimmune side-effects but interact with them in various settings , is imperative since early recognition of autoimmune toxicity would lead to appropriate treatment and, ultimately, better outcomes. Familiarity with management of autoimmune toxicity as well as drug availability are important considerations as well, along with changes in quality of life parameters that are seen in each of these trials.In spite of the advancements that have been made in the first-line treatment of advanced ccRCC, the majority of patients inevitably require subsequent lines of therapy due to development of disease progression. Several studies have evaluated various systemic single-agent and combination treatment regimens that have changed the landscape of ccRCC management in the second-line setting and beyond. These studies are outlined in p < 0.0001) after progression during or within 9 months of treatment with a VEGF-targeted therapy . The ORR for everolimus, however, was only 1.8% [The RECORD-1 trial, the results of which were reported in 2008, was the first study that led to the FDA approval of an mTOR inhibitor for second-line use in metastatic ccRCC. In this multi-centered, open-label, randomized controlled trial, prolongation of PFS was observed with those who received everolimus compared to placebo  [It became clear that mTOR inhibition alone is not highly effective in the treatment of metastatic ccRCC, based on the low response rate reported in the RECORD-1 trial with everolimus monotherapy. mTOR inhibitors have subsequently been studied both compared to and in combination with TKI agents as alternative second-line therapies in ccRCC. In 2015, a significant PFS benefit was reported with the use of everolimus in combination with lenvatinib (a multi-kinase inhibitor) in previously treated advanced ccRCC patients compared to those who received everolimus alone  . Similar= 0.005) , leadingp = 0.002). Nivolumab also demonstrated superior ORR compared to everolimus  and led to fewer grade 3 or 4 treatment-related adverse events (19% vs. 37%) compared to patients receiving everolimus [Though mTOR inhibitors and TKIs are active in ccRCC based on the aforementioned studies, there is certainly room for improvement in the second-line space. However, given the increasing use of immune checkpoint inhibition in the first-line setting in recent years, there has not been much activity with regard to ICI use in the second-line setting for advanced ccRCC since the CheckMate 025 trial. As previously mentioned, the CheckMate 025 trial was one of the first trials exploring the use of an ICI in previously treated advanced ccRCC before ICI use became widespread in the first-line setting. In this study, patients with advanced ccRCC who had progressed after one or two lines of antiangiogenic therapy were treated with nivolumab or everolimus. When compared to everolimus, nivolumab demonstrated a significant OS benefit  patients received first-line ICI in combination with targeted therapy, and 27 (39%) received ICI monotherapy. This study showed an ORR of 23% at ICI rechallenge, compared to an ORR of 37% with ICI exposure in the first-line setting. There were patients who responded to ICI rechallenge regardless of their response to initial ICI therapy, but the likelihood of response to rechallenge was higher among patients who had previously responded to ICI ORR of 29%) . A simil% . A simThese retrospective data prompted further study of salvage ipilimumab and nivolumab therapy after single-agent nivolumab in subsequent clinical trials. For example, HCRN GU16-260 NCT03117309) and OMNIVORE (NCT03203473) are evaluating the clinical outcomes of the addition of ipilimumab in patients with metastatic RCC who do not achieve an objective response to nivolumab monotherapy. The phase 2 TITAN-RCC  trial studied the use of nivolumab plus ipilimumab as an “immunotherapeutic boost” in 86 intermediate-/poor-risk or metastatic ccRCC patients who experienced progressive disease or stable disease after four doses of nivolumab monotherapy. This study included two independent patient cohorts: those who had no prior therapy (receiving nivolumab first-line) and those previously treated with a TKI agent (receiving nivolumab second-line). The primary endpoint of this study was ORR. Secondary outcomes included remission rate (RR), PFS, and OS. Preliminary results of the study showed that in patients treated in the first-line setting, the ORR to nivolumab alone was 28.7% compared to 37.0% in patients receiving nivolumab followed by the nivolumab/ipilimumab boost. In the second-line setting the ORR was 18.2% among patients receiving nivolumab alone and 28.3% in those receiving nivolumab followed by the nivolumab/ipilimumab boost [9 and OMNIn July 2020, an open-label phase III clinical trial, CONTACT-03, began recruitment. CONTACT-03 is studying the combination of an anti-PD-L1 checkpoint inhibitor, atezolizumab, plus cabozantinib versus cabozantinib alone as second- or third-line therapy after prior progression with an immune checkpoint inhibitor. Patients are included if they have a histologically confirmed locally advanced or metastatic ccRCC or nccRCC with radiographic disease progression during or following treatment with a PD-1/PD-L1 inhibitor .PDIGREE (Alliance A031704) is an adaptive phase III trial currently enrolling intermediate-/poor-risk advanced ccRCC patients which will investigate the use of nivolumab and/or cabozantinib after first-line induction with nivolumab and ipilimumab. Treatment of these patients beyond the initial induction phase consisting of four cycles of nivolumab and ipilimumab, as per the CheckMate 214 protocol, will depend on their response to induction therapy. Those who experience a CR with initial induction therapy will continue with nivolumab maintenance. Those patients who have non-CR or non-PD  will receive cabozantinib in addition to nivolumab. Patients who experience progressive disease with induction nivolumab and ipilimumab will subsequently be treated with cabozantinib monotherapy. The primary endpoint for this study will be 3-year OS, and this study will also investigate the use of IL-6 as a potential biomarker .Standard of care treatment for a localized ccRCC includes surgical resection via a partial or radical nephrectomy with curative intent in those who are acceptable candidates for surgery. Most patients with stage 1 and 2 ccRCCs go on an active surveillance protocol after surgery. The rate of recurrent RCC after definitive surgery ranges from 20 to 40% . These hBased on the disease-free survival (DFS) benefit demonstrated with 12 months of adjuvant sunitinib in high-risk , localized ccRCC patients post-nephrectomy in the S-TRAC trial, sunitinib is an FDA-approved option in the adjuvant setting . An updaAt the 2021 ASCO Annual Meeting, promising data regarding the use of adjuvant pembrolizumab from the KEYNOTE-564 were presented. In this trial, patients with intermediate-high risk , high risk , or M1 NED ccRCC were randomized to receive pembrolizumab 200 mg via intravenous infusion every 3 weeks or placebo for up to 17 cycles . The priThere are several trials studying the use of other ICIs in the adjuvant setting for localized ccRCC that are underway, including dual ICI regimens (PD-1 or PD-L1 inhibitor in combination with a CTLA-4 inhibitor). Immune checkpoint inhibitors are also being studied in the neoadjuvant setting in RCC patients for whom surgery is planned. There is one phase I clinical trial exploring the safety and efficacy of pre-operative or neoadjuvant nivolumab (NCT02575222), and the phase 3 PROSPER RCC trial (NCT03055013) entails treatment with nivolumab in both the pre- and post-nephrectomy periods. Combination regimens are also being studied in the neoadjuvant setting. The SPARC-1 pilot study (NCT04028245) is currently recruiting localized ccRCC patients to evaluate the combination of canakinumab  and spartalizumab  prior to radical nephrectomy. The phase II Cyto-KIK trial (NCT04322955) is another study evaluating pre-operative combination therapy. In this trial, however, metastatic ccRCC patients for whom a cytoreductive nephrectomy is planned are treated with nivolumab in combination with cabozantinib prior to surgery.Vaccines have also been explored as a new modality for adjuvant RCC therapy. However, to date, no investigational vaccines have demonstrated clear efficacy in RCC. Most recently, a phase III trial assessing the use of an autologous RNA-modulated dendritic cell vaccine AGS-003  in combination with adjuvant sunitinib was terminated early due to a clear lack of OS benefit compared to those receiving adjuvant sunitinib alone . There iClear cell renal cell carcinomas represent a very heterogeneous group of tumors. The mechanisms of ccRCC tumorigenesis are complex, but we are gaining a better understanding of molecular or genomic subtypes and the RCC tumor microenvironment (TME) as they relate to treatment response to both TKIs and ICIs. For example, Beuselinck et al. completed a global transcriptome analysis of 53 primary resected ccRCC tumors from patients who developed metastatic disease who were treated with sunitinib in the first-line setting. Four ccRCC molecular subtypes were identified that were associated with differential sensitivity to sunitinib. ccRCC2 and ccRCC3 subtypes were defined by tumors with high pro-angiogenic gene expression and demonstrated increased sensitivity to sunitinib. Conversely, ccRCC1 and ccRCC4 subtypes were defined by c-Myc upregulation and decreased response to sunitinib, with the ccRCC4 subtype being further characterized by an “immune-inflamed” gene signature . Thus, tThe IMmotion-151 phase III study of atezolizumab plus bevacizumab versus sunitinib in untreated metastatic RCC patients demonstrated an improvement in PFS with the combination ICI-based regimen in PD-L1-positive patients. Tumor gene expression analysis was performed by RNA sequencing in 823 patients from the IMmotion-151 trial, and differential outcomes based on T effector/IFNγ and angiogenesis gene expression signatures were demonstrated. A high T effector/IFNγ gene expression signature was associated with PD-L1 expression by IHC, as well as a prolonged PFS in patients treated with atezolizumab plus bevacizumab versus sunitinib. The low angiogenesis gene expressors also appeared to benefit more from atezolizumab plus bevacizumab versus sunitinib . Today, With the FDA approval of multiple ICI-TKI combination regimens, the treatment landscape for advanced ccRCC continues to transform rapidly. Due to the increasing use of ICIs in the first-line setting, their use in the second and third-line settings is decreasing given the general lack of data to support the use of an ICI beyond progression on one. Although there is an increasing number of TKIs becoming available for use in these settings, further studies are needed to clearly define the use of ICIs after progression on an ICI-based regimen in the first-line setting. The use of ICIs in earlier stages of ccRCC, such as in the pre- and/or post-op settings, shows promise. Furthermore, increasing knowledge of ccRCC tumor heterogeneity, tumorigenesis, resistance mechanisms, and the RCC TME will continue to provide us with new potential therapeutic targets and drug combinations. While we have come a long way from the use of IL-2 to immune checkpoint inhibitors in the treatment of renal cell carcinomas, this is still just the beginning of the immunotherapeutics era in RCC. New breakthroughs in the management of RCC are sure to come through the tireless work of our dedicated scientists, investigators, and patients.


Chronic pancreatitis (CP) is a risk factor for developing pancreatic ductal adenocarcinoma (PDAC). In addition, a patient with partial pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) can also lead to PDAC. In contrast, IPMN is a distinct disease entity, independent of CP, and there have been few reports that CP is the cause of IPMN. To the best of our knowledge, this is the first clinical case report of the metachronous occurrence of main-duct IPMN and PDAC with a 9 and half-year interval in a patient with chronic alcoholic pancreatitis.A 50-year-old man with a long medical history of recurrent alcoholic pancreatitis and hepatitis over a decade was diagnosed with another episode of acute pancreatitis based on laboratory findings and clinical symptoms. The patient underwent pylorus-preserving pancreaticoduodenectomy (PPPD) for a small nodular lesion in the main duct of the pancreatic head and was diagnosed with main-duct IPMN low-grade dysplasia and associated fibrosing CP. Nine and a half years later, a 59-year-old man lost 7 kg over 3 months and was diagnosed with new-onset diabetes mellitus.The patient was diagnosed with metachronous, well-differentiated PDAC with concomitant CP.The patient underwent radical antegrade modular pancreatosplenectomy (RAMPS) for a small nodular mass in the remnant pancreas.The patient was healthy for 44 months without evidence of tumor recurrence during clinical follow-up examinations including laboratory findings, tumor marker, and imaging studies.Early diagnosis of metachronous pancreatic neoplasia in a patient with chronic pancreatitis could be made by correlating newly developed clinical symptoms and signs with careful radiological examinations. IPMNs are a heterogeneous group of tumors with a wide range of grades and histological subtypes, diverse prognoses, and multifocal occurrences. Main-duct IPMN is less frequent and has a higher risk of malignant transformation than that of branch-duct IPMNs.,5 PDAC can be derived from an IPMN or could develop in the same pancreas apart from the IPMN and even after IPMN resection. Metachronous occurrence of IPMN or pancreatic ductal adenocarcinoma after partial resection of the pancreas due to IPMN has been reported to have a wide range of incidence rates.–8 However, to date, few reports support that CP may be the cause of IPMN, except for one study that mentioned CP may be an independent risk factor for developing IPMNs, especially main-duct IPMNs.Chronic pancreatitis (CP) is characterized by continuous inflammatory fibrosis of the pancreatic tissue. The most common etiology of CP is heavy alcohol consumption. CP and heavy drinking are recognized risk factors for developing pancreatic ductal adenocarcinoma (PDAC).This is the first clinical case report, in English-written medical literature, about the metachronous occurrence of main-duct IPMN and PDAC with a nine and half-year interval in chronic alcoholic pancreatitis patient.This study was approved and written informed consent was waived by institutional review board of Dankook University Hospital.2A 50-year-old man presented with epigastric pain, fever, and chills. At the time, carbohydrate antigen 19-9  and total bilirubin  values were elevated. Elevated amylase and lipase levels and white blood cell counts were also observed, and he was clinically diagnosed with acute pancreatitis.He had been a heavy drinker for 30 years and was hospitalized several times over a decade for recurrent alcoholic pancreatitis and hepatitis, associated with excessive drinking. Computed tomography (CT) images at those times showed diffuse dilatation of the main pancreatic duct without intraductal focal lesion and peripancreatic fluid collection or pseudocyst.However, unlike before, at this time of acute pancreatitis, excessive drinking was unclear.Contrast-enhanced CT (CECT) suggested an ill-defined small nodule in the head portion of the dilated main pancreatic duct Fig. A that neMagnetic resonance cholangiopancreatography (MRCP) showed an irregular margined small nodule 10 mm) at the head of the dilated main pancreatic duct .18F-FDG) positron emission tomography/computed tomography fusion image showing a focal FDG-avid lesion (SUVmax max 3.8) at the body of the remnant pancreas  infiltrative mass and no metastatic lymph nodes, and concomitant fibrosing CP  positron emission tomography/computed tomography.He had been healthy for 44 months without evidence of tumor recurrence during clinical follow-up examinations, including laboratory findings, tumor markers, and imaging studies like CT, MRI, and F-fluorodeoxyglucose , and a history of CP may be a relevant independent risk factor for IPMN, especially main-duct IPMN.Capurso et al. reported that the risk factors for PDAC, including CP, were not significantly associated with the malignant IPMN like high-grade dysplasia and associated invasive carcinoma.In contrast, Kamata et al.This patient had recurrent acute pancreatitis related to excessive alcohol consumption for more than a decade, and the associated computed tomography (CT) findings showed acute interstitial edematous pancreatitis with peripancreatic fluid or pseudocyst. CT scan 28 months before diagnosis of main-duct IPMN showed diffuse mild dilatation of the main pancreatic duct without focal lesions suggesting morphological changes in chronic pancreatitis, and there was no mucin expulsion or duct obstruction on the ERCP.The first surgery, PPPD, revealed main-duct IPMN low-grade dysplasia with associated chronic fibrosing pancreatitis.3.2–8,16,17Patients after a partial pancreatectomy due to IPMN remain at risk for developing metachronous IPMN or concomitant PDAC. However, the recurrent rate of metachronous IPMN following partial pancreatic resection is difficult to determine because of the multifocal occurrence of IPMN and the difficulty in the differentiation of recurrent main-duct IPMN from postoperative anastomotic stricture. So, the recurrence rates of IPMN after partial pancreatectomy due to IPMN were reported to be 0% to 20% and invasive recurrence rates of 2% to 7.8%.,8,17,18Patients with IPMN of high-grade dysplasia, pancreatobiliary subtype, resection margin positive previous surgery, and a family history of PDAC have a significantly higher rate of recurrence or metachronous IPMN. Metachronous high-risk lesions, such as high-grade dysplasia or invasive cancer can often develop more than 5 to 10 years after partial pancreatectomy and the cumulative 5-year incidence of concomitant high-risk lesions ranges from 2.2% to 8.8%.,6,8The PDAC derived from IPMN and concomitant with IPMN were reported to be significantly smaller at diagnosis and is less invasive than PDAC, independent of IPMN. In addition, after resection of the mainduct IPMN without macroscopic invasive carcinoma, the prognosis is usually favorable.In this case, PDAC developed in the remnant pancreas 115 months after resection of the main duct IPMN low-grade dysplasia.3.3,3Previous studies, mostly case-control studies, have reported that the relative risk of PDAC in patients with CP varied widely from 2.3 to 18.5.In a meta-analysis, they concluded that chronic pancreatitis has a markedly increased risk of PDAC. Five years after the diagnosis, patients with CP have a nearly 8-fold increased risk of PDAC; and the risk remains high for almost 10 years after the diagnosis, and then declines over time.However, another study reported that the risk of PDAC in patients with CP increased over time, approximately 1.8% at 10 years and 4% at 20 years.In this case, more than ten years had passed since the diagnosis of chronic pancreatitis due to recurrent alcoholic pancreatitis at the time of diagnosis of PDAC.3.4Both CP and IPMN are risk factors for developing PDAC. KRAS mutation is known to be an important event in IPMN and PDAC carcinogenesis and occurs at a relatively early stage in both the cases. In patients with PDAC, KRAS oncogene mutations have been identified in up to 95% to 100%.,23In addition, KRAS mutations have been found in patients with CP with a 3-year disease history. But, some chronic pancreatitis patients with KRAS mutations never develop PDAC.In this case, the patient had two potential risk factors of IPMN and CP for developing PDAC.However, he was not examined for KRAS expression.3.5A small papillary lesion with mucin in the main pancreatic duct appeared to cause acute pancreatitis in this patient with a long history of recurrent alcoholic pancreatitis. At that time, elevated CA 19-9 level and atypical cells with mucin on FNA biopsy led to the diagnosis of PPPD.Elevated CA 19-9 and total bilirubin levels at the time of IPMN diagnosis became normal after the surgery.For this patient, the diagnosis of new-onset DM made it possible to diagnose it as metachronous neoplasm of PDAC as a small-sized mass at an early stage after PPPD due to main-duct IPMN.The diagnosed PDAC was 1.2-cm in size and well-differentiated type without lymph node metastasis. And histopathology showed the concomitant fibrosing CP without associated recurrent IPMN.Although the relationship between main duct IPMN and the development of the PDAC is known, there have been no cases of PDAC occurring 115 months after resection for main-duct IPMN low-grade dysplasia.To the best of our knowledge, this is the first clinical case report of a metachronous occurrence of main-duct IPMN low-grade dysplasia and well-differentiated PDAC within a nine and half-year interval in a chronic alcoholic pancreatitis patient.The author thanks the Drs at the surgical and pathological departments for their comments and discussions about the case.Case review, study design, investigation, supervision, and writing: Keum Nahn Jee.Conceptualization: Keum Nahn Jee.Data curation: Keum Nahn Jee.Formal analysis: Keum Nahn Jee.Investigation: Keum Nahn Jee.Project administration: Keum Nahn Jee.Supervision: Keum Nahn Jee.Validation: Keum Nahn Jee.Writing – original draft: Keum Nahn Jee.Writing – review & editing: Keum Nahn Jee.


The effectiveness of continuous positive airway pressure (CPAP) is dependent on the degree of use, so adherence is essential. Cognitive components  and support during treatment have been found to be important in CPAP use. Video consultation may be useful to support patients during treatment. So far, video consultation has rarely been evaluated in thorough controlled research, with only a limited number of outcomes assessed.The aim of the study was to evaluate the superiority of video consultation over face-to-face consultation for patients with obstructive sleep apnea (OSA) on CPAP use (minutes per night), adherence, self-efficacy, risk outcomes, outcome expectancies, expectations and experiences with video consultation, and satisfaction of patients and nurses.A randomized controlled trial was conducted with an intervention (video consultation) and a usual care group (face-to-face consultation). Patients with confirmed OSA (apnea-hypopnea index >15), requiring CPAP treatment, no history of CPAP treatment, having access to a tablet or smartphone, and proficient in the Dutch language were recruited from a large teaching hospital. CPAP use was monitored remotely, with short-term (weeks 1 to 4) and long-term  assessments. Questionnaires were completed at baseline and after 4 weeks on self-efficacy, risk perception, outcome expectancies (Self-Efficacy Measure for Sleep Apnea), expectations and experiences with video consultation (covering constructs of the unified theory of acceptance and use of technology), and satisfaction. Nurse satisfaction was evaluated using questionnaires.P-interaction=.008) but not long-term (P-interaction=.68) CPAP use. CPAP use decreased in the long term (P=.008), but no significant difference was found between groups (P=.09). Change over time for adherence was not significantly different in the short term (P-interaction=.17) or long term (P-interaction=.51). A relation was found between CPAP use and self-efficacy (P=.001), regardless of the intervention arm (P=.25). No significant difference between groups was found for outcome expectancies (P=.64), self-efficacy (P=.41), and risk perception (P=.30). The experiences were positive, and 95% (60/63) intended to keep using video consultation. Patients in both groups rated the consultations on average with an 8.4. Overall, nurses (n=3) were satisfied with the video consultation system.A total of 140 patients were randomized . The use of video consultation for OSA patients does not lead to superior results on CPAP use and adherence compared with face-to-face consultation. A significant difference in change over time was found between groups for short-term (Support of OSA patients with video consultation does not lead to superior results on CPAP use and adherence compared with face-to-face consultation. The findings of this research suggest that self-efficacy is an important factor in improving CPAP use and that video consultation may be a feasible way to support patients starting CPAP. Future research should focus on blended care approaches in which self-efficacy receives greater emphasis.Clinicaltrials.gov NCT04563169; https://clinicaltrials.gov/show/NCT04563169 Telemedicine is increasingly used to support self-management in chronic diseases and is defined as the use of information and communication technology to deliver health care at a distance , but so Video consultation may be a useful way to support patients ,17,18 duP=.003). Isetta et al .Patients were included from January 2, 2019, until June 26, 2019. In total, 222 patients were screened for eligibility, and 50 patients did not meet the inclusion criteria: no tablet or smartphone (n=17), no proficiency in the Dutch language (n=10), AHI <15 (n=10), history of CPAP treatment (n=5), no OSA (n=4), psychiatric or cognitive disorder (n=3), and age <18 years (n=1). In total, 28 patients declined to participate, and 4 patients were not informed about the study for other reasons: 2 patients were not referred to the researcher due to logistical errors, 1 patient followed a different care process (there was no consultation with the pulmonologist that same day), and 1 patient had had CPAP for try out for a short period.In total, 140 patients were randomized, and 70 patients were allocated to the intervention group and 70 patients to the usual care group. During the intervention period, 2 patients discontinued the intervention: 1 preferred face-to-face consultation, and 1 had no working device. Four patients stopped CPAP treatment during the intervention period (first 4 weeks). In total, 10 patients were lost to follow-up in the intervention group (n=9 stopped CPAP treatment and n=1 died) and 3 in the usual care group (n=3 stopped CPAP treatment). See P=.048) and risk perception (P=.02) appeared to be significantly different between groups.Both groups had similar baseline characteristics , only ouP-interaction=.008). However, the specific time points  were not significantly different. See The use of video consultation does not lead to superior results on CPAP use compared with face-to-face consultation. A significant difference in change over time was found between groups for short-term (weeks 1 through 4) CPAP use (P-interaction=.68). CPAP use decreased for both groups in the long term (P=.008), but no significant difference was found between the intervention and usual care group (P=.09). See No significant difference in change over time for long-term CPAP use  was found between groups (P=.95) and long-term (P=.12) CPAP adherence. Also, no significant difference in change over time between the intervention and usual care group was found for short-term (P-interaction=.17) and long-term (P-interaction=.51) CPAP adherence. See The use of video consultation does not lead to superior results on CPAP adherence compared with face-to-face consultation. No significant difference was found between both groups for short-term (P=.64), self-efficacy (P=.41), and risk perception (P=.30). See No significant difference between groups was found for the SEMSA constructs: outcome expectancies (P=.001), meaning that patients with higher levels of self-efficacy showed higher CPAP use. There was no relation between CPAP use and risk perception (P=.34) or outcome expectancies (P=.76). Also, the difference between the intervention and usual care group was not significant (P=.25).After 4 weeks, a relation was found between CPAP use and self-efficacy  indicated that video consultation had a positive effect on control over their treatment, and 75% (47/63) indicated that it positively affected the treatment itself. The majority  implied it did not cost them effort, 95% (60/63) reported that they had enough skills to use a tablet or smartphone and that they received enough support . Although, 64% (44/69) expected to be stimulated by people in their direct environment to use video consultation, only 25% (16/63) were actually stimulated. Almost all patients  intended to keep using video consultation. See Patients in both groups were satisfied with the consultations. On average, the intervention group rated the consultations with an 8.5 and the usual care group with an 8.3 on a scale of 1 to 10 . Patients indicated  that health care professionals understood their problems  and listened to them . Almost all patients understood the content of the consultation , could easily express their feelings , and were satisfied with the information they received . However, more patients with video consultation reported that they did not miss important information . See The majority  of the patients were very satisfied with video consultation, the quality of the video , and sound of the system . It also saved them time  and provided better access to health care professionals . Almost all patients felt safe about their privacy and confidentiality  and preferred a video consultation over a face-to-face consultation . According to almost half  the patients, face-to-face consultation can be replaced by video consultation. See Nurses (n=3) rated the use of video consultation on average with a 7.3 (SD .57) on a scale of 1 to 10 . They were all satisfied with privacy and confidentiality and quality of the sound and video and would recommend its use to colleagues and patients. Two nurses agreed that its use fits in their work process. However, only one nurse was completely satisfied with the information she could provide. They did not think that the use of video consultation helped them save time or work more efficiently.The nurses reported that use of video consultation is not suitable for new patients, and they prefer to use it during follow-up:It is not suitable for a first consultation after starting CPAP because you cannot provide enough information.Not for new patients because providing information and checking the device and sleep mask is difficult using video consultation.The nurses also experienced some technical problems:Sometimes there were log-in problems and I had to call the patient first by phone.Sometimes it took long before there was a connection. This costs more time.They also provided suggestions for improvement and described advantages of video consultations:Plan the video consultations one after the other and not alternating with face-to-face consultations.It is a good alternative for follow-up consultations. It is more patient friendly than a face-to-face consultation.Saves time for patients.P-interaction=.008). However, the specific time points  were not significantly different. No significant difference in change over time was found for long-term CPAP use (P-interaction=.68). No significant difference in change over time between groups was found for short-term (P-interaction=.17) or long-term (P-interaction=.51) CPAP adherence. Self-efficacy appeared to have a statistically significant effect on CPAP use in both groups (P=.001) regardless of the intervention arm (P=.25). No significant difference between groups was found for outcome expectancies (P=.64), self-efficacy (P=.41), or risk perception (P=.30). The experiences with video consultation were very positive. Almost all patients  intended to keep using video consultation. Patients in both groups rated the consultations on average with an 8.4. All nurses (n=3) were satisfied with privacy and confidentiality aspects and quality of the sound and video. However, they expressed some recommendations for improvement .In this RCT, we evaluated the superiority of video consultation over face-to-face consultation for newly diagnosed OSA patients. For CPAP use, we found a significant difference in change over time between groups in the short term (P=.15). In a multicenter RCT, no statistically significant difference was found for CPAP use after 6 months  and adherence  [Unfortunately, change over time was not evaluated in previous controlled studies ,26,29, bP=.001) regardless of the intervention arm (P=.25). In order to improve self-efficacy, it is necessary to positively influence patient perceptions. Patients may benefit from a self-management approach [P<.001). Stepnowsky et al [Where previous studies mainly focused on CPAP use, adherence, and satisfaction with video consultation ,25,26,29approach ,41,42 wiapproach . Lai et approach  providedky et al .However, limited evidence was available about the effect of video consultation for newly diagnosed patients starting CPAP. Most previous RCTs were small, with sample sizes varying from 19 to 40 patients ,25. OnlyThe assessment of UTAUT components and self-efficacy can also be used to indicate technology use . To our The involvement of health care professionals is essential to achieve successful implementation of technology , but thiVideo consultation can be seen as a promising app to support OSA patients during treatment. Still, evidence was lacking and previous research was not strong enough in design or focused on a limited number of outcomes. With the evaluation of a broad range of outcomes affecting CPAP use and implementation of video consultation in clinical practice, this RCT adds value to current knowledge.However, proper evaluation in this field is challenging because research often lags behind the rapid development of technology . The useSeveral limitations should be considered. Risk perception and outcome expectancies were significantly different at baseline, despite randomization. For a limited number of patients , video consultations or face-to-face consultations were replaced with a telephonic consultation due to technical problems in the intervention group and because patients in the control group could not come to the hospital. The protocol process were not strictly followed because patients failed to attend their scheduled appointment  or there were organizational inaccuracies such as wrongly scheduled appointments. The percentage of patients that followed the process exactly as described  was highSupport of OSA patients with video consultation does not lead to superior results on CPAP use and adherence compared with face-to-face consultation. The findings of this research show that a significant difference in change over time was found between groups for short-term CPAP use (but not on specific time points), but not for long-term CPAP use. Levels of self-efficacy were positively related to CPAP use in both groups. Patients were very satisfied with video consultation and reported positive experiences.Therefore, the findings of this research suggest that self-efficacy is an important factor in improving CPAP use and that video consultation may be a feasible way to support patients starting CPAP. The integration in health care processes and tailoring video consultation use to patient and professional needs is essential to ensure successful use. A blended care setting, in which an initial video consultation is combined with face-to-face consults, may be beneficial. To our knowledge, this is the first RCT that examined the effects of video consultation on CPAP use over time for newly diagnosed OSA patients in combination with cognitive components and experience with technology use. Future research should focus on blended care approaches in which self-efficacy receives greater emphasis.


Background: Magnetic resonance spectroscopy (MRS) has been used to identify gamma-aminobutyric acid (GABA) alterations in mood disorders, particularly in the medial prefrontal cortex (mPFC) where decreased concentrations have been associated with anhedonia. In major depressive disorder (MDD), prior work suggests that repetitive transcranial magnetic stimulation (rTMS) increases mPFC GABA concentrations proportional to antidepressant response. To our knowledge, this has not been examined in acute bipolar depression.Methods: As part of a multicentre 4-week randomized, double-blind, sham-controlled trial using intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex (DLPFC) in individuals with acute bipolar depression, we quantified mPFC GABA and Glx (glutamate+glutamine) concentrations using a 3T MRS scan at baseline and after the intervention. Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale-17 (HRDS-17), and anhedonia was measured using the Snaith-Hamilton Pleasure Scale (SHAPS).Results: The trial was terminated for futility and magnetic resonance spectroscopy data was acquired for 18 participants. At baseline, there were no associations between GABA or Glx concentrations and anhedonia, however GABA was negative correlated with depressive symptom severity on the HRDS-17. Compared to the sham-iTBS group, participants receiving active-iTBS had a significant increase in mPFC GABA concentrations. This was unrelated to antidepressant outcomes or improvements in anhedonia.Conclusion: Our data suggests that iTBS targeting the DLPFC is associated with physiological changes in the mPFC. In acute bipolar depression, our preliminary data suggests that mPFC GABA is dissociated from antidepressant iTBS treatment outcomes and anhedonia. Bipolar disorder (BD) is a leading cause of global disability that is defined by episodes of mania or hypomania . Yet, paNon-invasive neurostimulation techniques, such as transcranial magnetic stimulation (TMS), are efficacious in the treatment of Major Depressive Disorder (MDD). Accordingly, they are often considered in acute bipolar depression, however the literature in BD is small , 5. Newe1H-MRS studies report decreases in cortical GABA in unipolar depression that correlate inversely with glutamate  and glutamate systems in mood disorders , 11. 1H-lutamate –15. Lowelutamate –18. Impolutamate , as welllutamate .Several lines of evidence highlight the importance of the mPFC, and the anterior cingulate cortex more specifically, in the therapeutic effects of rTMS when the target is the dorsolateral prefrontal cortex (DLPFC). Indeed, a single treatment to the left DLPFC is associated with sustained changes in fMRI BOLD response and the GABA/Glx ratio in the anterior cingulate . HyperacTo our knowledge, mPFC GABA concentrations during rTMS treatment in acute bipolar depression have not been measured. Therefore, in a randomized sham-controlled trial that examined the efficacy of iTBS in comparison to sham-iTBS , we usedClinicalTrials.gov (NCT02749006) and was approved by the clinical ethical review boards of the University of British Columbia and conjoint health ethical review board of the University of Calgary. The University of Calgary site, but not the University of British Columbia site, acquired GABA-edited MEGA-PRESS data in the mPFC.We conducted a double-blind randomized controlled study in two Canadian centers  between October 2016 and March 2020. The study was registered with The primary outcomes are described elsewhere . BrieflyParticipants were recruited by referral or by online and community advertisements. Participants provided written informed consent. Eligibility criteria included: males and females 18–70 years of age with a primary diagnosis of Bipolar I Disorder or Bipolar II (BD1 or BD2), experiencing a major depressive episode with ≥15 on the 17-item Hamilton Depression Rating Scale (HRDS-17) , and havExclusion criteria were acute suicidality; current psychosis; a substance use disorder within the last 3 months; seizures; a pacemaker or metallic implant; an unstable medical condition; previous TMS; current use of more than three antipsychotic agents; failed response to ECT in current episode; psychotherapy initiated within the last 3 months; a psychiatric condition other than BD that was deemed to be primary.We generated three 1:1 randomization sequences for patients treated with (a) mood stabilizers, (b) atypical antipsychotics, or (c) a combination of mood stabilizer and antipsychotics to ensure that randomization was stratified according to current pharmacotherapy. Eligible patients were randomized with allocation concealment. Patients and clinical evaluators remained blind to their treatment condition. We utilized a MagPro X100 stimulator , and a COOL-B70 or MCF-P-B70 placebo coil in conjunction with participant anatomical MRIs and neuronavigation . Resting motor threshold (rMT) was determined using electromyographic (EMG) electrodes placed over the first dorsal interosseous muscle, with threshold determined by the stimulus intensity required to elicit 5/10 EMG responses >50 μV.Patients were randomly allocated to either active or sham iTBS, consisting of a total of 600 pulses per session. Pulses were delivered as triplets at 50 Hz repeated at 5 Hz (2 on 8 s off) and at 120% rMT. These parameters reflect the stimulus parameters that have been shown to be non-inferior to gold standard high-frequency stimulation in a large single blind study . We targParticipants were assessed by an independent evaluator (AM) blinded to treatment conditions. The diagnosis of BD was confirmed with the MINI International Neuropsychiatric Interview 7.0. Clinician rated instruments included the Hamilton Rating Depression Scale 17-item (HRDS-17), the Montgomery-Asberg Depression Rating Scale (MADRS) , the You3 voxel in the mPFC using a GABA-edited MEGA-PRESS acquisition . Voxels were then placed parallel to the AC-PC line anterior to the genu of the corpus callosum . Because the GABA peaks are overlapped by more abundant metabolite peaks, advanced spectroscopy methods are required for its accurate quantification; the most common being J-difference editing . For voxcallosum . Gamma-acallosum  includincallosum , 37. Gamcallosum .Data quality was visually assessed, which included assessing the GABA peak and resolution of subtraction artifact following spectral alignment, confirming the stability of water frequency (indicative of movement or scanner drift), confirming the quality of creatine alignment and fit of the spectrum and residuals. The included MEGA-PRESS acquisitions had a GABA fit error of 7.74 ± 3.28, full-width half-maximum of 22.03 ± 4.48 Hz, and signal to noise ratio of 11.97 ± 3.05.The T1-weighted image from the follow-up session was registered to the baseline acquisition  andt-test or Mann Whitney U Test. Chi-square was used for dichotomized variables. One way ANOVA and linear regression was used to explore relationships between mPFC GABA and clinical characteristics. Change in mPFC GABA was quantified with repeated measures ANOVA. Two tailed significance was set at α < 0.05.Statistical analysis was performed in SPSS . Data normality was confirmed using the Shapiro-Wilk test and outliers were identified using Tukey's Fences . Cross-sn = 10) and active iTBS-rTMS groups (n = 11). Three individuals did not tolerate the MRI, and therefore we acquired valid GABA data at baseline from 18 participants (n = 7 sham-iTBS and n = 11 active-iTBS). Sociodemographic and clinical characteristics were comparable between groups at baseline, and treatment outcomes also did not differ  = −0.84, p = 0.41]. mPFC Glx concentrations were normally distributed and there was a trend toward higher Glx levels at baseline in the sham-iTBS group .mPFC GABA concentrations at baseline were skewed with one notable outlier >3 standard deviations from the mean. When this participant was removed, this data was normally distributed. There were no significant baseline differences in GABA levels between sham-iTBS and active-iTBS groups , medication regimen , MADRS score , or CGI-severity score , however there was a significant association withHRDS-17 scores . mPFC Glx did not significantly correlate with any clinical characteristic (p > 0.18).At baseline, there were no significant associations between GABA and SHAPS score . This significant effect persisted after controlling for percent change in MADRS scores . We found no evidence for mPFC Glx time or treatment group effects .At the conclusion of double-blind treatment, paired pre-post MRS data were available for To our knowledge, this is the first study to use GABA-edited MRS to investigate mPFC metabolite changes during TMS therapy in acute bipolar depression. Though preliminary, our data suggests that iTBS results in increased GABA in the mPFC, consistent with previous data in MDD samples for the mPFC  and in tThis data is interesting because it confirms a common physiological effect of DLPFC TMS stimulation in different pathologies. Yet, the lack of antidepressant effect in this subsample or in the larger multisite trial from which it is drawn highlights that not all physiological effects of therapeutic TMS are causally associated with improvement in depressive symptoms. Moreover, we did not observe associations between mPFC GABA and clinical features such as anhedonia, a replicated finding in MDD . While iGiven the small sample and inference from a null finding, further research is required to determine whether our findings represent a physiological difference between acute bipolar depression and unipolar depression. It is possible that MRS quantified GABA in the mPFC is not as tightly linked to mood state in BD, given that previous studies in BD have not found differences compared to healthy controls in either depression  or euthyOur preliminary data comes from a single site from a randomized controlled trial that was terminated for futility. As a result, the sample size is small, and the availability of paired pre-post MRS data is further reduced. As such, the magnitude of change seen in GABA concentrations in the active-iTBS group may be inflated due to to small sample size bias. Nevertheless, this increase is not observed in the sham-iTBS group, and therefore is likely to be a physiological effect of iTBS. Larger studies are required to more reliably determine the effect size, and independence from clinical improvements in acute bipolar depression. Participants in this trial were required to have stable dosing of an antimanic agent, which resulted in 20 of the 21 participants using medications known to influence GABA –50. Whil3, placed in the mPFC. This large voxel limits the regional specificity of our results as it encompasses multiple functionally or anatomically distinct structures. Secondly, the measured GABA signal at 3 ppm includes a macromolecule contribution due to the limited specificity of the editing pulses applied at 1.9 ppm (There is an inherent challenge in resolving GABA at 3 T due to its low concentration and overlapped, more abundant metabolites. The use of editing techniques, such as the MEGA-PRESS sequence used in this study, is preferable to the use of short-echo point resolved spectroscopy sequences for measuring GABA, particularly at 3 T –54. None 1.9 ppm , 56. Mac 1.9 ppm , 57. Fin 1.9 ppm , the scaOur sham-controlled data in acute bipolar depression suggests that iTBS targeting the DLPFC is associated with physiological changes in the mPFC. Unlike previous reports in MDD, in acute bipolar depression mPFC GABA concentrations appear to be dissociated from antidepressant treatment outcomes and anhedonia or have a much smaller effect. Future research is needed to better understand the clinical implications and network level changes associated with neural metabolites in acute bipolar depression.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by University of Calgary Conjoint Health Research Ethics Board. The patients/participants provided their written informed consent to participate in this study.Study conception: AM, LY, and AH; Securing study funding: LY; Data collection: JC and AM; Data analyses: CD, MD, AH, and AM; Figure generation: AH and AM; Drafting manuscript: CD; Editing and approval of final manuscript: MD, JC, LY, AH, and AM. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Radium-223 is a bone-seeking, alpha-emitting radionuclide used in metastatic castration-resistant prostate cancer (mCRPC). Radium-223 increases the risk of fracture when used in combination with abiraterone and prednisolone. The risk of fracture in men receiving radium-223 monotherapy is unclear.n = 36) matched for fracture risk and not treated with radium-223. Bone fractures were assessed using whole-body magnetic resonance imaging. The primary outcome was risk of new fractures.This was a prospective, multicenter phase II study of radium-223 in 36 men with mCRPC and a reference cohort (n = 36), 16 new fractures were identified in 12 patients over a median follow-up of 24 months. Across both cohorts, 67% of all fractures occurred at uninvolved bone.Thirty-six patients were treated with up to six 4-week cycles of radium-223. With a median follow-up of 16.3 months, 74 new fractures were identified in 20 patients. Freedom from fracture was 56%  at 12 months. On multivariate analysis, prior corticosteroid use was associated with risk of fracture. In the reference cohort (Men with mCRPC, and particularly those treated with radium-223, are at risk of fracture. They should receive a bone health agent to reduce the risk of fragility fractures. Radium-223 increases the risk of fracture in combination with abiraterone and prednisolone. The fracture risk of radium-223 monotherapy is unclear. This prospective study assessed fracture incidence in men treated with radium-223 matched with a cohort that did not have radium-223. We identified 74 new fractures in 20 patients receiving radium-223. Most fractures occurred in bones without apparent metastases. Bone health agents should be mandatory before starting radium-223. Radium-223 is a bone-seeking, alpha-emitting radionuclide that is approved for use in men with metastatic castration-resistant prostate cancer (mCRPC). The ALSYMPCA trial showed that radium-223 improves both overall survival and time to skeletal-related events.One hypothesis is that radium-223 increases the risk of fracture only if used in combination with other agents that have an adverse effect on bone health, such as abiraterone and prednisolone.We have conducted a prospective phase II study (REASURE) of radium-223 used as a single agent, incorporating routine whole-body magnetic resonance imaging (WB-MRI), in men with mCRPC. The primary objective of the study was to evaluate treatment response by whole-body diffusion-weighted MRI.Patients with chemotherapy-naïve, bone-only, progressive mCRPC were enrolled in a prospective study of radium-223. They received treatment with radium-223 every 4 weeks for up to six cycles. Patients were randomized to one of two dose-levels: 55 or 88 kBq/kg. WB-MRI scans were done at baseline, at cycles 2 and 4, and at 1 month after treatment. During the follow-up period, patients were evaluated every 4 months for 1 year, following which imaging was done according to routine clinical practice and scans were collected and reviewed centrally. The WB-MRI protocol included standard T1 weighted (T1w) and T2w sagittal spine supplemented by axial T1w Dixon, T2w HASTE, and diffusion-weighted imaging (DWI) sequences. The presence of a fracture was determined on T1w and T2w sequences; differentiation between a malignant cause and non-malignant cause (presumed osteoporotic) was accomplished by using all available sequences, including DWI and the T1 Dixon-derived fat fraction.9The REASURE trial was registered (ISRCTN17805587), approved by the National Research Ethics Service London–Surrey Borders Research Ethics Committee (14/LO/1385), co-sponsored by the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, and conducted in accordance with the principles of good clinical practice. All of the participants provided written informed consent prior to study entry. The Clinical Trials and Statistics Unit at the Institute of Cancer Research  coordinated the study.We also identified a separate reference cohort of men with mCRPC treated at The Royal Marsden Hospital but not treated with radium-223 to act as a benchmark for the fracture rate. This cohort was used in order to provide an estimate of the fracture rates among patients with similar disease pattern, utilization of bone-health agents, and corticosteroid usage compared with the REASURE population. Moreover, the extracted cohort also had regular use of WB-MRI during follow-up. Scans were done as part of routine clinical practice, with a median time between scans of approximately 5 months. The use of this reference cohort was approved by the Committee for Clinical Research of the Institute of Cancer Research and The Royal Marsden Hospital.The scans were reviewed by a radiologist experienced in mCRPC. Fractures were identified on whole body MRI in correlation with all other imaging available and the underlying bone was assessed as malignant or uninvolved depending on MRI appearances.Fractures identified prior to starting treatment were not included in analyses. All subsequent imaging tests were used for fracture assessment. Time to new fracture was calculated from the date of randomization in REASURE to the first scan showing a new fracture. Time to fracture was presented using Kaplan–Meier curves and association with other variables assessed via log-rank tests and Cox proportional hazards models. The reference cohort was used as a benchmark only; no formal comparisons were made between the REASURE trial population and the reference cohort.Between July 2015 and June 2017, 39 patients were randomized in a 1:1 ratio between the two radium-223 dose levels. Three patients were excluded from analysis of fractures: two due to unmet eligibility criteria and one due to poor MRI tolerance, leaving 36 evaluable patients. In the evaluable population, median age was 75 years . Baseline patient characteristics are provided in Out of 36 evaluable patients, 20 patients (56%) completed six cycles of radium-223, and the remaining 16 patients discontinued early due to disease progression. The median number of treatment cycles among patients who discontinued early was four .Table 2TIn total, 205 imaging scans after starting radium-223 were evaluated. Overall, 74 new fractures were identified in 20 patients (56%). Freedom from fracture was 79%  at 6 months and 56%  at 12 months . Median On univariate analysis, high disease burden and baseline alkaline phosphatase (ALP) were associated with risk of fracture. There was no significant association between radium-223 dose and risk of fracture . On multn = 36) was 70 years . Thirty-one patients (87%) were starting treatment with abiraterone or enzalutamide, 18 patients (50%) had prior corticosteroids, and two patients (6%) received bone health agents. The median follow-up time for the benchmarking group was 24.0 months . In total, 150 imaging scans were evaluated. Overall, 16 new fractures were identified in 12 patients (33%). Out of all fractures, 10 fractures (62%) occurred at a site of uninvolved bone.Median age for the reference cohort  were at sites of uninvolved bone and not at metastatic sites. This is consistent with results from the ERA 223 trial, in which 78% of fractures were at uninvolved sites.The fracture rates reported in men with mCRPC receiving radium-223 vary widely from one study to another. In ALSYMPCA, fractures were seen in 4% of patients receiving radium-223 versus 5% receiving placebo.We observed fractures in 33% of our reference cohort of men with bony mCRPC not treated with radium-223. This rate appears relatively high in comparison with previous studies, which may also reflect differences in the use of prior corticosteroids and bone health agents. In the PREVAIL trial, among patients receiving enzalutamide, fractures were seen in 12% compared with 8% for the control arm.The main strength of REASURE is that it is the first prospective study, to our knowledge, of men treated with radium-223 monotherapy with the use of imaging at prespecified intervals to enable assessment of fracture risk during and after treatment. However, it has several limitations. First, the observed fracture risk may be regarded as a worst-case scenario, given that only a small proportion of patients were receiving a bone health agent, and as many as half had received prior corticosteroids. Second, half of the patients received an escalated dose of radium-223 (88 kBq/kg); however, their fracture risk did not differ from those receiving the standard radium dose (55 kBq/kg). Third, some of the fractures seen on imaging may not be clinically relevant. However, even if, as we found, only half of patients with fractures are symptomatic, the risk of new fracture in mCRPC patients treated with radium-223 remains clinically important. Fourth, regular imaging will result in earlier detection of asymptomatic fractures. This would be true regardless of the imaging modality: MRI (bone edema), bone scan (osteoblastic reaction), or CT (sclerosis). Using bone scans or CT scans, care must be taken to avoid misinterpreting these fractures as new sites of disease. The advantages of WB-MRI are that it distinguishes fractures from disease progression and it allows timely differentiation between a malignant and non-malignant fracture.The magnitude of the difference in fracture risk between men receiving radium-223 in REASURE and those in the reference cohort should be interpreted with caution. Although the reference cohort was selected to be similar to the REASURE population with regard to major risk factors for fracture , it was not a randomized comparison. The two groups may have differed with respect to other risk factors for fracture, such as age, duration of prior hormone therapy, smoking, and alcohol intake. The frequency of scans in the reference cohort was less than in REASURE, so fractures may also have been detected later in the reference cohort. However, this would not have affected the overall number of fractures detected over the whole observation period.The study was not designed to assess the impact of bone health agents on fracture risk. However, bone health agents are known to reduce the risk of fracture in men with mCRPC, and it seems clear from the ERA 223 trial and the early results from the PEACE III trial that the use of bone health agents substantially reduces the risk of fracture in men treated with radium-223.There remains uncertainty as to when bone health agents should be started and what dose schedule should be used. Given that the aim of such treatment is to prevent fragility fractures, we believe that the use of bone heath agents should be similar to that in other populations at risk of fragility fracture, such as postmenopausal women. The European Society for Medical Oncology Clinical Practice Guidelines recommend that men starting long-term androgen deprivation should be offered an oral bisphosphonate or be monitored with dual-energy absorptiometry (DEXA) scanning and be treated according to the bone density results.In summary, regular imaging with WB-MRI shows that men with mCRPC, and particularly those treated with radium-223, have a high risk of developing new, predominantly non-malignant (osteoporotic) fractures. Men with mCRPC should receive a bone health agent to reduce their risk of fragility fractures.•Radium-223, used in mCRPC, has been shown to increase the risk of fracture when used in combination with abiraterone and prednisolone; however, the risk of fracture in men receiving radium-223 monotherapy is unclear.•In this prospective study of radium-223, regular imaging assessments were utilized to assess 36 men for fracture incidence. This was matched with 36 men not treated with radium-223 who had a similar fracture risk and also received regular imaging assessments. We identified 74 new fractures in 20 patients (56%) receiving radium-223, and 16 new fractures were identified in 12 patients (33%) not receiving radium-223. Of all fractures across both cohorts, 67% occurred at uninvolved bone .•Men with mCRPC, particularly those receiving radium-223, are at risk of fracture and should receive a bone health agent to reduce the risk of fragility fractures