To determine epidemiology of in-hospital cardiac arrest (IHCA) in a tertiary care hospital, pre- and during pandemic.This is a cross-sectional study of inpatients who experienced an in-hospital-cardiac arrest at a tertiary care hospital in Karachi between August 2019 and August 2020. Outcome variables were return of spontaneous circulation (ROSC) and survival to discharge (StD) and analysis was also done comparing pre- and during pandemic period.A total of 77 patients experienced at least one IHCA event during the 1-year study period. Comparing pre- and during pandemic, ROSC for women was higher during the pandemic albeit not significant (43% vs 50%) in comparison to men . During the pandemic, women with IHCA were significantly younger than men  whereas pre-pandemic, there was no gender differences in mean age. Non-shockable rhythm was more common (92.2%) than shockable rhythm (6.5%). Pre- and during pandemic, there were significant differences in the cause of IHCA for 4H4T (87% vs 100%) and cardiac (36% vs 9%). The proportion of hypoxic patients increased from 50% during pre-pandemic to 91% during the pandemic period, whereas hypo/hyperkalemia decreased from 53% to 34%.Despite the limitation of a small sample size, our study has provided important information regarding the epidemiology and outcomes of IHCA pre- and during pandemic in a busy Pakistani tertiary care hospital. Our finding that gender differences exist in survival pre- and during pandemic needs to be explored further with more hospitals doing comparative studies. In-hospital cardiac arrest (IHCA) is a major cause of death worldwide yet, data on the epidemiology of IHCA is limited.9The recent COVID-19 pandemic is further impacting the epidemiology and outcome with some studies indicating an increase in the burden of cardiac arrest in COVID-19 patients.11There is evidence elsewhere that recognizing the cause of arrest by the emergency team as well as minimizing health-care related risk factors may help in improving survival outcomes.A cross-sectional study was conducted on patients who experienced an IHCA event at the Korangi Campus of the Indus Hospital and Health Network between Aug 2019 and Aug 2020. It included patients admitted in Emergency (ER), wards, intensive care unit (ICU), critical care unit (CCU), high dependency unit (HDU) and COVID-19 ICU. Only the initial cardiac arrest was taken if any patient had more than one.A pre-coded questionnaire was used to capture data. Sociodemographic variables included were age, gender, and comorbidities whereas IHCA event variables were initial cardiac rhythm, Hs & Ts, event location, pre-arrest cerebral performance and any underlying factors present prior to arrest. Pre-pandemic period was defined as August 2019 to Feb 2020 and during-pandemic was from March 2020 to August 2020. An IHCA event was defined as a cardiac arrest that occurs in a hospital and for which resuscitation was attempted with chest compressions, defibrillation, or both. Outcome variables were return of spontaneous circulation (ROSC) and survival to discharge (StD).All patients included in the study were age 14 and above. In our hospital, 14-17 years are treated as adults. Patients excluded were those below 14 years, those who had an out-of-hospital-cardiac-arrest, were transferred in-patients from another hospital with a history of arrest prior to arrival to our hospital, patients on Temporary Pacemaker (TPM) or Permanent Pacemaker (PPM) and those post cardiac catheterization. Approval from Institution Review Board was taken (IRD_IRB_2019_06_006).Data was entered and analyzed using software SPSS 26. Mean ± SD was calculated for age based on normality. Frequency and percentage were calculated for all the categorical variables. Chi-square or Fischer exact test was applied to see the association of all the categorical variables with ROSC, StD and period of cardiac arrest.A total of 77 patients (57% men) experienced at least one IHCA event during the 1-year study period Approximately 58% of the IHCA events occurred pre-pandemic. Pre-pandemic for both ROSC as well as StD nearly half of our patients recovered. However, ROSC dropped to 25% and StD to 18.8% during the pandemic. Even though not statistically significant, there was an increase in the proportion of 30-39 year old age group experiencing an IHCA for men and women. There were also differences in ROSC between men and women pre-and during pandemic. For men, there was statistically significant reduction in recovery from 54% in pre-pandemic to just 10% during pandemic. However, for women, there was no difference in recovery pre- and during pandemic (43% vs 50%) Within non-shockable rhythm, PEA as a cause decreased from 18% to 6% pre- and during-pandemic, whereas unexpectedly, asystole as initial cardiac rhythm increased from 73% to almost 91% during pandemic. Pre- and during pandemic, there were significant differences in the cause of IHCA for cardiac  and 4H4T  respectively. The proportion of patients with sepsis remained the same (51% vs 41%). Within 4H4T causes, the proportion of hypoxic patients increased from 50% during pre-pandemic to 91% during the pandemic period, whereas hypo/hyperkalemia decreased from 53% to 34% p=0.006, .A few publications have started emerging regarding outcomes of in-hospital cardiac arrest during the COVID-19 pandemic yielding information regarding gender, age, common initial rhythm, survival to discharge, or achievement of ROSC.The number of IHCA episodes that took place pre- and during pandemic at our hospital were comparable. As expected, the proportion of those who survived cardiac arrest reduced during the pandemic. Sandroni et al aptly summarized some reasons for the pandemic affecting the epidemiology of in-hospital cardiac arrest.Our finding was similar to other studies in terms that a larger proportion of men have a cardiac arrest.Most of the in-hospital arrests noted were in COVID ICU possibly due to SARS-COV2 contributing to a greater severity of disease leading to arrests in the COVID unit. Thus making frequency of arrests more common in the ICU setting as opposed to wards when compared to previous studies.1Mean age of patients undergoing IHCA in our study was similar in pre pandemic period, where men were affected than women20As expected, our study also showed that lesser proportion of patients who were on mechanical ventilation achieved ROSC and STD as compared to others who were not on mechanical ventilation.214Hs and 4Ts were a common cause of poor outcomes as expected. The most common etiology of arrest in one such study was respiratory failure.A limitation of our study was the small sample size as well as not having COVID-19 status of those who died in Emergency. However, despite the sample size, we were able to show some differences in pre- and during pandemic epidemiology of IHCA. A limitation is our inability to have a covid-19 status on all the patients and so some explanations were not possible.As expected, fewer people achieved ROSC and StD during the pandemic period in comparison to the pre-pandemic period. The role of age and gender in similar sociodemographic population needs to be further explored and tertiary facilities are encouraged to analyze and compare their IHCA outcomes pre- and during pandemic.FA: Conceived, designed, collected data and prepared the manuscript.NG: Analyzed data and wrote some sections of manuscript.All authors did review, final approval of manuscript an are responsible for integrity of the study.


What factors are associated with adherence to recommended testing after initial lung cancer screening in the Veterans Health Administration?In this retrospective cohort study of 28 294 veterans, more than one-quarter of veterans received delayed or no follow-up testing. Veterans with higher risk findings and those in high-volume or academic centers were more likely to receive timely follow-up, while Black veterans, veterans with mental health disorders, and veterans with lower income were more likely to have delayed or absent follow-up.These findings suggest that even in an integrated health care system, inequities in adherence to lung cancer screening persisted. This cohort study examines adherence to follow-up testing recommendations after lung cancer screening among US veterans. Lung cancer screening (LCS) can reduce lung cancer mortality with close follow-up and adherence to management recommendations. Little is known about factors associated with adherence to LCS in real-world practice, with data limited to case series from selected LCS programs.To analyze adherence to follow-up based on standardized follow-up recommendations in a national cohort and to identify factors associated with delayed or absent follow-up.This retrospective cohort study was conducted in Veterans Health Administration (VHA) facilities across the US. Veterans were screened for lung cancer between 2015 to 2019 with sufficient follow-up time to receive recommended evaluation. Patient- and facility-level logistic regression analyses were performed. Data were analyzed from November 26, 2019, to December 16, 2020.Receipt of the recommended next step after initial LCS according to Lung CT Screening Reporting & Data System (Lung-RADS) category, as captured in VHA or Medicare claims.Of 28 294 veterans  who had an initial LCS examination, 17 863 veterans (63.1%) underwent recommended follow-up within the expected timeframe, whereas 3696 veterans (13.1%) underwent late evaluation, and 4439 veterans (15.7%) had no apparent evaluation. Facility-level differences were associated with 9.2% of the observed variation in rates of late or absent evaluation. In multivariable-adjusted models, Black veterans , veterans with posttraumatic stress disorder , veterans with substance use disorders , veterans with lower income , and those living at a greater distance from a VHA facility  were more likely to experience delayed or no follow-up; veterans with higher risk findings  and those screened in high LCS volume facilities  or academic facilities  were less likely to experience delayed or no follow-up. In sensitivity analyses, varying how stringently adherence was defined, expected evaluation ranged from 14 486 veterans (49.7%) under stringent definitions to 20 578 veterans (78.8%) under liberal definitions.In this cohort study that captured follow-up care from the integrated VHA health care system and Medicare, less than two-thirds of patients received timely recommended follow-up after initial LCS, with higher risk of delayed or absent follow-up among marginalized populations, such as Black individuals, individuals with mental health disorders, and individuals with low income, that have long experienced disparities in lung cancer outcomes. Future work should focus on identifying facilities that promote high adherence and disseminating successful strategies to promote equity in LCS among marginalized populations. Indeed, 95% of NLST participants were adherent with annual screening, and 93% were adherent with recommended evaluation of screen-detected findings. Inability to achieve such high adherence in nontrial settings is likely to reduce the effectiveness of LCS.2Lung cancer remains the leading cause of cancer mortality, with 1.8 million deaths annually worldwide. In the National Lung Screening Trial (NLST), yearly lung cancer screening (LCS) with low-dose computed tomography (CT) achieved a 20% relative reduction in lung cancer mortality.3 there has been limited evidence on follow-up after initial LCS in real-world settings, with selected institutions reporting adherence ranging from 37% to 86%.9 Barriers to adherence exist at the patient level ,12 clinician level ,15 and system level .16Although the US Preventive Services Task Force has recommended LCS for high-risk individuals since 2013,18 Although the Veterans Health Administration (VHA), the largest national integrated health care system in the US, was an early adopter of LCS, subsequent implementation has been inconsistent across VHA facilities.19 Thus, the VHA provides an ideal real-world setting to study adherence after initial LCS across the US. We sought to determine adherence to recommended next steps  in a national cohort of veterans screened for lung cancer and identify factors associated with delayed or absent follow-up.Veterans are at increased risk of lung cancer, given high rates of tobacco use, with a large population of veterans eligible for LCS.STROBE) reporting guideline for cohort studies.This cohort study was approved by the Bedford VA Healthcare System institutional review board. This was an observational study without any direct patient contact and considered to be of minimal risk; therefore, a waiver of informed consent was obtained from the Bedford VA Healthcare System institutional review board. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  generated by VHA’s LCS clinical reminder followed by a chest CT within 3 months or a chest CT used for LCS based on Current Procedural Terminology codes or CDW radiology tables , we used the subsequent LCS examination as the index LCS. Veterans were excluded if they had insufficient follow-up time after index LCS to receive expected evaluation according to Lung-RADS category , we identified veterans who had either a health factor for International Classification of Diseases, Ninth Revision (ICD-9)21 and Tenth Revision (ICD-10)22 and Current Procedural Terminology codes  for evidence of expected follow-up tests, including chest CT, positron emission tomography, or invasive procedures, defined by 26 For each veteran, we extracted data from VHA CDW on demographic characteristics and VHA priority status . We used the veteran’s residential zip code to estimate distance to nearest VHA facility, median income, and urbanization using the US Census Bureau’s rural-urban commuting area codes.27 We defined comorbidities based on ICD-9 and ICD-10 codes in VHA CDW or Medicare files and calculated Elixhauser comorbidity index scores.29 As a measure of health care utilization, the number of VHA outpatient visits in the year prior to index LCS was collected for each veteran. We performed log transformation of covariates that did not follow a normal distribution, including outpatient visits, median income, and distance to VHA facility.We a priori selected clinically relevant covariables based on prior studies of adherence to cancer screenings, including self-reported race/ethnicity.31 We used data from a national VHA survey conducted in 2013 to 2014 to determine whether facilities had capacity to perform thoracic surgery.32We assigned veterans to VHA facilities based on where they received the most outpatient visits in the year prior to index LCS. Facility-level covariates included academic status based on graduate medical education affiliations, US census region, and LCS volume.P = .05 as statistically significant. To address potential issues of multicollinearity, we computed variance inflation factors for each patient-level variable in the model. No variables had variance inflation factors greater than 10, a conventional threshold for collinearity concerns, suggesting that collinearity was not problematic.33 To quantify facility-level variation, we calculated an intraclass correlation coefficient on the model with patient fixed effects and random intercepts that varied by site.34 All analyses were performed using SAS statistical software version 9.4 (SAS Institute). Data were analyzed from November 26, 2019, to December 16, 2020.We conducted mixed-effects logistic regression analyses, including patient- and site-level variables, to determine factors associated with delayed or absent follow-up after index LCS compared with early or expected follow-up. Our models assumed that coefficients to patient-level variables were random effects that varied by site. We report the mean patient outcomes, accounting for site-specific random effects, in our 2-sided analytic testing. We a priori selected 35We performed sensitivity analyses to examine different definitions of adherence and to check the validity of our conclusions about factors associated with adherence to Lung-RADS recommendations. First, to explore the potential for error introduced into the model by creating cutoffs for adherence, we created 2 models with varying periods for expected evaluation, one more stringent than that used by NLST and one more liberal. All models defined early evaluation as follow-up testing occurring greater than 2 months before the recommended timeframe, to maintain consistency . In the 36 Because we were unable to capture care provided through private insurers, we performed a sensitivity analysis restricting our analysis to Medicare-eligible veterans , as veterans with VHA or Medicare coverage may be less likely to obtain screening through the private sector.38 Additionally, because Medicare claims data are only available through 2018, we performed a sensitivity analysis restricting our study period to January 1, 2015, to December, 31, 2018.To explore the outcomes associated with combining low-risk findings (Lung-RADS categories 1 and 2) with higher risk findings (Lung-RADS categories 3 and 4) into our model, which may have different mechanisms of adherence, we conducted a sensitivity analysis stratifying our regression model by low and high-risk findings. To account for potential error introduced by lack of evaluation among veterans with limited life expectancy, who are unlikely to benefit from LCS and may have elected to decline evaluation, we performed a sensitivity analysis excluding veterans with Care Assessment Needs score of 95 or greater. The validated Care Assessment Needs score is calculated in the VHA EHR to identify veterans with increased risk of hospitalization and death, and a score of 95 or greater is 89% specific for frailty and correlates with an approximately 20% risk of death within 1 year.To further explore the ability of our claims-based algorithm to detect recommended evaluation, a pulmonologist (E.R.N.) performed detailed EHR reviews on a randomly selected sample of veterans with low-risk  and intermediate risk  findings who received no apparent evaluation; as well as all veterans with Lung RADS category 4B or 4X findings (42 veterans) with no subsequent follow-up captured through VHA or Medicare claims.Overall, 35 699 veterans had initial LCS examinations with Lung-RADS recommendations; 7405 veterans (20.7%) were excluded owing to insufficient time to determine adherence to follow-up testing  had evidence of subsequent testing after the index LCS, with 2296 veterans (8.1%) receiving early testing, 17 863 veterans (63.1%) receiving testing in the expected timeframe, and 3696 veterans (13.1%) receiving delayed testing . Of noteIn our primary multivariable analysis, veterans with high-risk findings were less likely to have delayed or no evaluation  . Black vVeterans classified as severely disabled who had no copays  and those with partial disability with reduced copays  were less likely to have delayed or absent follow-up compared with veterans with copays to access VHA care. Additionally, veterans who had fewer outpatient visits or lived farther from a VHA facility were more likely to experience delayed or absent evaluation . The logA total of 122 facilities performed at least 1 index LCS examination in the study period. Veterans screened in high-LCS volume  facilities were less likely to have delayed or missing follow-up , as were those screened in academic facilities  . Our mulUsing alternate definitions of adherence resulted in expected follow-up ranging from 14 486 veterans (49.7%) in the stringent model to 20 579 veterans (78.8%) in the liberal model, indicating that rates of adherence can vary substantially depending on how adherence is defined . Other sEHR review of randomly selected veterans with low-risk or intermediate-risk findings with no apparent follow-up (based on claims data) confirmed absence of follow-up in 38 of 40 veterans (95.0%) with Lung-RADS category 1 or 2 findings and 36 of 40 veterans (90.0%) with Lung-RADS category 3 or 4 findings. By contrast, of 42 veterans with Lung-RADS category 4B or 4X findings with no apparent follow-up, 16 veterans (38.1%) were found on EHR review to have received evaluation outside of the VHA that our study did not capture . Of the remaining 26 veterans with 4B or 4X findings, the most common reasons for lack of follow up included patient declined follow-up (7 veterans [16.7%]), several attempts but unable to schedule (10 veterans [23.8%]), and no documented follow-up (8 veterans [19.0%]).1 and NELSON trials39 could in part be attributed to high adherence (>90%) to timely, appropriate follow-up after initial screening. In real-world practice, in addition to documented low uptake of initial LCS (estimated at 4%-14% of the eligible US population42), suboptimal adherence to follow-up evaluations could further erode the potential of LCS to reduce lung cancer death.In this national cohort study of 28 294 veterans who underwent initial LCS, we found suboptimal adherence to Lung-RADS recommendations, with approximately 13% receiving late evaluation and approximately 16% receiving no apparent follow-up. Our study, which captured follow-up testing from VHA and Medicare systems, illustrates the challenges of providing timely, recommended next steps after LCS in real-world practice. The mortality benefit of LCS observed in the NLST46 But we identified substantial variation across facilities, suggesting there is room for further improvement in some facilities. Indeed, veterans screened in academically affiliated or high LCS–volume facilities were less likely to have delayed or no follow-up, suggesting lessons could be learned from these LCS programs. Based on the included variables, our model identified a moderate amount of facility-level variation.47 It is likely that additional facility-level LCS infrastructure that we could not capture may be associated with improved adherence. For example, single institution studies suggest LCS coordinators and tracking systems, which are components recommended by the American Thoracic Society and American College of Chest Physicians, may improve adherence and timeliness of evaluation.48 Yet, even when facilities implement LCS coordinators and tracking software, significant interfacility variation in adherence remains.9 Thus, future work should evaluate LCS programs with high vs low rates of adherence to identify and spread best practices for timely, appropriate follow-up.At the patient level, veterans with higher-risk Lung-RADS categories were significantly more like to receive adherent follow-up care. This is reassuring, given that timely evaluation of high-risk findings is essential to identifying cancers at an early, treatable stage, thereby avoiding disease progression and improving lung cancer outcomes.51 which may be owing to the more uniform access to care typically experienced in integrated health systems. Yet, we found disparities in receiving the recommended next steps after LCS among marginalized populations, such as Black veterans and those with lower income, who were more likely to experience delayed or absent evaluation, reflecting the well-established finding of disparities in cancer care among those from underrepresented ethnic and racial backgrounds or lower socioeconomic status.54 We found that veterans with posttraumatic stress disorder and substance use disorders were more likely to have delayed or no follow-up, likely reflecting mental health barriers identified in other cancer screenings.56 Veterans with fewer VHA outpatient visits in the prior year, higher copays, and longer distances to travel to access VHA care were more likely to have delayed or absent follow-up after initial LCS. Prior studies illustrate the importance of health care utilization, insurance, and access to care as critical to ensuring appropriate cancer screening and reducing cancer mortality.61 Unfortunately, LCS access is not evenly distributed across the VHA system.62 Therefore, it is imperative for the VHA to continue to allocate resources to improve LCS access and adherence to reduce lung cancer mortality in high-risk veteran populations, with particular attention to marginalized groups, such as Black veterans, those with mental health conditions, and those with socioeconomic barriers to receiving appropriate and timely care.Disparities in cancer screening and lung cancer outcomes are typically decreased in VHA and military settings compared with the private sector,68 Thus the 63% rate of expected evaluation identified in this study may exceed that anticipated in other settings. Additionally, we were unable to measure patient-centered outcomes, such as lung cancer diagnoses and mortality, and instead focus on adherence to screening, which has been shown to be a key factor in lung cancer mortality.2This study has some limitations. First, we relied on administrative data, which can result in misclassified or missed data if there are errors in coding of LCS examinations or follow-up tests. We were unable to capture care received outside of VHA or Medicare, which may have resulted in an underestimate of adherence if substantial care was received through private insurers. However, our sensitivity analysis excluding veterans younger than 65 years who are more likely to be dual users of VHA and private insurance showed only minor differences in follow-up evaluation. Moreover, our EHR review of randomly selected veterans with Lung-RADS categories 1 through 4A findings, who constituted 97% of our cohort, showed our algorithm missed follow-up testing in less than 10% of veterans. Of note, our results may not be generalizable outside the VHA or among nonveteran populations. In particular, the VHA’s national integrated health care system has well-established processes to facilitate guideline-recommended, multidisciplinary cancer care and pulmonary nodule evaluation, and achieves equivalent or better quality of cancer care and survival than the private sector.To our knowledge, this cohort study represents the first national analysis of adherence to Lung-RADS recommendations among a large cohort with diverse geographic distribution and socioeconomic status. We found that even in an integrated health care system, many patients did not receive timely recommended follow-up after initial LCS. While it is encouraging that veterans with the highest risk findings were more likely to receive recommended follow-up care, disparities in timely follow-up were demonstrated among marginalized populations who have long experienced worse lung cancer outcomes, such as Black veterans and those with low income. To optimize the mortality benefit of LCS, it is clear that further work must be done to improve adherence overall and especially among marginalized populations. Future work should focus on learning effective strategies from LCS centers with high adherence to extend successful program features to the people and locations with greater barriers to care.


BRAF mutation status. Three treatment eras were defined based on drug access: prior to August 2013, August 2013 to November 2016, and November 2016 to July 2020. Across each era, there were improvements in median OS: 11.7 months, 15.9 months, and 33.6 months, respectively. Patients with BRAF mutant melanoma had improved median OS when they were treated with immunotherapy in the first line as opposed to targeted therapy (median OS not reached for immunotherapy versus 17.4 months with targeted treatment). Patients with BRAF wild-type melanomas had improved survival with ipilimumab and nivolumab versus those treated with a single-agent PD-1 inhibitor (median OS not reached and 21.2 months). Our real-world analysis confirms significant survival improvements with each subsequent introduction of novel therapies for advanced melanoma.Immune checkpoint and MAP kinase pathway inhibitors can significantly improve long-term survival for patients with melanoma. There is limited real-world data of these regimens’ effectiveness. We retrospectively analyzed 402 patients with unresectable and metastatic melanoma between August 2013 and July 2020 treated with immune checkpoint inhibitors and MAP kinase pathway targeted therapy in Alberta, Canada. Overall survival (OS) was compared using Kaplan–Meier and Cox regression analyses. Subgroup survival outcomes were analyzed by first-line treatment regime and  BRAF V600 mutation, occurring in around 40% of melanomas [The treatment landscape for melanoma has changed dramatically over the last decade, with major advances in both immune checkpoint inhibitors (ICIs) and targeted treatments. First, two classes of ICIs have demonstrated improvements in overall survival (OS): cytotoxic T lymphocyte antigen CTLA-4) and programmed cell death protein PD-1) inhibitors. They work as single agents and in combination by enhancing the ability of T-cells to mount an anti-cancer immune response  inhibito,3. Secon and progSignificant advancements in treatment of advanced melanoma started in 2010, when Ipilimumab, a CTLA-4 inhibitor, demonstrated an improvement in survival . By 2015BRAF V600 mutations. As single agents the BRAF inhibitors, vemurafenib in 2011 and Dabrafenib in 2012, demonstrated improved survival compared to chemotherapy [During the same period as the development of the ICIs, targeted agents were also examined in patients with advanced melanoma harboring otherapy ,15. By 2otherapy ,16. Longotherapy . AlthougBRAF mutant melanoma patients also have the option of combination BRAF and MEK inhibitors. Considering the results of these trials, we aimed to corroborate the survival benefits seen with these novel treatments in a real world setting by retrospectively examining melanoma patients treated in the Canadian province of Alberta from 2007 to 2020. Given there has never been a published inter-class comparison between these therapies, we also compared outcomes of immunotherapy and targeted BRAF/MEK inhibitors and investigated the difference in survival based on which treatment was received first-line.The advances in melanoma treatment allows patients to receive single agent PD-1 inhibitors or combination Ipilimumab and nivolumab. BRAF mutation status, treatments received and survival outcomes. Ethics approval was obtained from the Alberta Cancer Research Ethics Board prior to data collection for this study.Four hundred and two adult patients with advanced melanoma diagnosed with unresectable Stage III and Stage IV melanoma from 2007 to 2020 were identified from the Alberta Cancer Registry. Demographics were obtained from electronic medical records, including Eastern Cooperative Oncology Group (ECOG) performance status, Outcomes based on era of treatment: We divided the population based on treatment era, defined as when certain drugs became available in Alberta, Canada. Prior to August 2013 the only treatments available for advanced melanoma patients were dacarbazine, ipilimumab, and single agent vemurafenib. Combination dabrafenib and trametinib became available in August 2013, pembrolizumab became available in May of 2014, nivolumab became available in July 2015, and combination ipilimumab and nivolumab became available in November of 2016. All these dates are based on compassionate access programs and clinical trial participation. These programs and clinical trials continued until the drugs were approved for provincial funding and administration.Based on dates of drug availability, we defined three eras for the total population: prior to August 2013, August 2013–November 2016, and after November 2016. We assessed overall survival outcomes based on these eras and compared it to a cohort who never received treatment.BRAF mutation positive and negative cohorts, we also examined distinct eras based on when treatments became available  to after dabrafenib and trametinib (after August 2013) and to those who never received treatment. A similar analysis was performed for advanced BRAF wild-type and unknown BRAF status melanoma patients. We defined these eras as prior to access to PD-1 inhibitors (prior to May 2014), access to single agent PD-1 inhibitors (May 2014–November 2016), and access to the combination ipilimumab and nivolumab (after November 2016). This was compared to BRAF wild-type melanoma patients who never received treatment.For the BRAF mutant and BRAF wild type. For BRAF mutation patients, we only included patients who received treatment after August 2013 when dabrafenib and trametinib were accessible. As for patients with BRAF wild-type or unknown melanomas, we compared those patients that received single agent PD-1 inhibitor versus combination ipilimumab and nivolumab.Outcomes based on first treatment received: We analyzed if there was any difference in survival outcomes dependent on first line treatment received by patients that were p ≤ 0.05 level, and all tests were two-sided.OS was estimated by using the Kaplan–Meier (KM) method with 95% CI . Analyses were conducted using SAS 9.4 . Statistical significance was defined as BRAF mutations were found in 100 patients (24.9%), 137 (34.1%) had unknown BRAF status, and 165 (41%) were BRAF wild type. Previously described poor prognostic factors such as ECOG ≥ 2, elevated LDH at baseline and Stage 4 disease, are described in For this retrospective cohort study, we identified a total of 402 patients with unresectable Stage III or Stage IV melanoma treated in the province of Alberta, Canada. The mean age for all patients was 63 years and the majority were male . Most patients had an ECOG performance status of 0–1 (63.4%) and 36.6% had a score of ≥2. Most patients had been diagnosed with Stage IV disease (80.1%) and 80 patients (19.9%) with unresectable Stage III disease. BRAF mutant melanoma, and for patients with BRAF wild-type or unknown melanoma. In the total population, from prior to 2013, August 2013–November 2016, and November 2016–July 2020, there were stepwise improvements in median OS, 11.7, 15.9, and 33.6 months respectively  (In the patients with ctively) b.Over the last decade, there have been multiple practice changing clinical trials for patients with advanced melanoma. It is important to corroborate these clinical trial results with real-world data as patients are not necessarily reflected in the strict eligibility and exclusion criteria of clinical trials. As a result, the magnitude of benefit observed in a clinical trial may not be observed in a real-world setting. Moreover, because targeted and ICIs were developed independently at the same time, there is no study comparing which treatment is superior, nor evidence identifying the optimal sequence of these treatments. Analyzing real world data may help to answer some of these questions.This study corroborates the improvement in survival observed when each successive treatment became available in Alberta, Canada. With the introduction of each treatment, there were corresponding incremental improvements in median overall survival. For the total population, the best median OS was 33.6 months, and occurred between November 2016 to July 2020. This era marks the period during which the full current complement of treatments became available. At this time, the combination ipilimumab and nivolumab, dabrafenib and trametinib, and the single agent PD-1 inhibitors pembrolizumab and nivolumab were all available and funded.In the registration trials for these treatment options, the best survival is reported in the CHECKmate-067 study, which showed a 5-year OS of 52% with first line ipilimumab and nivolumab treatment in advanced melanoma patients . The infBRAF wild-type and unknown population, improvements in survival were observed with the introduction of ipilimumab, single agent PD-1 inhibitors, and combination ipilimumab and nivolumab. In the era when combination ipilimumab and nivolumab became available (after November 2016), the median survival was 37.0 months, almost identical to the median survival observed in the BRAF wild-type population of the CHECKmate-067 study. For the BRAF mutant population, there was an improvement in survival in the era after combined dabrafenib and trametinib became available compared to the era of when only single agent BRAF inhibitors were available (28.1 months and 13.7 months). Interestingly, our BRAF mutant cohort OS of 28.1 months is remarkably close to the median survival of 25.9 months in the COMBI-V study which demonstrated a superior OS with dabrafenib and trametinib versus single agent vemurafenib [BRAF mutant along with the BRAF wild-type and unknown populations when they are independently analyzed.For the BRAF mutant melanoma patients. In this real-world analysis, our data suggest that upfront immunotherapy with single agent PD-1 inhibitors or combination ipilimumab and nivolumab had better survival outcomes as compared to upfront dabrafenib and trametinib. One potential confounder for patients treated with immunotherapy having better outcomes is that single agent PD-1 inhibitors and combination immunotherapy did not become available until May 2014 and after November 2016, while combination dabrafenib and trametinib became available in 2013. It is possible, that the patients with BRAF mutant melanoma, treated with targeted therapy had worse outcomes because there was no access to PD-1 inhibitors or combination immunotherapy after progression, however, pembrolizumab was available within nine months of dabrafenib and trametinib access. Another possibility is that due to the rapid responses with targeted treatment, patients with poorer prognostic factors  were preferentially started on targeted treatment. Lastly, upfront immunotherapy may indeed be superior to targeted agents in the first line setting and another real-world analysis has demonstrated similar trends in this scenario [There is currently no clinical trial data to determine what is the optimal sequence for treating advanced scenario .BRAF mutant patients (60%) as compared to the BRAF wild-type patients (48%). The three-year survival with single agent nivolumab in the BRAF mutant group (46%) only modestly outperformed the wild-type group (43%). In our real-world analysis, first-line ipilimumab and nivolumab combined had a three-year survival of 71% and 79%, for the BRAF mutant and wild-type groups, respectively. Similarly, single agent PD-1 inhibitor in the first-line setting had a three-year survival of 71% compared to 48% for the BRAF mutant and wild-type groups. Possible reasons for these discrepancies are the retrospective nature of this analysis and the small sample size of each of the cohorts. These findings highlight that further research into predictive factors for combination immunotherapy versus single agent PD-1 inhibitor is required. This is especially important given the increased toxicity observed with ipilimumab and nivolumab versus single agent PD-1 inhibitor treatment. The SECOMBIT trial (NCT02631447) is evaluating the optimal sequencing of treatment in advanced BRAF mutant melanoma patients by randomizing patients 1:1:1 to first-line targeted BRAF and MEK inhibitors followed by ipilimumab and nivolumab at progression; upfront ipilimumab and nivolumab followed by targeted treatment at progression; or an initial run-in period of targeted treatment for eight weeks, followed by ipilimumab and nivolumab until progressive disease, then a switch back to targeted treatment [Our real world-data shows some discrepancies compared the CHECKmate-067 study, where the 3-year survival with ipilimumab and nivolumab was highest in the reatment ,20. HopeBRAF mutation positive melanoma. Lastly, there was a larger magnitude of benefit with combination immunotherapy as compared to single agent PD-1 inhibitor in the BRAF wild-type as opposed to the BRAF mutant groups, highlighting the need for more predictive tools to guide our use of combination versus single agent ICIs. Although this data suggest that first-line combination immunotherapy is the treatment of choice in the BRAF wildtype and mutant populations, a personalized approach is always warranted taking into account a variety of factors, such as the patient’s age, burden and pace of disease, comorbidities, and performance status.Finally, our real-world analysis confirmed significant survival improvements with the introduction of novel therapies for advanced and metastatic melanoma over the last decade. The best treatment era over the last decade corresponds to when combined ipilimumab and nivolumab became available. This era also represents the current standard of care options in the province of Alberta, in which patients can access ipilimumab and nivolumab combination or single agent PD-1 inhibitor and targeted treatment with dabrafenib and trametinib. This real-world analysis also demonstrated that first-line immunotherapy produced better survival outcomes compared to upfront targeted treatment in patients with


The rate of 1-year mortality  was significantly higher in patients with RV dysfunction compared with patients without. After propensity score matching, patients with RV dysfunction showed a worse long-term survival . The multivariable Cox regression model showed an independent association of RV dysfunction with 1-year mortality. RV dysfunction is a relatively common finding in hospitalized COVID-19 patients, and it is independently associated with an increased risk of 1-year mortality.The characteristics and clinical course of hospitalized patients with coronavirus disease 2019 (COVID-19) have been widely described, while long-term data are still poor. The aim of this study was to evaluate the long-term clinical outcome and its association with right ventricular (RV) dysfunction in hospitalized patients with COVID-19. This was a prospective multicenter study of consecutive COVID-19 patients hospitalized at seven Italian Hospitals from 28 February to 20 April 2020. The study population was divided into two groups according to echocardiographic evidence of RV dysfunction. The primary study outcome was 1-year mortality. The propensity score matching was performed to balance for potential baseline confounders. The study population consisted of 224 patients ; RV dysfunction was diagnosed in 63 cases (28%). Patients with RV dysfunction were older (75 vs. 67 years,  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic human coronavirus recognized as the cause of the coronavirus disease 2019 (COVID-19). The outbreak sparked in Wuhan, capital city of Hubei province in China, and spread rapidly to other countries, reaching devastating pandemic proportion . Among cThe aim of this multicenter study was to evaluate the long-term clinical outcome and to assess the association between RV dysfunction and one-year mortality in a multicenter, registry-based cohort of hospitalized patients with COVID-19.This was a multicenter prospective observational study including patients with confirmed diagnosis of COVID-19 admitted at 7 hospitals throughout the Italian Country  from 28 February to 20 April 2020. COVID-19 diagnosis was initially based on the World Health Organization criteria, and all cases were confirmed by real-time reverse transcriptase-polymerase chain reaction analysis of throat swab specimens .All patients included in this study were evaluated by the hospital cardiology service and underwent transthoracic echocardiography (TTE) within 48 h from admission. To minimize the exposure to COVID-19, each referral for TTE was confirmed as appropriate by one consultant cardiologist ,18. EchoThe baseline demographic, clinical, laboratory, and TTE data were collected and recorded on an electronic datasheet. In all patients, demographic , clinical , laboratory , and echocardiographic data were collected.Information on patient clinical course (admission in intensive care unit and respiratory support measures) and in-hospital complications were systematically recorded. Acute respiratory distress syndrome (ARDS) diagnosis was defined according to the Berlin definition . Acute mTTE was performed in accordance with the current guidelines ,22. EchoAll recovered patients had scheduled telephonic follow-up at 6 and 12 months from discharge. All other possible information gathered from hospital readmission charts or by referring physicians, relatives, or municipality vital registries, were prospectively entered into an electronical database.The primary endpoint of this study was to evaluate the association between the RV dysfunction and 1-year mortality.t-test; differences between non-normally distributed variables were tested with the Mann-Whitney U test. Categorical variables were compared with chi-squared test, or Fisher exact test, when appropriate. Survival curves were generated by using the Kaplan–Meier method, and differences among groups were investigated with the Log-Rank test.Distribution of continuous data was assessed with the Kolmogorov–Smirnov test. Normally distributed variables were expressed as mean ± standard deviation, whereas non-normal distributed ones were expressed as median and interquartile range. Categorical variables were reported as numbers and percentages. Continuous normally distributed variables were compared by using Student’s Due to differences in baseline characteristics between patients with vs. those without RV dysfunction, a propensity score-matched analysis (1:1) was conducted to obtain a covariate-balanced control group. Covariates included in the model were those that were significantly different between the two study groups . We performed nearest neighborhood matching with Mahalanobis distance . Bias reduction was assessed by comparing the standardized difference for propensity score and the other covariates before and after matching between the two groups .The risk of 1-year mortality in patients with vs. those without RV dysfunction was calculated using the Cox proportional hazard regression model and presented as unadjusted and adjusted hazard ratios (HR) with 95% confidence intervals.The proportional hazards assumption was assessed and satisfied graphically by plotting log (−log) survival curves against log survival time for each predictor category and verifying whether curves were parallel.p < 0.10 by the univariate test as a candidate for the multivariate analysis. The risk of overfitting was controlled by using a ratio of at least 1:10 for the number of explanatory variables and sample size. Model discrimination was assessed with the C statistic and goodness of fit with the Hosmer–Lemeshow test. Multicollinearity was assessed using collinearity diagnostics; the variance inflation factors showed no significant collinearity (<2.5) among the covariates.To account for potential confounders related to patients’ baseline clinical profile and the severity of in-hospital course, we performed a multivariable analysis. We used a parsimonious model including variables with p-value < 0.05 was considered significant. All tests were two-sided. Analyses were performed with SPSS statistical package, Version 21  and R version 3.5.1 .A p < 0.001), had higher prevalence of coronary artery disease , heart failure , chronic obstructive pulmonary disease , and chronic kidney disease . No differences in terms of COVID-19 in-hospital medications were reported.During the study period, 224 consecutive COVID-19 patients were enrolled and divided into two groups according to the TTE evidence of RV dysfunction. Normal RV function was detected in 161 (72%) patients and RV dysfunction was detected in 63 (28%) patients. The baseline demographic and clinical features of the two study groups and of the propensity-matched cohort are summarized in p < 0.001), while no statistical differences regarding the LVESV and LVEDV were observed (p < 0.001).Left ventricular ejection fraction (LVEF) was lower in patients with RV dysfunction (55% (53–60) vs. 50% (43–55); observed b. Of couOnly one patient was lost at follow-up (follow-up completion > 99%). The proportions of adverse events during the hospitalization are summarized in The mortality cumulative incidence was significantly higher in patients with RV dysfunction at different follow-up times as compared to patients with normal RV function . Kaplan–Meier curves confirmed the significantly lower survival free from overall mortality in patients with vs. those without RV dysfunction .After propensity score matching (1:1), 63 couples of patients with balanced baseline characteristics were found. The main baseline, clinical, and echocardiographic characteristics of the matched population are summarized in p < 0.001; p = 0.672 for Hosmer–Lemeshow test).At univariable Cox regression analysis, age, male gender, hypertension, CAD, chronic heart failure, LVEF, TAPSE, ARDS, and pulmonary embolism were associated with 1-year mortality. At the multivariable analysis, RV dysfunction, along with LVEF and ARDS, emerged as an independent predictor of 1-year mortality  and remaThe long-term clinical outcome of hospitalized COVID-19 enrolled in this multicenter registry-based population was substantially unfavorable;RV dysfunction is a common TTE finding in COVID-19 hospitalized patients;TAPSE, as an easy-to-measure echocardiographic parameter of RV systolic function, was associated to higher incidence of long-term mortality, independently from age, comorbidities, and LVEF.The main findings of this real-world multicenter study can be summarized as follows:Data on the long-term outcome of patients infected by SARS-CoV-2 are still poor. However, the potential long-term cardiovascular sequelae are emerging as a global health problem . BetweenThis multicenter registry-based study, although with a relatively limited sample size, provides timely information regarding long-term clinical outcome in COVID-19 patients. Our cohort of patients showed poor prognosis with a 1-year mortality rate of almost 40%, although it was partially driven by the high median age and the several comorbidities.In this study, the prevalence of RV dysfunction is almost one-third of the entire population, confirming previous evidence; García-Cruz et al. and Mahmoud-Elsayed et al. reported RV in about 27% of COVID-19 patients . The higRV dysfunction could also affect the LV loading and LVEF by ventricular interdependence. The resulting reduction of the cardiac output, which impairs the blood supply to vital organs, can further aggravate the critical condition of the patient by exposing the overloaded RV to ischemia . In COVIAlthough in-hospital mortality is described as probable in patients with RV dysfunction at presentation, the novelty of our study is that these patients had a poor prognosis also up to 1 year.Myocardial function and architecture have been extensively assessed using speckle tracking echocardiography and cardiac magnetic resonance; regardless of apparent normalization, the persistence of subtle ventricular systolic and diastolic abnormalities along with the development of microscopic fibrosis after myocardial oedema resolution has been demonstrated . PuntmanIn the present analysis, patients with normal RV function had fewer comorbidities and lower D-dimer, troponin, and Pro-BNP serum levels compared with patients with RV systolic dysfunction. After matching, although Pro-BNP and D-dimer serum levels were balanced between groups, patients with RV dysfunction showed a higher risk of pulmonary embolism. D-dimer is usually abnormal in COVID-19, and it has a lower discriminative ability for this life-threatening complication than in the general population . In thisFirst, RV dysfunction is highly probable in patients hospitalized with COVID-19 that should be considered as a life-threatening factor. Second, due to the high risk of mortality in the long term, COVID-19 patients complicated by RV dysfunction should be closely monitored after hospital discharge; whenever possible, they should be included in dedicated cardiovascular follow-up programs, particularly focused on RV assessment, that may be acknowledged as the cardiac chamber most affected in COVID-19 .Our study is limited by the prospective design and the relatively small simple size. Second, the registry included only hospitalized COVID-19 patients; therefore, the results could not be generalized to the overall SARS-CoV-2 infected population, which is often characterized by an asymptomatic or poorly symptomatic forms. Third, we did not include indexes of diastolic dysfunction as well as other measures of global right ventricular function , parameters from speckle tracking, or other advanced echocardiographic techniques. Indeed, the context of pandemic and the risk of infection for the operators limit the number of echocardiographic parameters routinely obtained in the enrolled patients and oriented to a clinical approach based on a limited standardized dataset quickly collected at bedside. Fourth, the pandemic and the urgent setting did not permit the assessment of inter- and intra-observer variability in echocardiographic measurements. Fifth, owing to the absence of TTE data before hospitalization and beyond 48 h after the admission, we cannot exclude the influence of pre-existent and/or late onset of LV and/or RV impairment. However, our aim was not to investigate the prognostic role of new-onset TTE abnormalities but to explore the association between echocardiographic findings at admission and long-term course in patients with COVID-19.Data from our multicenter Italian registry demonstrated that RV dysfunction is a relatively common finding in hospitalized patients with COVID-19, and it is independently associated with an increased risk of 1-year mortality. Data from larger studies are warranted to confirm our preliminary findings.


Noninvasive respiratory support (NIRS) has been diffusely employed outside the intensive care unit (ICU) to face the high request of ventilatory support due to the massive influx of patients with acute respiratory failure (ARF) caused by coronavirus-19 disease (COVID-19). We sought to summarize the evidence on clinically relevant outcomes in COVID-19 patients supported by NIV outside the ICU.We searched PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials register, along with medRxiv and bioRxiv repositories for pre-prints, for observational studies and randomized controlled trials, from inception to the end of February 2021. Two authors independently selected the investigations according to the following criteria: (1) observational study or randomized clinical trials enrolling ≥ 50 hospitalized patients undergoing NIRS outside the ICU, (2) laboratory-confirmed COVID-19, and (3) at least the intra-hospital mortality reported. Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines were followed. Data extraction was independently performed by two authors to assess: investigation features, demographics and clinical characteristics, treatments employed, NIRS regulations, and clinical outcomes. Methodological index for nonrandomized studies tool was applied to determine the quality of the enrolled studies. The primary outcome was to assess the overall intra-hospital mortality of patients under NIRS outside the ICU. The secondary outcomes included the proportions intra-hospital mortalities of patients who underwent invasive mechanical ventilation following NIRS failure and of those with ‘do-not-intubate’ (DNI) orders.Seventeen investigations (14 peer-reviewed and 3 pre-prints) were included with a low risk of bias and a high heterogeneity, for a total of 3377 patients. The overall intra-hospital mortality of patients receiving NIRS outside the ICU was 36% [30–41%]. 26% [21–30%] of the patients failed NIRS and required intubation, with an intra-hospital mortality rising to 45% [36–54%]. 23% [15–32%] of the patients received DNI orders with an intra-hospital mortality of 72% [65–78%]. Oxygenation on admission was the main source of between-study heterogeneity.During COVID-19 outbreak, delivering NIRS outside the ICU revealed as a feasible strategy to cope with the massive demand of ventilatory assistance.https://www.crd.york.ac.uk/prospero/, CRD42020224788, December 11, 2020.PROSPERO, The online version contains supplementary material available at 10.1186/s13054-021-03697-0. The rapid and massive spread of severe acute respiratory syndrome related to novel coronavirus (SARS-CoV-2) outbreak has put in crisis the healthcare systems of whole nations. Worldwide, the surge capacities of the hospitals have been severely stressed by the massive influx of patients admitted for acute respiratory failure (ARF) caused by coronavirus-19 disease (COVID-19) . Among CMoreover, at the very beginning of the pandemic, the rate of patients receiving noninvasive respiratory support (NIRS) upon ICU admission was reported to range from 11   guidelines  and was We sought information about the application of NIRS—i.e., continuous positive airway pressure (CPAP) or noninvasive bi-level ventilation—outside the ICU (I) in adult patients admitted for hypoxemic ARF COVID-19 related (P) with or without comparator (C) and aimed to ascertain the intra-hospital mortality (O). For overall intra-hospital mortality we intended the punctual intra-hospital mortality reported by each enrolled study at database closure.We searched PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials register from inception to February 2021 for observational studies and randomized controlled trials without language restrictions. The search was performed using the following terms, combined according to database syntax  independently evaluated titles and abstracts obtained from the search to select investigations responding to the following inclusion requests: (1) observational study or randomized clinical trials enrolling ≥ 50 symptomatic hospitalized patients undergoing NIRS outside the ICU, (2) laboratory-confirmed COVID-19 defined by a positive result on a reverse-transcriptase-polymerase chain reaction assay of a nasopharyngeal and oropharyngeal swab or a sputum specimen, and (3) at least the primary outcome reported by the study. Case reports and case series with less than 50 patients were excluded, as they may observe no events due to the small size . When muData extraction was independently performed by two authors (GC and TE) who screened and selected the included studies extracted. Any disagreement was resolved by discussion or involving a third review author (EDR). Extracted data included: investigation features , demographic characteristics , presence of comorbidities , characteristics at hospital admission , treatments, NIRS regulations, and clinical outcomes.The methodological quality of selected articles was assessed by an index that classifies nonrandomized studies as adequate, inadequate, or unclear .The analysis was carried out on the data extracted from peer-reviewed manuscripts in combination with data obtained from pre-print investigations.2 tests both, which were considered significant when the p-value was < 0.05 and I2 > 75%  of the cases . As depicted in Fig. p < 0.0001, I2 = 82.0%; nonintubation, p < 0.0001, I2 = 92.0%). In the subset of NIRS patients with DNI orders , while in those under NIRS deserving ‘full treatment’ .The summary estimate of nonintubated patients is depicted in Fig.  of 23% 1–32% of t of 23% 1–32% of tIn Additional file In the present systematic review and meta-analysis patients admitted for COVID-19 and requiring NIRS outside the ICU were characterized by an overall intra-hospital mortality of 36%.During COVID-19 outbreak, NIRS was demonstrated to be feasible both in- and outside ICU, in a percentage of patients ranging between 11 and 62% , 36. DesIn our population pooled intubation rate was of 26%. This finding kept with IMV onset reported in severe acute respiratory syndrome , but wasThe rate of DNI order application has increased over time in the last two decades, reaching 32% in patients admitted for ARF undergoing NIRS or high flow oxygen therapy , in nonp2/FiO2 on admission was the main factor sustaining the between-study heterogeneities of the investigated outcomes. These data suggest that, in our context, there was most likely a great variability in the modalities of proceeding toward intubation or continuing NIRS. In this regard, other factors, such as the availability of resources and the strategy of their allocation, might have adversely influenced the process of care [Among the variables investigated, PaO of care , 45.As a clinical implication, our findings, in agreement with previous suggestions , supportThe present investigation has several limitations requiring to be discussed. The enrolled studies were mainly retrospective investigations conducted during the first wave of COVID-19 pandemic from the end of February to the end of May 2020. Accordingly, it is worth to take into account the critical issues of the specific historical moment, characterized by the crisis of the hospital surge capacity response and the lack of a well-defined therapeutic approach. We could not provide insights on the modalities of NIRS application, conduction, and monitoring in the different settings explored because of the paucity of data retrieved. The leading part of the included studies was carried out in Italy. Thus, our conclusions cannot be generalized to other countries with different policies, practices, medical ethics, social attitudes, cultures, and religions –51. We cThis systematic review and meta-analysis summarized the evidence reported from the first wave of COVID-19 outbreak on the incidence of overall intra-hospital mortality in hospitalized patients undergoing NIRS outside the ICU. Despite the concerns arising from the crisis of hospital surge capacity response and the lack of a clinically effective therapy, delivering NIRS outside the ICU revealed overall as a feasible strategy to cope with the massive demand of ventilatory assistance even for those patients with care limitations. Our findings require to be confirmed in future investigations addressing the same topic over the following waves of COVID-19 outbreak.Additional file 1. Search strategy of electronic database.Additional file 2. Enrollment flow diagram.Additional file 3. Characteristics of the enrolled investigations, overall clinical characteristics of the populations investigated in the enrolled studies, and list of studies excluded after reading the full text.Additional file 4. Methodological quality of the included investigations.


Objective: To investigate the pharmacokinetics, pharmacodynamics, and exposure–response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG).Methods: The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study . One- and two-compartment population-pharmacokinetic models were evaluated, and the impact of covariates on pharmacokinetic parameters was assessed. Relationships between eculizumab exposure and free C5 concentration, in vitro hemolytic activity, clinical response, and tolerability were characterized.Results: Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained throughout the 26-week treatment period. The eculizumab pharmacokinetic data were well-described by a two-compartment model with first-order elimination, including effects of body weight on pharmacokinetic parameters and plasma-exchange events on clearance. Complete inhibition of terminal complement was achieved in nearly all patients at the time of trough and peak eculizumab concentrations at all post-dose timepoints assessed . Serum eculizumab concentrations of ≥116 μg/ml achieved free C5 concentrations of < 0.5 μg/ml. Clinical efficacy and tolerability were consistent across the eculizumab exposure range.Conclusions: Rigorous, quantitative, model-based exposure–response analysis of serum eculizumab concentration and response data demonstrated that the approved eculizumab dosing  for adults with anti-AChR antibody-positive refractory gMG rapidly achieved complete inhibition of terminal complement activation and provided sustained clinical efficacy across the eculizumab exposure range. Eculizumab is the first complement-targeting drug approved for the treatment of complement-mediated neurological autoimmune diseases, such as myasthenia gravis (MG) and neuromyelitis optica spectrum disorder (NMOSD). It binds specifically and with high affinity to human terminal complement component C5, inhibiting its cleavage to C5a and C5b during complement activation . StrategComplement activation is a major cause of disease pathogenesis in patients with generalized MG (gMG) , 4—a chrThe viability of this approach has been demonstrated by studies providing evidence that eculizumab improves clinical outcomes in adult patients with anti-AChR antibody-positive refractory gMG and is well-tolerated –12, whicThe present analysis of data from the REGAIN study was undertaken to further explore the pharmacokinetic/pharmacodynamic profile of the approved eculizumab dosing regimen in gMG. A model-based approach was used to characterize dose–concentration and concentration–free C5 and terminal complement activity relationships for eculizumab in patients with anti-AChR antibody-positive refractory gMG, and to identify patient-related factors that might influence these relationships. The relationships between eculizumab exposure and (i) clinical effect, (ii) adverse events (AEs), and (iii) the potential development of anti-drug antibodies (ADAs) were investigated.ClinicalTrials.gov identifier: NCT01997229) of eculizumab in patients with anti-AChR antibody-positive refractory gMG. Refractory gMG was defined as two or more immunosuppressive therapies (including corticosteroids), or at least one immunosuppressive therapy with intravenous immunoglobulin or plasma exchange given at least four times per year, for 12 months without symptom control.This analysis was based on pharmacokinetic, pharmacodynamic, efficacy, and safety data from the randomized, double-blind, placebo-controlled, multicenter, Phase 3 REGAIN study  for the first four doses (starting on Day 1), followed by 1,200 mg 1 week later at Week 4 (the fifth dose) and then every 2 weeks (14 ± 2 days) thereafter. The remaining 63 patients received placebo.in vitro hemolytic activity , and serum free C5 concentrations were taken 5–90 min before infusion of eculizumab at baseline and at Weeks 1, 4, 8, 12, 20, and 26. ADA titers were measured in the blood samples taken at baseline and at Weeks 4, 12, and 26. Blood samples for measurement of peak eculizumab concentrations, in vitro hemolytic activity, and serum free C5 concentrations were taken at least 60 min after the eculizumab infusion was completed at the first dose and Weeks 1, 4, 8, 12, 20, and 26.Each intravenous eculizumab dose was administered over ~35 min. Blood samples for measurement of baseline and trough eculizumab concentrations, Total (bound plus free) serum concentrations of eculizumab were measured by a validated enzyme-linked immunosorbent assay with a quantification range of 9.38–600 μg/ml.Anti-AChR antibody titers were determined by serological test in blood samples taken at screening and before eculizumab infusion at Weeks 12 and 26.Concentrations of free C5 in serum (as a measure of target engagement) were measured by a validated ligand-binding assay using eculizumab for capturing free C5 and chemiluminescent detection . The assay has a quantification range of 0.0274–20 μg/ml of C5. Serum free C5 <0.5 μg/mL represents complete inhibition of terminal complement .in vitro by lysis of chicken red blood cells (cRBCs) using a validated semi-quantitative assay. cRBCs were sensitized with an anti-cRBC polyclonal antibody, incubated with serum, centrifuged, and the supernatant measured for hemoglobin released from cell lysis by absorbance (415 nm). Percent hemolysis was expressed relative to pooled normal human serum, as proof of the pharmacology of eculizumab. cRBC hemolysis <20% represents complete terminal complement inhibition .Complement-mediated hemolytic activity in patient serum was measured via a ligand-binding assay for inhibition of C5 binding with electrochemiluminescent detection (MSD platform).To describe the presence or absence of an immune response to eculizumab, serum concentrations of ADAs against eculizumab were measured using a solution-phase bridging assay with electrochemiluminescent detection (MSD platform). The method used a tiered approach, with screening (sensitivity 6.26 ng/ml) and confirmatory competition steps to identify samples as positive or negative for the presence of ADAs to eculizumab. If ADAs to eculizumab were detected, the positive ADA samples were analyzed further for titer, and for the presence of neutralizing antibodies (NAbs) 1), intercompartmental clearance (Q), and volume of distribution in the peripheral compartment (V2) were allometrically scaled by body weight as part of the structural model development.One-compartment and two-compartment structural models were evaluated during model development. Body weight is known to be a predictive factor in the pharmacokinetics of therapeutic monoclonal antibodies. Therefore, the pharmacokinetic parameters clearance (CL), volume of distribution in the central compartment  during the study were permitted to receive rescue therapy, including plasmapheresis/plasma exchange (PLEX). To account for the increased clearance of eculizumab during PLEX, an effect of PLEX on CL was also included as part of the structural model development, rather than during the covariate search process.As a starting point for the analysis, between-subject variability terms were described by an exponential equation. An attempt was made to define a full covariance matrix for the between-subject random effects when possible. Additive, exponential, and combined additive and exponential residual-error models were evaluated and the best residual-error model was selected based on minimum objective function value (OFV) and visual inspection of the plots of residuals vs. population predictions of eculizumab concentration.p < 0.01 for 1 degree of freedom (DF)] and backward exclusion  process. Continuous covariates were initially tested using a linear relationship; if found to be statistically significant they were then tested using a power function. Covariate–parameter relationships were predefined based on scientific interest, mechanistic plausibility, or prior knowledge, and the final model was constructed to avoid correlation or collinearity in predictors.The effect of covariates on the base pharmacokinetic model was analyzed: pairwise correlations of covariates and random effects from the base model were explored both graphically and using mixed-effects modeling. Covariates were identified using a stepwise covariate modeling procedure. This involved stepwise testing of covariate relationships in a forward inclusion  and high  eculizumab-exposure groups. For comparison, 16/63 patients (25%) who received placebo experienced one or more events of clinical deterioration.The incidence and type of AEs was similar between placebo- and eculizumab-treated patients. No trends in the occurrence of AEs were observed with increasing eculizumab exposure, comparing patients treated with eculizumab stratified in terms of the steady-state eculizumab AUC quartiles.Results of this pharmacokinetic/pharmacodynamic analysis provide evidence-based confirmation of the recommended dosing regimen for intravenous eculizumab in adult patients with anti-AChR antibody-positive refractory gMG, which comprises 900 mg weekly for the first four doses, followed by 1,200 mg 1 week later and every 2 weeks thereafter. A two-compartment population-pharmacokinetic model with first-order elimination best describes the observed eculizumab pharmacokinetic profile following intravenous infusion in patients with anti-AChR antibody-positive gMG. The model confirmed that eculizumab clearance is affected by body weight and PLEX. Although some pharmacokinetic parameters were affected by body weight, the data suggest that no dose adjustments are needed in overweight patients with gMG. None of the other patient-related factors examined significantly affected eculizumab pharmacokinetics in these patients.The final model reflected the increased clearance and reduced elimination half-life of eculizumab in patients receiving PLEX or fresh frozen plasma infusions . Fresh fJapanese and non-Japanese patients appeared to have similar eculizumab pharmacokinetic profiles, and no differences were observed with regard to complement inhibition; however, it should be noted that data were only available for three Japanese patients. Nevertheless, based on the totality of the data, it would appear that eculizumab dose adjustment and dose-regimen changes are not required in specific populations  or based on renal or hepatic function.in vitro cRBC hemolysis < 20%; Alexion Pharmaceuticals, data on file) was achieved by the end of infusion of the first dose and was sustained throughout the 6-month treatment period in over 90% of patients. This supports terminal complement inhibition as the mechanism by which eculizumab exerts its therapeutic effects with rapid onset in patients with gMG , or pregnancy, which may increase C5 concentrations], and for slight variation in dosing schedules (± 2 days), without risk of incomplete terminal complement inhibition , 23. ComResults of exposure–response analyses were compatible with the use of a therapeutic dosing regimen that achieves full inhibition of terminal complement activation. Clinical efficacy  was consistent across the full exposure range, indicating that the maximum therapeutic effect had been achieved. No relationship was seen between eculizumab exposure and anti-AChR antibody titers; this is as expected based on the mechanism of action of eculizumab, which targets C5 in the complement cascade, distinct from targeting anti-AChR antibody. To date, there are no published data to suggest that anti-AChR antibody titer, which is highly variable, correlates with disease activity in patients with anti-AChR antibody-positive gMG.Consistent with the very low rate of samples testing positive for ADAs or NAbs in eculizumab studies in other indications –26, therNo safety trends were observed with increased serum eculizumab concentrations in this analysis. Results of the REGAIN study showed eculizumab to be generally well-tolerated in patients with gMG . The oveNeisseria meningitidis , and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents  pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at The studies involving human participants were reviewed and approved by independent Ethics Committees or institutional review boards at the 76 centers that participated in the study (see JM: pharmacometric strategy, pharmacokinetic/ pharmacodynamic simulations, report writing, critical review, editing, and approval of manuscript. XG: protocol design, analysis planning and strategy, data analyses and interpretation, report writing, critical review, editing, and approval of manuscript. HJK: data analysis, interpretation, report writing, critical review, editing, and approval of manuscript. FB: data analysis, interpretation, critical review, editing, and approval of manuscript. RP: bioanalyses, critical review, editing, and approval of manuscript. All authors contributed to the article and approved the submitted version.Editorial assistance was provided by Duncan Porter and Jennifer Coward of Piper Medical Communications, funded by Alexion Pharmaceuticals Inc.JM and RP are employed by Alexion Pharmaceuticals, Inc.; XG was employed by Alexion Pharmaceuticals, Inc. at the time the work described in this paper was undertaken; HJK and FB are employed by Certara Strategic Consulting, which received funding from Alexion Pharmaceuticals, Inc.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.


Is Children’s Hepatic Tumor International Collaboration–Hepatoblastoma Stratification (CHIC-HS) risk group prognostic of outcomes and are tumor histological characteristics associated with risk stratification?In this cohort of 96 pediatric patients with hepatoblastoma from a single institution who were independent of the CHIC-HS discovery cohort and treated with more recent therapy, CHIC-HS group was significantly associated with both event-free survival and overall survival. Data on the contribution of hepatoblastoma histologic subtype to risk stratification were also generated.These findings validate the CHIC-HS and suggest that incorporating pretreatment tumor histological characteristics into CHIC-HS may provide additional prognostic value. This cohort study assesses the Children’s Hepatic Tumors International Collaboration-Hepatoblastoma Stratification in an independent cohort of patients with hepatoblastoma and evaluates the association of pretreatment tumor histological characteristics with prognosis. Hepatoblastoma is the most common pediatric liver malignant neoplasm, and accurate risk stratification is essential for guiding treatment.To validate the Children’s Hepatic Tumors International Collaboration–Hepatoblastoma Stratification (CHIC-HS) in an independent cohort of patients with hepatoblastoma and evaluate the association of pretreatment hepatoblastoma histological subtype with prognosis.This is a single-institution retrospective cohort study of 96 pediatric patients with hepatoblastoma diagnosed and treated between June 1, 2000, and December 31, 2016, with recent therapy and independent of the CHIC-HS discovery cohort. Each patient was assigned a risk group according to CHIC-HS. The histological characteristics of each tumor were assessed based on the International Pediatric Liver Tumor Consensus Classification. Data were analyzed from May 2018 to May 2019.The main outcomes were event-free survival (EFS) and overall survival (OS). Cox regression analysis was used to examine the associations of patient characteristics and tumor histological characteristics with survival.P < .001) and OS . In the subcohort of 84 patients for whom pretreatment tumor histological data were available, tumor epithelial histological subtypes were found to be significantly associated with both EFS and OS. Patients in the CHIC-HS high-risk group and with embryonal-only histological subtype had the highest risk of relapse or disease progression  and death .A total of 96 patients  were assessed, including 15 with very low risk, 28 with low risk, 23 with intermediate risk, and 30 with high risk, according to CHIC-HS criteria. There were a total of 13 cancer-related deaths; median (range) follow-up was 3.5 (0.1-17.8) years for those alive at the last follow-up. The estimated 5-year OS rates were 100% in the very low-risk group, 94.7%  in the low-risk group, 89.2%  in the intermediate-risk group, and 57.9%  in the high-risk group. In a multivariable analysis, we confirmed that CHIC-HS significantly estimated EFS (high-risk group vs very low- and low-risk groups: hazard ratio [HR], 45.59; 95% CI, 9.39-209.5; This cohort study found that CHIC-HS performed as expected in an independent cohort that was more recently treated. Incorporation of pretreatment tumor histological data into CHIC-HS may provide additional prognostic value. Furthermore, given the rarity of this malignant neoplasm, collaboration among the 4 clinical trial groups is required to advance clinical outcomes in children with hepatoblastoma. To overcome this, leaders from these 4 groups came together to form a consensus group called the Children’s Hepatic Tumors International Collaboration (CHIC). Data from 8 prospective clinical trials conducted by these 4 groups were pooled to form the CHIC database, which included 1605 patients with hepatoblastoma treated between 1988 and 2008.9 Recently, CHIC developed a new consensus international risk stratification system for hepatoblastoma called Children’s Hepatic Tumors International Collaboration–Hepatoblastoma Stratification (CHIC-HS).10 CHIC-HS categorizes patients into 4 risk groups based on the following prognostic factors: PRETEXT stage, PRETEXT annotation factors, presence or absence of distant metastases, patient age at diagnosis, AFP level at diagnosis, and tumor resectability at diagnosis. Tumor histological characteristics were conspicuously not included, owing to sparse data. CHIC-HS is being implemented in an international prospective collaborative treatment trial, Paediatric Hepatic International Tumor Trial (PHITT) (NCT03017326), that includes patients with hepatoblastoma. However, to date, CHIC-HS has not been independently validated. The aim of this study was to assess the performance of CHIC-HS in an independent cohort and to investigate whether pretreatment tumor histological data might add value to CHIC-HS.Many clinicopathological features, such as pretreatment extent of disease (PRETEXT) stage, distant metastasis at diagnosis, serum α-fetoprotein (AFP) level at diagnosis, age at diagnosis, tumor histological characteristics, and genetic markers, have been reported to be prognostic for survival.This cohort study was approved by the institutional review board of the Children’s Hospital Los Angeles (CHLA). Informed consent was waived by the CHLA review board because the study was a retrospective review and it was not possible to contact all patients.10 was used to determine each patient’s risk group in our analytic cohort of 96 patients.The surgical pathology archives of CHLA were searched for all patients diagnosed with hepatoblastoma, transitional liver cell tumor, or hepatocellular neoplasm not otherwise specified (HCN-NOS) from June 1, 2000, to December 31, 2016. A total of 197 samples from 122 patients were found, 100 of whom were diagnosed and treated at our institution. Demographic data, clinical features, AFP levels at diagnosis, PRETEXT stage and annotation factors, tumor resectability, disease status, and vital status were collected by retrospective review of electronic medical records, radiological imaging, and pathology reports, and 98 of 100 patients had all the necessary information to be accurately classified by CHIC-HS. Two patients were excluded because they were included in the CHIC-HS discovery cohort. The CHIC risk stratification tree2 pathologists (S.Z. and L.W.). Based on the International Pediatric Liver Tumor Consensus Classification,11 each tumor was first assigned broadly to the histological type: epithelial vs mixed epithelial-mesenchymal variant, and further to 1 of the epithelial histological subtypes based on epithelial components: fetal, embryonal, fetal + embryonal (regardless of relative proportions of each component), HCN-NOS, and others, including 6 with small cell undifferentiated (SCU) histological characteristics, 1 with cholangioblastic histological characteristics, and 1 with macrotrabecular pattern. Representative examples of epithelial components are provided in the eFigure in the An immunohistochemistry panel of glypican 3, β-catenin and Sal-like protein 4 were performed in most samples. All hematoxylin and eosin and immunohistochemistry slides from tumor biopsy, resection, or liver explant were rereviewed by 2 test was used to examine differences in the distribution of patient characteristics and CHIC-HS risk strata. The primary end points were event-free survival (EFS) and overall survival (OS). EFS was defined as the interval between the date of diagnosis and the date of first relapse of disease, disease progression, or death, whichever occurred first. OS was defined as the interval between the date of diagnosis and the date of death from any cause. Patients without an event were censored at the time of last follow-up. Cox regression analysis was used to examine the associations of patient and tumor epithelial histological features with EFS and OS. Demographic- and tumor-related traits used in the CHIC-HS risk stratification, such as age at diagnosis, AFP levels, and PRETEXT stage, were excluded from the univariable and multivariable analyses since the association between these factors and the CHIC-HS risk strata are highly correlated. Factors examined in univariable models included patient sex, transplant, CHIC-HS risk strata, and tumor epithelial subtype histological features. Significant factors from the univariable analysis  were considered in the multivariable analysis. The final model was determined by a backward stepwise selection when all factors remaining achieved a likelihood ratio test P < .05. Owing to small sample size, the CHIC-HS very low- and low-risk groups were combined in the analysis. Tumors with SCU histological features were incorporated into the others group owing to small sample size. Well-differentiated and crowded fetal histological features were not analyzed separately. Twelve patients lacked pretreatment tumor histological data. Therefore, the association of tumor epithelial histological features among all patients and among 84 patients with pretreatment tumor histological data were examined separately. The Kaplan-Meier method12 was used to assess EFS and OS. The survival estimates included 95% CIs, which were calculated using the log-log transformation and Greenwood formula. Unless otherwise stated, all analyses were performed using 2-sided tests with significance set at P < .05 and completed using Stata statistical software version 2015 (StataCorp). Data were analyzed from May 2018 to May 2019.The χA total of 96 patients  formed the analytic cohort. There were 15 patients in the very low-risk group, 28 patients in low-risk group, 23 patients in the intermediate-risk group, and 30 patients in the high-risk group, according to CHIC-HS criteria. The associations among CHIC-HS risk group and various clinicopathologic features are listed in P = .001). Multivariable analysis found significant differences in EFS among groups (P < .001). Compared with patients in the very low-and low-risk groups, there was a higher risk of disease relapse or progression in the high-risk group ; the difference in risk was not statistically significant for the intermediate-risk group . The risk of death also varied significantly among groups (P < .001). Risk of death was also higher in the high-risk group , but the difference for the intermediate-risk group was not statistically significant   . We repe3-41.53) . Both CH3-41.53) , B, and 3-41.53) , C.P = .02), but there were no associations with EFS. When regrouped by epithelial subtype histological characteristics, histological subtype remained significantly associated with OS  (P = .007) but not EFS (P = .004) and OS  (P < .001) (P = .001) and OS  (P < .001)  . Tumors  < .001) . We also13 Poor prognostic factors identified individually in 4 clinical trials included PRETEXT stage IV, distant metastasis, AFP less than 100 ng/mL, and SCU histological characteristics.7 Recently, CHIC developed the most refined risk stratification system for hepatoblastoma by taking into account most known prognostic factors.This cohort study is the first independent validation of CHIC-HS and the largest study to investigate the prognostic role of tumor histological characteristics in hepatoblastoma, to our knowledge. Accurate risk stratification of patients with hepatoblastoma could improve patient care by optimizing treatment, facilitating clinical trial design, fostering international collaboration and the development of new therapeutic approaches, and improving communication among physicians. Over the last decade, individual clinical trial groups have attempted to define the relative importance of a variety of suspected prognostic factors.14 We also found that the estimated mortality closely matched observed mortality across the CHIC-HS risk groups.CHIC-HS performed well in our cohort. In the multivariable analysis, we found that CHIC-HS was the main prognostic factor for outcome and independently significantly estimated both EFS and OS. Notably, CHIC-HS maintained its value in a more recently treated group of patients with contemporary therapies. Our treatment approach during the study period was upfront surgical resection of PRETEXT stage I or II primary tumors followed by either observation for patients with pure fetal histological characteristics, or postoperative adjuvant chemotherapy for patients with other histological characteristics. For patients who had unresectable primary tumors at presentation, a biopsy was performed when feasible, followed by neoadjuvant chemotherapy, delayed tumor resection, including liver transplantation if indicated, and postoperative adjuvant chemotherapy. In our cohort, all patients in the very low-risk group had low PRETEXT stage, and 26 of 30 patients in the high-risk group had high PRETEXT stage. The 5-year OS estimate (81.8%) in our cohort was similar to the survival rate (81.9%) reported from the Surveillance, Epidemiology and End Results database.13; while patients with SCU histological characteristics are more likely to require more aggressive therapy and have a poorer prognosis than patients with other histological characteristics.16 Both well-differentiated fetal and SCU histological characteristics were incorporated in COG risk stratification and therapeutic protocols.2 Patients diagnosed with stage I pure well-differentiated fetal hepatoblastomas in COG AHEP0731 were treated with surgical resection alone.3 However, tumor histological characteristics were not incorporated in this initial CHIC-HS owing to lack of complete histological data. Historically, COG recommended biopsy or upfront primary resection before any chemotherapy was administered, when feasible. Therefore, pretreatment histological data were available for patients enrolled in COG trials. In contrast, the other 3 major clinical trial groups  recommended neoadjuvant chemotherapy prior to surgical resection; therefore, most patients only had postchemotherapy histological data.11 Of 96 patients in our cohort, 84 patients had pretreatment tumor histological data, which was assessed based on the International Consensus Histology Classification. Our data showed that pretreatment epithelial histological characteristics were independently significantly associated with EFS and OS. The patients in CHIC-HS high-risk group and with embryonal-only histological characteristics had the highest risk of progression, relapse, or death, while the patients in CHIC-HS very low- and low-risk groups and with some fetal histological characteristics had the lowest risk of adverse outcomes.Additionally, we found that integration of pretreatment epithelial histological data into CHIC-HS provided additional prognostic value. Previous clinical trials have identified that some histological types are associated with prognosis. For example, patients with pure well-differentiated fetal histological characteristics are likely to have an excellent outcome with complete primary tumor excision17 Four of these 5 patients were alive without evidence of disease. The sixth patient with focal SCU histological characteristics was also alive at the last follow-up. Although tumors with focal SCU histological characteristics were not separately analyzed owing to low case numbers, our data suggested that INI-1–retained SCU histological characteristics might not be an unfavorable prognostic factor. Of 10 patients with HCN-NOS histological characteristics, 9 patients were in the CHIC-HS high-risk group and 1 patient was in the intermediate-risk group. The contrarian excellent outcomes noted in patients with HCN-NOS are likely to be related to surgical intervention, including liver transplantation.18 All patients with HCN-NOS histological characteristics had complete resections of the primary tumor, and 5 of 10 patients underwent liver transplantation to achieve complete resection status. Ideally, any risk stratification should be independent of the results of any therapeutic modality. However, it is well known that complete tumor resection is a prerequisite for cure of hepatoblastoma and that any strategy leading to an increased resection rate will result in improved outcomes for patients with hepatoblastoma.5In this study, we had 2 patients with pure well-differentiated fetal histological characteristics. Both patients were classified in the very low-risk group and were cured with surgical treatment alone. Six patients had tumors with focal SCU histological characteristics (<1% to 80% of tumor), which were all INI-1 retained; 5 of these patients were previously reported.15 In this study, 5 patients had very low serum AFP at diagnosis. Of these, 2 patients had focal SCU histological characteristics, 2 patients had fetal + embryonal histological characteristics, and 1 patient had fetal histological characteristics. Only 1 of these patients died owing to complications following liver transplant.17 Our limited data suggest that very low AFP was not associated with either tumor histological characteristics or prognosis. Malignant rhabdoid tumors (loss of INI-1) are reported to develop in the liver and are often misdiagnosed as SCU hepatoblastomas.20 It is perhaps reasonable to speculate that some of malignant rhabdoid tumors may have been misclassified as low-AFP hepatoblastomas in the past.Very low serum AFP (<100 ng/mL) is included in CHIC-HS as a poor prognostic factor. An association between SCU histological characteristics and AFP levels that are low or with reference range for age has been suggested.This study has several limitations, including its retrospective nature, a relatively small sample size, and shorter follow-up time for patients diagnosed after 2014. Given the small number of patients and events in some epithelial histological subgroups, estimates from the multivariate models are prone to bias, and the corresponding 95% CIs can be imprecise. Therefore, these results should be interpreted with caution and thus, the contribution of histological characteristics to risk stratification should be validated independently and prospectively.The findings of this cohort study provide evidence to support the use of CHIC-HS in PHITT and advance previous knowledge on the prognostic role of tumor histological characteristics in hepatoblastoma. It is planned that PHITT will evaluate the role of pretreatment tumor histological characteristics within the context of the international multigroup collaborative clinical trial and elucidate more precisely the prognostic role of histological characteristics in hepatoblastoma, paving the way forward for the inclusion of pretreatment diagnostic histological characteristics into risk stratification for patients newly diagnosed with hepatoblastoma.