The impact of bone metastases (BM) on survival outcomes of combo-ICI-treated patients is unknown. (2) Methods: This single-center retrospective observational study involved 36 combo-ICI-treated patients with advanced RCC and 35 with melanoma. Clinical and laboratory data preceding the initiation of combo-ICI were collected. Univariate and multivariate Cox proportional hazard models were used to assess the effect of BM on overall survival (OS) and progression-free survival (PFS). (3) Results: zNine RCC and 11 melanoma patients had baseline BM. In unadjusted analysis, baseline BM was associated with a poorer OS in the RCC cohort. Baseline BM did not have any impact on survival outcomes in melanoma patients. After adjustment on baseline performance status and on neutrophil-to-lymphocyte ratio (NLR), the impact of BM was no longer significant, but a NLR ≥ 3 was significantly associated with a poorer OS in the RCC cohort. (4) Conclusions: The presence of baseline BM seems to be associated with worse outcomes in RCC combo-ICI-treated patients, while its effect might not be independent from the inflammatory state (approximated by the NLR). BM seems to have no impact on the outcomes of melanoma combo-ICI-treated patients. The last decade, the combination of two immune checkpoint inhibitors (ICI), namely ipilimumab (anti-CTLA4) and nivolumab anti-PD1), has dramatically improved patient outcomes in different malignancies including advanced melanoma and renal clear cell carcinoma (RCC): both conditions were the first for which these treatments obtained the approval of the European Medicines Agency. The use of this combination increased the progression-free survival (PFS) and overall survival (OS) of patients with advanced melanoma compared with ipilimumab alone; these results have been confirmed over a 5-year follow-up period , has dra. AdminisBone metastases (BM) occur in about 30% of patients with advanced RCC . In melaThe impact of BM on the survival outcomes of patients treated with combo-ICI is unknown, although this information might help in the selection of the best regimen for patients with advanced RCC or melanoma. We, therefore, conducted a real-world retrospective analysis including patients from two French units to assess the prognostic impact of BM on patients with advanced RCC or melanoma treated with combo-ICI.Patients included in this study were adults aged ≥18 years with advanced RCC or melanoma who initiated treatment consisting of at least one dose of combo-ICI administered intravenously in standard clinical practice or clinical trials at the Hôpital Lyon Sud, Hospices Civils de Lyon, France between July 2016 and January 2021. At the time of the study, the combo-ICI was not authorized in France for malignant pleural mesothelioma, non-small cell lung cancer or metastatic colorectal cancer; therefore, we did not include patients with these tumors. The study received the approval of the ethical review board of the Hospices Civils de Lyon (N° 21_244—22 June 2021) and Commission nationale de l’informatique et des libertés . Patients did not receive any compensation for their participation.Data collection was performed retrospectively from medical charts using a standardized data collection form by two dermatologists (F.P. and S.B.). Data collected included the following patient characteristics: age at treatment initiation, sex, history of autoimmune disease, Eastern Cooperative Oncology Group performance status (ECOG-PS), body mass index, smoking habits  before treatment with combo-ICI, type and grade of adverse events, red and white blood cell count, neutrophils-to-lymphocytes ratio (NLR) before the first dose of combo-ICI. An NLR threshold corresponding to the median value of the overall cohort was determined and used in regression models as a prognostic factor for survival outcomes. Disease characteristics were the following: tumor type (advanced melanoma or RCC), and number and localization of metastatic sites at treatment initiation. Treatment characteristics were the number of prior systemic treatments, prescribed dosage of combo-ICI, and prescription of a bone resorption inhibitor within 4 months after the finding of BM. The date of disease progression was determined by treating physicians according to standard practice. The progression had to be either clinical or radiological.The characteristics of patients in the two cancer groups were compared using two-tailed univariate analyses. A Fisher exact test was used to compare binary or qualitative variables. A Mann–Whitney test was used to compare quantitative variables.p value was less than 0.05. To assess the adjusted effect of BM on OS and PFS, we used multivariate Cox proportional hazard models. All variables that had a statistically significant impact on OS or PFS in univariate analysis (using a threshold for p at 0.10), as well as the bone metastasis status (present or absent), were included in the multivariate models.The primary endpoint was OS. The secondary endpoints were PFS and extra-bone PFS. OS was defined as the delay between combo-ICI initiation (baseline) and death from any cause. PFS was defined as the delay between combo-ICI initiation and progression according to the physician assessment, or subsequent therapy or death from any cause, whichever occurred first. Extra-bone PFS was defined as the delay between combo-ICI initiation and extra-bone progression according to RECIST 1.1 criteria or death from any cause, whichever occurred first. When a new anticancer treatment was initiated as a consequence of a bone-disease progression, extra-bone PFS was censored at the time of the bone-disease progression. Survival probabilities were estimated using the Kaplan–Meier method and compared between groups using two-tailed log-rank tests. Covariates, including BM, were considered as statistically associated with PFS or OS if the associated All analyses were performed using R statistical software . Database follow-up was closed in February 2021. Few data were missing, and no data imputation was performed through the analyses.p = 0.0039). Patients with BM more frequently had liver metastases  patients were treated for an advanced RCC and 35 (49%) for a metastatic melanoma. Patients treated for an advanced RCC received 4 injections of 1 mg/kg ipilimumab . Among the patients treated for a melanoma, 33/35 (94%) received 4 injections of 3 mg/kg ipilimumab, and the 2 remaining patients received 4 injections of 1 mg/kg ipilimumab. All patients received nivolumab  in combination with ipilimumab, and in maintenance after the discontinuation of ipilimumab. The median  follow-up duration after the initiation of combo-ICI was 22.1  months. A total of 9 (25%) patients with advanced RCC and 11 (31%) patients with melanoma had BM at presentation. In the overall cohort, patients with BM more frequently had an ECOG-PS ≥ 2  and PFS  compared with patients without initial BM  but remained consistent on PFS  compared with patients without baseline BM . Similarly, the presence of BM had no statistically significant impact on the PFS  or extra-bone PFS  and its ligand, RANKL, is dysregulated in BM-induced bone destruction . For insIn our study, NLR has appeared as an important factor associated with survival outcomes. Indeed, the association between baseline BM and OS in advanced RCC was not statistically significant after adjustment on the NLR and ECOG-PS. NLR is the neutrophils-to-lymphocytes ratio: it comes from a resuscitation score, and it has been successfully transferred in oncology settings initially in non-small cell lung carcinoma ,20. IndeIn melanoma, whereas a high NLR was associated with worse OS and PFS in two recent meta-analysis, this was not the case in our study ,23. It iOther predictive biomarkers have been proposed to better select patients who might benefit more from the combo-ICI or ICI in general than other treatments, but none is approved to date in melanoma or aRCC. For instance, the baseline PD-L1 expression level is used to prescribe pembrolizumab in metastatic non-small lung cancer but is not predictive of survival outcomes in melanoma treated with combo-ICI in the Checkmate-067 trial . In aRCCSurprisingly, patients with brain metastasis were not associated with poorer survival outcomes. Melanoma patients with brain metastases have always been the most challenging patients to treat, and this is particularly true for those with symptomatic brain metastases. The landmark trial Checkmate 204 has provided strong evidence of the intracranial activity and efficacy of ipilimumab plus nivolumab in melanoma patients with asymptomatic brain metastases . HoweverThere were several limitations in our study such as the small sample size resulting in a lack of statistical power owing to the monocentric nature of this study. Secondly, the retrospective nature of the study was inherently associated with residual confounding factors despite our effort to control it with a Cox model. iRECIST criteria were not considered in this study as they were not routinely used for all patients at the time they were treated with an ICI. We did not accurately describe the pattern of BM such as the number of skeletal localizations and their detailed topography. We also did not specifically investigate bone events such as fractures or whether the patients were discussed in bone metastatic multidisciplinary tumor boards. Therefore, it is critical not to extrapolate that combo-ICI might be less efficient in patients with baseline BM. The results of the present study are only exploratory, and no causal or definitive relationship can thus be inferred between baseline BM, elevated NLR and altered ECOG-PS in patients with RCC treated by combo-ICI.To overcome the limitations of our work, future studies could prospectively study the impact of the NLR and better describe the presence, number, location, and treatment of BM in a more coordinated and multicentric fashion. Furthermore, subgroup analyses specifically studying patients with versus without BM and patients with “low” versus “high” NLR could be performed in prospective trials evaluating combo-ICI. Finally, a meta-analysis of every prospective clinical trial of combo-ICI would be able to better understand the potential prognostic and predictive effect of NLR and baseline BM.Baseline BM in patients with advanced RCC and melanoma treated with combo-ICI were not significantly associated with worse OS, but our study certainly lacked statistical power. However, an elevated NLR was independently associated with poorer OS in patients with advanced RCC. Larger cohorts are needed to better understand the clinical and prognostic significance of BM and NLR in these populations.


Background: Patients with COVID-19 commonly present at healthcare facilities with moderate disease, i.e., pneumonia without a need for oxygen therapy. Aim: To identify clinical/laboratory characteristics of patients with moderate COVID-19, which could predict disease progression. Methods: 384 adult patients presented with moderate COVID-19 and admitted to two hospitals were retrospectively evaluated. In a multivariate analysis gender, age, BMI, Charlson Comorbidity Index (CCI) and National Early Weaning Score 2 were treated as co-variates. The development of hypoxemic respiratory failure, intubation rate and risk of death were considered as dependent variables. Estimated values are presented as odds-ratio (OR) with 95% confidence interval (CI). Results: Most of the patients were male (63.28%) with a mean (standard deviation) age of 59 (16.04) years. Median (interquartile range) CCI was 2 (1–4). A total of 58.85% of the patients developed respiratory failure; 6.51% were intubated, and 8.85% died. The extent of pneumonia in chest X-ray  , respiratory rate , SatO2 , systolic blood pressure  and lymphocyte count  at presentation were associated with the development of respiratory failure. The extent of pneumonia  was associated with intubation risk. Age  and the extent of pneumonia  were associated with increased risk of death. Conclusion: Older age, the extent of pneumonia, tachypnea, lower SatO2, higher systolic blood pressure and lymphopenia are associated with dismal outcomes in patients presenting with moderate COVID-19. What is the key question? What are the clinical/laboratory characteristics and the predictors of disease progression in patients with moderate COVID-19 ?Which are the main findings? Older age, tachypnea, lower SatO2, higher systolic blood pressure, lymphopenia and the extent of pneumonia in a chest X-ray at presentation were independently associated with dismal outcomes in patients with moderate COVID-19.Why read on? The present study focuses on patients with moderate COVID-19 at presentation and may help to identify those patients at risk for disease progression and hospitalization.2 ≥90% on room air) , systolic blood pressure , respiratory rate , SatO2  and blood lymphocyte count  at presentation were independent predictors of the development of hypoxemic respiratory failure , p = 0.021] were independent predictors of death  involvement of all four chest X-ray quartiles was significantly associated with increased risk of intubation; and (3) older age and the involvement of all four chest X-ray quartiles were significantly associated with increased risk of death.In this retrospective analysis, we evaluated 384 patients admitted with moderate COVID-19  to two d2< 94%) or multiple/severe co-morbidities. This approach was mainly based on the difficulty to estimate the individual patient risk, especially if one considers that SARS-CoV-2 infection is characterized by a highly variable clinical course, and worsening of respiratory function may appear several days after symptom onset [To our knowledge, this is the first study focusing entirely on patients with moderate COVID-19 at presentation. Although these patients were not in urgent need for hospital admission, they were admitted to both hospitals during the study period when presenting with significant hypoxemia  supports the clinical relevance of our findings. Far from being conclusive, our observations pave the way for prospective studies on patients with COVID-19 pneumonia (but without respiratory failure) seeking care in EDs or primary care facilities, which will define admission criteria for moderate COVID-19.2), older age, higher systolic blood pressure and lower blood lymphocyte count are associated with the development of respiratory failure and high risk of intubation or death in this distinct population. Although the decision for hospital admission is personalized and relies mainly on the physician’s clinical judgment, the presence of one or more of the aforementioned risk factors for the development of respiratory failure may help physicians identify patients with moderate COVID-19, who are in need of hospitalization. However, our study is “hypothesis generating” and validation of our findings with prospective studies is further required.In conclusion, we herein described the clinical, epidemiological and laboratory characteristics of patients with moderate COVID-19 at presentation, and we demonstrated that the severity of respiratory disease (involvement of all four chest X-ray quartiles, higher respiratory rate and lower SatO


The outcomes of surgery for acute Stanford Type A aortic dissection (ATAAD) extend beyond mortality and morbidity. The aim of this systematic review was to summarise the literature surrounding health related quality of life (HR-QOL) following ATAAD, compare the outcomes to the standardised population, and to assess the impact of advanced age on HRQOL outcomes following surgery.A systematic review of studies after January 2000 was performed to identify HR-QOL in patients following surgery for ATAAD. Electronic searches of three databases were performed and clinical studies extracted by two independent reviewers. Strict inclusion and exclusion criteria were applied. Quality appraisal was conducted utilizing predefined criteria on pilot forms. HR-QOL results were synthesized through a narrative review of included studies.There was significant attrition in HR-QOL of patients following surgery for ATAAD. Outcomes fared worse when compared to an age adjusted normative population. Of note, elderly patients were physically vulnerable, whereas younger populations may be more mentally vulnerable to postoperative sequalae. The included studies were quite heterogeneous in their study designs, methods, HR-QOL measures reported and follow up time-frames which limited direct comparison between studies.HR-QOL outcomes are adversely affected when compared to preoperative status and physical health demonstrates significant attrition over time. HR-QOL outcomes are worse off when compared to an age matched general population. In terms of age, advancing age is associated with worse physical component scores but emotional health may fare better than younger patients.The online version contains supplementary material available at 10.1186/s13019-022-01875-x. Acute Type A aortic dissection (ATAAD) represents a cardiothoracic emergency. Conventional wisdom dictates that mortality rate increases 1–2% per hour within the initial 48 h, with the postoperative 30-day mortality varying between 10 and 35% –8.The outcomes of surgery for ATAAD extend beyond mortality and morbidity rates. Postoperative health-related quality of life (HR-QOL) provides information on the physical, mental, emotional and functional well-being of patients following surgery. HR-QOL research is well validated within cardiac surgery, with the Short Form 36 (SF36) being the most common questionnaire , 10. ExiThis systematic review aims to summarise the literature surrounding HR-QOL following surgery for ATAAD, compare the outcomes to the standardised population, and assess the impact of age on HR-QOL outcomes following surgery.This systematic review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) recommendations and guidance , 31. An Studies were considered eligible if they demonstrated (1) Patients undergoing emergent surgery for ATAAD (2) published past the year 2000 (3) HR-QOL measures were clearly reported for patients who underwent surgery for ATAAD, and (4) published in English. Studies were excluded if they did not meet inclusion criteria.Quality appraisal was conducted by two independent reviewers (A.E and MW). Study quality was assessed with the Delphi Study Quality Appraisal tool . Qualitative analysis of HR-QOL data was performed, by extracting data from each study using a standardised pilot form. Studies were then grouped with regards to variable of interest and summarised in a series of tables below  defines HR-QOL as an individual’s perception of their position in life in the context of the culture and value systems that they live in, and in relation to their goals, expectations, standards and concerns . It can A number of HR-QOL measures are validated in cardiac surgery. Of these, the Short Form 36 (SF36) is most widely used . It consThe literature search identified 54 studies. An additional two articles were identified on manual searches of reference lists. After exclusion of irrelevant studies, 27 articles were deemed appropriate to undergo full-text review. Seventeen studies with a total of 2,388 patients were deemed suitable for inclusion for qualitative analysis in this review –29. ThreThe majority of studies utilised the SF36 or SF12 as a primary HR-QOL measurement , 26, 28.The mean age of patients ranged from 53 to 78 years old. The majority of patients were men, ranging from 33 to 86%. Tashima et al., reported the lowest incidence of preoperative neurological deficit at 6%, and Adam et al. reported the highest at 41%. Preoperative malperfusion was reported in 10 studies, and varied from 18 to 57%. Most commonly, patients underwent a replacement of the ascending aorta (ranging from 66 to 100%). Aortic arch replacement was performed variably, ranging from 0 to 33%. Reporting of deep hypothermic circulatory arrest (DHCA) and open distal anastomoses was variably reported. The use of DHCA varied from 52 to 100% (in 7 studies). Similarly, cerebral perfusion strategies were variably reported. The most common was selective antegrade cerebral perfusion (ACP), which varied from 26 to 100% (in three studies). The use of retrograde cerebral perfusion was reported in four studies. Baseline data is summarised in Additional file Short-term mortality was reported in 12 studies. This ranged from 8.9% to 40%. Six studies reported data in an elderly cohort of patients and the mortality rate ranged from 0 to 40%. Mortality data is summarised in Table Seven studies reported the change on HR-QOL measures of patients over time , 27, 29.Seven studies reported HR-QOL measures with reference to an age matched cohort , 26, 28.4Eight studies reported HR-QOL measures in the elderly Table  13–15, , 24, 29.Quality of life is a useful indicator of overall health as it captures information on the physical and mental health status of a patient. This provides a comprehensive assessment of the burden of disease. Evidence is mounting that HR-QOL outcomes are under utilised and have merit in assessing outcomes in cardiac surgical patients . There iStudy heterogeneity and variability of reporting prevented direct comparison of results. The primary outcome of four studies was to report patients undergoing surgery for thoracic aortic aneurysm with aortic dissection being a subset of patients included in the analysis , 26–28. The majority of studies were retrospective with only three studies being prospective , 17, 27.The HR-QOL over time is an important measure. Existing research in HR-QOL outcomes in cardiac surgery demonstrate that long-term follow up is required to truly evaluate the impact of an intervention , 41, 42.Three studies included in the current review measured preoperative scores in comparison to postoperative scores, which provides a valuable insight into the impact of surgery on these patients , 24, 29.According to previous guidelines, a follow up rate of > 85% is considered ideal in systematic reviews . None ofWell-designed prospective studies are required to make reliable conclusions on the HR-QOL outcomes after surgery for acute TAAD. These studies should utilise a standardised HR-QOL questionnaire such as SF-36 and make preoperative to postoperative comparisons along with long-term follow up. We appreciate that there are obstacles to this, as patients in the peri-operative setting are either unwell or the time critical nature of surgery prevents lengthy questionnaires. Furthermore, the mortality and morbidity of emergent ATAAD surgery produces attrition of follow up. As a result, the strength of evidence reviewed is limited.HR-QOL outcomes are adversely affected in the postoperative period , 27, 29.Patients demonstrate worse HR-QOL outcomes following surgery when compared to age matched cohorts , 19, 26.Studies that assessed elderly cohorts of patients undergoing emergent surgery for ATAAD demonstrated attrition in HR-QOL outcomes postoperatively , 24, 29.The sequelae of ATAAD poses an emotional toll on patients. This can lead to depressive disorders, PTSD and anxiety and are all linked with a loss of function , 21, 27.Schachner et al. reported the impact of malperfusion on postoperative HR-QOL, and found that patients with preoperative neurological symptoms and malperfusion had significantly lower postoperative activity [The presence of preoperative neurological sequelae and malperfusion increases mortality and may negatively impact postoperative HRQOL. Bojko et al. demonstrated a significant association between malperfusion and mortality, which was most apparent in the elderly cohorts . Only Scactivity .Endlich et al. did not demonstrate a significant QOL benefit from either perfusion strategy [Operative technique can affect the HR-QOL outcomes of patients with an ATAAD. The use of DHCA has been linked with poorer postoperative QOL in one study . Findingstrategy . Ghazy estrategy . Benefitstrategy . Short-tstrategy , 53. Unlstrategy .We aimed at minimizing bias by reporting the strength of the study in terms of the number of patients included, design, comparison to preoperative status and rate of follow up. Smaller, retrospective studies with non-standardised HR-QOL outcomes were interpreted in light of larger, well-designed studies. The heterogeneity of literature with regards to HR-QOL measures, reporting and the demographics of the study population limited the role of meta-analyses.Well designed prospective studies, with standardised HR-QOL outcomes such as SF12/SF36 utilizing preoperative and postoperative measurements are ideally suited to identifying the impact of ATAAD on quality of life. A further comparison to standardised HR-QOL measures would be useful. Long-term data provides useful insights into the chronic nature of the disease. Our review identified only four studies that assessed long-term outcomes, of these only one was prospective in nature. We also identified a paucity of research assessing operative strategy and its impact of HR-QOL outcomes. A further comparison of patients undergoing ascending aorta replacement only with an interposition graft, to a more aggressive strategy of total arch replacements and strategies of cerebral perfusion would be of great interest. We do acknowledge the emergent nature of the disease and the limited information that can be obtained in the preoperative setting as patients are often rushed to the operating theatre or are obtunded in the preoperative setting.HR-QOL outcomes are adversely affected when compared to preoperative status and physical health demonstrates significant attrition over time. HR-QOL outcomes are worse off when compared to an age matched general population. In terms of age, advancing age is associated with worse PCSs but emotional health may fare better than younger patients. To the authors’ knowledge, this is the only study to summarise HR-QOL literature in the setting of ATAAD. Well-designed prospective studies utilizing standardised HR-QOL measures would be of great value in drawing further conclusions.Additional file1: Table S1. Delphi quality appraisal tool. Table S2. Study characteristics. Table S3 Operative details and baseline patient characteristics.


Monocyte-to-lymphocyte ratio (MLR) predicted 2.5-fold increased odds for ICU admission and 2.2-fold increased odds for mortality. Conclusion: NLR and MLR followed up 8 days post-admission are predictive for adverse outcomes in mild or moderate COVID-19 patients.Background: The ongoing COVID-19 pandemic has put a constant strain on hospital resources, so there is a dire need for investigation methods that are widely available and that can predict mortality and the need for critical care. Hematological indices, which can be easily calculated from a complete blood count (CBC), are useful in determining a patient’s inflammatory response to infectious diseases. Aim: This was a prospective cohort study that aimed to assess the prognostic value of scores based on CBCs in hospitalized patients with mild or moderate COVID-19 and medical comorbidities regarding the need for intensive care unit (ICU) therapy and short-term mortality. Methods: We included 607 patients with confirmed COVID-19, followed up for the need for ICU admission (15.5%) and 30 day mortality post-discharge (21.7%). CBC-derived scores were tested upon emergency department (ED) admission and after a median of 8 days. Results: In a multivariate model, elevated followed-up neutrophil-to-lymphocyte ratio (NLR) predicted increased odds for ICU admission (OR: 1.14 [95%CI: 1.06–1.22],  The coronavirus disease has affected the entire world, with more than 622 million confirmed cases and 6.5 million deaths according to World Health Organization current data . This haCirculating biomarkers of inflammation  and inflammatory scores derived from the peripheral complete blood count (CBC), such as the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR), are quick, easy-to-obtain, inexpensive and widely available hematological indices that give insight into a patient’s inflammatory response to certain illnesses spanning multiple fields of medicine. Most commonly, these hematological indices have been used in oncology, where elevated values for the NLR and PLR can be predictors of poor outcomes in patients with non-small cell lung cancers , gastroiVirus infection can cause a variety of hematological changes. The degree of the changes in leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets, hemoglobin levels, mean corpuscular volume (MCV) and mean cell hemoglobin concentration (MCHC) are overall associated with lung involvement, oxygen demand and disease activity in COVID-19 patients. C-reactive protein (CRP), lactate dehydrogenase (LDH), the platelet-to-lymphocyte ratio (PLR) and the NLR are significantly higher in COVID-19 patients compared to patients who do not have COVID-19 . Marked Regarding COVID-19, several studies have analyzed the use of the NLR, MLR and PLR, among various other markers, as predictors of disease severity and the need for intensive care and mortality. Unlike our study, they mostly focused, with regard to intensive care unit (ICU) admission and in-hospital mortality, on patients with severe COVID-19 and generally used cohorts of fewer patients. The C-reactive protein/lymphocyte ratio (CLR) combined with the NLR was found to be predictive for mortality in COVID-19 patients with refractory disease admitted to the ICU . A recenOur study aimed to identify whether CBC-derived scores determined early, upon admission to the emergency department (ED), were useful for the prediction of the evolution towards a severe disease and the need for critical care in a large cohort of patients with non-critical COVID-19 disease and medical comorbidities. We also studied the evolution of these indices after a follow up of 8 (range 7–10) days and their relationship with ICU admission and short-term mortality. To our knowledge, no other studies have analyzed these indices with follow up. If these parameters can serve as predictors of disease severity, considered as the need for intensive care, then we have another inexpensive and widely available tool to identify severe cases of infection.This study was undertaken in line with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies.This was a prospective cohort study aimed at assessing the prognostic value of hematological indices in hospitalized patients with mild or moderate COVID-19 regarding the evolution towards critical disease and the need for ICU therapy. Patients aged over 18 years who were admitted for a medical condition to the Internal Medicine Department of “Sf. Spiridon” Emergency County Hospital in Iasi, Romania, between 1 October 2020 and 30 April 2022 and had confirmation of SARS-CoV-2 infection from an RNA reverse-transcriptase polymerase chain reaction assay were included in this study. Patients under 18, discharged against medical advice or with incomplete data upon admission to ED or follow up were excluded, while patients with multiple readmissions during the study period were evaluated as a single presentation. The patients were followed up 30 days post-discharge to evaluate short-term mortality. This study was approved by our Institutional Review Board, and individual written informed consent was waived based on legal standards for national healthcare alarm situations.For data extraction, we recorded demographics, vital signs, body mass index (BMI) and comorbidities. The studied variables were: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ration (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic inflammation index (SII), as well as neutrophil-to-monocyte ratio (NMR) and neutrophil-to-platelet ratio (NPR), erythrocyte sedimentation rate (ESR), red cell distribution width (RDW), mean platelet volume (MPV), mean platelet volume (MPV) to platelet count (PC) ratio (MPR), hemoglobin, white blood cells (WBCs), prothrombin time (PT), fibrinogen, C-reactive protein (CRP), C-reactive protein-to-lymphocyte ratio (CLR), creatinine, TGP, lactate dehydrogenase (LDH), presepsin and ferritin. The hematological indices were calculated using the mathematical division of their absolute values derived from CBCs from peripheral blood samples available upon ED admission and after follow up of a median 8 days (range 7–10). Additionally, the National Early Warning Score (NEWS2)  was extrp value < 0.1 were included in the multivariate models . Age was excluded from the list of potential confounders because it is already included in CCI score and is one of the criteria for giving patients access to ICU care. The calibration of the models was assessed using the Hosmer–Lemeshow goodness-of-fit statistic . We used bootstrapping for internal validation of the models. Data are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Receiver operating characteristic curves (ROCs) were built to analyze the diagnostic performance of the multivariate models for prediction of admission to the ICU and 30 day mortality. In addition, we calculated the positive predictive value (PPV) and the negative predictive value (NPV) of the models applied. A statistical test was significant when the p value was <0.05. All p values were the results of two-tailed tests. Statistical analyses were performed using SPSS software version 22 .Categorical variables were summarized as percentages and continuous variables as the number of non-missing observations and the mean and standard deviation (SD) or median and interquartile range (IQR). Variables were analyzed using Mann–Whitney or Chi-squared tests as appropriate. Missing data were excluded listwise where applicable. To evaluate independent factors, univariate and multivariate logistic regressions (enter method) were performed. Significant variables with a We included 607 hospitalized patients ) with a medical disease and associated confirmed mild or moderate COVID-19 as defined according to CDC guidelines . The maip < 0.001). Moreover, 30 day survival was significantly influenced by the viral strain, the Alpha variant and the Delta variant being responsible for 47.7% and 25% of deaths (p < 0.001), respectively. The oncologic comorbidities associated were solid cancers in 12 patients (2%) and hematologic malignancies in 102 patients (16.8%). The presence of an oncologic disease (OD), defined as a hematologic malignancy or a solid cancer, significantly influenced 30 day mortality . The median number of days in hospital was 12 days for patients who did not need transfer to the ICU and 10 days for patients transferred to the ICU. Thirty days after hospital discharge, data were available for 588 patients. Baseline characteristics of the cohort according to the main outcomes are presented in p = 0.072). The viral strains involved were the Alpha variant in 362 patients (59.6%), the Delta variant in 129 patients (21.3%), the Beta variant in 64 cases (10.5%) and Omicron in 52 cases (8.6%). We observed that viral strain significantly influenced the main outcomes analyzed. The patients infected with the Delta variant had significantly higher rates of ICU admission , upon admission and follow up. Other CBC-derived scores, such as NMR and NPR, were available only upon admission, as was the case for ESR, arterial lactate, presepsin, and ferritin. Lymphocytopenia, defined as lymphocyte count <1.5 × 10p < 0.05); however, in multivariate models, they were not significant or had little influence on the model itself. The NLR upon admission to the ED was statistically significant for our established outcome; however, we could not obtain a model with satisfactory sensitivity and specificity in the ROC curve. The follow-up values for the NLR . The PPV of the model was 98%, and the NPV was 31%.The NLR on follow up was tested through multivariate logistical regression alongside other inflammatory response markers, such as fibrinogen, CRP, LDH, presepsin and history of OD. In model 1, SII and presepsin showed no influence on the established outcome, while follow-up NLR significantly predicted 14% increased risk for ICU admission . The virp < 0.001), and the PPV was 97% and the NPV was 34%.Follow-up MLR was tested using a multivariate model including significant covariates (model 2). MLR predicted 2.4-fold increased odds for ICU admission and the viral strain Delta showed more than twofold increased odds for ICU admission, while SII, presepsin and LDH showed no influence for this outcome. Notably, SaO2 upon admission (<90%) predicted fivefold increased odds for the need for ICU therapy . The resp < 0.001) with a PPV of 98% and an NPV of 36%. Therefore, there is little benefit from a combined model when compared to independent models regarding ICU admission. Both the follow-up NLR and MLR were tested in a combined model using the same variables as the independent models for ICU admission (model 3). Out of the two, only follow-up NLR remained a statistically significant predictor for this outcome . Follow-p < 0.001). The PPV of this model was 93% and the NPV 72%.Follow-up hematological indices, including NLR, MLR, PLR and SII, and inflammatory biomarkers, including CRP, CLR, fibrinogen and LDH, assessed pre-discharge were significantly increased in non-survivors. However, only NLR, MLR, CCI and LDH showed significant predictive values for short-term mortality in our cohort. Further, the duration of illness significantly influenced this outcome. Follow-up NLR predicted a 30% increase in short-term mortality in model 1, which included pre-discharge CRP, fibrinogen, LDH SII, the duration of illness and the presence of an OD . The resp < 0.001). The PPV of the model was 90%, and the NPV was 52%.Although admission MLR was significantly increased in patients who did not survive 30 days post-discharge, in the multivariate analysis, only follow-up MLR significantly influenced short-term mortality. In model 2, which included pre-discharge CRP and LDH, fibrinogen, SII, CCI score, duration of sickness, the presence of an OD and admission SaO2 , follow-p < 0.001) for the combined model including follow-up NLR and MLR , in patients with bloodstream infection in the ED . A CCI sThe major strengths of our study were the larger sample size compared to other similar studies, including patients with complex medical comorbidities, and a larger timeframe, which made it possible to include many viral strains of concern. We tested more CBC-derived scores than previous studies, and we identified the follow-up NLR and MLR—easy, inexpensive and available markers—as suitable for predicting the need for ICU admission and short-term mortality in a cohort of hospitalized patients with mild or moderate COVID-19. One limitation of this study was that data were obtained from a single center in northeastern Romania and may not reflect the entire European population. Another limitation was the lack of ethnic variety in our cohort. A third limitation was the low number of patients with histories of hematologic malignancies or solid cancers, which made it difficult to quantify the exact influence of these comorbidities on the outcomes. A fourth limitation was that not all CBC-derived scores were available on follow up for analysis, and each patient could have been at a different stage of the disease. Finally, the small number of vaccinated patients in our cohort could have impacted the outcomes. Both the NLR and MLR have high value in predicting the need for intensive care and short-term mortality in hospitalized mild or moderate COVID-19 patients with associated medical comorbidities, and their predictive value is increased if they are calculated from a CBC taken 8 days from admission. Although it is arguable whether they alone are enough to determine if a patient needs to be admitted to the ICU, since they are calculated from a CBC, which is a laboratory test that is readily available in almost all hospitals worldwide, they can be used as another tool in the physicians’ arsenal in the fight against the coronavirus pandemic. We recommend systematically following up these indices in non-critically ill COVID-19 patients so that medical professionals can allocate timely ICU resources to the patients in need. Considering the high risk of short-term mortality, elevated follow-up NLR and MLR are significant in terms of planning the necessary strategies to reduce mortality.


NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken.2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival.Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/mThe most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment.NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation . To explore the activity of NC-6300 (nanoparticle epirubicin) in angiosarcoma, an expansion cohort was undertaken. The clinical trial results are reported here. Treatment for patients is challenging in many cases and the prognosis is poor. Anthracyclines are widely used in the treatment of many sarcomas, including angiosarcomas, but many patients suffer from rate-limiting side effects. Therefore, a safer treatment remains an area of unmet medical need. EPI, a stereoisomer of doxorubicin, was developed to circumvent the cardiotoxicity associated with the parent compound. Pegylated liposomes and other nanoparticle formulations have been developed to reduce the cardiotoxicity of conventional doxorubicin and other anthracycline derivatives. Although liposomal doxorubicin was designed to alleviate the cardiac toxicity associated with conventional doxorubicin, unique toxicities were reported. NC-6300 was developed to encapsulate EPI into the micellar nanoparticle to selectively deliver the drug into the acidic environment of the endosomal or lysosomal compartments of the target tumor cell.2 IV once every three weeks. The baseline characteristics of the patients are listed in In the phase Ib trial of NC-6300 in solid tumors and soft-tissue sarcomas, there were 2 patients with angiosarcoma who experienced a partial response by investigator assessment. Originally, a comparative phase II accruing 150 patients in total was planned to investigate NC-6300 + olaratumab vs olaratumab alone. However, the study protocol was amended to pursue an expansion cohort, using NC-6300 alone, due to market withdrawal of olaratumab. The expansion cohort was an open-label trial that enrolled 10 patients designed to further investigate the activity of NC-6300 in angiosarcoma. The primary endpoint was progression-free survival (PFS). Patients were treated with NC-6300 at 150 mg/mIn summary, NC-6300 was safe and tolerable in this expansion cohort, and had promising efficacy especially in angiosarcoma patients without prior anthracycline treatment. Further investigation is warranted.Angiosarcomas are a subtype of soft-tissue sarcoma that are aggressive, malignant endothelial-cell tumors of vascular or lymphatic origin. Anthracyclines, such as doxorubicin, are widely used in the treatment of many tumors, including angiosarcomas, but many patients suffer from significant treatment-related side effects. Treatment for patients is challenging in many cases and the prognosis is poor. As a result, there remains an unmet need for a safer anthracycline agent. Epirubicin, a novel stereoisomer of doxorubicin, was developed to circumvent the cardiotoxicity associated with the parent compound. Pegylated liposomes and other nanoparticle formulations have been developed to reduce the cardiotoxicity of conventional doxorubicin and other anthracycline derivatives. Although liposomal doxorubicin was designed to alleviate the cardiac toxicity associated with conventional doxorubicin, some unique toxicities were observed, including acute infusion-related reaction and Hand-Foot Syndrome, which were not common with conventional doxorubicin. NC-6300 was developed to encapsulate epirubicin into the micellar nanoparticle to selectively deliver the drug into the acidic environment of the endosomal or lysosomal compartments of the target tumor cell. NC-6300 was also designed to stay in the blood circulation for a long period of time and accumulate in the tumor based on the enhanced permeability and retention effects. Superior anti-tumor activity of NC-6300 was expected due to efficient drug release in the tumor.2 IV once every 3 weeks. The baseline characteristics of the patients are listed in The phase Ib does-escalation trial of NC-6300 monotherapy (NCT 03168061) enrolled 29 subjects: 17 with soft-tissue sarcoma, 1 with osteosarcoma, and 11 with other solid tumors. Among those patients, there were 2 patients with angiosarcoma who experienced a partial response by investigator assessment. Originally, a comparative phase II study, accruing 150 patients in total, was planned to investigate NC-6300 + olaratumab vs olaratumab alone. However, the study protocol was amended to pursue an expansion cohort, exploring NC-6300 alone in angiosarcoma, due to market withdrawal of olaratumab. The expansion cohort of angiosarcoma was an open-label, non-randomized trial that enrolled 10 patients designed to further investigate the activity of NC-6300. The primary endpoint of the expansion cohort was progression-free survival (PFS). Patient visits took place at screening; on days 1, 8, and 15 of every cycle; and end of treatment. AEs were graded using the NCI Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03). Patients were treated with NC-6300 at 150 mg/mAlthough immunotherapy has significantly changed the standard of care for many advanced malignancies, neither all patients nor all disease states benefit. As a result, chemotherapy remains an important treatment modality for many individuals with advanced disease. Anthracyclines, including doxorubicin, are some of the most commonly used chemotherapeutic agents, but are limited by hematologic and cardiac toxicities. As a result, novel anthracyclines, such as epirubicin, were developed.1 Progression-free survival was similar in patients pre-treated with chemotherapy and in chemotherapy-naïve patients.1While doxorubicin-based chemotherapy remains a treatment of choice in metastatic soft tissue sarcomas, paclitaxel seems to be an effective treatment, specifically in angosarcoma. In a multicenter phase II trial to assess the efficacy and toxicity of weekly paclitaxel in patients with metastatic or unresectable angiosarcomas, a median time to progression of 4 months was observed.2Our expansion trial demonstrated the tolerability and safety of NC-6300 with the most common adverse events ≥30% in all grades being neutropenia (90%), thrombocytopenia (60%), fatigue (60%), and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). Adverse events regardless of the causal relationship with NC-6300 are listed in 4 In subjects with prior anthracycline treatment, the mPFS in the study presented here was 3.8 months, similar to the expected mPFS for treatment of angiosarcoma .5 In contrast, in subjects without prior anthracycline treatment, the mPFS was 8.2 months, as shown in 1The Kaplan-Meier method was used to calculate the median progression-free survival. The overall mPFS by investigator assessment for all subjects included in the trial was 5.4 months, similar to what was achieved, in prior published studies, with anthracycline (4.9 months) and paclitaxel regimens (4 months) for patients with metastatic or unresectable angiosarcomas.2 IV every 3 weeks was well tolerated and showed promising anti-tumor activity in patients without prior anthracycline exposure in this expansion cohort. Further investigation of the activity of NC-6300 is warranted.NC-6300 at the recommended dose of 150 mg/m


The epithelial-to-mesenchymal transition (EMT) is a biological process in which epithelial cells transform into mesenchymal-like cells that are capable of invasion, migration, and metastasis. EMT-positive diffuse gastric cancer shows a strong association with extensive lymph nodal metastases, advanced pTNM stage, peritoneal dissemination, chemo-resistance, and poor prognosis. E-cadherin, CD44, and ZEB-1 are cheap immunohistochemical markers of the EMT phenotype. Within the Lauren diffuse histotype, EMT status identifies two different phenotypes (EMT− and EMT+) with distinct clinico-pathological and prognostic characteristics.p = 0.010), pTNM stage (p = 0.032), and vascular invasion (p = 0.037) were observed in this group. The median numbers of positive nodes (13 vs. 5) and involved nodal stations (4 vs. 2) were higher in the EMT-positive group. The cancer-related survival time was 26 months in EMT-positive cases vs. 51 in negative cases, with five-year survival rates of 17% vs. 51%, respectively (p = 0.001). The EMT status had an impact on the prognosis of patients with <70 years, R0 resections, or treatment with adjuvant chemotherapy. Tumor relapses after surgery and peritoneal spread were significantly higher in the EMT-positive tumors. Conclusions: EMT status, when assessed through immunohistochemistry, identified an aggressive phenotype of MSS diffuse-type tumors with extensive lymph nodal spread, peritoneal dissemination, and worse long-term outcomes.Background: Although the prognostic value of the epithelial-to-mesenchymal transition (EMT) in gastric cancer has been reported in several studies, the strong association with the diffuse type may represent a confounding factor. Our aim is to investigate potential correlations among EMT status, tumor advancement, and prognosis in diffuse gastric cancer. Methods: Between 1997 and 2012, 84 patients with microsatellite-stable (MSS) diffuse-type tumors underwent surgery. The EMT phenotype was assessed with the E-cadherin, CD44, and zinc finger E-box binding homeobox 1 (ZEB-1) immunohistochemical markers. Results: Forty-five out of 84 cases (54%) were EMT-positive; more advanced nodal status ( Despite its decreasing incidence, gastric cancer (GC) remains one of the most common causes of death for neoplasms worldwide. Recent epidemiological trends have indicated a relative increase in the rate of the diffuse histotype at the expense of the intestinal type in the West. This could explain the lack of improvements in survival and the increasing rates of peritoneal carcinomatosis in recent periods ,2. The iIn the last years, two molecular classifications of GC  have been introduced, and extensive research is now ongoing to explore potential clinical applications of different molecular subgroups ,9,10. BoThe clinical significance of the EMT has been investigated in several neoplasms, and it has been found to be associated with advanced stages and poor prognosis, including in GC ,12,15. HThe aim of the present retrospective study was to evaluate the potential impact of EMT status on the clinical–pathological characteristics and survival of patients with MSS diffuse-type tumors treated with gastrectomy and lymphadenectomy, with a long follow-up period.Patients with primary GC who submitted to surgical resection at the Department of General Surgery and Surgical Oncology, University of Siena, Italy, between 1997 and 2012 were considered. For the present study, the following selection criteria were adopted: (1) availability of a tumor specimen in the tissue bank; (2) the patients submitted to up-front resective surgery, and neo-adjuvant or non-resected cases were excluded; (3) MSS tumors, with the exclusion of MSI tumors; (4) diffuse histotype according to Lauren classification, with the exclusion of intestinal or mixed types. All clinical and pathological data were retrospectively retrieved from a prospectively collected database, as previously reported . InformeAfter routine clinical staging with a CT scan, patients with potentially resectable GC were addressed to surgery. The aim of the surgical procedure was complete resection of the tumor with negative resection margins and extended  lymphadenectomy. For tumors located in the lower and middle third, a subtotal gastrectomy was performed, maintaining a proximal margin of at least 5 cm from the tumor; in all other cases, a total gastrectomy was performed. After surgery, cases were classified as R1/R2 when microscopic  or macroscopic residual tumor was present.Immediately after surgical resection, lymph node mapping was performed in the fresh specimen according to the Japanese classification, as previously reported. The number of removed and involved lymph nodes for each station was recorded. Lymph node stations were also divided into perigastric (stations 1 to 7), second level (stations 8 to 12) and third level stations (stations 13 to 16) according to the Japanese guidelines . For TNMFrozen samples of tumor tissue were retrieved for each patient in our biological bank. Microsatellite analysis was evaluated by using 5 quasi monomorphic mononucleotide repeats, namely, BAT-26, BAT-25, NR -24, NR-21, and NR-27, as previously reported in detail . We consFor IHC, all procedures were automatically carried out on representative 2 µm thick paraffin sections from each case by Benchmark Ultra  by using extended antigen retrieval and with DAB as chromogen. The following antibodies and dilutions were used: E-cadherin , CD44 , and ZEB-1 . Counterstain with Mayer’s Hematoxylin was applied for 2 min to each section. For each case, the IHC expression in the malignant cells was compared to the immunoreaction in normal epithelial and/or stromal cells (positive control). All markers were scored independently by two observers who were blinded to clinical data and to each other.For E-cadherin, a three-tiered score of positivity was applied by evaluating the percentage of stained tumor cells , whereas for CD44 and ZEB-1, a two-tiered score was used .Different patterns of expression  were considered for different markers. The expression of E-cadherin was classified as follows: (1) “normal/positive”: membranous immunostaining in more than 10% of the epithelial tumor cells; (2) “lost/negative”: absence of immunostaining or positivity in less than 10% of the epithelial tumor cells; (3) “abnormal”: cytoplasmic or heterogeneous expression . Altered expression of E-cadherin was defined as either complete loss of membrane staining or an aberrant cytoplasmic staining pattern ,21. MembWe considered all samples in which E-cadherin was aberrant  and at least one of the EMT-related markers (CD44 or ZEB-1) was positive as showing an EMT phenotype ,24 Figu.Adjuvant chemotherapy was proposed after surgery according to the tumor stage, R-status, and the patient’s general conditions and age. Then, patients were subjected to regular outpatient follow-up examinations according to a standard protocol . The fol2 test for categorical variables and with a t-test or non-parametric tests (Mann–Whitney) for continuous variables. The linear regression (R2) was used to explore the correlations between two linear variables. Survival curves were estimated by using the Kaplan–Meier method. Death due to cancer  was considered as the endpoint; as such, deaths due to causes other than gastric cancer were considered censored cases at the time of death. Survival curves were compared by using the log-rank test. A p-value < 0.05 was considered statistically significant.Statistical analysis was performed by using the SPSS statistical software (21.0). Numerical variables were expressed as the mean and standard deviation (SD) when normally distributed and as the median and interquartile range (IQR) if not normally distributed. Statistical associations between clinicopathological characteristics and EMT status were assessed with a χA total of 84 patients  fulfilled the selection criteria and were included in the analysis. Most tumors (73%) were in the two distal thirds. A subtotal gastrectomy was performed in 45 patients (54%), and a total gastrectomy was performed in 39 patients. The median number of lymph nodes removed was 41 (IQR: 31–56). An R0 resection was obtained in 56 patients (67%). At histology, most cases were classified in advanced stages; the serosa was involved in 62 cases (74%), and only 11 patients had negative lymph nodes (13%). A median number of nine positive nodes (IQR: 2–22) was found, leading to an advanced nodal status in most patients. Twenty-five patients (30%) were classified as M1 due to macroscopic metastases, extra-regional positive nodes, or positive peritoneal washing.p-value 0.010) and TNM stages  were observed in EMT-positive cases. Vascular invasion was also more frequent in these groups , whereas no significant differences were found in the number of removed lymph nodes, R status, or adjuvant therapy after surgery.After the IHC analysis, 45 cases (54%) were classified as EMT-positive, and 39 (46%) were classified as EMT-negative. In p-value 0.010). Furthermore, the median number of metastatic nodal stations was also higher in the former   b. A signve cases c.p-value 0.001). Survival data were also stratified according to the main clinical–pathological variables . All other factors, including tumor stage and WHO histotype, were not significantly different .The interaction between age and the clinical-pathological variables under study revealed that, of all considered factors, only the use of adjuvant chemotherapy differed significantly according to the age groups  and the routinary mapping of lymph node stations allowed an accurate topographic analysis of nodal spread according to the molecular type. The median numbers of positive lymph nodes and involved nodal stations were notably higher in the EMT-positive group; only three patients (6.7%) had negative lymph nodes, and 71% of cases were pN3. Although it is well known that the Lauren histotype affects the incidence, number, and distant location of lymph node metastases in GC, the EMT status could characterize a phenotype with more extensive nodal spread. The strong linear correlation between the numbers of removed and positive nodes is indicative of the biological aggressiveness of EMT-positive tumors and their propensity to invade multiple nodal chains . HoweverAnother important finding of the present study is the prognostic impact of EMT status in diffuse-type tumors. Most EMT-positive patients died due to GC during follow-up, with a median survival of 26 months vs. 51 months for negative cases, and the prognosis was particularly poor in advanced nodal stages and neoplasms involving the serosa. A greater propensity of EMT-positive tumors for peritoneal dissemination was also observed; on the contrary, the long-term survival and peritoneal spread of EMT-negative cases resemble the characteristics of the intestinal type. As such, the EMT phenotype may play a crucial role in the clinical correlation between diffuse-type and peritoneal carcinomatosis. Although the diffuse type has been proposed to be included in a unique pathological/molecular category, the present data indicate that a phenotype with more aggressive clinical behavior can be identified . InteresThe present study included patients who were treated in the pre-neoadjuvant era and then submitted to up-front surgery, even for locally advanced forms. Although this may be considered a limitation, the analysis of the correlations among EMT status, tumor advancement, and lymph node spread is reliable in neoplasms that are not submitted to neo-adjuvant treatments. These results indicate that patients with EMT-positive diffuse-type tumors have a poor probability of surviving in the long term when submitted to up-front surgery. The prognostic value of EMT status in patients submitted to neo-adjuvant chemotherapy remains unclear and should be analyzed in future studies.In our series, a favorable prognostic impact of negative EMT status was observed in patients submitted to adjuvant chemotherapy. Interestingly, this phenotype was associated with better prognosis at younger ages, whereas the long-term survival of aged patients was generally poor in both groups, independently from EMT status. It is important to note that almost all patients (93%) in the younger group were treated with adjuvant chemotherapy, in comparison with 48% of the aged patients. These data may fit with the hypothesis that EMT status could affect the response to chemotherapy in GC ,33, but The limitations of the present study include its retrospective design, its relatively small sample size, and the methods used for EMT evaluation. Although IHC may represent a limitation when compared with genomic analysis, this method is strongly encouraged for the molecular characterization of GC due to its limited costs. When confirmed in further studies, it could be an important gain for potential applications in a clinical setting ,27,28.The present findings need confirmation in external validation studies, and correlation analyses that are performed on endoscopic biopsies are necessary before drawing clinical and therapeutic implications. Potential changes in EMT markers induced by chemotherapy should also be considered. However, the present results indicate that the analysis of EMT status could expand the molecular characterization of GC. Preoperative biopsy of GC should focus on the assessment of MSI, EBV, and EMT phenotypes. The evaluation of this panel of molecular markers could entail indications for neo-adjuvant therapy, up-front surgery, and, in EMT-positive cases, a multimodal approach that includes hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC), in consideration of the greater propensity for peritoneal spread . PotentiThe results of the present study indicate that EMT status could be able to be used to identify a phenotype of diffuse-type tumors with a more advanced stage, extensive lymph nodal spread, peritoneal dissemination, and poor prognosis. This could have important scientific and clinical implications in the context of a tailored therapeutic approach to GC.


N = 1,121), findings reveal a significant positive correlation between mask-wearing and other preventive behaviors. Moreover, knowledge of COVID-19 and trust in government significantly predicted mask-wearing. Implications of the results are also discussed in the cross-cultural context. Critically, findings could provide practical implications for public education and policymaking by uncovering how to more effectively promote compliance with recommended preventive behaviors during our ongoing struggle with COVID-19.Mask-wearing is the simplest yet most effective preventive behavior during COVID-19. However, it has sparked great controversy, particularly in America. Little is known about what psychosocial factors predict people’s decision to mask. This research challenges three myths about mask-wearing. First, does mask-wearing provide a false sense of security? Second, is knowledge of COVID-19 a more robust predictor than political ideology of mask-wearing behavior? Third, does resistance to masks reflect anti-authoritarianism or a lack of trust in government? With nationally representative samples across two cultures ( Indeed, universal mask-wearing has been recommended to limit the transmission of the novel coronavirus . Despiteairborne , with tiairborne .Nevertheless, mask-wearing has sparked great controversy . In the U.S., in particular, it is not merely an issue of public health but also a political one. Even over a year after the virus was first detected, resistance to masks still lingers. For example, the Federal Aviation Administration stated that airlines have reported 1,900 incidents of unruly passengers refusing to wear face masks . Given tThis research is exploratory in nature and aims to debunk three myths about mask-wearing to prevent the transmission of COVID-19. First, there are concerns that mask-wearing could engender a false sense of security in relation to other methods of infection control such as social distancing and handwashing. However, there is little empirical evidence to support the contention that wearing masks would mean other approaches to infection control would be overlooked . Does maSecond, the politics of mask-wearing has been coined the new culture war in the U.S. . There iFurthermore, during the avian influenza (AI) outbreak in East Asia, people who had correct knowledge about AI were more likely to practice AI preventive behavior . GreaterThird, one commonly cited resistance to masks is personal freedom. People do not want the government telling them what to do. Mask requirements have thus been considered a serious infringement or a threat to personal freedom. Escalating tension over the precaution has spurred protests, fights, and even a fatal shooting . This peThe most recent pandemic recorded prior to COVID-19 was the H1N1 influenza outbreak in 2009. Previous research with H1N1 responses revealed that trust in government was strongly associated with adherence to health guidelines –23. The In short, trust in government plays a crucial role in shaping people’s preventive behavior; the public does not necessarily trust the government’s recommendations and that lack of trust will impact the extent of its cooperation. Does resistance to masks reflect people’s anti-authoritarianism or rather a lack of trust in government? Building on previous findings reviewed above, we hypothesized that trust in government and knowledge of COVID-19 will make the strongest uniquely significant contribution to the explanation of mask-wearing behavior (H2).Beyond the U.S., masks have been broadly accepted in many European and Asian countries. The main aim of this research was to examine the topic in a cross-cultural context, in order to further validate the proposed hypotheses. As such, the initial focus was to understand the key predictors of mask use across cultures, above and beyond various sociocultural variables, as opposed to cross-cultural comparison per se.Interestingly, while there is thought to be a mask-wearing culture in East Asia, it is argued to be rather an impact of the SARS outbreak in 2003 . In TaiwThis research represents an important topic of current research as mask-wearing is the visual consequence of a pandemic that is present in the everyday lives of most people. Individual decisions made during the COVID-19 pandemic shape the course of the virus’s spread and the risks facing human populations. Critically, findings could provide practical implications for public education and policymaking by uncovering how to more effectively promote compliance with recommended preventive behaviors during our ongoing struggle with COVID-19.https://aspredicted.org/blind.php?x=jd8jz9). We examined what predicts mask-wearing in a representative Western culture, the U.S., by testing the proposed hypotheses with a nationally representative sample of American adults in late 2020. In addition, we investigated mask-wearing behavior in a benchmark case in East Asia, Taiwan, by testing the hypotheses with a nationally representative sample of Taiwanese adults in early 2021. Across both samples, we also sought to control for various psychosocial variables previously suggested to correlate with adherence to public health measures, such as perceived threat of COVID-19 [This research aims to debunk three myths about mask-wearing: (a) Mask-wearing provides a false sense of security, (b) Political ideology is the main predictor of people’s mask-wearing behavior, (c) It is all about personal freedom. Building on previous findings, our hypotheses were two-fold: (a) There will be a significant positive correlation between wearing masks and other approaches to infection control, i.e., handwashing and social distancing (H1), and (b) Knowledge of COVID-19 and trust in government will make the strongest uniquely significant contribution to the explanation of mask-wearing behavior (H2). Both hypotheses along with the study design, planned sample size, inclusion/exclusion criteria, and planned primary analyses were pre-registered on aspredicted.org . Each participant gave written consent before taking part online.f2 = .07). Twenty-four participants were excluded for failing to consent or complete the survey. Five participants were also excluded for failing the attention check questions, resulting in a valid sample size of 531 . Participants’ age ranged from 18 to 88 . For a snapshot of the sample characteristics, please refer to A nationally representative sample of 560 American adults in terms of age, gender, race, and ethnicity was recruited via Cloud Research for this study . Each participant was compensated USD $2 for their participation. A priori power analysis using G*Power  indicatestrongly agree to all survey questions) were excluded, resulting in a valid sample size of 547 . Participants’ age ranged from 21 to 81 .A nationally representative sample of 561 Taiwanese adults in terms of age, gender, and residence were recruited via a local market research agency for this study . Each participant was compensated TWD $60 (approximately USD $2) for their participation. To ensure data quality, fourteen participants whose responses demonstrated response sets . Specifically, three COVID-19 compliance behaviors were measured, including the frequency of mask-wearing, handwashing and social distancing. Participants responded by self-reporting the frequency of each behavior ranging from 0% to 100%. In particular, two items used to measure mask-wearing behavior read, “I wear a mask ___ of the time when around people indoors” and “I wear a mask ____ of the time when around people outdoors.” Higher scores indicate higher frequency of mask-wearing and other COVID-19 compliance behaviors.strongly disagree) to 5 (strongly agree). A sample item from the scale read, “Thinking about the coronavirus makes me feel threatened.” Higher scores indicate higher individual perceived threat of the COVID-19 pandemic.The 3-item short version of the Perceived Coronavirus Threat Questionnaire  was usedstrongly disagree) to 6 (strongly agree). Higher scores indicate higher individual perception of the reality of the COVID-19 pandemic.Items were adapted from Conway et al. (2020), participants were asked to indicate whether they have known someone infected with or died of COVID-19 and whether they have been tested for COVID-19  . Particistrongly disagree) to 5 (strongly agree). A sample item from the scale read, “What our country needs most is discipline, with everyone following our leaders in unity.” Higher scores indicate higher authoritarian tendency.We adopted the 6-item Very Short Authoritarianism (VSA) scale  to measuextremely liberal) to 5 (extremely conservative), with higher scores representing more conservative orientation. For validation in the U.S. sample, we used chi-square independence test to assess the association of self-report ideology with participants’ 2020 Presidential vote choice  and partisan affiliation . Results indicated that ideology had large effects associated with presidential vote choice  and partisan affiliation . Results indicated that ideology had medium effects associated with presidential vote choice (strongly disagree) to 6 (strongly agree). We then calculated a composite “knowledge of COVID-19” score to be used in subsequent analyses, with higher scores representing higher knowledge of the COVID-19 pandemic .To measure knowledge of the pandemic and prevention of the transmission of COVID-19, we used both a 5-item self-reported subjective knowledge scale  and a 6-item objective knowledge scale . Participants responded using a six-point Likert scale ranging from 1 (strongly disagree) to 6 (strongly agree). Items assessing general trust in government were modified  to fit the Taiwanese context. Higher scores indicate higher trust in the American/Taiwanese government.To measure trust in government, we asked participants to respond to 5 items assessing their trust in the government generally  in terms of percentage (0–100%) as well as their trust in the government’s response to the pandemic specifically  on a six-point Likert scale ranging from 1 (strongly disagree) to 6 (strongly agree).Given Taiwan’s previous SARS experience, we also included measures to assess its impact on people’s mask use during COVID-19. Three items were included to assess prior experience with SARS: “Prior experience with SARS taught me how to better take preventive measures,” “I trust the government’s guidance based on its SARS experience,” and “SARS showed that we must combat a pandemic with unity.” Participants responded on a six-point Likert scale ranging from 1 , race (dummy coded with Asian as the reference category), marital status (dummy coded with married as the reference category), residence (dummy coded with West Coast as the reference category), educational attainment, and annual household income.For the Taiwanese sample, the race (dummy coded with Han serving as the reference category) and residence (dummy coded with North as the reference) options were modified; participants were asked to report their monthly income in New Taiwanese Dollar (NTD).After giving their written consent at the beginning, participants responded to the questions outlined above in an online survey. All questions were randomized. They also answered the demographic questions before reading the debrief form and signing off the webpage.Since data collection took place amid the pandemic and our survey included questions asking whether participants have known someone died of COVID-19, participants were granted the right to skip any questions they did not feel comfortable answering. To handle missing data, we used the full information maximum likelihood (FIML) method and followed Newman’s (2014) guidelines . Of the F = 59.24, p < .001 under α = .05), suggesting that mask-wearing significantly predicted the covariance matrix between social distancing and handwashing. Next, as reported in To validate H1, we conducted multivariate regression to examine the effect of mask-wearing in predicting handwashing and social distancing . MANOVA was first performed to examine whether mask-wearing can explain the covariance matrix between handwashing and social distancing. Results indicated that Wilks’ Lambda = 0.803  at stage one (S1); authoritarianism and political ideology were entered at stage two (S2); knowledge of COVID-19 and trust in government were entered at stage three S3). Descriptive statistics and correlation matrix among key variables are displayed in Tables . Descrip2 (20%) remained less than a small effect. Adding S3 to the regression model explained an additional 8% of the variation in mask-wearing and this change made the overall R2 (28%) reached a large effect, suggesting that knowledge of COVID-19 and trust in government contributed significantly to the S3 model. When all the independent variables were included in S3 of the regression model, the most significant predictors of mask-wearing were perceived threat of COVID-19 , race , knowledge of COVID-19 , general trust  and specific trust in government .As shown in In line with previous research , resultsF = 65.02, p < .001 under α = .05), suggesting that mask-wearing significantly predicted the covariance matrix between social distancing and handwashing. Next, controlling for sociopolitical variables, mask-wearing positively predicted both social distancing and handwashing  reached a medium effect. Adding S3 to the regression model explained an additional 5% of the variation in mask-wearing and this change made the overall R2 (19%) much greater than a medium effect, suggesting that knowledge of COVID-19 and trust in government contributed significantly to the S3 model. When all the independent variables were included in S3 of the regression model, results showed that SARS experience was not a significant predictor. The most significant predictors of mask-wearing were perceived threat of COVID-19 , knowledge of COVID-19 , general trust  and specific trust in government , and authoritarianism .To validate H2, we repeated the three-stage hierarchical multiple regression analysis. As shown in By analyzing the dataset of a nationally representative sample in an East Asian cultural context, namely, Taiwan, we replicated results from the U.S. and provided evidence that people who adopt mask-wearing behavior also tend to social distance and wash hands frequently. Again, this finding supports H1 and debunks the myth that mask-wearing provides a false sense of security by overlooking other preventive measures. More importantly, results also showed that knowledge of COVID-19 and trust in government contributed significantly to mask-wearing behavior, replicating the pattern in the U.S. sample. This effect was robust to a host of control variables, including political ideology. In addition to threat perception, authoritarian tendency was found to significantly predict people’s decision to mask in the East Asian context. In short, our findings entail that while people’s general trust in government at the institutional level might be less likely to be built overnight, people’s specific trust in government including crisis management coupled with public education is also key in promoting adherence to guidance during a pandemic.What are the most important predictors of mask-wearing? Across two nationally representative samples, we show that mask-wearing significantly correlated with handwashing and social distancing during the COVID-19 pandemic cross-culturally . Furthermore, knowledge of COVID-19 and trust in government significantly predicted people’s decision to mask.Findings from the U.S. sample revealed that people who wore masks also took other preventive measures  against COVID-19; moreover, higher knowledge and general trust in government predicted mask-wearing behavior. These patterns were replicated in Taiwan. The converging results underscore the robustness of the link between knowledge as well as trust and mask-wearing across cultures, debunking Myths #2 and #3, respectively. Crucially, this link was robust to a broad set of control variables, including political ideology. The current findings thus debunk the myth that people who mask overlook other preventive measures (Myth #1). More importantly, they debunk the myth that ideology predicts people’s decision to mask (particularly in the U.S. context).Previous literature has identified several predictors of mask-wearing behavior, including perceptions of efficacy , 37, socIt should be noted that perceived threat of COVID-19 predicted mask-wearing most strongly in both cultures. We speculate that since our data collection took place during the height of the pandemic , this is understandable. Indeed, our results conform with existing COVID-19 research showing that more concerned individuals tend to display more behavioral compliance , 36. ForComparing the findings across cultures, it is interesting to note that authoritarian tendency significantly predicted Taiwanese decision to mask consistently. This suggests that in cultures where the tendency to rely on authorities is valued, such tendency can translate into safe behaviors amidst uncertain times such as a global pandemic. This also underscores our finding that even in the U.S. context, those who identified as Asian Americans tended to mask more compared with Whites. In short, the present research reminds us of the effect of culture on human behavior, including how people respond to crises like the COVID-19 pandemic .Altogether, our study extends the existing COVID-19 research by focusing on the simplest yet most effective preventive measure, mask-wearing, and examining psychosocial factors shaping its adoption. Furthermore, our study contributes to the cross-cultural psychological literature: on one hand, results highlight what motivates mask-wearing across cultures. On the other hand, results uncover why it is the most contentious preventive measure in some cultures while embraced unanimously in others.why  and the who  in predicting mask use and ultimately contributes to the development of a sound theory of mask-wearing behavior. We believe it is exactly this gap in research that makes the current study unique and valuable to extant literature.It should be noted that the present research is rooted in contemporary public discourse. We hope this initial inquiry sheds light on the importance of the Like all research, the current research has several limitations, providing opportunities for future research. First, given the risks of COVID-19, we relied on self-reported mask-wearing behavior rather than in-person observations. Future research could utilize the observational method or field experiments if possible. Second, while our research focused on two representative cases in the fight against COVID-19, future research should see if our results could be replicated in other cultural contexts. Third, future research could also examine how other psychological variables  might predict people’s mask-wearing behavior. Finally, as the pandemic progresses, whether and how the symbol of mask has changed  presents a fascinating topic for future research.sparking political debates similar to ones seen in the early days of the pandemic. Individual decisions made during the COVID-19 pandemic shape the course of the virus’s spread and the risks facing human populations. We hope that findings from this research shed light on what predicts people’s mask-wearing behavior during a pandemic both within and outside of the U.S. context. As mask-wearing is the visual consequence of a pandemic that is present in the daily lives of most people, this research represents an important topic of current research. Critically, we hope that the present findings provide practical implications for public education and policymaking by uncovering how to more effectively promote compliance with recommended preventive behaviors during our ongoing struggle with COVID-19 across the globe.As of early May 2021, more than 100 million Americans are fully vaccinated . Notwith


Liver transplantation (LT) is associated with high stress on the cardiovascular system. Ruling out coronary artery disease (CAD) is an important part of evaluation for LT. The aim of our study was to assess whether CT-derived fractional flow reserve (CT-FFR) allows for differentiation of hemodynamically significant and non-significant coronary stenosis in patients evaluated for LT.In total, 201 patients undergoing LT evaluation were included in the study. The patients received coronary computed tomography angiography (CCTA) to rule out CAD and invasive coronary angiography (ICA) to further evaluate coronary lesions found in CCTA if a significant (≥ 50 % on CCTA) stenosis was suspected. CT-FFR was computed from CCTA datasets using a machine learning–based algorithm and compared to ICA as a standard of reference. Coronary lesions with CT-FFR ≤ 0.80 were defined as hemodynamically significant.In 127 of 201 patients (63%), an obstructive CAD was ruled out by CCTA. In the remaining 74 patients (37%), at least one significant stenosis was suspected in CCTA. Compared to ICA, sensitivity, specificity, PPV, and NPV of the CT-FFR measurements were 71% (49–92%), 90% (82–98%), 67% (45–88%), and 91% (84–99%), respectively. The diagnostic accuracy was 85% (85–86%). In 69% of cases (52 of 75 lesions), additional analysis by CT-FFR correctly excluded the hemodynamic significance of the stenosis.Machine learning–based CT-FFR seems to be a very promising noninvasive approach for exclusion of hemodynamic significant coronary stenoses in patients undergoing evaluation for LT and could help to reduce the rate of invasive coronary angiography in this high-risk population.• Machine learning–based computed tomography-derived fractional flow reserve (CT-FFR) seems to be a very promising noninvasive approach for exclusion of hemodynamic significance of coronary stenoses in patients undergoing evaluation for liver transplantation and could help to reduce the rate of invasive coronary angiography in this high-risk population. Liver transplantation (LT) is associated with high stress on the cardiovascular system; cardiovascular complications can occur intraoperatively, early in the posttransplant period or later in follow-up , 2. SincThe aim of our study was to evaluate whether the assessment of CT-FFR allows for differentiation of hemodynamically significant and non-significant coronary stenoses in patients undergoing evaluation for LT.This retrospective study was approved by the institutional review board and the requirement to obtain informed consent was waived (21-10191-BO).Between September 2017 and March 2020, a total of 201 patients (128 men (64%), median age 57 years, mean age 57.4 ± 8.9 years, range 18–87 years, see Table CCTA was performed using a third-generation dual-source 384-slice CT scanner . Patients whose heart rates exceeded 65 bpm received up to 20 mg metoprolol intravenously. In addition, two jets of nitroglycerin spray (0.8 mg nitroglycerin) were applied in all patients. Prior to CCTA, a non-contrast scan was performed to determine the coronary calcium score. For CCTA a 70 ml bolus of iodine-containing contrast medium  was injected at an injection rate of 6 ml/s, followed by 20 ml of saline chaser at the same injection rate. Data acquisition was performed using a retrospective ECG-gated spiral acquisition with tube current modulation, targeting the 70–80% phase of the R-R interval and the mid-diastolic phase. For patients with a heart rate above 65 bpm, the 50–80% phase of the R-R interval was targeted. The examinations were performed with a reference of 300 mAs and 90 kV. For reporting, multiphase reconstructions in 5% steps of the R-R interval in 0.75-mm slice thickness were made as standard and archived in the PACS . CCTA examinations were evaluated using standardized procedures by two radiologists, a resident, and a board-certified cardiovascular radiologist with more than 15 years of experience. After assessment of the calcium score (Agatston score), visual morphological analysis of the individual coronary vessels was performed with the aid of axial data sets and multiplanar reconstructions as well as 3D imaging with regard to possible coronary anomalies and the presence of coronary plaques and stenoses. Post-processing was done using the software syngo.via . Coronary stenoses were graded according to the SCCT guidelines for the interpretation and reporting of coronary CT angiography  and a stComputation of machine learning–based CT-FFR was performed using a workstation-based, on-site solution  by a radiologist with 3 years of experience in cardiovascular radiology.The machine learning–based algorithm trained by Siemens Healthineers was described in detail by Itu et al : 12,000 The radiologist performing the analysis of CT-FFR was blinded to the results of the ICA. After loading the CCTA data, the centerline of each coronary artery was generated semi-automatically. If necessary, manual adjustment was performed to correct the centerline. In the next step, the software semi-automatically contoured the lumen of the coronary arteries. If necessary, manual adjustment was performed to correct the lumen contour. After confirming the centerline and the lumen contour, the stenotic region of the coronary vessel was defined manually. The final step in the workflow was the automatic computation of the CT-FFR values based on the segmented coronary tree model. The CT-FFR values were visualized as a volume rendering technique image of the ascending aorta and the coronary arteries with a colored representation of the CT-FFR values. By hovering with the mouse over the coronary tree, the CT-FFR values for a specific position could be displayed and saved for further analysis. In this study, the CT-FFR value was measured 1–2 cm distal to the stenosis.ICA was performed following local standards by an experienced, board-certified cardiologist via a radial or femoral approach including selective catheterization of the coronary arteries. The time interval between CCTA and ICA was between 1 and 4 weeks. The degree of stenosis of the coronary arteries was determined by visual assessment using quantitative coronary angiography (QCA). In addition to visual analysis, fractional flow reserve (iFFR) or instantaneous wave-free ratio (iFR) was determined for coronary lesions with visually uncertain hemodynamic significance, which was defined as coronary stenosis > 50% and < 80% in QCA. In the case of iFFR, adenosine was used as a hyperaemic agent. iFFR values ≤ 0.80 and iFR values ≤ 0.90 were considered hemodynamically significant.Statistical analysis including the determination of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy was done using the software R, version 4.1.0  and the software Microsoft Office 365 Excel (Microsoft Corporation).The mean Agatston score of all patients was 367 ± 882 . In 127 of 201 patients (63%), an obstructive CAD was ruled out by CCTA. In the remaining 74 patients (37%), at least one significant stenosis was suspected in CCTA; in these patients, CT-FFR was additionally measured and ICA was performed to further assess coronary artery lesions found in CCTA.In seven of the 74 patients for which CT-FFR was to be computed 10%), evaluation by the machine-learning-based algorithm was not possible because of the following reasons: (1) unrecognized coronary ostia, most likely due to motion artifacts; 2) insufficient contrast of a coronary artery in the periphery, which was wrongly assessed as total occlusion by the algorithm; (3) venous overlay with incorrect recognition of coronary arteries; (4) severe coronary calcifications with inadequate detection of the midlines; (5) insufficient contrast of the coronary arteries with erroneous detection of the same; (6) high-grade ostial stenosis of the RCA with erroneous detection of the following vessel; (7) noninterpretability in the presence of pulsation artifacts. The respective patients were therefore excluded from the study. Finally, a total of 67 patients , the CT-FFR was > 0.80 Fig. ; thus, tWhen CT-FFR ≤ 0.80 was used to determine the hemodynamic significance of a coronary artery stenosis Fig. , sensiti2, (2) tobacco use, (3) diabetes (both insulin- and non-insulin-dependent), (4) status post coronary revascularization, and (5) status post-stroke. All patients older than 50 years or patients that meet at least 2 of the above-mentioned risk factors are undergoing further cardiac evaluation. For patients with known CAD, this is done using ICA as a standard of reference. Patients with low to intermediate likelihood of CAD or contraindication for ICA receive CCTA to rule out coronary artery disease. If the result is negative, further evaluation by ICA is not deemed necessary. Patients with suspected coronary stenosis receive invasive cardiac catheterization for further evaluation. While further evaluation of multivessel coronary artery disease by ICA before liver transplantation seems appropriate, the reduction of invasive evaluation in patients with intermediate but finally hemodynamically non-significant coronary stenoses would be desirable. In ICA, different techniques exist for the quantification of hemodynamically significant stenosis. For example, fractional flow reserve (iFFR) or instantaneous wave-free ratio (iFR) can be used for this purpose. iFFR is a pressure wire–based index and represented by the ratio of pressure distal of a coronary stenosis and the pressure in the proximal coronary artery using a hyperaemic agent to assure maximum achievable blood flow in the coronary arteries [At our liver transplant center, all patients are screened for cardiovascular risk factors during transplant evaluation. Our protocol for cardiac workup for liver transplantation candidates encompasses the following items: (1) BMI ≥ 35 kg/marteries . iFR is arteries . For nonarteries . Howeverarteries , 18, shoIn our study, the high specificity and high NPV show that CT-FFR is well suited to correctly identify intermediate / not hemodynamically significant coronary stenoses. In about 70% of our cases, stenoses, initially rated as high-grade by visual assessment of CCTA data sets, were rated as hemodynamically non-significant after targeted analysis by use of the CT-FFR algorithm, which was confirmed by ICA. Thus, in the future, the additional use of CT-FFR might result that in a relevant proportion of patients ICA could be dispensed with.Other advantages of the on-site solution for CT-FFR calculation are the rapid availability and the short duration until the results are available. In our study, the time required for evaluation was not recorded separately, but other studies have evaluated the time required for evaluation with the algorithm we also used; Hu et al  requiredOur results are consistent with those of other research groups that have compared CT-FFR with the gold standard of invasively measured iFFR in different patient collectives: Coenen et al  showed iOur study has several limitations. First, patients being evaluated for LT are a very specific patient population with many comorbidities; furthermore, possible candidates may have been excluded during evaluation for LT for various reasons prior to receiving a CCTA for ruling out or confirming CAD; findings and results in this patient population cannot and should not be easily extrapolated to other collectives and an inclusion bias is possible. Second, patients with known CAD or high likelihood of CAD primarily underwent invasive evaluation by ICA at our center; they did not receive CCTA and are not included in this study. Third, not all patients who underwent ICA received measurements with iFFR or iFR; in fact, in most patients, hemodynamically significant stenosis was confirmed or excluded by visual analysis alone. Fourth, in this study, both iFFR and iFR were used if visual analysis using QCA was not sufficient to determine the hemodynamic significance of a coronary stenosis. In recent years, iFFR has been largely replaced by iFR at our institute but due to the recruitment period, both methods have been used in this study, though only in 2 patients that iFFR has been used. This could lead to a limited reproducibility of the results.Machine learning–based calculation of CT-FFR seems to be a very promising noninvasive approach for exclusion of hemodynamic significance of coronary stenoses in patients undergoing evaluation for liver transplantation and could help to reduce the rate of invasive coronary angiography in this high-risk population.