The phenotype of the chromosomal aberration 47, XXY exhibits considerable heterogenicity. In addition, epilepsy is extremely uncommon in individuals with this chromosomal disorder. As a result, the clinical characteristics of epilepsy in these patients remain poorly understood.Clinical data and the evolution of epilepsy in a boy diagnosed with chromosomal aberration 47, XXY were collected and analyzed. Furthermore, a systematic literature review was conducted to examine the relationship between chromosomal aberration 47, XXY and epilepsy in children.n = 9), epileptic spasms (n = 6), and generalized epilepsy (n = 4). There were six cases of infantile epileptic spasm syndrome (IESS) (n = 5) and developmental and epileptic encephalopathy (n = 1), one case of Lennox–Gastaut syndrome, and one case of D/EE‐SWAS. Apart from corticosteroids in IESS, 15 antiseizure medications (ASMs) were prescribed to eight children in this cohort, with valproate (n = 5) being the most frequently used.We identified a novel phenotype associated with the chromosomal anomaly 47, XXY in a 2‐year‐2‐month‐old boy who presented with self‐limited epilepsy with autonomic seizures at onset, followed by developmental and/or epileptic encephalopathy with spike‐wave activation in sleep (D/EE‐SWAS), which was responsive to corticosteroid treatment. Including the present case, we analyzed 21 cases of children diagnosed with epilepsy due to the presence of the 47, XXY chromosomal anomaly. The most common types of epilepsy were focal combined generalized epilepsy (The epilepsy types and syndromes associated with the chromosomal anomaly 47, XXY demonstrated considerable heterogeneity. Among the observed phenotypes, IESS and focal epilepsy, which displayed partial responsiveness to multiple ASMs, were the most prevalent. The epilepsy phenotypes of chromosomal anomaly 47, XXY are largely heterogeneous. Focal epilepsy that partially responds to multiple ASMs is the most common phenotypes. Supernumerary X chromosome may exist in males with an X‐linked gene phenotype. We extracted and summarized the clinical data from the aforementioned published cases for patients under 18 years of age.This study was approved by the Institutional Review Board of the Children's Hospital of Chongqing Medical of University . Written informed consent for the unpublished case was obtained from the patient's mother.33.1At the age of 2 years and 2 months, a previously developmentally normal boy experienced a unilateral tonic seizure lasting approximately 20 min after a minor head injury, without fever. The boy was born full‐term to non‐consanguineous parents after a normal pregnancy, and family history of seizures was unremarkable. Interictal EEG displayed a slow background and dominant spike‐waves in the temporal‐occipital area Figure . At the At 5 years and 8 months, his parents noted suspected intellectual disability. His tested intelligence quotient (IQ) score was 53, and S‐M score was borderline. According to the reported genetic variants associated with D/EE‐SWAS . For cases with data regarding neurological examination, 12 of 15 patients had varying degrees of mental retardation and/or behavioral problems . Hypotonia and hyperexcitable tendon reflex was reported in case 5. For the KS cases, only one individual (case 3) had a history of febrile seizure.n = 3), soft and delicate skin (n = 2), gynecomastia (n = 1), feminine fat distribution (n = 1), and sparse truncal hair (n = 1).For cases with endocrinological screening (cases 9−11), all presented with a feminine appearance, with a median onset age of 30 (7−36 years). Other symptoms included testicular atrophy , agenesis of corpus callosum , colpocephaly , lissencephaly , brain atrophy , punctate white matter lesions , and multiple cerebral infarctions .Brain imaging was performed in 20 cases, with eight individuals exhibiting non‐specific abnormal findings, including ventricular dilatation (3.4n = 5), followed by phenobarbital (n = 3) and carbamazepine (n = 3). At the end of follow‐up, except for cases 2 and 9 who were seizure‐free after VPA monotherapy, the other six cases were treated with two or more ASMs.In regard to epilepsy type, nine cases were diagnosed with focal combined generalized epilepsy , six cases were diagnosed with epileptic spasms (cases 1 and 17−21), four cases were diagnosed with generalized epilepsy , and two cases were diagnosed with unknown type (cases 13 and 15). For the epilepsy syndromes, there were five cases of IESS (cases 17−21), two cases of typical absence epilepsy (cases 8 and 9), one case of developmental and epileptic encephalopathy (case 1), one case of Lennox–Gastaut syndrome (case 6), and one case of D/EE‐SWAS (case 16). The remaining 11 cases were classified as non‐syndromic epilepsy. A total of 15 ASMs were introduced in a cohort of eight cases , excluding IESS and cases for which no ASM details were available. Among them, OXC and succinimide were eventually replaced by other ASMs. VPA was the most frequently used ASM , while four cases showed spikes predominantly in posterior regions, including the temporal, central, parietal, and occipital areas .4Our current case expanded the phenotype of 47, XXY abnormality with D/EE‐SWAS, which was responsive to corticosteroids. Furthermore, we also elucidated the clinical characteristics of this chromosomal disorder, particularly with respect to epilepsy. Apart from IESS, focal epilepsy and focal combined generalized epilepsy were the most frequently observed epilepsy types in individuals with KS. Most of these cases were non‐syndromic and exhibited varying degrees of intellectual disability.To the best of our knowledge, this study is the first to report on a case of 47, XXY chromosomal aberration with D/EE‐SWAS. Interestingly, this patient initially presented with EEG features of self‐limited epilepsy with autonomic seizures. However, due to the unresponsive nature of the individual to multiple ASMs, progressive deterioration in EEG findings, and the absence of acquired etiology, a genetic factor was suspected. Therefore, although chromosomal aberrations are rarely associated with D/EE‐SWAS, karyotypic analysis for 47, XXY should be considered and performed when necessary.n = 1). Given the extensive phenotypic heterogeneity associated with this abnormality, ASM selection was primarily based on specific epilepsy type. However, as other chromosomal abnormalities are associated with epilepsy (Singh et al., The estimated incidence of epilepsy linked to the 47, XXY chromosomal abnormality is ∼5.5% (Nieschlag, While testosterone deficiency, small and firm testes, and infertility are considered the primary symptoms of 47, XXY, there are no reliable indicators of KS in prepubertal children (Nieschlag, CDKL5 (Sartori et al., PCDH19 (Romasko et al., CDKL5 and PCDH19 phenotype, respectively, rather than the common features of KS in terms of onset age, epilepsy type, and hypogonadism. Aicardi syndrome, which primarily affects females, has also occasionally been reported in male cases with 47, XXY chromosomal aberrations (Chen et al., Unexpectedly, two patients have been reported to carry de novo The underlying mechanisms associated with the 47, XXY epileptic phenotype are yet to be fully understood. Alterations in brain structure and activation of the amygdala as well as epigenetics have been found in these patients (Skakkebæk et al., The main limitations of this research are the sample size of enrolled patients and the retrospective nature of the study, which make it difficult to gain a comprehensive understanding of this disorder, particularly long‐term prognosis, endocrinological disturbances, and responsiveness to ASMs. Hence, long‐term and multi‐center prospective studies are necessary to clarify the aforementioned concerns.Collectively, the epileptic phenotypes of the 47, XXY aberration are highly heterogeneous. Apart from IESS, the predominant epilepsy type was focal‐onset epilepsy. In cases of ASM‐unresponsive epilepsy with an “unknown” cause, karyotyping and chromosomal microarray analysis should be considered, particularly after conducting whole‐exome sequencing and other relevant tests and especially for males displaying X‐linked gene phenotypes.https://publons.com/publon/10.1002/brb3.3178.The peer review history for this article is available at


A higher intake of whole grain cereals, fruits, vegetables and fish and a lower intake of sweets were associated with higher HDL‐C and lower LDL‐C, LDL‐C/HDL‐C ratio, triglycerides, triglycerides/HDL‐C ratio, and TNF‐α at the 16th and 34th g.w. . No associations were found with the cord arterial and venous serum markers (p > 0.05). A greater MD adherence during pregnancy, driven by a higher intake of whole grain cereals, fruits, vegetables and fish, and a lower intake of sweets, was positively associated with the maternal lipid and inflammatory serum markers throughout gestation. MD adherence during pregnancy was not associated with cord serum markers.To examine the association of Mediterranean diet (MD) adherence during pregnancy with maternal and neonatal lipid, glycemic, and inflammatory markers. This study included 152 women from the GESTAFIT trial and a subsample of 35 newborns. The Mediterranean Diet Score, derived from food frequency questionnaires, was employed to assess MD adherence. Total cholesterol, high‐density lipoprotein‐cholesterol (HDL‐C), low‐density lipoprotein‐cholesterol (LDL‐C), triglycerides, and glucose were assessed in the mother  and in cord arterial and venous serum with standard procedures using an autoanalyzer. Pro‐inflammatory and anti‐inflammatory cytokines  were measured with Luminex xMAP technology. A greater MD adherence was associated with higher HDL‐C and lower LDL‐C, LDL‐C/HDL‐C ratio, triglycerides, triglycerides/HDL‐C ratio, and TNF‐α in the mother at the 16th and the 34th g.w. (|β|: 0.191–0.388,  A greater Mediterranean adherence during pregnancy, driven by a higher intake of fish, whole grain cereals, fruits and vegetables and a lower intake of sweets, was associated with healthier maternal lipid serum markers throughout the pregnancy course.Mediterranean adherence during pregnancy was not associated with the maternal glycemic profile.Mediterranean adherence during pregnancy was not associated with cord serum markers. Although measured weight is preferable, self‐report is a cost‐effective and practical measurement approach that shows very good concordance with measured body weight  were extracted from the antecubital vein in standardized fasting conditions (at the 16th and 34th g.w.), and arterial and vein cord blood samples were extracted immediately after delivery. All blood samples were collected in serum tubes and were allowed to clot (coagulation) at room temperature for 30 min. Subsequently, samples were centrifuged at 1750 rpm for 10 min at 4°C in a refrigerated centrifuge (GS−6R Beckman Coulter) to obtain serum, which was aliquoted and frozen at −80°C until analyzed.2.2.3Maternal concentrations of serum total cholesterol, HDL‐cholesterol, LDL‐cholesterol, glucose, phospholipids, triglycerides and C‐reactive proteins were measured with standard spectrophotometric enzyme assays . Cord arterial and venous serum total cholesterol, HDL‐cholesterol, LDL‐cholesterol, glucose, triglycerides, and CRP were measured with spectrophotometric determination . In addition, triglycerides/HDL‐cholesterol and LDL‐c/HDL‐c ratios were calculated  was measured with paramagnetic‐particle‐based chemiluminescence immunoassays .) were assessed with Luminex xMAP technology. The plate was read on a LABScan 100 analyzer (Luminex Corporation) with xPONENT software for data acquisition. Average values for each set of duplicate samples or standards were within 15% of the mean.Some maternal and cord arterial and venous pro‐inflammatory and anti‐inflammatory cytokines ‐IR was employed as previously described (HOMA‐IR = insulin × glucose/22.5)  with maternal and neonatal lipid, glycemic and inflammatory serum markers . The stepwise method was used, entering potential confounders  in Step 1 to test their association with each outcome . In Step 2 of the hierarchical regressions, we entered the MD adherence as a predictor and each lipid, glycemic, and inflammatory serum marker as outcomes in separate regression analyses after the inclusion of the relevant confounders  found in Step 1. These steps were the same in the cross‐sectional association models  and in the longitudinal association models . The longitudinal models were additionally adjusted for the exercise intervention in Step 2 to account for the possible effect of the intervention conducted within the GESTAFIT project on these outcomes. As an exploratory analysis, additional linear regressions were performed using the MD components as explanatory variables and maternal (at the 16th and 34th g.w.) and neonatal serum markers after adjusting for the confounders previously found relevant in the hierarchal linear regression.q = 0.05 .The Benjamini–Hochberg procedure , and the level of significance was set at 2.4The GESTAFIT project was approved by the Clinical Research Ethics Committee of Granada, Government of Andalusia, Spain .32) who had valid data in sociodemographic characteristics and MD adherence at the 16th g.w. , lower LDL‐C , LDL‐C/HDL‐C ratio , and lower triglyceride/HDL‐C ratio . There was evidence of statistical significance in the association of MD adherence with the total cholesterol level . After correcting for multiplicity, we observed that all the cross‐sectional associations between MD adherence and maternal immunometabolic serum markers remained significant.Differences in MD adherence and MD components between pre‐ and post‐intervention for the control and exercise groups (per protocol basis) are shown in Supporting Information: Table β = 0.348, p < 0.001), lower LDL‐C/HDL‐C ratio , triglycerides , triglyceride/HDL‐C ratio , and lower TNF‐α . After the multiple test correction, the associations between MD adherence, HDL‐C and triglyceride/HDL‐C ratio remained significant.Hierarchical linear regression analyses for the association of MD adherence with maternal glycemic, lipid, and inflammatory markers at the 34th g.w. are presented in Table p > 0.05).No associations were found between MD adherence and cord arterial and venous serum glycemic, lipid and inflammatory markers Table  . At the 34th g.w., a greater intake of whole grain cereals, vegetables and fish was associated with greater HDL‐C, lower LDL‐C/HDL‐C ratio, triglycerides, lower triglycerides/HDL‐C ratio and lower TNF‐α . After correcting for multiplicity, we observed that the cross‐sectional association between fish, HDL‐C, and LDL‐C/HDL‐C ratio remained significant. Additionally, the longitudinal associations between vegetables, fish and HDL‐C and the association between fish and triglycerides‐HDL‐C ratio remained significant.Table 4Our results suggest that a greater MD adherence during pregnancy, which seems to be driven by a higher intake of fish, whole grain cereals, fruits and vegetables and a lower intake of sweets, was associated with better maternal lipid serum markers  throughout the gestation. Notwithstanding, a greater MD adherence during pregnancy was not associated with cord arterial and venous serum markers.Our findings of an association between MD adherence and maternal cardiometabolic markers throughout gestation were generally consistent with results from other studies  that include predefined portions and absolute cut‐offs for each food group and assesses the frequency of consumption per month  in our study regarding cord blood could bias our findings. However, we found no differences in the baseline characteristics between women who provided cord serum samples and those who did not. Additionally, although our findings were corrected for multiple comparison testing, the likelihood of making a type I error might not be completely disregarded and future studies should confirm our findings. Several strengths of this study are worth considering. A detailed definition of the dietary habits and a valid assessment of the MD diet adherence were employed. Furthermore, lipid, glycemic, and inflammatory serum markers were assessed during the second and the third trimester of pregnancy and in the arterial and vein cord blood, which provides a more comprehensive understanding of materno‐foetal immunometabolic serum markers along the pregnancy course.Some limitations need to be highlighted. First, the observational design does not allow a clear cause–effect identification. Second, the results should be interpreted cautiously, as we could be limited to detect small association sizes. Larger studies should further explore these associations to corroborate our results. Third, the participants were enroled in an exercise intervention that might affect our findings. However, we included the group allocation as a confounder in our longitudinal analyses. Furthermore, we observed that the GESTAFIT exercise intervention did not have any effect on the MD adherence, nor on any of its components (except for legumes). Thus, the primary exposure  is not likely to have affected our findings. Fourth, the limited data (5Our results suggest a positive role of MD adherence during pregnancy on maternal lipid serum markers. Likewise, MD adherence might be positively associated with the inflammatory marker TNF‐alpha, although this finding should be corroborated in future studies. However, a greater MD adherence during pregnancy was not associated with neonatal lipid, glycemic, and inflammatory markers. Future studies are warranted to confirm these associations and determine the underlying mechanisms.Marta Flor‐Alemany was involved in conceptualization, formal analysis, methodology, validation, investigation, data curation, writing, original draft preparation, review and editing of the manuscript. Pedro Acosta‐Manzano was involved in the validation, investigation, data curation, writing, review and editing of the manuscript. Jairo H. Migueles was involved in the formal analysis, validation, data curation, writing, review and editing. Laura Baena‐García was involved in the, writing, review and editing of the manuscript. Pilar Aranda was involved in validation, writing, review and editing of the manuscript. Virginia A. Aparicio was involved in conceptualization, methodology, validation, resources, data curation, writing, review and editing, project administration and funding acquisition.The authors declare no conflict of interest.Supporting information.Click here for additional data file.


Patterns of treatment failure and subsequent treatment in non‐small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies.We identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)‐tyrosine‐kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed.p = 0.02; overall survival, not reached, p = 0.03).Eighty‐four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo‐progressive disease (PD) and central nervous system (CNS)‐sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM‐free , and 60% of patients (21/35) with pre‐existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M‐loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M‐loss (progression‐free survival, 5.4 vs. 16.5 months, EGFR‐mutated NSCLC with BM.PD during osimertinib treatment occurred preferentially in the thorax and pre‐existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies for  However, recent developments in molecular genetics have revealed multiple actionable oncogenic drivers in NSCLC, and treatment outcomes in patients with NSCLC with actionable mutations have improved in the last two decades.Sites of progressive disease (PD) and symptoms among patients with acquired resistance to the first‐ or second‐generation EGFR‐TKIs vary.Clinically authentic groups of EGFR‐TKI failure have been suggested, including dramatic, gradual, and local progression, according to the rapidity of PD.Despite osimertinib being the treatment of choice for EGFR T790M‐positive NSCLC, the pattern of osimertinib resistance and the appropriate subsequent treatment guidelines are limited in the real‐world setting.2This retrospective study included patients with NSCLC who commenced osimertinib treatment between June 2014 and November 2018 at the National Cancer Center in Korea. Clinical and demographic data, including age, sex, smoking status, performance status, and treatment modality, were collected from the medical record system. The disease extent was assessed using radiological reports. The study protocol and waiver of informed consent were approved by the institutional review board of the National Cancer Center (No. NCC 2019‐0305).Patient inclusion criteria were as follows: (1) recurrent or initially advanced or metastatic NSCLC with documented EGFR‐TKI sensitizing mutations, (2) treatment with osimertinib after disease progression following first‐ or second‐generation EGFR‐TKI treatment, (3) disease progression during osimertinib treatment, and (4) performance of imaging studies of affected organs and brain upon disease progression. Patient exclusion criteria were as follows: (1) treatment with other third‐generation EGFR‐TKIs prior to osimertinib treatment, (2) premature osimertinib treatment for less than 4 weeks, and (3) no T790M mutation confirmed after the failure of the previous EGFR‐TKI. Disease response during osimertinib treatment was evaluated using RECIST 1.1. Clinical variables, including anticancer treatment, results of imaging studies, and mutation profiles, were collected. Imaging modalities included computed tomography (CT), magnetic resonance imaging (MRI), whole‐body bone scans, and fluorodeoxygenase‐positron emission tomography/computed tomography (FDG‐PET/CT). After disease progression during osimertinib treatment was confirmed, the number of organs with metastases and the lesions in the organs from the imaging studies, additional EGFR mutation analysis, and types of subsequent treatment were detailed whenever possible. All patients were followed up until the date of death or March 2020, whichever occurred first.Patterns of PD during osimertinib treatment were classified as follows: (1) CNS‐ sanctuary PD, (2) oligoprogression (oligo‐PD), and (3) systemic PD. CNS‐sanctuary PD represents isolated CNS failure in the absence of systemic PD or leptomeningeal seeding. Oligo‐PD was defined as disease progression of no more than five lesions in no more than three organs when the remaining metastases were well‐controlled with systemic therapy. PD with pleural or pericardial effusion and ascites was excluded from oligo‐PD. The involvement of regional lymph nodes, including the hilar, mediastinal, and supraclavicular lymph nodes, was considered thoracic disease. PD other than CNS‐sanctuary PD and oligo‐PD were considered systemic PD.U test were used, when appropriate, to compare clinical and biological features among different groups. PFS and overall survival (OS) were determined using the Kaplan–Meier method, and survival curves were compared using the log‐rank test. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a logistic regression model, and hazard ratios (HRs) and 95% CIs were estimated using the Cox proportional‐hazards model. All statistical tests were two‐sided, and p‐values ≤0.05 were deemed statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 25 (IBM Corp.).Chi‐square test, Fisher's exact test, and Mann–Whitney 33.1n = 27), or had no documented T790M mutation after previous EGFR‐TKI (n = 10), or had no adequate brain imaging at the beginnings or end of the osimertinib treatment (n = 6), or treated with osimertinib less than 4 weeks (n = 4), or had no EGFR‐TKI before osimertinib (n = 1). As shown in Table n = 33, 39.3%), erlotinib , or afatinib . The remaining two patients were treated with erlotinib and bevacizumab according to the clinical trial protocol. After disease progression during initial EGFR‐TKI treatment, 58 (69%) patients were subsequently treated with osimertinib. Thirty patients (35.7%) were treated with cytotoxic chemotherapy before osimertinib, and the median number of chemotherapy regimens was 1.5. Sixteen patients (19.1%) received three or more chemotherapy regimens before osimertinib.Of the 132 patients screened for eligibility, 84 were included in the final analysis. In total, 48 patients were excluded because they were previously treated with another 3rd generation EGFR‐TKI other than osimertinib  and brain . Patients with isolated liver metastases  and metastases at other sites were rare . For the combination of metastases to the brain, the number of patients with different organ sites of metastasis was classified as one , two , and three or more . For combination metastases involving organs other than that of the brain, the proportion of patients with two and three or more organ sites of metastasis was 7.1% and 3.6%, respectively.At the start of osimertinib, the incidence of bone metastasis  was highest among all distant organs with metastases. The second most common organ with metastases was the brain . Many patients had metastasis to more than one organ, and patients with metastases to more than two organs were stratified by brain metastasis (BM) Figure . Twenty‐n = 67, 79.8%; brown bar from n = 49, 58.3%; blue bar), the fraction of PD involving BM decreased  from the baseline BM. The most frequent PD site was the thorax , which means PD occurred in the thorax, with or without PD in other organs. PD confined to only the thoracic region was observed in 38 (45.2%) patients. The other single organs that were frequently involved in PD were the bones  and brain . To better understand the interactions among the organs that were sites of metastasis from baseline to PD, the ORs of each combination were compared ; BM was related to PD in the brain ; bone metastasis was related to PD in the bones ; and liver metastasis was related to PD in the liver  and bones .Changes in metastatic lesions during osimertinib treatment are plotted as an alluvial diagram Figure . While td Figure . Each mep = 0.08, Table p = 0.05, Table Regarding the patterns of PD during osimertinib treatment, CNS sanctuary PD, oligo PD, and systemic PD were observed in 3 (3.6%), 15 (17.9%), and 67 patients (79.8%), respectively. When comparing clinicopathologic factors between oligo PD and systemic PD, the proportion of patients who received subsequent osimertinib treatment immediately after the previous EGFR‐TKIs seemed higher in oligo PD than in systemic PD  was not significantly longer than that in patients not treated with WBRT .The pattern of PD concerning BM is shown in Figure 3.3p = 0.04). Among the 84 patients included, 19 (22.6%) had died by the time of this analysis, including 2 and 17 patients in the oligo‐PD and systemic PD subgroups, respectively. The median OS was not reached in the oligo‐PD subgroup, and it was 44.9 months in the systemic PD subgroup (p = 0.05).Osimertinib yielded an objective response rate of 69.0% (58/84) and a disease control rate of 86.9% 73/84)  were subsequently treated with other modalities Table . Most pap = 0.04). Patients with systemic PD  received systemic treatment most frequently. They were administered post‐progression osimertinib with  or without  other agents, or switched to other EGFR‐TKIs , cytotoxic , and checkpoint inhibitors . Some patients with systemic PD  underwent radiation therapy . The subsequent treatment courses for patients with oligo‐PD comprised systemic therapy , post‐progression osimertinib , cytotoxic chemotherapy , and checkpoint inhibitors . Radiation therapy was administered with  or without  osimertinib. Moreover, radiation therapy was administered to the primary lung tumors in two patients with osimertinib and to the bone in one patient.The treatment pattern stratified by the predefined subtype is plotted in Figure 3.4EGFR mutations including exon 19 deletion , L858R mutation , G719X mutation , and T790M with other sensitizing mutations . T790M mutation was confirmed in all patients before osimertinib treatment was started, using either tissue  or plasma  samples; concomitant biomarkers were found in nine patients (10.7%) with PD‐L1 overexpression.At diagnosis, most tumors  showed sensitizing EGFR mutation analysis using tissue  or blood  samples. Genetic analysis was performed with either direct sequencing  or next‐generation sequencing . Pre‐existing EGFR sensitizing mutations persisted after the onset of osimertinib resistance in most cases . Some tested samples showed a T790M loss , whereas others did not , one had a CTNNB1 (p.D32Y) and a BRAF (p.V600E) mutation, and the other exhibited transformation to squamous cell carcinoma and contained a TP53 mutation (p.V73fs). In the nine samples with no T790M loss after osimertinib resistance, five had no additional mutations, and the other four had other mutations. There was a histological transformation from adenocarcinoma to large‐cell neuroendocrine carcinoma among the five samples without a T790M loss or additional mutations. Other genetic aberrations included TP53 mutations , an ATM mutation , a MET mutation , (1/5), and EGFR, EZH2, ERBB2, ERBB3, FGFR3, and GNA11 amplification (1/5) in the four samples without a T790M loss.After developing PD on osimertinib treatment, 23(27.4%) patients underwent an additional p = 0.05), and patients without a T790M loss showed significantly longer PFS to osimertinib  of PD cases during osimertinib treatment, a recent retrospective study reported that most patients with an EGFR‐mutant NSCLC, such as slow progression or oligo PD.Due to their superior potency over traditional cytotoxic chemotherapy, TKIs overcome some novel challenges in the therapeutic paradigm of Currently, concerning post‐osimertinib treatment, the focus is being placed on targeted therapies according to resistance mechanisms.Tumors that acquire resistance to osimertinib exhibit various survival mechanisms, including the C797S mutation, T790M loss, and other novel ones. Among recent investigations on the impact of resistance mechanisms, several studies have shown that the loss of T790M results in shorter PFS during osimertinib treatment.Our study is a retrospective analysis; thus, it presents limitations. However, we found that disease progression during osimertinib treatment preferentially involved previously affected organs. The thoracic region showed the highest prevalence of PD, while brain PD was relatively uncommon. Finally, systemic PD was more common than oligo‐PD or CNS‐sanctuary PD, which was associated with the interval between osimertinib treatment and prior EGFR‐TKI therapy.5, and brain PD was relatively uncommon, while systemic PD was more common than oligo‐PD or CNS sanctuary PD. We have also presented the various treatment options. When targeted therapy based on resistance mechanisms is unavailable, treatment strategies such as cytotoxic chemotherapy, osimertinib maintenance, and radiation should be considered.Our study showed that disease progression during osimertinib treatment preferentially involved the previously affected organs. The thoracic region most frequently showed PDHye Sook Kim: Data curation ; formal analysis ; investigation ; methodology ; project administration ; software ; supervision (supporting); validation ; visualization ; writing – original draft ; writing – review and editing . Kun Young Lim: Data curation ; investigation ; resources ; validation . Soo‐Hyun Lee: Data curation (supporting); investigation (supporting); resources ; validation . Hyae Young Kim: Data curation ; investigation ; resources ; validation . Youngjoo Lee: Conceptualization ; data curation (supporting); investigation ; project administration (supporting); resources . Ji‐Youn Han: Conceptualization (lead); data curation ; formal analysis ; funding acquisition (lead); investigation ; methodology ; project administration (lead); resources ; supervision (lead); validation ; writing – review and editing .This study was partly supported by a National Cancer Center Research Grant 2210551‐1. The study sponsor had no role in the study design, collection, analysis, and interpretation of data, writing of the report, and in the decision to submit the paper for publication.The authors declare that they have no conflicts of interest.The retrospective study protocol and waiver of informed consent was approved by the appropriate ethics review board .Table S1.Click here for additional data file.Figure S1.Click here for additional data file.


We hypothesized that the combination of 3D‐VPE and ERAS would improve the outcome of patients undergoing surgery for GBC.Three‐dimensional visualization preoperative evaluation This study aimed to determine if 3D‐VPE and ERAS can improve the outcomes and overall survival in patients with GBC, establishing a novel patient management strategy for GBC.n = 86; the control group) and those who underwent 3D‐VPE and ERAS between January 2011 and December 2017 (n = 141). Univariate and multivariate analyses were employed to assess the relationship among disease stages, lymph node invasion, and cell differentiation between the two groups. Cox regression analysis was used to investigate patient survival in these groups.A total of 227 patients with GBC were recruited and divided into two groups: those who received traditional treatment between January 2000 and December 2010 (p < 0.001) and dissected lymph node number (26.6 ± 12.6 vs. 16.3 ± 7.6 p < 0.001) compared to the control group. The median survival was 27.4 months, and the 1‐ and 3‐year survival rates were 84.4% and 29.8%, respectively, in patients who received combined management; in the control cohort, the median survival was 12.7 months, and the 1‐ and 3‐year survival rates were 53.5% and 15.1%, respectively. In addition, some postoperative complications and risk factors were diminished relative to the traditionally treated patients.Patients who underwent 3D‐VPE and ERAS showed a significantly higher R0 resection rate  treated at our institution over the course of 17 years. We show that three‐dimensional visualization preoperative evaluation and enhanced recovery after surgery can significantly improve prognosis and outcomes of patients with GBC and should be considered for wide use in clinical practice. All patients provided informed consent for the participation in this study.2.2The inclusion criteria included (1) pathologically proven GBC; (2) patients that were treated with cholecystectomy, radical cholectectomy, or GBC expanded radical operation; (3) patients that experienced enhanced‐computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and/or 3D visualization preoperative evaluation; or (4) patients that received ERAS management. The exclusion criteria were (1) lack of inageological examination; (2) lack of baseline characteristics including age, sex, gallstones, jaundices, albumin, AFP, CA19‐9, TNM stage, pathological diagnosis; (3)lack of perioperative and intraoperative management information; or (4) loss of follow‐up medical history.2.3Before 2011, two‐dimensional (2D) evaluation was performed routinely. All patients underwent enhanced computed tomography (CT), magnetic resonance imaging (MRI), and/or magnetic resonance cholangiopancreatography (MRCP). To clarify the relationship between the tumor and adjacent major blood vessels, CT angiography (CTA) is performed. The surgery was mainly dependent on the findings on 2D evaluation and on individual surgeon experience.After 2011, a 3D visualization system was used preoperatively and displayed intrahepatic and extrahepatic blood vessels and bile duct anatomy, the adjacent tissue associated with the tumor, the infiltration degree, and volume of the residual liver  after surgery to reduce postoperative stressIntravenous supplementation of albumin was administered to patients with low serum albumin levels (<30 g/L).Before 2011, an abdominal drainage tube was inserted, which was removed at least 7 days after surgery, and commencement of enteral nutrition was late. After 2011, patients received ERAS management, which included2.5CT scanning and testing for tumor serological markers were routinely performed at outpatient clinics every 3 months to monitor the progress of the GBC and the liver condition. Long‐term follow‐up was carried out via telephone every month after surgery, and information on postoperative survival, disease recurrence, and continued treatment were obtained.2.6p < 0.05 was considered statistically significant.A univariate analysis was conducted to compare patient characteristics, compliance variables, and outcomes between 3D‐VPE and ERAS protocol group and standard protocol group. Pearson chi‐squared or Fisher exact tests were used for categorical variables. The Kaplan–Meier method was used to estimate overall survival, which defined the time from first treatment or diagnosis to death from any cause. The log‐rank test was used to compare survival outcomes between the two groups. The restricted mean survival time (RMST) has been discussed extensively in survival analysis. Cox regression analyses were conducted to examine the associations among overall survival, demographics, and other covariates. All computations relied on the standard software . A two‐sided 33.1p > 0.05).The baseline characteristics of the patients in the absence before 2011) and presence (after 2011) of 3D‐VPE and ERAS are shown in Table 1 and pre3.2p < 0.001, Table p < 0.001, Table p > 0.05, Table p < 0.05, Table Patients who underwent surgery with standard protocol displayed a R0 resection rate of 67.4%, which was significantly higher than that in patients who underwent surgery with 3D‐VPE and ERAS protocol , and their 1‐ and 3‐year survival rate were 84.4% and 29.8%, respectively. In contrast, the median survival time in patients treated with standard protocol protocol was 12.7 months, (95% CI: 9.7–15.7) and their 1‐ and 3‐year survival rate were 53.5% and 15.1%, respectively. Evidently, the median survival time and 1‐year survival rates in patients who received the innovative combination management were significantly higher than those in patients treated conservatively with standard protocol (3.4p = 0.003), sex , TNM stage , tumor differentiation , and mortality  were significant risk factors of overall survival : 2.715–5.828, 4Over many decades, traditional surgical management techniques, including 2D imaging technology and personalized surgical pathways, have developed as the standard strategies for GBC resection.Cancer aggressiveness and subsequent metastasis contribute to the primary cause of GBC death.Radical R0 resection usually involves expanding the resection range and thus increases the potential for postoperative complications; hepatic failure and acute major bleeding of gastric mucosal lesions frequently occur in patients with obstructive jaundice, resulting in postoperative death.In the present study, patients enrolled from the two periods showed differences in diagnoses, presenting symptoms, and non‐perioperative variables that were not statistically significant. The homogeneity of the population in one local area may account for these similarities. Increased albumin, AFP, and CA19‐9 levels were associated with a higher incidence of morbidity; however, these factors were not significant predictors upon multivariate analysis.However, there were some limitations in this study: (1) Nonrandomized design experiment in a single institution; (2) Full‐ERAS protocol has been gradual completed in the past decade; (3) The sample size was not big enough; (4) Being retrospective in nature. Therefore, given the limits of a nonrandomized study from a single institution, in order to firmly establish this combined management as the standard regimen, increased sample size from multiple cancer centers with randomized trials is essential and thus favorable outcomes of the diseases are expected to benefit GBC patients.The anatomical specificity and aggressive nature of GBCs pose a challenge for effective surgical treatment; however, the widespread and routine use of the combination of 3D‐VPE and ERAS can pave the way for better surgical and postoperative outcomes for GBC and other cancers as well.5Our study demonstrate the association between implementation of 3D‐VPE/ERAS perioperative management and long‐term outcome of the gallbladder cancer patients with 23.1 and 12.7 months (3D‐VPE/ERAS vs. standard) of median survival time, 23.07 and 17.22 months (3D‐VPE/ERAS vs. standard) of estimate restricted mean survival time. Precision perioperative management implementation including 3D visualization preoperative evaluation and ERAS could benefit patients not only in‐hospital, short‐term outcomes, but also long‐term outcome with gallbladder cancer.Zi‐Yao Jia: Data curation ; formal analysis ; investigation ; methodology ; writing – original draft ; writing – review and editing . Yi‐Di Zhu: Formal analysis ; methodology ; resources ; writing – original draft ; writing – review and editing . Xiangsong Wu: Formal analysis ; resources ; writing – original draft . Jing‐Xiao Yang: Data curation ; formal analysis ; investigation ; methodology ; writing – original draft . Wen‐Guang Wu: Methodology ; resources ; writing – original draft . Xu'an Wang: Methodology ; resources ; writing – original draft . Min He: Methodology ; resources ; writing – original draft . Hui Wang: Methodology ; resources ; writing – original draft . Lin‐Hua Yang: Methodology ; resources ; writing – original draft . Jie Zhang: Methodology ; resources ; writing – original draft . Xue‐Chuan Li: Methodology ; resources ; writing – original draft . Lu Zou: Data curation ; investigation ; writing – original draft . Huai‐Feng Li: Methodology ; resources ; writing – original draft . Fei Zhang: Investigation ; methodology ; resources ; writing – original draft . Run‐Fa Bao: Methodology ; resources ; writing – original draft . Xu‐Ya Cui: Data curation ; investigation ; writing – original draft . Xiao‐Ling Song: Data curation ; investigation ; methodology ; writing – original draft . Wei Chen: Data curation ; methodology ; resources ; writing – original draft . Wei Gong: Conceptualization ; project administration ; supervision ; writing – review and editing . Maolan Li: Conceptualization ; funding acquisition ; project administration ; resources ; writing – review and editing . Yingbin Liu: Conceptualization ; funding acquisition ; methodology ; project administration ; supervision (lead); writing – review and editing .This study was supported by the National Key Research and Development Program of China (No. 2021YFE0203300), Shanghai Municipal Health Commission health Industry clinical research special project(No.20224Z0014), the National Natural Science Foundation of China (No. 82073206), the Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (No. 20SG14), the Basic Research Project of Science and Technology Commission of Shanghai Municipality , the Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center (No. SHDC12019110), Shanghai Clinical Medical Research Center for Digestive Diseases (No.19MC1910200).The authors declare no conflicts of interest that pertain to this work.


Gastric impactions (GI) have been identified as primary lesions  or associated with other intestinal lesions . Anecdotally, CGI resolve more rapidly with a better prognosis than LGI.To determine clinical, laboratory, and ultrasonographic findings, and short‐ and long‐term survival in horses with GI. We hypothesized that LGI carries a worse prognosis than CGI.Seventy‐one horses from 2 referral hospitals (2007‐2022).Retrospective cohort study. Gastric impactions were defined as feed extending to the margo plicatus after ≥24 hours of fasting. Clinical, diagnostic and outcome findings were compared between LGI and CGI. Long‐term survival was determined by a questionnaire.P = .003). Short‐  and long‐term survival  were not significantly different. However, Lone gastric impactions were more likely to experience gastric rupture . Lone gastric impactions were 8.7 times more likely to require dietary changes . Gastric impactions recurred in 21.7%  of affected horses.Twenty‐seven horses had LGI, 44 had CGI. Large intestinal lesions (32/44) were more common than small intestinal lesions (12/44). Concurrent gastric impactions resolved more slowly than LGI (LGI median 2 days, range 0‐8; CGI median 4 days, range 1‐10; Lone gastric impactions and CGI present similarly with a comparable prognosis, but LGI are more likely to rupture. Long‐term dietary changes are often necessary for horses with LGI. CIconfidence intervalCGIconcurrent gastric impactionsGIgastric impactionsIACUCInstitutional Animal Care and Use CommitteeLGIlone gastric impactionsSesensitivitySpspecificitySSRERBSocial Sciences Research Ethical Review BoardTNCCtotal nucleated cell countTPtotal protein1Gastric impactions (GI) are a well‐recognized but poorly understood cause of colic in horses. They have been defined as persistent, progressive accumulations of dehydrated ingesta that remain within the stomach after prolonged fasting, often defined as ≥24 hours.The primary aim of our retrospective cohort study was to describe and compare clinical and diagnostic findings, response to treatment and short‐ and long‐term outcomes in horses with LGI and CGI. We tested the hypothesis that treatment of horses with LGI took longer and carried a worse short‐ and long‐term prognosis than did treatment of those with CGI.2Clinical records from 2 equine referral centers were searched for horses diagnosed with GI from 2007 to 2022. Gastric impactions were defined as presence of feed material within the stomach, extending to the level of the margo plicatus, after at least 24 hours of fasting. Cases were excluded if the fasting period was <24 hours or if horses had known dental or hepatic disease. Horses <1 year old and donkeys also were excluded. A definitive diagnosis was achieved by gastroscopy, palpation of the stomach during exploratory laparotomy or necropsy. Confirmed cases were divided into CGI or LGI, depending on the presence or absence of concurrent intestinal lesions suspected of causing signs of colic.Clinical and laboratory information extracted from the case records included patient signalment, history, presenting clinical signs and laboratory findings. In cases of CGI, the nature of the concurrent lesion was noted. This classification was based on the interpretation of diagnostic or surgical findings by the attending clinician. Reports of ultrasonographic examinations, particularly stomach size but also descriptive abnormalities, were collated and compared if available. A gastric silhouette visible over ≥6 intercostal spaces during ultrasonographic examination was considered enlarged.Owners were contacted using an online or telephone questionnaire to evaluate long‐term outcome, recurrence of a GI or colic signs, and any management changes implemented. Ethical approval was obtained from the Social Sciences Research Ethical Review Board (SSRERB) of the Royal Veterinary College.2.1t‐test; nonparametric data comparisons were made using Mann‐Whitney U tests. Odds ratios were represented with 95% confidence intervals (CI). Significance was set at P ≤ .05.Data were analyzed using commercially available software (IBM SPSS Statistics 28.0.0.0). Normality of the data was assessed using Shapiro‐Wilk tests. Continuous data were represented as mean ± SD if normally distributed, or median and range (minimum‐maximum) if not normally distributed. Categorical data were represented as numbers and percentages. Chi‐squared tests and Fisher's exact tests were used to compare categorical measurements. Comparisons between parametric continuous data were made using a Student's 33.1Seventy‐one horses met the inclusion criteria; 38% 27/71) of cases were categorized as LGI and 62% (44/71) as CGI. The study population included 64.8% (46/71) geldings, 33.8% (24/71) mares and 1.4% (1/71) stallions. The mean age was 14 ± 5.6 years (n = 65); 6 horses were of unknown age. Twenty different breeds were represented including Warmblood and cross breeds (n = 15), Thoroughbreds and cross breeds (n = 9), Irish sport horses and cross breeds (n = 5), Welsh ponies (n = 5), Irish draught and cross breeds (n = 5), Cobs and cross breeds (n = 5), Arabians and cross breeds (n = 3), Shetland ponies (n = 3), ponies (n = 2), Connemaras and cross breeds (n = 2), New Forest ponies (n = 2), and 1 each of Polo ponies, Trotter horses, Andalusians, Selle Francais, Friesian, and Shires. Nine horses were of unknown breed. No significant differences in sex or age distribution were found between the 2 groups (Table  of casesP = .01). Seven percent (5/71) had experienced gastric rupture on arrival, which was confirmed by exploratory laparotomy (n = 3) or necropsy (n = 2). Of these, 60.0% (3/5) were classified as LGI and 40.0% (2/5) as CGI (P = .3).The most common reason for the presentation was acute colic , followed by chronic or recurrent colic . Other reasons included chronic esophageal obstruction, poor performance, pyrexia, anorexia, and weight loss. The median duration of clinical signs was 12 hours (1‐1344 hours). The horse that presented after 56 days (1344 hours) was excluded from the analysis involving the duration of clinical signs, because the clinical signs were intermittent in nature and the specific onset of signs before presentation could not be determined in this horse. Removing this horse, the median duration of clinical signs was 10 hours (1‐672 hours). The duration of clinical signs before presentation was significantly longer in the LGI group than in the CGI group  or during gastroscopy (P = 1.00). Using presence of large or very large GI during surgery as the gold standard, ultrasonographic findings had poor sensitivity and specificity of 67% and 20%, respectively, when used to diagnose GI. When comparing ultrasonographic enlargement with the presence of large or very large GI on gastroscopy, sensitivity was 55% and specificity was 50%. Rectal examination was performed in 54/71 (76.1%) cases . Rectal examination was performed in all horses with CGI that did not undergo immediate exploratory laparotomy or euthanasia. Of the LGI group, rectal examination was not performed in 4 horses; 3 of these did not present for colic signs. Two of these horses were referred for treatment of GI and 1 was referred for recurrent esophageal obstruction but gastroscopy identified an extensive GI. The fourth horse was a Shetland Pony and rectal examination was not performed because of its small size.Ultrasonographic measurements of the gastric silhouette were available in 26/71 (36.6%) cases. Of these gastric silhouettes, 24% (15/26) were considered enlarged, extending to ≥6 intercostal spaces. Ultrasonographically enlarged gastric silhouettes were not significantly associated with a large or very large size estimate of gastric impaction during surgery  cases, during surgical exploration of the abdomen in 34/71 (47.8%) cases, and at necropsy in 5/71 (7%) cases. In cases diagnosed during surgery, gastroscopy was later performed in 26/34 cases (76.5%): in 19/26 (73.0%) cases GI persisted, whereas in 7/26 (26.9%) it had resolved. The other 8/34 horses were subsequently euthanized. Overall, gastroscopy was performed in 58/71 (81.7%) cases . The median fasting period was 24 hours . No significant differences were found in gastroscopic findings, including gastric impaction size or presence of other gastric disease between groups  were diagnosed by gastroscopy, 2/6 (33%) by necropsy, and 1/6 (16.7%) at both gastroscopy and necropsy.P = .05).Necropsy was performed in 19/71 (26.8%) cases  and GI was confirmed in all but 1 horse (18/19). This horse was euthanized after GI resolution because of persistent colic signs, secondary to extensive adhesions throughout the abdomen. Gastric rupture was identified in 8/19 (42.1%) cases, 1/19 (5.2%) had a GI and duodenal rupture. Thirteen of 71 (18.3%) horses experienced gastric rupture. The LGI horses were significantly more likely to experience gastric rupture than CGI horses  consisting of 11.1% LGI (3/27) and 81.8% CGI (36/44) underwent exploratory laparotomy; 34/39 (87.1%) surgeries identified a GI (the remaining 5 cases developed postoperatively). Twenty‐five percent (9/34) were described as moderate GI, 28.6% (10/34) as large, and 42.8% (15/34) as very large.P = .03).A significant association was found between the size of the GI estimated at surgery and euthanasia  of horses underwent treatment for GI. Of the horses that were treated, 16.7% (10/60) received enteral fluid therapy only , 18.3% (11/60) received IV fluid therapy only  and 37/60 received both . Twenty‐seven percent (16/60) received carbonated, caffeine‐ and sugar‐free soft drink in combination with enteral fluid therapy (18.8% [3/16]), IV fluid therapy (6.3% [1/16]), or both (68.8% [11/16]). Prokinetics were not used in any horse during initial treatment. Because of the retrospective nature of the study, information regarding volumes of enteral fluids or carbonated soft drinks was not available. Of the horses receiving IV fluids, the median volume of fluids administered was 60 L (10‐170 L).P = .01). Median time to resolution of GI from the first day in hospital was 3 days . The CGI took significantly longer to resolve compared with LGI . Subjective evaluation of GI size at surgery  but not gastroscopy  was significantly associated with short‐term survival to discharge. One horse with CGI developed a second GI during hospitalization after attempted refeeding.During hospitalization, 19.7% of horses (14/71) experienced recurrent colic signs, more frequently in CGI cases than in LGI cases . Mean hospitalization time was 6.8 ± 2.9 days and did not differ between LGI (5 ± 3.2 days) and CGI .The percentage overall short‐term survival to discharge was 60.6% (43/71), which was not significantly different between LGI  and CGI . Long‐term follow‐up was available for 30/71 (42.3%) cases, consisting of 11/27 (40.7%) of LGI and 19/44 (43.2%) of CGI cases. Time since discharge ranged from 9 months to 10 years (3.7 ± 2.8 years). Of the 43 horses discharged, 9/43 (20.9%) were re‐admitted to the hospital for a recurrence of GI . At long‐term follow‐up, 5/28 (17.9%) were reported to have experienced a recurrence of GI . Combining these groups, the overall rate of recurrence was 21.7% . Recurrence was not significantly different between LGI and CGI.Of the 31 horses that did not survive, 28/31 (90.3%) were euthanized and 3/31 (9.7%) died; 14/31 (45.2%) of these horses were euthanized within the first 24 hours of presentation. Fourteen of 31 (45%) including 6/14 (42.9%) of the horses euthanized within 24 hours succumbed to fecal peritonitis secondary to gastric rupture, diagnosed at surgery or necropsy. Gastric rupture was more common in LGI than CGI  nor average age at death  were significantly different between LGI and CGI.Overall, 56.7% (17/30) of horses were still alive , whereas 12/30 (40%) had died . Two horses were sold shortly after discharge (both CGI cases), 1 was known to still be alive and the other was lost to follow‐up; both were excluded from analysis. Causes of death included colic , laminitis , chronic weight loss unresponsive to treatment , failure of gastric ulcer treatment , acute neurological disease , and fracture . The average number of years between discharge and death was 2.9 ± 2.1 years and the average age of death was 20.8 ± 7.1 years. Neither number of years between discharge and death . Altered diets varied from soaked short‐fiber diets, grass only diets to partial‐ or complete‐pelleted diets. The LGI cases were significantly more likely to require a partial‐ or complete‐pelleted diet compared with CGI cases . No significant difference in return to normal exercise was found . Five horses  still were being treated with metoclopramide; 40% (2/5) at the time of follow up, 40% (2/5) at the time of euthanasia. Metoclopramide was discontinued in 1 horse 4 months after discharge. This horse experienced intermittent recurrence of clinical signs despite maintenance on a partial‐pelleted diet and was eventually euthanized, because of a suspected gastric rupture.After discharge, 50.0% 14/28) of horses returned to a normal diet and exercise regimen. The remaining 50% (14/28) required ongoing management changes  did not. Short‐ and long‐term survival were similar for horses with LGI and CGI, but horses with LGI were significantly more likely to experience gastric rupture and require long‐term dietary modification, which might be associated with the longer duration of clinical signs before diagnosis and subsequent treatment.Gastric impactions in horses are not uncommon, but the literature on the condition remains sparse. Definition of GI as dehydrated feed material extending to the level of the margo plicatus is widely accepted,The presence of GI with another intestinal lesion only recently has been described, raising questions of whether GI occur first, potentially triggering an acute intestinal incident or whether GI are possibly secondary to concurrent intestinal lesions. The similar clinical presentation, response to treatment and short‐ and long‐term outcomes identified in our study suggest that the GI are the primary lesions with very similar etiology in LGI and CGI. However, other forms of colic also present with similar clinical signs despite different causes and it cannot be excluded that the 2 forms of GI are distinct diseases, despite their apparent similarities. Colon torsions previously have been associated with GIAlthough some clinical features differed between the LGI and CGI, the overall presentation and response to treatment were remarkably similar. Clinical and laboratory variables were largely comparable. Although rectal temperature was significantly higher in the LGI group, temperature remained within the normal range, and the difference was not clinically relevant. As might be expected, LGI cases had a significantly longer history of clinical signs before presentation, whereas clinical signs with CGI were usually more acute in onset. A previous study similarly reported a tendency of LGI to present subacutely or chronically, with a median duration of clinical signs of 3 days.Gastric impactions can be difficult to diagnose if gastroscopy is not performed and a less invasive method to determine stomach size would be useful. Unfortunately, ultrasonographic assessment of stomach size does not appear to be a sensitive or specific indicator for the presence of GI, and similar findings have been reported previously.Subjective evaluation of gastric impaction size at surgery, but not during gastroscopy, was significantly associated with short‐term survival, and horses with larger impactions at surgery were more likely to be euthanized. It appears that it is easier for surgeons to appreciate the full extent of a GI compared with gastroscopy. During gastroscopy, only the level of filling up to certain landmarks can be appreciated, and this feature may vary with the volume of gas insufflated during each procedure. With gradual feed accumulation, the stomach wall stretches, increasing to double or more of its original size.Contrary to clinical impression, CGI cases took significantly longer to resolve compared with LGI, whereas mean hospitalization time and short‐term survival were similar. Generally, during treatment, the acute concurrent intestinal lesion was addressed first, followed by treatment of the GI. This approach inevitably led to some delay in GI treatment in the CGI group, which could have contributed to the longer treatment times. The CGI cases also experienced recurrence of colic signs more commonly than did LGI cases, presumably because of recurring colic signs related to the concurrent lesion.In 5 CGI cases, GI developed acutely after surgical correction of intestinal lesions, whereas other CGI cases presented with acute intestinal lesions and GI were detected at surgery. Gastrointestinal inflammation and direct and indirect painful stimuli have been associated with changes in gastrointestinal motility in horses and other species.Against expectation, short and long‐term outcomes were not significantly different between the 2 groups. Gastric rupture was more common in LGI, which could be associated with the longer duration of clinical signs and later diagnosis and treatment of the condition in this group. Although short‐term recurrence of GI was rare, with only 1 horse developing a second GI during hospitalization, 22% of horses experienced at least 1 more GI after discharge, with no differences noted between LGI and CGI cases. This finding is higher than the 11% recurrence previously reported.Most limitations of our study are associated with its retrospective design. Reporting details differed among clinicians, hospitals, and over time, and information was not always complete. The exact time of diagnostic procedures such as ultrasonography was not always noted in the records. According to hospital protocols, most examinations were carried out within 1 to 2 hours of surgery or euthanasia, but in some cases more time could have elapsed and findings might have been affected. In addition, despite all efforts to rule out other intestinal lesions in the LGI group, some horses might have had unidentified reasons for their colic signs. Treatment details such as the exact volumes of enteral fluids and carbonated soft drinks often could not be obtained from the clinical records. Therefore, comparing the effects of certain treatments was not possible. Our study only included horses located in the south of England and results therefore might not be reflective of a broader international population. However, GI have been reported globally, arguing against distinct regional differences.In conclusion, GI can occur either alone or concurrently with other intestinal lesions and could be underdiagnosed in the presence of other intestinal diseases. Although their clinical presentations and outcomes are similar, gastric rupture and long‐term complications are more likely in LGI. The recurrence of GI might be higher than previously reported.Authors declare no conflict of interest.Authors declare no off‐label use of antimicrobials.Approved by the Social Sciences Research Ethical Review Board (SSRERB) of the Royal Veterinary College. URN: SR2022‐0119.Authors declare human ethics approval was not needed for this study.


The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in advanced upper tract urothelial carcinoma (UTUC) is less reported.In total, 106 consecutive advanced UTUC patients receiving ICI monotherapy were collected from nine high volume centers. Clinical outcomes were analyzed according to multiple parameters . Objective response rate (ORR), overall survival (OS) and progression‐free survival (PFS) were captured after ICI initiation.With a median follow‐up of 12.0 months, 25 patients in the first‐line group and 15 patients in the second‐line group died of UTUC. We reported a median OS of 18.0 months, a median PFS of 5.0 months, and an ORR of 38.6% for patients in the first‐line group; a median OS of 10.0 months, a median OS of 4.0 months, and an ORR of 27.8% for patients in the second‐line group. Complete response was observed in two patients in the first‐line group and one patient in the second‐line group with a total complete response rate of 2.8%. In the univariate and multivariate analysis, visceral metastasis with a hazard ratio of 2.4 was associate with poor OS. The most common treatment‐related adverse events included fatigue (11.3%), pruritus (10.4%), and diarrhea (6.6%).This real‐world study suggests that ICI monotherapy is active and has acceptable toxic effects for unresectable or metastatic UTUC as first‐line therapy in cisplatin‐ineligible patients or second‐line therapy in platinum‐refractory patients. PD‐1 inhibitor is active and has acceptable toxic effects as a first‐line or second‐line treatment in unresectable or metastatic UTUC. PD‐1 inhibitors could be an alternative choice for UTUC patients who are ineligible for cisplatin.. Single agent tislelizumab or toripalimab is generally well tolerated and has promising antitumor activities in patients who have received prior platinum‐based chemotherapy.Geographical factors were involved in various UTUC morbidities worldwide. A high proportion of UTUC patients were enrolled in clinical trials that were conducted in China. Given the inherent heterogeneity of UTUC, it is important to further explore the efficacy in the real‐world setting. Here, we focused on understanding the efficacy and safety of ICIs in UTUC patients.22.1After the study protocol was approved by the independent institutional review board, we retrieved data from the electronic medical records of UTUC patients who visited nine participating centers and received first‐ or second‐line anti‐PD‐1 antibody monotherapy between 2018 and 2021. We included adult patients aged 18 or older who had histologically or cytologically confirmed unresectable or metastatic renal pelvis and ureter urothelial cancer . The eligibility criteria for first‐line patients included ineligibility for cisplatin‐based therapy2.2n = 42, 40%), toripalimab , pembrolizumab , nivolumab , sintilimab , and camrelizumab . Patients were treated with anti‐PD‐1 antibody by intravenous infusion once every 3 weeks with tislelizumab 200 mg, toripalimab 240 mg, pembrolizumab 200 mg, sintilimab 200 mg, or camrelizumab 200 mg and nivolumab 240 mg once every 2 weeks. Dose discontinuation was performed by the manufacturer's instructions to manage adverse events (AEs). Treatment continued until disease progressed, intolerable toxicities, or death.ICIs used in this study were as follows: tislelizumab , partial response (PR), stable disease (SD) and progressive disease (PD). ORR and disease control rate (DCR) were defined as CR+PR and CR+PR+SD, respectively. OS was defined as the duration from the onset of ICI therapy to death from any cause. PFS was defined as the duration from the onset of ICI therapy to disease progression or death. Duration of confirmed response (DOR), defined as the time from the first documented complete or PR to disease progression or death.All observed AEs and the severity of AEs were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.2.4p < 0.05 was considered significant.Statistical analysis was performed using SPSS version 26.0 and GraphPad Prism 8. The PFS and OS curves were plotted using Kaplan–Meier method and survival outcomes were compared across groups using the log‐rank test. The Pearson chi‐squared test or Fisher exact test was used to compare categorical variables. The Cox proportional hazard model was used to evaluate the predictors of PFS or OS. 33.1Between 2018 and 2021, 188 consecutive UTUC patients were identified from nine sites around China. After excluding ineligible patients, 106 patients were included in this analysis , the 1‐year OS rate was 65.4%, and the median PFS was 5.0 months  guidelines recommended two ICIs in first‐line UTUC patients unfit for cisplatin depending on PD‐L1 status.The PFS of UTUC patients who received ICI monotherapy was rarely reported in clinical trials and retrospective studies. Our observations indicated that PFS after ICI initiation in first‐ and second‐line was 5.0 and 4.0 months, respectively. This is slightly higher than (2–3 months) in clinical trials enrolling first‐line cisplatin‐ineligible UC patients.p = 0.02). For UTUC patients, the exploratory subset analysis of this trial demonstrated prolonged OS in the pembrolizumab group .Since advanced UTUC patients usually present with renal impairment, they do not tolerate cisplatin combination therapy, which has promising efficacy in UC.In the present study, we retrospectively collected AEs in electronic medical record systems. The most common treatment‐related AEs included fatigue (11.3%), pruritus (10.4%), and diarrhea (6.6%). Serious AEs causing ICI discontinuation were infrequent. However, due to the inherent disadvantage of retrospective analysis, treatment‐related AEs might be underestimated.FGFR3) mutations are also more frequent in UTUC than lower tract UC.UTUC has been identified as a highly heterogeneous disease.Recently, many novel drugs, including erdafitinib, enfortumab vedotin, and sacituzumab govitecan, have emerged. Given the heterogeneity of UTUC, a combination strategy is promising in overcoming potential ICI resistance. Enfortumab vedotin plus pembrolizumab in first‐line cisplatin‐ineligible patients showed promising ORR PFS OS.We previously compared the efficacy and safety of PD‐1 inhibitors and carboplatin combined with gemcitabine in the first‐line treatment of cisplatin‐unfit UTUC patients.The major limitation of this study included relatively short follow‐up, retrospective design, and potential selection bias. Short follow‐up may affect the interpretation of survival outcomes including OS and PFS. While the ORR and AEs observed were much more convincing. In addition, most of the ICIs used in our study were tislelizumab, toripalimab, sintilimab, and camrelizumab that were only available in China, which limits the broad application of our results. Nevertheless, the strength of this study is its provision of a large cohort of real‐world patients from nine participating high‐volume medical centers.5In conclusion, ICI monotherapy is active and has acceptable toxic effects for unresectable or metastatic UTUC as first‐line therapy in cisplatin‐ineligible patients or second‐line therapy in platinum‐refractory patients.Ruopeng Su: Data curation ; formal analysis ; investigation ; methodology ; visualization ; writing – review and editing . Zeyu Chen: Data curation ; formal analysis ; investigation ; visualization . Daoping Hong: Data curation ; formal analysis ; investigation ; resources . Shuai Jiang: Data curation ; formal analysis ; investigation ; resources . Yichu Yuan: Data curation ; formal analysis ; investigation . Xingyun Cai: Data curation ; formal analysis ; investigation . Hai‐Long Hu: Data curation ; formal analysis ; investigation ; resources ; validation . Changde Fu: Investigation ; validation . Zhiyang Huang: Investigation ; validation . Zhenyu Wang: Investigation ; validation . Bing Zheng: Investigation ; validation . Jian Huang: Investigation ; validation . Zaoyu Wang: Investigation ; validation . Yige Bao: Investigation ; resources ; supervision ; validation . Ming Cai: Investigation ; supervision . Jianming Guo: Investigation ; supervision ; validation . Minfeng Chen: Investigation ; resources ; supervision . Qiang Wei: Investigation ; resources ; supervision . Jiwei Huang: Conceptualization ; data curation ; formal analysis ; funding acquisition ; supervision ; writing – original draft . Wei Xue: Conceptualization ; investigation ; project administration ; resources ; supervision .This study was supported by the Natural Science Foundation of Shanghai (grant number 21ZR1438900), the Incubating Program for Clinical Research Innovation of Renji Hospital (grant number PYIII20‐07), and Basic Oncology Research Program from Bethune Charitable Foundation (BCF‐NH‐ZL‐20201119‐024).The authors declare no potential conflicts of interest.This retrospective, multicenter study has obtained informed consent from participating patients.This retrospective, multicenter, real‐world study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the independent ethics committee at each participating center .Figure S1:Click here for additional data file.


Aspergillus ochraceus had a superior effect on HLF compared with COS from shrimp and crab shell with the same MWs. In conclusion, COSs could bind to and cause a conformational change in HLF. Therefore, COSs, especially those with low MWs, have potential as deproteinizing agents in contact lens care solution.Proteins in tears, including human lactoferrin (HLF), can be deposited and denatured on contact lenses, increasing the risk of microbial cell attachment to the lens and ocular complications. The surfactants currently used in commercial contact lens care solutions have low clearance ability for tear proteins. Chitosan oligosaccharide (COS) binds to a variety of proteins and has potential for use in protein removal, especially in contact lens care solutions. Here, we analyzed the interaction mechanism of COSs hydrolyzed from chitosan from different resources with HLF. The molecular weights (MWs) and concentrations of COSs were key factors for the formation of COS–HLF complexes. Lower MWs of COSs could form more stable COS–HLF complexes. COS from  Proteins in tears, including human lactoferrin (HLF), can be deposited and denatured on contact lenses. Here, we demonstrated chitosan oligosaccharide (COS) can bind to and cause a conformational change in HLF. The molecular weights and concentrations of COSs were key factors for the formation of COS–HLF complexes. The crystalline structures of COSs had less impact on COS–HLF complex formation. COSChitosan oligosaccharideGlcNd‐glucosamineGlcNAcd‐glucosamineN‐acetyl HLFhuman lactoferrinMWsmolecular weightsHuman tear is complex mixture of proteins, lipids, metabolites, electrolytes, and some small organic molecules . Over 40−1, accounting for around 25% of the total tear proteins [Lactoferrin is one of the most abundant protein in human tear. The average concentration of lactoferrin is around 2 g·Lproteins , 14. Lacproteins . The strproteins . TherefoThe surfactants currently used in commercial contact lens care solutions are mainly poloxamer (F127), polyethylene glycol‐400 (PEG‐400), and polyoxyethylene castor oil (EL‐35). However, these surfactants have low clearance ability for tear proteins , 18. In d‐glucosamine (GlcN) and N‐acetyl d‐glucosamine (GlcNAc) linked by β‐1,4‐glycosidic bonds between them [Chitosan oligosaccharide (COS) is composed of een them . The aveeen them , 23. COSeen them , 25, bioeen them , low viseen them , low alleen them . COS andeen them , 32, 33.This paper aims to study the mechanism of interaction between COS and lactoferrin, and to provide theoretical support for the addition of COS as a descaling agent into contact lens care solutions.Recombinant human lactoferrin (HLF) was purchased from Wuhan Heyuan Biotechnology Co., Ltd . Three COSs, named COS1, COS2, and COS3  of 1 : 8, 1 : 4, 1 : 2, 1 : 1, 2 : 1, and 4 : 1, and then, the final concentrations of COS reached 0.0025, 0.005, 0.01, 0.02, 0.04, and 0.08 g·L−1, respectively. All the mixtures were incubated for 30 min. Furthermore, all the experiments mentioned below were performed at 25 °C unless stated otherwise.The HLF was dissolved in 0.9% NaCl with a final concentration of 0.02 g·LF0 and F are the fluorescence intensities before and after the addition of the quencher, respectively; Q is the quencher concentration; Ksv is the Stern–Volmer quenching constant; Kq is the bimolecular quenching constant; and τ0 is the unquenched lifetime, which is 108 s.The binding parameters between COS and HLF were further investigated using Stern–Volmer equation :(1)F0FKa and n are the binding constant and the number of binding sites, respectively. Then, the number of binding sites in COS‐HLF complex could be determined from Eq. lgFlgF(2)ΔH, ΔG, and ΔS represent the enthalpy change, the free energy change, and the entropy change, respectively. R is the gas constant (8.314 J·mol−1·K−1), T is the Kelvin temperature, and Ka represents the binding constant at the corresponding temperature. The type of interaction force between COS and HLF can be determined using Eqs.  at 25 °C and 37 °C, respectively. The excitation wavelength was 280 nm, and the scanning wavelength was 250–500 nm. The fluorescence excitation and emission slit widths were 5.0 nm with a sampling interval of 1.0 nm.1FCK was obtained from Protein Data Bank (http://www.rcsb.org) with a resolution of 2.20 Å. The structure of COSs (chitobiose and chitopentaose) as ligands were generated in ChemDraw 3D. For construction of HLF, the pymol software was first used to remove the free water and the bound ions. Then, hydrogen atoms were added to the protein structure. The docking studies were performed with the autodock 4.0 software [pymol software.Molecular docking study was performed to determine the binding sites on HLF and the binding energy of protein–ligand complex. The 3D molecular model of HLF with PDB ID software . BrieflyN = 3). Statistical analysis was carried out by one‐way ANOVA using origin 2018. Differences in means were considered significant when the P < 0.05.All the experiments were conducted three times. Data were shown as the mean ± standard of three parallel experiments  on HLF at different concentrations were investigated using HLF as a model protein. Figure When the concentration ratios of COS1 : HLF were 2 : 1 and 4 : 1, the wavelength of UV absorption peaks was blue shifted from 280 nm to 275 nm. The results were probably due to the reduced hydrophobicity of HLF under these concentrations. However, blue or red shifts in the COS2‐HLF and COS3‐HLF complexes were not discovered. According to these data, the effect of COS1 for the structure changes in HLF was higher than those of COS2 and COS3. Chitobiose and chitotriose had more influence on the structure changes for HLF. The source of COS had less effect on HLF while the average MW for COS was more important.Fluorescence quenching of proteins is an effective method to determine the structural changes of polysaccharides when interacting with proteins. Figure max) of fluorescence for HLF in the absence of COS was around 330 nm, as shown in Fig. Aspergillus ochraceus, which had a different crystalline structure from COSs derived from shrimp and crab shells [The maximum emission wavelength  and the number of binding sites (n) can be calculated by Eq. (Ka value at the temperature of 310.15 K. The result indicated that a relatively high temperature improved the stability of COS1–HLF complex. The reaction between COS1 and HLF was a heat‐absorbing process. For COS2–HLF and COS3–HLF complexes, the maximum Ka values were at 298.15 K. The reactions were exothermic processes. These results demonstrated that the temperature affected the binding stability of COS–HLF complexes. Furthermore, the MWs (Table When COSs as small molecules bind independently to the set of equivalent sites on HLF, the binding constant (d by Eq. . Table 2ΔH > 0 and ΔS > 0 at temperatures of 298.15 K and 310.15 K meant the formation of COS1–HLF complex mainly relied on hydrophobic binding. In the COS structure, the –CH and –CH3 groups were hydrophobic [ΔH < 0 and ΔS < 0 indicated the formation of COS2–HLF and COS3–HLF complexes were mainly Van der Waals forces or hydrogen binding. Furthermore, ΔG < 0 in the three COS–HLF complexes demonstrated that the binding was spontaneous [In our study, COS–HLF complexes were always presented in solution, and no precipitation was observed. We determined the thermodynamic parameters of the complexes and studied the noncovalent interactions of the complexes to elucidate the binding properties of COS to HLF. Protein and polysaccharide complexes in aqueous media are generally driven by hydrogen bonding, hydrophobic interaction, Van der Waals forces, and intermolecular electrostatic forces to form complexes , 39, 40.rophobic . Therefontaneous . In brie−1. The amino acids bound to chitobiose were Asp217, Ser219, Asp220, and Glu223, surrounding with hydrophobic amino acids such as Val214, Phe215, Leu218, and Ala222 (Fig. −1. The amino acids bound to chitopentaose were Asn107, Pro134, Phe135, Asn137, and Thr139, as shown in Fig. The possible binding sites of COS on HLF were modeled using molecular docking. The conformation with the least free energy, which should be close to the experimental free energy, was chosen based on the results of the study Fig. . The bin222 Fig. . ChitobiChitosan oligosaccharide is an oligomeric mixture of glucosamine, which has no UV absorption from 190 nm to 500 nm. Lactoferrin has an UV absorption peak at 280 nm mainly due to the phenyl groups of Trp, Tyr, and Phe . With thThe intrinsic fluorescence of HLF was mainly contributed by the Trp residue alone, since Phe and Tyr have a very low quantum yield . If COS COS2 and COS3 had a static quenching on HLF (Table The molecular docking results verified that smaller MWs of COSs could form more stable binding of COSs to HLF. This analysis was consistent with our experimental results. Therefore, COS MWs and the concentrations had influence on the interaction between COS and HLF.A. ochraceus had different crystal structures [A. ochraceus on HLF was higher than that derived from shrimp and crab shells. These results demonstrated that different crystalline structures of COSs did not have significant influence on the interaction between COSs and HLF. However, under the same MWs, COS derived from A. ochraceus had better effect on HLF than COS from shrimp and crab shell. Our study suggested that COSs, especially low MWs, could be a good candidate to remove lactoferrin from tear proteins in contact lens care solutions.It was reported that source and treatment of chitosan had effect on its crystallinity, and further affected its characteristics . Chitosaructures , so COSsA. ochraceus had a greater effect on HLF compared with COS from shrimp and crab shell. Therefore, adding low MWs of COS from A. ochraceus to the contact lens care solutions could improve the HLF removal effect.In summary, the interaction mechanism between HLF and COSs from different crystalline structures and MWs was analyzed. The MWs and concentrations of COSs were key factors for the formation of COS–HLF complexes. The smaller the MWs of COS were, the more stable the binding of the complexes. The crystalline structures of COSs had less impact on the formation of COS–HLF complexes. However, under the same MWs, COS from The authors declare no conflict of interest.QL and SR conceived and designed the study. JL, SG, and BC performed the experiments. JL, SG, BC, QL, and SR analyzed the data. JL and QL wrote the original draft. SG and SR revised the paper. QL and SR supervised and acquired funding. All authors reviewed the results and approved the final version of the manuscript.


Hispanic patients with PAH have a high mortality rate. Our analysis suggests that guideline proposed risk assessment at baseline yields important prognostic information in this patient population.Pulmonary arterial hypertension (PAH) is a cardiovascular disease with high mortality rate. Current guidelines propose initiation and escalation of PAH‐targeted treatment based on a goal‐directed approach targeting hemodynamic, functional, and biochemical variables. This approach has been successfully validated in large Caucasian cohorts. However, given the low number of Hispanic patients enrolled in large PAH trials and registries, it is unknown if the same prognostic tools can be applied to this patient population. We analyzed a single‐center outpatient cohort that consisted of 135 Hispanic patients diagnosed with PAH. Baseline characteristics were calculated based on COMPERA, COMPERA 2.0 and REVEAL 2.0 risk scores before the initiation of PAH‐targeted therapies. The survival rate at 1 year after diagnosis was 88% for the entire cohort. The three established risk scores to predict PAH outcomes yielded similar results with reasonable discrimination of mortality in the different risk strata (all  Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature and an important cause of right heart failure and death. Over the years, treatment options for PAH have evolved, leading to substantial improvement in quality of life and outcomes.Most of these risk assessment tools are derived from PAH registries, which are mainly comprised of a Caucasian population and only a small percentage of patients were of Hispanic ethnicity. For example, in the REVEAL registry, less than 10% of the enrolled patients were identified as Hispanics.This was a single‐center retrospective study conducted in a large referral center, University Medical Center (UMC) at the American Mexican border with access to all advanced PAH‐targeted therapies. Of 232 total patients with PAH, 135 Hispanic PAH patients who met the inclusion criteria and were consecutively managed at the University Center between January 2015 and December 2021 were included. Patients were enrolled in this registry as inpatients with outpatient follow‐up or as outpatients only. Since the hemodynamic definition of PAH has changed, we used different enrollment criteria before and after 2019. We chose only patients who met the following criteria based on previous and most recent guidelinesAll patients were followed‐up with regular outpatient visits after the diagnosis of PAH. Survival was assessed from the date of the initial diagnosis and as a composite endpoint of death or lung transplantation. The survival status was censored in January 2021. All outcomes were retrospectively extracted from medical records. Mortality was based on reviewing the UMC medical record documentation such as discharge summaries.Risk stratification based on European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines:We categorized patients as low, intermediate, intermediate low, intermediate high, or high risk based on two abbreviated versions of the 2022 European PAH guidelines, including the World Health Organization Functional Class (WHO‐FC), 6‐min walking distance (6mwd), NT‐pro‐B‐type Natriuretic Peptide (NT‐proBNP).Risk stratification based on Registry to Evaluate Early and Long‐Term PAH Disease Management (REVEAL 2.0):Patients were classified into low‐, intermediate‐, and high‐risk groups based on the REVEAL 2.0 scoring system (see Supporting Information).All variables were assessed for symmetrical distributions. Means and standard deviations were reported for variables with uniform distribution. For asymmetrical variables, the median and interquartile ranges were reported. Table The median age of this cohort was 57 years (interquartile range [IQR]) 15, of which 76% were female. The database consists of 135 Hispanic patients diagnosed with PAH from 235 patients with PAH. Half of the patients had idiopathic pulmonary arterial hypertension (IPAH50.4%), followed by connective tissue disease‐associated pulmonary arterial hypertension , congenital heart disease‐associated pulmonary arterial hypertension , portopulmonary hypertension , and drug‐ and toxin‐induced pulmonary arterial hypertension . Most patients were classified as WHO‐FC III . In addition, 21% of the entire cohort had chronic kidney disease (CKD) based on the KDIGO criteria, 12% had reduced DLCO on initial pulmonary function testing, and 5% had evidence of pericardial effusion on baseline echocardiography. Baseline hemodynamic characteristics, medical comorbidities, NT‐proBNP values, vital signs, and hospitalization rates are shown in Table At baseline, only four patients (2.9%) were vasoreactive and treated with calcium channel blocker (CCB) therapy, while 46 patients (34%) and 89 patients (66%) were on PAH‐targeted monotherapy and combination therapy, respectively. The entire cohort's median follow‐up duration was 2.9 years (IQR 1.9–6 years). The observed 1, 3, and 5‐year median survival rates were 88%, 78%, and 71%, respectively. Thirty‐six patients (26.7%) died during follow‐up with a total of 34 deaths(95%) from a known cause: 27 deaths related to PH complications (81%) and 2 deaths (5.5%) from other causes.p < 0.001), 0.64  for COMPERA 1.0 and 0.79  for COMPERA 2.0, respectively  patients were in the low‐risk category, 20 (15%) were at intermediate risk, and 50 (37%) were at high risk. Stratification according to the modified ERS/ESC 3‐strata model Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 1.0 (described in Supporting Information: This study aimed to fill a knowledge gap in the outcomes and risk stratification of Hispanic PAH patients, the largest minority group in the United States. This study found that the Hispanic PAH cohort's baseline demographics, functional class, hemodynamics, and PAH‐targeted therapies are comparable to non‐Hispanic PAH cohorts. We found a higher proportion of patients with PAH‐CHD than in other Caucasian‐predominant cohorts. Similar to other PAH cohorts, mortality among Hispanic PAH patients remains high. Using the proposed REVEAL 2.0 and 3‐ or 4‐ category stratification of the modified ESC/ERS models allows for accurate risk prediction for Hispanic PAH patients at baseline. All risk scores seem to apply broadly to Hispanic PAH population, regardless of PAH subgroup.Even though some differences exist between the REVEAL and the abridged ESC/ERS risk stratifications, both strategies yield excellent prognostic value in largely Caucasian patients with PAHSeveral factors may have contributed to this observation. Compared to the REVEAL registry, our cohort consisted only of incident patients, which are prone to survivor bias compared to prevalent cohorts.Both the REVEAL 2.0 and the ESC/ERS risk scores, as early as 1 year after treatment and throughout the study period of 5 years, accurately differentiated between patients in our cohort with low, intermediate, and high‐risk for poor outcomes (see Figure Another considerable difference between REVEAL and COMPERA is that the former score uses weighted variables based on the contribution of each variable to the overall risk. Variables for the original REVEAL formula were calibrated from a cohort of only 9% Hispanic PAH patients and only 12% CHD‐PAHThis study has several limitations, including a relatively small number of patients, single‐center retrospective design, lack of a control group and lack of systematic follow‐up data that would allow REVEAL and ESC risk score assessments after the initiation of PAH‐targeted therapies. Furthermore, our cohort included incident patients only, which are susceptible to survivor bias. To optimize risk prediction, our study was not powered to elucidate which risk factors might carry more weight than others in Hispanic patients.In summary, our study shows that the REVEAL 2.0, the abridged ESC/ERS 3‐strata, and the 4‐strata risk stratification tools accurately predict outcomes in the treatment of treatment‐nave Hispanic patients at baseline. REVEAL 2.0 can be used to determine a treatment strategy when hemodynamic variables are present. For a noninvasive assessment, the 3‐ and 4‐strate ESC/ERS risk tools provide essential information about the clinical trajectory of an individual patient. Risk assessment in PAH is determined by many nonmodifiable risk factors, such as age, gender, and type of PAH, as well as modifiable factors such as comorbidities and symptoms. Future studies are needed to further understand modifiable risk factors based on ethnicity. This will contribute to a personalized medicine approach for the risk stratification and the management of PAH patients.Jose B. Cruz Rodriguez, and Khan O. Mohammad collected data; Kahtan Fadah, and Nils P. Nickel wrote the original manuscript; Debabrata Mukherjee, Haider Alkhateeb, Hernando Garcia, Dan Schuller, and Sandeep Sahay revised the manuscript and provided key feedback and insights. Kahtan Fadah, and Nils P. Nickel analyzed and created figures, tables, and Supporting Information. Nils P. Nickel supervised the project.Sandeep Sahay declare he is an advisor for Janssen, Bayer, United Therapeutics, Gossamer Bio, Altavant sciences, MERCK; Speaker United Therapeutics, Janssen; Steering committee member for Bayer and Liquidia technologies; Clinical Trial support from Bayer, Janssen, United Therapeutics, Gossamer Bio, Altavant Sciences, Keros; Received Research Grant from United Therapeutics. The remaining authors declare no conflict of interest.Written informed consent was not required for this study and was performed in accordance with Texas Tech University Institutional Review Board.Supporting information.Click here for additional data file.