Large Multicenter Cohort Study Research Articles

Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study

Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy13. This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome. A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %. Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.

Lung transplantation outcomes in underweight recipients: A single center experience

BackgroundCurrent guidelines recommend a body mass index (BMI) of 16 kg/m2 as the minimum threshold for lung transplantation, despite mixed evidence on outcomes in underweight patients. The current study aimed to describe survival outcomes of underweight patients who underwent lung transplantation at a single center. MethodsThis retrospective observational study included adult lung transplant recipients who underwent transplantation for the first time between March 2010 and March 2022 at King Faisal Specialist Hospital and Research Center and excluded patients with obesity. We defined an underweight status as a BMI <17 kg/m2. ResultsForty-eight of the 202 lung transplant recipients were underweight at the time of surgery. The underweight patients had similar lengths of hospital (p = 0.53) and intensive care unit (p = 0.81) stays compared to other patients. Thirty-three percent of underweight patients had died within 5-year follow-up, compared to 34% of patients who were not underweight. There was no significant difference in mortality risk between underweight patients and patients with normal BMIs in our multivariable Cox regression model (adjusted HR 1.57, 95%CI: 0.77–3.20, p = 0.21). Exploratory analyses revealed that a pre-transplant BMI <13 kg/m2 was associated with a trend towards increased 5-year mortality (adjusted HR 4.00, 95%CI: 0.87–18.35, p = 0.07). ConclusionsOur findings suggest that patients with BMIs of 13–17 kg/m2 may be candidates for lung transplantation. Large multi-center cohort studies are needed to confirm the lower BMI limit for safely transplanting patients.

Omicron BA.4/5 Neutralization and T-Cell Responses in Organ Transplant Recipients After Booster Messenger RNA Vaccine: A Multicenter Cohort Study.

In solid organ transplant (SOT) recipients, the primary vaccination series against Coronavirus Disease 2019 is 3 doses followed by boosters. We determined whether a fourth dose booster induced Omicron BA.4/5 neutralizing antibodies (nAbs) and T cells in a large multicenter cohort study. Serum was collected 4-6 weeks post-third and post-fourth doses of messenger RNA vaccine in 222 SOT recipients. nAbs were measured using a pseudovirus neutralization assay that targeted the Omicron BA.4/5 spike protein. A subset underwent T-cell testing. The median age of the cohort was 63 years (interquartile range [IQR], 50-68) with 61.7% men. BA.4/5 nAb detection increased from 26.6% (59 of 222) post-third dose to 53.6% (119 of 222) post-fourth dose (P < .0001). In patients with breakthrough infection prior to the fourth dose (n = 27), nAbs were detected in 77.8% and median nAb titers were significantly higher compared with those with 4 vaccine doses alone (P < .0001). Factors associated with a low BA.4/5 neutralization response after the fourth dose were older age (odds ratio [OR], 0.96; 95% confidence interval [CI], .94-.99), mycophenolate use (OR, 0.39; 95% CI, .20-.77) and prednisone use (OR, 0.34; 95% CI, .18-.63), and vaccine type (OR, 0.72; 95% CI, .51-.99), while breakthrough infection prior to the fourth dose (OR, 3.6; 95% CI, 1.3-9.9) was associated with a greater nAb response. Polyfunctional BA.4/5-specific CD4+ T cells significantly increased after 4 doses and were identified in 76.9% of patients at a median frequency of 213/106 cells (IQR, 98-650). In summary, a booster significantly increases BA.4/5-specific neutralization and polyfunctional CD4+ T-cell responses, suggesting protection from severe disease even with new Omicron variants. However, SOT recipients who are older and on mycophenolate and prednisone need additional preventative strategies.

Artificial intelligence annotated clinical-pathologic risk model to predict outcomes of advanced gastric cancer.

Gastric cancer with synchronous distant metastases indicates a dismal prognosis. The success in survival improvement mainly relies on our ability to predict the potential benefit of a therapy. Our objective is to develop an artificial intelligence annotated clinical-pathologic risk model to predict its outcomes. In participants (n=47553) with gastric cancer of the surveillance, epidemiology, and end results program, we selected patients with distant metastases at first diagnosis, complete clinical-pathologic data and follow-up information. Patients were randomly divided into the training and test cohort at 7:3 ratio. 93 patients with advanced gastric cancer from six other cancer centers were collected as the external validation cohort. Multivariable analysis was used to identify the prognosis-related clinical-pathologic features. Then a survival prediction model was established and validated. Importantly, we provided explanations to the prediction with artificial intelligence SHAP (Shapley additive explanations) method. We also provide novel insights into treatment options. Data from a total 2549 patients were included in model development and internal test (median age, 61 years [range, 53-69 years]; 1725 [67.7%] male). Data from an additional 93 patients were collected as the external validation cohort (median age, 59 years [range, 48-66 years]; 51 [54.8%] male). The clinical-pathologic model achieved a consistently high accuracy for predicting prognosis in the training (C-index: 0.705 [range, 0.690-0.720]), test (C-index: 0.737 [range, 0.717-0.757]), and external validation (C-index: 0.694 [range, 0.562-0.826]) cohorts. Shapley values indicated that undergoing surgery, chemotherapy, young, absence of lung metastases and well differentiated were the top 5 contributors to the high likelihood of survival. A combination of surgery and chemotherapy had the greatest benefit. However, aggressive treatment did not equate to a survival benefit. SHAP dependence plots demonstrated insightful nonlinear interactive associations among predictors in survival benefit prediction. For example, patients who were elderly, or poor differentiated, or presence of lung or bone metastases had a worse prognosis if they undergo surgery or chemotherapy, while patients with metastases to liver alone seemed to gain benefit from surgery and chemotherapy. In this large multicenter cohort study, we developed an artificial intelligence annotated clinical-pathologic risk model to predict outcomes of advanced gastric cancer. It could be used to discuss treatment options.

Lung Mycobiota α-Diversity Is Linked to Severity in Critically Ill Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) affects more than 200 million people worldwide. The chronic course of COPD is frequently worsened by acute exacerbations (AECOPD). Mortality in patients hospitalized for severe AECOPD remains dramatically high, and the underlying mechanisms are poorly understood. Lung microbiota is associated with COPD outcomes in nonsevere AECOPD, but no study specifically investigated severe AECOPD patients. The aim of this study is thus to compare lung microbiota composition between severe AECOPD survivors and nonsurvivors. Induced sputum or endotracheal aspirate was collected at admission from every consecutive severe AECOPD patient. After DNA extraction, the V3-V4 and ITS2 regions were amplified by PCR. Deep-sequencing was performed on a MiSeq sequencer (Illumina); the data were analyzed using DADA2 pipeline. Among 47 patients admitted for severe AECOPD, 25 (53%) with samples of sufficient quality were included: 21 of 25 (84%) survivors and 4 of 25 (16%) nonsurvivors. AECOPD nonsurvivors had lower α-diversities indices than survivors for lung mycobiota but not for lung bacteriobiota. Similar results were demonstrated comparing patients receiving invasive mechanical ventilation (n = 13 [52%]) with those receiving only noninvasive ventilation (n = 12 [48%]). Previous systemic antimicrobial therapy and long-term inhaled corticosteroid therapy could alter the lung microbiota composition in severe AECOPD patients. In acidemic AECOPD, lower lung mycobiota α-diversity is linked to the severity of the exacerbation, assessed by mortality and the requirement for invasive mechanical ventilation, whereas lung bacteriobiota α-diversity is not. This study encourages a multicenter cohort study investigating the role of lung microbiota, especially fungal kingdom, in severe AECOPD. IMPORTANCE In AECOPD with acidemia, more severe patients-i.e., nonsurvivors and patients requiring invasive mechanical ventilation-have lower lung mycobiota α-diversity than survivors and patients receiving only noninvasive ventilation, respectively. This study encourages a large multicenter cohort study investigating the role of lung microbiota in severe AECOPD and urges investigation of the role of the fungal kingdom in severe AECOPD.

A252 LONG-TERM OUTCOMES IN INFLAMMATORY BOWEL DISEASE PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS: KINGSTON HEALTH SCIENCES CENTER LOCAL EXPERIENCE

Abstract Background IBD-PSC remains a poorly understood entity due to it’s low incidence and the heterogeneity found within this patient population. Patients with IBD-PSC have 0.3-2.8% lifetime risk of developing hepatocellular carcinoma, up to a 20% lifetime risk of developing Cholangiocarcinoma and a 20-30% lifetime risk of developing Colorectal Cancer (Fung et al. World J Gastroenterol 2019). To better understand long-term outcomes in this population, the use of large population level data can be useful but requires case validation. Purpose A large multicenter Canadian retrospective cohort study is ongoing with the goals of identifying an algorithm to identify IBD-PSC patients and compare long-term outcomes of IBD-PSC patients with a matched IBD cohort (Ricciuto et al, ongoing). This abstract describes the local data within Kingston Health Sciences Centre (KHSC) from this Canadian multi-center study and evaluates the use of ICD codes for the identification of IBD-PSC. Method This is a single centre retrospective cohort study of patients with IBD-PSC within KHSC from January 1993 - December 2021. Patients with potential IBD-PSC were initially identified locally using ICD codes for IBD and cholangitis. Charts were reviewed and IBD-PSC diagnosis was confirmed using pathology from liver biopsies and imaging. Those confirmed to have IBD-PSC then had data manually extracted from the local health administrative system. Outcomes of interest were divided into patient demographics, disease phenotype at diagnosis of IBD-PSC and therapies. Patients were followed until death, leaving the KHSC network or the end of the follow-up period. Result(s) Of the 862 patients identified using ICD codes, 16 (2%) were confirmed to have IBD-PSC after chart review. 50% of included patients had other autoimmune diseases. The median age of diagnosis of PSC was 34 years (IQR=22-43) while the median age of diagnosis of IBD was 22 (IQR=15-38). Large duct PSC was found in 88% of patients. Six patients had disease that was exclusively intra-hepatic. Two patients were found to have PSC with auto-immune hepatitis overlap. Mean ALP at diagnosis was 402 (IQR=208-506). Four patients developed cirrhosis, two of which experienced hepatic decompensation. Three patients underwent liver transplant. 81% of patients had ulcerative colitis. At the index lower endoscopy, 33% of patients had Mayo 3 colitis and 75% had involvement of the right colon. During follow up in our study, 81% of patients required systemic steroids and 33% required biologic therapy. Conclusion(s) ICD codes alone cannot reliably identify patients with IBD-PSC. The characteristics of the patients in our local experience are in keeping with existing literature. Completion of this multi-center study will allow for a greater sample size, a matched control group and a better understanding of the long-term impacts of this disease. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

The Longitudinal Relationship Between Hearing Loss and Cognitive Decline

The Longitudinal Relationship Between Hearing Loss and Cognitive Decline

Bilateral Internal Thoracic Arteries Improve 10-Year Outcomes of Coronary Artery Bypass Grafting

BackgroundThis observational cohort study was designed by the PRIORITY (PRedictIng long-term Outcomes afteR Isolated coronary arTery bypass surgery) steering committee to evaluate the 10-year follow-up outcome of bilateral internal thoracic arteries (BITA) versus single internal thoracic artery. MethodsThe PRIORITY project was designed to evaluate long-term outcome of 2 large prospective multicenter cohort studies of coronary artery bypass grafting. Clinical data on isolated coronary artery bypass grafting were merged with administrative data to collect follow-up information. The primary endpoint was the composite outcome of major adverse cardiac and cerebrovascular events at 10-year follow-up. Secondary endpoints were individual components of major adverse cardiac and cerebrovascular events at 10 years and surgical site complications or infections. A propensity score–based inverse probability treatment weighting (IPTW) was used to overcome the selection bias related to the observational nature of the study. ResultsThe study population consisted of 10,988 patients who underwent isolated coronary artery bypass grafting. BITA was used in 23.5%. The use of BITA is related to lower incidence of major adverse cardiac and cerebrovascular events at 10 years (adjusted hazard ratio [HR] 0.88, 95% CI 0.79-0.98, P < .001). BITA correlated with better 10-year survival (IPTW adjusted HR 0.87, 95% CI 0.78-1.00, P = .05), re-revascularization (IPTW adjusted HR 0.83, 95% CI 0.74-0.92, P < .001), and myocardial infarction (IPTW adjusted HR 0.86, 95% CI 0.77-0.95, P = .005) but to increased incidence of surgical site complications or infections (HR 2.12, 95% CI 1.39-3.24, P < .001). ConclusionsIn propensity-matched patients, use of BITA was associated with improved 10-year survival, freedom from repeat revascularization, and myocardial infarction but also higher incidence of surgical site complications.

Abstract 53: Long-term Treatment Risk Of Hemorrhage In Unruptured Brain Arteriovenous Malformation Patients

Introduction: The long-term effects of interventional treatment (with surgery, stereotactic radiosurgery, or endovascular embolization) for unruptured brain arteriovenous malformations (uBAVM) are uncertain. We address this in a large multi-center international cohort study comparing risk of intracranial hemorrhage (ICH) in the treated and untreated course of uBAVM patients. Methods: We pooled individual patient data (n=3,291) from 10 cohorts and imputed missing data. Survival analysis was performed from time of uBAVM diagnosis to intracranial hemorrhage (ICH) using Cox models, stratified by cohort, censoring at death or last follow-up, and including BAVM interventional treatment as a time-varying covariate. We tested for an interaction of treatment with follow-up time, then estimated the association of interventional treatment with ICH, adjusting for propensity quintile. Individual treatment propensity scores were calculated using logistic regression with Spetzler-Martin grade, sex, diagnosis age and year, cohort, and presence of presenting symptoms (seizures, headaches, and/or deficits). Results: Median cohort age was 36 years, 48% were female, and 77% received ≥1 treatment modality for uBAVM during follow-up. 373 ICH occurred during 32,054 person-years of follow-up (median=6.6y), for an ICH rate of 1.16 per 100 P-Y. Overall, treatment was not associated with risk of ICH (HR=1.12, 95% CI=0.89-1.51, p=0.33). However, we observed a strong interaction between treatment and follow-up time (p&lt;0.001): between 0-1 year, treatment was associated with higher risk of ICH (HR=3.48, 95% CI: 2.26-5.37, p&lt;0.001); between 1-10 years, we found no association between treatment and risk of ICH (HR=1.02, 95% CI: 0.73-1.45, p=0.87); after 10 years, treatment was associated with a lower risk of ICH (HR=0.46, 95% CI: 0.30-0.70, p&lt;0.001). Survival curves for untreated and treated courses crossed around 17 years. Conclusion: After accounting for treatment propensity for uBAVM, we found an initial increased risk of ICH in the treated relative to untreated course, which continually declined over time with survival curves crossing around 17 years. These results require confirmation in a randomized controlled trial of uBAVM with long-term follow-up.

Cost per responder for vedolizumab and ustekinumab in Crohn’s disease patients after failure of TNF-α inhibitors in Italy

Background: The aim of this economic evaluation was to compare the cost per responder between vedolizumab and ustekinumab in patients with Crohn’s disease (CD) after failure of tumor necrosis factor-α inhibitors in Italy. Methods: Clinical efficacy was assessed using the results of an Italian large multicentre observational retrospective cohort study. The aim of the study was to compare the effectiveness of ustekinumab and vedolizumab as second line therapy in Crohn’s disease patients in which tumour necrosis factor-α inhibitors failed. Clinical efficacy of vedolizumab and ustekinumab was measured by clinical response and clinical remission. Treatment costs were based on the number of administrations at 26 or 52 weeks. Cost per responder, based on clinical efficacy and clinical response, was used as a cost-effectiveness indicator. Results: Regardless of the clinical efficacy measure used and the treatment duration considered, the cost per responder was consistently lower for vedolizumab compared with ustekinumab on all clinical measures. Considering the clinical response, the cost per responder at 26 weeks was € 15,640 for vedolizumab and € 23,667 for ustekinumab and at 52 weeks was € 23,927 for vedolizumab and € 30,820 for ustekinumab. Considering the clinical remission, the cost per responder at 26 weeks was € 22,832 for vedolizumab and € 33,786 for ustekinumab and at 52 weeks was € 29,488 for vedolizumab and € 46,847 for ustekinumab. Sensitivity analysis confirmed the validity of results. Conclusion: These results suggest that vedolizumab is a cost-effective option compared with ustekinumab from the perspective of the Italian health service in patients with CD after failure of TNF-α inhibitors.

Prevalence and associated factors of post-traumatic stress disorder in parents whose infants have single ventricle heart disease.

Post-traumatic stress disorder occurs in parents of infants with CHD, contributing to psychological distress with detrimental effects on family functioning and well-being. We sought to determine the prevalence and factors associated with post-traumatic stress disorder symptoms in parents whose infants underwent staged palliation for single ventricle heart disease. A large longitudinal multi-centre cohort study evaluated 215 mothers and fathers for symptoms of post-traumatic stress disorder at three timepoints, including post-Norwood, post-Stage II, and a final study timepoint when the child reached approximately 16 months of age, using the self-report questionnaire Impact of Event Scale - Revised. The prevalence of probable post-traumatic stress disorder post-Norwood surgery was 50% of mothers and 39% of fathers, decreasing to 27% of mothers and 24% of fathers by final follow-up. Intrusive symptoms such as flashbacks and nightmares and hyperarousal symptoms such as poor concentration, irritability, and sudden physical symptoms of racing heart and difficulty breathing were particularly elevated in parents. Higher levels of anxiety, reduced coping, and decreased satisfaction with parenting were significantly associated with symptoms of post-traumatic stress disorder in parents. Demographic and clinical variables such as parent education, pre-natal diagnosis, medical complications, and length of hospital stay(s) were not significantly associated with symptoms of post-traumatic stress disorder. Parents whose infants underwent staged palliation for single ventricle heart disease often reported symptoms of post-traumatic stress disorder. Symptoms persisted over time and routine screening might help identify parents at-risk and prompt referral to appropriate supports.

Favorable surgical and obstetric outcomes in pre-and postconceptional laparoscopic abdominal cerclage: large multicenter cohort study

Favorable surgical and obstetric outcomes in pre-and postconceptional laparoscopic abdominal cerclage: large multicenter cohort study

451: MANAGEMENT OF STENOTROPHOMONAS MALTOPHILIA PNEUMONIA IN MECHANICALLY VENTILATED PATIENTS

Introduction: Stenotrophomonas maltophilia is a gram negative opportunistic pathogen that most often causes infections in critically ill patients. S. maltophilia infections are associated with high morbidity and mortality. Common treatment options include sulfamethoxazole/trimethoprim (SMX/TMP), levofloxacin, and tetracyclines. SMX/TMP has been shown to have resistance rates up to 19%, and levofloxacin has shown minimal resistance rates (2%). Regardless of resistance rates, S. maltophilia is associated with a treatment failure rate of around 30%. The objective of this study is to evaluate the effectiveness of monotherapy treatment with SMX/TMP or levofloxacin in critically ill patients with S. maltophilia pneumonia on mechanical ventilation. Methods: Retrospective analysis of patients >/=18 years of age with a positive respiratory culture for S. maltophilia between January 1, 2018, to August 31, 2021. At the time of culture patients must have been on mechanical ventilation for at least 48 hours and treated with monotherapy SMX/TMP or levofloxacin for at least 48 hours. Patients were excluded if they received less than 48 hours of monotherapy, received concomitant treatment with an additional agent with activity agents S. maltophilia (minocycline, ceftazidime, cefiderocol), were pregnant, received combination therapy, had a diagnosis of cystic fibrosis, or had a history of S. maltophila positive culture within the previous 12 months. Results: A total of 105 patients were assessed for eligibility and 92 met inclusion criteria. Of these patients, 51 (55%) received SMX/TMP and 41 (45%) received levofloxacin. Treatment failure occurred more often in those treated with levofloxacin 20% compared to SMX/TMP 16%, p=0.045. Mortality was greater in the levofloxacin group 37% vs. 15%, p=0.011. Clinical cure, 30-day microbiological cure, ICU length of stay and hospital length of stay were similar between groups. Acute kidney injury occurred significantly more in patients treated with SMX/TMP. Conclusions: SMX/TMP was associated with less treatment failure and mortality compared to levofloxacin when treating S. maltophilia pneumonia in patients on mechanical ventilation. A large multicenter cohort study comparing SMX/TMP and levofloxacin is warranted to validate these findings.

Cytology Smears: An Enhanced Alternative Method for Colorectal Cancer pN Stage-A Multicentre Study.

Stage II colorectal cancer (CRC) recurrence remains a clinical problem. Some of these patients are true stage III CRC with a pN0 pathology stage. This large prospective multicentre cohort study aimed at evaluating the diagnostic ability of lymph node (LN) cytology smears to perform the pN stage and compare it with the conventional haematoxylin and eosin (H&E) pathology pN stage. Additionally, we used the One-Step Nucleic Acid Amplification (OSNA), a high-sensitive molecular method of LN staging. A total of 3936 fresh LNs from 217 CRC surgical specimens were examined by three methods, H&E, LN cytology smears, and OSNA. H&E detected 29% of patients with positive LNs, cytology smears 35%, and OSNA 33.2% (p &lt; 0.0001). H&E and cytology concordantly classified 92.2% of tumours, and 88.5% between OSNA and H&E. Cytology had 96.8% sensitivity and 90.3% specificity to discriminate positive/negative patients compared to H&E (p = 0.004), and 87.3% sensitivity and 89% specificity when compared to OSNA (p = 0.56). Patients with positive LNs detected by any of the three methods had significantly worse disease-free and overall survival. We conclude that pN stage accuracy for detecting positive LNs is superior with LN cytological smears than with conventional H&E, which would enable a better pN stage and management of early-stage CRC patients.

Incidence of falls and fall-related injuries and their predictive factors in frail older persons with cancer: a multicenter study

BackgroundFalls and fall-related injuries are a major public health problem. Data on falls in older persons with cancer is limited and robust data on falls within those with a frailty profile are missing. The aim of this study is to investigate the incidence and predictive factors for falls and fall-related injuries in frail older persons with cancer.MethodsThis study is a secondary data analysis from data previously collected in a large prospective multicenter observational cohort study in older persons with cancer in 22 Belgian hospitals (November 2012–February 2015). Patients ≥70 years with a malignant tumor and a frailty profile based on an abnormal G8 score were included upon treatment decision and evaluated with a Geriatric Assessment (GA). At follow-up, data on falls and fall-related injuries were documented.ResultsAt baseline 2141 (37.2%) of 5759 included patients reported at least one fall in the past 12 months, 1427 patients (66.7%) sustained an injury. Fall-related data of 3681 patients were available at follow-up and at least one fall was reported by 769 patients (20.9%) at follow-up, of whom 289 (37.6%) fell more than once and a fall-related injury was reported by 484 patients (62.9%). Fear of falling was reported in 47.4% of the patients at baseline and in 55.6% of the patients at follow-up. In multivariable analysis, sex and falls history in the past 12 months were predictive factors for both falls and fall-related injuries at follow-up. Other predictive factors for falls, were risk for depression, cognitive impairment, dependency in activities of daily living, fear of falling, and use of professional home care.ConclusionGiven the high number of falls and fall-related injuries and high prevalence of fear of falling, multifactorial falls risk assessment and management programs should be integrated in the care of frail older persons with cancer. Further studies with long-term follow-up, subsequent impact on cancer treatment and interventions for fall prevention, and integration of other important topics like medication and circumstances of a fall, are warranted.Trial registrationB322201215495.

The Emicizumab Switch: Real-World Data of 251 Pediatric Patients from the Pednet Registry

Background: Despite the rapid uptake of emicizumab in the pediatric hemophilia A (HA) population, real-world data on emicizumab safety and efficacy outcomes are limited to the HAVEN-2 trial (N = 85) and single center cohort studies. Aim: To report on bleeding and safety in children and adolescents with HA receiving emicizumab prophylaxis in a large prospective multicenter cohort study. Methods: Data were extracted from the ongoing PedNet Registry (Clin.gov.trial-NCT02979119; date of extraction: Jan 2022). Patients were included if they had a diagnosis of congenital hemophilia A with a baseline factor FVIII up to 25% and were < 18 years old at start of emicizumab. Patients were required to have maintenance therapy of emicizumab and bleeding data available for a minimum of 4 weeks. Patients with concomitant coagulopathies were excluded (N = 2). Bleeding data were compared during emicizumab to bleeding data before emicizumab up to a maximum of two years prior to the start of emicizumab. Patient characteristics were summarized as numbers (%) and median with IQR (P25-P75). Mean annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were estimated and compared between prophylactic regimens by negative binomial regression modelling. Results: 251 patients were included from 30 hemophilia treatment centers, see Table 1 for patient characteristics. The median age at start of emicizumab therapy was 6.1 years (IQR: 2.1 - 12.0). Median follow-up time before emicizumab was 1.51 years and during emicizumab was 1.23 years with a total of 361 patient years reported on emicizumab therapy. Most patients (94%) had severe HA and 76% of the patients were younger than 12 years at start of emicizumab therapy. Approximately one third (37%) of the patients had an inhibitor at start of emicizumab with a median peak titer of 128 BU/ml (IQR: 34 - 600). The ABR and AJBR significantly improved during emicizumab therapy in patients with and without inhibitors, see Figure 1. In patients without inhibitors the mean ABR reduced from 2.8 prior to emicizumab to 1.1 during emicizumab (p < 0.001), while the AJBR reduced from 0.8 to 0.3 (p < 0.001). Similar results were seen in patients with inhibitors. The mean ABR reduced from 5.5 to 1.1 (p<0.001), while the AJBR reduced from 2.3 to 0.3 (p<0.001). In this cohort, two serious adverse events and six adverse events were reported during emicizumab therapy in eight patients (3% of total cohort). Serious adverse events included one death unrelated to emicizumab therapy (retroperitoneal bleed in a baby treated with LMWH for CVL thrombosis) and one patient developed anti-drug antibodies without breakthrough bleeding, who continued emicizumab therapy. Non serious adverse events were all related to local injection site reaction in six patients. No TMA or thrombotic events were observed. Conclusions: This large cohort study with prospectively collected data showed improved bleeding control compared to previous therapy and a favorable safety profile during emicizumab treatment in pediatric patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome and risk factors for recurrence of early onset fracture-related infections treated with debridement, antibiotics and implant retention: Results of a large retrospective multicentre cohort study

IntroductionEarly Fracture-Related Infections (FRIs) are a common entity in hospitals treating trauma patients and are often treated with a Debridement, Antibiotics and Implant Retention (DAIR) procedure. Aims of this study were to 1) evaluate the recurrence rate after DAIR procedures for early onset FRI, 2) establish the number of surgical procedures to gain control of the initial infection and 3) identify independent predictors for recurrence in this cohort. MethodsA retrospective multicentre cohort study was conducted in two level 1 trauma centres. Consecutive patients who underwent a DAIR procedure between January 1st 2015 and July 1st 2020 for confirmed FRI with an onset of <6 weeks after the latest osseous operation were included. Recorded data included patient demographics, treatment characteristics and follow-up. Univariate and multivariate logistic regression analyses were performed to assess predictors for recurrent FRI. ResultsA total of 141 patients with early FRI were included in this study with a median age of 54.0 years (interquartile range (IQR) 34.5–64.0). The recurrence rate of FRI was 13% (n = 19) at one year follow-up and 18% (n = 25) at 23.1 months (IQR 15.3–36.4) follow-up. Infection control was achieved in 94% (n = 127/135) of cases. In total, 73 patients (52%) underwent at least two surgical procedures to treat the ongoing initial episode of FRI, of whom 54 patients (74%) required two to three procedures and 17 patients (23%) four to five procedures. Predictors for recurrent FRI were use of an intramedullary nail during index operation (odds ratio (OR) 4.0 (95% confidence interval (CI) 1.1–13.8)), need for additional surgical procedures to treat ongoing infection during the treatment period following the first presentation of early FRI (OR 1.9 (95% CI 1.1–3.5)) and a decreased Injury Severity Score (ISS) (inverted OR 1.1 (95% CI 1.0–1.1)). ConclusionThe recurrence rate after treatment of early onset FRI in patients treated with a DAIR procedure was 18% at 23.1 months follow-up. At least two surgical procedures to gain control of the initial infection were needed in 52% of patients. Independent predictors for recurrent FRI were the use of an intramedullary nail during index operation, need for additional surgical procedures and a decreased ISS.

Clinical and genetic correlates of mitral valve pathology in patients with heritable thoracic aortic disease: results from the montalcino aortic consortium

Abstract Background Mitral valve (MV) pathology, including prolapse and regurgitation, is a well-known cardiovascular manifestation associated with the genes that predispose to Heritable Thoracic Aortic Disease (HTAD). The extent to which there are differences in prevalence, presentation and severity of MV pathology as a function of the underlying genetic cause has not been investigated in detail. Purpose Assess the prevalence, presenting features and outcome of mitral valve pathology according to the underlying genetic defect in patients with HTAD. Study design We leveraged clinical and genetic data of a large international multicenter retrospective cohort study. Probands and relatives with a validated (likely) pathogenic (LP/P) variant in 8 HTAD genes were included. Genes were categorized in 2 groups: Group 1 encoding for components of the TGFβ pathway (TGFBR1, TGFBR2, SMAD3 and TGFB2) and Group 2 encoding for proteins involved in vascular smooth muscle cell contraction (VSMC) (ACTA2, MYLK, PRKG1, MYH11). Comparison between these groups was performed. MV pathology was defined as at least moderate MV regurgitation, MV prolapse and past MV surgeries. Results A total of 459 patients. 68.8% of the patients carried a variant in one of the Group 1 genes and 31.2% had a Group 2 gene variant. 52 patients (11.3%) presented MV pathology. Significant differences in MV status according to the gene group were present: 15.5% of the patients in group 1 presented MV disease, versus 2.1% in group 2, (p&amp;lt;0.001). Within Group 1, LP/P variants in SMAD3 were most common (32.7%), followed by TGFBR2 (25.0%) and TGFB2 (23.1%) (p=0.006). The remaining 5.8% of MV pathology cases were patients carrying ACTA2 variants. No MV pathology was found in MYLK, PRKG1 and MYH11 variant carriers. Compared to patients without MV pathology, patients with MV pathology more often underwent aortic aneurysm repair (34.6% vs 15.5%, p&amp;lt;0.001). To the contrary, aortic dissection/rupture occurred less frequently in patients with MV pathology (7.7% vs 26.8%, p&amp;lt;0.001). No differences were observed for prevalence of congenital heart defects, left ventricular dilatation, arrhythmic events or heart failure. Conclusion Patients with HTAD carrying LP/P variants in genes encoding TGFβ components present more frequently with MV pathology than patients carrying variants in genes encoding proteins involved in VSMC contraction. In the latter group, only patients carrying ACTA2 variants presented MV pathology. Patients with MV pathology are more likely to undergo aortic aneurysm repair and present less frequently with aortic dissection/rupture. Whether the presence of MV pathology accelerates the diagnosis and hence leads to a more aggressive management/stricter surveillance in these patients and/or whether biological differences between these genetic entities explain these differences requires further study. These data provide tools for developing improved, gene-tailored management of patients with HTAD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Baillet Latour FoundationFunds for Scientific Research Flanders

LARGE-SCALE, MULTICENTER, RETROSPECTIVE STUDY ON NEPHROTOXICITY ASSOCIATED WITH EMPIRIC, BROAD-SPECTRUM ANTIBIOTICS IN CRITICALLY ILL PATIENTS

LARGE-SCALE, MULTICENTER, RETROSPECTIVE STUDY ON NEPHROTOXICITY ASSOCIATED WITH EMPIRIC, BROAD-SPECTRUM ANTIBIOTICS IN CRITICALLY ILL PATIENTS

607. COMPARISON OF RECURRENCE PATTERNS AND SURVIVAL AFTER NEOADJUVANT CHEMORADIOTHERAPY VS. CHEMOTHERAPY FOR ESOPHAGEAL CANCER, A MULTI-CENTER EUROPEAN COHORT STUDY

Abstract Curative treatment for esophageal cancer requires local and systemic disease control. Neoadjuvant treatment increases long-term survival, but the evidence to date is insufficient to determine if neoadjuvant chemoradiotherapy (nCRT) with focus on local control or neoadjuvant chemotherapy (nCT) with focus on systemic control, is more beneficial. In this analysis of the ENSURE study we aimed to compare recurrence patterns and survival between nCRT and nCT in a large multicenter European cohort study. All patients treated with neoadjuvant therapy and esophagectomy for cancer from 2009-2015 in the ENSURE study (NCT03461341) were included. Univariable and multivariable logistic regression and Cox proportional hazard models were used to compare recurrence pattern, diseases-free, and overall survival. Results are shown as odds ratios (OR), hazard ratios (HR) and 95% confidence intervals (CI). The multivariable model was pre-specified and included age, sex, clinical tumor stage, and tumor histology. In total 3267/4682 (69.8%) patients were treated with neoadjuvant therapy and were included in the study. nCRT was given to 1798 (55.0%) patients, and nCT was given to 1496 (45.0%) patients. Median age for nCRT was 63 vs. 64 for nCRT, 65.5% in the nCRT group had adenocarcinoma vs. 81.4% in the nCT group. In the nCRT group 38.7% of patients had tumor stage III-IV compared to 61.3% in the nCT group. Multivariable adjusted OR for local recurrence comparing nCRT to nCT was 1.31 (95% CI: 1.08-1.59), distant recurrence OR 1.87 (95% CI: 1.57-2.22), and combined recurrence 1.49 (95% CI: 1.26-1.76). Adjusted HR for disease specific survival comparing nCRT to nCT was 1.38 (95% CI: 1.24-1.55), disease free survival: 1.39 (95% CI: 1.25-1.54), and for overall survival: 1.44 (95% CI: 1.30-1.60). The results of the study show significantly increased risk for recurrent disease and decreased survival after nCRT compared to nCT for esophageal cancer. nCRT is administered with a lower total dose of chemotherapy compared to nCT. Radiotherapy is given for local control, which is also achieved with adequate lymphadenectomy. The results indicate that effective systemic treatment with nCT might be beneficial compared to nCRT in curative intended treatment of esophageal cancer.