Disease-related Outcomes Research Articles

Polychlorinated biphenyls and incident coronary heart disease-related outcomes in Great Lakes fish consumers

BackgroundExposure to polychlorinated biphenyls (PCBs) has been linked to risk factors for cardiovascular disease such as increased inflammation, accelerated atherosclerosis, diabetes, and sex hormone dysregulation. Furthermore, there is increasing evidence suggesting associations between internal dose of PCBs and cardiovascular outcomes. ObjectivesThe purpose of this study is to investigate longitudinal associations of PCBs with coronary heart disease (CHD)-related outcomes in a cohort of Great Lakes sport fish consumers. MethodsThe Great Lakes Sport Fish Consumer cohort was established in the early 1990's. Eight hundred nineteen participants were followed from 1993 to 2017. Serum PCBs were measured in 1994/1995 (baseline), in 2001, and in 2004, while health history questionnaires were administered in 1996, 2003, 2010, and 2017. Cox models were used to prospectively investigate associations of total PCBs and PCB groupings, based on aryl hydrocarbon receptor activity, with incident self-reported physician diagnosis of coronary heart disease (CHD), myocardial infarction (MI), and angina pectoris. ResultsA 2-fold increase in phenobarbital-type PCBs was associated with a 72% increase in likelihood of self-reported incident diagnosis of CHD (HR=1.72, 95% CI: 1.06–2.81; p=0.0294). Similar results were observed for total PCBs (HR=1.68, 95% CI: 1.05–2.69; p=0.0306) and mixed methacholine/phenobarbital type (mixed-type) PCBs (HR=1.60, 95% CI: 1.02–2.52; p=0.0427), but not methacholine-type PCBs. PCBs were not strongly associated with risk of MI or angina. ConclusionsThis study presents evidence that exposure to PCBs increases the risk of developing coronary heart disease. Given the large number of risk factors and causal pathways for CHD, future research is required to better understand biological mechanisms of action for PCBs on CHD.

Abstract PO1-19-06: Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial

Abstract Introduction In early breast cancer, neoadjuvant chemotherapy (NACT) is increasingly used. The proof of efficacy is pathologically complete response (pCR), i.e. the absence of invasive tumour in breast and lymph nodes at surgery. Today, pCR is a common endpoint in pharmaceutical trials since it is significantly associated with survival especially in triple-negative and HER2-positive subtypes. Apart from the mitigation of treatment-related toxicity and symptoms, physical exercise mediates anti-tumoral systemic effects associated with tumour regression in preclinical and clinical models. The aim of Neo-ACT is to test the hypothesis that physical exercise can improve pCR rates in breast cancer patients receiving NACT. Method The Neo-ACT trial is an international prospective clinical trial, randomising T1-3N0-2 breast cancer patients planned for NACT to either a home-based physical exercise intervention supported by a mobile application or routine care. The primary endpoint is pCR; secondary endpoints are patient-reported quality of life, toxicity-related outcomes, and oncological outcomes such as Residual Cancer Burden, objective radiological tumour response, as well as overall, breast cancer-specific and disease-free survival at 2, 5 and 10 years. The intervention consists of a combination of high-intensity interval and resistance training of progressing intensity, and includes two weekly 60-min exercise sessions plus at least 150 min of moderate to vigorous physical activity per week. The Neo-ACT has been registered at clinicaltrials.gov on January 11, 2022 (NCT05184582). Statistical methods Patients will be randomized in a 1:1 fashion. It is anticipated that the rate of the primary endpoint pCR will be approximately 30% in the control arm (all subtypes). We aim to increase the rate of pCR in the experimental arm to 40%, i.e. a 10 percentage points increase, which is regarded clinically relevant since it would translate into improved disease-related outcomes. With a power of 80% and an alpha of 5%, a total of 712 patients have to be included; 356 in each arm. Accounting for a drop-out of 10%, we aim to include 790 patients. Stratification at the moment of computerized randomization is based on site of treatment (hospital) and biological tumour subtype (ER+HER2-, ER+HER2+, ER-HER2+, ER-HER2-). All outcomes will primarily be analysed using an intention-to-treat approach, i.e. all study subjects will belong to the treatment group (exercise intervention or control) they were assigned to, disregarding compliance. As sensitivity analysis, all outcomes will also be analysed using a per-protocol approach, meaning that participants in the intervention group who comply with less than 65% of the prescribed physical exercise program, and participants who complete less than 40% of the planned neoadjuvant systemic therapy (around two 3-weekly courses) will be excluded from analysis. Present accrual The Neo-ACT trial has started enrolment at the first site in December 2022 and since then initiated a further five Swedish and one Finnish site. Until June 15, 2023, 26 participants had been randomized in the trial. A feasibility questionnaire is distributed via the EUBREAST network which officially supports this trial and has added the designation EUBREAST12-R. Further participating sites can be accommodated depending on volume, competing trials and language requirements for the mobile application. Contact: jana.de-boniface@ki.se Citation Format: Jana de Boniface, Cecilia Haddad Ringborg, Renske Altena, Yvonne Wengström. Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-06.

Abstract PO5-06-14: Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma

Abstract Background: Triple-negative (TN) invasive lobular carcinoma (ILC) of the breast is a rare entity, comprising roughly 2% of primary ILC. Clinicopathologic studies have shown that TN ILC is associated with more pleomorphism, higher nuclear grade, older patient age, and worse disease-related outcomes compared to estrogen receptor-positive (ER+) ILC. Intrinsic subtyping indicates that TN ILC less frequently expresses basal markers than TN invasive ductal carcinoma (IDC). This prompted investigation of the genomic landscape and clinical management of TN ILC to provide insight into potential therapeutic approaches. Methods: Twenty patients with TN ILC were included in this study. Three patients were treated at a single academic center and underwent comprehensive genomic profiling (CGP) of breast or metastatic tissue; clinicopathologic details were obtained from their electronic health records. Seventeen patients with TN ILC who underwent CGP of breast or metastatic biopsies were included from the Foundation Medicine, Inc. database. PD-L1 testing for all patients was determined by immunohistochemistry (IHC) using the VENTANA SP142 or Dako 22C3 commercial assays. HER2 expression was determined by IHC. Negative HER2 expression was defined as an IHC score of 0, or IHC 1+ or 2+ with non-amplified fluorescence in situ hybridization (FISH). Results: In the Foundation Medicine database of patients with TN ILC, the most frequent genomic alterations were in CDH1 (15/17 patients [88.2%]), TP53 (10/17 patients [58.8%]), and PIK3CA (10/17 patients [58.8%]). Short variant mutations in ERBB2 were found in 3/17 patients (17.6%). Fourteen patients were HER2-low (HER2 IHC 1+ or 2+ with non-amplified FISH). No cases were MSI high or expressed PD-L1 (8 of 17 cases underwent PD-L1 assessment by SP142). Median tumor mutational burden (TMB) was 5 muts/Mb. Among the three patients with TN ILC treated at a single center, the most common somatic mutations were in CDH1 and TP53, and no cases were MSI high or expressed PD-L1 (by SP142 or 22C3). All three patients had pleomorphic ILC, histologic grade 2 or 3, and HER2 IHC 0. One patient with mpT1cN1a(sn) ER+/HER2- ILC of the right breast in 2011 received adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide), breast/axillary radiation, and ten years of adjuvant endocrine therapy. She was diagnosed with TN ILC of the left supraclavicular nodes in 2022; she did not exhibit a response to docetaxel and carboplatin with pembrolizumab, and she subsequently received palliative radiation followed by capecitabine. Another patient with locally advanced TN ILC progressed on the KEYNOTE-522 regimen, immediately developed metastases, and is currently receiving palliative sacituzumab govitecan. The third patient with cT3N1 TN ILC progressed on neoadjuvant therapy (through the I-SPY 2 trial) with oral paclitaxel, encequidar, and dostarlimab, followed by dostarlimab with dose-dense doxorubicin and cyclophosphamide. Her surgical pathology demonstrated ypT3N3a disease with 10 × 7 cm of tumor, and she developed skin metastases on the chest wall within weeks post-operatively. She received comprehensive chest wall and nodal radiation and is currently receiving palliative capecitabine with neratinib given a high variant allele frequency driver somatic ERBB2 mutation. Conclusions: The most common somatic mutations among TN ILC patients included in this study were in CDH1, TP53, and PIK3CA. Currently the management of TN ILC is extrapolated from that of TN IDC, however our patients did not respond to chemoimmunotherapy. The presence of HER2-low status or somatic ERBB2 mutations may provide opportunities for treatment with an anti-HER2 antibody-drug conjugate or tyrosine kinase inhibitor. Studies with larger sample sizes of TN ILC are needed for molecular profiling and assessment of outcomes with specific therapeutic approaches. Citation Format: Hemali Batra-Sharma, Smruthy Sivakumar, Prashanth Ashok Kumar, Ethan Sokol, Rebecca Shatsky, Jeffrey Ross. Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-14.

1535: Development of individual prognostic model to predict disease related outcomes in oral cavity cancer

1535: Development of individual prognostic model to predict disease related outcomes in oral cavity cancer

MARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models. Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum.

High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy.

Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2-6 months) vs. 11 months (95% CI: 6-26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25-3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21-3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02-3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02-3.88, p = 0.043). CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma.

Diabetes as a risk factor for pneumococcal disease and severe related outcomes and efficacy/effectiveness of vaccination in diabetic population. Results from meta-analysis of observational studies

AimsTo collect all available evidence on the effect of diabetes mellitus (DM) as a risk factor for pneumococcal disease incidence and related complications, and on the efficacy/effectiveness of vaccines in patients with DM.MethodsTwo distinct systematic searches on MEDLINE, Cochrane, ClinicalTrials.gov and EMBASE databases were performed, one for each meta-analysis, collecting all observational (cohort and case–control) studies and randomized clinical trials performed on humans up to June 1st, 2023.ResultsWe retrieved 36 observational studies comparing risk for pneumococcal disease and related complications in people with or without DM, and 11 studies (1 randomized clinical trial and 10 observational studies) assessing conjugated and polysaccaridic vaccines efficacy/effectiveness on preventing such outcomes. People with DM were at higher risk for Invasive Pneumococcal Disease (unadjusted OR 2.42 [2.00; 2.92]); Case-Fatality Rate (unadjusted OR 1.61 [1.25; 2.07], Pneumococcal pneumonia (unadjusted OR 2.98 [2.76; 3.22), and Intensive care unit admission for pneumococcal disease (unadjusted OR 2.09 [1.20; 3.66]). In diabetic individuals vaccinated with conjugated vaccine, incidence of pneumonia specific for vaccine type in a clinical trial (OR 0.237 [0.008; 0.704]), and hospitalization for overall pneumonia during the year following the polysaccharide vaccination in observational studies (unadjusted OR 0.63 [0.45–0.89]) were significantly lower in comparison with unvaccinated DM subjects, with no significant differences for other outcomes.ConclusionsPeople with diabetes mellitus are at higher risk for less favourable course of pneumococcal disease and should be therefore targeted in vaccination campaigns; more evidence needs to be collected on vaccination outcomes in people with diabetes.

Racial disparities in outcomes of patients with stage I-III triple-negative breast cancer after adjuvant chemotherapy: a post-hoc analysis of the E5103 randomized trial.

Breast cancer mortality is higher in Black women than other racial groups. This difference has been partially attributed to a higher proportion of triple-negative breast cancer (TNBC). However, it is uncertain if survival disparities exist in racially diverse TNBC patients receiving similar treatments. Here, we examine racial differences in disease-related outcomes in TNBC patients treated on the E5103 clinical trial. From 2007 to 2011, 4,994 patients with stage I-III HER2-negative breast cancer were randomized to adjuvant chemotherapy with or without bevacizumab. This analysis was limited to the subset of 1,742 TNBC patients with known self-reported race. Unadjusted Kaplan-Meier curves and adjusted Cox-Proportional Hazards models were used to determine breast cancer events and survival outcomes. Of the analysis population, 51 (2.9%) were Asian, 269 (15.4%) Black, and 1422 (81.6%) White. Median age was 51 years. Patient characteristics, treatment arm, and local therapies were similar across racial groups. White women were more commonly node-negative (56% vs. 49% and 44% in Asian and Black women, respectively; p < 0.01). At a median follow-up of 46 months, unadjusted Kaplan-Meier locoregional and distant recurrence, and disease-free and overall survival, did not differ significantly by race. In Cox models adjusted for patient and tumor characteristics and treatment arm, race was not associated with any disease event. Larger tumor size and nodal involvement were consistently associated with breast cancer events. This clinical trial population of similarly treated TNBC patients showed no racial differences in breast cancer outcomes. Disease extent, rather than race, was associated with disease events.

Using a Dynamic Model to Estimate the Cost-Effectiveness of HPV Vaccination in Iran.

This study aimed to determine the cost-effectiveness of vaccination against HPV. An age-sex structured dynamic disease transmission model was created to estimate the spread of HPV and the HPV-related incidence of cervical cancer (CC) in Iran. Sixteen age groups of men and women were incorporated to reflect the differences in sexual preferences, vaccination uptake, and disease-related outcomes. Three scenarios were evaluated by using an Incremental Cost-Effectiveness Ratio (ICER) with gained quality-adjusted life years (QALYs). ICER values below one gross domestic product (GDP) per capita are evaluated as highly cost-effective. Vaccination reduces the number of infections and CC-related mortality. Over time, the vaccinated group ages and older age groups experience protection. An initial investment is required and savings in treatment spending reduce the impact over time. Vaccinating girls only was found to be cost-effective, with an ICER close to once the GDP per capita. Vaccinating both sexes was shown to be less cost-effective compared to girls only, and vaccinating boys only was not found to be cost-effective, with an ICER between once and three times, and greater than three times the GDP per capita, respectively. The estimates are conservative since societal cost-saving and the impact of other HPV-related illnesses were not considered and would likely reduce the ICERs.

Effectiveness of the SARS-CoV-2 Vaccination in Preventing Severe Disease-Related Outcomes: A Population-Based Study in the Italian Province of Bolzano (South Tyrol).

Objective: To investigate the effectiveness of SARS-CoV2 vaccination in preventing ordinary or intensive care unit (ICU) admissions and deaths among cases registered during a variant transitional pandemic phase in the geographically and culturally unique territory of the Province of Bolzano (South Tyrol), an Italian region with low vaccination coverage. Methods: We collected data from 93,643 patients registered as positive for SARS-CoV-2 by health authorities during the winter of 2021-22. The data were analyzed retrospectively using descriptive statistics and multiple logistic regression. Results: 925 patients were hospitalized (0.99%), 89 (0.10%) were in intensive care, and 194 (0.21%) died. Vaccinated patients had a significantly lower risk of being hospitalized: adjusted Odds Ratio (aOR): 0.39; 95% CI: 0.33-0.46, ICU admission: aOR: 0.16; 95% CI: 0.09-0.29 and death: aOR: 0.41; 95% CI: 0.29-0.58. Similar risk reductions were also observed in booster-vaccinated patients, independent of sex, age, and predominant variant. Furthermore, the median length of stay (LoS) in the ICU was significantly longer for unvaccinated individuals compared to vaccinated subjects (9 vs. 6days; p < 0.003). Conclusion: Primary series vaccination and ongoing campaign booster doses were effective in preventing all severe disease-related outcomes and in reducing ICU Length of Stay, even during a transitional pandemic phase and in a unique territorial context.

A Dedicated Celiac Disease Program Improves Celiac Quality Care Metrics and Short-Term Outcomes in Real Life

Background and AimsDedicated multidisciplinary programs in gastroenterology are emerging with the goal to improve care. There is little information about the effects of a celiac disease program on disease-related quality care metrics and outcomes. We aimed to compare quality care metrics, symptom resolution, and serological response among patients diagnosed and treated in a celiac disease program with a standard of care cohort.MethodsWe performed a retrospective cohort study with adult celiac disease patients. We divided patients into two groups: celiac disease patients treated in our program and those treated by gastroenterologists not affiliated with the program (standard of care). We abstracted data from electronical medical records and compared frequency at which guideline-driven quality care metrics were obtained, assessed symptom resolution, and serological response based on IgA anti-tissue transglutaminase levels.ResultsWe included 340 patients, 120 in the celiac disease program (89 women) and 220 (166 women) in the standard of care. Frequency of quality care metrics implementation in program patients was significantly greater for all variables (p < 0.0005). Diarrhea resolved in 38/46 (82.6%) in the CD program and 63/98 (64.2%) in the standard of care after starting a gluten-free diet (p = .025); bloating also resolved significantly more often in the former (26/34) than the latter (31/58; p = 0.03). Otherwise, there were no significant differences in resolution of clinical symptoms or serological response.ConclusionA celiac disease program improves celiac-related quality care metrics and may improve outcomes such as diarrhea resolution compared to standard of care.

Implications of Protein and Sarcopenia in the Prognosis, Treatment, and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a common cause of chronic liver disease globally, with prevalence rapidly increasing in parallel with rising rates of obesity and metabolic syndrome. MASLD is defined by the presence of excess fat in the liver, which may induce inflammatory changes and subsequent fibrosis in high-risk patients. Though MASLD occurs frequently, there is still no approved pharmacological treatment, and the mainstay of therapy remains lifestyle modification via dietary changes, enhancement of physical activity, and management of metabolic comorbidities. Most nutrition research and clinical guidance in this disease centers on the reduction in fructose and saturated fat in the diet, although the emerging literature suggests that protein supplementation is important and implicates muscle mass and sarcopenia in disease-related outcomes. This review will assess the current data on these topics, with the goal of defining best practices and identifying research gaps in care.

A233 PHENOTYPE OF MUSCULOSKELETAL MANIFESTATIONS IN A CANADIAN INCEPTION COHORT OF PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract Background Musculoskeletal (MSK) manifestations, including arthritis and arthralgia, are among the most common extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD), reported in 20-30% of adult patients [1]. However, there is a paucity of data regarding MSK EIMs in the pediatric IBD population. A recent systematic review [2] found only 13 studies with limited results, due to heterogenous study design and data reporting methods. As such, little is known regarding frequency of MSK EIMs, their phenotype, or factors associated with their development. Aims The purpose of this study was to determine the frequency of MSK EIMs in a contemporary cohort of Canadian pIBD patients and describe the phenotype of MSK EIMs in this population. Methods This was a prospective longitudinal cohort study with data from the inception cohort of CIDsCaNN (Canadian Children IBD Network) comprising patients aged 2-17 from 12 Canadian pediatric centres, from 2014 to 2021. MSK EIM frequency was calculated for the cohort, and for subgroups by age, sex, and IBD type. MSK-EIM phenotype was described from case report forms with specific MSK features reported. Variables were compared with Pearson Chi-square or Fisher’s exact test. For patients without MSK EIM at IBD diagnosis, a Cox regression survival analysis was used for time to MSK development, with right censoring for patients who never reported MSK EIMs. Results 1,330 pIBD patients were included, with 761 males (57.2%) and 569 females (42.8%). There were 824 CD (62.0%), 382 UC (28.7%), and 124 IBD-U patients (9.3%). 81 patients (6.1%) reported MSK EIMs, with 63 CD (7.6%), 10 UC (2.6%), and 8 IBD-U (6.4%). CD patients were more likely to have MSK EIMs (7.6% vs 3.6% UC/IBD-U, p=0.002). 47 patients (58.0%) had MSK EIMs at or before diagnosis while 34 had them ampersand:003E4 weeks after diagnosis. There was no difference in overall frequency between sex or age groups, or time to MSK EIM development by age or ethnicity. Females were more likely to develop MSK EIMs, with odds increasing by 4.68 for each year after diagnosis (p=0.047). 59 (74.7%) MSK patients were seen by a rheumatologist. Peripheral MSK disease was in 51 patients (63%), axial disease only in 37. Peripheral and axial MSK symptoms followed the course of bowel disease in 40.3% and 28.1% of patients respectively, which were not significantly different. Conclusions MSK EIMs affect 6.1% of a contemporary cohort of Canadian pIBD patients.This is less than reported in literature, likely due to physician-reported nature of our data. Our next step is to compare pIBD patients with MSK EIMs to a matched group without, for bowel disease-related outcomes and response to medications. Funding Agencies Cassie and Friends Care and Research Network (CREW) funding.

The effect of infectious diseases on lung transplantation in Japan.

Lung transplantation in Japan is an increasingly accessible treatment option for end-stage lung disease; however, the lack of donor organs is a persisting challenge. Five- and 10-year survival rates of lung transplant recipients in Japan are comparable, if not superior, to international standards. The outcomes of lung transplantation in Japan are likely affected by multiple factors. Infectious disease complications are a significant burden to transplant recipients and account for approximately 30% of recipient mortality in Japan, presenting a major challenge in peri-transplant management. Herein, we explore the current status of infectious disease epidemiology, available evidence surrounding infectious diseases in lung transplantation, and potentially influential factors pertinent to lung transplantation outcomes in Japan. Although infection remains the major cause of morbidity and mortality associated with lung transplantation in Japan, there is limited data and evidence. Despite some uncertainties, publicly available data suggests a low rate of antimicrobial resistance in Gram-negative bacteria and a distinct set of endemic pathogens that recipients may encounter. As a countermeasure against the burden of infectious diseases, 8 out of 10 transplant centers in Japan have a dedicated infectious diseases department. Despite these efforts, specific surveillance, prevention, and management are indispensable to improving post-transplantation infectious disease management. We accordingly lay out potential areas for improving infectious disease-related outcomes among lung transplant recipients in Japan.

P198 Systematic review to highlight practices and programmes for transition for adolescents with Inflammatory bowel disease

Abstract Background Adolescents with inflammatory bowel disease (IBD) will eventually transition from the family-centric paediatric healthcare team to the adult service. This process happens at an appropriate age or level of development and depends on a number of factors such as transition readiness, disease specific factors, and local policies and practice. This transition period is challenging for patients, families and healthcare providers. The use of structured transition programmes is increasingly incorporated into standards of care, yet the optimal format is not yet fully delineated, and practices vary considerably. The aim of this study was to carry out a systematic review of structured transition programmes and their components to assess impact on disease-specific and transition-related outcomes. Methods A literature review was carried out in four main databases (PubMed, CINAHL, CENTRAL, EMBASE) and relevant publications from the year range 1970-2023 reviewed. Inclusion criteria: reporting on adolescent IBD patients and investigating structured transition programmes/interventions. Exclusion criteria: not reporting outcomes relating to transition readiness/skills or disease related outcomes. Two investigators reviewed the articles, extracted data, and two assessed bias. Results There were 3432 articles identified from initial searches, and 38 included in the final review. Twenty-six studies reported the use of structured transition programmes, and 12 investigated discrete interventions. The key outcomes studies included knowledge, self-efficacy, adherence, clinic attendance and transition readiness. These outcomes consistently improved with the use of structured transition programmes. Those adolescents with IBD transitioning with no structured programme experienced a 3.5-fold increase in IBD related surgical rates, and 2-fold increase in hospital admission rates. Structured transition programmes were shown to significantly improve transition readiness assessment scores. Transitional care programmes consistently improved the following outcomes; relapse/admission rates, corticosteroid use, quality of life, and surgery. The bias assessment showed between-study heterogeneity, low quality of evidence, and high risk of bias. Conclusion Transition outcomes for adolescents with IBD were consistently improved with the use of structured transition programmes. This literature review highlights the considerable variation in delivery of transition care, and the need for optimization of strategies. There is no current standardized model for adolescent IBD patients in Australasia, and this review will guide development of regional IBD transitional care consensus statements.

Disparities in Cardiovascular Disease-Related Outcomes Among Cancer Survivors in the United States: A Systematic Review of the Literature

Cancer and cardiovascular disease (CVD) are major causes of morbidity and mortality in the United States (US). Cancer survivors have increased risks for CVD and CVD-related mortality due to multiple factors including cancer treatment-related cardiotoxicity. Disparities are rooted in differential exposure to risk factors and social determinants of health (SDOH), including systemic racism. This review aimed to assess SDOH's role in disparities, document CVD-related disparities among US cancer survivors, and identify literature gaps for future research. Following the Peer Review of Electronic Search Strategies (PRESS) guidelines, MEDLINE, PsycINFO, and Scopus were searched on March 15, 2021, with an update conducted on September 26, 2023. Articles screening was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, a pre-defined Population, Exposure, Comparison, Outcomes, and Settings (PECOS) framework, and the Rayyan platform. A modified version of the Newcastle-Ottawa Scale was used to assess the risk of bias, and RAW Graphs for alluvial charts. This review is registered with PROSPERO under ID #CRD42021236460. Out of 7,719 retrieved articles, 24 were included, and discussed diverse SDOH that contribute to CVD-related disparities among cancer survivors. The 24 included studies had a large combined total sample size (n=7,704,645; median=19,707). While various disparities have been investigated, including rural-urban, sex, socioeconomic status, and age, a notable observation is that non-Hispanic Black cancer survivors experience disproportionately adverse CVD outcomes when compared to non-Hispanic White survivors. This underscores historical racism and discrimination against non-Hispanic Black individuals as fundamental drivers of CVD-related disparities. Stakeholders should work to eliminate the root causes of disparities. Clinicians should increase screening for risk factors that exacerbate CVD-related disparities among cancer survivors. Researchers should prioritise the investigation of systemic factors driving disparities in cancer and CVD and develop innovative interventions to mitigate risk in cancer survivors.

Clinical and Radiographic Characteristics in Segmental Colitis Associated With Diverticulosis, Diverticulitis, and Crohn’s Disease

Background and AimsSegmental colitis associated with diverticulosis (SCAD) is an underrecognized disease characterized by chronic segmental inflammation surrounding colonic diverticula. SCAD is recognized as an autonomous entity, although shares similar pathogenic and therapeutic aspects to inflammatory bowel disease (IBD) and may be considered a complication of diverticulitis. We aimed to characterize the clinical, endoscopic, and radiographic findings of SCAD and its potential overlap with diverticulitis and IBD. MethodsAll patients with suspected diagnosis of SCAD were identified using a bioinformatics search tool from January 1996 to October 2021 at our institution. Relevant demographic, clinical, endoscopic, and radiographic data were abstracted. Disease-related outcomes and radiographic characteristics were determined. ResultsSeventy-five patients with SCAD were included (48.0% female) with average age at diagnosis 62.5 years. Thirty-seven (49.3%) had a prior episode of diverticulitis. The most common presenting symptoms were abdominal pain (33.3%) and hematochezia (22.7%). Antibiotics (42.7%) and mesalamine (36.0%) were most used as first-line treatment options. Twenty (26.7%) required surgical intervention. The most common initial endoscopic finding was isolated sigmoid inflammation (86.7%). Fifty-one patients with confirmed SCAD, 72 with diverticulitis, and 12 with Crohn’s disease (CD) had imaging available for review. Penetrating disease was seen in 7 (13.7%) with SCAD compared to 7 (9.7%) and 2 (16.6%)with diverticulitis and CD, respectively (P = .14). Blinded radiologists diagnosed SCAD, CD, or diverticulitis correctly in 43.8%, 8.3%, and 27.1%, respectively. ConclusionSCAD should be considered when isolated sigmoid colon inflammation is seen on cross-sectional imaging. Penetrating disease is not a specific radiologic feature for either SCAD or diverticulitis. Further prospective studies are needed to correlate imaging characteristics with endoscopic findings to better describe radiographic features in SCAD.

Efficacy of rituximab on disease activity, severity, and disease-related damage in patients with immunosuppressive-resistant systemic sclerosis.

B-cell depletion with rituximab (RTX) is widely used as a rescue therapy in patients with systemic sclerosis (SSc). The aim herein was to analyze the progress of disease-related outcomes after RTX therapy in severe SSc patients. Included in this study were 27 SSc patients who were followed-up between 2012 and 2020 and received at least 1 cycle of RTX for active disease, despite receiving standard immunosuppressives (ISs). In addition to the European Scleroderma Study Group and European Scleroderma Trials and Research Group activity scores, Medsger's severity, and the recently developed Scleroderma Clinical Trials Consortium Damage Index values were evaluated initially and at 1 year after the first infusion. The progress of individual organ damage was also assessed at the end of the follow-up period (at least 6 months after the last infusion) using the data extracted from the medical records. Disease activity and severity-improved and disease-related overall damage worsened after the first year of RTX therapy (p < 0.001, p = 0.008, and p = 0.005). Some of the disease-related organ damage had improved at the end of the follow-up period, indicating its reversibility. Overall damage scores ≥11 after the first year of RTX therapy were found to be associated with mortality (p = 0.035). RTX contributed to reducing the activity and severity in SSc patients with severe disease, nonetheless the efficacy related to the damage was limited. High damage scores in the first year were found to be associated with mortality. Spontaneous progress of manifestations requiring a longer period to improve and irregular consecutive RTX courses might lead to difficulties in differentiation between activity and damage.

Association of p16, a Biomarker of Cellular Senescence, with Receipt of Therapy for Plasma Cell Disorders

Introduction Multiple myeloma (MM) and immunoglobulin light chain (AL) amyloidosis are clonal plasma cell disorders (PCDs) of aging, with median ages at diagnosis of 69 and 76 years, respectively. The care of adults with these disorders is often challenging due to the higher prevalence of vulnerabilities with advancing age. We examined patterns of senescence biomarkers and associations with therapy receipt among adults treated for plasma cell disorders. Methods Adults undergoing treatment for PCDs were recruited to a longitudinal observational study (NCT03717844) from 2018 to 2020. Study participants provided blood samples and completed study assessments at pre-specified intervals. Cellular senescence was quantified by measuring mRNA expression of p16 in peripheral blood T lymphocytes. Expression of p16 is reported as log2 arbitrary units. A linear regression formula previously derived from p16 expression in 633 subjects was utilized to translate p16 expression levels into an age equivalent. These values were used to calculate the p16AgeGap, a difference between an individual's p16 expression and their chronological age. Subjects with p16 levels below the age-appropriate population mean have a negative p16AgeGap, and those with p16 above the population mean have a positive p16AgeGap. Exposures included both treatment receipt and duration of therapy. Treatment was assessed via categorical classification of treatment intensity, and treatment duration was quantified from diagnosis to time of p16 blood draw. Descriptive statistics were calculated for baseline demographic and disease characteristic variables. The p16 and p16AgeGap variables were summarized in terms of means and 95% confidence intervals (CI). The significance of associations between p16/p16AgeGap and categorical variables was assessed via Kruskal-Wallis or Wilcoxon rank-sum tests. Associations between continuous variables were assessed via calculation of Pearson correlation coefficients. Results The cohort consisted of 109 individuals (88 with multiple myeloma and 21 with other plasma cell disorders). Mean age was 68 years (range 39-91). The sample was predominantly male (56.9%) and White (70.6%). Samples for p16 were drawn prior to any treatment in 20 subjects. The remainder had received prior therapy and 36 had relapsed/refractory disease. There was a significant association between the treatment receipt and p16 as well as between the treatment receipt and p16AgeGap (Figure 1). We observed a significant modest positive correlation between the duration of treatment and p16 (correlation coefficient 0.27, p=0.007) and p16AgeGap (0.22, p=0.03). Among those who had undergone transplant, we observed higher mean p16 (mean 12.84 [95% CI 12.46-13.23] vs 11.81 [11.51-12.11] for non-recipients, p=0.0001) and p16AgeGap (mean 50.6 [39.6-61.6] vs 16.9 [8.4-25.4], p &amp;lt;0.0001). There was a significant association between receipt of bortezomib-containing regimens with both p16 levels p16AgeGap, with higher mean p16 &amp; mean p16AgeGap for those who did not receive bortezomib. For the subset of patients with transplant date before the p16 collection date (N=38), there was no significant association between time since transplant and either p16 level or p16AgeGap. Conclusion This study elucidates the relationship between markers of cellular senescence, specifically p16 levels and the p16AgeGap, and the impact of treatment receipt and duration in a cohort of patients undergoing treatment for plasma cell disorders. There was a clear significant association between the receipt of treatment and both markers of senescence, along with a modest positive correlation between the duration of treatment and these markers. Further analyses involving this cohort will evaluate the relationship between these biomarkers and patient-centered endpoints, including disease-related symptoms and functional outcomes.

Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease.

Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 [94%], mean age 0.58 years), compared to an initial seizure (N = 41 [80%], mean age 2.80 years), and macrocephaly (N = 28 [55%], mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.