Entire Cohort Research Articles

Real-world prescription of anti-COVID-19 drugs in hospitalized patients with COVID-19 in Japan.

Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in clinical practice in Japan. The longitudinal and cross-sectional study was conducted utilizing data from January 1, 2019 to December 31, 2021 of the MID-NET® medical information database, which stored the electronic medical records, administrative claim data, and diagnosis procedure combination data of patients in Japan. Hospitalized patients with a COVID-19-related diagnosis who received at least one anti-COVID-19 drug between April 1, 2020 and December 31, 2021. The following 14 drugs were included in this study: remdesivir, baricitinib, combination product of casirivimab and imdevimab, favipiravir, dexamethasone, ivermectin, azithromycin, nafamostat mesylate, camostat mesylate, ciclesonide, tocilizumab, sarilumab, combination product of lopinavir and ritonavir, and hydroxychloroquine. We identified 5,717 patients hospitalized with COVID-19 and prescribed at least one anti-COVID-19 drug. The entire cohort generally included patients over 41-50 years and more males. The most common prescription pattern was dexamethasone monotherapy (22.9%), followed by the concomitant use of remdesivir and dexamethasone (15.0%), azithromycin monotherapy (15.0%), remdesivir monotherapy (10.2%), and nafamostat mesylate monotherapy (8.5%). However, an often prescribed anti-COVID-19 drug differed depending on the period. This study revealed the real-world situation of anti-COVID-19 drug prescriptions in hospitalized COVID-19 patients in Japan. A prescribed drug would depend on the latest scientific evidence, such as efficacy, safety, and approval status, at the time of prescription. Understanding the prescription of anti-COVID-19 drugs will be important for providing the most up-to-date treatments to patients and evaluating the benefit and/or risk of anti-COVID-19 drugs based on the utilization of an electronic medical record database.

FECAL URGENCY ASSOCIATED WITH POOR QUALITY OF LIFE IN QUIESCENT IBD: A CROSS-SECTIONAL STUDY OF SPARC IBD COHORT

Abstract BACKGROUND Fecal urgency (FU) is common in patients with active inflammatory bowel disease (IBD) and has been associated with reduced well-being and poor quality of life (QOL). Despite greater therapeutic options, clinical symptoms may persist in some patients. Data is lacking regarding FU in patients with objectively documented quiescent disease. OBJECTIVE Among endoscopic quiescent disease: (1) estimate prevalence of urgency, (2) assess predictors of FU, (3) describe its impact on validated QOL measures. METHODS This cross-sectional study used prospectively collected data from SPARC (Study of a Prospective Adult Research Cohort) IBD, a multicenter longitudinal study of well-phenotyped adult IBD patients initiated by the Crohn’s & Colitis Foundation in 2016. Quiescent IBD was defined as Mayo endoscopy score <2 for ulcerative colitis (UC) and SES-CD score <3 for Crohn’s disease (CD). Patient reported outcomes (PROs) within 30 days of endoscopy were analyzed. Patients with ostomy or IPAA were excluded. Self-reported urgency was categorized as none, mild, or moderate/severe. Univariate statistics used Pearson’s Chi-square and Kruskal-Wallis tests. RESULTS A total of 943 patients with quiescent IBD (579 CD; 364 UC) were included in the study (Table 1). Fecal urgency was more commonly reported in quiescent CD (37.5% mild, 27.8% moderate/severe) as compared to quiescent UC (33.5% mild, 19.8% moderate/severe) (p<0.001). In the entire quiescent cohort, those with mild or moderate/severe FU were more likely to be female sex (58.4%; 63.2%), higher BMI (28.2; 29.5) and have an IBD-related surgery (p=0.030). Mild and moderate/severe urgency was associated with subjective abdominal pain, stool frequency, and bloody stool (all p<0.001). There was a trend towards ileocolonic involvement and penetrating disease in quiescent CD with moderate/severe urgency. General well-being was poorer for those with more severe urgency (p<0.001), and they were more likely to utilize the emergency department (p=0.016). Figure 1 depicts the PROMIS responses. There were significant differences across all domains, and notably those with moderate/severe urgency reported pain (38.8%) and fatigue (60.0%) interfered with enjoyment of life at least some of the time compared to those without urgency (3.9%; 10.0%) or with mild urgency (15.1%; 32,2%). CONCLUSION In this study of patients in SPARC IBD with endoscopic quiescent IBD the overall prevalence of fecal urgency was 65.2% for CD and 53.3% for UC. Fecal urgency was common in quiescent IBD and associated with poorer general well-being and quality of life. Further research is needed to elucidate the pathophysiology for presence of fecal urgency in quiescent IBD and develop personalized management approaches. Table 1 Demographics and IBD characteristics of SPARC IBD patients with quiescent Crohn’s disease (CD) and ulcerative colitis (UC) with symptoms of mild versus moderate/severe fecal urgency. Table 2 Severity of Fecal Urgency on Quality of Life for Patients with Endoscopic Quiescent IBD using PROMIS (Patient-Reported Outcomes Measurement Information System) Scores for Fatigue, Pain Interference† and Social Interference†*. †Responses indicate the degree and frequency of interference with each of the activities listed. *Polarity of Social Interference subscale reversed for consistency and interpretability of the figure.

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci

Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease.

Therapeutic drug monitoring (TDM) and dose optimization have been shown to improve clinical outcomes with antitumor necrosis factor and recent studies in adults suggest an exposure-response relationship with drug levels associated with improved clinical outcomes. However, these levels are not universally recognized as therapeutic targets for vedolizumab dosing. We aimed to assess the impact of a TDM quality improvement (QI) initiative on 52-week clinical outcomes and describe proactively obtained vedolizumab levels during the induction period in children with inflammatory bowel disease (IBD). A QI initiative to proactively obtain TDM levels at Week 6 was implemented in 2019. A retrospective review of pediatric patients with IBD treated with vedolizumab from 2018 to 2022 was performed. Baseline demographic data, medication dosing details, disease characteristics, lab results, and 12-month clinical outcomes were recorded. For this study, we defined therapeutic target levels (>20 μg/mL at Week 6 and >12 μg/mL during maintenance) based on existing data correlating these levels with improved clinical outcomes. Fifty-nine patients (31 Crohn disease [CD], 28 ulcerative colitis [UC]/indeterminate colitis [IC]) were included in the study. In total, 68% (40/59) of patients had vedolizumab levels at Week 6and 90% (53/59) had levels drawn at Week 6 or 14. Thirty-five percent of Week 6 trough levels were below our defined target of 20 μg/mL. Fifty-two of 59 patients had available data at 52 weeks. Over 80% (42/52) of patients remained on vedolizumab 52 weeks after initiation (CD 79% [23/29], UC/IC 83% [19/23]). Sixty-two percent (26/42) of patients that remained on vedolizumab at 52 weeks were treated with an intensified dosing interval of <8 weeks. Thirty-one of these 42 (74%) were in clinical remission (CR)rate at 52 weeks with 29/42 (69%) in corticosteroid-free remission. The CR rate for the entire cohort including those who discontinued therapy due to a lack of efficacy before 52 weeks was 60% (31/52). Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.

P244 The first step to IBD prevention exploring rate of pre-clinical inflammation in subset of asymptomatic subjects at risk of IBD: screening stage of the PIONIR trial

Abstract Background With the increasing prevalence of inflammatory bowel diseases (IBD) globally, it is necessary to start focusing efforts on prevention of the diseases. The Genetic, Environmental, Microbial (GEM) study identified biological signatures predictive of developing IBD in first degree relatives (FDR) of patients with Crohn’s disease (CD). The ongoing PIONIR (Preventing IBD ONset in Individuals at Risk) study is a randomized controlled trial aimed to explore whether the Tasty &amp; Healthy diet can change the CD-risk associated biomarkers of healthy FDRs who are particularly high risk of developing CD, originally followed in the GEM cohort. We report here the rate of IBD and pre-IBD inflammation in a subset cohort. Methods Subjects, 6-35 years of age from the GEM cohort who were identified by a combination of predictors at recruitment to GEM to have an increased risk for persistently elevated fecal calprotectin (FC) (i.e. Microbiome Risk Score (MRS), increased gut permeability and/or multiplex family of CD) were approached to perform a new FC test. Subjects who had FC&amp;gt;70µg/g, confirmed by a second sample, were offered a panenteric video capsule endoscopy (VCE), but some elected to proceed to ileocolonoscopy instead. Results For the PIONIR recruitment, a total of 450 subjects were approached from 7 sites in Israel and Canada, of whom 183 consented and provided a stool sample for FC (Figure). FC was elevated in 57 (31%) subjects, confirmed by re-testing in 36 (20%); 25/36 underwent VCE/ileocolonoscopy (Figure). In total, 8 (4.4% of the screened cohort) had normal-appearing mucosa, in 10 (5.5%) there were non-specific mucosal changes (e.g. several erosions or erythema), 6 (3.3%) had ulcers compatible with CD and 1 (0.6%) was inconclusive. The median FC of those eventually diagnosed with CD (816 [IQR 361-1123) was higher than the remaining 30 without IBD with elevated FC (175 [111-281], p=0.003). FC&amp;gt;275µg/g was highly predictive of CD in the entire cohort (AUROC 0.97 (95%CI 0.93-0.99); sensitivity 83%, specificity 94%). Conclusion Preclinical mucosal inflammation in VCE/ileocolonoscopy was found in 18 of 183 (9.8%) screened subjects (i.e. elevated FC with either normal or nonspecific mucosal findings), 134 (73%) had normal FC and 11 (6%) with elevated FC had missing VCE/ileocolonoscopy data. Six had CD (3.3%, or 17% of the 36 with elevated FC). Detecting subjects at risk at their preclinical stages, possibly with FC&amp;gt;275µg/g, is the first necessary step in developing preventive strategies for IBD.

P1207 Microbiome composition determines sustained remission after the Crohn’s Disease Exclusion Diet (CDED) with or without Partial Enteral Nutrition in adults with mild-moderate Crohn’s disease; Results from the CDED-AD Pilot Randomized Controlled Trial

Abstract Background The Crohn's Disease (CD) Exclusion Diet (CDED) is an established dietary therapy for children with active mild-to-moderate CD. A recent randomized controlled trial showed efficacy in mild-to-moderate CD in adults. We have previously demonstrated the impact of CDED on the microbiome of children. The aim of this work was to assess if we can determine sustained clinical remission (SCR) from the baseline microbiome composition and examine the effect of CDED on microbiome composition in adult CD. Methods This was an open-label, prospective, randomized, controlled pilot trial involving patients with mild-to-moderate CD and evidence of active inflammation. Patients were randomly assigned to receive CDED with partial Enteral Nutrition (PEN) or CDED alone, both for 24 weeks. The V4V5 region of the 16S rRNA gene was amplified and sequenced, and reads were processed using QIIME2 and the SILVA database. Relationships between the microbiome, SCR, and Fecal Calprotectin (FC) were analyzed using logistic regression, Poisson Principal Component Analysis, paired T-Tests and subsampling ranking forward selection. Results Clinical remission (CR) at weeks 6, 12 and 24 was achieved in 62.5%, 52.5%, and 50% of patients, respectively. Week 0, 6, 12 and 24 stool samples were available for 35,32,30 and 26 patients, respectively. In patients with SCR, defined as remission at both weeks 12 and 24, the baseline microbiome revealed lower alpha diversity compared to those without SCR (p=0.018), and differing Microbiome principal components (PC) scores (p &amp;lt; 0.01). PC1 and PC3, characterized mainly by Alistipes, Faecalibacterium and UCG-002 predicted SCR (P&amp;lt;0.01). PC2 predicted elevated FC&amp;gt;250 µg/g at week 12 (p=0.004). Baseline abundance of Haemophilus was associated with decreased SCR probability (p&amp;lt;0.01). At week 6 in the entire cohort, there was a significant decrease in Actinobacteriota (p=0.035) and a significant increase in Bacteroidota (p=0.003). Additionally, there was a significant increase in several genera, including beneficial Alistipes and Oscillibacter (p&amp;lt;0.02) in those who achieved CR after 6, 12, or 24 weeks. Higher Firmicutes at week 6 were associated with FC&amp;lt;250 at week 12 (p=0.031). An uncultured genus from the Oscillospiraceae family was significantly associated with a decrease in the probability of SCR (p&amp;lt;0.01) and was significantly increased at week 6 in patients who did not attain CR (p&amp;lt;0.05). Conclusion The baseline microbiome composition was associated with SCR and FC&amp;lt;250 at week 12 in adult patients treated with CDED (with or without PEN) over 24 weeks. This suggests that the microbiome could be useful tool to identify patients who would benefit from long-term dietary intervention.

Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (β = 0.23, P = 0.024) and lower indices of cortical remyelination (β = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

P459 The prevalence and characteristics of inflammatory bowel disease-related ocular involvement in children

Abstract Background Ocular manifestations (OM) in patients with inflammatory bowel disease (IBD) are uncommon, particularly in children. We aimed to explore the prevalence, characteristics and risk factors of IBD associated OM in a large epidemiologic cohort-based study. Methods A cross-sectional study was performed using the Maccabi Healthcare Services (MHS) database. The eligible population included all patients diagnosed with IBD as children (&amp;lt;18 years) between January 2005 and July 2023. An additional analysis was conducted on patients diagnosed with ocular disease during childhood (&amp;lt;18 years) and IBD during childhood or adulthood. Results Out of 2,567 children with IBD (males 55%, Crohn’s disease 64%), 78 (3%) were diagnosed with OM at any time during disease course. In 54 patients (69%), the OM occurred after IBD diagnosis with a median time of 2.6 (0.47-7) years between the two events, whereas in 24 patients (31%) OM preceded IBD diagnosis with a median time of 2.1 (0.6-5.7) years. OM was significantly associated with Crohn’s disease, compared with ulcerative colitis (78.2% vs. 63.6% in the entire cohort; p=0.03). The presence of OM was associated with increased usage of systemic corticosteroids (p&amp;lt;0.001), biologic agents (p=0.04) and longer duration since IBD diagnosis (p=0.04). There were 55 patients with OM during childhood who were ever diagnosed with IBD. In this population OM was also associated with increased usage of systemic corticosteroids (p&amp;lt;0.001) and increased hospitalization rate per year (p=0.048). The annual prevalence of OM increased gradually from 10/1000 patients in 2005 to 22/1000 patients in 2022 (p=0.55). Conclusion Ocular involvement in children with IBD is rare and more common in patients with Crohn’s disease with a stable prevalence rate. It is associated with a longer duration of disease, greater usage of systemic corticosteroids and biologic agents and with a higher rate of hospitalizations, potentially representing a more severe disease course.

P1175 Abdominal Pain is Associated with Poor Quality of Life in Quiescent Inflammatory Bowel Disease: A Cross-sectional Study of the SPARC Inflammatory Bowel Disease Cohort

Abstract Background Abdominal pain (AP) is common in patients with active inflammatory bowel disease (IBD) and has been associated with poor quality of life (QOL). Despite greater therapeutic options, symptoms persist in a subset of patients. Data is lacking regarding AP in patients with objectively documented quiescent disease. Among endoscopic quiescent disease: (1) estimate prevalence of AP, (2) assess predictors of worse AP, (3) describe its impact on validated QOL measures. Methods This cross-sectional study used prospectively collected data from SPARC (Study of a Prospective Adult Research Cohort) IBD, a multicenter longitudinal study of well-phenotyped adult IBD patients initiated by the Crohn’s &amp; Colitis Foundation in 2016. Quiescent IBD was defined as Mayo endoscopy score &amp;lt;2 for ulcerative colitis (UC) and SES-CD score &amp;lt;3 for Crohn’s disease (CD). Patient reported outcomes (PROs) within 30 days of endoscopy were analyzed. Patients with ostomy or IPAA were excluded. Self-reported AP was categorized as none, mild, or moderate/severe. Univariate statistics used Pearson’s Chi-square and Kruskal-Wallis tests. Results A total of 973 patients with quiescent IBD (606 CD; 367 UC) were included in the study (Table 1). AP was more commonly reported in quiescent CD (31.2% mild, 15.5% moderate/severe) as compared to quiescent UC (23.4% mild, 10.1% moderate/severe) (p&amp;lt;0.001). In the entire quiescent cohort, those with mild or moderate/severe AP were more likely to be female sex (63.1% mild; 67.4% moderate/severe; p&amp;lt;0.001), higher BMI (28.4 mild; 30.0 moderate/severe; p=0.008) and have more recent tobacco use (p=0.004). Ileocolonic involvement was more commonly seen in moderate/severe AP. Mild and moderate/severe AP was associated with subjective fecal urgency, stool frequency, and bloody stool (all p&amp;lt;0.001). Disease behavior in CD was not associated with abdominal pain. General well-being was poorer for those with more severe AP (p&amp;lt;0.001), though this did not appear to result in more frequent recent ED visits or hospitalizations. Figure 1 depicts the PROMIS responses. Overall, worse AP was associated with universal worse scores on all PROMIS measures and subscales (all p&amp;lt;0.001). Data suggested that more severe AP had the greatest impacts on the "Fatigue" subscale. Conclusion In this study of patients in SPARC IBD with endoscopic quiescent IBD the overall prevalence of AP was 41.7% overall and more commonly reported in CD as compared to UC. AP was associated with a greater prevalence of other symptoms, worse general well-being, and poorer quality of life across all measures. Further research is needed to elucidate the pathophysiology for presence of AP in quiescent IBD and develop personalized management approaches.

DNA methylome, R-loop and clinical exome profiling of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.

P1180 Smoking behaviour and changes after diagnosis in patients with Crohn's disease in a tertiary referral hospital: A retrospective explorative study

Abstract Background Smoking is the best-known environmental risk factor for poor outcome of Crohn’s disease (CD). Since smoking cessation improves the prognosis of CD, patients are encouraged to quit smoking. This study aimed to assess the smoking behaviour among CD patients and explore changes after diagnosis of CD. Methods This is a retrospective single tertiary center cohort study of 1267 patients with CD with a median follow-up of 16.8 years (IQR - 18.3) whose characteristics are recorded via a validated data software (IBDIS, Inflammatory Bowel Disease Information System). Smoking behaviour was categorized into never smokers, current smokers, and ex-smokers (those who quit smoking at any point). The primary objective was smoking cessation during follow-up. The probability of smoking was calculated for those CD patients who smoked at the time of diagnosis of CD by means of Kaplan-Meier estimates. Statistical analyses were conducted using R software, employing log-rank tests for estimating differences with a significance level of alpha = 0.05. Results In total 1,128 CD patients with a complete data set were analysed (Table 1). 161 (14.2%) patients started and stopped smoking prior to diagnosis of CD. At the time of diagnosis, 541 patients (47.9%) were smokers, and 239 (44.2%) of them quit smoking during follow up. The median time from CD diagnosis to cessation for the 239 patients who were smokers at the time of diagnosis and subsequently quit was 8.6 years (IQR - 10.6 years). 80 patients (7%) started smoking after diagnosis, with 50 of these patients quitting thereafter. The probability of smoking in those CD patients who smoked at the time of diagnosis decreased over time to 0.96 (95% CI 0.95-0.98) at 1yr, 0.85 (95% CI 0.83-0.89) at 5 yrs, 0.71 (95% CI 0.67-0.76) at 10 yrs, and 0.52 (95% CI 0.47-0.57) at 20 yrs after diagnosis for the entire cohort with no significant difference between genders (p=0.76) (Figure 1a). Patients who were diagnosed 2010 and later (n=182) were more likely to stop smoking than patients diagnosed before 2010 (n=359) (p&amp;lt;0.001) (Figure 1b). However, the probability to smoke 10 years after the diagnosis was still high in both groups (0.62 (95% CI 0.52-0.74) and 0.75 (95% CI 0.71-0.79), respectively). Conclusion A substantial proportion of CD patients smoked at the time of diagnosis. 20 years after diagnosis around half of the patients still continued to smoke. Improved smoking cessation programs are needed to reduce the impact of smoking on the course of the disease.

Different minimal alcohol consumption in male and female individuals with metabolic dysfunction-associated fatty liver disease.

The relationship between moderate alcohol intake and health outcomes among individuals with metabolic dysfunction-associated fatty liver disease (MAFLD) is complex. Our aim was to investigate the association of minimal alcohol consumption with all-cause and cause-specific mortality among MAFLD individuals of different genders. Our study included 2630 MAFLD individuals from the Third National Health and Nutrition Examination Survey. Cox regression analysis was performed to assess the association between alcohol use measures and all-cause and cause-specific mortality. Restricted cubic spline curves were used to evaluate the relationship between alcohol consumption per week and all-cause mortality. In the entire MAFLD cohort, we observed significant disparities in clinical characteristics between male and female individuals with MAFLD. Higher weekly alcohol consumption was significantly associated with all-cause and cause-specific mortality (male, hazard ratios [HRs]: 1.009, 95% CIs: 1.004-1.014; female, HRs: 1.032, 95% CIs: 1.022-1.042). In males with MAFLD, a linear association with all-cause mortality was observed for weekly alcohol consumption (p for non-linearity = .21). Conversely, in females with MAFLD, the risk of all-cause mortality remained relatively stable until 2 drinks per week, after which it rapidly increased with each additional drink consumed, and the increase in mortality risk was higher than that observed in males (p for non-linearity < .05). Our findings indicate that any increase in weekly alcohol consumption was associated with increased all-cause mortality in men with MAFLD. Conversely, consuming less than 2 drinks per week had minimal impact on the risk of mortality among female.

Role of CYFRA 21-1 and CEA as prognostic and predictive markers in locally advanced and metastatic gastric carcinoma.

Tumor-associated serum markers have demonstrated predictive and prognostic value in patients being treated for malignancies. However, the clinical importance of tumor markers in gastric cancers (GC) is poorly standardized. The objective is to assess the clinical utility of cytokeratin-19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA) as serum tumor markers in advanced GC. In this prospective study, CYFRA 21-1 and CEA levels were measured at baseline and after three cycles of chemotherapy in patients with advanced GC. The association of tumor marker levels with prognosis and decline of tumor markers with radiological overall response rates (ORR) and survival were analyzed. In the 105 patients, the proportion of patients with elevated baseline CYFRA 21-1 and CEA levels was 55% (N = 58) and 37% (N = 39) based on predefined cutoffs. Response assessment was done for 61 patients who received a minimum of three cycles of chemotherapy. A 15% and 13% reduction of serum levels from baseline for CYFRA 21-1 and CEA were selected for defining "CYFRA 21-1 response" and "CEA-response," respectively. Both responses were significant predictors of radiological ORR. The median overall survival (OS) was 9.6 months in the entire cohort and 13 months for patients who received at least three cycles of chemotherapy. In multivariate analysis, baseline CEA levels and ECOG status were significant predictors of OS. In a subset analysis of patients receiving palliative chemotherapy, any of the tumor marker responses predicted improved 1-year OS. In advanced GC, CYFRA 21-1 and CEA decline from baseline appeared to be reliable surrogate markers of chemotherapy efficacy and improved survival.

Extrahepatic cholangiocarcinoma: Genomic variables associated with anatomical location and outcome.

554 Background: Genomic determinants of outcome in intrahepatic cholangiocarcinoma have become clear but remain ill-defined in extrahepatic cholangiocarcinoma (ECA). We aimed to clarify the genomic alterations that define ECA, analyze differences between perihilar (PCA) and distal (DCA) disease, and determine clinicopathologic and genomic factors associated with survival. Methods: Patients with EHC with tissue available for targeted next-generation sequencing at Memorial Sloan Kettering Cancer Center were identified. Differences between PCA and DCA were compared, stratified by disease extent and treatment. Associations between genomic alterations and clinicopathologic features and outcomes were analyzed. Univariable and then multivariable cox proportional hazards regression were used to compare survival, which was reported from operation in resected patients and from diagnosis in non-resected patients. Results: Two-hundred-twenty-four patients (n=127 PCA, n=97 DCA, 2006-2022) met inclusion criteria. Median survival was 29 months (IQR [25, 35]; 43 months [35, 48] resection, 17 months [13, 19] without). Compared to PCA, DCA was enriched in TP53mut (67 [69%] vs. 42 [33%]), Q&lt;0.01) and epigenetic pathway alterations (44 [45%] vs. 37 [29%], Q=0.041) and had more altered pathways (3 vs. 2, Q&lt;0.01). KRASmut was similar between PCA (46 [36%]) and DCA (36 [37%]); however, PCA was enriched in KRAS G12V (16 [13%] vs. 4 [4%]) and Q61H (11 [9%] vs. 3 [3%], P=0.002). No other clinicopathologic or genomic variables distinguished PCA from DCA (Table). MDM2mut occurred in 19/141 (13%) patients with nodal/metastatic disease compared to 1/83 (1%) patients with local disease ( Q=0.03), but conferred no survival disadvantage. In resected patients, survival was similar between PCA and DCA and no genomic alterations were associated with outcome. By contrast, in patients without surgery, CDKN2Adel (HR 2.59, 95% CI [1.48, 4.52]) and APCmut (HR 5.11, 95% CI [1.96, 13.3]) were associated with survival disadvantages. Lack of resection (HR 3.13, 95% CI [2.25, 4.36]), CDKN2Amut (HR 1.80 [95% CI 1.80, 2.68), and APCmut (HR 2.00 [95% CI 1.04, 3.87]) were associated with poor survival in the entire cohort. Conclusions: In this study, aside from a higher incidence of TP53mut in DCA and some differences in KRAS subtype alteration patterns, genomic alterations were comparable between PCA and DCA. CDKN2Amut and APCmut were associated with poor survival in all patients but no biomarkers provided significant prognostic information when tumors were resected. [Table: see text]

Impact of Hispanic ethnicity on immunotherapy outcomes in hepatocellular carcinoma: Insights from the National Cancer Database.

438 Background: Hepatocellular carcinoma (HCC) is the fastest-growing cancer in the US with more age-adjusted incident cases in Hispanics compared to non-Hispanics. Immunotherapies are considered integral part of treatment for most unresectable HCC. Recent multinational phase III trials suggest the benefit of immunotherapies may differ based on geographic region and underlying etiology of HCC. We hypothesized that Hispanic ethnicity might influence responses to immunotherapy in HCC. Methods: We analyzed the National Cancer Database (NCDB) to assess the impact of immunotherapy on overall survival (OS) in Hispanic patients with HCC. The database was queried for liver cancer from 2004 to 2020. Kaplan Meier method was used to assess OS and a log-rank test was used to compare survival distribution between Hispanic and non-Hispanic groups. Cox regression analysis was performed to estimate the adjusted effect of ethnicity on OS based on immunotherapy status. NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoCÕs NCDB are the source of the de-identified data used herein. Results: A total of 225079 patients were identified of whom 2036 patients (0.9%) received immunotherapy as first-line treatment. Patients with non-Hispanic ethnicity, male sex, who received treatment at academic/research institutions, and were insured were more likely to receive immunotherapy. In the entire cohort, there was no difference (p=0.94) in survival between those who did not receive immunotherapy (median OS,11.63 months; IQR: 2.79, 34.83) vs. those who did (median OS, 10.68 months, IQR: 5.19, 23.29[DA2]). There were more Hispanics in the cohort who did not receive immunotherapy (12.28% vs. 10.61%). In the adjusted Cox analysis, Hispanics had a reduced risk of death than non-Hispanics among patients who did not receive immunotherapy (HR: 0.873, 95%CI, 0.858-0.889; p&lt;0.001). Among patients with immunotherapy, there was no OS difference between ethnicities (HR 0.904, 95% CI, 0.755-1.082; p 0.271). Conclusions: Hispanics were less likely to receive immunotherapy than non-Hispanics. Although Hispanics had a better OS than non-Hispanics among patients without immunotherapy, the differences no longer persist among patients who received immunotherapy. These findings suggest that Hispanic ethnicity may influence responses to immunotherapy. As compared to non-Hispanic whites, Hispanics with HCC have significantly more nonalcoholic fatty liver disease and alcohol-related liver disease as contributing factors. A better understanding of the impact of immunotherapies on alcoholic and nonalcoholic liver disease-related HCC is needed.

Real-world assessment of capecitabine and oxaliplatin (CAPOX) tolerability in patients with localized colorectal cancer undergoing curative-intent therapy: A comprehensive single institution analysis.

90 Background: The combination of capecitabine and oxaliplatin (CAPOX) is commonly used in patients with localized colorectal cancer (CRC) receiving curative-intent treatment. However, real-world data on the tolerability of CAPOX in this patient population are limited. This study aimed to assess the tolerability of CAPOX in a single-institution cohort of patients with localized CRC. Methods: A retrospective analysis was conducted using our institutional pharmacy database to identify patients with localized CRC who received neoadjuvant or adjuvant CAPOX. Demographic information, clinical characteristics, and treatment details were extracted from electronic health records. The primary endpoint was the rate of treatment completion, defined as the receipt of all planned chemotherapy cycles at full dosage, for both the overall cohort and patients aged 65 and above. Secondary outcome measures included the rate of grade 3 or higher adverse events, the frequency of hospital admissions due to CAPOX-related toxicities, and dose reductions. Results: A total of 153 patients were included in the analysis, with a median age of 61 years (range 32-84). Among them, 49% were female, 78.4% had stage III CRC, and the remaining had stage II disease. The racial distribution was 81% White and 15.7% Black. The proportion of patients who completed all planned CAPOX doses was 55.5% (85/153) in the entire cohort and 38% (23/60) in patients aged 65 and above (p = 0.22). Among patients intended to receive 4 cycles of CAPOX, only 57% (37/65) completed all 4 cycles. Female patients were less likely to complete treatment than male patients (p = 0.01). Dose reductions for oxaliplatin and capecitabine were observed in 37% (57/153) and 39% (59/153) of patients, respectively. Hospitalizations related to CAPOX-induced toxicities occurred in 18% (27/153) of patients, and 31% (47/153) experienced grade 3 or higher adverse events. A switch to FOLFOX was observed in 5% (8/153) of patients. Conclusions: This study highlights that a substantial number of patients with localized CRC undergoing curative-intent treatment with CAPOX do not complete the planned courses, potentially impacting their overall survival. Moreover, a significant proportion of patients experience grade 3 or higher toxicities with CAPOX, necessitating hospital admissions. These findings underscore the need for careful patient selection and management strategies to optimize the therapeutic benefits of CAPOX in this setting.

Survival trends in gastric cancer in Brazil: Real-life data from a large cancer center.

413 Background: Gastric cancer (GC) is the fourth leading cause of cancer deaths globally. There is a paucity of real-life data on GC in Brazil. Our study aimed to evaluate survival trends in gastric adenocarcinoma (GA) in a large cancer center in Brazil during 2000-2017. Methods: Based on our Hospital Cancer Registry Database, all individuals diagnosed with GA between 2000 and 2017, and treated at A.C. Camargo Cancer Center, were retrospectively included. The primary objectives were to describe the patient demographics, clinicopathological characteristics, treatment modalities, and survival trends during four separate periods of diagnosis (2000-2004; 2005-2009; 2010-2014; and 2015-2017). χ2 test was performed between two specified periods (2000-2004 and 2015-2017) to compare categorical variables. Overall survival (OS) curves were stratified by four separate periods and compared with log-rank tests. Results: The current analysis comprises a retrospective cohort of 1406 patients (552 female and 854 male individuals). Across all periods, most patients were men aged 50 to 69 and presented with Lauren’s intestinal subtype. There were significant differences between staging groups during the study. Specifically, between 2000-2004, stage IV varied from 43.6% to 32.8% in 2015-2017 (P&lt;0.001). The most substantial variation in nonmetastatic cases occurred in stage II, comprising 9.4% of cases from 2000-2004 and rising to 24.8% in 2015-2017 (P&lt;0.001). Concerning treatment modalities, we observed an increased utilization of a combined approach involving chemotherapy and surgery throughout the investigation. Specifically, from 2000-2004, only 12% of patients received a multimodal treatment regimen consisting of chemotherapy and surgery, whereas, between 2015-2017, this proportion increased to 36.3% (P&lt;0.001). Also, patients receiving surgery + radiotherapy + chemotherapy varied from 12.4% of patients in 2000-2004 to 4.5% in 2015-2017 (P&lt;0.001). When the entire cohort was analyzed, the predicted 5-year OS of patients with GA between 2000-2004 was 27.8%, which increased to 53.9% in the period from 2015-2017 (P&lt;0.001). Among females, 5-year OS increased from 31.3% between 2000-2004 to 58.5% between 2015-2017 (P=0.001). Among males, 5-year OS increased from 25.2% to 51.0% in the same comparison (P&lt;0.001). Conclusions: Our hospital-based data shows an upward trend in survival rates across patients with GA. We observed that 5-year OS almost doubled among men and women during the analyzed period. Recent improvements in staging methods and treatment have increased cure rates. Nevertheless, further investigation is essential to determine significant differences in OS between males and females.

Real-world evaluation of clinical outcomes and long-term survivors in patients with BRAF-V600E metastatic colorectal cancer.

166 Background: BRAF-V600E mutant metastatic colorectal cancer (BRAF-V600E mCRC) is associated with poor prognosis but confers response to combination BRAF/EGFR blockade. The goal of this study is to evaluate the clinicopathologic features and natural history of BRAF-V600E mCRC in the era prior to combination BRAF/EGFR inhibitors. Methods: This is a retrospective study of patients treated at the Ottawa Hospital Cancer Centre with BRAF-V600E mCRC who did not receive combination BRAF/EGFR therapy. Patients diagnosed with colorectal cancer prior to March 31, 2021, were included. Demographic, clinical, pathologic and cancer characteristics were abstracted from electronic medical records. Outcomes of interest included duration of therapy, as a surrogate of progression free survival, and overall survival (OS). Long-term survivor was defined as OS greater than 2 years. Results: 74 patients were included. Median age was 70 years (IQR=61-78), and 39 (53%) patients were female. There were 17 (23%) patients alive at the end of the follow-up period. 31 (42%) patients had poorly differentiated grade and 26 (35%) were mismatch repair deficient (dMMR). Locations of metastases included liver (40, 54%), peritoneum (30, 41%), lung (18, 24%), bone (5, 7%) and brain (5, 7%). Overall, 64 (86%) patients received first line systemic therapy, 19 (26%) second line, and 5 (7%) third line (see Table). Median duration of therapy in the first line was 4.3 months (IQR=2.0-9.6), second line was 2.9 months (IQR=1.4-4.1), and third line 1.0 months (IQR=1.0-1.9). Overall survival in the entire cohort was 13.2 months (IQR=4.6-25.4). Importantly, 21 (28%) patients were long-term survivors, of which 8 (11%) were dMMR. Conclusions: Patients with BRAF-V600E mCRC generally have poor clinical outcomes with traditional systemic therapies. In this study, we identified approximately 25% of patients who are long-term survivors (OS &gt;2 years). This reflects the real-world heterogeneity of clinical outcomes for patients with BRAF-V600E mCRC who did not receive BRAF/EGFR targeted therapy.[Table: see text]

Has management of locally advanced intrahepatic cholangiocarcinoma evolved with the evidence? Trends and practice patterns from the National Cancer Database.

464 Background: Intrahepatic cholangiocarcinoma (IHC) is often advanced at presentation. Mounting evidence suggests a limited role for surgical resection in the setting of multifocal hepatic and regional lymph node involvement in favor of initial treatment with systemic therapy. We sought to characterize trends and practice patterns in the management of patients with locally advanced IHC without distant extrahepatic metastasis. Methods: We queried the National Cancer Database (NCDB) for patients with IHC between 2004-2020. Patients with inadequate data quality, carcinoma in situ, other primary cancers prior to IHC diagnosis, distant metastasis (M1), unknown M status (MX), and no treatment were excluded. Lymph node involvement was categorized using clinical N stage to reflect clinical decision-making. Due to AJCC staging updates and coding limitations, subgroup analysis of patients with multifocal disease (T2bNXM0 in the 7th AJCC edition) was confined to 2010-2017. A two-sided Cochran-Armitage test was used to evaluate time trends and Kaplan Meier methods were used to summarize overall survival (OS). Results: Of 11,368 patients treated for IHC without distant metastasis between 2004-2020, 2,467 / 10,183 (24%) with clinical lymph node staging had positive nodes; the subgroup with multifocal disease comprised 1,384 patients staged T2bNXM0 between 2010-2017. Overall, 36% of patients received formal resection as first treating modality and 59% received systemic or radiation therapy first. The use of perioperative chemotherapy in combination with formal resection increased from 39% pre 2010 to 70% in 2018-2020 (p&lt;0.001), most often delivered post-operatively: 49% received adjuvant, 13% neoadjuvant, and 8% both in 2018-2020. Among those with clinically positive lymph nodes, there was a decreasing trend in upfront resection (p&lt;0.001) and an increase in systemic or radiation therapy first (p&lt;0.001). Similarly, in the multifocal disease subgroup analysis, the proportion of upfront formal resection trended down from 33% in 2010 to 12% in 2017 (p&lt;0.001). Across the entire cohort, median OS improved from 16 months (IQR 15, 18) to 27 months (IQR 26, 29) for patients diagnosed 2018-2019 compared to &lt;2010. Conclusions: Over the last decade, increasing evidence has demonstrated unfavorable outcomes of surgical resection in locally advanced IHC even without distant extrahepatic disease, and supported the use of multimodality therapy. The most significant overall trends have been increasing use of perioperative systemic therapy in combination with formal resection compared to resection alone and an improvement in overall survival. On subgroup analysis, there was a significant and appropriate trend away from resection as first treatment modality for patients with clinically positive lymph nodes or multifocal disease.

Tissue factor: A link between metastatic colorectal cancer and thrombosis in patients in the CALGB (Alliance)/SWOG 80405 trial.

198 Background: Tissue factor (TF) is a transmembrane protein that plays a crucial role in thrombosis. TF expression is elevated in various types of cancer, including colorectal cancer (CRC) and is associated with more aggressive disease and poor prognosis. The aim of this study was to evaluate TF expression in patients (pts) with metastatic CRC (mCRC) enrolled in the CALGB (Alliance)/SWOG 80405 clinical trial. Understanding the relationship between TF expression and mCRC will provide insights into the role of coagulation in the progression and prognosis of this disease and may have therapeutic implications, particularly in the setting of recent approval of a TF antibody drug conjugate for metastatic cervical cancer and other agents in the pipeline. Methods: 433 pts with mCRC treated with bevacizumab (Bev, n = 226) or cetuximab (Cet, n =207) in combination with first-line chemotherapy in CALGB/SWOG 80405 were included in the analysis. TF RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of TF expression: high (H), medium (M) and low (L). Sensitivity analyses were conducted after stratifying by side. Logrank P-values describe differences without adjustment for pt characteristics. Transcriptome-wide gene association analysis was performed using linear regression, adjusting for age, sex, ethnicity, ECOG PS, location, number of metastases, KRAS, MSI status, treatment with FOLFOX or FOLFIRI, and the first 3 principal components from the RNA-seq data. Gene Ontology enrichment analysis was conducted with the top 100 TF-associated genes. Results: TF expression is associated with genes related to maintenance of epithelium, cell adhesion, and migration, immunoregulatory cytokine production, and metabolic, HER2, and MAP/Kinase pathways. TF-L showed significantly longer median (m)PFS (13.4 vs 10.1 vs 9.2 months (mo), p=0.0022) and mOS (35.4 vs 30.9 vs 25.2, p=0.0051) in the entire cohort. In Cet treated pts, TF-L had significantly longer mOS (41.3 vs 29.9 vs 26.1 mo, p=0.0013). In pts treated with FOLFOX, TF-L had significantly longer PFS (13.2 vs 10.9 vs 8.2 mo, p=0.0014) and OS (33.4 vs 30.9 vs 22.4 mo, p=0.0044). Pts with liver metastases and TF-H had worse PFS (9.2 vs 9.9 vs 13.5 mo, p=0.006) and OS (23.6 vs 29.9 vs 35.1 mo, p=0.016). Conclusions: Our results suggest that pts with TF-L tumors with liver metastases have improved prognosis compared to pts with TF-H and may benefit from FOLFOX and Cet-based treatment. Findings provide rationale for further evaluation of TF as a predictive biomarker and potential therapeutic target in CRC. Trial Identifier NCT00265850. Support: P30CA014089, U10CA180821, U10CA180882, U10CA180820 and UG1CA233277; UG1CA180830, U10CA180888; Pfizer, Genentech. https://acknowledgments.alliancefound.org.