Citations

22 Background: Glycosylation plays a pivotal role in host immune response during cancer development. Recently, we have reported specific changes in blood-based glycoforms for the early detection of advanced adenomas (AAs) and colorectal cancer (CRC). This study aims to identify glycoproteomic biomarkers associated with various polyp types, as glycosylation abnormalities are linked to neoplastic transformation, and CRC risk varies by polyp histology. Methods: Samples from an observational study (NCT05445570) were used to identify three distinct histologic polyp groups: adenomatous (AP), hyperplastic (HP), or serrated (SP). Combining liquid-chromatography/mass-spectrometry and artificial-intelligence powered data processing, our glycoproteomic profiling platform assessed glycopeptide (GP) and non-glycosylated peptide quantification transitions from the serum samples. We used multi-nominal response logit models to examine the relationship between polyp types and biomarkers. An a priori biomarker panel was interjected as exposures in the model. Each marker is assessed independently for inclusion into our final model. The final model utilized biomarkers found to have a significant association with the presence of AP, SP, or HPs along with age, sex, and BMI. Results: We identified 1,035 subjects with distinct polyp histologies and 1,300 polyp-free controls. We found a significant increase in relative risk (RR) for polyp presence in patients who were: >60 years (AP RR 1.40), male (AP RR 1.74), or had a BMI> 25. From the GP biomarker panel, 15 GPs were associated with risk of polyp presence; however, only 7 GP markers were significantly associated after adjusting for age, sex, and BMI. Two biomarkers were found to have a protective effect for the risk of an adenomatous polyp (RR 0.37; RR 0.39). Three biomarkers increased the risk of an adenomatous polyp (RR 1.31; RR 1.42; RR 1.98). One biomarker was found to increase the risk of a hyperplastic polyp (RR 1.42). Two biomarkers were found to increase the risk of serrated polyps (RR 1.67; RR 2.08) and one biomarker was found to decrease the risk of serrated polyps (RR 0.77). Conclusions: This is a novel exploratory study using GP biomarkers as it relates to risk of polyp presence by distinct histology. The use of these biomarkers allows us to harness the power of glycobiology in the liquid biopsy domain for AAs/CRC detection. The exact function of these GP markers during the development of different polyp types needs to be further explored through future studies.

200 Background: We developed and validated a quantitative segmentation algorithm (QuantCRC) to predict disease recurrence in stage I-III colorectal cancer patients (pts) based on the analysis of digitized hematoxylin and eosin (H+E) stained pathology slides. In this study, we aim to determine if QuantCRC analysis on pre-treated RC biopsies can predict pathological complete response (pCR) after NAT which include total neoadjuvant therapy (TNT), chemoradiation (CRT) and others. Methods: Stage II-IV RC pts treated with curative intent modalities between 2005-2023 at Mayo Clinic and University of Pittsburgh were evaluated. Eligible pts had pre and post-treatment tissue available for analysis. Clinical characteristics, treatment, and outcome data were extracted from the medical record. QuantCRC extracted 15 features: %tumor, %stroma, tumor:stroma ratio, %TB/PDC, %mucin, %necrosis, %high-grade, %signet ring cells, tumor-infiltrating lymphocytes (TILs) per cm2 of a tumor, %immature stroma (tumor bed), %inflammatory stroma (tumor bed), %mature stroma (tumor bed), %immature (stromal region), %inflammatory (stromal region), and %mature (stromal region). The associations between the QuantCRC features and pCR were evaluated using Wilcoxon rank-sum tests and logistic regression models while adjusting for primary tumor location and NAT. Results: The identified 288 pts had the following demographics: median age 60, 59% male, 52% distal tumor, 42% TNT. Pts who achieved pCR had smaller pre-treatment tumors (p=0.03), higher TILS, and lower %immature (stroma) (Table 1). After multivariable adjustment, higher TILS and lower %immature (stroma) remain to be significantly associated with a higher likelihood of pCR. A higher %mature (stroma) and %mature stroma (tumor bed) were also identified, in multivariable models, to be associated with a higher rate of pCR. NAT protocol and tumor location (proximal vs. distal) were not associated with pCR. Conclusions: The ability to integrate pathological features with AI may allow for personalized treatment. Using this technology, we recognize that patients who harbor a more mature stromal archetype and inflammatory tumor predisposition, are more likely to achieve pCR to conventional NAT. These pathological features are not currently incorporated into risk stratification in RC. Additional validation and integration into current risk stratification methods is warranted. [Table: see text]

175 Background: Alterations to mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2, can lead to microsatellite instability-high (MSI-H) tumors. MMR mutations can be inherited in Lynch syndrome (LS) but can also be a result of de novo alterations resulting in MSI-H malignancies. Treatment with immune checkpoint inhibitors (ICIs) have been shown to improve survival in such patients (pts) compared to systemic chemotherapy. However, there is a paucity of information in the literature with respect to outcomes of pts with germline vs somatic MMR mutations in MSI-H colorectal cancer (CRC). Furthermore, the presence of underlying BRAF mutation confers resistance to chemotherapy in pts with CRC, however data regarding outcomes with immunotherapy in such pts with MSI-H CRC is lacking. Methods: Pt records from the Mayo Clinic (AZ, MN, FL) between 2008-2023 denoted as MSI-H CRC, were included for retrospective review. Pt demographics, treatment courses, and genomic profiles were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups were accessed with the log rank test and univariate analyses were assessed with Cox-regression. Results: A total of 81 pt records were identified (n = 18 LS, n = 63 non-LS). Stage IV disease was found in 28% of LS pts vs 59% of non-LS pts at diagnosis. Pembrolizumab was the most common ICI selected for metastatic CRC pts for both LS and non-LS pts (65% vs 94%) with median treatment duration for each group 11.7 vs 8.8 months. There were no differences in OS or PFS for any stage between LS vs non-LS. Median OS for all patients was 82 months. For all stage IV patients, median OS was 44 months, and median PFS was 19 months. Interestingly, for stage IV pts treated with immunotherapy, tumors that harbored BRAF V600E mutation (n = 21) vs BRAF wild type (n = 20) had a significantly lower median OS 19 vs 113 months (HR = 2.69, p = 0.043) as well as median PFS 12 vs 95 months (HR = 2.48, p = 0.041). Conclusions: In this study, we found that patient treated with ICIs have similar outcomes in the presence of germline vs. somatic MMR mutations in MSI-H CRC. The presence of an associated BRAF V600E mutation, which occurs in non-LS MSI-H CRC conferred worse outcomes.

162 Background: There is a need to improve current risk stratification of stage II and III colorectal cancer (CRC) to better inform risk of recurrence and guide adjuvant chemotherapy. The purpose of this study is to examine whether integration of QuantCRC, an AI-based digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Methods: ASCO and QuantCRC-integrated risk schemes were applied to an observational cohort of 1,068 stage II and III CRCs. The stage II integrated scheme utilizes pT3 vs. pT4 and QuantCRC-derived risk groups. The stage III integrated scheme utilizes pT1-3 vs. pT4, pN1 vs. pN2, and QuantCRC-derived risk groups. Performance metrics included log-rank test, hazard ratios and Somers’ Dxy rank correlation. Results: Integration of QuantCRC provides improved risk stratification compared to the ASCO scheme for stage II and III CRC. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared to the ASCO scheme (69.3% vs. 60.4%) without decreased 3-year RFS. The QuantCRC-integrated scheme provided larger hazard ratios (HR) for both intermediate-risk (3.04, 95%CI 1.81-5.10, P=2.8x10-5) and high-risk (4.62, 95%CI 2.02-10.61, P=0.0003) groups compared to ASCO intermediate-risk (2.09, 95%CI 1.21-3.63, P=0.008) and high-risk (3.08, 95%CI 1.57-6.01, P=0.001) groups. The QuantCRC-integrated scheme for stage III tumors identified a small group of 80/518 (15.4%) CRCs at very high risk of recurrence with HR of 4.08 (95%CI 2.68-6.23, P=6.5x10-11) compared to a HR of 2.42 (95%CI 1.72-3.38, P=3.1x10-7) for 228/518 (44.0%) high-risk CRCs in the ASCO scheme. QuantCRC-integrated risk groups remained prognostic in stage III CRCs when stratified by presence or absence of any adjuvant chemotherapy. No difference in RFS were seen in QuantCRC-integrated low-risk and intermediate-risk stage III CRCs stratified by 3 vs. 6-months of oxaliplatin-based adjuvant chemotherapy suggesting that these two groups can be treated with 3-months of adjuvant therapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance.

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Abstract Background The Patient Cloud ePRO app was adopted by the National Cancer Institute National Clinical Trials Network (NCTN) to facilitate capturing electronic patient-reported (ePRO) outcome data, but use has been low. The study objectives were to test whether a patient-targeted ePRO educational resource (ePRO-E) would increase ePRO intent (number of users) and improve data quality (high quality: ≥80% of the required surveys submitted) within an ongoing NCTN study. Methods The ePRO-E intervention, a patient-targeted educational resource (written material and 6-minute animated YouTube video), was designed to address ePRO barriers. ePRO intent and data quality were compared between 2 groups (N = 69): a historical control group and a prospectively recruited intervention group exposed to ePRO-E. Covariates included technology attitudes, age, sex, education, socioeconomic status, and comorbidity. Results Intervention group ePRO intent (78.8%) was statistically significantly higher than historical control group intent (47.1%) (P = .03). Patients choosing ePRO versus paper surveys had more positive and higher technology attitudes scores (P = .03). The odds of choosing ePRO were 4.7 times higher (95% Confidence Interval [CI] = 1.2 to 17.8) (P = .02) among intervention group patients and 5.2 times higher (95% CI = 1.3 to 21.6) (P = .02) among patients with high technology attitudes scores, after controlling for covariates. However, the 80% submission rate (percentage submitting ≥80% of required surveys) in the ePRO group (30.6%) was statistically significantly lower than in the paper group (57.9%) (P = .05). Conclusions ePRO-E exposure increased ePRO intent. High technology attitudes scores were associated with ePRO selection. Since the ePRO survey submission rate was low, additional strategies are needed to promote high-quality data submission.

ABSTRACT The growing threat of antibiotic-resistant bacterial pathogens necessitates the development of alternative antimicrobial approaches. This is particularly true for chronic wound infections, which commonly harbor biofilm-dwelling bacteria. A novel electrochemical bandage (e-bandage) delivering low-levels of hypochlorous acid (HOCl) was evaluated against Pseudomonas aeruginosa murine wound biofilms. 5 mm skin wounds were created on the dorsum of mice and infected with 10 6 colony-forming units (CFU) of P. aeruginosa . Biofilms were formed over 2 days, after which e-bandages were placed on the wound beds and covered with Tegaderm. Mice were administered Tegaderm-only (control), non-polarized e-bandage (no HOCl production), or polarized e-bandage (using an HOCl-producing potentiostat), with or without systemic amikacin. Purulence and wound areas were measured before and after treatment. After 48 hours, wounds were harvested for bacterial quantification. Forty-eight hours of polarized e-bandage treatment resulted in mean biofilm reductions of 1.4 log 10 CFUs/g ( P = 0.0107) vs non-polarized controls and 2.2 log 10 CFU/g ( P = 0.004) vs Tegaderm-only controls. Amikacin improved CFU reduction in Tegaderm-only ( P = 0.0045) and non-polarized control groups ( P = 0.0312) but not in the polarized group ( P = 0.3876). Compared to the Tegaderm-only group, there was less purulence in the polarized group ( P = 0.009). Wound closure was neither impeded nor improved by either polarized or non-polarized e-bandage treatment. Concurrent amikacin did not impact wound closure or purulence. In conclusion, an HOCl-producing e-bandage reduced P. aeruginosa in wound biofilms with no impairment in wound healing, representing a promising antibiotic-free approach for addressing wound infection.

A commentary on Canterino et al. (2024) and Munsiff et al. (2024), articles where clinicians from two large OPAT programs

Abstract The Infectious Diseases Society of America Training Program Directors Committee met in October 2022 and discussed an observed increase in clinical volume and acuity on infectious diseases (ID) services, and its impact on fellow education. Committee members sought to develop specific goals and strategies related to improving training program culture, preserving quality education on inpatient consult services and in the clinic, and negotiating change at the annual IDWeek Training Program Director meeting. This paper outlines a presentation of ideas brought forth at the meeting and is meant to serve as a reference document for infectious diseases training program directors seeking guidance in this area.