Safety of Immunosuppression in a Prospective Cohort of Inflammatory Bowel Disease Patients With a HIstoRy of CancEr: SAPPHIRE Registry.

BACKGROUND & AIMS: In patients with inflammatory bowel disease (IBD) and a history of cancer, retrospective studies have suggested that exposure to immunosuppressive agents does not increase the risk of incident (recurrent or new) cancer compared with unexposed patients. SAPPHIRE is a prospective registry aimed at addressing this issue. METHODS: Since 2016, patients with IBD and confirmed index cancer before enrollment were followed up annually. Patients receiving chemotherapy or radiation at enrollment, or recurrent cancer within 5 years, were excluded. The primary outcome was development of incident cancer related to exposure to immunosuppressive medications. RESULTS: Among 305 patients (47% male, 88% white), the median age at IBD diagnosis and cancer were 32 and 52 years, respectively. Index cancers were solid organ (46%), dermatologic (32%), gastrointestinal (13%), and hematologic (9%). During a median follow-up period of 4.8 years, 210 patients (69%) were exposed to immunosuppressive therapy and 46 patients (15%) developed incident cancers (25 new, 21 recurrent). In unadjusted analysis, the crude rate of incident cancer in unexposed patients was 2.58 per 100 person-years vs 4.78 per 100 person-years (relative risk, 1.85; 95% CI, 0.92-3.73) for immunosuppression-exposed patients. In a proportional hazards model adjusting for sex, smoking history, age and stage at index malignancy, and nonmelanoma skin cancer, no significant association was found between receipt of immunosuppression and incident cancer (adjusted hazard ratio, 1.41; 95% CI, 0.69-2.90), or with any major drug class. CONCLUSIONS: In this interim analysis of patients with IBD and a history of cancer, despite numerically increased adjusted hazard ratios, we did not find a statistically significant association between subsequent exposure to immunosuppressive therapies and development of incident cancers.

Survey Finds Gender Disparities Impact Both Women Mentors and Mentees in Gastroenterology.

INTRODUCTION: Gastroenterologists at all levels of practice benefit from formal mentoring. Much of the current literature on mentoring in gastroenterology is based on expert opinion rather than data. In this study, we aimed to identify gender-related barriers to successful mentoring relationships from the mentor and mentee perspectives. METHODS: A voluntary, web-based survey was distributed to physicians at 20 academic institutions across the United States. Overall, 796 gastroenterology fellows and faculty received the survey link, with 334 physicians responding to the survey (42% response rate), of whom 299 (90%; 129 women and 170 men) completed mentorship questions and were included in analysis. RESULTS: Responses of women and men were compared. Compared with men, more women preferred a mentor of the same gender (38.6% women vs 4.2% men, P < 0.0001) but less often had one (45.5% vs 70.2%, P < 0.0001). Women also reported having more difficulty finding a mentor (44.4% vs 16.0%, P < 0.0001) and more often cited inability to identify a mentor of the same gender as a contributing factor (12.8% vs 0.9%, P = 0.0004). More women mentors felt comfortable advising women mentees about work-life balance (88.3% vs 63.8%, P = 0.0005). Nonetheless, fewer women considered themselves effective mentors (33.3% vs 52.6%, P = 0.03). More women reported feeling pressured to mentor because of their gender (39.5% vs 0.9% of men, P < 0.0001). Despite no gender differences, one-third of respondents reported negative impact of the COVID-19 pandemic on their ability to mentor and be mentored. DISCUSSION: Inequities exist in the experiences of women mentees and mentors in gastroenterology, which may affect career advancement and job satisfaction.

Whites and blacks have similar risk of metachronous advanced colorectal neoplasia.

BACKGROUND: Current guidelines for surveillance of colonic neoplasia are based on data from predominantly white populations, yet whether these recommendations are applicable to blacks is unknown. AIM: To define the prevalence of advanced colorectal neoplasia (ACN) among whites and blacks undergoing surveillance colonoscopy. METHODS: This was a retrospective, cross-sectional analysis of asymptomatic, average-risk non-Hispanic white (N = 246) and non-Hispanic black (N = 203) patients with colorectal neoplasia who underwent baseline screening colonoscopy between January 1, 2000, and December 31, 2007, and a surveillance colonoscopy before December 31, 2010, at an academic safety-net hospital. The main outcome measure was the prevalence of ACN, defined as a tubular adenoma or sessile serrated adenoma (SSA) ≥ 10 mm, any adenoma with villous histology or high-grade dysplasia, any serrated lesion with dysplasia, or invasive cancer at surveillance. RESULTS: During a median follow-up of 4.3 years, the overall prevalence of ACN at surveillance was similar among blacks and whites (11.3 vs. 9.8 %; P = 0.59) with an odds ratio of 1.18 (95 % CI 0.65-2.16) [corrected]. Blacks and whites with non-advanced neoplasia had similar rates of ACN at the 1-3, 4-5, and >5 year follow-up intervals. Blacks with ACN or multiplicity at baseline had higher rates of ACN at the 1- to 3-year interval compared with whites, but the difference was non-significant (26.7 vs. 12.5 %; P = 0.32). No interval cancers were observed for either group. CONCLUSIONS: The overall prevalence of ACN was similar between non-Hispanic blacks and non-Hispanic whites undergoing surveillance in a safety-net healthcare setting suggesting that current surveillance guidelines are appropriate for both blacks and whites.

Gastrointestinal angiodysplasia in heart failure and during CF LVAD support.

Angiodysplasias (AGD) are common sites of bleeding in the gastrointestinal (GI) tract after Continuous Flow Left Ventricular Assist Device (CF-LVAD) implantation. We sought to investigate whether AGDs are formed as a result of LVAD physiology or preexist as a consequence of heart failure. Thirty-six subjects with HF reduced EF (HFrEF) underwent video capsule endoscopy (VCE) to assess for the presence of AGD. Fifty-three subjects without HF who underwent VCE for a nonbleeding indication formed a control group. The prevalence of AGD was significantly higher in the HFrEF compared to the non-HF controls (50% vs 13%, p = 0.0002). This association persisted after controlling for age and comorbidities. Within the HFrEF cohort, higher Ang2, NT-proBNP and BUN were associated with the presence of AGD. AGD in the GI tract are associated with HFrEF. This is the first description of a new pathology associated with HFrEF and adds to our understanding of CF LVAD associated GI bleeding.

Structure-based design of mimetics for granulocyte-macrophage colony stimulating factor (GM-CSF).

Granulocyte-macrophage colony stimulating factor (GM-CSF) activity has been linked to pro-inflammatory effects in autoimmune syndromes, such as rheumatoid arthritis. Thus GM-CSF mimetics with antagonist activity might play a therapeutic role in these diseases. The human GM-CSF core structure consists of a four alpha-helix bundle, and GM-CSF activity is controlled by its binding to a two-subunit receptor. A number of residues located on the B and C helices of GM-CSF are postulated to interact with the alpha chain of the GM-CSF receptor (GM-CSFR). Several approaches have been successfully utilized to develop peptide mimetics of this site, including peptides from the native sequence, a peptide derived from a recombinant antibody (rAb) light chain which mimicked GM-CSF receptor binding activity, and structurally guided de novo design. Analysis of the rAb light chain had suggested mimicry of GM-CSF with residues mostly contributed by the CDR I region. Key residues involved in CDR I peptide/GM-CSFR binding were identified by truncation and alteration of individual residues, while the structural elements required to antagonize the biological action of GM-CSF were separately tested in binding and inhibitory activity assays of multiple cyclic analogues. A peptide designed to retain the loop conformation of the CDR I region of the rAb light chain competed with GM-CSF for both antibody and receptor binding, but the role of specific residues in antibody versus receptor binding differed markedly. These studies suggest that structural analysis of peptide mimetics can reveal differences in receptor and antibody binding, perhaps including key interactions that impact binding kinetics. Peptide mimetics of other four-helix bundle cytokines are reviewed, including helical and reverse turn mimetics of helical structures. Use of peptide mimetics coupled with structural and kinetic analysis provides a powerful approach to identifying important receptor-ligand interactions, which implications for rational design of novel therapeutics.

Current and Future Status for Evaluation of Dysplasia and Carcinoma in IBD.

OPINION STATEMENT: Endoscopic surveillance is an important method to identify colorectal neoplasia in patients with inflammatory bowel disease. Advances in endoscopic techniques using pancolonic chromoendoscopy have improved the detection of dysplasia compared to white-light endoscopy, which has the potential to decrease the risk of colorectal cancer. Currently, pancolonic chromoendoscopy is readily available for use, and in the future, it will likely become the standard of care for endoscopic surveillance. Pancolonic chromoendoscopy followed by confocal laser endomicroscopy may further increase the yield on surveillance endoscopy, although confocal laser endomicroscopy is not readily available outside of a limited number of institutions. Other endoscopic tools such as narrow band imaging have not been shown to be beneficial over white-light endoscopy. Emerging tools such as stool DNA testing show promise as an adjunct to colonoscopy but are still in the early stages of development. For management, patients with well-demarcated circumscribed dysplastic lesions should be resected endoscopically, followed by a continued endoscopic surveillance program. Patients with lesions that cannot be resected completely or that have features suggestive of invasive carcinoma on either endoscopy or histology should undergo colectomy. Patients with flat high-grade dysplasia should undergo colectomy. Patients with flat low-grade dysplasia should have a discussion about the risks and benefits of undergoing colectomy versus continuing in an endoscopic surveillance program. If they opt for surveillance, these patients should have more frequent follow-up surveillance examinations (every 3 to 6 months) with pancolonic chromoendoscopy.