RECENT ADVANCES IN PHYTOCHEMICAL-BASED NANOPARTICLES FOR COLON-SPECIFIC DRUG DELIVERY

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review

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Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the management of many types of malignancies, including microsatellite instability high (MSI-H) colorectal cancers (CRC), but pose a unique challenge to patients with underlying inflammatory disorders such as inflammatory bowel disease (IBD). The safety and efficacy of ICI therapy for CRC in patients with underlying IBD has not been described. Methods: We queried the electronic health database for patients with IBD and CRC who were treated with ICI at tertiary care cancer center in New York City. We collected demographic data, IBD and cancer history, and outcomes of both IBD and CRC after treatment with ICIs. Results: Four patients with underlying IBD were treated with ICIs for MSI-H colorectal cancer (Table). All patients had long-standing IBD for greater than 20 years. Two of the patients were diagnosed with concomitant Lynch syndrome at the time of MSI-H cancer diagnosis. No patients were on active IBD therapies at the time of ICI initiation. All four patients were treated with anti-PD-1 therapy (Pembrolizumab) for stage 3 (n=2) or stage 4 (n=2) CRC. All four patients had robust cancer responses to ICI, three with partial responses and one with a complete response over a median follow-up time of 34 months. One patient with locally advanced rectal cancer had a complete response and has avoided the need for surgical resection and permanent stoma.Three patients had a flare of IBD while on ICI requiring initiation of 5-ASA (n=2) or immunosuppressive therapy (n=1) (Table). One patient required hospitalization for IBD flare. ICI therapy was held due to IBD flare for two patients who had already achieved significant response to ICI with stable disease. Conclusion: In this small series of patients with IBD and MSI-H colorectal cancer, treatment with ICIs was effective at achieving cancer response in all patients while IBD flares were common but manageable with standard medical therapy. Larger studies are needed to explore the safety and efficacy of ICIs for CRC in patients with IBD. Table 1. - Baseline Characteristics and Outcomes of CRC and IBD after ICI Therapy Patient Age of ICI Initiation & IBD type IBD Duration (years) & Prior IBD Medications Lynch Syndrome Cancer Stage ICI Type & Doses of ICI Treatment for IBD Flare Best overall Cancer Response to ICI Surgery for CRC 1 51, Crohn's 38; SSZ, CS, IFX No IV PD- 1, 33 Prednisone, Adalimumab, Ustekinumab Partial Response Subtotal colectomy (before ICI) 2 50, Crohn's 23; 6-MP No IV PD- 1, 10 N/A Partial Response Total proctocolectomy with end ileostomy (before ICI) 3 35, UC 22; 5-ASA Yes III PD- 1, 33 5-ASA Complete Response None 4 34, UC 22; 5-ASA, CS,AZA Yes III PD- 1, 4 5-ASA Partial Response Total proctocolectomy with ileoanal anastomosis (after ICI) ADA: adalimumab, AZA: azathioprine; CRC- Colorectal Cancer; CS: corticosteroids; CTCAE: Common Terminology Criteria for Adverse Events, IBD: inflammatory bowel disease, ICI: immune checkpoint inhibitor; IFX: infliximab; PD-1: Programmed Death 1; SSZ: sulfasalazine; 5-ASA: 5-aminosalicylate; 6- MP : 6-mercaptopurine; UC: ulcerative colitis

Diagnosis and Management of Primary Sclerosing Cholangitis

Background Individuals with inflammatory bowel disease (IBD) face an increased risk for colorectal cancer (CRC) and high grade dysplasia (HGD) compared with individuals without IBD.1,2 Low-grade dysplasia (LGD) is recognized as a key risk factor for HGD and CRC development in IBD.3 However, the risk for progression from LGD to HGD or CRC is still debated. Studies report diverging results and are often limited by small sample sizes and selection bias.4 The influence of diagnosis-year and medications is particularly underexplored. Therefore, we sought to utilize the Danish healthcare registers to examine the impact of candidate risk factors for progression from LGD to either HGD or CRC among Danish individuals with IBD. Methods We conducted a cohort study, including all Danish individuals diagnosed with IBD and LGD between 1977 and 2022. IBD with LGD was defined as individuals with a LGD diagnosis up to 180 days before or any time after their first IBD diagnosis, using the latest date as index date. Individuals with a colectomy, HGD, or CRC before the index date were excluded. We investigated the cumulative incidence of progression to HGD or CRC, treating death as a competing risk. A univariate Cox regression model was used to assess hazard ratios (HRs) for potential risk factors. Variables with a P-value of ≤ 0.1 were included in the final multivariable cox regression model. Results We included 7,082 individuals with IBD and LGD for further analysis. As illustrated in figure 1 the cumulative incidence of progression from LGD to HGD or CRC at 15 years post-index was 6.70% (95% CI: 5.93–7.54). Several risk factors were identified (table 1). Of particular interest was the influence of index-year and treatment with prednisone and anti-TNF-α. In the final model, we observed a reduction in progression risk over time, with a decreased risk for progression in the period 2018-2021 (HR: 0.32 [95% CI: 0.21-0.50]) and 2015-2018 (HR: 0.53 [95% CI: 0.34-0.69]) relative to 1977-2010. High-dose prednisone treatment was associated with progression to HDG or CRC (HR: 1.77 [95% CI: 1.23-2.57]), whereas anti-TNF-α treatment was not (HR: 0.81 [95% CI:0.38–1.74]). Conclusion Among Danish individuals with IBD the risk of progression from LGD to HGD or CRC declined over time. Treatment with High-dose prednisone was associated with an increased risk of progression, whereas anti-TNF-α treatment was not. We speculate that recent advancements in biological treatments of IBD, the implementation of 'treat-to-target' strategies, and improved detection and resection of LGD lesions, may partly explain declining progression risk.

During aging, chronic inflammation can promote tumor development and metastasis. Patients with chronic inflammatory bowel diseases (IBD) are at an increased risk of developing colorectal cancer (CRC). However, the molecular mechanism underlying is still unclear. We conducted a large-scale single-cell sequencing analysis comprising 432,314 single cells from 92 CRC and 24 IBD patients. The analysis focused on the heterogeneity and commonality of CRC and IBD with respect to immune cell landscape, cellular communication, aging and inflammatory response, and Meta programs. The CRC and IBD had significantly different propensities in terms of cell proportions, differential genes and their functions, and cellular communication. The progression of CRC was mainly associated with epithelial cells, fibroblasts, and monocyte-macrophages, which displayed pronounced metabolic functions. In particular, monocyte-macrophages were enriched for the aging and inflammation-associated NF-κB pathway. And IBD was enriched in immune-related functions with B cells and T cells. Cellular communication analysis in CRC samples displayed an increase in MIF signaling from epithelial cells to T cells, and an increase in the efferent signal of senescence-associated SPP1 signaling from monocyte-macrophages. Notably, we also found some commonalities between CRC and IBD. The efferent and afferent signals showed that the pro-inflammatory cytokine played an important role. And the activity of aging and inflammatory response with AUCell analysis also showed a high degree of commonality. Furthermore, using the Meta programs (MPs) with the NMF algorithm, we found that the CRC non-malignant cells shared a substantial proportion of the MP genes with CRC malignant cells (68% overlap) and IBD epithelial cells (52% overlap), respectively. And it was extensively involved in functions of cell cycle and immune response, revealing its dual properties of inflammation and cancer. In addition, CRC malignant and non-malignant cells were enriched for the senescence-related cell cycle G2M phase transition and the p53 signaling pathway. Our study highlights the characteristics of aging, inflammation and tumor in CRC and IBD at the single-cell level, and the dual property of inflammation-cancer in CRC non-malignant cells may provide a more up-to-date understanding of disease transformation.

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Background Patients with inflammatory bowel disease (IBD) and concomitant primary sclerosing cholangitis (PSC-IBD) have a 25-year cumulative risk of up to 50% to develop colorectal neoplasia (CRN). Mucosal inflammation is an important driver of CRN development in IBD, but it is unknown whether this also applies to PSC-IBD patients. Aims We aimed to assess the impact of active mucosal inflammation per colonic segment and endoscopic remission on CRN risk. Methods This is a single-center case-control study, including cases with PSC-IBD with CRN, and controls with PSC-IBD without CRN. Exclusion criteria were a CRN diagnosis prior to IBD or PSC diagnosis, familial CRC syndromes, and insufficient endoscopic follow-up (ampersand:003C2 available colonoscopy reports, and for cases, ampersand:003C2 available endoscopy reports before CRN diagnosis). Data was collected on demographics, IBD and PSC disease characteristics, and IBD medication use. Data from all available colonoscopy and sigmoidoscopy reports between 2002 and 2023, including endoscopic and histologic disease severity, disease extent, and CRN lesions, was collected. The primary outcome was a diagnosis of CRN, secondary outcomes included CRN grade and location, inflammatory burden per colonic segment harboring CRN, and colonic surgery. Results We included 247 PSC-IBD patients (163 ulcerative colitis, 80 Crohn’s disease) with a median follow-up of 6.3 years (IQR: 4.1-12.6) and 6 endoscopic procedures (IQR: 4.0-8.0). Median disease duration was 19 years for IBD (IQR: 11.0-26.0) and 13 years for PSC (IQR: 7.0-18.0). In 50 cases a total of 113 CRN lesions were observed, of which 11 (10%) were advanced CRN (aCRN; HGD or CRC). 23 patients (45%) were diagnosed with ampersand:003E 1 lesion while 45 lesions (40%) were identified in the right-sided colon, 27 (24%) in the transverse colon, 28 (25%) in the left-sided colon, and 10 (9%) in the rectum (3 lesions unknown). Endoscopic remission was observed in 24 cases (48%) during the 2 endoscopies prior to lesion detection vs. in 83 controls (42%) for their last 2 endoscopies. Of all CRN lesions, 39 (35%) were found in a colonic segment with confirmed previous endoscopic and/or histologic inflammation during the 1-2 endoscopies prior to lesion detection (31 low-grade and 8 aCRN). Of the 32 patients who underwent (sub)total colectomy or proctocolectomy, 20 (63%) had an indication due to CRN diagnosis. Mortality was 13% (n=32) during follow-up. Conclusions The risk for CRN and associated colectomy is high in PSC-IBD. Active mucosal inflammation preceded CRN in the affected colonic segment in only 35% of the lesions. Future expansion and additional analysis of our cohort will focus on the impact of persistent endoscopic remission and impact of biologic therapy on CRN risk in PSC-IBD. Funding Agencies None

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

BackgroundData on clinical characteristics of patients with inflammatory bowel disease (IBD)-related colorectal cancer (CRC) are scarce and mainly originate from tertiary referral centres. We studied patient and disease characteristics of IBD-related CRC in a nationwide IBD cohort in general hospitals. Main outcome parameters were time to develop CRC, and factors associated with early CRC development.MethodsAll IBD patients diagnosed with CRC between 1 January 1990 and 1 July 2006 were identified using a nationwide automated pathology database (PALGA). Patient charts were assessed to confirm diagnosis and collect clinical data. Early CRC was defined as CRC diagnosed less than 8 years after IBD diagnosis. Statistical analysis was performed using descriptive statistics, independent t tests, binary logistic regression and Cox-regression analysis.ResultsDiagnosis of IBD-related CRC was confirmed in 251 patients (171 ulcerative colitis, 77 Crohn’s disease, 3 unclassified colitis), 161 males (64 %). Median time from IBD diagnosis to CRC diagnosis was 12 years (IQR 4–20); 89 patients (35 %) developed early CRC. Type of IBD, gender, concomitant PSC, pseudopolyps, extent of inflammation, and medication use were not related to early CRC (p > 0.05). IBD diagnosis at older age (HR for 10 years older age 2.25; 95 % CI 1.92–2.63) was related to early CRC. Twenty-three patients (12 %) had been included in a surveillance programme prior to CRC diagnosis. Patients in the surveillance group had a significantly better tumor stage (p = 0.004).ConclusionsWe emphasize the problem of a high proportion of IBD-associated CRCs developing before the recommended start of surveillance. Therefore, we suggest that older age at IBD onset could be an additional factor to start surveillance in IBD patients.

Nitric oxide (NO) is a critical signaling molecule with significant therapeutic potential for biomedical applications, particularly in wound healing, antimicrobial activity, and tissue repair. However, its clinical translation is hindered by its instability and rapid degradation in biological environments. In this study, we employed chemometric techniques to optimize the synthesis of glutathione-loaded chitosan nanoparticles (GSH-CSNPs) produced via ionotropic gelation. GSH serves as a precursor molecule for S-nitrosoglutathione (GSNO), a key NO donor. A multivariate experimental design was applied to systematically investigate eight synthesis parameters, optimizing particle size, polydispersity index (PDI), zeta potential (ZP), stability, storage conditions, and NO release kinetics. The optimized nanoparticles exhibited a hydrodynamic diameter of 77.1 ± 1.5 nm, a PDI of 0.209 ± 0.010, and a ZP of +15.3 ± 2.1 mV, ensuring considerable colloidal stability for at least 60 days at room temperature. NO release kinetics demonstrated a sustained and controlled release profile from GSNO-CSNPs compared to free GSNO, enhancing NO availability. Franz permeation cell assays revealed efficient GSNO permeation through synthetic skin membranes, and in vitro cytotoxicity assays using human fibroblast cells confirmed the biocompatibility of GSNO-CSNPs up to a NO donor concentration of 250 μmol L-1. Additionally, S-nitrosylated protein quantification in FN1 cells showed that GSNO-CSNPs at 500 μM induced a significant increase in S-nitrosylation levels, approximately 3 fold-higher than free GSNO at the same concentration, without a corresponding increase in cytotoxicity. This suggests that CSNPs enhance intracellular GSNO delivery, facilitating protein S-nitrosylation while maintaining cell viability. These findings highlight the pivotal role of Design of Experiments (DoE)-driven optimization in fine-tuning nanoparticle properties, providing a deeper understanding of how synthesis parameters influence their characteristics, and ultimately enhancing NO delivery systems for biomedical applications, particularly in skin-related therapies.

Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) may have an increased risk of developing colorectal cancer (CRC) after liver transplantation (LT). We evaluated our patients with PSC after LT to identify risk factors for CRC and its impact on survival. A total of 152 patients (108 men, 100 with IBD) with PSC who underwent 173 LTs between 1986 and May 2000 were analyzed in three groups: (1) PSC without IBD (n=52); (2) PSC with colectomy (pre-LT and at LT) (n=17, colectomy pre-LT in 13 and simultaneous colectomy at LT in four); and (3) PSC with IBD and an intact colon (n=83). The following factors were studied: age, gender, liver, and renal biochemistry, international normalized ratio, Child-Pugh stage, operative time, blood use, hospital stay, immunosuppression, risk of CRC, retransplantation rate, and mortality. The incidence of CRC after LT was 5.3% (8/152) compared with 0.6% (7/1,184) in non-PSC cases (P<0.001). All CRCs in the PSC group were in patients with IBD and an intact colon. The cumulative risk of developing CRC in the 83 patients with an intact colon and IBD was 14% and 17% after 5 and 10 years, respectively (PSC non-IBD group 0% risk after 10 years, P<0.06). The multivariate analysis showed three significant variables related to the risk of developing CRC: colonic dysplasia after LT (P<0.0003), duration of colitis more than 10 years (P<0.002), and pancolitis (P<0.004). The cause of death in patients with CRC was cancer related in 75% of cases with a reduced 5-year survival of 55% versus 75% without CRC (not significant). Patients with PSC undergoing LT with a long history of ulcerative colitis and pancolitis have an increased risk of developing CRC with reduced survival. We advocate long-term aggressive colonic surveillance and colectomy in selected high-risk patients with longstanding severe colitis.

To determine the expression of neurokinin-1 receptor (NK-1R), phosphorylated epidermal growth factor receptor (pEGFR), cyclooxygenase-2 (Cox-2), and vitamin D receptor (VDR) in normal, inflammatory bowel disease (IBD), and colorectal neoplasia tissues from Puerto Ricans. Tissues from patients with IBD, colitis-associated colorectal cancer (CAC), sporadic dysplasia, and sporadic colorectal cancer (CRC), as well as normal controls, were identified at several centers in Puerto Rico. Archival formalin-fixed, paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R, pEGFR, Cox-2, and VDR. Pictures of representative areas of each tissues diagnosis were taken and scored by three observers using a 4-point scale that assessed intensity of staining. Tissues with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia, in addition to the areas of cancer, within each tissue. Differences in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons test. The mean scores for normal tissues and tissues with IBD, dysplasia, CRC, and CAC were calculated and statistically compared using one-way analysis of variance and Dunnett's multiple comparisons test. Correlations between protein expression patterns were analyzed with the Pearson's product-moment correlation coefficient. Data are presented as mean ± SE. On average, patients with IBD were younger (34.60 ± 5.81) than normal (63.20 ± 6.13, P < 0.01), sporadic dysplasia (68.80 ± 4.42, P < 0.01), sporadic cancer (74.80 ± 4.91, P < 0.001), and CAC (57.50 ± 5.11, P < 0.05) patients. NK-1R in cancer tissue (sporadic CRC, 1.73 ± 0.34; CAC, 1.57 ± 0.53) and sporadic dysplasia (2.00 ± 0.45) were higher than in normal tissues (0.73 ± 0.19). pEGFR was significantly increased in sporadic CRC (1.53 ± 0.43) and CAC (2.25 ± 0.47) when compared to normal tissue (0.07 ± 0.25, P < 0.05, P < 0.001, respectively). Cox-2 was significantly increased in sporadic colorectal cancer (2.20 ± 0.23 vs 0.80 ± 0.37 for normal tissues, P < 0.05). In comparison to normal (2.80 ± 0.13) and CAC (2.50 ± 0.33) tissues, VDR was significantly decreased in sporadic dysplasia (0.00 ± 0.00, P < 0.001 vs normal, P < 0.001 vs CAC) and sporadic CRC (0.47 ± 0.23, P < 0.001 vs normal, P < 0.001 vs CAC). VDR levels negatively correlated with NK-1R (r = -0.48) and pEGFR (r = -0.56) in normal, IBD, sporadic dysplasia and sporadic CRC tissue, but not in CAC. Immunohistochemical NK-1R and pEGFR positivity with VDR negativity can be used to identify areas of sporadic colorectal neoplasia. VDR immunoreactivity can distinguish CAC from sporadic cancer.

Traditional alternative medicine providers are widely patronized in many parts of Africa. Inflammatory bowel diseases (IBD), anorectal and gastrointestinal disorders (AGD) usually designated as piles could be signs of early stage polyposis and are significant risk factors in colorectal cancers. A survey report reveals that over 20% of adults in Northern Nigeria have piles or symptoms of IBD or AGD and majority of them consume herbal preparations because they believed that such disorders are better managed using traditional medicine. Herbalist as such are important first contact for this particular group with IBD and AGD in Nigeria. Existing literatures have established that cultural practices and beliefs contribute to late-stage diagnosis of cancers in Africa. The study evaluated the ethno-medicinal practices used by herbalist in the management of piles and their knowledge and perceptions about colorectal cancers. Survey information including knowledge on colorectal cancer, herbal remedies used, methods of preparation and administration, as well as incidence of anal or bowel inflammation or hemorrhage in consulted patients were collected using a self-administered questionnaire. A total of 145 herbalists selling “pile” remedies in northern Nigeria were sampled for the study. The results identified 75 plants used for preparation of pile remedies, many of which contain toxic alkaloids and saponins; with those in the family leguminosae leading followed by euphorbiaceae and rubiaceae. Literature searches on these plants indicate that 31% are relatively safe for consumption, 15% contained quantified toxic phytochemicals with established toxicity status while the rest (46%) contained toxic phytochemicals with no evaluated toxicity. The main methods of preparation are infusion and decoction while main means of administration is by ingestion through oral route; 15% of respondents however indicated usage of herbs as suppositories and anal washes. Almost all the respondents (96%) are conversant with the term “Cancer” , 44% have an idea of what colorectal cancers are, while only 19% have correct knowledge of the sign and symptoms of colorectal cancers or believed that inflammation and hemorrhages are potential early signs of polyposis. Knowledge of association between IBD or AGD and colorectal cancers among herbalist showed weak correlation (r2 = 0.33). Findings concluded that there is a poor knowledge on colorectal cancer among herbalist and a general perception that AGDs are not risk factors for colon cancers. The study recommends for increased cancer education with particular attention at enlightenment of herbalist and patients with IBD and AGD on benefits of clinical treatments and importance of screening for early detection of colorectal cancers and possible intervention. Citation Format: Mubarak L. Liman, Sunday E. Atawodi, Uju E. Iliemene, Abdulrazaq Yusuf, Abduljalal Danbaba. Ethnomedicinal practices and herbalists' perception of inflammatory bowel diseases as risk factor for colorectal cancer among patients with anorectal or gastrointestinal disorders in northern Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5283.

INTRODUCTION: Inflammatory bowel disease (IBD) is an idiopathic inflammatory process affecting the gastrointestinal tract. Patients with IBD have been shown in several studies to be at higher risk of venous thromboembolism (VTE) and colorectal cancer (CRC) compared to the general population. IBD and CRC have different prothrombotic properties; it is unknown how the interaction of these prothrombotic properties in patients with both IBD and CRC predicts the development of VTE in hospitalized patients necessitating the current study. METHODS: The national inpatient sample (NIS) from 2005-2014 was queried for all patients with a co-diagnosis of IBD and CRC who were hospitalized with a diagnosis of VTE as one of the top three discharge diagnosis using ICD9 codes 4534.X, 4533.X, 4511.X, 4518.X, 4151.X, 4538.X and 4151.X. The main outcome was the predictors of VTE. While secondary outcomes were trend in prevalence, length of stay, total charge and in-patient mortality among patients with VTE. All analysis was done using STATAv14. RESULTS: 7,585 adults with a co-diagnosis of IBD and CRC were included, among which 197 (2.5%) were coded to have VTE as one of their top three diagnoses. Multivariate logistic regression showed that black race patients (10.6% vs 5.2%; aOR 2.33 [1.40-3.89], P = 0.001), patients with metastasis (27.9% vs 16.7%; aOR 1.67 [1.17-2.40], P = 0.005) and with pulmonary circulation disorders (27.4% vs 1.2%) aOR 28.52 [18.8-43.1], P = &lt; 0.001) had more odds of having VTE while patients with uncomplicated diabetes (8.1% vs 15.5%; aOR 0.47 [0.26-0.84], P = 0.012) had less odds of having VTE. Obesity and anemia were significantly associated with VTE in univariate logistic regression analysis but lost its significance on multivariate logistic regression analysis. VTE was also associated with more length of stay (8.41 vs 6.87 days, P = 0.005) and more total charges ($64,388 vs $50,874, P = 0.009). There was no significant trend in the prevalence of VTE neither was VTE associated with a higher odds of mortality. CONCLUSION: VTE was more common in patients with metastatic cancer and pulmonary circulation disorders compared to patients with localized disease while obesity and anemia lost significance after multivariate logistic regression analysis. Patients with IBD and CRC might have peculiar procoagulant properties different from patients with only IBD or CRC and might require tailored strategies to stratify these population into a different category so as to develop more directed VTE prophylaxis regimen.