The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to ...target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.
Background/Aims
Infliximab is currently used for the treatment of moderate‐to‐severe ulcerative colitis (UC) with an inadequate response to conventional agents. The efficacy and safety of infliximab ...in Korean patients with UC were assessed.
Methods
This was a retrospective multicenter study including all adult patients who received at least one infliximab infusion for UC. Short‐ and long‐term clinical outcomes and adverse events of infliximab therapy were evaluated, and predictors of response were identified.
Results
A total of 134 UC patients were included. The indications for infliximab therapy were acute severe UC in 28%, steroid‐dependency in 38%, and steroid‐refractoriness in 33%, respectively. The rates of clinical response and remission were 87% and 45% at week 8. In multivariate analysis, we found significant predictors of clinical remission at week 8: immunomodulator‐naïve (odds ratio OR = 4.89, 95% confidence interval CI: 1.44–16.66, P = 0.01), hemoglobin ≥ 11.5 g/dL (OR = 4.47, 95% CI: 1.48–13.45, P = 0.008), C‐reactive protein ≥ 3 mg/dL (OR = 4.77, 95% CI: 1.43–15.94, P = 0.01), and response at week 2 (OR = 20.54, 95% CI: 2.40–175.71, P = 0.006). Long‐term clinical response and remission rates were 71% and 52%, respectively, and mucosal healing was the only factor influencing long‐term response. Adverse events related to infliximab occurred in 15% of patients, and most of them were mild and transient.
Conclusions
Infliximab is effective and safe in the treatment of active UC in Korea. No history of previous immunomodulator use and high baseline C‐reactive protein are independent predictors of good response.
AIM To investigate the factors affecting diagnostic delay and outcomes of diagnostic delay in inflammatory bowel disease（IBD） METHODS We retrospectively studied 165 patients with Crohn’s disease（CD） ...and 130 patients with ulcerative colitis（UC） who were diagnosed and had follow up durations > 6 mo at Korea University Ansan Hospital from January 2000 to December 2015. A diagnostic delay was defined as the time interval between the first symptom onset and IBD diagnosis in which the 76th to 100th percentiles of patients were diagnosed.RESULTS The median diagnostic time interval was 6.2 and 2.4 mo in the patients with CD and UC, respectively. Among the initial symptoms, perianal discomfort before diagnosis（OR = 10.2, 95%CI: 1.93-54.3, P = 0.006） was associated with diagnostic delays in patients with CD; however, no clinical factor was associated with diagnostic delays in patients with UC. Diagnostic delays, stricturing type, and penetrating type were associated with increased intestinal surgery risks in CD（OR = 2.54, 95%CI: 1.06-6.09; OR = 4.44, 95%CI: 1.67-11.8; OR = 3.79, 95%CI: 1.14-12.6, respectively）. In UC, a diagnostic delay was the only factor associated increased intestinal surgery risks（OR = 6.81, 95%CI: 1.12-41.4）.CONCLUSION A diagnostic delay was associated with poor outcomes, such as increased intestinal surgery risks in patients with CD and UC.
Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim ...of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T).
This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared.
There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 7.0-43.3 minutes vs 16.5 6.3-38.1 minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 12-72) compared with the HDCE-T group (9 1-20; P < 0.001).
On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.
Low-volume preparations for colonoscopy are gaining attention for their higher acceptability. However, the efficacy and safety of oral sulfate solution (OSS) preparations in patients with ulcerative ...colitis (UC) has not been well known. Therefore, we aimed to compare OSS and 2-L polyethylene glycol with ascorbic acid (PEG+Asc) for bowel preparation in inactive UC.
A multicenter, randomized, single-blind study was conducted at six tertiary referral hospitals in Korea. Outpatients with UC who had stable disease activity were randomly allocated to the OSS group or the 2-L PEG+Asc group for bowel preparation before colonoscopy. The study outcomes included treatment efficacy, safety, tolerability, and acceptability. Bowel cleansing was assessed using the Boston Bowel Preparation Scale and rated as successful cleansing if the score was ≥6. Patient acceptance and tolerability were assessed using a 4-point ordinal scale. Additionally, disease activity and laboratory data before and after colonoscopy were evaluated to check for safety.
The OSS and 2-L PEG+Asc groups included 92 and 93 participants, respectively. No significant between-group difference was noted in successful cleansing (OSS 96.7% vs 2-L PEG+Asc 97.8%, p=0.64). Moreover, the safety, acceptance, and tolerability were not significantly different (all p>0.05). Furthermore, no significant changes were found in serum electrolytes or disease activity in either group.
OSS is effective for colonoscopy cleansing, has acceptable tolerability, and does not affect disease activity; thus, it can be used safely for bowel preparation in patients with inactive UC.
Polyethylene glycol (PEG)-based bowel preparations are effective cleansing agents for colonoscopy. However, they require relatively large volumes to be used even with agents such as 2 L PEG with ...ascorbate (2LPEG). This phase 3, randomized, single-blinded, multicenter, parallel-group study compared the efficacy of 1 L PEG with high-dose ascorbate, TJP-008, to 2LPEG.
Patients undergoing colonoscopy were randomized (1:1:1) to receive TJP-008 as 1-day split dose (TJP-008-1) or 2-day split dose (TJP-008-2) regimen or to receive 2LPEG as a 2-day split dose regimen. Cleansing efficacy was evaluated using the Harefield Cleansing Scale. The primary endpoint was overall bowel cleansing success. Full analysis set (FAS) and per protocol set (PPS) analyses were performed.
Of the 314 screened patients, efficacy was assessed in the following patient numbers (FAS/PPS): total (293/285), TJP-008-1 (98/94), TJP-008-2 (97/95), and 2LPEG (98/96). FAS revealed noninferiority between TJP-008 and 2LPEG with regard to overall success (TJP-008-2, 99.0%; TJP-008-1, 95.9%; 2LPEG, 94.9%; p=0.100 and p=0.733, respectively). PPS also showed noninferiority (p=0.721 and p=0.211, respectively). However, the PPS analyses showed a higher bowel cleansing score for TJP-008-2 for high-quality cleansing in the right colon (TJP-008-2 83.2% vs 2LPEG 62.5%; p=0.005).
TJP-008 is a new low-volume cleansing agent with a colon cleansing efficacy comparable to that of standard 2LPEG that exhibits significant safety and tolerability.
Objective Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified ...163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations. Methods We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls. Results We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10−14), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10−10) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10−9), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10−12) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10−5)) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans. Conclusions Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.
In patients who undergo cholecystectomy after endoscopic common bile duct (CBD) stone extraction, CBD stones found postoperatively could be problematic. This study aimed to investigate the incidence ...and risk factors of postoperative CBD stones after cholecystectomy.
A total of 278 patients (mean age, 59.2 years; 71 men 51.1%) who underwent endoscopic removal of CBD stones followed by cholecystectomy from January 2013 to December 2017 were included. An endoscopic nasobiliary drainage (ENBD) tube was placed immediately after endoscopic clearance of the CBD stones in all patients until cholecystectomy. An ENBD tubogram was obtained in all patients to determine the presence of postoperative CBD stones.
Postoperative CBD stones were detected in 20.1% (56/278). An ENBD tubogram was obtained after an average of 2.42 days postoperatively. Based on univariate analysis, the statistically significant risk factors for postoperative CBD stone were CBD stones >2, CBD stone size >10 mm, cholesterol stone, maximum diameter of CBD >15 mm, treatment with endoscopic sphincterotomy alone, and use of endoscopic mechanical lithotripsy (EML). In multivariate analysis, cholesterol stone, CBD stones >2, CBD stone size >10 mm, and EML were related to postoperative CBD stones after cholecystectomy.
Based on the relatively high rate of postoperative CBD stones after cholecystectomy, careful follow-up should be considered in patients with high-risk factors to detect CBD stones early.
The pathophysiology of functional bowel disorders is complex, involving disruptions in gut motility, visceral hypersensitivity, gut-brain-microbiota interactions, and psychosocial factors. Light ...pollution, as an environmental stressor, has been associated with disruptions in circadian rhythms and the aggravation of stress-related conditions. In this study, we investigated the effects of environmental stress, particularly continuous light exposure, on intestinal motility and inflammation using zebrafish larvae as a model system. We also evaluated the efficacy of probiotics, specifically
(
), at alleviating stress-induced constipation. Our results showed that continuous light exposure in zebrafish larvae increased the cortisol levels and reduced the intestinal motility, establishing a stress-induced-constipation model. We observed increased inflammatory markers and decreased intestinal neural activity in response to stress. Furthermore, the expressions of
and
, crucial for regulating water transport and intestinal motility, were altered in the light-induced constipation model. Administration of probiotics, specifically
, ameliorated the stress-induced constipation by reducing the cortisol levels, modulating the intestinal inflammation, and restoring the intestinal motility and neural activity. These findings highlight the potential of probiotics to modulate the gut-brain axis and alleviate stress-induced constipation. Therefore, this study provides a valuable understanding of the complex interplay among environmental stressors, gut function, and potential therapeutic strategies.
Ulcerative colitis (UC) is an uncommon inflammatory bowel disease (IBD). However, its incidence has recently increased in South Korea. Moreover, UC diagnoses are frequently delayed, and the ...relationship between diagnostic delay and UC prognosis has not been extensively studied in South Korean patients.
To identify meaningful diagnostic delay affecting UC prognosis and to evaluate risk factors associated with diagnostic delay in South Korean patients.
Medical records of 718 patients with UC who visited the outpatient clinic of six university hospitals in South Korea were reviewed; 167 cases were excluded because the first symptom date was unknown. We evaluated the relationship between the prognosis and a diagnostic delay of 3, 6, 12, 18, and 24 mo by comparing the prognostic factors anti-tumor necrosis factor (TNF)-α use, admission history due to acute flare-ups, frequent admission due to flare-ups, surgery associated with UC, and the clinical remission state at the latest follow-up at each diagnostic interval.
The mean diagnostic interval was 223.3 ± 483.2 d (median, 69 d; 75
percentile, 195 d). Among the prognostic factors, anti-TNFα use was significantly increased after a diagnostic delay of 24 mo. Clinical risk factors predictive of a 24-mo diagnostic delay were age < 60 years at diagnosis odd ratio (OR) = 14.778, 95% confidence interval (CI): 1.731-126.121, smoking history (OR = 2.688, 95%CI: 1.239-5.747,
0.012), and misdiagnosis of hemorrhoids (OR = 11.066, 95%CI: 3.596-34.053). Anti-TNFα use was associated with extensive UC at diagnosis (OR = 3.768, 95%CI: 1.860-7.632) and 24-mo diagnostic delay (OR = 2.599, 95%CI: 1.006-4.916).
A diagnostic delay > 24 mo was associated with increased anti-TNFα use. Age < 60 years at diagnosis, smoking history, and misdiagnosis of hemorrhoids were risk factors for delayed diagnosis.
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