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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Schmit, S, Díez-Obrero, V, Hsu, L, Fernandez-Tajes, J, Palles, C, et al
Nature genetics. 2023;(1):89-99
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Abstract
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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Efficacy of a Synbiotic Containing Lactobacillus paracasei DKGF1 and Opuntia humifusa in Elderly Patients with Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
Oh, JH, Jang, YS, Kang, D, Kim, HS, Kim, EJ, Park, SY, Kim, CH, Min, YW, Chang, DK
Gut and liver. 2023;17(1):100-107
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Plain language summary
Irritable bowel syndrome (IBS) affects 1 in 10 people globally and is a common health problem for the elderly. Recent studies have shown that changes in the gut microbiome may play an important part in IBS and there is evidence that using pre and pro biotics have positive effects on IBS. The aim of this randomized, double-blind, placebo-controlled trial was to determine the effects of a new synbiotic formulation (L. paracasei DKGF1 and prebiotics extracted from O. humifusa) on GI symptoms in elderly patients with IBS. 67 participants were randomly divided into 2 groups. For 4 weeks one group took the synbiotic and the other group took a placebo. Symptoms were recorded via questionnaires. The consumption of the synbiotic combination was associated with overall relief of IBS symptoms in elderly patients. In particular, abdominal pain and psychological well-being noticeably improved. In conclusion this synbiotic is effective and safe to use in elderly patients with global IBS symptoms.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The management of IBS in elderly people is more complicated than in younger populations.
- Synbiotic formulations containing both probiotics and prebiotics have reported gastrointestinal health benefits.
- This randomized controlled trial indicated that the synbiotic containing L. paracasei DKGF1 and Optuntia humifusa extracts might be effective and safe for treating IBS symptoms in elderly patients.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
This study involved a randomized, double-blind, placebo-controlled trial to investigate the impact of a synbiotic combination, comprising of L. paracasei DKGF1 and prebiotics extracted from Optuntia humifusa, on Irritable Bowel Syndrome (IBS) in elderly patients.
Method
Sixty-seven IBS patients (mean age: 64 years) were randomly assigned to either a synbiotic group (n=33) or a placebo group (n=34) for a 4-week intervention. The synbiotic group received a daily sachet containing one billion colony-forming units of L. paracasei DKGF1, 0.2g of O. humifusa extract and 1.59 grams of maltodextrin, while the placebo group received an identical sachet containing only maltodextrin.
During the study period
- Participants recorded the degree of symptom improvement using a Subject Global Assessment (SGA) scale.
- IBS symptoms, abdominal pain, gas, bloating, and psychological well-being were recorded using a Visual Analogue Scale (VAS).
- Stool form and consistency were assessed using a Bristol Stool Chart (BSC).
Results
The primary findings from the study were as follows:
- There was significant improvement in IBS symptoms as measured by the SGA score, in the synbiotic group versus the placebo group (+50.5% vs +23.5%, p=0.017). The synbiotic group consistently demonstrated improved response rates.
The secondary findings were as follows:
- Participants also reported an improvement in psychological well-being in the synbiotic group (from 1.3 to 1.0) compared to the placebo group (from 3.0 to 2.0) (p=0.003).
- Responders reported a significant improvement in stool form and consistency in the synbiotic group (+85.7%) compared to the placebo group (+22.2%) (p=0.04).
- Among the patients with IBS constipation, patients in the synbiotic group reported a positive response compared to the placebo group (0% and +100%, p=0.029).
- . However, there was no significant improvement among the patients with IBS diarrhoea in the synbiotic group compared to the placebo group (+33.3% and +66.6%,, p=0.52).
Conclusion:
This randomized, double-blind, placebo-controlled trial, reported that the synbiotic combination of L. paracasei DKGF1 and Optuntia humifusa, may be associated with the relief of IBS symptoms in elderly patients, particularly in terms of abdominal pain and psychological well-being.
Clinical practice applications:
- The human microbiota undergoes changes in diversity and variation with age, emphasising the importance of understanding age-specific interventions.
- Managing IBS in the elderly is challenging, and synbiotics, containing both probiotics and prebiotics, have reported gastrointestinal health benefits.
- Most clinical trials have excluded elderly patients, and there has been uncertainty about whether synbiotic use is safe for the elderly.
- This study focused exclusively on elderly patients with IBS, indicating the potential safety and effective use of a synbiotic containing L. paracasei DKGF1 and Optuntia humifusa in improving IBS symptoms.
Considerations for future research:
- Only elderly patients were included in this study, therefore further investigation is needed to explore the effects of synbiotics on participants of different age groups.
- Microbial analysis was not done in this study. It would be useful to include this in future research to gain more insight into the microbiome’s diversity in elderly patients with IBS.
- The study did not quantify food intake or variety which might have impacted the results, therefore future research needs to consider the impact diet has on the microbiome and IBS.
- Since patient reports are subjective, future research should consider involving researchers during patient-reported assessments to enhance the accuracy and reliability of the data.
Abstract
BACKGROUND/AIMS: There is increasing evidence that supplementation with pre- and probiotics appears to have positive effects on irritable bowel syndrome (IBS). The aim of this study was to determine the effects of a new synbiotic formulation on gastrointestinal symptoms in elderly patients with IBS. METHODS Sixty-seven IBS patients aged ≥60 years were randomly assigned to either a placebo group (n=34) or a synbiotic group (n=33). During a 4-week intervention, subjects used a placebo or a synbiotic containing Lactobacillus paracasei DKGF1 and extracts of Opuntia humifusa once a day. Patients were evaluated with the subject global assessment, visual analog scale, and Bristol stool chart. The primary outcome was the overall responder rate and the secondary outcome was the responder rates for abdominal symptom reduction at week 4. RESULTS Overall, responder rates were significantly higher in the synbiotic group (51.5%) than in the placebo group (23.5%) (p=0.017). Abdominal pain (58.8% vs 81.8%) and psychological well-being (26.4% vs 60.6%) were noticeably improved in the synbiotic group (p=0.038 and p=0.004, respectively). However, there were no significant differences in gas and bloating symptoms (p=0.88 and p=0.88, respectively). In patients with constipation-dominant and diarrhea-dominant IBS (n=16), the synbiotic significantly improved abdominal pain and defecation symptoms (responder rates for the placebo vs the synbiotic: 22.2% vs 85.7%, p=0.04). There were no adverse events in either group. CONCLUSIONS The results indicate that this new synbiotic supplement can potentially relieve abdominal symptoms in elderly IBS patients.
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Randomised clinical trial: comparison of tegoprazan and lansoprazole as maintenance therapy for healed mild erosive oesophagitis.
Cho, YK, Kim, JH, Kim, HS, Kim, TO, Oh, JH, Choi, SC, Moon, JS, Lee, SK, Jung, SW, Kim, SS, et al
Alimentary pharmacology & therapeutics. 2023;(1):72-80
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Abstract
BACKGROUND Tegoprazan is a novel potassium-competitive acid blocker used to treat acid-related disorders. AIM: To compare tegoprazan 25 mg with lansoprazole 15 mg as maintenance therapy in healed erosive oesophagitis (EE) METHODS In this phase 3, double-blind, multi-centre study, patients with endoscopically confirmed healed EE were randomised 1:1 to receive tegoprazan 25 mg or lansoprazole 15 mg once daily for up to 24 weeks. The primary efficacy endpoint was the endoscopic remission rate after 24 weeks. The secondary efficacy endpoint was the endoscopic remission rate after 12 weeks. Safety endpoints included adverse events, clinical laboratory results and serum gastrin and pepsinogen I/II levels. RESULTS We randomised patients to tegoprazan 25 mg (n = 174) or lansoprazole 15 mg (n = 177). Most had mild EE (Los Angeles (LA) grade A: 57.3%, LA grade B: 37.3%). The endoscopic remission rate after 24 weeks was 90.6% with tegoprazan and 89.5% with lansoprazole. Tegoprazan was not inferior to lansoprazole for maintaining endoscopic remission at 24 weeks and 12 weeks. In subgroup analysis, tegoprazan 25 mg showed no significant difference in maintenance rate according to LA grade (p = 0.47). The maintenance effect of tegoprazan was consistent in CYP2C19 extensive metabolisers (p = 0.76). Increases in serum gastrin were not higher in tegoprazan-treated than lansoprazole-treated patients. CONCLUSIONS Tegoprazan 25 mg was non-inferior to lansoprazole 15 mg in maintenance of healing of mild EE. In this study, tegoprazan had a similar safety profile to lansoprazole.
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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.
Thomas, M, Su, YR, Rosenthal, EA, Sakoda, LC, Schmit, SL, Timofeeva, MN, Chen, Z, Fernandez-Rozadilla, C, Law, PJ, Murphy, N, et al
Nature communications. 2023;(1):6147
Abstract
Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Schmit, S, Díez-Obrero, V, Hsu, L, Fernandez-Tajes, J, Palles, C, et al
Nature genetics. 2023;(3):519-520
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The effect of nicorandil on cardiac function and clinical outcomes in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a randomised trial.
Choe, JC, Oh, JH, Lee, HC, Lee, JW, Park, TS, Park, JH, Kim, E, Kim, MS, Ahn, J, Park, JS, et al
Acta cardiologica. 2023;(8):880-888
Abstract
BACKGROUND We investigated the effect of nicorandil on infarct size, cardiac function assessed by cardiac magnetic resonance imaging (CMR) and outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). METHODS In a prospective, randomised, controlled trial, 83 patients with STEMI receiving primary PCI were randomised into the nicorandil (n = 40) or placebo (n = 43) groups. Nicorandil was administered in the emergency room before primary PCI as an intravenous bolus of 4 mg followed by a continuous infusion of 6 mg/h for 24 h and as 2-mg intracoronary injections prior to balloon dilatation and coronary stenting. Nicorandil was continued orally at 10-20 mg/d for 6 months. Infarct size and cardiac function were measured by CMR at 5 d and 6 months after primary PCI. Furthermore, major adverse cardiac events (MACEs) including all-cause death, nonfatal myocardial infarction (MI), any revascularisation, stroke, and definite/probable stent thrombosis (ST) were compared. RESULTS There were no significant differences in baseline clinical characteristics between the groups. Infarct size at baseline and 6 months as well as infarct size changes during 6 months as measured by CMR were similar between the groups. Similarly, other CMR parameters were comparable at baseline and 6 months between the groups. MACEs occurred in four patients (4.8%) during 6 months. No significant difference in the risk of MACEs was observed between the groups. CONCLUSIONS Treatment with nicorandil for 6 months after primary PCI was not associated with any improvement in infarct size, CMR-determined cardiac function, and outcomes in STEMI patients.
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Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07.
Kim, ST, Kim, SY, Lee, J, Yun, SH, Kim, HC, Lee, WY, Kim, TW, Hong, YS, Lim, SB, Baek, JY, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;(33):3868-3877
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Abstract
PURPOSE The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481).
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Large-scale Integrated Analysis of Genetics and Metabolomic Data Reveals Potential Links Between Lipids and Colorectal Cancer Risk.
Shu, X, Chen, Z, Long, J, Guo, X, Yang, Y, Qu, C, Ahn, YO, Cai, Q, Casey, G, Gruber, SB, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022;(6):1216-1226
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Abstract
BACKGROUND The etiology of colorectal cancer is not fully understood. METHODS Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis. RESULTS Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini-Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer. CONCLUSIONS This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data. IMPACT The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
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FOVEAL MÜLLER CELL CONE AS A PROGNOSTIC OPTICAL COHERENCE TOMOGRAPHY BIOMARKER FOR INITIAL RESPONSE TO ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT IN CYSTOID DIABETIC MACULAR EDEMA.
Choi, M, Yun, C, Oh, JH, Kim, SW
Retina (Philadelphia, Pa.). 2022;(1):129-137
Abstract
PURPOSE To investigate the effect of the foveal Müller cell cone structure on the anatomical and functional response to intravitreal bevacizumab treatment in patients with diabetic macular edema. METHODS In 93 treatment-naive eyes with center-involved cystic type diabetic macular edema, spectral-domain optical coherence tomography scans of baseline were retrospectively evaluated to determine the foveal Müller cell cone structure and prognostic features including length of disorganization in the retinal inner layers and ellipsoid zone disruption. The area and circularity of the foveal avascular zone of the superficial and deep capillary plexus 1 month after intravitreal bevacizumab treatment were evaluated using optical coherence tomography angiography. RESULTS Destruction of the foveal Müller cell cone structure and a large foveal avascular zone in the deep capillary plexus (mm2) correlated strongly with a poor anatomical response (CST > 250 µm) at 1 month after first intravitreal bevacizumab (Exp [B] = 29.444, P = 0.002 and Exp [B] = 12.419, P = 0.013, respectively). A destroyed Müller cell cone structure (P = 0.008) and length of ellipsoid zone disruption (P < 0.001) at baseline were associated with poor visual acuity at 1 month after the first intravitreal bevacizumab. CONCLUSION The foveal Müller cell cone structure correlates with the response to initial antivascular endothelial growth factor treatment.
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Efficacy of Intraoperative Platelet-Rich Plasma Augmentation and Postoperative Platelet-Rich Plasma Booster Injection for Rotator Cuff Healing: A Randomized Controlled Clinical Trial.
Liu, B, Jeong, HJ, Yeo, JH, Oh, JH
Orthopaedic journal of sports medicine. 2021;(6):23259671211006100
Abstract
BACKGROUND Platelet-rich plasma (PRP) has been applied as an adjuvant treatment for arthroscopic rotator cuff repair (ARCR) to enhance rotator cuff healing. However, it remains debatable whether PRP enhances tendon-to-bone healing. PURPOSE To assess the efficacy of intraoperative augmentation and postoperative injection of PRP that was prepared using the double-spin method and calcium activation without thrombin in patients with ARCR. STUDY DESIGN Randomized controlled trial; Level of evidence, 1; and cohort study; Level of evidence, 3. METHODS A total of 58 patients underwent ARCR using intraoperative PRP augmentation. Half of the patients were randomly assigned to receive an additional ultrasound-guided PRP injection at the repair site at 2 weeks postoperatively (PRP-booster group); the other half did not receive the booster injection (PRP-only group). A control group that did not receive any PRP treatment was retrospectively matched using propensity score matching. Structural integrity was assessed using magnetic resonance imaging at 1 year postoperatively, and healing rates were compared between patients with tear sizes ≤2 cm versus >2 cm. Functional outcomes were assessed using the visual analog scale (VAS) for pain; VAS for satisfaction; shoulder range of motion; and Constant, American Shoulder and Elbow Surgeons, and Simple Shoulder Test scores at minimum 2-year follow-up. RESULTS In patients with tears >2 cm, the rate of healing failure at 1-year follow-up was significantly less in the overall PRP group than in the control group (12.9% vs 35.7%, respectively; P = .040), however, the PRP-booster group did not present a better healing rate than did the PRP-only group. The overall PRP group had lower VAS for pain scores compared with the control group (0.5 ± 1.1 vs 1.3 ± 1.8, respectively; P = .016) and higher VAS for satisfaction scores (9.2 ± 1.2 vs 8.6 ± 1.7; P = .023) at the final follow-up, whereas no statistical difference was found between the PRP-only and PRP-booster groups in functional outcomes. CONCLUSION Intraoperative PRP augmentation during ARCR demonstrated superior anatomic healing results in patients with rotator cuff tears >2 cm as well as reduced pain and increased subjective satisfaction. PRP booster injection provided no additional benefit to tendon integrity or functional recovery.