Introduction

Genetic predisposition to accumulate fat by carrying risk alleles of PNPLA3, TM6SF2 and HSD17B13, has been shown to influence the probability of developing cirrhosis and hepatocellular carcinoma (HCC) in several liver diseases characterized by hepatic steatosis including non-alcoholic steatohepatitis, chronic hepatitis C and alcoholic liver disease. Whether these variants have any role in the progression of chronic hepatitis B (CHB) disease, without hepatic steatosis, remains unknown.

Aims & Methods

In this cross-sectional case-control study, we determined PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 variants in a cohort of 148 healthy controls, 91 CHB (57 cirrhotic and 34 non-cirrhotic), and 84 CHB-related HCC patients from a tertiary center. Associations between control and case groups with the alleles and genotypes were investigated using logistic regression analyses, and adjustment for age and sex was applied. Survival analyses were performed using Kaplan-Meier Curves with the log-rank test in the CHB-related HCC cohort.

Results

The genotype and allelic distribution of PNPLA3, TM6SF2 and HSD17B13 were not different between healthy controls, CHB, cirrhosis and HCC groups. No genotype or allele, including the haplotype analysis, was found to be associated with susceptibility to CHB and increased risk for cirrhosis or HCC. Survival analysis revealed that none of the three variants has any influence on overall survival in patients with CHB-related HCC.

Conclusion

Our findings demonstrated that PNPLA3, TM6SF2, and HSD17B13 genetic variants, known for modulating liver fat and disease progression in hepatic steatosis, have no association with disease progression in patients with CHB and survival in CHB-related HCC.

References

1. Abul-Husn NS, Cheng X, Li AH, et al. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med. 2018 Mar 22;378(12):1096-1106.
2. Gellert-Kristensen H, Richardson TG, Davey Smith G, et al. Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population. Hepatology. 2020 Sep;72(3):845-856.
3. Kang Q, Xu J, Luo H, et al. Evaluation of the association of a variant in PNPLA3 and TM6SF2 with fibrosis progression in patients with chronic hepatitis C infection after eradication: A retrospective study. Gene. 2022 Apr 30;820:146235.
4. Stickel F, Buch S, Nischalke HD, et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018 Oct;113(10):1475-1483.

Introduction

Endoscopic mucosal resection has been associated with lesion recurrence in 16%-27% of cases. Guidelines recommend endoscopic follow-up but it is unclear if endoscopic assessment has to include biopsies.

Aims & Methods

This study aims to evaluate the recurrence prediction of white light endoscopy (WLE) and narrow band imaging (NBI) in the assessment of colorectal mucosal resection scar. We performed a systematic review in PubMed, Embase, Cochrane and Web of Science databases, searching for studies comparing WLE and NBI. Statistical analysis included data pooling and heterogeneity testing. Quality of the included studies was assessed by Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2).

Results

The meta-analysis included 5 studies and 798 mucosal resections. The pooled sensitivity and specificity and AUC for WLE were 80.9% (95% CI 71.8% to 87.5%), 95.6% (95% CI 92.0% to 97.6%) and 0.917 (95% CI 0.885 to 0.972), respectively. The pooled sensitivity and specificity and AUC for NBI were 92.1% (95% CI 87.3 to 95.2%), 94.1% (95% CI 91.9% to 95.7%) and 0.935 (95% CI 0.772 to 0.972), respectively. There was no difference in AUC of WLE and NBI (p=0.633).

Conclusion

Our study demonstrates a high sensitivity, specificity and accuracy for endoscopic diagnosis of recurrent lesions after colorectal mucosal resection, specially with NBI. In all cases of low confidence assessment, biopsy is required.

References

1. Desomer L, Tutticci N, Tate D, Williams S, McLeod D, Bourke M. A standardized imaging protocol is accurate in detecting recurrence after EMR. Gastrointest Endosc. 2017 Mar;85(3):518–26.
2. Kandel P, Brand EC, Pelt J, Ball CT, Chen WC, Bouras EP, et al. Endoscopic scar assessment after colorectal endoscopic mucosal resection scars: when is biopsy necessary (EMR Scar Assessment Project for Endoscope (ESCAPE) trial). Gut. 2019 Sep;68(9):1633–41.
3. Pu L, Chiam K, Yamamura T, Nakamura M, Berzin T, Mir F, et al. Narrow-band imaging for scar (NBI-SCAR) classification: From conception to multicenter validation. J Gastroenterol Hepatol. 2019 Sep;34:227–8.
4. Riu Pons F, Andreu M, Gimeno Beltran J, Álvarez-Gonzalez MA, Seoane Urgorri A, Dedeu JM, et al. Narrow band imaging and white light endoscopy in the characterization of a polypectomy scar: A single-blind observational study. World J Gastroenterol. 2018 Dec 7;24(45):5179–88.

Introduction

The modality for colorectal cancer (CRC) screening has transferred from guaiac fecal occult blood testing (gFOBT) to fecal immunochemical testing (FIT), but its sensitivity remains lower. While total colonoscopy (TCS) has been anticipated as a new modality for CRC screening, conclusive results based on randomized controlled trials (RCTs) are still pending. Test performance RCTs have been utilized to predict the effectiveness of new modalities for CRC screening. They were adopted for the evaluation of cancer screening using a stepwise approach in the World Endoscopic Evaluation (Young et al. Cancer 2016).

Aims & Methods

A systematic review of test performance RCTs for CRC screening was conducted. Candidate articles were searched from inception to October 14, 2023, using Ovid MEDLINE, Cochrane Central Registry, Embase, and Ichushi-web. We compared the test performance of TCS screening, referring to the following modalities: gFOBT, FIT, flexible sigmoidoscopy (FS), and CT colonography (CTC). Single and multiple rounds were searched. Test performance indicators included participation rates in CRC screening, advanced neoplasia (AN) detection rates, and CRC detection rates. The primary results were evaluated using an intention-to-screen (ITS) based network meta-analysis, and a per-protocol analysis was also performed.

Results

Seventeen RCTs (13 from Europe, two from the US, and one each from Israel and China), involving a total of 341,123 healthy screening invitees, were included. The median participation rates for the programs based on FIT, FS, and TCS were 50.4 % (28.6-94.0%), 32.3% (7.9-52.1%), and 21.5% (10.0-42.5%), respectively. In the network meta-analysis, participation rates for TCS screening were significantly lower than the programs based on FS (RR=0.58; CI: 0.37-0.89), FIT (RR=0.45; CI: 0.31-0.65), and gFOBT (RR=0.45; CI: 0.30-0.69). Detection rates for AN were consistently higher for TCS than for FIT (RR= 2.18, 95%CI:1.46-3.26) but not statistically significant for FS (RR=1.06, 95CI: 0.65-1.73). Similarly, TCS had higher CRC detection rates compared to FIT (RR= 1.80, 95%CI:1.04-3.12) and FS (RR= 1.52, 95%CI:0.87-2.64). While AN and CRC detection rates for TCS were higher than those of CTC, the differences were not statistically significant (AN: RR= 1.02, 95%CI:0.65-1.73, CRC: RR= 0.73 95%CI: 0.32-1.64). The follow-up period of single-round RCTs was limited until diagnosis, but the screening frequency varied depending on the follow-up duration, which could affect effectiveness. Screening intervals were typically two years for FIT, five years for FS, and ten years for CS. One quasi-experimental study combined the following arms from different RCTs with extended follow-up: one-time CS, one-time FS, and four rounds of FIT (Grobbee et al. Clin Gastroenterol Hepatol 2020). The participation rate was higher for FIT (73%) compared to FS (31%) and CS (24%). Cumulative AN and CRC detection rates were higher for FIT (AN = 4.5%, 95%CI:4.2-4.9, CRC =0.5% 95%CI: 0.4–0.6), but nearly equivalent for CS (AN = 2.2%, 95%CI:1.8-2.6, CRC =0.2% 95%CI: 0.1–0.3) and FS (AN = 2.3%, 95%CI:2.0-2.7, CRC =0.2% 95%CI: 0.1–0.3).

Conclusion

The single-round test performance of colonoscopy screening might be superior to that of other modalities. To confirm the priority of TCS, it is insufficient to draw conclusions based on the results of a single-round performance, given variations in screening intervals and frequencies among other modalities. Cumulative effects among different modalities should be compared within the same follow-up period.

References

Young GP, Senore C, Mandel JS, et al. Recommendations for a step-wise comparative approach to the evaluation of new screening tests for colorectal cancer. Cancer. 2016;122(6):826-39.

Grobbee EJ, van der Vlugt M, van Vuuren AJ, et al. Diagnostic yield of one-time colonoscopy vs one-time flexible sigmoidoscopy vs multiple rounds of mailed fecal immunohistochemical tests in colorectal cancer screening. Clin Gastroenterol Hepatol. 2020;18(3):667-75.

Introduction

Vedolizumab (VDZ) is approved in Europe and the USA for the treatment of moderately to severely active ulcerative colitis (UC). Real-world evidence is needed to assess the effectiveness and benefit–risk profile of VDZ for UC outside clinical trial settings. A systematic literature review (SLR) and meta-analysis published in 2018 confirmed the real-world effectiveness and positive benefit–risk profile of VDZ treatment for up to 1 year in patients with inflammatory bowel disease.¹ Further real-world evidence is required to support the long-term (> 1 year) effectiveness of VDZ in patients with UC.

Aims & Methods

The aims of the current meta-analysis based on the SLR were to evaluate the rates of treatment persistence at 1 and at 2 years and of mucosal healing and corticosteroid-free clinical remission at 1 year (overall and stratified by biologic-naive versus biologic-experienced patients). Literature searches identified studies published from 2014 to 2022. For the SLR overall, outcomes of interest included clinical remission, mucosal healing, treatment patterns (including treatment persistence) and safety. Data on adults with UC treated with vedolizumab in a real-world setting were extracted for meta-analysis if there were at least 2 studies for each timepoint and population. Weighted proportions and corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Laird random-effects model to account for between-study heterogeneity.

Results

Data from 68 studies of 21 774 patients with UC had at least one outcome of interest for analysis. The mean age ranged from 34.0–53.0 years (16 studies), the mean disease duration ranged from 4.9–10.4 years (5 studies) and the mean partial Mayo score ranged from 4.1–6.1 (6 studies). In the 28 and 9 studies that assessed treatment persistence at 1 and at 2 years, the rates of treatment persistence were 72.4% (95% CI 68.7–75.8) and 64.2% (95% CI 55.3–72.2), respectively. Similar treatment persistence rates at 1 year were observed among biologic-naive vs biologic-experienced patients, but at 2 years higher rates were observed for biologic-naive patients vs overall (Table). The overall mucosal healing rate at 1 year (assessed in 29 studies) was 42.6% (95% CI 37.0–48.3), and similar rates were observed in biologic-naive vs biologic-experienced patients (Table). The corticosteroid-free clinical remission rates at 1 year were 42.7% (95% CI 38.4–47.1; 22 studies) and at 2 years 43.4% (95% CI 27.9–60.2; 5 studies); higher rates were observed among biologic-naive vs biologic-experienced patients at 1 year (Table).

Conclusion

This meta-analysis of real-world studies of VDZ demonstrated high rates of long-term treatment persistence, mucosal healing and corticosteroid-free clinical remission in patients with UC, indicating effective disease management for these outcomes. However, the assessment of mucosal healing rates may not have been systematically conducted across all studies.
This study was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.
Writing assistance provided by E Sugrue, PhD, of Oxford PharmaGenesis.

References

Schreiber S et al. J Gastroenterol. 2018;53:1048–64.

Disclosure

MC has served as a speaker or consultant, or has received funding for research or education, from AbbVie, Biogen, Dr Falk Pharma, Eli Lilly, Ferring, Gilead, Hospira, Janssen, MSD, Pfizer, Shire Pharmaceuticals, Takeda and Tillotts Pharma.
AA has received advisory board/lecture fees from AbbVie, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Lion Health, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceuticals and Tillots Pharma.
PB is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
MM is an employee and stockholder of Takeda Pharma AG, Zurich, Switzerland.
ER is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
CS is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
SS has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, ProventionBio, Takeda, Theravance Biopharma and Ventyx.
SV has received financial support for research from AbbVie, Galapagos, J&J, Pfizer and Takeda, and speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG, VectivBio, Ventyx and Zealand Pharma.

Introduction

Vedolizumab (VDZ) is approved in Europe and the USA for the treatment of moderately to severely active ulcerative colitis (UC). A previous systematic literature review (SLR) and meta-analysis published in 2018 demonstrated the real-world effectiveness and positive benefit–risk profile of VDZ treatment for up to 1 year in patients with inflammatory bowel disease.¹ There is limited real-world evidence on the long-term (> 1 year) treatment persistence and safety of VDZ compared with anti-tumour necrosis factor-alpha (TNFα) treatment in biologic-naive patients with UC.

Aims & Methods

The aims of this meta-analysis were to assess the real-world effectiveness and treatment persistence of VDZ in patients with UC. We report an exploratory analysis of treatment persistence and serious adverse events (SAEs) among biologic-naive patients with UC treated with VDZ compared with anti-TNFα treatment at 1 and at 2 years. Literature searches were conducted to identify studies published from 2014 to 2022. For the primary analysis, outcomes of interest included clinical remission, mucosal healing, treatment patterns (including treatment persistence) and safety. Data on adults with UC treated with VDZ or anti-TNFα treatment in a real-world setting were extracted if there were at least 2 studies for each timepoint and population. Weighted proportions and corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Laird random-effects model to account for between-study heterogeneity. No formal statistical significance testing between treatments was applied.

Results

Among comparative studies of VDZ and anti-TNFα treatment, 8 studies were identified (10 486 biologic-naive patients with UC). Of these, 5 and 2 studies, respectively, reported the rates of treatment persistence in biologic-naive patients at 1 and at 2 years. The rate of treatment persistence at 1 year was 74.9% with VDZ (95% CI 64.3–83.3) and 59.0% with anti-TNFα treatment (47.2–69.8). Similarly, the rate of treatment persistence at 2 years was 77.6% with VDZ (70.8–83.2) and 60.0% with anti-TNFα treatment (48.3–70.7). Three retrospective cohort studies of 775 biologic-naive patients with UC treated with VDZ (n=465) versus anti-TNFα treatment (n=310) reported SAEs. In the first study, safety outcomes were followed from treatment initiation up to five half-lives after treatment discontinuation; 6.8% treated with VDZ experienced SAEs compared with 19.2% with anti-TNFα treatment.² In the second study, the rate of SAEs was similar between patients treated with VDZ (4.5%) and anti-TNFα treatment (5.0%).³ In the third study that reported SAEs within the first year of treatment; the rates of SAEs were 14.3% and 10.9% among patients who received VDZ and anti-TNFα treatment, respectively.⁴

Conclusion

This analysis of comparative studies in biologic-naive patients with UC suggested that treatment persistence rates were higher with VDZ than with anti-TNFα treatment both at 1 and at 2 years. In addition, these data support a comparable safety profile, with similar rates of SAEs between VDZ and anti-TNFα treatment.
This study was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.
Writing assistance provided by E Sugrue, PhD, of Oxford PharmaGenesis.

References

1. Schreiber S et al. J Gastroenterol. 2018;53:1048–64.
2. Bressler B et al. J Crohn's Colitis. 2021;15:1694–706.
3. Helwig et al. BMC Gastroenterol. 2020;20:211.
4. Moens et al. Inflamm Bowel Dis. 2022;28:1135–1142.

Disclosure

SV has received financial support for research from AbbVie, Galapagos, J&J, Pfizer and Takeda, and speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG, VectivBio, Ventyx and Zealand Pharma.
SS has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, ProventionBio, Takeda, Theravance Biopharma and Ventyx.
PB is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
MM is an employee and stockholder of Takeda Pharma AG, Zurich, Switzerland.
ER is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
CS is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
AA has received advisory board/lecture fees from AbbVie, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Lion Health, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceutical and Tillots Pharma.
MC has served as a speaker or consultant, or has received funding for research or education, from AbbVie, Biogen, Dr Falk Pharma, Eli Lilly, Ferring, Gilead, Hospira, Janssen, MSD, Pfizer, Shire Pharmaceuticals, Takeda and Tillotts Pharma.

Introduction

Colorectal malignancy ranks third in global cancer incidence, with 1.9 million cases and nearly 1 million deaths reported in 2020. Total mesorectal excision (TME) is the gold-standard treatment for rectal cancer. Our meta-analysis evaluated surgical and functional outcomes of various anastomoses types, comparing end-to-end (EEA) to either side-to-end (SEA) or colonic J pouch (CJP).

Aims & Methods

Our protocol was registered on PROSPERO (CRD42022368907) beforehand. The systematic search was conducted on the 8th of November, 2022 in three major databases (Pubmed, Embase and CENTRAL). Randomized controlled trials (RCT) assessing adult patients following TME, where EEA was compared to another type of anastomosis were included. For data synthesis a random-effects model was used. In the case of categorical outcomes such as anastomotic leakage (AL) and mortality, the effect size was risk ratio (RR) with a 95% confidence interval (CI), whereas in the case of bowel movement mean difference (MD) with a 95% CI was used. The Risk of bias was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (ROB-2). The certainty of evidence level of the included studies was performed using GRADE-Pro.

Results

Following a careful search and selection process, 29 studies out of 4459 were included in our analysis. Comparing EEA to CJP, in terms of early (30 days) morbidity, we have found no difference in either AL (RR: 1.03; CI: 0.84;1.26) or mortality (RR: 0.77; CI: 0.30; 1.98). The functional outcome of patients was evaluated, and daily bowel movement was assessed at two-time points. At 6 months postoperatively, the EEA group had a slightly higher number of stools per day (MD: 1.89; CI: 0.39; 3.39), however at one year the MD dropped down to 1.59 (CI: -0.66; 3.84), reaching a statistically non-significant result. Because of limited data, only AL was assessed for the comparison with SEA, where no difference was found (RR: 1.19; CI= 0.60; 2.35). Twelve RCTs showed a high risk of bias due to unblinded surgeons, intervention deviations, and loss of follow-up data. According to the GRADE approach, the quality of evidence was moderate (AL, mortality) to low (bowel movement) because of the high risk of bias and imprecision.

Conclusion

In terms of early postoperative morbidity, EEA is not inferior to other types of reconstruction techniques. Regarding bowel movement, the slightly impaired intestinal function will resolve within one year following surgery. EEA should be used routinely following TME.