Colon to Rectum
Inflammatory bowel disease (IBD) is associated with an increased risk of incident acute arterial events (AAEs):
In a prospective cohort, there was an increased risk of incident AAEs and premature AAEs in IBD participants. Beyond traditional AAE risk factors, quantifiable indices of IBD disease activity and severity were independent predictors of AAEs.
Clin Gastroenterol Hepatol. 2023;21(3):761–70.e13
Alayo QA, Loftus EV, Jr., Yarur A, Alvarado D, Ciorba MA, de las Fuentes L, Deepak P
Background and aims: Population-based studies have suggested an increased risk of acute arterial events (AAEs) in patients with inflammatory bowel disease (IBD). The authors aimed to assess the risk of incident AAEs and premature AAEs, adjusted for diet, physical activity, and inflammation biomarkers, in participants with IBD in the United Kingdom Biobank (UKB)
Methods: UKB participants with IBD and without prevalent AAEs at enrollment were matched to random non-IBD controls. A Cox regression model, adjusting for baseline cardiovascular and IBD risk factors, diet, physical activity, and high-sensitivity C-reactive protein (CRP), estimated adjusted hazard ratios (aHRs) for association between IBD and AAEs or premature AAEs (age < 55 years for men and < 65 years for women). Predictors of AAEs within the IBD cohort were identified in a Cox model adjusting for disease severity (IBD-related hospitalizations or surgeries).
Results: Among 455,950 UKB participants, 5094 with IBD were matched to 20,376 non-IBD controls. After a median follow-up period of 12.4 years, participants with IBD had a higher incident rate of AAE (924.1 vs. 730.9 per 100,000 person years; p < 0.001), risk of all AAEs (aHR = 1.19; 95% confidence interval [CI]: 1.08–1.31; p < 0.001), and premature AAEs (aHR = 1.38; 95% CI: 1.11–1.72; p = 0.001). High-sensitivity CRP levels (highest quartile: aHR = 1.53; 95% CI: 1.15–2.03) and disease severity (aHR = 5.40; 95% CI: 4.03–7.22) were independent predictors of AAEs in IBD.
Conclusions: In a prospective cohort, there was an increased risk of incident acute arterial events (AAEs) and premature AAEs in participants with inflammatory bowel disease (IBD). Beyond traditional AAE risk factors, quantifiable indices of IBD disease activity and severity were independent predictors of AAEs.
P. Deepak, M.D., Associate Professor of Medicine, Inflammatory Bowel Diseases Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA,
Biopsy of non-tumor sites after biopsy of a colorectal cancer is not associated with metachronous cancers:
Metachronous cancers were not significantly associated with biopsy of non-tumor sites after biopsy of the primary cancer in this large case-control study involving more than 14,000 patients.
Clin Gastroenterol Hepatol. 2023;21(2):487–96.e3
Lam AY, Lee JK, Merchant S, Jensen CD, Sedki M, Corley DA
Background and aims: Recent research has demonstrated biologic plausibility for iatrogenic tumor seeding via colonoscopy as a cause of metachronous colorectal cancers (CRC). This study evaluated the association between biopsy of non-tumor sites after CRC biopsy and risk of metachronous CRC in a large community-based health care organization.
Methods: This was a retrospective case-control study of adults with an initial CRC diagnosed by colonoscopy between January 2006 and June 2018 who underwent curative resection. Cases developed a second primary (metachronous) CRC diagnosed 6 months to 4 years after the initial CRC, and were matched by age, sex, diagnosis of inflammatory bowel disease, race, and ethnicity with up to 5 controls without a second CRC diagnosis. The exposure was biopsy in the colonic segment of the metachronous CRC (or corresponding segment in controls) after tumor biopsy, ascertained with blinding to case status. Associations were evaluated using conditional logistic regression and adjusted for potential confounders.
Results: Among 14,119 patients diagnosed with an initial CRC during colonoscopy, 107 received a second CRC diagnosis. After exclusions for recurrent or synchronous CRC, 45 cases and 212 controls were included. There was no significant association between biopsy of non-tumor sites after initial CRC biopsy and risk of metachronous CRC in the segment of the additional biopsy site (adjusted odds ratio = 2.29; 95% confidence interval: 0.77–6.81).
Conclusions: Metachronous cancers are not significantly associated with biopsy of non-tumor sites after biopsy of the primary cancer. Although the sample size does not allow definite exclusion of any association, these findings do not support iatrogenic tumor seeding as a common risk factor for metachronous colorectal cancer.
A.Y. Lam, M.D., Department of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, CA, USA,
E-Mail: xangela.y.lam@kp.org
Liver and Bile
Critique and systematic review of the utility of hepatitis B core-related antigen (HBcrAg) as biomarker in chronic hepatitis B:
New biomarkers could be of great benefit on the way to functional cure of chronic hepatitis B virus infection. Indeed, the hepatitis B core-related antigen (HBcrAg) is a possible candidate as suitable biomarker. A recent critique and systematic review, however, concludes that HBcrAg correlates poorly with HBsAg loss and response to antiviral therapy, and thus has limited clinical utility.
J Hepatol. 2023;78(4):731–41
Adraneda C, Tan YC, Yeo EJ, Kew GS, Khakpoor A, Lim SG
Background and aims: Hepatitis B core-related antigen (HBcrAg) is a new biomarker for chronic hepatitis B (CHB) whose performance has not been critically or systematically appraised. Herein, a systematic review was performed to determine its clinical utility.
Methods: The authors evaluated the biological pathway of HBcrAg and performed a systematic review of PubMed for clinical trials, cohort studies, and case-control studies that evaluated the clinical utility of HBcrAg. The effectiveness of HBcrAg in predicting hepatitis B virus (HBV)-specific clinical events (e.g. hepatitis B e antigen (HBeAg) seroconversion, phases of CHB, hepatitis B surface antigen (HBsAg) loss, treatment response, and relapse after stopping therapy) was examined using receiver-operating characteristic curves (ROC). The correlation coefficients of HBcrAg with HBV DNA, quantitative HBsAg (qHBsAg), HBV RNA, and cccDNA were summarized from published studies. Median values were used as estimates.
Results: HBcrAg consists of 3 precore/core protein products: hepatitis B core antigen (HBcAg), HBeAg, and a 22 kDa precore protein. HBcrAg assays have been associated with false-positive rates of 9.3% and false-negative rates of between 12–35% for CHB. The new iTACT-HBcrAg is more sensitive but does not reduce the false-positive rate. A PubMed search found 248 papers on HBcrAg, of which 59 were suitable for analysis. The clinical performance of HBcrAg was evaluated using AUROC (area under ROC) analyses, with median AUROCs of 0.860 for HBeAg seroconversion, 0.867 for predicting HBeAg-negative hepatitis, 0.645 for HBsAg loss, 0.757 for treatment response, and 0.688 for relapse after stopping therapy. The median correlation coefficient (r) was 0.630 with HBV DNA, 0.414 with qHBsAg, 0.619 with HBV RNA and 0.550 with cccDNA. Correlation decreased during antiviral therapy, but combined biomarkers improved performance.
Conclusions: Hepatitis B core-related antigen (HBcrAg) has a mixed performance and has a poor correlation with loss of hepatitis B surface antigen and antiviral therapy, hence HBcrAg results should be interpreted with caution.
Prof. Dr. S.G. Lim, Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore,
E-Mail: mdclimsg@nus.edu.sg
Analysis of acute severe non-A-E hepatitis (NAEH) in children in North-West Germany:
NAEH is a rare but serious disease that often leads to acute liver failure. The 2022 global NAEH epidemic has been linked to adenovirals infections. A current evaluation from 2North-West German centers (Hanover and Essen) indicates an increasing incidence of NAEH since 2019. However, adenoviral infections played no role, which indicates other potential triggers of similar NAEH cases.
J Hepatol. 2023;78(5):971–8
Leiskau C, Tsaka S, Meyer-Ruhnke L, Mutschler FE, Pfister ED, Lainka E, Baumann U
Background and aims: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. The authors aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic.
Methods: They analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to May 16, 2022. They separated cases into a historic cohort (1990–2018) and a COVID-19 era cohort (2019–2022).
Results: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were human herpes virus (HHV)-6 (4), cytomegalie virus (CMV), human simplex virus (HSV), Epstein-Barr virus (EBV) (3). 69 patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. 25 patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died.
Conclusions: Acute non-A-E-hepatitis (NAEH) in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in this current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in authors’ centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases.
Prof. Dr. U. Baumann, Klinik für pädiatrische Nieren-, Leber- und Stoffwechselerkrankungen, Zentrum für Kinderheilkunde & Jugendmedizin, Medizinische Hochschule Hannover (MHH), Hanover, Germany,
E-Mail: baumann.u@mh-hannover.de
Risk of liver fibrosis associated with long-term methotrexate (MTX) therapy may be overestimated:
Based on retrospective data, it was concluded that long-term MTX therapy has a significant risk of hepatic fibrosis. However, a recent longitudinal cohort study of patients with rheumatoid arthritis and psoriasis indicated that neither the cumulative MTXf dose nor the duration of therapy were associated with increased liver stiffness. In contrast, age and BMI were independently associated with increased liver stiffness.
J Hepatol. 2023;78(5):989–97
Atallah E, Grove JI, Crooks C, Burden-Teh E, Abhishek A, Moreea S, Jordan KM, Ala A, Hutchinson D, Aspinall RJ, Murphy R, Aithal GP
Background and aims: The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. The authors evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using 2 non-invasive markers.
Method: Between 2014–2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥ 2 years were recruited prospectively from 6 UK sites. The MTX group included patients who received MTX for ≥ 6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements.
Results: A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥ 7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥ 9.8. Age and body mass index were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥ 7.9 kPa (adjusted odds ratio [OR] = 3.19; 95% confidence interval [CI]: 1.95–5.20; p < 0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥ 9.8 (OR = 1.76; 95% CI: 1.20–2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis.
Conclusion: The risk of liver fibrosis attributed to methotrexate (MTX) itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX.
Prof. Dr. G.P. Aithal, Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK,
E-Mail: guru.aithal@nottingham.ac.uk
Esophagus to Small Intestine
Endoscopic surveillance in patients at risk of hereditary gastric cancer:
Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer.
Lancet Oncol. 2023;24(1):107–16
Lee CYC, Olivier A, Honing J, Lydon AM, Richardson S, O'Donovan M, Tischkowitz M, Fitzgerald RC, di Pietro M
Background: Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma (SRCC). Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic SRCC foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterization of SRCC foci in hereditary diffuse gastric cancer. Aim of the present study was to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterization of endoscopic lesions.
Methods: For this prospective longitudinal cohort study, the authors included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal SRCC foci. They assessed the detection rate and anatomical location of SRCC in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci.
Findings: 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 patients (40%) were diagnosed with invasive SRCC over a median follow-up time of 51 months (interquartile range, 18–80). The first diagnosis of SRCC was most commonly made from random biopsies (29/58 patients [50%]), rather than targeted biopsies (15 patients [26%]). The anatomical distribution of SRCC foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in the cohort would have led to an underdiagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing SRCC were predicted with a sensitivity of 67.3% and a specificity of 90.2%.
Interpretation: Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer.
Dr. M. di Pietro, Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK,
E-Mail: md460@cam.ac.uk
Real-world effectiveness of risankizumab for luminal Crohn’s disease (CD):
In a cohort of highly refractory patients with luminal CD and multiple prior drug failures including ustekinumab, risankizumab induction provided a clinical response in about 3 out of 4 patients and steroid-free clinical remission in about half of patients.
Aliment Pharmacol Ther. 2023;57(4):426–34
Fumery M, Defrance A, Roblin X, Altwegg R, Caron B, Hébuterne X, Stefanescu C, Meyer A, Nachury M, Laharie D, Nancey S, Le Berre C, Serrero M, Geyl S, Giletta C, Ah-Soune P, Duveau N, Uzzan M, Abitbol V, Biron A, Tran-Minh ML, Paupard T, Vuitton L, Elgharabawy Y, Peyrin-Biroulet L
Background: Phase 3 trials have demonstrated the efficacy of risankizumab in moderate-to-severe Crohn's disease (CD), but no real-world data are currently available. The authors aimed to assess the short-term effectiveness and safety of risankizumab in patients with CD.
Methods: From May 2021 to May 2022, all patients with refractory luminal CD treated with risankizumab in 22 French GETAID centers were retrospectively included. The primary end point was steroid-free clinical remission at week 12 (Harvey-Bradshaw [HB] score < 5). Secondary end points included clinical response (≥ 3-point decrease of HB score and/or (HB) score < 5), biochemical remission (C-reactive protein ≤ 5 mg/l), need for CD-related surgery and adverse events (AEs).
Results: Among the 100 patients included, all have been previously exposed to anti-tumor necrosis factor agents, 94 to vedolizumab, 98 to ustekinumab (all exposed to at least 3 biologics) and 61 had a previous intestinal resection. All but 3 (97%) received a 600 mg risankizumab intravenous induction at weeks 0-4-8. At week 12, steroid-free clinical remission was observed in 45.8% of patients, clinical remission in 58% and clinical response in 78.5%. In subgroup analysis restricted to patients with objective signs of inflammation at baseline (n = 79), steroid-free clinical remission at week 12 was observed in 39.2% of patients. Biochemical remission was observed in 50% of patients. Six patients discontinued risankizumab before the week 12 visit due to lack of efficacy. CD-related hospitalization was needed in 6 patients, and 3 underwent intestinal resection. In multivariable analysis, only a history of ustekinumab loss of response (vs. primary failure) (odds ratio = 2.80; 95% confidence interval: 1.07–7.82; p = 0.041) was significantly associated with clinical remission at week 12. 20 AEs occurred in 20 patients including 7 serious AEs corresponding to 6 CD exacerbation and 1 severe hypertension.
Conclusion: In a cohort of highly refractory patients with luminal Crohn’s disease and multiple prior drug failures including ustekinumab, risankizumab induction provided a clinical response in about 3 out of 4 patients and steroid-free clinical remission in about half of patients.
Prof. Dr. M. Fumery, Department of Gastroenterology, Amiens University Hospital, and PeriTox, Université de Picardie, Amiens, France,
E-Mail: fumery.mathurin@chu-amiens.fr
DOI: 10.1111/apt.17358
Pancreas
Molecular diagnostics for cystic pancreas lesions:
Next generation sequencing of 22 genes (PancreaSeq) was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts in a multi-institutional prospective trial, but also revealed the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
Gastroenterology. 2023;164(1):117–33.e7
Paniccia A, Polanco PM, Boone BA, Wald AI, McGrath K, Brand RE, Khalid A, Kubiliun N, O'Broin-Lennon AM, Park WG, Klapman J, Tharian B, Inamdar S, Fasanella K, Nasr J, Chennat J, Das R, DeWitt J, Easler JJ, Bick B, Singh H, Fairley KJ, Sarkaria S, Sawas T, Skef W, Slivka A, Tavakkoli A, Thakkar S, Kim V, Vanderveldt HD, Richardson A, Wallace MB, Brahmbhatt B, Engels M, Gabbert C, Dugum M, El-Dika S, Bhat Y, Ramrakhiani S, Bakis G, Rolshud D, Millspaugh G, Tielleman T, Schmidt C, Mansour J, Marsh W, Ongchin M, Centeno B, Monaco SE, Ohori NP, Lajara S, Thompson ED, Hruban RH, Bell PD, Smith K, Permuth JB, Vandenbussche C, Ernst W, Grupillo M, Kaya C, Hogg M, He J, Wolfgang CL, Lee KK, Zeh H, Zureikat A, Nikiforova MN, Singhi AD
Background and aims: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time.
Methods: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year time frame, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens.
Results: Among 1933 pancreatic cysts prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 patients (66%; median, 23 months). Based on 251 patients (21%) with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterological Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss-of-heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥ 3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations.
Conclusions: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
M.N. Nikiforova, M.D., Professor of Medicine or A.D. Singhi, M.D., Ph.D., Associate Professor, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA,
E-Mail: nikiforovamn@upmc.edu
E-Mail: singhiad@upmc.edu