Temporal Trends of Inflammatory Bowel Diseases in Taiwan from 2016 to 2020: A Population-Based Study.

BACKGROUND: There are scanty population-based studies investigating the incidence and prevalence rates of inflammatory bowel disease (IBD) in Taiwan. AIMS: This study aimed to estimate the nationwide prevalence and incidence of IBD and identify its noticeable trends in Taiwan between 2016 and 2020. METHODS: A retrospective study by analyzing the data from the National Health Insurance Research Database of Taiwan. RESULTS: A total of 2595 patients with catastrophic IBD illness were registered from 2016 to 2020 in Taiwan (CD, 880; UC, 1715). The male-to-female ratio in the study sample was 1.83:1 for CD and 1.69:1 for UC. The median age of those registered with CD and UC was 37 and 47 years, respectively. The incidence rate of CD was 0.65 per 100,000 persons in 2016 and it was increased to 0.81 per 100,000 persons in 2020. The incidence rate of UC was 1.16 per 100,000 persons in 2016 and it was increased to 1.53 in 2020. Overall, the incidence of IBD was increase from 1.81 per 100,000 persons to 2.34 per 100,000 persons between 2016 and 2020. Overall, the prevalence rates of IBD was increase from 14.95 per 100,000 persons to 20.02 per 100,000 persons between 2016 and 2020. CONCLUSION: The epidemiological stages of IBD in Taiwan was considered in the acceleration in incidence stage, during which incidence rises and prevalence is relatively low. Understanding these geographical differences is important for the rising global burden of IBD.

An SNP Marker Predicts Colorectal Cancer Outcomes with 5-Fluorouracil-Based Adjuvant Chemotherapy Post-Resection.

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan-Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.

The Role of Clips in Preventing Delayed Bleeding After Colorectal Polyp Resection: An Individual Patient Data Meta-Analysis.

BACKGROUND & AIMS: Nonpedunculated colorectal polyps are normally endoscopically removed to prevent neoplastic progression. Delayed bleeding is the most common major adverse event. Clipping the resection defect has been suggested to reduce delayed bleedings. Our aim was to determine if prophylactic clipping reduces delayed bleedings and to analyze the contribution of polyp characteristics, extent of defect closure, and antithrombotic use. METHODS: An individual patient data meta-analysis was performed. Studies on prophylactic clipping in nonpedunculated colorectal polyps were selected from PubMed, Embase, Web of Science, and Cochrane database (last selection, April 2020). Authors were invited to share original study data. The primary outcome was delayed bleeding ≤30 days. Multivariable mixed models were used to determine the efficacy of prophylactic clipping in various subgroups adjusted for confounders. RESULTS: Data of 5380 patients with 8948 resected polyps were included from 3 randomized controlled trials, 2 prospective, and 8 retrospective studies. Prophylactic clipping reduced delayed bleeding in proximal polyps ≥20 mm (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.44-0.88; number needed to treat = 32), especially with antithrombotics (OR, 0.59; 95% CI, 0.35-0.99; number needed to treat = 23; subgroup of anticoagulants/double platelet inhibitors: n = 226; OR, 0.40; 95% CI, 0.16-1.01; number needed to treat = 12). Prophylactic clipping did not benefit distal polyps ≥20 mm with antithrombotics (OR, 1.41; 95% CI, 0.79-2.52). CONCLUSIONS: Prophylactic clipping reduces delayed bleeding after resection of nonpedunculated, proximal colorectal polyps ≥20 mm, especially in patients using antithrombotics. No benefit was found for distal polyps. Based on this study, patients can be identified who may benefit from prophylactic clipping. (PROSPERO registration number CRD42020104317.).

Anticoagulant drugs with or without proton pump inhibitor and colorectal cancer risk: a population-based, case-control study.

BACKGROUND: Low-dose aspirin and clopidogrel have demonstrated potential chemoprevention for colorectal cancer (CRC). Proton-pump inhibitors (PPI) are commonly prescribed with anticoagulation drugs, but the relationship between PPI and CRC is unclear. Moreover, evidence of CRC risk under direct oral anticoagulant (DOAC) is limited. This study aimed to investigate the effects of anticoagulation drugs combined with or without PPI on the risks of CRC in Taiwan. METHODS: A retrospective case-control study of 1,024,227 cases based on the Chang Gung Research Database from 2010 to 2017 was performed. Clinical characteristics, indications, duration of anticoagulation and PPI use, and CRC occurrence data were collected. Logistic regression was employed to adjust for known confounders of CRC risk. RESULTS: Monotherapy of clopidogrel decreased the risk of CRC (AOR 0.70; 95% CI 0.60-0.83), while no protective effect was observed in aspirin alone or aspirin plus clopidogrel. DOAC did not affect CRC significantly. The risk of CRC increased in patients with PPI (AOR 1.38; 95% CI 1.28-1.49) and PPI plus DOAC (OR 3.91; 95% CI 1.49-10.27), while PPI plus aspirin decreased the risk of CRC (OR 0.48; 95% CI 0.32-0.73). PPI plus clopidogrel showed no significant effect on the CRC. CONCLUSION: This study suggests clopidogrel alone and PPI plus aspirin offer a preventative benefit against CRC in the Taiwanese population studied. The same effect was not observed in DOAC. Moreover, a significant increase in CRC was observed in patients on PPI monotherapy and PPI plus DOAC, suggesting a possible risk.

Functional Role of Mitochondrial DNA in Cancer Progression.

Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.

Albumin-Bilirubin Grade as a Novel Predictor of the Development and Short-Term Survival of Post-Banding Ulcer Bleeding Following Endoscopic Variceal Ligation in Cirrhotic Patients.

Background and Objectives: Endoscopic variceal ligation (EVL) is the primary and secondary treatment for acute esophageal variceal bleeding. Post-banding ulcer bleeding (PBUB) may lead to bleeding episodes following EVL, increasing mortality. The aim of this study was to evaluate the risk factors for PBUB and predict the 6-week mortality risk after PBUB. Materials and Methods: We retrospectively analyzed the data collected from cirrhotic patients with EVL from 2015 to 2017. The incidence of PBUB and the 6-week mortality rate were evaluated. Risk factors for PBUB and predictive factors for mortality after PBUB were analyzed. Results: A total of 713 patients were enrolled in this study. Among the studied subjects, the incidence of PBUB was 5.8% (N = 41). The 6-week mortality rate was 63.4% (26/41). In multivariate analysis, MELD score ≥20 (OR: 3.77, 95% CI: 1.94−7.33, p < 0.001), ALBI score of 3 (OR: 2.67, 95% CI: 1.34−5.3, p = 0.005) and the presence of gastric varices (OR: 2.1, 95% CI: 1.06−4.16, p = 0.03) were associated with the development of PBUB. Patients with ALBI grade 3 (OR: 4.8, 95% CI: 1.18−19.6, p = 0.029) and Child-Pugh scores B and C (OR: 16.67, 95% CI: 1.75−158.1, p = 0.014) were associated with 6-week mortality after PBUB. Conclusions: PBUB is a complication with low incidence but increased mortality following EVL. The ALBI grade is a useful score to predict not only the development of PBUB but also the 6-week mortality after PBUB.

Plasma interleukin-17 and alpha-fetoprotein combination effectively predicts imminent hepatocellular carcinoma occurrence in liver cirrhotic patients.

BACKGROUND: Predicting imminent hepatocellular carcinoma (HCC) in liver cirrhotic patients is an unmet medical need. We aimed to investigate circulatory biomarkers and their optimum combinations in a prospective study. METHODS: We investigated plasma interleukin 17 (IL-17) concentrations, quantified using enzyme-linked immunosorbent assay (ELISA), for the prediction of HCC in a large cohort of 404 HCC-naïve liver cirrhotic patients regularly followed after recruitment. Additionally, IL-17 in surgically resected tumor tissues were evaluated using immunohistochemistry staining. RESULTS: IL-17 was detected in HCC tissues. The IL-17 concentrations in the peripheral blood do not have correlation with an extensive list of 31 common demographic, metabolic and liver function variables in the cohort of liver cirrhotic patients. Furthermore, patients stratified by IL-17 and alpha-fetoprotein (AFP) showed distinctive cumulative incidence of HCC. Imminent HCC, defined here as HCC occurrence within 1 year, can be predicted by IL-17 alone with an area under the receiver operating characteristic curve [AUC] of 0.762 (P = 0.002). An multivariate analysis showed that age, hepatitis C viral infection, AFP and IL-17 were four independent factors associated with imminent HCC (adjusted P = 0.03, 0.041, 0.024 and 0.008 respectively). An explicit risk score (R) combining the concentrations of two plasma biomarkers, AFP and IL-17, achieved a high AUC of 0.933 (95% confidence interval 0.893-0.972, P < 0.001) in predicting imminent HCC, with 100% sensitivity and 79.9% specificity at the optimum cutoff. The score is defined as: [Formula: see text] CONCLUSIONS: The circulatory IL-17 concentration is a predictor of subsequent HCC occurrence in liver cirrhotic patients. The combination of AFP and IL-17 is highly effective in predicting imminent HCC within 1 year.

Impact of an MT-RNR1 Gene Polymorphism on Hepatocellular Carcinoma Progression and Clinical Characteristics.

Mitochondrial DNA (mtDNA) mutations are highly associated with cancer progression. The poor prognosis of hepatocellular carcinoma (HCC) is largely due to high rates of tumor metastasis. This emphasizes the urgency of identifying these patients in advance and developing new therapeutic targets for successful intervention. However, the issue of whether mtDNA influences tumor metastasis in hepatoma remains unclear. In the current study, multiple mutations in mtDNA were identified by sequencing HCC samples. Among these mutations, mitochondrially encoded 12S rRNA (MT-RNR1) G709A was identified as a novel potential candidate. The MT-RNR1 G709A polymorphism was an independent risk factor for overall survival and distant metastasis-free survival. Subgroup analysis showed that in patients with cirrhosis, HBV-related HCC, α-fetoprotein ≥ 400 ng/mL, aspartate transaminase ≥ 31 IU/L, tumor number > 1, tumor size ≥ 5 cm, and histology grade 3-4, MT-RNR1 G709A was associated with both shorter overall survival and distant metastasis-free survival. Mechanistically, MT-RNR1 G709A was clearly associated with hexokinase 2 (HK2) expression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel associations among MT-RNR1 G709A and HK2 are an important risk factor in HCC patients.

Decreasing seroprevalence of anti-hepatitis D virus antibodies in the antiviral era with inverse association with hepatitis B virus DNA, Taiwan, 2006 to 2019.

We examined the seroprevalence change of anti-hepatitis D virus (HDV) antibodies in Taiwan from 2006 to 2019. A total of 1147 patients who had chronic hepatitis B virus (HBV) infection were assessed. Of them, 51 (4.4%) were positive for anti-HDV antibodies. Comparison between anti-HDV-positive and negative groups was performed to examine clinical and virological factors related to anti-HDV positivity. It was found that the median HBV-DNA concentration was 1.6 × 105 IU/mL (range, <20-4.5 × 1010 IU/mL) and <20 IU/mL (range, <20-2.0 × 109 IU/mL) for patients with negative and positive anti-HDV antibodies, respectively (P < .001). In addition, a progressive year-to-year decrease of anti-HDV seroprevalence was unveiled. For patients who had HBV-DNA >15 000 IU/mL, the year-to-year (calculated every 2 years) seropositive rates of anti-HDV were 10.0%, 7.9%, 0.7%, 0.3%, 0%, 0%, and 0% (P < .001). For patients who had HBV-DNA <15 000 IU/mL, the year-to-year seropositive rates were 18.6%, 12.8%, 7.8%, 5.0%, 7.3%, 8.0%, and 3.7% (P < .001). In conclusion, seropositive of anti-HDV was inversely associated with HBV-DNA levels. A progressive decrease of anti-HDV seroprevalence was found with no anti-HDV-positive cases detected in high HBV-DNA patient group after 2014.

The effect of prophylactic hemoclip placement and risk factors of delayed post-polypectomy bleeding in polyps sized 6 to 20 millimeters: a propensity score matching analysis.

BACKGROUND: Delayed post-polypectomy bleeding (PPB) is a major complication of polypectomy. The effect of prophylactic hemoclipping on delayed PPB is uncertain. The aim of this study was to evaluate the effectiveness of prophylactic hemoclipping and identify the risk factors of delayed PPB. METHODS: Patients with polyps sized 6 to 20 mm underwent snare polypectomy from 2015 to 2017 were retrospectively reviewed. The patients with prophylactic hemoclipping for delayed PPB prevention were included in the clipping group, and those without prophylactic hemoclipping were included in the non-clipping group. The incidence of delayed PPB and time to bleeding were compared between the groups. Multivariate analysis was used to identify the risk factors of delayed PPB. Propensity score matching was used to minimize potential bias. RESULTS: After propensity score matching, 612 patients with 806 polyps were in the clipping group, and 576 patients with 806 polyps were in the non-clipping group. There were no significant differences in the incidence of delayed PPB and days to bleeding between two groups (0.8% vs 1.3%, p = 0.4; 3.4 ± 1.94 days vs 4.13 ± 3.39 days, p = 0.94). In the multivariate analysis, the polyp size [Odds ratio (OR):1.16, 95% confidence interval (CI):1.01-1.16, p = 0.03), multiple polypectomies (OR: 4.64, 95% CI:1.24-17.44, p = 0.02) and a history of anticoagulant use (OR:37.52, 95% CI:6.49-216.8, p < 0.001) were associated with delayed PPB. CONCLUSIONS: In polyps sized 6 to 20 mm, prophylactic hemoclip placement did not decrease the risk of delayed PPB. Patients without risk factors including multiple polypectomies and anticoagulant use are no need to performing prophylactic hemoclipping.

Rescue therapy with rifabutin regimen for refractory Helicobacter pylori infection with dual drug-resistant strains.

BACKGROUND: There is no current standard rescue treatment for dual drug-resistant strains of Helicobacter pylori (H. pylori). This aim of this study was to investigate the efficacy of rifabutin-based triple therapy for patients infected with dual drug-resistant strains to clarithromycin and levofloxacin. METHODS: After 2 or 3 H. pylori treatment failures, patients underwent upper endoscopy with tissue biopsies. Phenotypic and genotypic resistances were determined using agar dilution test and polymerase chain reaction with direct sequencing, respectively. Patients infected with dual drug-resistant (clarithromycin and levofloxacin) strains and receiving rifabutin-based triple therapy (rifabutin 150 mg bid, amoxicillin 1 g bid and esomeprazole 40 mg bid for 10 days) were enrolled. Eradication status was determined by 13C-urea breath test 4 weeks after treatment completion. RESULTS: A total of 39 patients infected with dual drug-resistant strains were enrolled in this study, with a mean age of 55.9 years. The eradication rate was 79.5% (31/39) (95% confidence intervals: 54.96% ~ 111.40%). Adverse event was reported in 23.1% (9/39) of patients but they were mild and tolerable. In univariate analysis, no factor was identified as an independent predictor of eradication failure. CONCLUSIONS: Our current study demonstrated that rifabutin-based triple therapy was well tolerated and yielded an acceptable eradication rate for patients infected with dual drug-resistant strains of H. pylori.

Bile ductular reactions in the liver: similarities are only skin deep.

Extensive bile ductular reactions (DRs) accompany many cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis (PSC) as well as parenchymal liver cell diseases such as alcoholic liver disease, non-alcoholic steatohepatitis and HCV and HBV infections. DRs originate from bile ducts or hepatocytes after damage and can be identified by expression of markers associated with cholangiocytes, often being associated with disease progression and fibrosis. In a recent issue of The Journal of Pathology, Govaere et al employed high-throughput RNA sequencing to compare the transcriptomic profiles of DR cells from liver diseases of different aetiology; HCV infection affecting hepatocytes and PSC initially affecting biliary epithelial cells. Both DR transcriptomes were markedly different from that of their neighbouring hepatocytes and 330 genes were significantly differently expressed between the DRs of the HCV and PSC liver diseases. Exploring such gene expression profiles could enable therapeutic targeting of DRs, on the one hand to inhibit liver fibrosis and inflammation and conversely to promote hepatocyte and cholangiocyte regeneration. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

GALNT14: An Emerging Marker Capable of Predicting Therapeutic Outcomes in Multiple Cancers.

Members of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family function as the initiating enzymes that catalyze mucin-type O-glycosylation of proteins, and their dysregulated expression can alter cancer cell behaviors such as de novo occurrence, proliferation, migration, metastasis, and drug resistance. Recent studies have demonstrated that one of the family's members, GALNT14, is aberrantly expressed in multiple cancers and involved in a variety of biological functions. Moreover, the single nucleotide polymorphisms (SNPs) of GALNT14-rs9679162 have been shown to predict therapeutic outcomes in patients with hepatocellular carcinoma as well as several other different types of gastrointestinal cancer. This review summarizes the structural features of GANLT14, its functional roles, and the predictive values of GALNT14 genotypes and enzyme levels in multiple cancers receiving distinct anticancer therapies.

Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study.

BACKGROUND: The incidence of cefepime-induced neurotoxicity (CIN) has been previously underestimated, and there have only been sporadic reports from critical neurological settings. The present study aimed to investigate the potential factors associated with disease development, electroencephalography (EEG) sub-classification, and outcome measures. METHODS: The 10-year medical records of patients who underwent EEG between 2007 and 2016 at a tertiary medical center in Taiwan, and developed encephalopathy after cefepime therapy were retrospectively reviewed. Age- and sex-matched controls were included for further analysis. Demographic data, the occurrence of clinical seizures, non-convulsive status epilepticus (NCSE), use of antiepileptic drugs (AEDs), receiving maintenance or urgent hemodialysis, EEG findings, and functional outcomes were analyzed. The Chi-square test and a logistic regression model were applied to survey significant prognostic factors relating to mortality. RESULTS: A total of 42 CIN patients were identified, including 25 patients from wards and 17 from intensive care units; their mean age was 75.8 ± 11.8 years. Twenty-one patients (50%) had chronic kidney disease, and 18 (43%) had acute kidney injury. Among these patients, 32 (76%) received appropriate cefepime dose adjustment. Three patients had a normal renal function at the time of CIN onset. The logistic regression model suggested that maintenance hemodialysis and longer duration of cefepime use were independently associated with the development of CIN, with odds ratios of 3.8 and 1.2, respectively. NCSE was frequently noted in the CIN patients (64%). Generalized periodic discharge with or without triphasic morphology was the most common EEG pattern (38%), followed by generalized rhythmic delta activity and generalized spike-and-waves. AEDs were administered to 86% of the patients. A total of 17 patients (40%) did not survive to hospital discharge. Adequate cefepime dose adjustment and early cefepime discontinuation led to a better prognosis. CONCLUSIONS: CIN was associated with high mortality and morbidity rates. Neurotoxic symptoms could still occur when the cefepime dose was adjusted, or in patients with normal renal function. Patients with maintenance hemodialysis or a longer duration of cefepime therapy tended to develop CIN. Early recognition of abnormal EEG findings allowed for the withdrawal of the offending agent, resulting in clinical improvements and a better prognosis at discharge.

Development of a fibrosis index including hepatitis B virus basal core promoter A1762T mutation for pretherapeutic evaluation.

BACKGROUND AND AIM: Commonly used non-invasive fibrosis scores usually included serum transaminase levels in the equations, including Aspartate transaminase to Platelet Ratio Index (APRI) and fibrosis-4 (FIB-4). Transaminases fluctuated significantly in chronic hepatitis B patients with exacerbations, leading to unsteady score values. As such, here, we aim to develop a transaminase-free score suitable for pretherapeutic evaluation of fibrosis stages. METHODS: Firstly, 1082 treatment-naïve chronic hepatitis B patients were enrolled and divided into modeling (n = 541) and verification (n = 541) cohorts. Secondly, 265 patients having received liver biopsy, with known Ishak fibrosis stages, were included for independent correlation. RESULTS: Cross-sectional analysis of 1082 patients revealed age-dependent variation of association between virological factors and cirrhosis. A fibrosis score including Anti-hepatitis B e antibody, Basal core promoter (BCP) A1762T mutation, and Platelet count Index (named ABPI) was derived from the modeling cohort. ABPI performed better than APRI and FIB-4 in the verification cohort for identifying cirrhotic patients (comparison of area under the receiver operating characteristic curves: ABPI vs APRI and FIB-4 = 0.785 vs 0.563 [P < 0.001] and 0.700 [P = 0.026], respectively). The performance of ABPI was even better in young (< 40 years old) hepatitis B patients (area under the receiver operating characteristic curves: 0.856 vs 0.402 [P < 0.001] and 0.599 [P = 0.009], respectively). Finally, in the independent cohort of 265 patients with known Ishak fibrosis stages, it was found that ABPI effectively distinguished between Ishak fibrosis stages 3 and > 3 and between 4 and > 4 (P < 0.001 for each). CONCLUSIONS: We developed a transaminase-free fibrosis score (ABPI) utilizing basal core promoter A1762T data, which outperformed APRI and FIB-4.

Phenotypic and Genotypic Shifts in Hepatitis B Virus in Treatment-Naive Patients, Taiwan, 2008-2012.

We examined the characteristic changes of hepatitis B virus (HBV) in antiviral drug treatment-naive patients referred for pretreatment evaluation in Taiwan during 2008-2012. Over time, we observed substantial decreases in the prevalence of HBV e antigen (HBeAg) and increasing prevalence of the precore G1899A mutation and HBV-DNA levels in HBeAg-positive patients.

Diverse routes to liver regeneration.

The liver's ability to regenerate is indisputable; for example, after a two-thirds partial hepatectomy in rats all residual hepatocytes can divide, questioning the need for a specific stem cell population. On the other hand, there is a potential stem cell compartment in the canals of Hering, giving rise to ductular reactions composed of hepatic progenitor cells (HPCs) when the liver's ability to regenerate is hindered by replicative senescence, but the functional relevance of this response has been questioned. Several papers have now clarified regenerative mechanisms operative in the mouse liver, suggesting that the liver is possibly unrivalled in its versatility to replace lost tissue. Under homeostatic conditions a perivenous population of clonogenic hepatocytes operates, whereas during chronic damage a minor population of periportal clonogenic hepatocytes come to the fore, while the ability of HPCs to completely replace the liver parenchyma has now been shown.

Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus.

BACKGROUND & AIMS: The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients. METHODS: Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m(2) body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses. RESULTS: No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine). CONCLUSIONS: LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required.