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- Gehlen, J., et al.
(författare)
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First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B
- 2022
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Ingår i: Human Genetics and Genomics Advances. - : Elsevier BV. - 2666-2477. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes. © 2022 The Authors
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| 2. |
- Engstrand, J., et al.
(författare)
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Liver resection and ablation for squamous cell carcinoma liver metastases
- 2021
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Ingår i: BJS Open. - Oxford, United Kingdom : Oxford University Press. - 2474-9842. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Limited evidence exists to guide the management of patients with liver metastases from squamous cell carcinoma (SCC). The aim of this retrospective multicentre cohort study was to describe patterns of disease recurrence after liver resection/ablation for SCC liver metastases and factors associated with recurrence-free survival (RFS) and overall survival (OS).METHOD: Members of the European-African Hepato-Pancreato-Biliary Association were invited to include all consecutive patients undergoing liver resection/ablation for SCC liver metastases between 2002 and 2019. Patient, tumour and perioperative characteristics were analysed with regard to RFS and OS.RESULTS: Among the 102 patients included from 24 European centres, 56 patients had anal cancer, and 46 patients had SCC from other origin. RFS in patients with anal cancer and non-anal cancer was 16 and 9 months, respectively (P = 0.134). A positive resection margin significantly influenced RFS for both anal cancer and non-anal cancer liver metastases (hazard ratio 6.82, 95 per cent c.i. 2.40 to 19.35, for the entire cohort). Median survival duration and 5-year OS rate among patients with anal cancer and non-anal cancer were 50 months and 45 per cent and 21 months and 25 per cent, respectively. For the entire cohort, only non-radical resection was associated with worse overall survival (hazard ratio 3.21, 95 per cent c.i. 1.24 to 8.30).CONCLUSION: Liver resection/ablation of liver metastases from SCC can result in long-term survival. Survival was superior in treated patients with liver metastases from anal versus non-anal cancer. A negative resection margin is paramount for acceptable outcome.
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- Pammi, Mohan, et al.
(författare)
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Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis : a systematic review and meta-analysis
- 2017
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Ingår i: Microbiome. - : BIOMED CENTRAL LTD. - 2049-2618. ; 5
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Forskningsöversikt (refereegranskat)abstract
- Background: Necrotizing enterocolitis (NEC) is a catastrophic disease of preterm infants, and microbial dysbiosis has been implicated in its pathogenesis. Studies evaluating the microbiome in NEC and preterm infants lack power and have reported inconsistent results. Methods and results: Our objectives were to perform a systematic review and meta-analyses of stool microbiome profiles in preterm infants to discern and describe microbial dysbiosis prior to the onset of NEC and to explore heterogeneity among studies. We searched MEDLINE, PubMed, CINAHL, and conference abstracts from the proceedings of Pediatric Academic Societies and reference lists of relevant identified articles in April 2016. Studies comparing the intestinal microbiome in preterm infants who developed NEC to those of controls, using cultureindependent molecular techniques and reported a and beta-diversity metrics, and microbial profiles were included. In addition, 16S ribosomal ribonucleic acid (rRNA) sequence data with clinical meta-data were requested from the authors of included studies or searched in public data repositories. We reprocessed the 16S rRNA sequence data through a uniform analysis pipeline, which were then synthesized by meta-analysis. We included 14 studies in this review, and data from eight studies were available for quantitative synthesis (106 NEC cases, 278 controls, 2944 samples). The age of NEC onset was at a mean +/- SD of 30.1 +/- 2.4 weeks post-conception (n = 61). Fecal microbiome from preterm infants with NEC had increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes prior to NEC onset. Alpha-or beta-diversity indices in preterm infants with NEC were not consistently different from controls, but we found differences in taxonomic profiles related to antibiotic exposure, formula feeding, and mode of delivery. Exploring heterogeneity revealed differences in microbial profiles by study and the target region of the 16S rRNA gene (V1-V3 or V3-V5). Conclusions: Microbial dysbiosis preceding NEC in preterm infants is characterized by increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes. Microbiome optimization may provide a novel strategy for preventing NEC.
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| 11. |
- Debelius, J. W., et al.
(författare)
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The Local Tumor Microbiome Is Associated with Survival in Late-Stage Colorectal Cancer Patients
- 2023
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Ingår i: Microbiology Spectrum. - : AMER SOC MICROBIOLOGY. - 2165-0497. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiome is associated with survival in colorectal cancer. Single organisms have been identified as markers of poor prognosis. However, in situ imaging of tumors demonstrate a polymicrobial tumor-associated community. To understand the role of these polymicrobial communities in survival, we conducted a nested case-control study in late-stage cancer patients undergoing resection for primary adenocarcinoma. The microbiome of paired tumor and adjacent normal tissue samples was profiled using 16S rRNA sequencing. We found a consistent difference in the microbiome between paired tumor and adjacent tissue, despite strong individual microbial identities. Furthermore, a larger difference between normal and tumor tissue was associated with prognosis: patients with shorter survival had a larger difference between normal and tumor tissue. Within the tumor tissue, we identified a 39-member community statistic associated with survival; for every log(2)-fold increase in this value, an individual's odds of survival increased by 20% (odds ratio survival 1.20; 95% confidence interval = 1.04 to 1.33). Our results suggest that a polymicrobial tumor-specific microbiome is associated with survival in late-stage colorectal cancer patients.
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| 16. |
- Engstrand, J, et al.
(författare)
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Synchronous and metachronous liver metastases in patients with colorectal cancer-towards a clinically relevant definition
- 2019
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Ingår i: World journal of surgical oncology. - : Springer Science and Business Media LLC. - 1477-7819. ; 17:1, s. 228-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundApproximately 25% of patients with colorectal cancer (CRC) will have liver metastases classified as synchronous or metachronous. There is no consensus on the defining time point for synchronous/metachronous, and the prognostic implications thereof remain unclear. The aim of the study was to assess the prognostic value of differential detection at various defining time points in a population-based patient cohort and conduct a literature review of the topic.MethodsAll patients diagnosed with CRC in the counties of Stockholm and Gotland, Sweden, during 2008 were included in the study and followed for 5 years or until death to identify patients diagnosed with liver metastases. Patients with liver metastases were followed from time of diagnosis of liver metastases for at least 5 years or until death. Different time points defining synchronous/metachronous detection, as reported in the literature and identified in a literature search of databases (PubMed, Embase, Cochrane library), were applied to the cohort, and overall survival was calculated using Kaplan-Meier curves and compared with log-rank test. The influence of synchronously or metachronously detected liver metastases on disease-free and overall survival as reported in articles forthcoming from the literature search was also assessed.ResultsLiver metastases were diagnosed in 272/1026 patients with CRC (26.5%). No statistically significant difference in overall survival for synchronous vs. metachronous detection at any of the defining time points (CRC diagnosis/surgery and 3, 6 and 12 months post-diagnosis/surgery) was demonstrated for operated or non-operated patients. In the literature search, 41 publications met the inclusion criteria. No clear pattern emerged regarding the prognostic significance of synchronous vs. metachronous detection.ConclusionSynchronous vs. metachronous detection of CRC liver metastases lacks prognostic value. Using primary tumour diagnosis/operation as standardized cut-off point to define synchronous/metachronous detection is semantically correct. In synchronous detection, it defines a clinically relevant group of patients where individualized multimodality treatment protocols will apply.
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| 20. |
- Henstrom, M., et al.
(författare)
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
- 2018
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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| 28. |
- Ruiter, SJS, et al.
(författare)
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3D Quantitative Ablation Margins for Prediction of Ablation Site Recurrence After Stereotactic Image-Guided Microwave Ablation of Colorectal Liver Metastases: A Multicenter Study
- 2021
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 11, s. 757167-
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Tidskriftsartikel (refereegranskat)abstract
- Three-dimensional (3D) volumetric ablation margin assessment after thermal ablation of liver tumors using software has been described, but its predictive value on treatment efficacy when accounting for other factors known to correlate ablation site recurrence (ASR) remains unknown.PurposeTo investigate 3D quantitative ablation margins (3D-QAMs) as an algorithm to predict ASR within 1 year after stereotactic microwave ablation (SMWA) for colorectal liver metastases (CRLM).Materials and MethodsSixty-five tumors in 47 patients from a prospective multicenter study of patients undergoing SMWA for CRLM were included in this retrospective 3D-QAM analysis. Using a previously developed algorithm, 3D-QAM defined as the distribution of tumor to ablation surface distances was assessed in co-registered pre- and post-ablation CT scans. The discriminatory power and optimal cutoff values for 3D-QAM were assessed using receiver operating characteristic (ROC) curves. Multivariable logistic regression analysis using generalized estimating equations was applied to investigate the impact of various 3D-QAM outputs on 1-year ASR while accounting for other known influencing factors.ResultsTen of the 65 (15.4%) tumors included for 3D-QAM analysis developed ASR. ROC analyses identified i) 3D-QAM <1 mm for >23% of the tumor surface, ii) 3D-QAM <5 mm for >45%, and iii) the minimal ablation margin (MAM) as the 3D-QAM outputs with optimal discriminatory qualities. The multivariable regression model without 3D-QAM yielded tumor diameter and KRAS mutation as 1-year ASR predictors. When adding 3D-QAM, this factor became the main predictor of 1-year ASR [odds ratio (OR) 21.67 (CI 2.48, 165.21) if defined as >23% <1 mm; OR 0.52 (CI 0.29, 0.95) if defined as MAM].Conclusions3D-QAM allows objectifiable and standardized assessment of tumor coverage by the ablation zone after SMWA. Our data shows that 3D-QAM represents the most important factor predicting ASR within 1 year after SMWA of CRLM.
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| 37. |
- Tinguely, P, et al.
(författare)
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Stereotactic and Robotic Minimally Invasive Thermal Ablation of Malignant Liver Tumors: A Systematic Review and Meta-Analysis
- 2021
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 11, s. 713685-
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- Stereotactic navigation techniques aim to enhance treatment precision and safety in minimally invasive thermal ablation of liver tumors. We qualitatively reviewed and quantitatively summarized the available literature on procedural and clinical outcomes after stereotactic navigated ablation of malignant liver tumors.MethodsA systematic literature search was performed on procedural and clinical outcomes when using stereotactic or robotic navigation for laparoscopic or percutaneous thermal ablation. The online databases Medline, Embase, and Cochrane Library were searched. Endpoints included targeting accuracy, procedural efficiency, and treatment efficacy outcomes. Meta-analysis including subgroup analyses was performed.ResultsThirty-four studies (two randomized controlled trials, three prospective cohort studies, 29 case series) were qualitatively analyzed, and 22 studies were included for meta-analysis. Weighted average lateral targeting error was 3.7 mm (CI 3.2, 4.2), with all four comparative studies showing enhanced targeting accuracy compared to free-hand targeting. Weighted average overall complications, major complications, and mortality were 11.4% (6.7, 16.1), 3.4% (2.1, 5.1), and 0.8% (0.5, 1.3). Pooled estimates of primary technique efficacy were 94% (89, 97) if assessed at 1–6 weeks and 90% (87, 93) if assessed at 6–12 weeks post ablation, with remaining between-study heterogeneity. Primary technique efficacy was significantly enhanced in stereotactic vs. free-hand targeting, with odds ratio (OR) of 1.9 (1.2, 3.2) (n = 6 studies).ConclusionsAdvances in stereotactic navigation technologies allow highly precise and safe tumor targeting, leading to enhanced primary treatment efficacy. The use of varying definitions and terminology of safety and efficacy limits comparability among studies, highlighting the crucial need for further standardization of follow-up definitions.
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| 38. |
- Vaga, S., et al.
(författare)
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Compositional and functional differences of the mucosal microbiota along the intestine of healthy individuals
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Gut mucosal microbes evolved closest to the host, developing specialized local communities. There is, however, insufficient knowledge of these communities as most studies have employed sequencing technologies to investigate faecal microbiota only. This work used shotgun metagenomics of mucosal biopsies to explore the microbial communities' compositions of terminal ileum and large intestine in 5 healthy individuals. Functional annotations and genome-scale metabolic modelling of selected species were then employed to identify local functional enrichments. While faecal metagenomics provided a good approximation of the average gut mucosal microbiome composition, mucosal biopsies allowed detecting the subtle variations of local microbial communities. Given their significant enrichment in the mucosal microbiota, we highlight the roles of Bacteroides species and describe the antimicrobial resistance biogeography along the intestine. We also detail which species, at which locations, are involved with the tryptophan/indole pathway, whose malfunctioning has been linked to pathologies including inflammatory bowel disease. Our study thus provides invaluable resources for investigating mechanisms connecting gut microbiota and host pathophysiology.
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| 41. |
- Agreus, Lars, et al.
(författare)
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Towards a healthy stomach? : Helicobacter pylori prevalence has dramatically decreased over 23 years in adults in a Swedish community
- 2016
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Ingår i: United European Gastroenterology journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 4:5, s. 686-696
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Tidskriftsartikel (refereegranskat)abstract
- Background In Western countries the prevalence of Helicobacter pylori (H. pylori) infection may be declining but there is a lack of recent longitudinal population studies. We evaluated the changing epidemiology over a 23-year period in Sweden.Materials and methods In 1989, the validated Abdominal Symptom Questionnaire (ASQ) was mailed to a random sample of inhabitants (ages 22-80 years) in a Swedish community, and 1097 (87%) responded. H. pylori serology was analysed in a representative subsample (n=145). Twenty-three years later, the ASQ was mailed again using similar selection criteria, and 388 out of 1036 responders had an upper endoscopy with assessment of H. pylori and corpus atrophy status.Results The prevalence of positive H. pylori serology decreased from 37.9% (1989) to 15.8% (2012), corresponding to a decrease in odds of 75% per decade (odds ratio (OR): 0.25; 95% confidence interval (CI): 0.11-0.59, p=0.001) independent of age, gender, body mass index (BMI) and level of education, with a pattern consistent with a birth cohort effect. The prevalence increased with increasing age (p=0.001). The prevalence of H. pylori on histology in 2012 was 11.4% (95% CI 8.6-15.0). The prevalence of corpus atrophy on serology and/or histology in 2012 was 3.2% (95% CI 1.8-5.5); all cases were 57 years old.Conclusion The stomach is healthier in 2012 compared with 1989. H. pylori prevalence in adults has decreased over the last two decades to a level where clinical management might be affected.
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| 43. |
- Alexandersson, Bjarki T., et al.
(författare)
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Diverticulosis is not associated with altered gut microbiota nor is it predictive of future diverticulitis : a population-based colonoscopy study
- 2023
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 58:10, s. 1131-1138
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Tidskriftsartikel (refereegranskat)abstract
- Background: The etiopathogenesis of diverticular disease is unknown.Objective: To compare the fecal and mucosa-associated microbiota between participants with and without diverticulosis and participants who later developed diverticulitis versus those that did not from a population-based study.Methods: The PopCol study, conducted in Stockholm, Sweden, invited a random sample of 3556 adults to participate, of which 745 underwent colonoscopy. Overall, 130 participants (17.5%) had diverticulosis. 16S rRNA gene sequencing was conducted on available sigmoid biopsy samples from 529 and fecal samples from 251 individuals. We identified individuals who subsequently developed acute diverticulitis up to 13 years after sample collection. In a case-control design matching for gender, age (+/−5 years), smoking and antibiotic exposure, we compared taxonomic composition, richness and diversity of the microbiota between participants with or without diverticulosis, and between participants who later developed acute diverticulitis versus those who did not.Results: No differences in microbiota richness or diversity were observed between participants with or without diverticulosis, nor for those who developed diverticulitis compared with those who did not. No bacterial taxa were significantly different between participants with diverticulosis compared with those without diverticulosis. Individuals who later developed acute diverticulitis (2.8%) had a higher abundance of genus Comamonas than those who did not (p = .027).Conclusions: In a population-based cohort study the only significant difference was that those who later develop diverticulitis had more abundance of genus Comamonas. The significance of Comamonas is unclear, suggesting a limited role for the gut microbiota in the etiopathogenesis of diverticular disease.
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| 46. |
- Aro, Pertti, et al.
(författare)
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Use of tobacco products and gastrointestinal morbidity : an endoscopic population-based study (the Kalixanda study)
- 2010
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 25:10, s. 741-750
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Tidskriftsartikel (refereegranskat)abstract
- The impact of snus (smokeless tobacco or snuff) on gastrointestinal symptoms and pathological findings is largely unknown. The authors aimed to investigate whether the exposure to different forms of tobacco influences upper gastrointestinal symptoms, histology and frequency of Helicobacter pylori infection. A random sample (n = 2,860) of the adult population of two northern Swedish municipalities Kalix and Haparanda (n = 21,610) was surveyed between December 1998 and June 2001 using a validated postal questionnaire assessing gastrointestinal symptoms (response rate 74.2%, n = 2,122) (The Kalixanda Study). A random sub-sample (n = 1,001) of the responders was invited to undergo an esophagogastroduodenoscopy (participation rate 73.3%) including biopsies, Helicobacter pylori culture and serology and symptom assessment and exploration of present and past use of tobacco products. No symptom groups were associated with snus use. Snus users had a significantly higher prevalence of macroscopic esophagitis univariately but snus use was not associated with esophagitis in multivariate analysis. Snus use was associated with basal cell hyperplasia (OR = 1.74, 95% CI: 1.02, 3.00) and with elongation of papillae (OR = 1.79, 95% CI: 1.05-3.05) of the squamous epithelium at the esophago-gastric junction. Current smoking cigarettes was associated with overall peptic ulcer disease (OR = 2.32, 95% CI: 1.04, 5.19) whereas snus use was not. There were no significant association between current Helicobacter pylori infection and different tobacco product user groups. Snus significantly alters the histology of the distal esophagus but does not impact on gastrointestinal symptoms or peptic ulcer disease.
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