Anna Lepistö

Hospital District for Helsinki and Uusimaa, Helsinki, Uusimaa, Finland

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Publications (21)95.27 Total impact

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    ABSTRACT: Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.
    Nature Genetics 06/2015; DOI:10.1038/ng.3335 · 29.65 Impact Factor
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    ABSTRACT: Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under-investigated disease. We extracted DNA from 19 appendix-derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer-related genes by amplicon-based next-generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6, and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low-grade and high-grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations, and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high-grade tumors as compared to low-grade ones (31.3% vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high-grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2, and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA, and APC mutations are rare. Aberrantly expressed p53 is associated with high-grade histology and reduced survival. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; DOI:10.1002/ijc.29245 · 5.01 Impact Factor
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    ABSTRACT: Patients with pseudomyxoma peritonei (PMP) benefit from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reports on this modality usually have included only patients with successful HIPEC treatment, which can potentially cause biased results. We report the survival of a PMP population treated by CRS and HIPEC, including patients who were not eligible for HIPEC. The outcome of the whole population of 87 patients with PMP treated by CRS and HIPEC in Helsinki University Central Hospital between 2008 and 2011 was evaluated. The results of treatment were compared with 33 patients treated by serial debulking in our unit between 1984 and 2008. Of the 87 patients in the HIPEC-era group, 56 received HIPEC, 12 were treated non-radically in an attempt at HIPEC, 9 were debulked and 10 were referred back or transferred to palliative care without surgery. The 5-year overall survival for the debulking-era group and the HIPEC-era group were 67 and 69 %, respectively. The number of patients with no evidence of disease was higher in the HIPEC-era group (47/87) than that in the debulking-era group (8/33) at the end of the follow-up. Overall survival for patients who underwent successful CRS and HIPEC at 2 and 5 years was 95 and 93 %, respectively. The improved survival from using the CRS and HIPEC was not apparent after 5-year follow-up, when the whole patient population was included in the analysis. Even so, patients successfully treated by CRS and HIPEC manage well.
    International Journal of Colorectal Disease 06/2014; 29(8). DOI:10.1007/s00384-014-1933-8 · 2.42 Impact Factor
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    ABSTRACT: Gastric outlet obstruction (GOO) commonly occurs in advanced gastric cancer. Our aim was to evaluate the results of endoscopic stenting (ES), palliative resection (PR), and gastrojejunostomy (GJ) as palliation of GOO. A total of 97 patients (50 ES, 26 PR, 21 GJ) were included in this retrospective study. All the patients had primary gastric cancer and symptoms of GOO. Compared to surgery, ES resulted in a faster improvement on oral intake and symptom relief (P < 0.001) and a shorter hospitalization (P < 0.001). Complication rates, hospital re-admissions, occurrence of biliary obstruction, and the number of patients receiving chemotherapy were similar. The median symptom-free and overall survival were longest in the PR group (P < 0.001). In multivariate survival analysis, independent prognostic factors were age, BMI, pre-procedure GOOSS, palliative resection as treatment modality, and chemotherapy. In gastric cancer and GOO, the clinical condition of the patient before treatment affects survival and should be taken into account in determining the treatment. PR seems to provide a survival benefit and should be considered as treatment option for patients suitable for surgery. For patients unfit for surgery, ES provides rapid and efficient palliation. Chemotherapy also seems to improve survival in gastric cancer and GOO. J. Surg. Oncol. 2013; 108:537-541. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 12/2013; 108(8):537-41. DOI:10.1002/jso.23442 · 2.84 Impact Factor
  • Tiina Saarto, Pia Osterlund, Anna Lepistö
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    ABSTRACT: Intestinal obstruction is a common complication in peritoneal cancers. Obstructions occur especially as the cancer advances, at a time when life expectancy is often only a few months. Characteristic symptoms include nausea, vomiting, constipation, lack of bowel function, colicky and persistent abdominal pains. Conservative treatment aims to secure intestinal transit by applying pharmacologic therapies in cases where surgical therapy in partial or functional obstruction is not possible or reasonable. Pharmacologic therapy consists of antisecretory and antiemetic drugs combined with opioids.
    Duodecim; lääketieteellinen aikakauskirja 01/2013; 129(4):410-7.
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    ABSTRACT: Self-expanding metal stents (SEMS) are used for colorectal obstruction preoperatively and palliatively. Limited data on the use of stents for obstruction caused by extracolonic malignancies exist, and the results are unclear. Our goal was to evaluate the efficacy and safety of SEMS for patients stented as a bridge to surgery and as palliation for colorectal cancer or extracolonic malignancies. Between 1998 and 2009, a total of 101 patients underwent 108 stenting procedures for malignant colorectal obstruction. The results were studied retrospectively. Of the study cohort, 11 patients were stented as a bridge to surgery. For palliatively stented patients, the etiology of obstruction was colorectal cancer in 66 patients and extracolonic malignancy in 24. Overall technical success was 99% and clinical success 88%. Complications occurred for 20 (20%) patients in 22 of 108 procedures. Complications included perforation (n = 6), recurrent obstruction (n = 8), and stent migration (n = 4). A median time to complication was 81.5 days. The overall stent placement-related mortality was 2/101 (2%). For patients stented as a bridge to surgery, a primary anastomosis in elective operations was achieved for 90% (9/10). In the palliation groups, patients with colorectal cancer had significantly higher clinical success rates than patients with extracolonic malignancies (94% vs. 65%, P = 0.0005). There was no difference in complications, operation, and stoma rates between the palliation groups. SEMS is a safe and effective treatment for patients stented as a bridge to surgery or as palliation due to colorectal cancer. Stents are also useful in relieving obstruction due to extracolonic malignancies, but the clinical failure rate is higher than for colorectal cancer.
    Surgical Endoscopy 09/2011; 26(2):423-30. DOI:10.1007/s00464-011-1890-z · 3.31 Impact Factor
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    ABSTRACT: Self-expanding metal stents (SEMS) have been successfully used as a "bridge to surgery" or as palliation for acute malignant colorectal obstruction. Little data on the use of stents for benign obstruction exists and the results vary. The purpose of this study was to evaluate the efficacy and safety of SEMS in benign colorectal obstruction. A total of 21 patients with 23 SEMS procedures between the years 1998 and 2008 were retrospectively studied. Eight patients had an obstruction in the surgical anastomosis. In addition, there were two patients with anastomotic strictures due to Crohn's disease. In 10 patients the obstruction was caused by diverticular disease and one patient had a stricture after radiation therapy. Technical success was achieved for all the patients. Clinical success was achieved for 76% (16/21) of the patients. The anastomotic strictures were resolved with SEMS in 5 out of 8 cases (63%). Three patients with diverticular stricture (30%) were eventually resolved with SEMS. Nine (43%) patients in 10 out of 23 procedures (43%) had a complication, the majority being in patients with diverticular stricture. SEMS is a good treatment option for patients with anastomotic stricture of the colon and for patients with benign colonic stricture who are unfit for surgery. SEMS can be used as a bridge to surgery in diverticular obstruction but there seems to be a considerable risk of complications. If a SEMS is placed into a diverticular stricture, the planned bowel resection should be performed within a month.
    Scandinavian Journal of Gastroenterology 03/2010; 45(6):725-31. DOI:10.3109/00365521003663696 · 2.33 Impact Factor
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    ABSTRACT: In pseudomyxoma peritonei a mucinous tumor of the appendix spreads into the abdominal cavity. Cytologic picture of the tumor may be benign, malignant or intermediary. The symptoms were previously relieved by repeated resections of the tumor mass, whereby even the most benign form of the disease progressed slowly. A method has now emerged in which radical-aimed surgery is combined with intraperitoneal lavage with a warmed solution of a cytotoxic agent. This treatment is associated with a morbidity of 33 to 56% and a mortality of 0 to 18%. Controlled studies have not been carried out on the novel treatment.
    Duodecim; lääketieteellinen aikakauskirja 01/2010; 126(14):1693-9.
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    ABSTRACT: BACKGROUND: Malignant gastric outlet obstruction (GOO) leads to malnutrition and limits quality of life. Gastrojejunostomy has been the traditional treatment for GOO. Recently, the results of releasing duodenal obstruction with self-expandable metal stents (SEMS) have been encouraging. METHODS: After the exclusion of 13 patients with gastrojejunal or jejunal strictures and 1 patient with intraabdominal lymphoma, the authors palliated the malignant GOO in 104 patients with 130 SEMS at a single center during the years 1999-2007. RESULTS: The GOO was caused by pancreatic (n = 51), gastric (n = 24), duodenal (n = 7), biliary (n = 5), and other (n = 17) malignancies. Of the 104 patients, 76 (73%) did well with only one enteral stent placement, 21 (20.2%) required two stent placements, 4 (3.8%) required three stent placements, and 1 required four stent placements. The median dysphagia score was 0 before stenting and 2 after treatment (p < 0.001). Immediate failure occurred after 10 procedures (7.7%). Among the 104 patients, 6 (5.8%) died of stent placement-related reasons. Complications occurred for 13 patients (12.5%). The median hospital stay was 3 days, and the overall survival time was 62 days (range, 1-933 days). Of 11 patients with concomitant biliary obstruction and GOO, 10 (91%) underwent successful enteral and biliary stent placement within the same session. Of 15 patients experiencing jaundice after enteral stent placement, 6 (40%) underwent endoscopic biliary drainage successfully. CONCLUSION: Enteral stenting is a safe and effective way to treat GOO. Gastrojejunostomy should be preserved for cases in which endoscopic stenting is not successful or possible.
    Surgical Endoscopy 09/2009; 24(4). DOI:10.1007/s00464-009-0686-x · 3.31 Impact Factor
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    ABSTRACT: The prevalence of primary sclerosing cholangitis (PSC) among patients with ulcerative colitis needing proctocolectomy is about 12%. The study aim was to evaluate the progression of the liver disease after surgery. PSC progression in 68 patients with UC after restorative proctocolectomy was evaluated after a median follow-up of 11 years (range 0 to 21). Magnetic resonance imaging (MRI) of the liver, histological examination of a core needle liver specimen, and liver function tests were used in addition to clinical history. Of the 68 patients, 30 participated in follow-up examinations. Ductal changes in MRI suggesting a diagnosis of PSC occurred in 21 (72%) of them. One carcinoma of the gallbladder was found in MRI. Histopathologic changes suggesting PSC were observable in 15 (50%) patients. Compared to stage in peroperative biopsies taken at proctocolectomy, PSC stage increased in four (13%) patients, decreased in 15 (50%), and remained unchanged in 11 (37%). Immunohistochemical staining for cytoceratin-7 in hepatocytes was positive in nine (30%) indicating cholestasis. After IPAA surgery, five patients underwent liver transplantation at 1, 1, 5, 6, and 11 years, respectively. Of the 68, six patients have, to date, developed cholangiocarcinoma. Progression of PSC in patients with minor ductal changes at the time of restorative proctocolectomy is unlikely. Those patients with more advanced disease at surgery are at risk for disease progression and liver transplantation. We lack accurate diagnostic methods to detect premalignant changes of the biliary epithelium.
    International Journal of Colorectal Disease 08/2009; 24(10):1169-74. DOI:10.1007/s00384-009-0773-4 · 2.42 Impact Factor
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    ABSTRACT: Colonic carcinoma is the third most common cancer in Finland. Cardinal symptoms include a change in bowel function and rectal hemorrhage. The first line treatment of this cancer, both localized and metastatic, is surgery. Before surgery, the patient is subjected to colonoscopy and computed tomography scanning of the body, and the concentration of carcinoembryonic antigen in serum is determined. The surgical operation aspires to a local radicality by excising the part of colon bearing the tumor along with the corresponding mesocolon. If metastases are detected in the mesenteric lymph nodes or elsewhere, use of chemotherapy is considered postoperatively.
    Duodecim; lääketieteellinen aikakauskirja 02/2009; 125(6):619-28.
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    ABSTRACT: Since benign and malignant mucin-producing tumors of the pancreas may be difficult to distinguish from each other; preoperative methods for differential diagnosis would reduce unnecessary surgery. To compare syndecan-1 and tenascin immunoexpression in benign and malignant cystic pancreatic tumors. We used immunohistochemical staining for syndecan-1 and tenascin antibodies in tumor tissue samples. Helsinki University Central Hospital. Tissue material came from 33 patients undergoing surgery from 1979 to 2005 for cystic pancreatic tumors. A statistically significant difference appeared in syndecan-1 expression between benign (mucinous cystic neoplasms and intraductal papillary mucinous neoplasms) and mucinous carcinomas, but there was no significant difference in tenascin immunoexpression between these tumor groups. Our findings suggest that low syndecan-1 expression might serve as a predictive factor for malignancy in cystic tumors of the pancreas.
    JOP: Journal of the pancreas 02/2009; 10(4):378-82.
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    ABSTRACT: The most common symptom of rectal cancer is bleeding. The average diagnostic delay is half a year. Colonoscopy, magnetic resonance imaging of the pelvis and computed tomography scanning of the body are carried out before the operation to assess the extent, and the level of carcinoembryonic antigen is determined from the serum. In cancers grown through the intestinal wall or spread to the mesorectal lymph nodes, local radiotherapy is applied preoperationally. The surgical operation involves total mesorectal excision with low-rectal anastomosis. Cytotoxic chemotherapy of a disseminated cancer will improve the quality of life.
    Duodecim; lääketieteellinen aikakauskirja 02/2009; 125(8):857-65.
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    ABSTRACT: Background: This study aimed to determine the prevalence of primary sclerosing cholangitis (PSC) among patients with ulcerative colitis (UC) needing proctocolectomy.Methods: The study sample included 441 consecutive patients who underwent proctocolectomy with ileal pouch-anal anastomosis from 1993 to 2004 at the Helsinki University Central Hospital. Liver biopsy samples were taken at operation. Patient groups with and without PSC were compared.Results: PSC was present in 52 (11.8%) patients. Only 19 of these had been diagnosed before surgery; 40 patients with PSC were detected by liver biopsy at the operation, making the sensitivity of perioperative liver biopsy to diagnose PSC 83.3%. The cumulative incidence of colorectal dysplasia or cancer in the UC patients with PSC (19% after 10 years and 43% after 20 years) was not significantly different than that of UC patients without PSC (24% after 10 years and 39% after 20 years). Pouchitis occurred more often in patients with PSC (25 of 52; 48.1% versus 101 of 389, 26.0%; P = 0.001). The failure rate of ileal pouch–anal anastomosis did not significantly differ between the 2 groups.Conclusions: The prevalence of PSC among patients with UC needing proctocolectomy was higher than in patients with UC in general. Liver biopsy can be recommended as a safe adjunct at proctocolectomy for surveillance of any liver effects.(Inflamm Bowel Dis 2008)
    Inflammatory Bowel Diseases 01/2008; 14(6):775 - 779. DOI:10.1002/ibd.20384 · 5.48 Impact Factor
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    ABSTRACT: Grade III and IV anal sphincter ruptures after vaginal delivery are an increasing problem. We assessed the outcome of an overlap technique in primary repair. In this retrospective observational study, from 2002 to 2004, 61 consecutive women with grade III and IV obstetric tears were included. Of the 61 women, 42 had complete rupture of the external sphincter and underwent sphincter repair using standardised overlap technique. The outcome was assessed by clinical examination, Wexner questionnaire, and endoanal ultrasonography (EAUS), after a median follow-up of 9.4 months. Main outcome measure was continence following primary repair. At follow-up, 64% of the patients had no symptoms of anal incontinence. A total of 29% experienced occasional incontinence to flatus, 1 patient (2%) experienced occasional incontinence to liquid stools, and 1 patient to liquid or normal stools. EAUS revealed intact external sphincter in 29 of the 35 patients (83%). In 6 patients (17%), EAUS showed partial discontinuity of the sphincter muscle. The results show that the primary overlap technique in the repair of anal sphincter rupture following vaginal delivery is highly successful.
    Acta Obstetricia Et Gynecologica Scandinavica 02/2007; 86(12):1458-62. DOI:10.1080/00016340701709372 · 1.99 Impact Factor
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    ABSTRACT: The potential association of CD2AP with the adherens junction protein E-cadherin, co-localization with the actin cytoskeleton, and involvement in cell migration was investigated in cultured rat gastric mucosal cells. In stationary cells, CD2AP was localized perinuclearly while E-cadherin was expressed along cell-cell contacts and F-actin formed a branched network and adhesion belts. In migrating cells, CD2AP appeared as thread-like accumulations in the leading edges, colocalizing with F-actin and occasionally with E-cadherin. Intracellular injection of anti-CD2AP significantly retarded the migration speed of the cells suggesting a crucial role for CD2AP in mucosal cell migration, possibly as a scaffolding protein between cell membrane proteins and actin cytoskeleton. Co-immunoprecipitation assays revealed that CD2AP and E-cadherin are in a complex in HGF stimulated cells. It is concluded that CD2AP interacts with E-cadherin and co-localizes with F-actin in the leading edge of migrating cells, and significantly contributes to cell migration in restituting gastric epithelium.
    Biochemical and Biophysical Research Communications 08/2005; 332(2):426-32. DOI:10.1016/j.bbrc.2005.04.140 · 2.28 Impact Factor
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    ABSTRACT: Peutz-Jeghers syndrome (PJS) is typically manifested as severe gastrointestinal polyposis. Polyps in PJS patients and in Lkb1(+/-) mice that model PJS polyposis are frequently characterized by elevated cyclooxygenase-2 (COX-2). This study was designed to determine whether COX-2 inhibition would reduce tumor burden in Lkb1(+/-) mice or Peutz-Jeghers patients. Genetic interactions between Cox-2 and Lkb1 in polyp formation were analyzed in mice with combined deficiencies in these genes. Pharmacologic inhibition of COX-2 was achieved by supplementing the diet of Lkb1(+/-) mice with 1500 ppm celecoxib between 3.5-10 and 6.5-10 months. In PJS patients, COX-2 was inhibited with a daily dose of 2 x 200 mg celecoxib for 6 months. Total polyp burden in Lkb1(+/-) mice was significantly reduced in a Cox-2(+/-) (53%) and in a Cox-2(-/-) (54%) background. Celecoxib treatment initiating before polyposis (3.5-10 months) led to a dramatic reduction in tumor burden (86%) and was associated with decreased vascularity of the polyps. Late treatment (6.5-10 months) also led to a significant reduction in large polyps. In a pilot clinical study, a subset of PJS patients (2/6) responded favorably to celecoxib with reduced gastric polyposis. These data establish a role for COX-2 in promoting Peutz-Jeghers polyposis and suggest that COX-2 chemoprevention may prove beneficial in the treatment of PJS.
    Gastroenterology 11/2004; 127(4):1030-7. DOI:10.1053/j.gastro.2004.07.059 · 13.93 Impact Factor
  • Duodecim; lääketieteellinen aikakauskirja 02/2004; 120(19):2353-4.
  • Anna H Lepistö, Heikki J Järvinen
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    ABSTRACT: The purpose of this study was to determine the cumulative success rate of Kock continent ileostomy and the reasons leading to excision and to compare the results with pelvic pouch and ileal pouch-anal anastomosis. The data were collected from the histories of 96 patients, who underwent a Kock continent ileostomy operation from 1972 to 2000 at Helsinki University Central Hospital. The failure rate was calculated by the Kaplan-Meier method. Overall, the continent ileostomy was converted to conventional stoma in 21 patients (24 percent). The cumulative success rate was 96 percent at 1 year, 86 percent at 10 years, 77 percent at 15 years, and 71 percent at 29 years. The most common reason for pouch excision was partial or total nipple-valve sliding. Eighty-five re-reconstructions were performed among 57 patients (59 percent), the most common indication being nipple-valve dysfunction. Of these patients, 14 later ended up with pouch excision. The success rate of continent ileostomy was significantly lower than that of ileoanal anastomosis (P < 0.01). The durability of continent ileostomy is mainly related to the mechanism of the nipple valve and not to ileitis or other systemic effects of the basic disease. Kock continent ileostomy can offer satisfactory long-term function in more than two-thirds of patients up to 30 years.
    Diseases of the Colon & Rectum 07/2003; 46(7):925-8. DOI:10.1097/01.DCR.0000075207.34462.05 · 3.20 Impact Factor
  • Gastroenterology 04/2003; 124(4). DOI:10.1016/S0016-5085(03)82258-8 · 13.93 Impact Factor

Publication Stats

270 Citations
95.27 Total Impact Points


  • 2015
    • Hospital District for Helsinki and Uusimaa
      Helsinki, Uusimaa, Finland
  • 2009–2014
    • University of Helsinki
      • IV Department of Surgery
      Helsinki, Uusimaa, Finland
  • 2002–2014
    • Helsinki University Central Hospital
      • • Department of Surgery
      • • Division of Gastroenterology
      Helsinki, Southern Finland Province, Finland