Krzysztof Grzyb

Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients.

Background: Inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) seems to differ from IBD without PSC, but a systematic, prospective study of IBD in PSC has until now not been reported. We aimed to describe the clinical, endoscopic, and histopathologic features of PSC‐IBD in liver‐transplanted and nontransplanted patients. Methods: PSC patients (n = 184) were included and underwent ileocolonoscopy with assessment of segmental histopathology. Results: A total of 155 (84%) patients had IBD, of whom 39 (25%) had undergone colectomy. The patients with an intact colon and complete tissue samples (n = 110) were further investigated. Forty‐two (38%) patients had undergone liver transplantation. The median IBD duration was 11 (range, 0–50) years. The majority (65%) had no or sparse IBD symptoms. Inflammatory findings were more frequent by histology than by endoscopy (89% versus 47%, P < 0.001). Histopathological signs of inflammation involved the right colon in 86% of patients and were purely right‐sided in 23%. The findings of inflammation were higher in the right compared to the left colon (P < 0.001), but the general inflammatory activity was low. Backwash ileitis was demonstrated in 20% (17/87) of patients and rectal sparing in 65% (70/107). The liver‐transplanted patients had lower clinical (P = 0.035) and histological (P = 0.013) IBD activity than the nontransplanted group. Conclusions: PSC‐IBD may represent a distinct entity of colitis in which low endoscopic activity may mask an active histologic inflammation that possibly contributes to an increased risk of malignancy. Circumstances related to liver transplantation seem to act favorably on colonic inflammation in PSC. (Inflamm Bowel Dis 2012;)

Laparoscopic resection of exocrine carcinoma in central and distal pancreas results in a high rate of radical resections and long postoperative survival

BACKGROUND The role of laparoscopic resection in patients with pancreatic cancer remains to be clarified, because previous reports have not clearly defined oncologic outcomes. The objective of the present study was to investigate this question with the rate of R0 resection and long-term survival as endpoints. METHODS This retrospective observational study included prospectively collected data from 40 patients operated laparoscopically with curative intent for exocrine pancreatic malignancies identified among 250 consecutive patients undergoing laparoscopic pancreatic operations since 1997. All 40 patients had histologically verified exocrine pancreatic carcinoma. RESULTS Ten patients (25%) with typical ductal adenocarcinoma of the pancreas were deemed nonresectable by laparoscopic staging. Laparoscopic distal pancreatectomy was performed in 29 patients; 8 resections were combined with resections of adjacent organs and 1 removal of a malignant intraductal papillary mucinous neoplasm what appeared to be ectopic pancreatic tissue. In 1 patient, the resection was completed by hand-assisted technique, and 1 procedure was converted to open resection. Postoperative morbidity was 23% (n = 7). The median hospital stay was 5 days (range, 1-30). The rate of R0 resections was 93%. Postoperative 3-year survivals rates were 36% for the entire cohort (n = 30) and 30% in typical ductal adenocarcinoma (n = 21). CONCLUSION Laparoscopic distal pancreatectomy for exocrine pancreatic carcinoma is comparable with outcomes after open surgery and supports the concept that laparoscopic distal pancreatectomy is a safe, oncologic procedure.

Long-term risk of colorectal cancer in individuals with serrated polyps

Objective Although serrated polyps may be precursors of colorectal cancer (CRC), prospective data on the long-term CRC risk in individuals with serrated polyps are lacking. Design In a population-based randomised trial, 12 955 individuals aged 50–64 years were screened with flexible sigmoidoscopy, while 78 220 individuals comprised the control arm. We used Cox models to estimate HRs with 95% CIs for CRC among individuals with ≥1 large serrated polyp (≥10 mm in diameter), compared with individuals with adenomas at screening, and to population controls, and multivariate logistic regression to assess polyp risk factors for CRC. Results A total of 103 individuals had large serrated polyps, of which 81 were included in the analyses. Non-advanced adenomas were found in 1488 individuals, advanced adenomas in 701. Median follow-up was 10.9 years. Compared with the control arm, the HR for CRC was 2.5 (95% CI 0.8 to 7.8) in individuals with large serrated polyps, 2.0 (95% CI 1.3 to 2.9) in individuals with advanced adenomas and 0.6 (95% CI 0.4 to 1.1) in individuals with non-advanced adenomas. A large serrated polyp was an independent risk factor for CRC, adjusted for histology, size and multiplicity of concomitant adenomas (OR 3.3; 95% CI 1.3 to 8.6). Twenty-three large serrated polyps found at screening were left in situ for a median of 11.0 years. None developed into a malignant tumour. Conclusions Individuals with large serrated polyps have an increased risk of CRC, comparable with individuals with advanced adenomas. However, this risk may not be related to malignant growth of the serrated polyp. Trial registration number The Norwegian Colorectal Cancer Screening trial is registered at clinicaltrials.gov (NCT00119912).

Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems

Abstract Objective. The aim of this study was to delineate the clinical outcomes and pathological characteristics of surgically resected endocrine tumors of the pancreas and to determine the importance of the World Health Organization (WHO) and tumor-node metastasis (TNM) classifications, resection status, and Ki-67 expression for long-term survival. Patients and methods. Sixty-nine patients underwent surgical tumor resection with curative intent during 1990–2007. Hospital records were reviewed retrospectively for medical, surgical, pathological, and radiological data. Results. Forty-one patients (59%) had non-functional tumors, 28 (41%) patients had functional tumors. Thirty-seven (54%) tumors were classified as WHO group 1 and the remaining 32 as WHO group 2. There were no poorly differentiated endocrine carcinomas. The overall R0-resection rate was 68%. Patients in whom all gross tumor was resected (R0/R1) had significantly better survival compared to patients with macroscopic residual disease (R2) (p < 0.001). There was no difference in survival between patients with R0 and R1 resections. Both the WHO (p < 0.001) and the TNM (p < 0.001) classifications significantly predicted five and 10-year survival after resection of the primary tumor. Survival analysis revealed significantly better outcome for patients with tumors with Ki-67 index < 2% (p = 0.003). Conclusions. Both WHO and TNM classifications reliably predict long-term survival in patients with resectable pancreatic endocrine tumors. R2 resection status predicted poor prognosis. R0 status did not improve prognosis relative to R1 status. Ki-67 index > 2% is a predictor of poor long-term survival.

Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer

BACKGROUND Primary adenocarcinomas removed by pancreatoduodenectomy originate from the duodenum (DC), ampulla (AC), distal bile duct (DBC), or pancreas (PC). Pathobiology, staging, survival, and adjuvant chemotherapy vary among these cancers. The proximity of the structures of possible origin renders it difficult to obtain a correct diagnosis, which might lead to inconsistencies in reported data and inappropriate adjuvant treatment. METHODS Records of 207 patients undergoing pancreatoduodenectomy (1998-2009) for periampullary adenocarcinoma were reviewed. Routine histopathology reports of tumour origin performed by multiple pathologists were independently re-evaluated based on predetermined criteria by two experienced pancreatic pathologists. RESULTS Slide review changed the diagnosis in 55 (27%) patients. After reclassification, final distribution was 29 (14%) DC, 52 (25%) AC, 57 (28%) DBC, and 69 (33%) PC. The diagnosis was revised in 4 (14%) DC, 7 (17%) AC, 30 (53%) DBC and 14 (19%) PC. The underestimation of DBC during routine histopathology was caused by misinterpretation of DBC either PC or AC. Misclassification of PC was mainly due to erroneous diagnosis of AC. Reassignment of tumour origin caused no significant changes in survival within cancer type, but resulted in a significant difference in survival between DBC and PC (p = 0.004). CONCLUSION Specialist slide review resulted in reassignment of tumour origin in 27% of periampullary adenocarcinomas. Distal bile duct cancer was found to be most frequently misdiagnosed (53%). Correct diagnosis of tumour origin is crucial for data quality, appropriate adjuvant therapy, and patient inclusion in clinical trials.

Pancreas Transplantation With Enteroanastomosis to Native Duodenum Poses Technical Challenges—But Offers Improved Endoscopic Access for Scheduled Biopsies and Therapeutic Interventions

To facilitate endoscopic access for rejection surveillance and stenting of the pancreas, we have abandoned the duodenojejunostomy (DJ) in favor of duodenoduodenostomy (DD) in pancreas transplantation (PTx). From September 2012 to September 2013 we performed 40 PTx with DD; 20 solitary‐PTx (S‐PTx) and 20 simultaneous pancreas and kidney transplantation (SPK). We compared the outcomes with results from 40 PTx‐DJ (10 S‐PTx and 30 SPK) from the preceding era. The DD‐enteroanastomoses were performed successfully. Endoscopic pancreas biopsies (endoscopic ultrasound examination [EUS]) yielded representative material in half of the cases. One exocrine fistula was treated by endoscopic stenting. PTxs‐DD were associated with a higher rate of thrombosis compared to PTx‐DJ (23% vs. 5%) and reoperations (48% vs. 30%), as well as inferior graft survival (80% vs. 88%). Time on waiting list, HLA A + B mismatches and reoperations were associated with graft loss. Only recipient age remained an independent predictor of patient death in multivariate analysis. PTx‐DD showed a higher rate of thrombosis and inferior results, but facilitated a protocol biopsy program by EUS that was feasible and safe. Given that technical difficulties can be solved, the improved endoscopic access might confer long‐term benefits, yet this remains to be proven.

Colectomy for patients with ulcerative colitis and primary sclerosing cholangitis — What next?☆☆☆

BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) occurs in 2%-8% of patients who suffer from ulcerative colitis (UC). For patients who require colectomy, ileal pouch-anal anastomosis (IPAA) or ileorectal anastomosis (IRA) is employed to preserve continence.We evaluated the outcomes after IPAA and IRA for patients with UC-PSC, using patients with UC but without PSC as controls (UC-only group). PATIENTS In a case-control study conducted at Sahlgrenska University Hospital, Sweden, patients with UC-PSC (N=48; 31 IPAA and 17 IRA) were compared to patients with UC only (N=113; 62 IPAA and 51 IRA). Functional outcomes (Öresland score), pouchitis, surgical complications, and failure were evaluated. RESULTS For patients with IPAA, the median Öresland scores were similar for the two groups: 5 (range, 0-13) for the UC-PSC group and 5 for the UC-only group (range, 0-12; p>0.05). However, the IRA scores were significantly different at 7 (range, 2-11) and 3 (range, 0-11) for the respective groups (p=0.005). Pouchitis was more frequent in patients with UC-PSC. Complication rates did not differ. For patients with IPAA, the failure rate was 16% for those in the UC-PSC group versus 6% for those in the UC-only group (p>0.05); the corresponding results for IRA were 53% versus 22% (p=0.03). CONCLUSIONS For cases of IPAA, pouchitis seems to be more common in patients with UC-PSC. However, the functional outcomes and failure rates are unaffected by concurrent PSC. For patients with UC-PSC, functional outcome is poor and the failure rate is high after IRA.

Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications

ABO‐incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO‐compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13–75); 33 patients were transplanted on urgent indications, 13 had malignancy‐related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10–86). Forty‐four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty‐four patients received induction with IL‐2 antagonist or anti‐CD20 antibody. Median follow‐up time was 29 months (range 0–200). The 1‐, 3‐, 5‐, and 10‐year Kaplan–Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1‐, 3‐, 5‐, and 10‐year GS for A2 grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non‐A2 grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A2 grafts is associated with acceptable graft survival and can be used safely in urgent cases.

Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma

BackgroundSeveral studies have described an increased cyclooxygenase-2 (COX-2) expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis.MethodsImmunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin (αSMA). Pancreatic stellate cells (PSC) were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by [3H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [3H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR.ResultsImmunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β (IL-1β), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-β1 (TGFβ). Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase (ERK). Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis.ConclusionsThe present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors.

Oncogene Mutations in Colorectal Polyps Identified in the Norwegian Colorectal Cancer Prevention (NORCCAP) Screening Study

Data are limited on oncogene mutation frequencies in polyps from principally asymptomatic participants of population-based colorectal cancer screening studies. In this study, DNA from 204 polyps, 5 mm or larger, were collected from 176 participants of the NORCCAP screening study and analyzed for mutations in KRAS, BRAF, and PIK3CA including the rarely studied KRAS exons 3 and 4 mutations. KRAS mutations were identified in 23.0% of the lesions and were significantly associated with tubulovillous adenomas and large size. A significantly higher frequency of KRAS mutations in females was associated with mutations in codon 12. The KRAS exon 3 and 4 mutations constituted 23.4% of the KRAS positive lesions, which is a larger proportion compared to previous observations in colorectal cancer. BRAF mutations were identified in 11.3% and were associated with serrated polyps. None of the individuals were diagnosed with de novo or recurrent colorectal cancer during the follow-up time (median 11.2 years). Revealing differences in mutation-spectra according to gender and stages in tumorigenesis might be important for optimal use of oncogenes as therapeutic targets and biomarkers.