Diagnostic and Prognostic Impact of Circulating YKL-40, IL-6, and CA 19.9 in Patients with Pancreatic Cancer.

PURPOSE: We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival. PATIENTS AND METHODS: In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (n = 448) and Germany (n = 111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay. RESULTS: Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: OR = 2.28, 95% CI 1.97 to 2.68, p<0.0001, AUC = 0.94; YKL-40: OR = 4.50, 3.99 to 5.08, p<0.0001, AUC = 0.87; IL-6: OR = 3.68, 3.08 to 4.44, p<0.0001, AUC = 0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HR = 2.51, 1.22-5.15, p = 0.013; IL-6: HR = 2.03, 1.11 to 3.70, p = 0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HR = 1.30, 1.03 to 1.64, p = 0.029; IL-6: HR = 1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HR = 1.54, 1.06 to 2.24, p = 0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months). CONCLUSIONS: Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.

Prognostic microRNAs in cancer tissue from patients operated for pancreatic cancer--five microRNAs in a prognostic index.

BACKGROUND: The aim of the present study was to identify a panel of microRNAs (miRNAs) that can predict overall survival (OS) in non micro-dissected cancer tissues from patients operated for pancreatic cancer (PC). METHODS: MiRNAs were purified from formalin-fixed paraffin embedded (FFPE) cancer tissue from 225 patients operated for PC. Only a few of those patients received adjuvant chemotherapy. Expressions of miRNAs were determined with the TaqMan MicroRNA Array v2.0. Two statistical methods, univariate selection and the Lasso (Least Absolute Shrinkage and Selection Operator) method, were applied in conjunction with the Cox proportional hazard model to relate miRNAs to OS. RESULTS: High expression of miR-212 and miR-675 and low expression of miR-148a, miR-187, and let-7g predicted short OS independent of age, gender, calendar year of operation, KRAS mutation status, tumor stage, American Society of Anesthesiologists (ASA) score, localization (not miR-148a), and differentiation of tumor. A prognostic index (PI) based on these five miRNAs was calculated for each patient. The median survival was 1.09 years (Confidence Interval [CI] 0.98-1.43) for PI > median PI compared to 2.23 years (CI 1.84-4.36) for PI < median. MiR-212, miR-675, miR-187, miR-205, miR-944, miR-431, miR-194, miR-148a, and miR-769-5p showed the strongest prediction ability by the Lasso method. Thus miR-212, miR-675, miR-187, and miR-148a were predictors for OS in both statistical methods. CONCLUSIONS: The combination of five miRNAs expression in non micro-dissected FFPE PC tissue can identify patients with short OS after radical surgery. The results are independent of chemotherapy treatment. Patients with a prognostic index > median had a very short median OS of only 1 year.

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma.

MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced). Several of these microRNAs have not before been related to diagnosis of pancreatic cancer (eg, miR-492, miR-614, miR-622). MiR-614, miR-492, miR-622, miR-135b and miR-196 were most differently expressed. MicroRNA profiles of pancreatic and ampullary adenocarcinomas were correlated (0.990). MicroRNA expression profiles for pancreatic cancer described in the literature were consistent with our findings, and the microRNA profile for pancreatic adenocarcinoma (miR-196b-miR-217) was validated. We identified a more significant expression profile, the difference between miR-411 and miR-198 (P=2.06 × 10(-54)) and a diagnostic LASSO classifier using 19 microRNAs (sensitivity 98.5%; positive predictive value 97.8%; accuracy 97.0%). We also identified microRNA profiles to subclassify ampullary adenocarcinomas into pancreatobiliary or intestinal type. In conclusion, we found that combinations of two microRNAs could roughly separate neoplastic from non-neoplastic samples. A diagnostic 19 microRNA classifier was constructed which without micro-dissection could discriminate pancreatic and ampullary adenocarcinomas from chronic pancreatitis and normal pancreas with high sensitivity and accuracy. Ongoing prospective studies will evaluate if these microRNA profiles are useful on fine-needle biopsies for early diagnosis of pancreatic cancer.

Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas.

OBJECTIVES: The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied. METHODS: KRAS and BRAF mutations were analyzed in formalin-fixed, paraffin-embedded tumor samples from primarily chemotherapy-naive patients operated on with radical intentions for PDAC (n = 170) and A-AC (n = 107). RESULTS: Eighty percent of PDAC patients had KRAS mutations (codon 12 mutations: 74%) and 67% with A-AC (codon 12 mutations: 54%). BRAF mutations were less common, 16% in PDAC and 12% in A-AC, and no V600E mutations were found. Fourteen percent with PDAC and 7% with A-AC had mutations in both KRAS and BRAF. Multivariate analysis, including KRAS status, stage, and American Society of Anesthesiologists physical status classification system score, demonstrated that KRAS mutations in patients with A-AC were associated with short recurrence-free survival (RFS) (hazard ratio, 2.45; 95% confidence interval, 1.19-5.06; P = 0.015) and overall survival (OS) (1.93, 95% 1.12-3.31; P = 0.018). KRAS mutations in patients with PDAC were not associated with RFS and OS. BRAF mutations were not associated with RFS and OS. CONCLUSIONS: KRAS mutations frequencies were high in PDAC and A-AC. KRAS mutations were associated with poor prognosis in patients with A-AC, but not in patients with PDAC.

[Signet ring cell carcinoma of the gallbladder]. / Signetringscellekarcinom i galdeblæren.

Cancer in the gallbladder is rare, and each year about 160 cases are registered in Denmark. Most malignant tumours in the gallbladder are adenocarcinomas. We present a rare case of signet ring cell carcinoma of the gallbladder. Signet ring cell carcinomas are particularly aggressive. The tumours are often disseminated at the time of diagnosis, and it may be difficult to determine the primary origin.

Malignant gastric outlet obstruction managed by endoscopic stenting: a prospective single-centre study.

OBJECTIVE: Endoscopic stenting for malignant gastric outlet obstruction was chosen as the primary strategy by which to palliate this complication, which is dominated by weight loss and anorexia. Advanced upper gastrointestinal tract cancers present late and life expectancy is limited. Only smaller multicentre studies point to endoscopic stenting as superior to surgery in terms of clinical outcome and cost. MATERIAL AND METHODS: Forty-five consecutive patients with gastric outlet obstruction as a result of advanced upper GI-tract malignancy were enrolled in accordance with the intention-to-treat principle. All patients were offered endoscopic stenting. Oral intake before and after stenting was assessed using the gastric outlet obstruction score system (GOOSS). Various lengths of duodenal Hanaro self-expanding nitinol stents were delivered through a therapeutic endoscope. Outcome criteria were successful deployment, clinical effect, length of stay in hospital, survival, need for re-intervention and complications. RESULTS: Forty-one patients (91%) were successfully stented. The mean pre-procedure GOOSS improved significantly from 0.39 (95% CI 0.22-0.56) to 2.29 (95% CI 2.01-2.58) after stenting (p<0.0001). Twenty-six patients (63%) improved GOOSS at least one point, whereas 5 patients (12%) did not change GOOSS at all. Mean length of hospital stay was 13 days (95% CI 9-17 days). Mean survival was 121 days (95% CI 62-181 days). Two patients (4%; numbers 6 and 19) sustained perforation without fatalities. Three patients (7%) had stent migration. Procedure-related mortality was zero. CONCLUSIONS: Palliative stenting for advanced malignant upper GI-tract tumours at a tertiary Hepato-Pancreato-Biliary Unit is a safe, feasible and effective alternative to surgical bypass with a short hospital stay and prompt improvement of food intake.

Perforated peptic ulcer: how to improve outcome?

Despite the introduction of histamine H2-receptor antagonists, proton-pump inhibitors and the discovery of Helicobacter pylori, both the incidence of emergency surgery for perforated peptic ulcer and the mortality rate for patients undergoing surgery for peptic ulcer perforation have increased. This increase has occurred despite improvements in perioperative treatment and monitoring. To improve the outcome of these patients, it is necessary to investigate the reasons behind this high mortality rate. In this review we evaluate the existing evidence in order to identify significant risk factors with an emphasis on risks that are preventable. A systematic review including randomized studies was carried out. There are a limited number of studies of patients with peptic ulcer perforation. Most of these studies are of low evident status. Only a few randomized, controlled trials have been published. The mortality rate and the extent of postoperative complications are fairly high but the reasons for this have not been thoroughly explained, even though a number of risk factors have been identified. Some of these risk factors can be explained by the septic state of the patient on admission. In order to improve the outcome of patients with peptic ulcer perforation, sepsis needs to be factored into the existing knowledge and treatment.

[New liver surgery techniques. Few complications and more advantages?]. / Nye leverkirurgiske teknikker. Få komplikationer og flere fordele?

INTRODUCTION: Most blood loss in hepatic resections occurs during transection of the liver. To reduce this blood loss and avoid blood transfusions, initial experience with radiofrequency based dissecting devices are presented. Curative liver surgery requires combinations of classical resections and tumorablations. MATERIALS AND METHODS: Retrospective analysis of 22 patients who underwent various hepatic resections for colorectal liver metastases. Two commercially available devices were used for transection, either the TissueLink or the Habib Sealer. RESULTS: Mortality was zero and morbidity low. No blood transfusions were needed following the use of the Habib Sealer, whereas four patients received blood after TissueLink. 27% of the patients needed a combination of resection and tumorablation. CONCLUSION: Liver surgery and transection of the liver can be performed safely with radiofrequency based dissecting devices. Theoretical advantage could be more candidates to curative surgery.

[Surgical treatment of liver metastases and liver cancer]. / Kirurgisk behandling af levermetastaser og levercancer.

Hepatic resection is the golden standard in treatment of tumours from primary liver cancer and colorectal liver metastases, but is appropriate for a variety of other benign and malignant tumours in the liver. The selection of patients and criteria are discussed. Curative liver surgery is a prerequisite for treatment, whereas the size, number and localization of the tumours do not affect operability per se, but the prognosis is influenced by these factors. Surgical strategies, techniques and adjuvant chemotherapy are discussed. Recurrence or newly-evolved tumours can be treated.