Outcome after surgery for invasive intraductal papillary mucinous neoplasia compared to conventional pancreatic ductal adenocarcinoma - A Swedish nationwide register-based study.

BACKGROUND: The clinical importance of intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Long-term survival after resection for invasive IPMN (inv-IPMN) compared to conventional pancreatic ductal adenocarcinoma (PDAC) is not thoroughly delineated. OBJECTIVE: This study, based on the Swedish national pancreatic and periampullary cancer registry aims to elucidate the outcome after resection of inv-IPMN compared to PDAC. METHODS: All patients ≥18 years of age resected for inv-IPMN and PDAC in Sweden between 2010 and 2019 were included. Clinicopathological variables were retrieved from the national registry. The effect on death was assessed in two multivariable Cox regression models, one for patients resected 2010-2015, one for patients resected 2016-2019. Median overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: We included 1909 patients, 293 inv-IPMN and 1616 PDAC. The most important independent predictors of death in multivariable Cox regressions were CA19-9 levels, venous resection, tumour differentiation, as well as T-, N-, M-stage and surgical margin. Tumour type was an independent predictor for death in the 2016-2019 cohort, but not in the 2010-2015 cohort. In Kaplan-Meier survival analysis, inv-IPMN was associated with longer median OS in stage N0-1 and in stage M0 compared to PDAC. However, in stage T2-4 and stage N2 median OS was similar, and in stage M1 even shorter for inv-IPMN compared to PDAC. CONCLUSION: In this population-based nationwide study, outcome after resected inv-IPMN compared to PDAC is more favourable in lower stages, and similar to worse in higher.

Pharmacokinetics of preoperative intraperitoneal 5-FU in patients with pancreatic ductal adenocarcinoma.

PURPOSE: The aim was to investigate the pharmacokinetics of preoperatively administered intraperitoneal (IP) 5-FU in patients with resectable pancreatic ductal adenocarcinoma (PDAC) by analyzing levels of 5-FU and target metabolites in peritoneal fluid, plasma, liver, lymph nodes, pancreatic tumour, and pancreatic tissue. These results were correlated to expression of genes encoding enzymes of the 5-FU pathway and cell membrane transporters of 5-FU and FdUMP. METHODS: Twenty-two patients with PDAC were treated with IP 5-FU before surgery. The postoperative treatment followed a routine clinical protocol. 5-FU and its metabolites were analyzed by LC-MS/MS. The expression of genes encoding enzymes and transporters in the 5-FU pathway was analyzed by qPCR. RESULTS: After IP treatment, 5-FU could be detected in plasma, lymph nodes, liver, pancreatic tumour, and pancreatic tissue. The highest 5-FU concentration was found in the liver, also expressing high levels of the 5-FU transporter OAT2. 5-FU was converted to active FdUMP in all tissues and the highest concentration was measured in lymph nodes, liver and pancreatic tumour (18.5, 6.1 and 6.7 pmol/g, respectively). There was a correlation between the FdUMP and dUr levels in lymph nodes (r = 0.70, p = 0.0076). In tumours, there was an association between OAT2 expression and FdUMP concentration. CONCLUSION: The study shows uptake of IP 5-FU and drug metabolism to active FdUMP in pancreatic tumour, liver, and lymph nodes. Extended studies are warranted to evaluate the IP route for 5-FU administration in PDAC patients.

Analysis of the mechanism of injury in non-fatal vehicle-to-pedestrian and vehicle-to-bicyclist frontal crashes in Sweden.

The aim of this paper is to analyse and compare injuries and injury sources in pedestrian and bicyclist non-fatal real-life frontal passengercar crashes, considering in what way pedestrian injury mitigation systems also might be adequate for bicyclists. Data from 203 non-fatal vehicle-to-pedestrian and vehicle-to-bicyclist crashes from 1997 through 2006 in a city in northern Sweden were analysed by use of the hospitals injury data base in addition to interviews with the injured. In vehicle-to-pedestrian crashes (n = 103) head and neck injuries were in general due to hitting the windscreen frame, while in vehicle-to-bicycle crashes (n = 100) head and neck injuries were typically sustained by ground impact. Abdominal, pelvic and thoracic injuries in pedestrians and thoracic injuries in bicyclists were in general caused by impacting the bonnet. In vehicle-to-pedestrian crashes, energy reducing airbags at critical impact points with low yielding ability on the car, as the bonnet and the windscreen frame, might reduce injuries. As vehicle-to-bicyclist crashes occurred mostly in good lighting conditions and visibility and the ground impact causing almost four times as many injuries as an impact to the different regions of the car, crash avoidance systems as well as separating bicyclists from motor traffic, may contribute to mitigate these injuries.

Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma.

BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort. METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls. RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre- nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival. CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

Abdominal injuries in a low trauma volume hospital--a descriptive study from northern Sweden.

BACKGROUND: Abdominal injuries occur relatively infrequently during trauma, and they rarely require surgical intervention. In this era of non-operative management of abdominal injuries, surgeons are seldom exposed to these patients. Consequently, surgeons may misinterpret the mechanism of injury, underestimate symptoms and radiologic findings, and delay definite treatment. Here, we determined the incidence, diagnosis, and treatment of traumatic abdominal injuries at our hospital to provide a basis for identifying potential hazards in non-operative management of patients with these injuries in a low trauma volume hospital. METHODS: This retrospective study included prehospital and in-hospital assessments of 110 patients that received 147 abdominal injuries from an isolated abdominal trauma (n = 70 patients) or during multiple trauma (n = 40 patients). Patients were primarily treated at the University Hospital of Umeå from January 2000 to December 2009. RESULTS: The median New Injury Severity Score was 9 (range: 1-57) for 147 abdominal injuries. Most patients (94%) received computed tomography (CT), but only 38% of patients with multiple trauma were diagnosed with CT < 60 min after emergency room arrival. Penetrating trauma caused injuries in seven patients. Solid organ injuries constituted 78% of abdominal injuries. Non-operative management succeeded in 82 patients. Surgery was performed for 28 patients, either immediately (n = 17) as result of operative management or later (n = 11), due to non-operative management failure; the latter mainly occurred with hollow viscus injuries. Patients with multiple abdominal injuries, whether associated with multiple trauma or an isolated abdominal trauma, had significantly more non-operative failures than patients with a single abdominal injury. One death occurred within 30 days. CONCLUSIONS: Non-operative management of patients with abdominal injuries, except for hollow viscus injuries, was highly successful in our low trauma volume hospital, even though surgeons receive low exposure to these patients. However, a growing proportion of surgeons lack experience in decision-making and performing trauma laparotomies. Quality assurance programmes must be emphasized to ensure future competence and quality of trauma care at low trauma volume hospitals.

Surgery for acute gallbladder disease in Sweden 1989-2006--a register study.

OBJECTIVE: Since early 1970s, prospective randomized controlled trials have emphasized the advantages of early cholecystectomy in patients with acute cholecystitis, compared to elective delayed cholecystectomy. The aim of this investigation was to study surgery for acute gallbladder disease in Sweden during a 15-year period when open cholecystectomy was replaced by a laparoscopic procedure. MATERIAL AND METHODS: Data from the Swedish National Patient Register and the Cause of Death Register 1988-2006 comprising hospital stays with a primary diagnosis of gallbladder/gallstone disease in Sweden were retrieved. Patients were analyzed with reference to timing of cholecystectomy, length of hospital stay, and mortality. RESULTS: Emergency cholecystectomy at index (first) admission or at readmission within 2 years of index admission was performed in 32.2% and 6.1% of patients, respectively. Elective cholecystectomy within 2 years of index admission was performed in 20.3% patients, whereas 41.3% of all patients did not undergo cholecystectomy within 2 years. Standardized mortality ratio did not significantly change during the audit period. Total hospital stay (days at index stay and subsequent stay(s) for biliary diagnoses within 2 years) was shorter for patients who had emergency cholecystectomy at first admission compared to patients with later or no cholecystectomy within 2 years. CONCLUSIONS: Around 30% of patients with acute gallbladder disease were operated with cholecystectomy during the first admission with no time trend from 1990 through 2004. A total of 40% of patients with acute gallbladder disease were not cholecystectomized within 2 years. Analysis of outcome of long-term conservative treatment is warranted.

Fatal Vehicle-to-Bicyclist Crashes in Sweden - an In-Depth Study of injuries and vehicle sources.

Designing effective vehicle-based countermeasures for vulnerable road users demands an understanding of the relationship between injury and injury source. The aim of this study was to explore this association for bicyclists in fatal real-life-crashes. All fatal crashes in Sweden where a bicyclist was killed when hit by the front of a passenger car between 2002 and 2008 were studied in detail using on-scene data. An analysis was performed to determine the body region containing the injury causing death, and the point of the car accountable for the fatal injury. These crashes were then compared to a previous study with the same selection criteria for vehicle-to-pedestrian fatal crashes.A combined analysis revealed that the dominating injury mechanism was head/neck injury from the windshield area. The most frequent injurious windshield parts were structural; the frame and lower parts of the glass area with instrument panel situated within the head's line of motion. This study indicates that bicyclists' injury sources were located more rearwardly on the car (e.g. windshield relative to hood), in comparison to injury sources in fatal vehicle-to-pedestrian crashes.If countermeasures to prevent fatal bicyclist injury in vehicle impacts were to be concentrated on mitigating head and thorax impact to the structural parts of the windshield, a dominant share of fatal bicyclist crashes could be prevented. This study shows that pedestrian countermeasures also have a potential for reducing injury in bicyclist crashes, but indicating that these countermeasures should be extended to address higher areas of the windshield.

Treatment of common bile duct stones in Sweden 1989-2006: an observational nationwide study of a paradigm shift.

BACKGROUND: The preferred strategies for treatment of common bile duct stones have changed from choledochotomy with cholecystectomy to sphincterotomy with or without cholecystectomy. The aim of the present study was to compare the effectiveness of these treatment strategies on a nationwide level in Sweden. METHODS: All patients with hospital care for benign biliary diagnoses 1988-2006 were identified in Swedish registers. Patients with common bile duct stones and a first admission with choledochotomy and or endoscopic sphincterotomy from 1989 through 2006 comprised the study group. These patients were analyzed with respect to readmission for biliary diagnoses and acute pancreatitis. RESULTS: Incidence of open and laparoscopic choledochotomy decreased from 19.4 to 5.2, whereas endoscopic sphincterotomy increased from 5.1 to 26.1 per 100,000 inhabitants per year, respectively. Among patients treated for common bile duct stones (n = 26,815), 60.0 % underwent cholecystectomy during the first hospital admission in 1989-1994, compared to 30.1 % in 2001-2006. The treatment strategy that included endoscopic sphincterotomy was associated with more readmissions for biliary diagnoses and increased risk for acute pancreatitis than the treatment strategy with choledochotomy. However, patients treated with endoscopic sphincterotomy and concurrent cholecystectomy at the index admission had the lowest risk of readmission. CONCLUSIONS: Cholecystectomy has been increasingly separated from treatment of bile duct stones, and endoscopic sphincterotomy has superseded choledochotomy as a first alternative for bile duct clearance in Sweden. In patients fit for surgery, clearance of the common bile duct can be combined with cholecystectomy, as it probably reduces the need for biliary related readmissions.

Cholecystectomy and sphincterotomy in patients with mild acute biliary pancreatitis in Sweden 1988 - 2003: a nationwide register study.

BACKGROUND: Gallstones represent the most common cause of acute pancreatitis in Sweden. Epidemiological data concerning timing of cholecystectomy and sphincterotomy in patients with first attack of mild acute biliary pancreatitis (MABP) are scarce. Our aim was to analyse readmissions for biliary disease, cholecystectomy within one year, and mortality within 90 days of index admission for MABP. METHODS: Hospital discharge and death certificate data were linked for patients with first attack acute pancreatitis in Sweden 1988-2003. Mortality was calculated as case fatality rate (CFR) and standardized mortality ratio (SMR). MABP was defined as acute pancreatitis of biliary aetiology without mortality during an index stay of 10 days or shorter. Patients were analysed according to four different treatment policies: Cholecystectomy during index stay (group 1), no cholecystectomy during index stay but within 30 days of index admission (group 2), sphincterotomy but not cholecystectomy within 30 days of index admission (group 3), and neither cholecystectomy nor sphincterotomy within 30 days of index admission (group 4). RESULTS: Of 11636 patients with acute biliary pancreatitis, 8631 patients (74%) met the criteria for MABP. After exclusion of those with cholecystectomy or sphincterotomy during the year before index admission (N = 212), 8419 patients with MABP remained for analysis. Patients in group 1 and 2 were significantly younger than patients in group 3 and 4. Length of index stay differed significantly between the groups, from 4 (3-6) days, (representing median, 25 and 75 percentiles) in group 2 to 7 (5-8) days in groups 1. In group 1, 4.9% of patients were readmitted at least once for biliary disease within one year after index admission, compared to 100% in group 2, 62.5% in group 3, and 76.3% in group 4. One year after index admission, 30.8% of patients in group 3 and 47.7% of patients in group 4 had undergone cholecystectomy. SMR did not differ between the four groups. CONCLUSION: Cholecystectomy during index stay slightly prolongs this stay, but drastically reduces readmissions for biliary indications.

First attack of acute pancreatitis in Sweden 1988 - 2003: incidence, aetiological classification, procedures and mortality - a register study.

BACKGROUND: Population-based studies suggest that the incidence of first attack of acute pancreatitis (FAAP) is increasing and that old age is associated with increased mortality. Because nationwide data are limited and information on standardized mortality ratio (SMR) versus age is lacking, we wanted to describe incidence and mortality of first attack acute pancreatitis (FAAP) in Sweden. METHODS: Hospital discharge data concerning diagnoses and surgical procedures and death certificate data were linked for patients with FAAP in Sweden. Mortality was calculated as case fatality rate (CFR), i.e. deaths per 1000 patients and SMR using age-, gender- and calendar year-specific expected survival estimates, and is given as mean with 95% confidence intervals. Data are presented as median values with 25% and 75% percentiles, means and standard deviations, or proportions. Proportions have been compared using the chi square test, Poisson-regression test or Fisher exact test. Location of two groups of ratio scale variables were compared using independent samples t-test or Mann-Whitney U-test. RESULTS: From 1988 through 2003, 43415 patients (23801 men and 19614 women) were admitted for FAAP. Age adjusted incidence rose from 27.0 to 32.0 per 100000 individuals and year. Incidence increased with age for both men and women. At index stay 19.7% of men and 35.4% of women had biliary diagnoses, and 7.1% of men and 2.1% of women alcohol-related diagnoses. Of 10072 patients who underwent cholecystectomy, 7521 (74.7%) did so after index stay within the audit period. With increasing age CFR increased and SMR decreased. For the whole period studied SMR was 11.75 (11.34-12.17) within 90 days of index admission and 2.03 (1.93-2.13) from 91 to 365 days. Alcohol-related diagnoses and young age was associated with increased SMR. Length of stay and SMR decreased significantly during the audit period. CONCLUSION: Incidence of FAAP increased slightly from 1988 to 2003. Incidence increased and SMR declined with increasing patient age. Although the prognosis for patients with FAAP has improved it remains an important health problem. Aetiological classification at index stay and timing of cholecystectomy should be improved.

Expression pattern and circulating levels of endostatin in patients with pancreas cancer.

Endostatin is a potent inhibitor of angiogenesis that is cleaved from the basement membrane protein type XVIII collagen. Expression of endostatin has recently been shown by Western blot analysis of tissue lysates in normal pancreas and pancreas cancer tissue. We show here that the expression pattern of type XVIII collagen/endostatin is shifted from a general basement membrane staining and is mainly located in the vasculature during tumor progression. This shift in type XVIII collagen/endostatin expression pattern coincides with an up-regulation of MMPs involved in endostatin processing in the tumor microenvironment, such as MMP-3, MMP-9 and MMP-13. The circulating levels of endostatin was analyzed in patients with pancreas cancer and compared to that of healthy controls, as well as after surgical treatment or in a group of nonoperable patients after intraperitoneal fluorouracil (5-FU) chemotherapy. The results show that patients with pancreas cancer have increased circulating levels of endostatin and that these levels are normalized after surgery or intraperitoneal chemotherapy. These findings indicate that endostatin could be used as a biomarker for pancreas cancer progression.